Q3 2021 PTC Therapeutics Inc Earnings Call

October 28, 2021

unknown: Our actual results could materially differ from these forward-looking statements. As such, they are subject to risks that can materially and adversely affect our business and results of operations. For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent quarterly report on Form 10-Q and annual report on Form 10-K, filed with the Securities and Exchange Commission, as well as the company's other SEC filings. We will disclose certain non-GAAP information during this call. Information regarding our use of GAAP to non-GAAP financial measures and a reconciliation of GAAP to non-GAAP is available in today's earnings release. With that said, let me pass the call over to our CEO, Stuart Peltz.

Today's conference is scheduled to begin shortly please continue to standby and thank you for your patience.

Unknown Executive: Stuart Peltz. Thanks, Kylie, and thank you all for dialing in. I'm excited to tell you about our progress this quarter as we have continued to demonstrate remarkable commercial revenue and have been making good progress across our robust pipeline. At PTC, we are committed to creating both short and long-term value for all our stakeholders. To accomplish this, we have built a company that discovers, develops, and commercializes therapies to treat patients of higher medical need.

Unknown Executive: We are building a sustainable pipeline that, at steady state, will develop new therapies that reach commercialization on a continuous basis. This will allow us to substantially grow our revenue so that it will continue to increase in the years to come. The results of all these efforts are bearing fruit.

[music].

Unknown Executive: We see continuous and impressive commercial revenue growth for our product. And we now have five ongoing registration directive studies, with an increasing number of preclinical and clinical studies in progress. We are building a sustainable, enduring biopharmaceutical company. Turning to this quarter's DMV franchise commercial revenue, we continue to deliver impressive year-over-year growth. The DMV franchise has grown by 39% compared to the third quarter of 2020, with $114 million in

Unknown Executive: This was primarily driven by new patient starts for both Inflasa and TransLarna and geographic expansion for TransLarna. I'm pleased to announce that we are raising our 2021 revenue guidance for the DMD franchise to $400 to $420 million from $370 to $390 million. Eric and Emily will go into more detail shortly.

Unknown Executive: Now I'd like to highlight the significant milestones achieved in Brazil with both Tecfeti and Ray Lever this quarter. In August, we were pleased to announce the approval of WayLibre in Brazil. This is the first approved treatment for familial chylomicronemia syndrome, or FCS, and we're excited to be able to bring this therapy to patients in need. However, this was not the only milestone for Brazil this quarter.

Good day, and thank you for standing by welcome.

Welcome to the PTC Therapeutics third quarter, 2021, corporate update and financial results Conference call.

Unknown Executive: I'm also happy to report that TXETI, which is for the treatment of HATTR amyloidosis, received Category 1 pricing. Category 1 pricing is given to innovative treatments that show benefits over current standards of care. Due to Portuguese descent, there is a higher prevalence of HATTR patients in the Brazilian population.

At this time all payments are in a listen only mode.

After the speaker's presentation, there will be a question and answer session.

To ask a question. During this session you will need to press star one on your telephone.

Please be advised that today's conference is being recorded.

Any further assistance please press star zero.

Now like to hand, the conference over to your speaker today karaoke head of Investor Relations. Please go ahead.

Unknown Executive: Eric will go into more detail on the remarkable progress of the commercial team later in this call. Now, let me turn to Everett, which is the first commercial product from our innovative SPICe platform. And RISD continues to show strong revenue this quarter, with approximately 20% total market share in just over a year after launch.

Good afternoon, and thank you for joining us today to discuss the PTC Therapeutics third quarter 2021, corporate update and financial results. Joining me on today's call is our Chief Executive Officer Stuart Peltz.

Our Chief Development Officer, Matthew Klein, and our Chief Business Officer, Eric Palace, and our Chief Financial Officer Emily Hill.

Unknown Executive: RISD is the most prescribed FMA treatment in the United States, and Roche expects further growth in 2021, with approval in 63 countries, and has continued focus on pricing and reimbursement efforts outside of the U.S. The success of our commercial portfolio demonstrates our ability to utilize our commercial engines to grow revenues to further invest in the pipeline, which I'll now discuss in more detail. In particular, I'd like to start with our near-term value. I'm excited to announce that we have initiated a registration-directed trial called Affinity for PTC 923 in PKU.

Before we start let me remind you that today's call will include forward looking statements based on current expectations.

Please take a moment to review the slides posted on our Investor Relations website in conjunction with the KOL.

Which contains our forward looking statements our actual results could materially differ from these forward looking statements as.

Such statements are subject to risks that can materially and adversely affect our business and results of operation.

For a detailed description of applicable risks and uncertainties. We encourage you to review the company's most recent quarterly report on Form 10-Q, and annual report on Form 10-K filed with the Securities and Exchange Commission as well as the company's other SEC filings.

We will disclose certain non-GAAP information during this call infant.

Unknown Executive: We view this as a significant opportunity, as there is a well-defined patient population through newborn screening, known centers of excellence, and a clear pathway to approval with a blood-based biomarker as an endpoint, as well as having an enriched population through a run-in responder analysis that increases our chance of success. Now, let me talk about our next two registration-directed trials from our BioE platform. The BioE platform targets access to electronics and the Acts of Davis Stress that Contributes to Multiple Disease States. The first compound from this platform, tiquinone, inhibits 15-lipoxygen. A key regulator that controls the oxidative stress response

Information regarding our use of GAAP to non-GAAP financial measures and a reconciliation of GAAP to non-GAAP is available in today's earnings release with that let me pass the call over to our CEO Stuart Peltz Stuart.

Thanks Cai.

Thank you all for dialing in.

I'm excited to tell you about our progress this quarter.

Continued to demonstrate remarkable commercial revenue and have been making good progress across our robust pipeline.

If you can see we are committed to creating both short and long term value for all our stakeholders.

To accomplish this we have built a company that discover develop and commercialize it.

Patients with high unmet medical need.

We are building a sustainable pipeline.

We'll develop new therapies, the reach commercialization on a continuous basis.

Unknown Executive: The first of the registration-directed trials with patiquinone is the MITE-E study in patients with mitochondrial disease associated with seizures. We expect results in the third quarter of 2022, and if positive, will be the basis of our NDE. Our second registration-directed particular known trial, MOVE-FA, is in patience with three-trick attacks, a mitochondrial disease that affects neuromuscular function.

This will allow us to surpass.

As we grow our revenue base.

It will continue to increase in the years to come.

The result of all these efforts are bearing fruit.

Continuous and impressive commercial revenue growth of our products.

And we now have five ongoing registration directed study.

With an increasing number of preclinical and clinical studies in progress.

We are building a sustainable enduring biopharmaceutical company.

Unknown Executive: We're grateful for the collaboration and support from the FA community in helping us to drive enrollment. We anticipate results in 2020. We're also moving ahead with the Next Generation Compound from the BioE platform, PTC 857. We have selected ALS as the first indication and are aiming to initiate the Phase 2 trial for PTC 857 in the first quarter of next year. I'll now discuss our innovative splicing platform with a focus on PTC 518 for the treatment of Huntington's.

Turning to this quarter's DMD franchise commercial revenue, we continued to deliver impressive year over year growth.

The franchise has grown by 39% compared to the third quarter of 2020 with $114 million in total revenue.

This was primarily driven by new patient starts for Bolton Plaza in front line.

And geographic expansion for Translarna and.

I'm pleased to announce that we are raising our 2021 revenue guide for the DMD franchise too.

Operator: Today's conference is scheduled to begin shortly. Please continue to stand by, and thank you for your patience.

$400 million to $420 million from the $370 million to $390 million.

Unknown Executive: We recently reported results from the PTC 518 Healthy Volunteer Tribe. We were able to show dose-dependent lowering of both HPT, mRNA, and protein and achieve the targeted 30% to 50% reduction. We also demonstrated that PCC 518 passes the blood-brain barrier and has minimal e-brain. These are key attributes that treat Huntington's disease.

Eric and Emily will go into more detail shortly.

No I'd like to highlight the significant milestones achieved in Brazil, with both tech savvy and re lever this quarter.

In August we were pleased to announce the approval of <unk>.

Unknown Speaker: [inaudible] Thank you for watching! BF-WATCH TV 2021, Nodal, Nodal, Nodal, Nodal, Nodal, Nodal, Nodal, Nodal, Nodal, Nodal, Nodal, Nodal, Nodal, Nodal, Nodal, Nodal, Nodal, Nodal, Nodal, Nodal, Nodal, Nodal, No

Phil.

Operator: Good day, and thank you for standing by. Welcome to the PTC Therapeutics third quarter 2021 corporate update and financial results conference call. At this time, all persons are in a listening mode. After the speaker's presentation, there will be a question and answer session. To ask a question during this session, you will need to press star 1 on your telephone. Please be advised that today's conference is being recorded. If you require any further assistance, please press star zero. I would now like to hand the conference over to your speaker today, Kylie O'Keefe, Head of Investor Relations. Please go ahead.

This is the first approved treatment for familial Carlo Micronesia syndrome or Fcs.

We're excited to be able to bring the therapy to patients in need.

Kylie O'Keefe: Good afternoon, and thank you for joining us today to discuss the PTC Therapeutics third quarter 2021 corporate update and financial results. Joining me on today's call is our Chief Executive Officer, Stuart Peltz, our Chief Development Officer, Matthew Klein, and our Chief Business Officer, Eric Pauwels, and our Chief Financial Officer, Emily Hill. Before we start, let me remind you that today's call will include forward-looking statements based on current expectations. Please take a moment to review the slide posted on our Investor Relations website in conjunction with the call, which contains our forward-looking statements.

Unknown Executive: We remain very excited about this program and are moving as rapidly as possible into phase two. In the Phase 2 trial, we will replicate the safety, tolerability, and pharmacology of PTC50 and 80, as well as decreases in Huntington mRNA and protein levels in the Huntington's disease patients. Matt will go into more detail on our phase two program shortly. Now moving on to AADC.

This was not the only milestone for Brazil this quarter.

Also happy to report that Tech center, which is for the treatment of H ATT amyloidosis received category one pricing.

Category, one pricing is given to innovative treatments that show benefit over current standards of care.

Kylie O'Keefe: Our actual results could materially differ from these forward-looking statements. As such, they are subject to risks that can materially and adversely affect our business and results of operations. For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent quarterly report on Form 10-Q, and the annual report on Form 10-K, filed with the Securities and Exchange Commission, as well as the company's other SEC filings. We will disclose certain non-GAAP information during this call. Information regarding our use of GAAP to non-GAAP financial measures and a reconciliation of GAAP to non-GAAP is available in today's earnings release. With that said, let me pass the call over to our CEO, Stuart Peltz. Stuart?

Is it the Portuguese descent, there was a higher prevalence of H E T. Our patients in the Brazilian population.

Eric will go into more detail on the remarkable progress of the commercial team later in the call.

Unknown Executive: In Europe, we still expect to see an HMT opinion by the end of this year and look forward to bringing this transformational therapy to AADC deficiency patients. I'm also pleased that we recently held a ribbon-cutting ceremony for our Gene Therapy Manufacturing Center of Excellence in Hopewell, New Jersey. Our new state-of-the-art facility is well-equipped and staffed to produce high-quality plasmid and AAV vectors for gene therapy applications. I'm very proud of the progress we've made over the past quarter, with exciting commercial achievements and steady state progress across our pipeline.

Now, let me turn to for instance, which is the first commercial product from our innovative splicing platform.

Everything continues to show strong revenue this quarter with approximately 20% total market share in just over a year after launch.

Originally at the most.

That's what many estimated treatment in the United States and Roche expects further growth in 2021 with approval in 63 countries and a continued focus on the pricing and reimbursement efforts outside of the U S.

The success of our commercial portfolio demonstrates our ability to utilize our commercial age to grow revenues to further invest in the pipeline.

Unknown Executive: This speaks to the dedication of our people, who have worked incredibly hard in the face of the ongoing challenges. Brought by the Penn, The past 18 months have required perseverance, and I'm proud to say that we've continued to execute across all fronts. We have all the ingredients.

I will now discuss in more detail.

In particular I'd like to start with our near term value driver.

Stuart Peltz: Thanks, Kylie, and thank you all for dialing in. I'm excited to tell you about our progress this quarter as we have continued to demonstrate remarkable commercial revenue and have been making good progress across our robust pipeline. At PTC, we are committed to creating both short and long-term value for all our stakeholders. To accomplish this, we have built a company that discovers, develops, and commercializes therapies to treat patients of higher medical need.

I'm excited to announce that we have initiated the registration directed trial called the opinion or PTC 19, three in PKU.

We view this as a significant opportunity as there was a well defined patient population through newborn screening no centers of excellence and a clear pathway to approval with a blood based biomarker as an endpoint as well as having an enriched population through a run in responder analysis, let me grief.

Unknown Executive: Research, Development, and Commercialization, a place that positions us to be a growing revenue-generating, enduring biopharmaceutical company. I now turn the call over to Matt for an update on the development program.

Stuart Peltz: We are building a sustainable pipeline that, at steady state, will develop new therapies that reach commercialization on a continuous basis. This will allow us to substantially grow our revenue so that it will continue to increase in the years to come. The results of all these efforts are showing proof.

Our chance of success.

Let me talk about our next two registration directed trials from our bio E platform.

Matt: Thanks, Stu. I'm happy to provide an update on the continued progress of our pipeline program. I will begin with our PTC 923 PKU program. As planned, we initiated enrollment in the affinity trial, our global phase three registration-directed trial of PTC 923 in pediatric and adult PKU patients. This double-blind, placebo-controlled trial will include a run-in phase to identify responders to PTC 923, who will then be randomized to receive either PTC 923 or a placebo for six weeks. As with previous approved therapies for PKU, the primary endpoint of the affinity trial is reduction of phenylalanine bubbles. Following completion of the placebo-controlled trial, subjects will then be enrolled in a long-term open-label extension study.

The bio E platform targets excess electrons and the oxidative stress that contribute the multiple disease states.

First compound from this platform particular node inhibits 15 lipoxygenase.

Stuart Peltz: We see continuous and impressive commercial revenue growth for our products. And we now have five ongoing registration directive studies, with an increasing number of preclinical and clinical studies in progress. We are building a sustainable, enduring biopharmaceutical company. Turning to this quarter's DMV franchise commercial revenue, we continue to deliver impressive year-over-year growth. The DMV franchise has grown by 39% compared to the third quarter of 2020, with $114 million in

Key regulators that controls the occupancy that stress response.

The first of the registration directed trial with particular known as the <unk> study in patients with mitochondrial disease associated with failures.

Expect results in the third quarter of 2022, and if positive will be the basis of our NDA.

Stuart Peltz: This was primarily driven by new patient starts for both Inflasa and TransLarna and geographic expansion for TransLarna. I'm pleased to announce that we are raising our 2021 revenue guidance for the DMD franchise to $400 to $420 million from $370 to $390 million. Eric and Emily will go into more detail shortly.

Our second registration directed particular known trial move ethane.

<unk> been patience with greater catastrophe.

Mitochondrion.

<unk> neuromuscular function.

We're grateful for the collaboration and support from the community.

Helping us to drive enrollment.

We anticipate results in 2023.

We're also moving ahead with the next generation compounds from the bio E platform.

TTP eight 5%.

We have selected AOS is the person the kitchen and are aiming to initiate the phase two trial for PTC 857 in the first quarter of next year.

Matt: We expect to have results from the placebo-controlled trial by the end of 2022. Now, turning now to our PTC 518 Huntington's Disease Program. Following the announcement of the successful Phase 1 study results in healthy volunteers, we are moving forward with our Phase 2 study in Huntington's Disease patients. This study, PIVOT-HD, will include a 12-week double-blind placebo-controlled phase, followed by a one-year open-label extension. The study will enroll approximately 100 to 150 subjects who will be randomized to receive placebo for one of two dose levels of PTC518. The primary objective of the placebo control phase is to demonstrate safety, pharmacology, and evidence of HTT, mRNA, and protein lowering in HD patients.

Stuart Peltz: Now I'd like to highlight the significant milestones achieved in Brazil with both Tecfeti and Ray Lever this quarter. In August, we were pleased to announce the approval of WayLibre in Brazil. This is the first approved treatment for familial chylomicronemia syndrome, or FCS, and we're excited to be able to bring this therapy to patients in need. However, this was not the only milestone for Brazil this quarter.

I'll now discuss our interface with pricing platform with a focus on PTC 518 for the treatment of Huntington's disease. We recently reported results from PTT coordinate healthy volunteer trial, we were able to show dose dependent lowering about HCP.

<unk> mrna and protein and achieved the targeted 30% to 50% reduction.

Stuart Peltz: I'm also happy to report that TxETI, which is for the treatment of HATTR amyloidosis, received Category 1 pricing. Category 1 pricing is given to innovative treatments that show benefits over current standards of care. Due to Portuguese descent, there is a higher prevalence of HATTR patients in the Brazilian population.

We also demonstrated the PTC five Monday passes the blood brain barrier and has minimal E plus.

These are key attributes to treat huntington's disease.

We remain very excited about this program and are moving as rapidly as possible.

The phase two.

Moving into the phase III trial.

We will replicate safety Tolerability and pharmacology of PTC 518, as well as decreases in Huntington mrna and protein levels in the Huntington's disease patients.

Stuart Peltz: Eric will go into more detail on the remarkable progress of the commercial team later in this call. Now, let me turn to Everett, which is the first commercial product from our innovative SPICe platform. And RISD continues to show strong revenue this quarter, with approximately 20% total market share in just over a year after launch.

Matt will go into more detail on our phase III program shortly.

Now moving on to a D C.

In Europe, we still expect to see HMP opinion by the end of this year and look forward to bringing this transformational therapy to ADC deficiency patients.

Matt: In addition, we will collect CSF, plasma, and CNS radiographic biomarkers in both the placebo-controlled and long-term extension phases of the study that could provide evidence of meaningful PTC518 treatment effects. As we discussed in our program update last month, the inclusion criteria for the PIVOT-HD trial were carefully constructed to ensure enrollment of a study population in whom we can demonstrate treatment effects over the course of the study. The criteria for this Goldilocks population were developed based on extensive analyses of HD clinical and biomarker natural history data.

Stuart Peltz: RISD is the most prescribed FMA treatment in the United States, and Roche expects further growth in 2021, with approval in 63 countries, and has continued focus on pricing and reimbursement efforts outside of the U.S. The success of our commercial portfolio demonstrates our ability to utilize our commercial engines to grow revenues to further invest in the pipeline, which I'll now discuss in more detail. In particular, I'd like to start with our near-term value. I'm excited to announce that we have initiated a registration-directed trial called Affinity for PTC 9Q3 in PKU.

I'm also pleased that we recently held a ribbon cutting ceremony for our gene therapy manufacturing center of excellence in Hopewell, New Jersey.

Our new state of the art utility as well equipped and staffed to produce high quality plasma.

The vector for <unk>.

Gene therapy applications.

I'm very proud of the progress we've made over the past quarter with exciting commercial achievement and steady state progress across our pipeline.

This speaks to the dedication of our people who have worked incredibly hard in the face of the ongoing challenges.

Brought by the pandemic.

Past 18 months have required perseverance.

Matt: We look forward to initiating the Phase 2 study by the end of this year. Next, I'll provide updates on our BioE class. As Stu mentioned, we are continuing enrollment in the two registration-directed trials of the tiquinone in Mitochondrial Disease-Associated Seizures, the MITEI trial, and in Fraser-Icataxia, the MOVE-FA trial. I am proud of the progress our teams have made in activating our global study sites to allow for enrollment of these trials during the pandemic.

I would just say that we've continued to execute across all fronts.

Stuart Peltz: We view this as a significant opportunity, as there is a well-defined patient population through newborn screening, known centers of excellence, and a clear pathway to approval with a blood-based biomarker as an endpoint, as well as having an enriched population through a run-in responder analysis that increases our chance of success. Now, let me talk about our next two registration-directed trials from our BioE platform. The BioE platform targets XS electronic stress and the acts of dangerous stress that contributes to multiple disease states. The first compound from this platform, retiquinone, inhibits 15-lipoxygen. A key regulator that controls the oxidative stress response

We have all the ingredients.

Research development and commercialization that place that positions us to be a growing revenue generating dirty biopharmaceutical company.

I'll now turn the call over to Matt for an update on the development program Matt.

Thanks, Dale and happy to provide an update on the continued progress of our pipeline programs I will begin with our PTC 19th the PKU program.

Matt: We expect results from the MITEI trial in Q3 2022 and from the MOVE-FA trial in 2023. As we reported last quarter, we completed the Phase 1 Healthy Volunteer Trial of PTC 857 and are now moving forward with the Phase 2 trial in patients with ALS. As a reminder, PTC 857 inhibits the enzyme 15-lipoxygen, a key regulator of the Inflammation and Oxidative Stress Pathway, known as Ferribtosis. Ferroctosis is a recently described cell death pathway that has been demonstrated to be key to neurodegenerative disease pathology, including ALS and Parkinson's. In a series of preclinical studies, we have demonstrated that PTC 857 is a potent protector of neuronal cell death and neuropathology in a number of in vitro and in vivo neurodegenerative disease test systems.

As planned we initiated enrollment in the affinity trial, our global Phase III registration directed trial of PTC 93 in pediatric and adult PKU patients.

This double blind placebo controlled trial will include a running phase to identify responders to PTC Ninety-three, who will then be randomized to receive either PTT 93 or placebo for six weeks.

Stuart Peltz: The first of the registration-directed trials with patiquinone is the MIGHTY-E study in patients with mitochondrial disease associated with seizures. We expect results in the third quarter of 2022, and if positive, will be the basis of our NDE. Our second registration-directed particulate note trial, MOVE-FA, is inpatient with pre-trick attacks. A Mitochondrial Disease That Affects Neuromuscular Function.

As a previous approved therapies for PKU. The primary endpoint of the affinity trial is reduction of phenylalanine.

Following completion of placebo controlled trial subjects will then be enrolled a long term open label extension study.

We expect to have results from the placebo controlled trial by the end of 2022.

Turning now to our PTC 508, Huntington's disease program. Following the announcement of the successful phase one study results in healthy volunteers, we are moving forward with our phase two study in Huntington's disease patients.

Stuart Peltz: We're grateful for the collaboration and support from the FA community in helping us to drive enrollment. We anticipate results in 2020. We're also moving ahead with the Next Generation Compound from the BioE platform, PTC 857. We have selected ALS as the first indication and are aiming to initiate the Phase 2 trial for PTC 857 in the first quarter of next year. I'll now discuss our innovative splicing platform with a focus on PTC 518 for the treatment of Huntington's disease.

His study pivotal HD will include a 12 week double blind placebo controlled phase followed by a one year open label extension fee.

Eric: We plan to initiate the Phase 2 study in the first quarter of 2022 and will provide additional details on the study design once it is finalized. We are excited about the progress we have been making in our ongoing registration-directed trials and look forward to initiating the Phase 2 trials with PTC 518 and PTC 857 in the near future. I'll now turn the call over to Eric for an update on our commercial business. Thanks, Matt.

Study will enroll approximately 100 to 150 subjects will be randomized to receive placebo or one of two dose levels of PTC five eight.

Primary objective of the placebo controlled phase demonstrated safety pharmacology, and evidenced that each T T mrna and protein lowering in HD patients.

In addition, we will collect CSF plasma and CNS radiographic biomarker data in both the placebo controlled and long term extension phase of the study that can provide evidence of meaningful PTC five treatment effect.

Stuart Peltz: We recently reported results from the PTC 518 Healthy Volunteer Trial. We were able to show dose-dependent lowering of both HPT, mRNA, and protein and achieve the targeted 30% to 50% reduction. We also demonstrated that PCC 518 passes the blood-brain barrier and has minimal impact, which are key attributes that treat Huntington's disease.

Eric: Our PTC customer facing team has delivered another outstanding quarter in our global DMD franchise. We have built a strong foundation for our potential launch of the PTC AADC gene therapy, which will follow the anticipated EMEA approval and will continue to drive our geographic expansion across the globe to strengthen our commercial engines. Our strong revenue growth continues in our DMV franchise with a 39% increase year over year. This brings our year-to-date sales for the DMV franchise to $306 million.

As we discussed in our program update last month, the inclusion criteria for the pivotal <unk> trial, we're carefully constructed to ensure enrollment of the study population in whom we can demonstrate treatment effect over the course of the study.

Stuart Peltz: We remain very excited about this program and are moving as rapidly as possible into phase two. In the Phase 2 trial, we will replicate the safety, tolerability, and pharmacology of PTC5.0 and 8, as well as decreases in Huntington mRNA and protein levels in the Huntington's disease patients. Matt will go into more detail on our phase two program shortly. Now, moving on to AADC.

The criteria for this goldilocks population were developed based on extensive analysis of the HD clinical and biomarker natural history database.

Look forward to initiating the phase two study by the end of this year.

Next I'll provide updates on our bio E platform.

As Steve mentioned, we are continuing enrollment in two registration directed trials, particularly in mitochondrial disease associated seizures that might be.

And in <unk> ataxia, the move FH trial I am proud of the progress our teams have made in activating our global study sites to allow for enrollment of these trials during the pandemic.

Stuart Peltz: In Europe, we still expect to see an HMP opinion by the end of this year and look forward to bringing this transformational therapy to AADC deficiency patients. I'm also pleased that we recently held a ribbon-cutting ceremony for our Gene Therapy Manufacturing Center of Excellence in Hopewell, New Jersey. Our new state-of-the-art facility is well-equipped and staffed to produce high-quality plasmid and AAV vectors for gene therapy applications. I'm very proud of the progress we've made over the past quarter, with exciting commercial achievements and steady state progress across our pipeline.

Results from that might be trial in Q3 2022 in front of me move at a trial in 2023.

As we reported last quarter, we completed the phase one healthy volunteer trial of PTC eight five set and are now moving forward with the phase II trial in patients with ALS.

As a reminder, PTC 857 inhibits the end by 15 lipoxygenase.

A key regulator of the inflammation and oxidative stress pathway.

Eric Joseph.

Fair closest as it recently described sell desktop way that has been demonstrated to be key to neuro degenerative disease pathology, including ALS and Parkinson's disease.

Stuart Peltz: This speaks to the dedication of our people, who have worked incredibly hard in the face of the ongoing challenges. [inaudible] The past 18 months have required perseverance, and I'm proud to say that we've continued to execute across all fronts. We have all the ingredients.

Eric: This is a substantial increase over the original guidance.

Eric: New Patient Starts, Continued High Compliance, and a Focus on Operational Excellence have fueled sustained growth of employees. This quarter, we achieved $47 million in revenue, which is a 22% increase over the third quarter of 2020. Turning to TransLarnap, we achieved $67 million in revenue this quarter, a 55% growth over the third quarter of 2020. As a reminder, especially in rare diseases, significant international markets, like Brazil, can produce large orders that create lumpiness due to the uneven government-driven orders that vary over the course of the year.

In a series of preclinical studies, we have demonstrated that PTC 857 is a potent protector of neuronal cell death, and neuropathology and a number of in vitro and in vivo data oriented you guys heard disease test systems.

Stuart Peltz: Research, Development, and Commercialization, a place that positions us to be a growing revenue-generating, enduring biopharmaceutical company. I now turn the call over to Matt for an update on the development program.

We plan to initiate the phase II study in the first quarter of 2022 and will provide additional details on the study design once it is finalized.

We are excited about the progress we've been making in our ongoing registration directed trials and look forward to initiating the phase II trials. The PTC 508, PTC five seven in the near future.

Matt: As with previous approved therapies for PKU, the primary endpoint of the affinity trial is reduction of phenylalanine bubbles. Following completion of the placebo-controlled trial, subjects will then be enrolled in a long-term open-label extension study. We expect to have results from the placebo-controlled trial by the end of 2022. Now, turning now to our PTC 518 Huntington's Disease program. Following the announcement of the successful phase one study results in healthy volunteers, we are moving forward with our phase two study in Huntington's disease patients. This study, Pivot HD, will include

I'll now turn the call over to Erik for an update on our commercial business Eric.

Thanks, Matt our PTC customer facing team has delivered another outstanding quarter in our global DMD franchise.

We have built a strong foundation for a potential launch.

Eric: This drives large quarter over quarter growth in comparison to others. In this quarter, the successful launch in Russia was a key driver of our growth. As we received centralized reimbursement in Russia and obtained a significant order for a large group of nonsense mutation DMD patients. Additionally... We are seeing continued growth in the main European markets and driving geographical expansion in Central and Eastern Europe, Latin America, the Middle East, and Asia-Pacific, which remains important to our future growth.

PTC ADC gene therapy, which will follow the anticipated EMEA approval and will continue to drive our geographic expansion across the globe to strengthen our commercial engine.

Our strong revenue growth continued in our DMD franchise with a 39% increase year over year.

This brings our year to date sales for the DMD franchise to $306 million.

Our 2021 revenue guidance was originally at $355 million to $375 million at the beginning of 2021, which in Q2 was raised to $370 million to $390 million.

Matt: 12-Week Double Blind Placebo Control phase, followed by

Matt: Following a one-year open-label extension. The study will enroll approximately 100 to 150 subjects who will be randomized to receive placebo for one of two dose levels of PTC518. The primary objective of the placebo control phase is to demonstrate safety, pharmacology, and evidence of HTT, mRNA, and protein lowering in HD patients. In addition, we will collect CSF, plasma, and CNS radiographic biomarkers in both the placebo-controlled and long-term extension phases of the study that could provide evidence of meaningful PTC518 treatment effects.

Eric: We are also excited to recently share the real-world results from the STRIDE patient registry demonstrating that treatment with translarna delays loss of ambulation by more than five years in boys with Duchenne muscular dystrophy, compared to standard of care alone. This is further adding to the totality of evidence for the benefit of translarna. We are making continued progress for access to TransLarna, with reimbursement agreements now established for patients in Finland and the Netherlands, and broader coverage for two to five-year-olds for patients in Italy.

Based on the continued strong year to date performance. We are pleased to announce that we are raising our 2021 revenue guidance for the DMD franchise to 400.

The $420 million.

Abstention will increase over the original guidance.

New patient starts continued high compliance and our focus in operational excellence has fuel sustained growth of plaza.

This quarter, we achieved $47 million in revenue, which is a 22% increase over the third quarter of 2020.

Turning to trade in Florida, we achieved $67 million in revenue this quarter, a 55% growth over the third quarter of 2020.

Matt: As discussed in our program update last month, the inclusion criteria for the PIVOT-HD trial were carefully constructed to ensure enrollment of a study population in whom we can demonstrate treatment effect over the course of the study. The criteria for this Goldilocks population were developed based on extensive analyses of the HD clinical and biomarker natural history data.

As a reminder, especially in rare diseases.

Eric: Despite significant COVID-19 challenges in Brazil, we are pleased with that.

Difficult international markets, like Brazil, and produce large orders create lumpiness due to the uneven government driven orders that vary over the course of the year.

Eric: We are pleased with Advisa's approval of the expansion of the TransLarder label to include patients in the 2-5 year old range. Across Latin America, we continue to see increases in newly diagnosed DMD patients and expect to fulfill an order for translarin in Brazil in the fourth quarter this year to treat both new and existing DMD patients in the country. Now, turning to Tech Study in Leningrad, we are excited to announce that we have successfully received Category 1 Innovation Classification from CMED, the Drug Market Regulation Chamber in Brazil. CMED price categorization is the first critical step in getting pricing and reimbursement.

Eric: We look forward to initiating the Phase 2 study by the end of this year. Next, Humberbyte updates on our BioE class. As Stu mentioned, we are continuing enrollment in the two registration-directed trials of Tiquinone for Mitochondrial Disease-Associated Seizures, the MITEI trial, and in Fraser-Icataxia, the MOVE-FA trial. I am proud of the progress our teams have made in activating our global study sites to allow for enrollment of these trials during the pandemic.

This drives large quarter over quarter growth in comparison to others.

In this quarter the successful launch in Russia with a key driver of our growth.

As we received centralized reimbursement in Russia and obtained a significant order for a large group of nonsense mutation DMD patients.

Additionally.

We are seeing continued growth in main European markets.

Eric: We expect results from the MITEI trial in Q3 2022 and from the MOOV-FA trial in 2023. As we reported last quarter, we completed the Phase 1 Healthy Volunteer Trial of PTC 857 and are now moving forward with the Phase 2 trial in patients with ALS. As a reminder, PTC 857 inhibits the enzyme 15-lipoxygen, a key regulator of the Inflammation and Oxidative Stress Pathway, known as Ferribtosis. Ferruptosis is a recently described cell death pathway that has been demonstrated to be key to neurodegenerative disease pathology, including ALS and Parkinson's.

And driving geographical expansion in central and Eastern Europe, Latin America, the Middle East and Asia Pacific, which remains important to our future growth.

We are also excited to recently share of the real world results from the stride patient registry.

Illustrating that treatment with <unk>, Florida delays loss of emulation by more than five years in boys with nonsense mutation Duchenne muscular dystrophy compared to standard of care alone.

Eric: Category 1 classification is given to innovative treatments that provide greater efficacy than current standards of care and allows for pricing in line with international markets. Take studies categorization as an innovative treatment is a key milestone towards optimizing value in Latin America. We will continue to provide named patient access and now commence reimbursement negotiations with Conitec, Brazil's health technology assessment body, for inclusion of Tegceti in the Brazilian public health system or SUS.

This is further adding to the totality of evidence for the benefit of trends, Florida.

We are making continued progress for access to trend, Florida with reimbursement agreements now established for patients in Finland.

Eric: In a series of preclinical studies, we have demonstrated that PTC 857 is a potent protector of neuronal cell death and neuropathology in a number of in vitro and in vivo neurodegenerative disease test systems. We plan to initiate the Phase 2 study in the first quarter of 2022 and will provide additional details on the study design once it is finalized. We are excited about the progress we have been making in our ongoing registration-directed trials and look forward to initiating the Phase 2 trials with PTC 518 and PTC 857 in the near future. I'll now turn the call over to Eric for an update on our commercial business.

And the Netherlands, and broader coverage for two to five year olds for patients in Italy.

Despite significant COVID-19 challenges in Brazil, we.

We are pleased with that visa approval of expansion of the trend, Florida label to include patients in the two to five year old range.

Across Latin America, we continue to see increases in newly diagnosed <unk> patients and expect to fulfill in order for trend in Florida, and Brazil in the fourth quarter. This year to treat both new and existing DMD patients in the country.

Now turning to Chegg study and way Libra, we are excited to announce that we have successfully received category one innovation classification consume that the.

Eric: Thanks, Matt. Our PTC customer facing team has delivered another outstanding quarter in our global DMD franchise. We have built a strong foundation for our potential launch of

Eric: As a reminder, there are an estimated 5,000 patients with ATTRM Legosis in Brazil. KSETI is the first antisense medicine available for patients in Brazil to address the underlying causes. We were thrilled to announce that Waylivre was approved by INVISA in Brazil as of August 2021. Following the approval, we have commenced discussions with TMED, the Brazilian Pricing Authority. Wade Lever is the first treatment for FGS in Brazil. FCS is a rare metabolic genetic disease that results in a significant disease burden to patients, including potentially fatal pancreatitis and other chronic complications.

The drug market regulation chamber in Brazil.

He met price categorization is the first critical step in getting pricing and reimbursement in Brazil.

Eric: PTC AAC Gene Therapy

Eric: will follow the anticipated EMEA approval and will continue to drive our geographic expansion across the globe to strengthen our commercial engine. Meanwhile, our strong revenue growth continues in our DMV franchise.

Category, one classification is given to innovative treatments that provide greater efficacy than current standards of care and allows for pricing in line with international markets.

Eric: DMV Franchise with a 39% increase year over year. This brings our year-to-date sales for the DMV franchise to $306 million.

Take studies categorization as an innovative treatment is a key milestone towards optimizing the value in Latin America.

We will continue to provide named patient access and now commence reimbursement negotiations with contact Brazil's health technology assessment bodies for inclusion of Chegg study and the Brazilian public health system or Sis.

Eric: Our 2021 revenue guidance was originally at $350,000.

Operator: https://www.youtube.com.au

Eric: which in Q2 was raised to $370,000 to $390,000. Based on the continued strong year-to-date performance, we are pleased to announce that we are raising our 2021 revenue guidance for the DMD franchise to $400,000 to 420 million. A substantial increase over

As a reminder.

There are an estimated 5000 patients with H <unk> amyloidosis in Brazil.

Eric: We have been engaging in patient finding in Latin America with ongoing success and now have patients on treatment in LATAM through early access programs. I will now touch on the preparations for PTC's first gene therapy launch for PTC AADC. We have built the foundation to support a strong launch, which we anticipate will occur in Europe shortly after final approval. PTC continues to accelerate patient screening activities in enriched high-risk populations. Significant progress has also been made with the identification and preparation of expert pediatric neurological centers of excellence throughout the United States and the EU to ensure treatment center readiness at the time of launch, and we remain focused on identifying patients worldwide in markets where gene therapy access is available.

TEG study is the first antisense medicine available for patients in Brazil to address the underlying cause of the disease.

We were thrilled to announce that way Libra was approved by visa in Brazil as of August 2021.

Eric: New Patient Starts, Continued High Compliance, and a Focus on Operational Excellence have fueled

Following the approval we have commenced discussions with team that the Brazilian pricing authorities.

Eric: [inaudible] This quarter, we achieved $47 million in revenue, which is a 22% increase over the third quarter of 2020. Turning to TransLarnap, we achieved $67 million in revenue this quarter, a 55% growth.

<unk> is the first treatment for FCS in Brazil.

FCS is a rare metabolic genetic disease, which results in a significant disease burden to patients, including potentially fatal pancreatitis and other chronic complications.

Eric: 25% growth over the third quarter of 2020.

Eric: As a reminder, especially in rare diseases, significant international markets like Brazil can produce large orders and create lumpiness due to the uneven government-driven orders that vary over the course of the year. This drives large quarters.

We have been engaged in a patient finding in Latin America with ongoing success and now have patients on treatment in Latam through early access programs.

I will now touch on the preparations for PTC first gene therapy launch for PTC.

Eric: Over a quarter of growth in comparison to others. In this quarter, the successful launch in Russia.

We have built the foundation to support a strong launch, which we anticipate to occur in Europe. Shortly after final approval.

Eric: The successful launch in Russia was a key driver of our growth, as we received centralized reimbursement in Russia and obtained a significant order for a large group of nonsense mutation DMD patients.

DTC continues to accelerate patient screening activity and enriched high risk population.

Eric: We are proud to have commemorated October 23rd as AADC Deficiency Awareness Day together with the AADC family network and look forward to bringing this much needed treatment to patients very soon. The third quarter has been yet another strong quarter with sustained growth in the DMD franchise. I am looking forward to a strong Q4 as our global customer-facing teams continue to execute flawlessly against their strategic initiatives. I will now turn the call over to Emily for a financial update. Emily?

Significant progress has also been made with the identification and preparation of expert pediatric neurological centers of excellence throughout the United States and the EU to ensure treatment center readiness at the time of launch and we remain focused on identifying patients globally markets, where gene therapy access is.

Eric: We are seeing continued growth in the main European markets and driving geographical expansion in Central and Eastern Europe, Latin America, the Middle East, and Asia-Pacific, which remains important to our future growth. We are also excited to recently share the real-world results from the STRIDE patient registry demonstrating that treatment with translarna delays loss of ambulation by more than five years in boys with non-sense mutation Duchenne muscular dystrophy compared to standards of care alone This is further adding to the totality of evidence for the benefit of translarna.

Is available.

We are proud to have commemorated October 23rd ADC deficiency awareness day together with the agency.

<unk> network and look forward to bringing this much needed treatments of patients very soon.

Emily: Thanks, Eric. We have continued to see each other.

The third quarter has been yet another strong quarter with sustained growth in the DMD franchise I am looking forward to a strong Q4 as our global customer facing teams continue to execute flawlessly against our strategic initiatives.

Emily: Financial Revenue Growth from our Commercial Portfolio this quarter, and we remain in a strong position to continue to support strategic advancement across our diverse pipeline. We look forward to continuing to deliver.

I will now turn the call over to Emily for financial update Emily.

Thanks, Eric we have continued to see substantial revenue growth from our commercial portfolio. This quarter and we remain in a strong position to continue to support strategic advancement across our diverse pipeline.

Emily: We are continuing to deliver on important milestones across all of our programs.

Eric: Translator Label to Include Patients in the 2- to 5-Year-Old Group

Emily: The press release issued earlier this afternoon summarizes the details of our third quarter 2021 financial results.

Eric: Across Latin America, we continue to see increases in newly diagnosed DMD patients and expect to fulfill an order for translarin in Brazil in the fourth quarter this year to treat both new and existing DMD patients in the country. Now, turning to Tech Study in Leningrad, we are excited to announce that we have successfully received Category 1 Innovation Classification from CMED, the drug market regulatory chamber in Brazil. Key Med price categorization is the first critical step in getting pricing and reimbursement.

We look forward to continuing to deliver on important milestones across all of our programs.

Emily: I will take a few minutes now to review these financial results, but please refer to the press release for further detail.

The press release issued earlier this afternoon summarizes the details of our third quarter 2021 financials yourself.

I will take a few minutes now to review these financial results. Please refer to the press release for further detail.

Emily: Beginning with top-line results, total revenue...

Emily: The total revenues were $138.7 million for the third quarter of 2021, a 17% increase over the third quarter of 2020. This revenue included $115.6 million.

Beginning with top line results total revenues were $138 7 million for the third quarter of 2021.

17% increase over the third quarter of 2020.

This revenue included the $115 six and net product sales and 23.1 and royalty and collaboration revenue.

Emily: 15.6 in Net Product Sales and 23.1 in Royalty and Collaboration Revenue. The strong growth of the DMD franchise continued this quarter with TransVarna net product sales of $67.2 million, compared to $43.4 million in the third quarter of 2020. Continued geographic expansion, particularly in Russia, has been driving this growth. Year over year, MFLAZA revenue is also up this quarter, with net product revenue of $47.1 million, compared to $38.5 million in the third quarter of 2020.

Eric: Reimbursement Information Category 1 classification is given to innovative treatments that provide greater efficacy than current standards of care and allows for pricing in line with international markets.

This strong growth after the DMD franchise, continuing that's quicker with Translarna net product sales of $67 2 million compared to $43 4 million in the third quarter of 2020.

Eric: Type studies categorization as an innovative treatment is a key milestone towards optimizing value in Latin America.

Continued geographic expansion, particularly in Russia has been driving this growth.

Eric: We will continue to provide named patient access and now commence reimbursement negotiations with Conitech, Brazil's health technology assessment body, for inclusion of Tegceti in the Brazilian public health system, or SUHT.

Year over year I'm Plaza revenue was also up this quarter with net product revenue of $47 1 million over $38 5 million in the third quarter of 2020. This has primarily been driven by better compliance of new prescription starts.

Emily: This has primarily been driven by better compliance and new prescriptions starting. Due to this strong performance, we have raised revenue guidance for the DMD franchise to $400 to $420 million, from $370 to $390 million. Turning now to Evrizdi, where our partner Roche has reported year-to-date revenue of 396 million Swiss francs, resulting in 33.3 million in year-to-date royalties to PTC.

Eric: As a reminder, there are an estimated 5,000 patients with

Due to this strong performance, we have raised revenue guidance for the DMD franchise to $400 million to $420 million from $370 million to $390 million.

Eric: with ATTR Amlogosis in Brazil.

Eric: Keg Steady is the first antisense medicine available for patients in Brazil to address

Eric: in Brazil to address the underlying cause of the disease.

Turning now to our Brisbane, where our partner Roche has reported year to date revenue of 396 million Swiss franc, resulting in $33 3 million and year to date royalties to PTC.

Eric: We were thrilled to announce that Waylivre was approved by INVISA in Brazil as of August 2021. Following the approval, we have commenced discussions with TMED, the Brazilian Pricing Authority. Wade Lever is the first treatment for FGS in Brazil.

Emily: Royalties to PTC for the 3rd

Royalties to PTC for the third quarter were $13 1 million in royalty revenue.

Emily: This quarter we're $13.1 million in royalty revenue. As a reminder, PTC also retains sales-based cash milestones, and the $10 million milestone payment for the first commercial sale in Japan was received by PTC this quarter. In addition to this, PTC has an additional $325 million in sales-based milestones remaining, with a $25 million payment expected when the threshold of $5 is reached.

As a reminder, PTC also routine sales base cash milestone and the 10 million milestone payment for the first commercial sale in Japan.

Eric: FCS is a rare metabolic genetic disease which results in a significant

Seems like PTC this quota.

Eric: [inaudible] We have been engaging in patient finding in Latin America with ongoing success, and now we have patients.

In addition to this PTC has an additional 325 million in sales based milestones remaining with a 25 million payment expected when the threshold of $500 million in revenue with rates.

Emily: The threshold of $500 million in revenue is reached.

Eric: On Treatment in LATAM through the Early Access Program

Emily: Non-GAAP R&D expenses were $117.8 million for the third quarter of 2021, excluding $13 million in non-cash stock-based compensation.

Non-GAAP R&D expenses were $117 8 million for the third quarter of 2021, excluding $13 million in noncash stock based compensation expense.

Eric: I will now touch on the preparations for PCC's first gene therapy launch for PTC AADC. We have built the foundation to support a strong launch, which we anticipate will occur in Europe shortly after final approval. PTC continues to accelerate patient screening activities in enriched high-risk populations. Significant progress has also been made with the identification and preparation of expert pediatric neurological centers of excellence throughout the United States and the EU to ensure treatment center readiness at the time of launch, and we remain focused on identifying patients globally in markets where

Emily: This is the third quarter of 2020, excluding $9.2 million in non-cash, stock-based compensation.

Compared to $83 8 million for the third quarter of 2020, excluding $9 2 million in noncash stock based compensation expense.

Emily: Non-cash, stock-based compensation expense

Emily: Non-GAAP SG&A expenses were $56.4 million for the third quarter of 2021, excluding $12.8 million in non-cash stock-based compensation expense, compared to $50.3 million for the third quarter of 2020, excluding $7.6 million in non-cash stock-based compensation. We have lowered and narrowed the range of our non-GAAP R&D and SG&A expense for the full year 2021 to $750,000

Non-GAAP SG&A expenses were $56 4 million for the third quarter of 2021, excluding $12 8 million of noncash stock based compensation expense.

<unk> to $50 3 million for the third quarter of 2020.

Excluding $7 6 million of noncash stock based compensation expense.

Eric: Markets where gene therapy access is available

We have lowered and narrowed the range of our non-GAAP R&D and SG&A expense for the full year 2021.

Eric: We are proud to have commemorated October 23rd as AADC Deficiency Awareness Day together with the AADC family network and look forward to bringing this much needed treatment to patients very soon. The third quarter has been yet another strong quarter with sustained growth in the D&D franchise. I am looking forward to a strong Q4 as our global customer-facing teams continue to execute.

Emily: 735,000,000 from $725,000 to $755,000,000. Cash, Cash Equivalents, and Marketable Securities totaled $867.9 million as of September 30, 2021, compared to $1.1 billion as of December 31, 2020. I will now turn the call over to the operator for Q&A.

715 to 735 million from $7 $25 million to $755 million.

Cash cash equivalence and marketable securities totaled $867 9 million as of September 30th 2021.

Compared to $1 1 billion as of December 31, 2020.

I will now turn the call over to the operator for Q&A.

Operator.

Emily Luisa Hill: Continue to execute flawlessly against their strategic initiative. I will now turn the call over to Emily for a financial update.

Thank you.

Operator: As a reminder, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from Eric Joseph with JP Morgan. Your line is open.

A reminder to ask a question you will need to press star one on your telephone to withdraw your question press the pound key please standby, while we compile the Q&A roster.

Emily Luisa Hill: Thanks, Eric. We have continued to see substantial revenue growth from our commercial portfolio this quarter, and we remain in a strong position to continue to support strategic advancement across our diverse pipeline. We look forward to continuing to deliver on important milestones across all of our programs. A press release issued earlier this afternoon summarizes the details of our third quarter 2021 financial results. I will take a few minutes now to review these financial results, but please refer to the press release for further details. Beginning with top line results, total revenues were $138.7 million for the third quarter of 2020.

Our first question comes from Eric Joseph with Jpmorgan. Your line is open.

Hannah: Hi, good afternoon. This is Hannah on behalf of Eric. Thanks for taking the questions. Just a few from us.

Hi, Good afternoon. This is Hannah on for Eric Thanks for taking the question just a few from us.

Hannah: So first, with respect to your oral slicing platform, just wondering if there are any other CAG trinucleotide repeat disorders that you might be looking to expand into over the near term, such as mitonic dystrophy or efferentiate taxidermy?

First with respect to your oral splicing platform and just wondering if there are any other kind of triangulate that.

And it Triangulates IBP disorders that you might be looking to expand into over the near term.

My tonic dystrophy artificially ataxia.

Hannah: And then next, with regard to PTC 299, the site...

And then next with regard to PTC to 99.

unknown: The FITE-19 COVID-19 study, just wondering if you're able to talk about powering assumptions for your primary endpoint of time-to-respiratory improvement and maybe what some of the entry criteria are as it relates to prior vaccine exposure or COVID-19 seropositivity. Sure. Okay, I'll start with the

The fight 19, COVID-19 study just wondering if you're able to talk about powering assumptions for your primary endpoint of time, Joe spiritual improvement.

Emily Luisa Hill: 3rd Quarter of 2021. A 17% increase over the 3rd quarter of 2020.

Just maybe what some of the entry criteria are as it relates to prior vaccine exposure or COVID-19 care of positivity.

Emily Luisa Hill: This revenue includes $115.6 in net product revenue.

Emily Luisa Hill: Project Sales, and 23.1 in Royalty and Collaboration Revenue. The strong growth of the DMD franchise.

Sure, Okay I'll start with the.

unknown: Sure. Okay, I'll start with the...

unknown: The Oral Splicing, I think that's the splicing one, and the platform is what we've been talking about in terms of the splicing that, you know, it's really quite interesting that we, you know, we've been able to build an informatics program that allows us to identify which sort of U1 sites that we can monitor. We've been particularly interested in the nucleotide repeats as So, I'll speak more generally and just say we've built a platform that's capable of looking at those, and we have a high interest in multiple other repeats like myotonic dystrophy as well as others. But we've always been interested in the ability to produce the expression of these using our technologies so that we can. So, I think that it's being used quite well.

Oral splicing.

Slide 31.

Emily Luisa Hill: TransVarna Net Product Sales were $67.2 million, compared to $43.4 million in the third quarter.

Platform and what we are.

<unk> been talking about in terms of.

Pricing, but it's really quite interesting that we you know.

Emily Luisa Hill: in the third quarter of 2020.

Emily Luisa Hill: Continued geographic expansion, particularly...

We've been able to bill.

Build the informatics program that allows us to identify.

Emily Luisa Hill: Only Russia has been driving this growth. Year over year, MFLAZA revenue is also up this quarter, with net product revenue of $47.1 million, compared to $38.5 million in the third quarter of 2020. This has primarily been driven by better compliance and new prescription starts.

Which would sort of your one sites that we can monitor we've been particularly interested in.

And.

The nuclear type of pizza as well, so I'll speak more generally and just say we built the platform that's capable of looking at those and we have a high interest in multiple other.

Emily Luisa Hill: Due to this strong performance, we have raised revenue guidance for DMD-Franc.

Emily Luisa Hill: Thank you for your guidance for the DMD franchise to $400 to $420 million from $370 to $390 million. Turning now to Evrisdi, where our partner Roche has reported year-to-date revenue of $396 million Swiss francs, resulting in $33.3 million in year-to-date royalties to PTC. Royalties to PTC for the third quarter were $13.1 million in royalty revenue. As a reminder, PTC also retains sales-based cash milestones, and the $10 million milestone payment for the first commercial sale in Japan was received by PTC this quarter.

Repeat like marathon dystrophy, So you said that as.

As well as others and.

And we think that we can use the platform in interesting ways of being able to tackle other ones.

We talked previously about what we disclose is a scarf.

Godfrey.

Paul.

So we have a bunch of other and then we probably have five.

Five or six more programs that we haven't disclosed yet, but we've always been interested in the ability to be able to produce the expression of these using our technologies. We can so I think all of that being used quite well in the case of 299 and fight 19, I'll pass that over to Ivor matter tightly on that one.

unknown: In the case of 299 and Site 19, I'll pass that over to either Matt or Kylie on that one. I have a question about the FITE-19 trial. So, as you mentioned, our primary endpoint in that trial is Time to Sustain Respiratory Improvement, which is defined as an oxygen saturation of 94% on remare, which is sustained until discharge from the hospital or the end of the study, which is day 28. Basically, the powering assumptions here were based on an estimation of median time to respiratory improvement in the placebo group, which we've taken, which is based on existing data, which was roughly 11 days, and then we had a hypothesized treatment effect, and then basically looked at a hazard ratio of about 1.38, you know, a two-sided type one error, which got us to our sample size of 380 subjects, which we believe In terms of your question regarding vaccination, we don't have any criteria that include or

Emily Luisa Hill: In addition to this, PTC has an additional $325 million in sales-based milestones remaining, with a $25 million payment expected when the threshold of $500 million in revenue is reached. Non-GAAP R&D expenses were $117.8 million for the third quarter of 2021. Excluding $13 million in non-cash stock-based compensation expense, compared to $83.8 million for the third quarter of 2020, excluding $9.2 million in non-cash stock-based compensation expenses.

I know your question on the fight 19 trials. So as you mentioned our primary endpoint in that trial is.

Time to sustaining or Tom just stainless trade agreement, which is defined as the oxygen saturation of 90% to 94% on there which is sustained until discharged from the hospital or the end of the study which is day 28, basically the the powering assumptions here.

Based on a explanation of median time to respiratory approved mentioned the placebo group, which we've taken basically based on some data which was.

Emily Luisa Hill: Non-GAAP SG&A expenses

Emily Luisa Hill: $56.4 million for the third quarter of 2021, excluding $12.8 million in non-

Emily Luisa Hill: Uncashed Stock-Based Compensation Expense compared to $50.3 million for the third quarter of 2020, excluding $7.6 million in non-cash stock-based compensation.

Roughly 11 days.

Outside of the treatment effect.

And then basically looks at a hazard ratio of about 1.382 sided telco carrier, which got us to our sample size of 380 subjects, which we believe gives us.

Emily Luisa Hill: $6,000,000 in non-cash, stock-based compensation. We have lowered and narrowed the range of our non-GAAP R&D and SG&A expense for the full year 2021 to $715 to $735 million, from $725 to $755 million. Cash, Cash Equivalents, and Marketable Securities totaled $867.9 million as of September 30, 2021, compared to $1.1 billion as of December 31, 2020.

More than 80% power to detect that difference in terms of your question regarding the vaccination.

We don't have any criteria that include or exclude that previous constellation before it.

unknown: Okay, great. Thanks for taking the question.

Relates to.

Cheryl positivity.

Okay, great. Thanks for taking the question.

Danielle Brill: Thank you. Our next question comes from Danielle Brill with Raymond James. Your line is open.

Yeah.

Operator: I will now turn the call over to the operator for Q&A. Operator. Thank you. As a reminder, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from Eric Joseph with JP Morgan. Hi, good afternoon. This is Hannah on behalf of Eric.

Thank you. Our next question comes from Danielle Brill with Raymond James Your line is open.

Danielle Brill: Hi guys. Good afternoon. Thanks so much for the questions. I guess...

Yes.

Hi, guys. Good afternoon. Thanks, so much for the questions I guess first on the doses for phase two.

Danielle Brill: First on the doses for...

Danielle Brill: Thank you for joining us today for the 518 study. I'm presuming 30 mg will be one of the two doses you're thinking of using. Are you contemplating going higher or lower for the second dose? And then do you think it's reasonable to assume we may have data to

Eight study.

I am presuming 30 milligram will be one of the two doses youre thinking of.

Using and are you are you contemplating going higher or lower for the second dose and then do you think.

Hannah Temiloluwa Adeoye: Thanks for taking the questions. Just a few from us. So first, with respect to your oral slicing platform, just wondering if there is.

It's reasonable to assume we may have data.

Danielle Brill: And that's it. It's probably data next year. Thanks. Yeah.

Probably data next year.

Yeah, maybe I'll start and then I'll pass it on.

Unknown Executive: Yeah, maybe I'll start and then I'll pass it on to Matt. You might remember that we did a Phase 1 study where we did 15 and 30 milligrams, and we saw in the 30 milligram that up to 65% of the RNA was reduced. And we would anticipate that at steady states, the protein levels would go down as well to this number. I think what we'd be initially targeting is what we've said is the 30 to 50% of that to be able to get to that.

To Matt you might remember that we you know we did a.

One study where we were.

We did a 15 and 30 milligram and we saw.

In the 30 milligram up to 60 or 65% of the RNA.

That was reduced.

Unknown Executive: and just maybe what some of the entry criteria are as it relates to prior vaccine exposure or COVID-19 seropositivity. Sure, okay, I'll start with the...

We would anticipate that.

That he thinks the protein levels go down.

Number.

I think what we'd be initially targeting is what we've said is the 30% to 50% of that to be able to get to that and the way. We're thinking about this as well as probably also thinking about taking advantage of some of them are.

Unknown Executive: The Oral Splicing, I think that's the splicing one, and the platform is what we've been talking about in terms of the splicing that, you know, it's really quite interesting that we've been able to build an informatics program that allows us to identify which sort of U1 sites that we can monitor. We've been particularly interested in the nucleotide repeats as well. So, I'll speak more generally and just say we've built a platform that's capable of looking at those, and we have a high interest in multiple other repeats like myotonic dystrophy as well as others.

Unknown Executive: And the way we're thinking about this as well is probably also thinking about taking advantage of some of the fact that we see a bit higher levels in the CFF. So that gives us really an opportunity to actually look at a range of doses. So Matt, maybe I'll pass it on to you to give the thinking on that. Yeah, absolutely.

The fact that we see a bit higher levels in the CSF. So that gives us an opportunity to actually looked at a range of them.

Oh doses, so Matt maybe I'll pass on to you.

The thinking on that.

Yeah, absolutely so.

Matt: So, the 30 milligram dose was the dose that we used for the protein cohort, as Stu said, which really got us to the 65% mRNA and model protein reduction. And again, as you said all along, we've been using the inputs from phase one, which was the Blood mRNA and Protein Reduction as well as Plasma Exposure and CSF Exposure to come up with a range of dose levels that would put us in that 5 to 20, 30 to 50 percent range, which we believe will be somewhere, target doses, somewhere between 5 and 20.

The 30 milligram dose was the dose that we used for the protein cohort as stew said, which really got us too.

65% mrna and novel protein reduction and she said all along we've been using the inputs from phase, one which was the blood mrna and protein reduction as well as plasma exposure in CSF exposure to come up with a range of dose levels that would put us in that 5% to 23% to 50% range.

Unknown Executive: And we think that we can use the platform in interesting ways to be able to tackle other ones. We've talked previously about what we've disclosed, SCAR3 and NAPTOW. So, we have a bunch of other programs, and then we probably have five or six more programs that we haven't disclosed yet. But we've always been interested in the ability to be able to reduce the expression of these using our technologies, and we think we can. So, I think that it's being used quite well.

Which we believe will be somewhere target doses somewhere between five and 20.

Matt: We generally don't give out all the details of the design until the protocol is up and running and we're ready to start, so we'll have more specific information on that as we get closer. But needless to say, we'll be leveraging the titratability of the molecule.

Generally don't give out all the details of the.

Design until the protocol is up and running and we're ready to start so we'll have more specific information on that as we get closer, but needless to say with.

We'll be leveraging the titrated ability of the molecule and as we learn from that first placebo control phase about.

Matt: And as we learned from that first placebo control phase about the relationship between dose for PKPD in terms of hunting mRNA and protein reduction in patients, we'll have the opportunity to titrate that dose if, in fact, there are any differences between what we observed in Phase I and what we observed in HD patients. In terms of design and data, you alluded to the 12-week placebo-control phase. We said that we are looking to start that study before the end of the year.

<unk> shipped between dose PK PD in terms of hunting Huntington mrna and protein reduction in patients will have the opportunity to titrate that dose. If in fact, there is any differences between what we observed in phase one and what we observed in HD patients in terms of the design and data.

Unknown Executive: In the case of 299 and 219, I'll pass that over to either Matt or Kylie on that one. I have a question about the FITE-19 trial. So, as you mentioned, our primary endpoint in that trial is Time to Sustain Respiratory Improvement, which is defined as an oxygen saturation of 94% on remair, which is sustained until discharge from the hospital or the end of the study, which is day 28. Basically, the powering assumptions here were based on an estimation of median time to respiratory improvement in the placebo group, which we've taken, which is based on existing data, which was roughly 11 days.

Okay.

The 12 week placebo control Phase, we said that we were looking at and we plan to start that study in the city end of the year. The subjects will then roll over into a long term extension, where we'll be focusing on leisure won't changes in important biomarkers of disease, including the reduction in Huntington.

Matt: Those subjects will then roll over to a long-term extension where we'll be focusing on measuring changes in important biomarkers of disease, including the reduction in Huntington mRNA and protein in the blood, as well as in the CSF, and look at other important biomarkers such as NFL, as well as volumetric changes on MRI. In terms of time and data, I think we'll have more. There will be more detailed information on time to results once we get the trial started, so we can give you more information on that in the future.

Protein in the blood as well as in the CSF and look at other important biomarkers of disease, including cell as well as volumetric changes on MRI.

Unknown Executive: And then we had a hypothesized treatment effect, and then basically looked at a hazard ratio of about 1.38, you know, a two-sided type one error, which brought us to our sample size of 380 subjects, which we believe gives us more than 80% power to detect that difference. In terms of your question regarding the vaccination, we don't have any criteria that include or exclude that previous vaccination or anything that relates to seroposit

In terms of time at the data I think we'll have more.

Do you have any more detailed information on time to our results. Once we get the trial started giving more information on that in the future.

Matt: So just to clarify, Matt, would you intend to provide data after the placebo-controlled trial?

So I'm sorry, just to clarify Matt would you would you intend to provide data after that the placebo controlled portion or would you wait.

unknown: Transcription by Transcription Outsourcing, LLC.

Until the one year crossover complete.

Matt: Yeah, I expect we'll share the data after the placebo control phase because that first part of the study is very important in terms of establishing the PK-PK relationship in Huntington disease patients and will be very important in informing the dose level for the efficacy trial, whether that's done as a phase three, or we were able to take advantage of the accelerated approval pathway as a post-markinate. So we do believe that this data set is very important, and we'd share it.

I expect we will share the data after the placebo controlled phase because that first part of this study is very important in terms of establishing the PK and PD relationship and Huntington's disease patients that will be very important and formerly the dose level for the efficacy trial, whether that's done is that a.

Unknown Executive: Okay, great. Thanks for sharing the questions. Thank you. The next question comes from Danielle Brill with Raymond James. Your line is open. Hi guys. Good afternoon. Thanks so much for the questions. I guess, first, on the doses for Phase 2, the 518 study, I'm presuming 30 mg will be one of the two doses you're thinking of using. Are you contemplating going higher or lower for the second dose? And then do you think it's reasonable to assume we may have data, 12-week data, next year? Yeah, maybe I'll start, and then I'll pass it on.

A phase III.

Well to take advantage of the accelerated approval pathway as post marketing. So we do believe that that is that's very important.

Okay. It makes sense. Thank you so much for clarifying.

Thank you. Our next question comes from Tim <unk> with Bank of America. Your line is open.

Okay.

Hi, good afternoon, thanks for taking my questions.

Danielle Brill: Okay, that makes sense. Thank you so much for clarifying.

A question for you do and how are you thinking about.

Tazeen Ahmad: Thank you. Our next question comes from Tazeen Ahmad with Bank of America. Your line is open.

The transfer in a franchise in Europe.

Danielle Brill: Yeah, maybe I'll start and then I'll pass it on to Matt. You might remember that we did a Phase I study where we did 15 and 30 milligrams, and we saw in the 30 milligram up to 65% of the RNA that was reduced, and we would anticipate that at steady states the protein levels would go down as well to this number. I think what we'd be initially targeting is what we've said is the 30 to 50% of that to be able to get to that.

Specifically given that it's a relatively mature product now.

Tazeen Ahmad: Hi, good afternoon. Thanks for taking my questions. I have a question for you, Stu.

Where do you see most of the new uptake coming from these days and then I have a couple of follow up thanks.

Tazeen Ahmad: How are you thinking about the TransLarna franchise in Europe? Specifically, given that it's a relatively mature product now, where do you see most of the new uptake coming from these days? And then I have a couple follow-up questions.

Yeah sure so.

I think you're seeing still growth.

Predominantly.

New patients and geographic expansion, which we're continuing to do and it's been quite it's been going quite well.

Unknown Executive: Yeah, sure. So, um... Okay. I think you're still seeing growth, which is predominantly new patients and geographic expansion which we're continuing to do, and it's been quite, it's been going quite well.

Eric Why don't you go through what your team has been good.

Sure.

Yeah, Yeah, yeah. Thanks Bruce.

Danielle Brill: And the way we're thinking about this as well is probably also thinking about taking advantage of some of the fact that we see a bit higher levels in the CFS. So that gives us really an opportunity to actually look at a range of doses. So Matt, maybe I'll pass it on to you to give the thinking on that. Yeah, absolutely.

I'm sorry can you hear me okay.

Yeah, Hi, Eric Yes.

Yes, Hi, Kristine how are you sorry, I'm, having a little connection problems here.

Yeah right.

Right now a lot of our growth that we've seen in the quarter as continued to come from a lot of the main markets. We're seeing very high compliance. We're also implementing a lot of dose adjustments as patients are getting.

Unknown Executive: Eric, why don't you go through what your team has been doing? Unknown Attendee. Unknown Speaker. Yeah, yeah, thanks, yeah, thanks, Drew.

Stuart Peltz: So, the 30 milligram dose was the dose that we used for the protein cohort, as Stu said, which really got us to the 65% mRNA and model protein reduction. And again, as you said all along, we've been using the inputs from phase one, which was the blood mRNA and protein reduction as well as plasma exposure and CSF exposure to come up with a range of dose levels that would put us in that 5 to 20, 30 to 50% range, which we believe will be somewhere, target doses, somewhere between 5 and 20.

Get out older and heavier.

Seeing growth in many of the main markets, where we have been quite mature.

And have launched the product over at least 567 years, but we're also seeing growth in other parts of Europe and other international markets as I mentioned.

Eric: I'm sorry, can you hear me okay? Yeah. Hi, Eric. Yeah. Hi, Tazeen. How are you? Sorry, I'm having some connection problems here. So, Tazeen, yeah, you know, right now, a lot of our growth...

During the call we.

We have recently launched in Russia, and very quickly we were able to get a centralized reimbursement in Russia and also very quickly a significant order came in for a group of patients. So that dynamic is quite interesting is it similar to Brazil. So.

Eric: that we've seen in the quarter has continued to come from a lot of the main markets. We're seeing very high compliance. We're also implementing a lot of dose adjustments as patients are getting

Stuart Peltz: We generally don't give out all the details of the design until the protocol is up and running and we're ready to start, so we'll have more specific information on that as we get closer. But needless to say, we'll be leveraging the titratability of the molecule.

It is their large orders for a number of patients, which creates a little bit of lumpy revenues quarter over quarter, but what we see continued growth with translarna is that patients are staying on drug for long periods of time.

unknown: [inaudible]

unknown: And also, very quickly, a significant order came in for a group of patients, so that dynamic is quite interesting.

Matt: And as we learn from that first placebo control phase about the relationship between dose for PKPD in terms of hunting mRNA and protein reduction in patients, we'll have the opportunity to titrate that dose if, in fact, there are any differences between what we observed in Phase I and what we observed in HD patients. In terms of design and data, you alluded to the 12-week placebo control phase. We said that we are looking to start that study before the end of the year.

There are dosing with the Doc.

There is long.

unknown: TransLarna is

There are patients that we are seeing new patients that are coming in.

unknown: that we are seeing new patients that are coming in from areas in Central and Eastern Europe and Latin America and many others, many other areas.

In areas in central and Eastern Europe, and Latin America, and many others, but many other areas. So the collective route in Europe and international is extremely important and in some of the top players even some payers that we've had to fight with for a number of years have opened up and find new agreement. So even smaller countries like the net.

unknown: The collective around Europe and international is extremely important. And in some of the tough pairs, even some pairs that we've had to fight with for a number of years, have

Matt: Those subjects will then roll over to a long-term extension, where we'll be focusing on measuring changes in important biomarkers of disease, including the reduction in Huntington mRNA protein in the blood, as well as in the CSF, and look at other important biomarkers such as NFL, as well as volumetric changes on MRI. In terms of time with the data, I think we'll have more. There will be more detailed information on time to results once we get the trial started, so we can give you more information on that in the future.

unknown: opened up and signed new agreements. So even smaller countries like the Netherlands and Finland have shown

And Finland have shown that they're willing to pay.

Each have been more restrictive in the past.

unknown: https://www.youtube.com.au And then the number of...

And then there are there's obviously a lot of the label expansions that have occurred.

We had a label expansion for children.

unknown: [inaudible]

unknown: Unknown Speaker, Unknown Attendee, Unknown Attendee, Unknown Attendee, [inaudible] Okay.

Beginning of two years and really broadening the number of eligible patients.

And then there are a number of less restrictions that are going on right now in terms of patients who go non ambulatory. So physicians are making if you will.

Danielle Brill: So, sorry, just to clarify, Matt, would you intend to provide data after the placebo-controlled portion, or would you wait until the one-year crossover completes?

Sort of risk benefit decision before taking patients who are not off drug before non ambulatory. So if I had to actually look at it collectively it is a combination of good patient compliance dosing adjustments geographic expansion and particularly in key markets and this quarter.

Tazeen Ahmad: Okay, that was super detailed, and thank you for that. So related to what you just said, the guidance and sales that you introduced today, would you say that's coming more from Confidence and TransLarna or from Uptake for M-Plaza? And then my last question, probably for Emily here, is can you just talk to us about your expense estimates? It looks like they're going lower relative to last year, and why is that? Thank you.

Matt: I expect we'll share the data after the placebo control phase because that first part of the study is very important in terms of establishing the TK-PK relationship in Huntington's disease patients and will be very important in informing the dose level for the efficacy trial, whether that's done as a phase three or we're able to take advantage of the accelerated approval pathway as opposed to post-marketing. So we do believe that this data set is very important to share.

Clearly, Russia and our main market have really driven translarna in what is probably one of our strongest revenue quarter to date.

Okay that was super detailed and thank you for that so really related to what you just said.

Our guidance in sales that you introduced today would you say that's coming more from confidence in transplant or from uptake for <unk> Plaza and then my last question probably for Emily here is.

Unknown Executive: Sure. Okay. So, obviously, there's a lot of confidence. Eric Pauwels, Yihan Li, Paul Choi, Ania Muntau, John Bohnsack, Yeah, absolutely. I mean, we saw 22% quarter growth within Plaza.

Danielle Brill: Our next question comes from Tazeen Ahmad with Think America. Your line is open. Hi, good afternoon. Thanks for taking my questions. A question for you, Stu. How are you thinking about the TransLarna franchise in Europe? Specifically, given that it's a relatively mature product now, where do you see most of the new uptake coming from these days?

Can you just talk to us about your expense estimate it looks like there.

Tazeen Ahmad: Page PAGE of NUMPAGES www.verbalink.com Page PAGE of NUMPAGES

Lower relative to last year and why is that.

Sure Okay. So.

Obviously, there's a lot of confidence in bulk trains, one and plaza and they both have been growing it. So Eric you want to talk a little bit about growth. So both of those two.

Operator: Yeah, sure. So, um... Okay. I think you're still seeing growth, which is predominantly new patients and geographic expansion which we're continuing to do, and it's been quite, it's been going quite well. Eric, why don't you go through what your team has been doing for the health? Yeah, sure. Yeah, yeah, thanks, yeah, thanks, Drew.

Yeah, absolutely I mean, we saw 22%.

Corporate growth within Plaza with a $47 million in the quarter.

Eric: Unknown Speaker We've seen that as, again, a combination of different things, but primarily, again, very high compliance. We've also been working on dose adjustments. We've minimized dropouts, but we've also seen a lot of new patients that have gone on to EMPLASA. Not only new patients who are naive, but many patients who are switching based on a number of key publications and scientific data now, and, of course, the experience that we've generated that shows that EMPLASA is superior to prednisone.

<unk> seen that as yet.

<unk>.

A combination of different things, but primarily again very high compliance.

We've been also working on dose adjustment.

Stuart Peltz: I'm sorry, can you hear me okay? Yeah, hi, Eric. Yeah, hi, Tazeen. How are you? Sorry, I'm having a few connection problems here.

Minimize drop out, but we've also seen a lot of new patients that have gone to a plaza not only new patients who are naive, but many patients who are switching based on a number of key publications and scientific data now and of course the experience that we've generated that shows that a plaza is superior to <unk>.

Eric: So, Tazeen, yeah, you know, right now, a lot of our growth that we've seen in the quarter has continued to come from a lot of the main markets. We're seeing very high compliance. We're also implementing a lot of dose adjustments as patients are getting, uh, you know, older and heavier, and we're seeing

Eric: So we see a lot of those tailwinds of EMPLASA continuing as the base of patients grows with EMPLASA. For TransLuna, I think we are equally confident based on the things that I mentioned, and we're looking forward to continued geographic expansion. Keep in mind, all the work that we did over the last probably year, year and a half to expand in many of these markets is paying off, and we've continued those investments in Asia Pacific and also in other places in Latin America, and we expect those to continue to provide us growth. So overall, I think we're very confident.

So we see a.

This tailwind at the Plaza continuing at the base of patients is growing within Plaza per transport I think we are equally confident based on the things that I mentioned and we're looking forward to continued geographic expansion keep in mind all of the work that we did over the last public a year year and a half to expand in many of these markets.

Eric: We're seeing growth in many of the main markets where we have been quite mature and have launched the product for at least five, six, seven years. But we're also seeing growth in other parts of Europe and in international markets. As I mentioned during the call, we recently launched in Russia. And very quickly, we were able to get centralized reimbursement in Russia.

Is paying off and we've continued those investments in Asia Pacific and also in other places in Latin America, we expect us to.

We continue to provide us growth. So overall I think we're very confident.

Eric: and also very quickly became a significant

Eric: Water came in for a group of patients, so they

Emily: And then this is Emily Tazeen. When it comes to your OPEX question, I think it's really just a result of 2021 being a full year impact of COVID versus 2020. So obviously, we greatly reduced our travel expenses. And then Eric's team has very successfully transitioned to holding most of their physician seminars and consortiums virtually.

Yeah.

And then this is Emily to Zane when it comes to your Opex question.

I think it's really just a result of 2021 being a full year impact of Covid versus 2020. So obviously, we've greatly reduced our travel expense and then Eric's team has very successfully transitioned to holding most of their physician seminars and consortium's virtually.

Alicia Young: Thank you. The next question comes from Alicia Young with Cantor Fitzgerald.

Eric: [inaudible]

Helpful. Thank you.

Eric: that we are seeing new patients that are coming in from areas in Central and Eastern Europe and Latin America and many others, many other areas. So the collective around Europe and

Thank you. Our next question comes from Alicia Young with Cantor Fitzgerald.

Nina: Hi, thanks for taking our questions and congratulations on all the progress. This is Nina from Aletheia. We are wondering what gives you confidence in the MI-E readout in the third quarter of 2022? And what do you think of the risks for that trial?

Eric: International cooperation is extremely important.

Your line is open hi.

Hi, Thanks for taking our questions and congrats on all the progress this is neena on for Alethia.

Eric: And in some of the tough pairs, even some pairs that we've had to fight with for a number of years.

Operator: https://www.patreon.com

We're wondering what gives you confidence and then my E readout in the third quarter of 2022, and how do you think of us for that trial.

Eric: [inaudible]

And also another one I'm weird curious how you were planning to update us on the FDA feedback for the phase two P. P. C 518 trial next year. Thanks.

Nina: We are curious how you are planning to update us on the FDA feedback for the Phase 2 PTC518 trial next year.

Unknown Executive: Sure. The mighty Matt. You want to go through that? Yeah, absolutely. That's our mighty trial.

Sure there might be a Matt do you want to go through that.

Eric: and really broadening the number of eligible patients.

Yeah, absolutely, that's our sort of <unk>.

Trial is being.

Eric: And then the number of less restrictions that are going on right now in terms of patients who go non-ambulatory.

Registration directed trial in children with mitochondrial disease associated seizures. He.

Operator: https://www.youtube.com.au

Matt: So the MITEI trial is the only...

Talk a bit about before this is a highly morbid.

Matt: Registration Directed Trial in Children with Mitochondrial Disease-Associated Seizures. And as we've talked a bit about before, this is a highly morbid and severe symptom of mitochondrial disease that occurs across many different disease subtypes.

Severe symptomatic casualties that occurs across many different disease subtypes and so the trial.

Operator: Transcripts provided by Transcription Outsourcing, LLC.

Eric: Good Patient Compliance, Dose and Adjustments, Geographic Expansion, and particularly in key markets. And this quarter...

KC three trial is really constructed based upon a number of mechanistic.

<unk> data as well as previous clinical data, we have in the treatment of mitochondrial disease children with seizures, who have a variety of different genotype and phenotype and so what we've been able to demonstrate our previous studies is that we were able to reduce seizure frequency reduce the occurrence and arrest the occurrence of.

Eric: Clearly, Russia and our...

Eric: And our main markets have really driven TransLarna in what is probably one of our strongest revenue quarters to date.

Matt: And so the trial, this phase two, three trial is really constructed based on a number of mechanistic data as well as previous clinical data we have in the treatment of mitochondrial disease children with seizures who have a variety of different genotypes and phenotypes. And so what we've been able to demonstrate in our previous studies is that we are able to reduce seizure frequency, reduce the occurrence, and arrest the occurrence of status epilepticus, which is the condition of continued seizures.

Tazeen Ahmad: Okay, that was super detailed, and thank you for that. So related to what you just said, the guidance and sales that you introduced today, would you say that's coming more

Status Epilepticus, which is the condition of continuing seizures in one specific subtype of mitochondrial epilepsy, we've been able to demonstrate that we can reduce disease related hospitalization and that cohort of children on average at 52 days in the hospital over the course of the year over year that was reduced in euro.

Tazeen Ahmad: Would you say that's coming more from confidence in TransLarna or from uptake for MFLAZA? And then my last question, probably for Emily here, is can you just talk to us about your expense estimates?

Operator: Page PAGE of NUMPAGES www.verbalink.com Page PAGE of NUMPAGES

And the hospital following two and three years on therapy and in that cohort. We were also able to demonstrate and mortality benefit. So when we looked across not only that one subtyping again across all the different subtypes of treated we've been able to demonstrate that we're able to affect seizure frequency and teacher related savings children and again, the fact that.

Stuart Peltz: Sure, okay, so obviously there's a lot of confidence, both TransLondon and Plaza, and they both have been growing it. So Eric, do you want to talk a little bit about the growth of both of those too?

Matt: In one specific subtype of mitochondrial epilepsy, we've been able to demonstrate that we can reduce disease-related hospitalizations. In that cohort, the children on average had 52 days in the hospital over the course of a year. That was reduced to zero days in the hospital following two and three years on therapy.

Eric: Yeah, absolutely. I mean, we saw 22%.

Particularly on targets.

Eric: Go to Whitson Plaza, and we put 47 million dollars in the quarter. We've seen that as

The 15 lipoxygenase enzyme and the axiom of stress response pathway that is common to the disease pathology, regardless of the underlying genotype or phenotype is what gives us further confidence that we are able to demonstrate the treatment benefit across the whole family of mitochondrial disorders, Okay independent of the specific mutation.

Eric: Again, a combination of different things, but primarily, again, very high compliance. We've also been working on those.

Matt: And in that cohort, we were also able to demonstrate mortality benefits. So when we looked across not only that one subtype but again, across all the different subtypes we've treated, we were able to demonstrate that we're able to affect seizure frequency and seizure-related morbidity in these children. And again, the fact is the tick-borne target. The 15-lipoxygenase enzyme and the oxidative stress response pathway that is common to the disease pathology regardless of the underlying genotype and phenotype gives us further confidence that we're able to demonstrate the treatment benefit across the whole family of mitochondrial disorders, again, independent of the specific patient.

Eric: We've minimized dropouts, but we've also seen a lot of new patients that have gone on to Mplaza. Not only new patients who are naive, but many patients who are switching based on a number of key publications and scientific data now. And, of course, the experience that we've generated that shows that Mplaza is superior to prednisone. So we see a lot of those tailwinds of Mplaza continuing as the base of patients grows.

So that trials enrolling 60 children it centers around the world, we've been able to work closely with our global network.

And close relationships with patient populations around the world that we've been able to develop over the course of many years.

We are moving forward with enrollment in that trial and as we said expecting the data data and results in the third quarter of 2022.

I missed the second part of your question. If you could just repeat it related to that trial.

Just how how do you think about risks for that child.

Operator: We're looking forward to continuing.

Yes, so I think obviously in constructing this trial, we leveraged our many years of experience of doing trials in children with mitochondrial disease and I think when you talk about mitochondrial disease. One of the biggest challenges in drug development is the heterogeneity in disease, not only heterogeneity in genotype, but also heterogeneity in genotype peanuts.

Operator: Transcripts provided by Transcription Outsourcing, LLC.

Eric: [inaudible]

Matt: So that trial is enrolling 60 children at centers around the world. We've been able to work closely with that global network and close relationships with patient foundations around the world that we've been able to develop over the course of many years and are moving forward with enrollment in that trial. And as we said, we expect data results in the third quarter of 2022. You know, I missed the second part of your question, if you could just repeat it related to that trial.

[noise] type relationship and so we took that into careful consideration in designing this trial and to overcome that we again are pleased him a focus on a symptom that is common to all of these different subtypes. So we don't have to worry about it different constellation of symptoms. We know that all the children in the trial had the symptoms theaters and we're also on <unk>.

Emily Luisa Hill: And then this is Emily Tazeen. When it comes to your OPEX question, I think it's really just a result of 2021 being a full year impact of COVID versus 2020. So obviously, we greatly reduced our travel expenses. And then Eric's team has very successfully transitioned to holding most of their physician seminars and consortiums virtually.

A strategy that has been used in several successful approval trials for pediatric epilepsy syndromes that utilizes a running phase to ensure a minimum frequency of seizures and then having subsequent parallel arm only enrolling those children.

Operator: Helpful. Thank you. Thank you. Our next question comes from Alicia Young with Cantor Fitzgerald.

Matt: Just how do you think about risks for that trial? Yeah, so I think obviously in constructing a trial.

That threshold.

In addition to account for any heterogeneity that might still come into play where stratify randomization for the most common subtype, so ensure balance across both the placebo and the control group and we think all of those are very good measures.

Matt: Yes, I think obviously, in constructing this trial, we leveraged our many years of experience in doing trials in children with mitochondrial disease. And I think when you talk about mitochondrial disease, one of the biggest challenges in drug development is the heterogeneity of not only heterogeneity and genotype but also heterogeneity and the genotype-phenotype relationship.

Alicia Young: Hi, thanks for taking our questions and congrats on all the progress. This is Nina on behalf of Aletheia.

By addressing what we know could be potential risks in the design of that trial.

Yeah.

Got it thank you.

And I guess for the second question just how do you plan on updating.

I was on the Fda's feedback for the phase two trials or a P. T. C 518 next year.

Nina: We are wondering what gives you confidence in the MI-E readout in the third quarter of 2022? And how do you think of the risks for that trial? And also another one. We are curious how you were planning to update us on the FDA feedback for the phase two PTC 518 trial next year. Thanks.

Matt: And so we took that into careful consideration in designing this trial. And to overcome that, we're again pleased that we're focused on a symptom that's common to all of these different subtypes. So we don't have to worry about different constellations of symptoms. We know that all the children in the trial have symptoms and seizures, and we're also employing a strategy that's been used in several successful approval trials for pediatric epilepsy syndromes.

So I think what we'll be doing this.

Obviously once we initiate the trial will be felt with you.

Stuart Peltz: Sure. The mighty Matt. You want to go through that?

Well, we'll look to grow we'll let everyone know and also after we we.

Matt: Yeah, absolutely. That's our Mighty Trial, the Registration Directed Trial in Children with Mitochondrial Disease Associated Seizures. And as we talked a bit about before, this is a highly morbid and severe symptom of mitochondrial disease that occurs across many different disease subtypes. And so the trial, this phase two, three trial is really constructed based on a number of mechanistic data as well as previous clinical data we have in the treatment of mitochondrial disease children with seizures who have a variety of different genotypes and phenotypes.

The results for the 12 weeks, where you would actually talked about that as well.

Okay. Thank you that was helpful.

No.

Thank you. Our next question comes from Rajiv Prasad with William Blair. Your line is open.

Thanks for taking the question I know you guys recently opened the gene therapy facility.

Matt: And so what we've been able to demonstrate in our previous studies is that we are able to reduce seizure frequency, reduce the occurrence and arrest the occurrence of status epilepticus, which is the condition of continued seizures. In one specific subtype of mitochondrial epilepsy, we have been able to demonstrate that we can reduce disease-related hospitalizations. In that cohort, the children on average had 52 days in the hospital over the course of a year, but that was reduced to zero days in the hospital following two and three years of therapy.

Matt: That's utilizing a run-in phase to ensure a minimum frequency of seizures and then having the subsequent parallel arms only enroll those children who meet that threshold. In addition, to account for any heterogeneity that might still come into play, we're stratifying the randomization for the most common subtypes so we ensure balance across both the placental and the control group. And we think all those are very good measures at addressing what we know could be potential risks in the design of that trial.

Can you talk a little bit about your plans for scaling it up with.

Obviously, the ADC program as well as some of the follow on gene therapy program, just kind of getting a sense of what type of scale youll have in GMP.

Compliance and things of that nature.

Yeah sure in terms of compliance.

If a fully operating facility we have.

We have about 220000 square feet of both.

Suites.

Where we can.

Matt: And in that cohort, we were also able to demonstrate mortality benefits. So when we looked across not only that one subtype but again, across all the different subtypes we've treated, we were able to demonstrate that we're able to affect seizure frequency and seizure-related morbidity in these children. And again, the fact that the tick-borne target, the 15-life oxygenase enzyme, and the oxidative stress response pathway that is common to the disease pathology regardless of the underlying genotype and phenotype gives us further confidence that we're able to demonstrate the treatment benefit across the whole family of mitochondrial disorders, again, independent of the specific mutation.

Grow and prepare the viral vector as well as the ability to do both TMT.

Matt: And I guess for the second question: just how?

unknown: Question: just how do you plan on updating us on FDA feedback for the phase two trial for PTC 518 next year?

Plasmids as well in that manner and so we've built the team is now fully capable of not only.

Our preparation of our own plasma in house, but also preparation all.

unknown: So I think what we'll be doing is, obviously, once we initiate the trial, we'll be telling you, we'll let everyone know, and also after we get the results after 12 weeks, we will actually talk about that as well.

Of all the all the viral vector that's required to do that and we have all of our manufacturing capabilities to do that in house.

As well as all the.

Quality and analytical.

We're able to perform those as well so that's all.

unknown: Okay, thank you. That was helpful.

Being done and we've been doing this for our other programs that are going on.

Unknown Attendee: Thank you. Our next question comes from Raju Prasad with William Blair. Your line is open.

Like what we've talked about for FAA as well as for.

Angelman syndrome, and others as well.

Unknown Executive: I know you guys recently opened the gene therapy facility. Can you talk a little bit about your plans for scaling it up with obviously the ADT program, as well as some of the follow-on gene therapy programs, kind of getting a sense of what type of scale you'll have and GMP compliance and things of that nature? Thanks.

The team is capable of doing that both on the G. G. M. P. <unk> hundred can do it from 30 liters to 1000 liter facility and make the playoffs with as well.

Also been as I said and I think I've talked about in the past.

Nina: Just how do you think about the risks for that trial? Yeah, so I obviously

We'll be doing it for external.

Potential external customers, we don't anticipate yet will be who will take a little bit timed poorly functional and somewhere you somewhat.

The extra.

Unknown Executive: In terms of compliance, and it's a fully operating facility, we have, you know, we have about 220,000 square feet of both. The team is now fully capable of not only We're also doing a lot of preparation of our own plasmids in-house, but also preparation of all the viral vector that's required to do that. And we have all of the manufacturing capabilities to do that in-house, as well as all the quality and analytical equipment to be able to perform those as well.

Extra space, we have to be able to bring in port.

Bring in potential customers and especially with classes.

In a sense locally.

Bring them not only you know.

Work through that but also being able to.

Bringing in revenue as well so the system itself is now.

The site is all up and running and capable of making both plasma from DNA.

And we've been making both vectors as well as plasma now and we're confident we can do this and so we're going to be doing fulfill all the needs we have as we grow into more and more.

Matt: That's utilizing a run-in phase to ensure a minimum frequency of seizures and then having the subsequent parallel arms only enroll those children who meet that threshold. In addition, to account for any heterogeneity that might still come into play, we're stratifying the randomization for the most common subtypes so we ensure balance across both the placental and the control group. And we think all of those are very good measures at addressing what we know could be potential risks in the design of that trial.

And then also be able to have some customers on the outside.

Unknown Executive: So that's all being done, and we've been doing this for our other programs that are going on, like what we talked about for FA, as well as for Angelman Syndrome and others as well. So the team's capable of doing that both in a GMP manner, can do it from 30 liters to 1,000-liter facilities, and make the plasmids as well. We'll be doing it for external, potential external customers. We don't anticipate yet that we'll be, you know, it will take a little bit of time to be fully functional.

Great.

With regards to affinity I may have missed this but do you have a sense of the number of patients enrolled in the arms and just given kind of the.

The penetration of generic Kuban into the market.

Just wondering if you think the delta that you've seen kind of a phase III recapitulate that cause you think that'll be enough to.

Convert most patients over or do you think that you'll need kind of a bigger effect or you can go into Kuban failures, just kind of tourists in other strategy based on.

Nina: Got it. Thank you. And, for the second question, just how do you plan on updating us on FDA feedback for the phase two trial for PTC 518 next year?

What you may see in the registration trial.

Yeah, no. So I think that's an excellent point that while there's a large number of patients both patients.

Stuart Peltz: So I think what we'll be doing is, obviously, once we initiate the trial, we'll be telling you, we'll let everyone know, and also after we get the results after 12 weeks, we will actually talk about that as well.

Unknown Executive: And so we'll use some of the extra space we have to be able to bring in potential customers, especially with classes where, you know, in a sense, we'll be able to bring in not only work through that, but also revenue as well. So the system itself is now all, the site is all up and running, capable of making both plasmids and DNA. And we've been making both vectors as well as plasmids now, and we're confident we can do this. And so we're going to be fulfilling all the needs we have as we grow and do more and more. And then I would also be able to have some customers on the outside.

That had been on coogan.

[laughter] failed.

Failed or have never shown any.

Improvement on it so there's a large number of patients.

Our proven doesn't.

Do well.

Nina: Okay, thank you.

For patients. So we don't think even with the generic that it's going to be a problem for bringing in to be able to bring in enough patients to do this we're targeting about 80 patients for the primary analysis.

Operator: Thank you. Our next question comes from Raju Prasad with William Blair. Your line is open.

Unknown Attendee: Thanks for taking the question. I know you guys recently opened the gene therapy facility. Can you talk a little bit about your plans for scaling it up with obviously the ADT program as well as some of the follow-on gene therapy programs, kind of getting a sense of, you know, what type of scale you'll have and GMP compliance and things of that nature? Yeah, sure.

Cohort.

Obviously, just to remind everyone will have a run in for that so we'll know people will be responsive to it. So it's already set up I think for a high chance of success.

We've been rich the study population.

Patients who are.

Stuart Peltz: Yes, sure, in terms of compliance, it's a fully operating facility. We have about 220,000 square feet of both.

Who respond to that and just to remind everybody.

Unknown Executive: Great And with regard to affinity, I may have missed this, but do you have a sense of the number of patients that you're going to try and enroll in the arms, and just given kind of the penetration of generic Kuvan into the market, just wondering if the delta that you've seen kind of stays true if you recapitulate that, but do you think that'll be enough to convert most patients over, or do you think that you'll need kind Just kind of curious to know the strategy based on what you may see in the registration trial. Thanks. Yeah, no, so I think that's an excellent point.

We had done a preview.

These two studies show.

Directly comparing.

Stuart Peltz: [inaudible] We have prepared our own plasmids in-house, but also prepared all the viral vector that's required to do that, and we have all of the manufacturing capabilities to do that in-house as well as all the quality and analytical equipment to be able to perform those as well. So that's all being done, and we've been doing this for our other programs that are going on, like what we talked about for FA as well as for Angelman Syndrome and others as well.

Kuban too.

<unk> two <unk>.

Through our drug and so and I think what we've shown is that we see a higher number of <unk>.

Patients about 50% more responders and they had a greater effect.

Of reducing spend or Alan or anything we saw.

Since on Cuvette, So we've taken.

Obviously, better we view this look really up quite a significant.

Difficult opportunity.

Really if you think about it as a very well defined patient population, there's newborn screening centers of excellence.

You know the pathway to approval is well known.

Blood based biomarker, where you can measure phenylalanine and a large number of patients.

Unknown Executive: And while there's a large number of patients, there are both patients that have been on Kuven and have failed or have never shown any improvement on it. So there are a large number of patients. [inaudible] Adieu.

And with many of them are need for improvement of our better.

Stuart Peltz: So the team's capable of doing that both in a GMP manner, can do it from 30 liters to 1,000-liter facility and make the plasmids as well. We've also been, as I said, and I think I've talked about in the past. We'll be doing it for external, potential external customers. We don't anticipate yet that we'll be, you know, it will take a little bit of time to be fully functional. And so we'll use some of the extra space we have to be able to bring in potential customers, especially with classes where, you know, in a sense, we'll be able to bring in not only work through that but also be able to bring in revenue as well.

A better drug so we're excited about that.

Think that does obviously that will be increasing.

Because we have a run in in the responder analysis.

Unknown Executive: Wow. So, we don't think, even with the generic, that it's going to be a problem to be able to bring in enough patients to do this. We're targeting about 80 patients for the primary analysis cohort. You know, obviously, just to remind everyone, we'll have a run-in for that, so we'll know people will be responsive to it, so it's already set up, I think, for a high chance of success. We've enriched the study population of patients who respond to it, and just to remind everybody, we had done a previous... This is obviously better.

The affinity study.

In our view, there's a very high unmet medical need because U S.

As the majority of patients for language untreated.

And they are not well controlled controlled even though there are two.

Commercial products that are available. So we think this is a significant opportunity.

Great. Thank you.

Thank you. Our next question comes from Brian Abrams with our capital markets. Your line is open.

Hi, This is Steve on for Brian. Thanks for taking our question on 515 and building off an earlier question I'm curious can you speak a bit more on what you might have to show for safety. There. How long you might have to follow patients for a potential accelerated approval and if you looked at differences in transcriptome transcriptome or protium cost about 518 in preclinical models or clinical tissue.

Stuart Peltz: So the system itself is now all, the site is all up and running, capable of making both plasmids and DNA. And we've been making both vectors as well as plasmids now, and we're confident we can do this. And so we're going to be fulfilling all the needs we have as we grow and do more and then also be able to have some customers on the outside.

Unknown Executive: We view this as really quite a significant opportunity. You know, really, if you think about it, it's a very well-defined patient population. There are newborn screening centers of excellence. The pathway to approval is well known. It's a blood-based biomarker where you can measure phenylalanine and a large number of patients, many of whom are in need of improvement by a better drug.

Comparing healthy in Huntington samples and does that hindered any possible differences in safety.

Yes.

Unknown Attendee: Great. And with regard to affinity, I may have missed this, but do you have a sense of the number of patients that you're going to try and enroll?

So we.

I'll make a couple of points one is obviously dependent upon both you know how it doesn't and patients as well as some things he talked battology, either I will say that these molecules.

Unknown Attendee: I was wondering if you think the delta that you've seen, kind of phase two, if you recapitulate that, but you think that'll be enough to, you know, convert most patients over? Or do you think that you'll need kind of a bigger effect, or are you going to go into Kuvan failures? Just kind of curious to know the strategy based on what you might see in the registration trail.

Our highly selective molecule.

Unknown Executive: So we're excited about this, and we think that, obviously, we'll see increasing success because we have a run in the responder analysis, in the Affinity Study. So, in our view, there is a very high amount of medical need in PKU, as the majority of patients remain untreated, and they're not well controlled, even though there are two commercial products that are available.

And I think we spend a lot of and I think that's really a differentiating factor for us it's an orally bio available small molecule, where we really worked on that.

Selectivity and specificity.

Oh Wow.

So that it's very highly specific for each.

H T T and for that particular unit one site.

Unknown Executive: So I think that's an excellent point in that while there are a large number of patients, there are patients that have been on QVAN and have failed or have never shown any improvement on it. So there are a large number of patients where QVAN doesn't... work well.

Unknown Executive: Yeah, no.

And so obviously, what we're gonna do is we'll review the results.

I mean in terms of you know the safety will be following that and what we're gonna be doing this in a placebo controlled study.

We review the results from the Phase two study.

Brian Corey Abrahams: So we think this is a significant opportunity. Great, thank you. Thank you. Our next question comes from Brian Abrahams with Ard Capital Markets. Your line is open. Hi, this is Steve. I'm for Brian. Thanks for taking our call.

To see how patients do in terms of the level of book.

Unknown Executive: So, we don't think even with the generic that it's going to be a problem to be able to bring in enough patients to do this. We're targeting about 80 patients for the primary analysis cohort. You know, obviously, just to remind everyone, we'll have a run-in for that, so we'll know people will be responsive to it, so it's already set up, I think, for a high chance of success. We've enriched the study population of patients who respond to it, and just to remind everybody, we had done a previous trial. This is obviously better. We view this as really quite a significant opportunity. You know, really, if you think about it, it's a very well-defined patient population. There are newborn screening centers of excellence.

Reduction both the blood within the club E T T RNA and protein and the levels of change within the team.

TSS as well and we'll be monitoring a number of others.

Of other Biomarkers as well and then to your question a potential accelerated approval that's why we.

Operator: Thank you. Our next question comes from Brian Abrams with Arby's Capital Markets. Your line is open.

Why we're actually going beyond the 12 12 weeks.

Brian Corey Abrahams: Yes. So we make a couple of points. One is obviously safety, which is usually dependent upon both, you know, how it does in patients as well as safety toxicology. See that I will say that these molecules are highly selective molecules. And I think that's really a differentiating factor for us. It's an orally bioavailable small molecule that we really worked on the selectivity and specificity of 518 so that it's very highly specific for HTT and for that particular U1 site.

Following that as they transition on to an open label study for <unk>.

We're still be on for a total of 15 months and like is the long term.

Safety is a consequence of that so we think if there's a potential for an accelerated approval on what we're interested in and that is that we will have not only the looking at the.

H T T.

RNA and protein levels, but other biomarkers as well.

And so.

What we found in the transcriptome, Yeah, we've looked at a lot of.

Brian Corey Abrahams: And so obviously, what we're going to do is we'll review the results. In terms of, you know, safety, we'll be following that. And what we're going to be doing is, in the placebo-controlled study, we'll review the results of the phase two study to see how patients do in terms of the levels of reduction in both the blood, within the blood of HTT RNA and protein, and the levels that change within the CSF as well.

Ourselves and we've seen.

That at the concentrations.

Ah I see we see really only very few.

Changes in gene expression or an alternative or twice a week. So it's highly selective and specific.

Great. Thanks for that was really helpful. I appreciate it.

Unknown Executive: You know, the pathways approval is well known. It's a blood-based biomarker where you can measure phenylalanine and a large number of patients, many of them are in need of improvement with a better drug. So we're excited about this, and we think that this obviously will see increasing success because we have a run in the responder analysis. In the affinity study, so in our view, there is a very high amount of medical need in PKU, as the majority of patients remain untreated and are not well controlled, even though there are two commercial products that are available. So we think this is a significant opportunity.

Thank you. Our next question comes from the Wang with Barclays. Your line is open.

Oh, Hi, this is Michel and Al Pacino. Thanks for taking my question well, we have maybe two questions. So first congrats on that.

On the good quarter.

Could you frame for us how long.

Brian Corey Abrahams: And we'll be monitoring a number of other biomarkers as well. And then to your question of potential accelerated approval, that's why we're actually going beyond the 12 weeks, following that they transition on to an open-label study for, and we'll still be on for a total of 15 months, and that gives long-term safety as a consequence of that. So we think if there's a potential for an accelerated approval, what we're interested in is that we'll have not only the HTT RNA and protein levels but other biomarkers as well.

The rigid in order and also the fashion launch contribution in Q3 number.

And how should we think about the going forward run rate.

And the next question is about five when they place.

Phase II trial have you got any feedback from FDA on what Biomarkers will be theme.

Good predictor of clinical benefit.

Yeah sure so you.

You know obviously.

In terms of.

The F D a four.

For Huntington's disease, we have not yet talked to them on the Biomarkers clearly it's important and we think so we will be measuring the biomarkers are both RNA and protein in blood as well.

Operator: Thank you. Our next question comes from Brian Abrams with Ard Capital Markets. Your line is open. Hi, this is Steve. I'm on behalf of Brian.

Operator: Our Capital Markets, your line is open.

Brian Corey Abrahams: Thanks for taking our question. On 518 and building off an earlier question, I'm curious, can you speak a bit more on what you might have to show for safety there? And how long you might have to follow patients for potential

Changes in Huntington protein in the CSF and then other biomarkers.

Brian Corey Abrahams: And so, what we've found in the transcriptome, yeah, we looked in a lot of cells, and we saw that at concentrations I can see, we see really only very few changes in gene expression or in alternative splicing.

And then we'll be looking at the other.

MRI measurements and volumetric measurements as well.

Both kind of fell into the sea.

The CSF and plasma as well.

So I think you know that along and obviously, if you think about Huntington disease.

Unknown Executive: So it's highly selective and specific. Great. Thanks for that. Really helpful. Appreciate it. Thank you. Our next question comes from Huidong Wang with Barclays. Your line is open. Hi, this is Sheldon from Q&A. Thanks for taking our questions. We have maybe two questions. First, congratulations on the good news.

Versus say Alzheimer's, it's a monitoring tool.

Unknown Executive: Yes. So we make a couple of points. One is obviously safety, which is usually dependent upon both how it does in patients as well as safety toxicology. See that I will say that these molecules are highly selective molecules.

Order.

We know it was a gain of function and we know that.

Consequences of the H D T with the pag repeat.

And that lower levels, and there's both animal data as well as natural history in clinical.

Unknown Executive: And I think we spend a lot, and I think that's really a differentiating factor for us. It's an orally bioavailable small molecule that we really worked on to have selectivity and specificity of 518 so that it's very highly specific for HTT and for that particular U1 site. And so obviously, what we're going to do is we'll review the results. In terms of, you know, safety, we'll be following that, and what we're going to be doing is, in the placebo-controlled study, we'll review the results of the phase two study. [inaudible] Why we're actually going beyond 12 weeks.

From patients that showed that reducing that improve the outcomes for patients. So I think you know if you've ever biomarker, where you could show a reduction of H D D.

Huidong Wang: Thank you. Our next question comes from Huidong Wang with Barclays. Your line is open. Hi, good to see you.

<unk> levels.

unknown: You know, obviously, in terms of the FDA for Huntington's disease, we have not yet talked to them about the biomarkers. Clearly, it's important, we think so. We will be measuring the biomarkers of both RNA and protein in blood as well as. In terms of lower levels delaying the progression of the disease, you're in a pretty good spot to be able to say that you know you're hitting the gene, lowering the levels of the protein in RNA, and the results of that should be better outcomes. So I think there are pretty good arguments that could be made. And that's coupled with looking at the CSS and other biomarkers, like Preservation of Brain Volume, and others.

No.

The consequence of the visa dues of H T T RNA and protein.

And I'm back.

About level actually help patients.

In terms of lower levels delays the progression of the disease.

You're in a pretty good spot.

To be able to say that that you know you're hitting the <unk> in the sense that the GE lowering the levels of protein and RNA and as a result of that should be better outcome. So I think that's pretty good arguments.

And that coupled with looking at the CFS and other biomarkers.

Preservation of rate volume and others, there's a package of information that we think would be important.

Unknown Executive: There's a package of information that we think would be important. In terms of growth, yes, I think Eric already gave a little bit, saying that, you know, we're obviously, the beauty of continuing to grow in that geographic expansion is that while things may be lumpy, different, groups are ordering at different times. That helps smooth it out a little bit more.

In terms of the.

Growth, Yes, I think.

Unknown Executive: Following that, they transition on to an open-label study for, and we'll still be on for a total of 15 months, and that gives long-term safety as a consequence of that. So we think if there's a potential for an accelerated approval, and what we're interested in in that is that we'll have not only the HTT RNA and protein levels but other biomarkers as well. And so, what we've found in the transcriptome, you know, we looked in a lot of cells, and we saw that at concentrations I see, we see really only very few changes in gene expression or in alternative splicing. So it's highly selective and specific.

Erik already gave a little bit for saying that.

Obviously, you know the beauty of continuing to grow and have geographic expansion as well.

Things may be lumpy different.

Groups are ordering at different times, but help smooth it out with a little bit more.

Unknown Executive: And so while Brazil, you know, this year was hit relatively hard with COVID, the commercial team has been working tirelessly with the Minister of Health to secure a group purchase. We do expect one in the fourth quarter of this year. And maybe Eric, you want to talk a little bit about that?

And so while Brazil, and this year was hit relatively hard with Covid.

The commercial team has been working on.

Tirelessly with the Minister of health to secure group purchase we do expect one in the fourth quarter of this year and maybe Eric you want to talk a little bit about this.

Unknown Executive: Yeah, I think you have to characterize Russia in this quarter very similarly to what, perhaps, four or five years ago, was Brazil.

Sure.

Yeah.

Yes, I think we have to characterize Russia in this quarter very similar to what perhaps four or five years ago was Brazil.

Eric: So, in some of these countries, the government will order, or will provide access and reimbursement, and will provide a single order for a very large number of patients for a number of months. So that creates the lumpiness. And while we don't necessarily provide specific details about the size of the orders and the revenue of the orders within that quarter,

So in these some of these countries.

The government will order Oh, we'll provide access in reimbursement and will provide a single order for a very large number of patients for a number of months. So that's correct creates the lumpiness and while we don't necessarily provide a specific.

Operator: Thank you. Our next question comes from Huidong Wang with Barclays. Your line is open.

Huidong Wang: Hi, this is Sheldon Nong from Kena. Thanks for taking our questions. We have maybe two questions. First, congrats on a good quarter. Could you please frame for us how big is the Brazilian order and also the Russian launch contribution in the Q3 numbers? And how should we think about the going forward run rate? And my next question is about the 518 phase two trial. Have you got any feedback from FDA on what biomarkers will be deemed a good predictor of clinical benefits? Thanks.

The size of the orders and the revenue of the orders that within that quarter.

You can easily go back four or five years and start to look at where we've had some lumpy quarter, particularly when we started adding new patients in Brazil, and getting multiple orders or at least one or two orders a year.

For a large group of patients.

unknown: https://www.patreon.com

The dynamic in this quarter was that Russia.

It was a key driver of that growth and it's centralized reimbursement in that order is what helped us have one of our best quarters ever and as Steve mentioned.

Unknown Executive: Yeah, sure. So obviously, you know, in terms of the FDA for Huntington's disease, we have not yet talked to them about the biomarkers. Clearly, it's important, and we think so. We will be measuring the biomarkers of both RNA and protein in blood as well as, In terms of lower levels delaying the progression of the disease, you're in a pretty good spot. Unknown Attendee, And that's coupled with looking at the CSS and other biomarkers, such as Preservation of Brain Volume, and others.

Eric: and getting multiple orders or at least one or two orders a year for a large group of patients. The dynamic in this quarter was that Russia was a key driver of that growth, and its centralized reimbursement in that order is what helped us have one of our best quarters ever. And as Steve mentioned, We anticipate, we're working tirelessly right now, we have an agreement in Brazil, and we anticipate

We anticipate that.

We're working tirelessly right now.

We have an agreement in Brazil, and we anticipate filling that order for a large group of patients as well or in the fourth quarter. So it's very hard to predict.

Governments tend to have erratic buying patterns and they do sometimes pick the number of patients in a number of months, which is not always predictable.

Kind of hard to say what would that be in the sort of long quarter quarter forecast, but what I'd like to emphasize is that on an annualized basis translarna growing consistently.

unknown: [inaudible]

And we're seeing like like what Eric said before so we opened up new areas in like Russia, but also central and Eastern Europe Middle East North Africa region.

unknown: [inaudible] So it's kind of hard to say what that would be in sort of a long-term quarterly forecast. But what I'd like to emphasize is that on an annualized basis, you see Transluna growing consistently. And we're seeing what Eric said before. So we opened up new areas in like Russia, but also Central and Eastern Europe, the Middle East, and North Africa. We just got, you know, Latin America and Asia Pacific we're working on.

Scott.

Uh huh.

America Asia Pacific, we're working on so that's on top of maintaining all of the patients who've been on it we've had incredible compliance.

There's just continue with the amount of data that we're having to like the stride data that Eric talked about where kids are at five and a half years longer in terms of ambulation better.

Better capabilities in terms of a lung function if the data is becoming.

unknown: So on top of maintaining all the patients who've been on it, we've had incredible compliance. And there's just a continuous amount of data that we're adding too, like the stride data that Eric talked about, where kids are at five and a half years longer in terms of ambulation, better, better capabilities in terms of lung function. If the data is becoming, It is just so strong that patients are on for a long time. We keep those, we maintain them, and then we get more and more patients as we get geographic expansion.

Just so strong that it's.

Patients around for a long time, we keep those we maintain them and then we're getting more and more patients as we get to geographic expansion.

Got it thank you very much.

Thank you. Our next question comes from the phone.

<unk> company.

Your line is open good afternoon, and thank you for taking my question.

First one just on the ADC submission in the U S.

Can you just let us know what's sort of the cadence of interactions with the FDA. If there are any.

<unk> expected before the BLA submission and they signed off on the surgeries that have happened and then second just in the Friedrich Ataxia study can you just remind us a little bit how you arrived at that.

Unknown Executive: There's a package of information that we think would be important. In terms of growth, yes, I think Eric already gave a little bit saying that, you know, we're obviously, the beauty of continuing to grow and have geographic expansion is that while things may be lumpy, different, groups are ordering at different times. That helps smooth it out a little bit more.

The 72 endpoint at six months, maybe some a little bit of a high placebo response in me.

unknown: Thank you. Our next question comes from the phone with Helen, and Hello, good afternoon. Thank you for taking my questions. The first one, just on the AADC submission in the U.S., can you just let us know sort of the cadence of interactions with the FDA, if there are any expected before the BLA submission? Have they signed off on the surgeries that have happened? And then second, just in the Friedrich ataxia study, can you just remind us a little bit how you arrived at that 72 endpoint? I know at six months, maybe I saw a little bit of a high placebo response in the prior studies. So to me, what were the

Prior studies so to me.

What were the changes that were made in this pivotal to potentially limit that placebo response.

Yeah. Thanks for the question, Matt you want to take some of this.

Yes sure.

Of course to the question about the the BLA as we've talked about we were going to complete the surgeries collect those data and then meet with the agency to rely on the package ensure everything is in place to make this submission.

We.

Had not had that interaction yet do you expect that will have any interaction will be able to submit the BLA.

Eric: Yeah, yes, I think you have to characterize Russia in this quarter very similarly to what, perhaps,

The first quarter of 2022.

Operator: Transcripts provided by Transcription Outsourcing, LLC.

In terms of the move up based study.

Alluded to we have based a lot of this study on our previous phase III trial, and particularly on Ctrip ataxia, which had the six week placebo control phase followed by the long term treatment duration locations were treated up to 24 months importantly may be quiet, a placebo effect in that six months, which prevented us achieving statistical significance.

Operator: https://www.patreon.com

Eric: All in all, this is a very large number of patients for a number of months, so that creates the lumpiness. And while we don't necessarily provide specific details on the size of the orders and the revenue of the orders within that quarter,

Matt: Pivotal to potentially limit that placebo response. Yeah, thanks for the question. Matt, do you want to take some of this?

Matt: Yeah, sure. So first, to the question about the DLA, as we've talked about, we were going to complete the surgeries, collect the data, and then meet with the agency to align on the package, and ensure everything's in place to make the submission. We have not had that interaction yet.

The way that comp if you look across for example, you have the August trial had that trials and stop at six months. It would not have hit their primary endpoint again because of a known placebo effect on that Fars outcome measure, but also importantly, what we looked at the patients in our phase III study, we found that over a two year period, we were able to demonstrate an overall.

Operator: You can easily go back for...

Operator: Transcribed by https://otter.ai

Operator: Transcripts provided by Transcription Outsourcing, LLC.

Matt: We expect that we'll have the interaction to be able to submit the DLA in the first quarter of 2022. In terms of the MOVE-FA study, as you alluded to, we have based a lot of this study on our previous Phase 2 trial of atypia node and atypia pataxia, which had the six-week placebo control phase, followed by a long-term treatment duration where patients were treated Importantly, we recorded a placebo effect during that six months, which prevented us from achieving statistical significance. And by the way, that's common.

<unk> disease that is a reversal in disease progression and it really reinforces the important concept that one we're able to achieve a therapeutic benefit and two at over longer treatment to tie you can actually see a meaningful impact. So when we put that together along with the concern of a placebo effect. We believe that the 72 week study put us in a very strong.

Eric: The dynamic in this

Eric: This quarter was in Russia.

Eric: [inaudible] We anticipate, we're working tirelessly right now, we have an agreement in Brazil, and we anticipate filling that order for a large group of patients as well in the fourth quarter. So it's very hard to predict. These governments tend to have erratic buying patterns, and they do sometimes pick the number of patients and the number of months, which is not always predictable. So it's kind of hard to say what that would be.

<unk> position.

Not only have <unk>.

Limited and perhaps no placebo effect that impacted results, but importantly be able to reinforce the long term potential benefit to quit on therapy in Friedrich ataxia with regards not only disease progression as measured by the Empire sale, but other than the key secondary endpoints that reflect in the study.

Eric: So it's kind of hard to say what that would be in sort of a long-term quarterly forecast. But what I'd like to emphasize is that on an annualized basis, you see TransLuna growing consistently. And we're seeing what Eric said before. So we opened up new areas in like Russia, but also Central and Eastern Europe, the Middle East, and North Africa. We just got, you know, Latin America and Asia Pacific we're working on.

Great. Thank you.

Sorry, that's all right.

So I was just saying I think we're look we're learning a lot in terms of a neuromuscular diseases, where youre not necessarily people see necessarily kids improve but you are stabilizing but youre going to need you need more time within the trial.

Matt: If you look across, for example, even the latest trial, had that trial been stopped at six months, they would not have hit their primary endpoint again because of a known placebo effect on that FARS outcome measure. But also importantly, when we looked at the patients in our Phase 2 study, we found that over a two-year period, we were able to demonstrate an overall improvement in disease, that is, a reversal of disease progression.

To be able to get better better clinical results.

Yeah, I think that makes a lot of sense.

And then just last quick one now that the gene therapy facility is up and going and we were on <unk> ataxia are there any updates to the predicted taxi gene therapy program win when we could maybe see that when you enter the clinic.

Unknown Executive: So on top of maintaining all the patients who've been on it, we've had incredible compliance. And there's just a continuous amount of data that we're adding, too, like the stride data that Eric talked about, where kids are at five and a half years longer in terms of ambulation, and better capabilities in terms of lung function. The data's becoming... It's just so strong that patients are on for a long time. We keep them, we maintain them, and then we're getting more and more patients as we get geographic expansion.

Yeah.

Yeah that one was.

Matt: And that really reinforced the important concept that, one, we're able to achieve a therapeutic benefit, and, two, that over longer periods of time, you can actually see a meaningful impact. And so when we put that together, along with the concern about a placebo effect, we believe that the 72-week study put us in a very strong position to not only have limited and perhaps no placebo effect that would impact our results, but importantly, be able to reinforce the long-term potential benefit of the 2.0 therapy in Friedrich ataxia with regard to not only disease progression, as measured by the MPAR scale, but other key secondary endpoints that were collected in Great, thank you. Let me just...

You know, obviously hit by Covid as well in terms of getting the animals completed the long term toxicology studies are ongoing.

Because we said we were still on track and expect to dose the first patient.

Patient in the first half of 2022.

So that's where we're at right now is obviously the key here will be.

Demonstrates safety of the gene therapy product and then.

Operator: Thank you. Our next question comes from the phone with Kellyn and company. The line is open. Hello.

For stereotactic surgical procedure.

That will that will be using.

Operator: Your line is open. Hi there, good afternoon.

Within the pivotal trial. So that's the goal of those experiments.

Operator: Thank you for taking my questions. The first one, just on the AADC submission in the U.S., can you just let us know sort of the cadence of interactions with the FDA, if there are any expected before the BLA submission? Have they signed off on the surgeries that have happened? And then second, just in the Friedrich ataxia study, can you just remind us a little bit how you arrived at that 72 endpoint? I know at six months, we maybe saw a little bit of a high placebo response in the prior studies.

I mean, it's just we're.

We're looking forward to get this growing as rapidly as possible.

Perfect. Thank you and congrats on the progress.

Thanks, a lot.

Thank you. Our next question comes from Kornacki with Truth Securities. Your line is open.

Hey, guys. This is kipp on for Robyn. Thank you so much for squeezing me in and congrats on the progress this quarter am I had a question about the Huntington's program. So in deciding what you call. The Goldilocks population for your study you said that you've looked at natural history database is firstly, how comfortable are you that or what what.

unknown: Sorry, is that all right? I think we're learning a lot in terms of neuromuscular diseases where you're not necessarily seeing kids improve, but you realize that you're going to need more time within the trial to be able to get better clinical results. The Gene Therapy Facility is up and running. Are there any updates to the Pregigitaxia Gene Therapy Program when we can maybe see that one enter the clinic? Yeah, there's, yeah, that one was. Um, you know, obviously hit by COVID as well in terms of getting the animals completed. The long-term toxicology studies are ongoing.

Operator: Transcripts provided by Transcription Outsourcing, LLC.

Matt: Yeah, thanks for the question. Matt, do you want to take some of this?

Kind of feedback did you get from the FDA, if you've already talked to them about it that natural history study do you do yourself does not need to be a part of the package.

And when we see data from the control part of the trial. The 12 week Park, what can we expect in terms of Readouts will it be safety and Huntington RNA and protein.

Others are or do you think that is enough time to see a separation in some of the other biomarkers for example, like NFL. It. Thank you.

unknown: Uh, and we, as we said, we were still on track and expect to dose the first patient in the first half of 2022. So that's where we're at right now. Obviously, the key here will be to demonstrate the safety of the gene therapy product and then the sero-tactic surgical procedure that we'll be using within the pivotal trial. So that's the goal for those experiments, and it's ongoing; it's just we're looking forward to getting this going as rapidly as possible. Thank you and congrats on the progress.

Matt: We expect that we'll have the interaction to be able to submit the DLA in the first quarter of 2022. In terms of the MOVE-FA study, as you alluded to, we have based a lot of this study on our previous Phase 2 trial of atypia nephritic ataxia, which had the six-week placebo control phase, followed by a long-term treatment duration where patients were treated for Importantly, we recorded a placebo effect during that six months, which prevented us from achieving statistical significance. And, by the way, that's common.

Yeah. Thanks for the question.

In terms of the you know for the.

The study and natural history.

The B b.

H D community has a lot of natural history that helps us.

Fine.

Where theres over on one database with over 20000 patients that one could look at it it will help us define obviously within the trial that we're doing we're doing a placebo control to compare with them before.

12 weeks and then it goes over so will have that much information.

Matt: If you look across, for example, even Leota's trial, had that trial been stopped at six months, they would not have hit their primary endpoint again because of a known placebo effect on that FARS outcome measure. But also, importantly, when we looked at the patients in our Phase 2 study, we found that over a two-year period, we were able to demonstrate an overall improvement in disease, that is, a reversal of disease progression.

Karnauskas: Thank you. Our next question comes from Karnauskas with Truist Securities. Your line is open.

The natural history, what we're using to what is critical is really to help us inform the criteria.

All of which patients you can actually see a change in response right because what you need to you know the goldilocks.

Kripa: Hey guys, this is Kripa on behalf of Robyn. Thank you so much for squeezing me in, and congratulations on the progress this quarter. I had a question about the Huntington's program. So in deciding, you know, what you call the Goldilocks population for your study, you said that you looked at natural history databases. Firstly, how comfortable are you that, or what sort of feedback did you get from the FDA, or did you talk to them about it, that a natural history study that you do yourself does not need to be part of the package?

Matt: And that really reinforced the important concept that, one, we're able to achieve a therapeutic benefit, and, two, that over longer periods of time, you can actually see a meaningful impact. And so, when we put that together, along with the concern of a placebo effect, we believe that the 72-week study put us in a very strong position to not only have a limited and perhaps no placebo effect that would impact our results, but, importantly, be able to reinforce the long-term potential benefit of 2-quinone therapy in phrasal ataxia with regard to not only disease progression, as measured by the MFAR scale, but Great, thank you. Let me just...

As Matt has talked.

About for some time now is like it's very much true in many of these types of diseases, where.

The area, there's a time, where if they don't change you won't see a.

A change that that's not useful and then does it does.

What normally happens is if they are so far down the line, it's very hard to see any changes to park on very similar to how we do it.

In BMD. So we're trying to make sure we pick the right population, where theres a decline the decline isn't so.

Unknown Executive: Thank you. Thank you. So I was just saying, I think we're learning a lot in terms of neuromuscular diseases, where you're not necessarily seeing kids improve, but you're stabilizing that you're going to need more time within the trial to be able to get better clinical results. And then just last quick one, now that the gene therapy facility is up and running, and we were on Pregicataxia, are there any updates to the Pregicat Yeah, there's, yeah, that one was.

Kripa: And when we see data from the controlled part of the trial, the 12-week part, what can we expect in terms of readout? Will it be safety and Huntington RNA and protein levels, or do you think that is enough time to see a separation in some of the other biomarkers, for example, like NFL? Thank you.

Is that you can actually change the course of that.

That you would see you.

You would be able to measure that is different so the goldilocks population really helps to ensure that we're enrolling those subjects.

I'm not too early in the disease progression.

But have a higher risk of declining over the course of the trial and therefore.

<unk> versus that gives you the possibility of feedback and so we're hopeful that if we measure that obviously will be mix of the biomarkers. The most.

Kripa: Yeah, you know, thanks for the question. In terms of the, you know, for the study of natural history, obviously, there's the, the, the HD community has a lot of natural history that helps us define where there are over 20,000 patients that one could look at, and it will help us define that. Obviously, within the trial that we're doing, we're doing a placebo control to compare it to the first Unknown Speaker So, the natural history of what we're using is critical, it's really to help us inform the criteria for which patients you can actually see a change in response, right?

See the reduction in Q T. R. M protein that will be important but we would also then anticipate seeing changes in the CSF.

Unknown Executive: You know, obviously hit by COVID as well in terms of getting the animals completed. The long-term toxicology studies are ongoing, and we, as we said, we're still on track and expect to dose the first patient in the first half of 2022. So that's where we're at right now; obviously, the key here will be to demonstrate the safety of the gene therapy product and then the serotected surgical procedure that we'll be using within the pivotal trial. So that's the goal for those experiments, and it's ongoing, it's just we're looking forward to getting this going as rapidly as possible. Perfect, thank you, and congrats on the progress.

As well as nerve right chip.

Okay.

Well look in both the CSF and plasma and then of course.

The presentation of brain volume.

As assessed by MRI imaging, so we think that package.

It will be quite interesting and so the.

The short term 12 weeks will allow us to get that in the longer term.

Pardon me.

College and Pharmacodynamic measurement.

All the others that will go on for the year, we think we'll be able to see something there in terms of the biomarkers.

Kripa: Because what you need to, you know, and the Gobi Locks, you know, as Matt has talked about, are not too early in the disease progression but have a higher risk of declining over the course of the trial, and therefore, treatment versus that gives you the possibility to conceive. And so we're hopeful that as we measure that, obviously, we'll be measuring the biomarkers, and we'll see a reduction in CTR and AM protein. That will be important.

Great. Thank you that was very helpful. And then I had a quick follow up question on the PKU program.

Operator: Thank you. Our next question comes from Karnauskas with Truist Securities. Your line is open.

Biomarin has heard that a lot of the PKU clinics are still not operating at full capacity and do you see any any challenges.

Kripalan: Hey guys, this is Kripalan for Robyn. Thank you so much for squeezing me in.

Kripalan: and congrats on the progress this quarter. I had a question about the Huntington's program.

Unknown Executive: So in deciding, you know, what you call the Goldilocks population for your study, you said that you've looked at natural history databases. First, how comfortable are you with that, or what sort of feedback did you get from the FDA, if you've already talked to them about it, that a natural history study that you do your

In terms of being able to find enough patients for the trial pivotal trials.

Are you seeing that you know it's it's.

It's easy to enroll.

Kripa: But we would also then anticipate seeing changes in the CSF, as well as in the neuron, so that light change, and we'll look at both the CSF and plasma and then, of course, monitor the preservation of brain volume, as assessed by MRI imaging. So we think that package... It will be quite interesting, and so the short-term 12 weeks will allow us to get that, and the longer-term safety and pharmacology and pharmacodynamic measurements of all the others that will go on for a year, we think we'll be able to see something there in terms of the biomarkers.

So we just initiated the trial.

Hard to give you any hard numbers of what we're looking at we think we're doing as well.

The good news, obviously, we have a global infrastructure. So it won't be able to get not only in the U S, but global but globally.

Well in there.

We have a lot of investigators and so you know obviously, that's what I think that's one of the things to make sure that you're able to expand the number of investigators that will help pull through so that you can get those patients and that's why we're doing that so that we still expect the result.

Unknown Executive: Great, thank you. That was very helpful.

By the end of 2022.

Kripa: And then I had a quick follow-up question on the PKU program. You know, Banerjee has said that a lot of the PKU clinics are still not operating at full capacity. Do you see any, you know, any challenges in terms of being able to find enough patients for your pivotal trial, or are you seeing that it's easy to enroll?

Great. Thank you so much.

Thank you.

Thank you and I'm showing no questions at this time I'd like to turn the call back over to Stuart Peltz for closing remarks.

Well, great. So thanks for joining us today, and I think as you can see where <unk>.

<unk> to build P. T C into a revenue generating company.

That's the PTC has made what we've done this quarter.

Unknown Executive: Um, we just initiated the trial, so it's hard to give you any hard numbers on what we're looking at.

You can see we've delivered substantial continued year over year revenue growth and once again, raising our DMD franchise 2021 revenue guidelines.

Unknown Executive: But we think, and this is what we're doing is, um, you know, the good news, obviously, we have a global infrastructure. So we'll be able to get only sites, not only in the US but worldwide, as well. And, you know, we have a lot of investment. And so, obviously, that's one of the things to make sure is that if you have an expanded number of investigators, that will help pull through so that you can get those patients. And that's why we're doing that. So that's, we still expect results by the end of 2020.

Revenue growth. In addition to the continued advancement of our pipeline with the initiation of our yeah.

Registration directed trial in PKU.

The progress this progress really allows us to continue.

The mission that we have and delivering life changing.

Our therapies to patients around the globe. So thanks for taking the time.

And thanks for your question.

This concludes today's conference call. Thank you for participating you may now disconnect.

Okay.

[music].

Unknown Executive: Thank you. And I'm showing no questions at this time. I'd like to turn the call back over to Stuart Peltz for closing remarks.

Unknown Executive: Well, great. So, you know, thanks for joining us today. And I think, as you can see, we're continuing to build PTC into a revenue-generating company. And I'm proud that the PTC team has made what we have done this quarter. I think you can see we've delivered substantial continued year-over-year revenue growth and once again raised our DMD franchise 2021 revenue guidelines. This revenue growth, in addition to the continued advancement of our pipeline with the initiation of our fifth registration-directed trial in BKU. This progress really allows us to continue the mission that we have of delivering life-changing therapies to patients around the globe. So thanks for taking the time to listen, and thanks for your questions.

unknown: This concludes today's conference call. Thank you for participating. You may now go... Thank you for watching!

unknown: © BF-WATCH TV 2021 [inaudible] ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ??

unknown: Good day, and thank you for standing by. Welcome to the PTC Therapeutics Third Quarter 2021 Corporate Update and Financial Results Conference Call. At this time, all persons are in a listening mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1 on your telephone. Please be advised that today's conference is being recorded. If you require any further assistance, please press star zero. I would now like to hand the conference over to your speaker today, Kylie O'Keefe, Head of Investor Relations. Please go ahead.

[music].

unknown: Good afternoon, and thank you for joining us today to discuss the PTC Therapeutics third quarter 2021 corporate update and financial results. Joining me on today's call is our Chief Executive Officer, Stuart Peltz, our Chief Development Officer, Matthew Klein, and our Chief Business Officer, Eric Pauwels, and our Chief Financial Officer, Emily Hill. Before we start, let me remind you that today's call will include forward-looking statements based on current expectations. Please take a moment to review the slide posted on our Investor Relations website in conjunction with the call, which contains our forward-looking statements.

unknown: We will disclose certain non-GAAP information during this call.

unknown: Information regarding our use of GAAP to non-GAAP financial measures and a reconciliation of GAAP to non-GAAP is available in today's earnings release. With that, let me pass the call over to our CEO, Stuart Peltz.

Unknown Executive: Thanks, Kylie, and thank you all for dialing in. I'm excited to tell you about our progress this quarter as we have continued to demonstrate remarkable commercial revenue and have been making good progress across our robust pipeline. At PTC, we are committed to creating both short and long-term value for all our stakeholders. To accomplish this, we have built a company that discovers, develops, and commercializes therapies to treat patients of higher medical need.

Unknown Executive: We see continuous and impressive commercial revenue growth for our products, and we now have five ongoing registration-directed studies, with an increasing number of preclinical and clinical studies in progress. We are building a sustainable, enduring biopharmaceutical company. Turning to this quarter's DMV franchise commercial revenue, we continue to deliver impressive year-over-year growth. The franchise has grown by 39% compared to the third quarter of 2020, with $114 million in total revenue.

Unknown Executive: This was primarily driven by new patient starts for both Inflaza and TransLarna and geographic expansion for TransLarna. I'm pleased to announce that we are raising our 2021 revenue guidance for the DMD franchise to $400 to $420 million from $370 to $390 million. Eric and Emily will go into more detail shortly.

Unknown Executive: Now, I'd like to highlight the significant milestones achieved in Brazil with both Tecsede and Waileber this quarter. In August, we were pleased to announce the approval of WayLibre in Brazil. This is the first approved treatment for familial chylomicronemia syndrome, or FCS, and we're excited to be able to bring this therapy to patients in need. But this was not the only milestone for Brazil this quarter.

Unknown Executive: I'm also happy to report that TxETI, which is for the treatment of HATTR amyloidosis, received Category 1 pricing. Category 1 pricing is given to innovative treatments that show a benefit over current standards of care. Due to Portuguese descent, there is a higher prevalence of HATTR patients in the Brazilian population.

Unknown Executive: Eric will go into more detail on the remarkable progress of the commercial team later in this call. Now, let me turn to everyone, which is the first commercial product from our innovative SPICe platform. And RISD continues to show strong revenue this quarter, with approximately 20% total market share in just over a year after launch.

[music].

Unknown Executive: The RISD is the most prescribed SMA treatment in the United States, and ROSH expects further growth in 2021, with approval in 63 countries, and has continued focus on pricing and reimbursement efforts outside of the U.S. The success of our commercial portfolio demonstrates our ability to utilize our commercial engines to grow revenues to further invest in the pipeline, which I'll now discuss in more detail. In particular, I'd like to start with our near-term value. I'm excited to announce that we have initiated a registration-directed trial called Affinity for PTC 923 in PKU.

Unknown Executive: We view this as a significant opportunity, as there is a well-defined patient population through newborn screening, known centers of excellence, and a clear pathway to approval with a blood-based biomarker as an endpoint, as well as having an enriched population through a run-in responder analysis that increases our chance of success. Now, let me talk about our next two registration-directed trials from our BioE platform. The BioE platform targets excess electricity and the oxidative stress that contributes to multiple disease stages.

Good day, and thank you for standing by.

Welcome to the PTC Therapeutics third quarter, 2021, corporate update and financial results Conference call.

At this time all persons are in a listen only mode.

After the Speakers' presentation there'll be a question answer session.

Unknown Executive: The first compound from this platform, tiquinone, inhibits 15 lepoxic, a key regulator that controls the oxidative stress response. The first of the registration-directed trials with patiquinone is the MIGHTY-E study in patients with mitochondrial disease associated with seizures. We expect results in the third quarter of 2022, and if positive, will be the basis of our NDE. Our second registration-directed particulate note trial, MOVE-FA, is in patience with creature attacks. A Mitochondrial Disease That Affects Neuromuscular Function

To ask a question. During this session you will need to press star one on your telephone.

Please be advised that today's conference is being recorded.

Any further assistance please press star zero.

Now like to hand, the conference or whats your speaker today, Kellie O'keefe head of Investor Relations. Please go ahead.

Good afternoon, and thank you for joining us today to discuss the PTC therapeutics third quarter 2021 corporate update and financial results. Joining me on today's call is our Chief Executive Officer Stuart Peltz.

Our Chief Development Officer, Matthew Clark, and our Chief Business Officer, Eric Palace, and our Chief Financial Officer Emily Hill.

Before we start let me remind you that today's call will include forward looking statements based on current expectations.

Please take a moment to review the slides posted on our Investor Relations website in conjunction with the KOL.

Which contains our forward looking statements our actual results could materially differ from these forward looking statements.

Such statements are subject to risks that can materially and adversely affect our business and results of operation.

Unknown Executive: We recently reported results from the PTC 518 Healthy Volunteer Tribe. We were able to show dose-dependent lowering of both HPT, mRNA, and protein and achieve the targeted 30% to 50% reduction. We also demonstrated that PCC 518 passes the blood-brain barrier and has minimal... These are key attributes that treat Huntington's disease.

We will disclose certain non-GAAP information during this call infill.

Thanks Cai.

Unknown Executive: We remain very excited about this program and are moving as rapidly as possible into phase two. In the Phase 2 trial, we will replicate the safety, tolerability, and pharmacology of PTC501A, as well as decreases in Huntington mRNA and protein levels in the Huntington's disease patients. Matt will go into more detail on our phase two program shortly. Now, moving on to AADC.

Thank you all for dialing in.

I'm excited to tell you about our progress this quarter and as we have.

Continued to demonstrate remarkable commercial revenue and they have been making good progress across our robust pipeline.

And did you see we are committed to creating both short and long term value for all our stakeholders.

To accomplish this we have built a company that discover develop and commercialize it.

Unknown Executive: In Europe, we still expect to see HDM opinions by the end of this year and look forward to bringing this transformational therapy to AADC deficiency patients. I'm also pleased that we recently held a ribbon-cutting ceremony for our Gene Therapy Manufacturing Center of Excellence in Hopewell, New Jersey. Our new state-of-the-art facility is well-equipped and staffed to produce high-quality plasmid and AAV vectors for gene therapy applications. I'm very proud of the progress we've made over the past quarter, with exciting commercial achievements and steady state progress across our pipeline.

Sure.

With high unmet medical need.

We are building a sustainable pipeline.

We'll develop new therapies that reached commercialization on a continuous basis.

This will allow us to substantially grow our revenue base.

That it will continue to increase in the years to come.

The result of all these efforts are bearing fruit.

Continuous and impressive commercial revenue growth of our product and.

And we now have five ongoing registration directed study.

With an increasing number of preclinical and clinical studies in progress.

We are building a sustainable enduring biopharmaceutical company.

Turning to this quarter's DMD franchise commercial revenue, we continued to deliver impressive year over year growth.

Unknown Executive: This speaks to the dedication of our people, who have worked incredibly hard in the face of the ongoing challenges. The past 18 months have required perseverance, and I'm proud to say that we've continued to execute across all fronts. We have all the ingredients.

Our franchise has grown by 39% compared to the third quarter of 2020 with $114 million in total revenue.

This was primarily driven by new patient starts for Bolton Plaza in Translarna and geographic expansion for Translarna and <unk>.

Matt: Research, Development, and Commercialization, a place that positions us to be a growing revenue-generating, enduring biopharmaceutical company. I now turn the call over to Matt for an update on the development program. Matt

Pleased to announce that we are raising our 2021 revenue guide for the DMD franchise.

Unknown Executive: [inaudible]

$400 million to $420 million from the $370 million to $390 million.

Matt: Thanks, Stu. I'm happy to provide an update on the continued progress of our pipeline program. I will begin with our PTC 923 PKU program. As planned, we initiated enrollment in the affinity trial, our global phase three registration-directed trial of PTC 923 in pediatric and adult PKU patients. This double-blind placebo-controlled trial will include a run-in phase to identify responders to PTC-923 who will then be randomized to receive either PTC-923 or a placebo for six weeks. As with previous approved therapies for PKU, the primary endpoint of the affinity trial is reduction of phenylalanine bubbles.

Eric and Emily will go into more detail shortly.

No I'd like to highlight the significant milestone.

In Brazil, with both tech savvy anybody Libre this quarter.

In August we were pleased to announce the approval of where you are in Brazil.

Unknown Executive: Thanks for the question. In terms of the study of natural history, obviously, the HD community has a lot of natural history that helps us define where there's over, you know, in one database, there are over 20,000 patients that one could look at, and it will help us define that. Obviously, within the trial that we're doing, we're doing a placebo control to compare within the first Unknown Speaker 12 weeks, and then it goes on so we'll have that much information.

This is the first approved treatment for familial kylo micro anemia syndrome or Fcs.

We're excited to be able to bring the therapy to patients in need.

Unknown Executive: So the natural history that we're using is what is critical is really to help us inform the criteria for which patients you can actually see a change in response, right? Because what you need to, you know, and the Gobi Locks, you know, as Matt has talked, where there's a decline, but the decline isn't so great, is that you can actually, if you change the course of that, you would see the, you would be able to measure that difference.

This was not the only milestone for Brazil this quarter.

I'm also happy to report that Tech savvy.

For the treatment of H ATT amyloidosis.

Category one pricing.

Category, one pricing is given as an innovative treatment that show benefit over current standards of care.

Unknown Executive: So the Go-B-Lax population really helps to ensure that we're enrolling those subjects that are not too early in the disease progression but have a higher risk of declining over the course of the trial, and therefore, treatment versus that gives you the possibility of a fever. And so we're hopeful that as we measure that, obviously, we'll be measuring the biomarkers, and we'll see a reduction in CTR and AM protein. That will be important.

The Portuguese descent, there was a higher prevalence of H H T T. Our patients in the Brazilian population.

Matt: Following completion of the placebo-controlled trial, subjects will then be enrolled in a long-term open-label extension study. We expect to have results from the placebo-controlled trial by the end of 2022. Turning now to our PTC 518 Huntington's Disease Program. Following the announcement of the successful Phase 1 study results in healthy volunteers, we are moving forward with our Phase 2 study in Huntington's Disease patients. This study, PIVOT-HD, will include a 12-week double-blind placebo-controlled phase, followed by a one-year open-label extension.

Eric will go into more detail on the remarkable progress of the commercial team later in the call.

Now, let me turn to every entity, which is the first commercial product from our innovative splicing platform.

Everything continues to show strong revenue in the quarter was approximately 20% total market share in just over a year after launch.

Our reasoning is the most prescribed.

Many estimated treatment in the United States and Roche expects further growth in 2021 with approval in 63 countries and a continued focus on the pricing and reimbursement efforts outside of the U S.

Matt: The study will enroll approximately 100 to 150 subjects who will be randomized to receive placebo for one of two dose levels of PTC518. The primary objective of the placebo control phase is to demonstrate safety, pharmacology, and evidence of HTT, mRNA, and protein lowering in HD patients.

The success of our commercial portfolio demonstrates our ability to utilize our commercial age.

ROE revenues to further invest in the pipeline, which I'll now discuss in more detail.

Unknown Executive: But we would also then anticipate seeing changes in the CSF, as well as neural cell and light changes, and we'll look at both the CSF and plasma and then, of course, monitoring the preservation of brain volume as assessed by MRI Imaging, so we think that package. It will be quite interesting, and so the short-term 12 weeks will allow us to get that, and the longer-term safety and pharmacology and pharmacodynamic measurements of all the others that will go on for a year, we think we'll be able to see something there in terms of the biomarkers.

In particular I'd like to start with our near term value driver.

Kripalan: Great, thank you. That was very helpful. And then I had a quick follow-up question on the PKU program. You know, Bandran has said that a lot of the PKU clinics are still not operating at full capacity.

I'm excited to announce that we have initiated the registration directed trial called the opinion or PTC 19, three in PKU.

Right.

Significant opportunity as there was a well defined patient population through newborn screening no centers of excellence and a clear path to approval with a blood based biomarker and then endpoints as well as having an enriched population.

Kripalan: Do you see any, you know, any challenges in terms of being able to find enough patients for the clinic?

Rondon responder analysis.

Operator: Transcribed by https://otter.ai

Chris This is our chance of success.

Let me talk about our next two registration directed trials from our bio E platform.

Our bio E platform targets excess electrons and the oxidative stress that contribute the multiple disease states.

First compound from this platform particular node.

If it's 15 lipoxygenase.

Key regulators that controls the occupancy that's threat response.

Matt: We look forward to initiating the Phase 2 study by the end of this year. Next, I'll provide updates on our BioE client. As Stu mentioned, we are continuing enrollment in the two registration-directed trials of Tiquinone in Mitochondrial Disease-Associated Seizures, the MITEI trial, and in Friedreich ataxia, the MOVE-FA trial. I am proud of the progress our teams have made in activating our global study sites to allow for enrollment of these trials during the pandemic.

The first of the registration directed trial with particular known as the <unk> study in <unk>.

Patients with mitochondrial disease associated with things yours.

Expect results in the third quarter of 2022, and if positive will be the basis of our NDA.

Our second registration directed particular known trial move ethane.

You've been patient with greater ataxia.

Mitochondrial disease that affects neuromuscular function.

We're grateful for the collaboration and support from the Epic community.

Matt: We expect results from the MITEI trial in Q3 2022 and from the MOOV-FA trial in 2023. As we reported last quarter, we completed the Phase 1 Healthy Volunteer trial of PTC 857 and are now moving forward with the Phase 2 trial in patients with ALS. As a reminder, PTC 857 inhibits the enzyme 15-lipoxygen, a key regulator of the Inflammation and Oxidative Stress Pathway, known as Ferribtosis. Ferriptosis is a recently described cell death pathway that has been demonstrated to be key to neurodegenerative disease pathology, including ALS and Parkinson's. In a series of preclinical studies, we have demonstrated that PCC 857 is a potent protector of neuronal cell death and neuropathology in a number of in vitro and in vivo neurodegenerative disease test systems.

And helping us to drive enrollment we anticipate results in 2023.

Operator: Do you think that it's easy to enroll?

We're also moving ahead with the next generation compounds from the bio E platform.

C H type stuff.

We have selected <unk> as the first indication and are aiming to initiate the phase two trial for PTC 857 in the first quarter of next year.

Unknown Executive: Um, we just initiated the trial, so it's hard to give you any hard numbers on what we're looking at.

Unknown Executive: But we think, and this is what we're doing is, um, we, you know, the good news, obviously, we have a global infrastructure. So we'll be able to get only sites, not only in the US but worldwide, as well. And, you know, we have a lot of investment. And so, obviously, that's one of the things to make sure is that if you have an expanded number of investigators, that will help pull through so that you can get those patients. And that's why we're doing that. So that's, we still expect results by the end of 2020.

Kripalan: Great! Thank you so much.

I'll now discuss our interface with fighting platform with a focus on PTC 518 for the treatment of Huntington's disease.

We recently reported results from PTC five Monday, how Peabody.

And to your trial.

We're able to show dose dependent lowering.

<unk> H T T mrna and protein and achieved the targeted 30% to 50% reduction.

We also demonstrated that PTC five Monday passes the blood brain barrier and then minimal blocks.

These are key attributes to treat huntington's disease.

We remain very excited about this program and are moving as rapidly as possible into phase II.

Moving into the phase III trial.

Matt: We plan to initiate the Phase 2 study in the first quarter of 2022 and will provide additional details on the study design once it is finalized. We are excited about the progress we have been making in our ongoing registration-directed trials and look forward to initiating phase two trials with PTC 518 and PTC 857 in the near future. I'll now turn the call over to Eric for an update on our commercial business. Eric. Thanks, Matt.

We will replicate safety Tolerability and pharmacology of PTC 518.

As well as decrease.

Creases in Huntington mrna and protein levels in the Huntington's disease patients.

Operator: Thank you. And I'm showing no questions at this time. I'd like to turn the call back over to Stuart Peltz for closing remarks.

We'll go into more detail on our phase III program shortly.

Now moving on to an ADC in Europe, we still expect to see HMP opinion by the end of this year and look forward to bringing this transformational therapy.

A D C deficiency patient.

I'm also pleased that we recently held a ribbon cutting ceremony for our gene therapy manufacturing center of excellence in Hopewell, New Jersey.

Eric: Our PTC customer facing team has delivered another outstanding quarter in our global DMD franchise. We have built a strong foundation for our potential launch of the PTC AADC gene therapy, which will follow the anticipated EMEA approval and will continue to drive our geographic expansion across the globe to strengthen our commercial engines. Our strong revenue growth continues in our DMV franchise with a 39% increase year-over-year. This brings our year-to-date sales for the DMV franchise to $306 million.

Our new state of the art utility is well equipped and staffed to produce high quality plasma.

The vector for gene therapy applications.

I'm very proud of the progress we've made over the past quarter with exciting commercial achievement and steady state progress across our pipeline.

Speaks to the dedication of our people who have worked incredibly hard in the face of the ongoing challenges.

Unknown Executive: Well, great. So, you know, thanks for joining us today. And, I think, as you can see, we're continuing to build PTC into a revenue-generating company. And I'm proud that the PTC team has made what we have done this quarter. I think you can see we've delivered substantial continued year-over-year revenue growth and once again raised our DMD franchise 2021 revenue guidelines. This revenue growth, in addition to the continued advancement of our pipeline with the initiation of our fifth registration-directed trial in BKU. This progress really allows us to continue the mission that we have of delivering life-changing therapies to patients around the globe. So thanks for taking the time to listen, and thanks for your questions.

Operator: This concludes today's conference call. Thank you for participating. You may now... Thank you for watching! (inaudible)

Operator: © BF-WATCH TV 2021 ??? ?? ?? ?? ?? ?? ?? Good day and thank

<unk> depends damage.

Last 18 months have required perseverance I'm proud to say that we've continued to execute across all fronts.

Operator: Good day, and thank you for standing by. Welcome to the PTC Therapeutics Third Quarter 2021 Corporate Update and Financial Results Conference Call. At this time, all persons are in a listening mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1 on your telephone. Please be advised that today's conference is being recorded. If you require any further assistance, please press star zero. I would now like to hand the conference over to your speaker today, Kylie O'Keefe, Head of Investor Relations. Please go ahead.

We have all the ingredients research development and commercialization that place that positions us to be a growing revenue generating enduring biopharmaceutical company.

Eric: Our 2021 revenue guidance was originally at $355 to $375 million at the beginning of 2021, which in Q2 was raised to $370 to $390 million. Based on the continued strong year-to-date performance, we are pleased to announce that we are raising our 2021 revenue guidance for the DMD franchise to $400,000 to 420 million. A substantial increase over the original guidance. New patient starts, continued high compliance, and a focus on operational excellence have fueled sustained growth of EMPLASA.

I'll now turn the call over to Matt for an update on the development program Matt.

Thanks, Dale I am happy to provide an update on the continued progress of our pipeline programs payroll beginning with our PTC 19th the PKU program.

Kylie O'Keefe: Our actual results could materially differ from these forward-looking statements. As such, they are subject to risks that can materially and adversely affect our business and results of operations. For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent quarterly report on Form 10-Q and annual report on Form 10-K, filed with the Securities and Exchange Commission, as well as the company's other SEC filings. We will disclose certain non-GAAP information during this call. Information regarding our use of GAAP to non-GAAP financial measures and a reconciliation of GAAP to non-GAAP is available in today's earnings release. With that said, let me pass the call over to our CEO, Stuart Peltz. Stu?

As planned we initiated enrollment in the affinity trial, a global phase III registration directed trial of <unk> 93 in pediatric and adult PKU patients.

This double blind placebo controlled trial will include a running phase to identify responders PTC ninety-three, who will then be randomized to receive either P. T.

Eight or placebo for six weeks.

As a previous approved therapies for PKU. The primary endpoint of the affinity trial is reduction of phenylalanine blah blah blah.

Following completion of a placebo controlled trial subjects will then be enrolled a long term open label extension study.

Eric: This quarter, we achieved $47 million in revenue, which is a 22% increase over the third quarter of 2020. Turning to TransLarna, we achieved $67 million in revenue this quarter, a 55% growth over the third quarter of 2020.

We expect to have results from the placebo controlled trial by the end of 2022.

Turning now to our PTC five Huntington's disease program. Following the announcement of the successful phase one study results in healthy volunteers, we are moving forward with our phase two study in Huntington's disease patients.

This study pivotal HD will include a 12 week double blind placebo controlled phase followed by a one year open label extension phase.

Eric: As a reminder, especially in rare diseases, significant international markets like Brazil.

Study will enroll approximately 100 to 150 subjects will be randomized to receive placebo or one of two dose levels of PTC 518.

unknown: Transcripts provided by Transcription Outsourcing, LLC, create lumpiness due to the uneven government-driven orders that vary over the course of the year. This drives large quarter-over-quarter growth in comparison to others. In this quarter, the successful launch in Russia was a key driver of our growth, as we received centralized reimbursement in Russia and obtained a significant order for a large group of non-sense mutation DMD pigs. Additionally... We are seeing continued growth in the main European markets and driving geographical expansion in Central and Eastern Europe, Latin America, the Middle East, and Asia-Pacific, which remains important to our future growth.

Primary objective of the placebo controlled phase is to demonstrate safety pharmacology and evidenced that each TT mrna and protein lowering in HD patients.

In addition, we will collect CSL plasma and CNS radiographic biomarker data in both the placebo controlled and long term extension phases of the study that can provide evidence of meaningful PTC 518 treatment effect.

The criteria for this goldilocks population were developed based on extensive analysis of the HD clinical and biomarker natural history database.

Eric: We are also excited to recently share the real-world results from the STRIDE patient registry demonstrating that treatment with translarna delays loss of ambulation by more than five years in boys with nonsense mutation Duchenne muscular dystrophy, compared to standard of care alone. This is further adding to the totality of evidence for the benefit of translarna. We are making continued progress for access to TransLarna, with reimbursement agreements now established for patients in Finland and the Netherlands, and broader coverage for two to five-year-olds for patients in Italy.

Look forward to initiating the phase II study by the end of this year.

Next I'll provide updates on our bio E platform.

As Steve mentioned, we are continuing enrollment in two registration directed trials, particularly in mitochondrial disease associated seizures, the night, each health and <unk> ataxia.

A trial I am proud of the progress our teams have made in activating our global study sites to allow for enrollment of these trials during the pandemic.

We expect results from the Mighty trial in Q3, 2022 and from the move at a trial in 2023.

As we reported last quarter, we completed the phase one healthy volunteer trial a P. P C eight five.

Eric: Despite significant COVID-19 challenges in Brazil, we are pleased with Ed Visa's approval of the translator label to include patients in the two to five year old range. Across Latin America, we continue to see increases in newly diagnosed DMD patients and expect to fulfill an order for translarin in Brazil in the fourth quarter this year to treat both new and existing DMD patients in the country. Now, turning to Tech Study Limebra, we are excited to announce that we have successfully received Category 1 Innovation Classification from CMED, the Drug Market Regulation Chamber in Brazil.

And are now moving forward with the phase II trial in patients with E. L F.

As a reminder, PTC 857 inhibits the end by 15 lipoxygenase a can.

Key regulator of the inflammation and oxidative stress pathway.

Totally fair.

Closest as it recently described sell desktop way that has been demonstrated to be key neuro degenerative disease pathology, including ALS and Parkinson's disease.

A series of preclinical studies, we have demonstrated that PTC 857 is a potent protector of neuronal cell death, and neuropathology and a number of in vitro and in vivo neuro degenerative disease test systems.

We plan to initiate the phase II study in the first quarter of 2022 and will provide additional details on the study design once it is finalized.

Eric: CMED Price Categorization is the

Unknown Executive: Now, I'd like to highlight the significant milestones achieved in Brazil with both Tecsede and ReLiver this quarter. In August, we were pleased to announce the approval of WayLibre in Brazil. This is the first approved treatment for familial chylomicronemia syndrome, or FCS, and we're excited to be able to bring this therapy to patients in need. However, this was not the only milestone for Brazil this quarter.

Eric excited about the progress we have been making in our ongoing registration directed trials and look forward to initiating the phase II trials. The PTC 508, PTC five seven in the near future.

Eric: This is the first critical step in getting pricing and reimbursement in place. Category 1 classification is given to innovative treatments that provide greater efficacy than current standards of care and allows for pricing in line with international markets. The take studies categorization as an innovative treatment is a key milestone towards optimizing the value in Latin America. We will continue to provide named patient access and now commence reimbursement negotiations with Conitech, Brazil's health technology assessment body, for inclusion of Tegceti in the Brazilian public health system or SUS.

Unknown Executive: I'm also happy to report that TxETI, which is for the treatment of HATTR amyloidosis, received Category 1 pricing. Category 1 pricing is given to innovative treatments that show benefits over current standards of care. Due to Portuguese descent, there is a higher prevalence of HATTR patients in the Brazilian population.

I'll now turn the call over to Erik for an update on our commercial business Eric.

Thanks, Matt our PTC customer facing team has delivered another outstanding quarter in our global DMD franchise.

We have built a strong foundation for our potential launch of the PTC ADC gene therapy, which will follow the anticipated EMEA approval and we will continue to drive our geographic expansion across the globe to strengthen our commercial engine.

Our strong revenue growth continued in our DMD franchise with a 39% increase year over year.

This brings our year to date sales for the DMD franchise to $386 million.

Our 2021 revenue guidance was originally at $355 million to $375 million at the beginning of 2021, which in Q2 was raised to $370 million to $390 million.

Eric: As a reminder, there are an estimated 5,000 patients with HIV in Singapore.

Eric: with ATTR Amlogosis in Brazil. KegCeti is the first antisense medicine available for patients in Brazil to address the underlying causes. We were thrilled to announce that WayLibre was approved by INVISA in Brazil as of August 2021. Following the approval, we have commenced discussions with TMED, the Brazilian pricing authority. Weight Lever is the first treatment for FGS in Brazil. FCS is a rare metabolic genetic disease that results in a significant disease burden for patients, including potentially fatal pancreatitis.

Based on the continued strong year to date performance. We are pleased to announce that we are raising our 2021 revenue guidance for the DMD franchise to 400.

It's a $420 million.

Substantial increase over the original guidance.

New patient starts continued high compliance and our focus and operational excellence has fuel sustained growth of in plaza.

This quarter, we achieved $47 million in revenue, which is a 22% increase over the third quarter of 2020.

Turning to try in Florida, we achieved $67 million in revenue this quarter, a 55% growth over the third quarter of 2020.

Eric: Anne Greenspider and Other Chronic Complications

As a reminder, especially in rare diseases significant international markets like Brazil, and produce large orders create lumpiness due to the uneven government driven orders that vary over the course of the year.

This drives large quarter over quarter growth in comparison to others.

In this quarter the successful launch in Russia with a key driver of our growth.

Eric: Therapy Lodge or PTC AADC. We have built the foundation to support a strong launch, which we anticipate will occur in Europe shortly after final approval. PTC continues to accelerate patient screening activities in enriched high-risk populations. Significant progress has also been made with the identification and preparation of expert pediatric neurological centers of excellence throughout the United States and the EU to ensure treatment center readiness at the time of launch. And we remain focused on identifying patients in global markets where gene therapy access is available.

As we received centralized reimbursement in Russia and obtained a significant order for a large group of nonsense mutation DMD patients.

Additionally.

We are seeing continued growth in main European market.

And driving geographical expansion in central and Eastern Europe, Latin America, the Middle East and Asia Pacific, which remains important to our future growth.

We are also excited to recently share their real world results from the stride patient registry demonstrating that treatment with <unk>, Florida delays loss of ambulation by more than five years in boys with nonsense mutation Duchenne muscular dystrophy compared to standard of care alone.

This is further adding to the totality of evidence for the benefit of Florida.

We are making continued progress for access to trend, Florida with reimbursement agreements now established for patients in Finland.

And the Netherlands, and broader coverage for two to five year olds for patients in Italy.

Despite significant COVID-19 challenges in Brazil.

We are pleased with that visa approval of expansion of the trend of Florida label to include patients in the two to five year old range.

Unknown Executive: Eric will go into more detail on the remarkable progress of the commercial team later in this call. Now, let me turn to Everest, which is the first commercial product from our innovative SPICe platform. And RISD continues to show strong revenue this quarter, with approximately 20% total market share in just over a year after launch.

Now turning to tech studying way Libra, we are excited to announce that we have successfully received category one innovation classification foreseen that.

Unknown Executive: RISD is the most prescribed SMA treatment in the United States, and ROSH expects further growth in 2021, with approval in 63 countries, and has continued focus on pricing and reimbursement efforts outside of the U.S. The success of our commercial portfolio demonstrates our ability to utilize our commercial engines to grow revenues to further invest in the pipeline, which I'll now discuss in more detail. In particular, I'd like to start with our near-term value. I'm excited to announce that we have initiated a registration-directed trial called Affinity for PTC 923 in PKU.

Unknown Executive: We view this as a significant opportunity, as there is a well-defined patient population through newborn screening, known centers of excellence, and a clear pathway to approval with a blood-based biomarker as an endpoint, as well as having an enriched population through a run-in responder analysis that increases our chance of success. Now, let me talk about our next two registration-directed trials from our BioE platform. The BioE platform targets access electronic and the oxidative stress that contributes to multiple disease states. The first compound from this platform, tiquinone, inhibits 15-lipoxygen. A key regulator that controls the oxidative stress response

Emily: Thanks, Eric. We have continued to see substantial revenue growth from our commercial portfolio this quarter, and we remain in a strong position to continue to support strategic advancement across our diverse pipelines. We look forward to continuing to deliver on

Unknown Executive: The first of the registration-directed trials with particulinone is the MIGHTY-E study in patients with mitochondrial disease associated with seizures. We expect results in the third quarter of 2022, and if positive, will be the basis of our NDE. Our second registration-directed particulate note trial, MOVE-FA, is in patience with pre-trick attacks.

The drug market regulation chamber in Brazil.

Unknown Executive: These are key attributes that treat Huntington's disease. We remain very excited about this program and are moving as rapidly as possible into phase two. Moving into the Phase 2 trial, we will replicate the safety, tolerability, and pharmacology of PTC508, as well as decreases in Huntington mRNA and protein levels in Huntington's disease patients. Matt will go into more detail on our Phase II program shortly. Now moving on to AAGC.

Unknown Executive: In Europe, we still expect to see HMT opinion by the end of this year and look forward to bringing this transformational therapy to AAGC deficiency patients. I'm also pleased that we recently held a ribbon-cutting ceremony for our Gene Therapy Manufacturing Center of Excellence in Hopewell, New Jersey. Our new state-of-the-art facility is well-equipped and staffed to produce high-quality plasmid and AAV vectors for gene therapy applications. I'm very proud of the progress we've made over the past quarter, with exciting commercial achievements and steady state progress across our pipeline.

He met price categorization is the first critical step in getting pricing and reimbursement in Brazil.

Category, one classification is given to innovative treatments that provide greater efficacy than current standards of care and allows for pricing in line with international markets.

Emily: We are continuing to deliver on important milestones across all of our programs.

Emily: The press release issued earlier this afternoon summarizes the details of our third quarter 2021 financial results. I will take a few minutes now to review these financial results.

Taste studies categorization as an innovative treatment is a key milestone towards optimizing the value in Latin America.

We will continue to provide nave patient access and now commenced reimbursement negotiations with Coty attack Brazil's health technology assessment body for inclusion of Chegg study and the Brazilian public health system or suits.

Emily: Please refer to the press release for further details.

Unknown Executive: This speaks to the dedication of our people, who have worked incredibly hard in the face of the ongoing challenges. [inaudible] The past 18 months have required perseverance, and I'm proud to say that we've continued to execute across all fronts. We have all the ingredients.

Emily: Beginning with top-line results, total revenues were $138 million.

Matt: I'm happy to provide an update on the continued progress of our pipeline program. I will begin with our PTC 923 PKU program. As planned, we initiated enrollment in the affinity trial, our global phase three registration-directed trial of PTC 923 in pediatric and adult PKU patients. This double-blind placebo-controlled trial will include a run-in phase to identify responders to PTC-923 who will then be randomized to receive either PTC-923 or a placebo for six weeks.

Emily: $138.7 million for the third quarter of 2021, a 17% increase over the third quarter of 2020.

As a reminder.

There are an estimated 5000 patients with H <unk> amyloidosis in Brazil.

Case study is the first antisense medicine available for patients in Brazil to address the underlying cause of disease.

Emily: This revenue includes $115.6 in net product sales and $23.1 in royalty and collaboration revenue. The Strong Growth of the DMV Franchise

We were thrilled to announce that way Libra was approved by visa in Brazil as of August 2021.

Emily: This exercise continues this quarter.

Emily: TransVarna Net Product Sales of $67.2 million compared to $43.4 million in

Following the approval we have commenced discussions with team that the Brazilian pricing authorities.

Where labor is the first treatment for FCS in Brazil.

Emily: 4 million in the third quarter of 2020.

<unk> is a rare metabolic genetic disease, which results in a significant disease burden to patients, including potentially fatal pancreatitis and other chronic complications.

Matt: As with previous approved therapies for PKU, the primary endpoint of the affinity trial is reduction of phenylalanine bubbles. Following completion of the placebo-controlled trial, subjects will then be enrolled in a long-term open-label extension study. We expect to have results from the placebo-controlled trial by the end of 2022. Now, turning now to our PTC 518 Huntington's Disease Program. Following the announcement of the successful Phase 1 study results in healthy volunteers, we are moving forward with our Phase 2 study in Huntington's Disease patients. This study, PivotAge,

Emily: Continued geographic expansion, particularly in Russia, has been driving this growth. Year over year, MFLAZA revenue is also up this quarter, with net product revenue of $47.1 million, over $38.5 million in the third quarter of 2020. This has primarily been driven by better compliance and new prescriptions start. Due to this strong performance, we have raised revenue guidance for the DMD franchise to $400 to $420 million.

Matt: The study will include a 12-week double-blind placebo-controlled phase.

We have been engaged in a patient finding in Latin America with ongoing success and now have patients on treatment in Latam through early access programs.

Matt: Control phase, followed by a one-year open-label extension. The study will enroll approximately 100 to 150 subjects who will be randomized to receive placebo for one of two dose levels of PTC518. The primary objective of the placebo control phase is to demonstrate safety, pharmacology, and evidence of HTT, mRNA, and protein lowering in HT patients. In addition, we will collect CSF, plasma, and CNS radiographic biomarkers in both the placebo-controlled and long-term extension phases of the study that could provide evidence of meaningful PTC518 treatment effects.

Matt: We look forward to initiating the Phase 2 study by the end of this year. Next, I'll provide updates on our BioE class. As Stu mentioned, we are continuing enrollment in the two registration-directed trials of Tiquinone in Mitochondrial Disease-Associated Seizures, the MITEI trial, and in Friedreich ataxia, the MOVE-FA trial. I am proud of the progress our teams have made in activating our global study sites to allow for enrollment of these trials during the pandemic.

Matt: We expect results from the MITEI trial in Q3 2022 and from the MOVE-FA trial in 2023. As we reported last quarter, we completed the Phase 1 Healthy Volunteer Trial of PTC 857 and are now moving forward with the Phase 2 trial in patients with ALS. As a reminder, PTC 857 inhibits the enzyme 15-lipoxygen, a key regulator of the Inflammation and Oxidative Stress Pathway known as Barreptosis. Ferriptosis is a recently described cell death pathway that has been demonstrated to be key to neurodegenerative disease pathology, including ALS and Parkinson's.

Matt: In a series of preclinical studies, we have demonstrated that PTC 857 is a potent protector of neuronal cell death and neuropathology in a number of in vitro and in vivo neurodegenerative disease test systems. We plan to initiate the Phase 2 study in the first quarter of 2022 and will provide additional details on the study design once it is finalized. We are excited about the progress we have been making in our ongoing registration-directed trials and look forward to initiating the Phase 2 trials with PTC 518 and PTC 857 in the near future. I'll now turn the call over to Eric for an update on our commercial business.

Eric: Thanks, Matt. Our PTC customer facing team has delivered another outstanding quarter for us

I will now touch on the preparations for PTC first gene therapy launch for PTC.

We have built the foundation to support a strong launch, which we anticipate to occur in Europe. Shortly after final approval.

DTC continues to accelerate patient screening activity and enriched high risk population.

Emily: 420 million from $370 to $390 million.

Emily: Turning now to Evrizdi, where our partner Roche has reported year-to-date revenue of 396 million Swiss francs, resulting in 33.3 million in year-to-date royalties to PTC.

Emily: Royalties to PTC for the third quarter were

Is available.

We are proud to have commemorated October 23rd ADC deficiency awareness day together with the agency.

Emily: As a reminder, PTC also retains sales-based cash milestones, and the $10 million milestone payment for the first commercial sale in Japan was received by PTC this quarter. In addition to this, PTC has an additional $325 million in sales-based milestones remaining, with a $25 million payment expected when the threshold of $500 million in revenue is reached. Non-GAAP R&D expenses were $117.8 million for the third quarter of 2021,

<unk> network and look forward to bringing this much needed treatments of patients very soon.

I will now turn the call over to Emily for a financial update Emily.

Thanks, Eric we have continued to see substantial revenue growth from our commercial portfolio this quarter.

We remain in a strong position to continue to support strategic advancement across our diverse pipeline.

Emily: excluding $13 million in non-cash stock-based compensation expense.

Emily: Compared to $83.8 million for the third quarter of 2020, excluding $9.2 million.

We look forward to continuing to deliver unimportant milestones across all of our programs.

The press release issued earlier this afternoon summarizes the details of our third quarter 2021 financials yourself.

Emily: excluding $9.2 million in non-cash, stock-based compensation expenses.

I will take a few minutes now to review these financial results. Please refer to the press release for further detail.

Beginning with top line results total revenues were $138 7 million for the third quarter of 2021.

17% increase over the third quarter of 2020.

This revenue included the $115 six and net product sales and $23, one and royalty and collaboration revenue.

This strong growth of the DMD franchise continues that's quicker with Translarna net product sales of $67 2 million compared to 43 4 million in the third quarter of 2020.

Emily: excluding $7.6 million in non-cash, stock-based compensation.

Emily: We have lowered and narrowed the range of our non-GAAP R&D activities

Emily: Last GNA Exempts for the full year 2021 increased from $715 to $735 million from $725 to $755 million. Cash, Cash Equivalents, and Marketable Securities totaled $867.9 million as of September 30, 2021, compared to $1.1 billion as of December 31, 2020. I will now turn the call over to the operator for Q&A. Operator.

Continued geographic expansion, particularly in Russia has been driving this growth.

Year over year I'm Plaza revenue is also up this quarter with net product revenue of $47 1 million over $38 5 million in the third quarter of 2020.

This has primarily been driven by better compliance of new prescription starts.

Due to this strong performance, we have raised revenue guidance for the DMD franchise to $400 million to $420 million from $370 million to $390 million.

Turning now to a risky where our partner Roche has reported year to date revenue of 396 million Swiss francs, resulting in $33 3 million and year to date royalties to PTC.

Operator: Operator for Q&A.

Royalties to PTC for the third quarter were $13 1 million in royalty revenue.

Operator: Thank you. As a reminder, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from Eric Joseph on JP Morgan. Your line is open.

As a reminder, PTC also routine sales base cash milestone and the 10 million milestone payment for the first commercial sale in Japan was received by PTC This quarter.

In addition to this PTC has an additional 325 million in sales based milestones remaining with a 25 million payment expected when the threshold of $500 million in revenue with rates.

Hannah: Hi, good afternoon.

Hannah: Hannah on behalf of Eric. Thanks for taking the questions. Just a few from us.

Non-GAAP R&D expenses were $117 8 million for the third quarter of 2021, excluding $13 million in noncash stock based compensation expense.

Hannah: So first, with respect to your oral health.

Eric: PMD Franchise We have built a strong foundation for our potential launch of the PTC AADC gene therapy, which will

unknown: Transcription by Transcription Outsourcing, LLC.

Compared to $83 8 million for the third quarter of 2020, excluding $9 2 million and noncash stock based compensation expense.

Eric: Following the anticipated EMEA approval, we'll continue to drive our geographic expansion across the globe to strengthen our commercial engine. Meanwhile, our strong revenue growth continues in our DMV.

unknown: PTC 299, COVID-19 Study, Powering Assumptions for the Primary Endpoint of Time-Through Respiratory Improvement, Prior Vaccine Exposure, COVID-19 Seropositivity Sure. Okay, I'll start with the... The Oral Splicing, I think that's the splicing one and the platform. And as for what we've been talking about in terms of the splicing, it's really quite interesting that we, you know, we've been able to build an informatics program that allows us to identify. So I think that's being used quite well.

Non-GAAP SG&A expenses were $56 4 million for the third quarter of 2021, excluding $12 8 million of noncash stock based compensation expense.

<unk> to $50 3 million for the third quarter of 2020, excluding $7 6 million of noncash stock based compensation expense.

We have lowered and narrowed the range of our non-GAAP R&D and SG&A expense for the full year 2021 to $715 million to $735 million from $725 million to $755 million.

Cash cash equivalents and marketable securities totaled $867 9 million as of September 30th 2021.

unknown: In the case of 299 and Site 19, I'll pass that over to either Matt or Kylie on that one. But I have a question about the Fight 19 trial. So, as you mentioned, our primary end point in that trial is Time to Sustain Respiratory Improvement, which is defined as an oxygen saturation of 94% on remair, which is sustained until discharge from the hospital or the end of the study, which is day 28.

Operator: https://www.youtube.com.au This brings our year-to-date sales for the DMD franchise to $306 million. Our 2021

Compared to $1 1 billion as of December 31, 2020.

Operator: https://www.patreon.com

I will now turn the call over to the operator for Q&A.

Operator.

Thank you.

As a reminder to ask a question you will need to press star one on your telephone to withdraw your question press the pound key please standby, while we compile the Q&A roster.

Eric: The program was raised $355 to $375 million at the beginning of 2021, which in Q2 was raised to $370 to $390 million. Based on the continued strong year-to-date performance, we are pleased to announce that we are raising our 2021 Revenue Guidance for the DMD franchise to $400,000 to 420 million. A substantial increase over the original guidance. New Patient Starts, Continued High Compliance, and a focus on operational excellence have fueled

Our first question comes from Eric Joseph with Jpmorgan. Your line is open.

Hi, Good afternoon. This is Hannah on for Eric Thanks for taking the question just a few from us.

First with respect to your oral splicing platform and just wondering if there any other kind of triangulate that.

unknown: Basically, the powering assumptions here were based on an estimation of median time to respiratory improvement in the placebo group, which we've taken, which is based on existing data, which was roughly 11 days, and then we had a hypothesized treatment effect, and then basically looked at a hazard ratio of about 1.38, you know, a two-sided type one error, which got us to our sample size of 380 subjects, which we believe In terms of your question regarding the vaccination, we don't have any criteria that include or exclude that previous vaccination, or nothing that relates to seropositive.

Unknown Speaker: Big growth in employees. This quarter, we achieved $47 million in revenue, which is a 22% increase over the third quarter of 2020. Turning to TransLarna, we achieved $67 million in revenue this quarter, a 55% growth over the third quarter of 2020. As a reminder, especially in rare diseases, significant international markets, like Brazil, can produce large orders that create lumpiness due to the uneven government-driven orders that vary over the course of the year. This drives large quarter-over-quarter growth in comparison to others. In this quarter, our successful launch in Russia was a key driver of our growth. As we received centralized reimbursement in Russia and obtained a

And it Triangulates IDP disorders that you might be looking to expand into over the near term.

My tonic dystrophy or appreciates axiom.

And then next with regard to PTC to 99.

The slide 19, COVID-19 study just wondering if you're able to talk about powering assumptions for your primary endpoint of time, Joe spiritual improvement and just maybe what some of the entry criteria are as it relates to prior vaccine exposure or COVID-19 nature of positivity.

Eric: Unidentified Speaker This is a significant order for a large group of non-sense mutation DMD patients. Additionally... We are seeing continued growth in the main European markets and driving geographical expansion in Central and Eastern Europe, Latin America, the Middle East, and Asia-Pacific, which remains important to our future growth.

Eric: We are also excited.

Eric: I'm excited to share the real-world results from the STRIDE patient registry, demonstrating that treatment with translarna delays loss of ambulation.

Eric: by more than five years in Boise.

Eric: [inaudible]

Eric: We are making continued progress for access to TransLarna with reimbursement agreements now established for patients in Finland and the Netherlands and broader coverage for two to five-year-olds for patients in Italy, despite significant COVID-19 challenges in Brazil. We are pleased with Edvisa's approval of the expansion of the translator label to include patients in the two to five-year-old range. Across Latin America, we continue to see increases in newly diagnosed DMD patients and expect to fulfill an order for translarin in Brazil in the fourth quarter this year to treat both new and existing DMD patients in the country. Now, turning to Tech Study in Lamingra, we are excited to announce that we have successfully received Category 1 Innovation Classification from CMED.

Eric: The Drug Market Regulation Chamber in Brazil.

Sure, Okay I'll start with the.

The oral splicing.

Eric: CMED Price Categorization is the first critical step

Operator: Category 1 classification is given to innovative treatments that provide greater efficacy than current standards of care and allows for pricing in line with international markets. Tyseti's categorization as an innovative treatment is a key milestone towards optimizing the value in Latin America. We will continue to provide named patient access and now commence reimbursement negotiations with Connie.

Eric: Negotiations with CONATEC, Brazil's health technology assessment body, for inclusion of Tegceti in the Brazilian Public Health System, or SUS. As a reminder... There are an estimated 5,000 patients.

Slide 31 in the platform.

Eric: with ATTR Amlogosis in Brazil. Next, the study is

What we are.

<unk> been talking about in terms of.

Operator: Transcripts provided by Transcription Outsourcing, LLC.

Eric: We were thrilled to announce that Waylivre was approved by INVISA in Brazil as of August 2021.

Pricing, but it's really quite interesting.

Eric: Following the approval, we have commenced discussions with TMED, the Brazilian Pricing Authority.

Eric: First Treatment for FGS in Brazil. FCS is a rare metabolic genetic disease which results in a significant disease burden.

Eric: [inaudible] We have been engaging in patient finding in Latin America with ongoing success and now have patients on treatment in LATAM through early access programs. I will now touch on the preparations for PTC's first gene therapy launch for PTC AADC. We have built the foundation to support a strong launch, which we anticipate to occur in Europe shortly after the final approval.

Eric: The third quarter has been yet another strong quarter with sustained growth in the DMD franchise. I am looking forward to a strong Q4 as our global customer-facing teams continue to execute well.

We've been able to build.

Eric: PTC continues to accelerate patient screening activities in enriched high-risk populations. Significant progress has also been made with the identification and preparation of expert pediatric neurological centers of excellence throughout the United States and the EU to ensure treatment center readiness at the time of launch. And we remain focused on

Eric: Unidentified Patients Global Markets Where Gene Therapy Access Is Available We are proud to have commemorated October 23rd as AABC Deficiency Awareness Month.

Build the informatics program that allows us to identify.

Eric: Agency's Efficiency Awareness Day, together with the AADC Family Network, and look forward to bringing this much-needed treatment to patients very soon.

Which would sort of your one sites that we can monitor we've been particularly interested in.

unknown: Okay, great. Thanks for taking the question.

In the nuclear type of pizza as well, so I'll speak more generally and just say we built the platform that's capable of looking at those and we have a high interest in <unk>.

Danielle Catherine Brill Bongero: Thank you. Our next question comes from Danielle Brew with Raymond James. Your line is open.

Multiple other.

Repeat like marathon dystrophy as.

As well as others and.

And we think that we can use the platform in interesting ways to be able to tackle other ones.

Danielle Catherine Brill Bongero: Hi guys. Good afternoon. Thanks so much for the questions.

We've talked previously about what we've disclosed.

Danielle Catherine Brill Bongero: First, on the doses...

Scot free.

Danielle Catherine Brill Bongero: for Phase 2, the 518 study. I'm presuming 30 mg will be one of the two doses you're thinking of using. Are you contemplating going higher or lower for the second dose?

In that trial, so we have a bunch of other and then we probably have.

Five or six more programs that we haven't disclosed yet, but we've always been interested in the ability to be able to produce.

Freshen of these using our technologies, we can so I think all of that being used quite well in the case of 299 and COVID-19 I'll pass that.

unknown: Transcripts provided by Transcription Outsourcing, LLC.

Unknown Executive: Yeah, maybe I'll start and then I'll pass it on to Matt. You might remember that we did a Phase 1 study where we did 15 and 30 milligrams, and we saw in the 30 milligram that up to 65% of the RNA was reduced. And we would anticipate that at steady states, the protein levels would go down as numbers. I think what we'd be initially targeting is what we've said is the 30 to 50% of that to be able to get to that.

Over to you as a matter of Kylie on that one.

Okay.

Your question on the fight 19 trials. So as you mentioned our primary endpoint in that trial is.

Time to sustain our tonnages.

Tom just stainless trade program, which is defined as oxygen saturation of 90, 94% on road map, which is sustained until discharged from the hospital or the end of the study which is day 28 basically the.

The powering assumptions here or based on any estimation of median time to respiratory approve mentioned the placebo group, which we've taken but should they started testing data which was.

Unknown Executive: And the way we're thinking about this as well as probably also thinking about taking advantage of some of the fact that we see a bit higher levels in the CFF. So that gives us really an opportunity to actually look at a range of doses. So Matt, maybe I'll pass on to you to give the thinking on that. Yeah, absolutely.

Roughly 11 days and then the hydro hypothesized treatment effect.

And then they looked at it a hazard ratio of about 1382 sided telco carrier, which status to our sample size of 380 subjects, which we believe in this.

More than 80% power to detect that difference in terms of your question regarding the vaccination.

We don't have any criteria that include or exclude that previous explanation.

That's what that relates to.

Cheryl positivity.

Okay, great. Thanks for taking the question.

Yeah.

Eric: to execute flawlessly against their strategic initiative. I will now turn the call over to Emily for a financial update.

Thank you. Our next question comes from Danielle Brill with Raymond James Your line is open.

Yes.

Hi, guys. Good afternoon. Thanks, so much for the questions I guess.

First on on the doses for phase two.

In a study.

Emily Luisa Hill: Thanks, Eric. We have continued to see substantial revenue growth from our commercial portfolio this quarter, and we remain in a strong position to continue to support strategic advancement across our diverse pipelines. We look forward to continuing to deliver on important milestones across all of our programs. A press release issued earlier this afternoon summarizes the details of our third quarter 2021 financial results. I will take a few minutes now to review these financial...

I am presuming 30 milligram will be one of the two doses youre thinking of using them or you are you contemplating going higher or lower for the second dose and then do you think.

Emily Luisa Hill: Please refer to the press release for more information.

Emily Luisa Hill: for further details. Beginning with top line results, total revenues were $138.7 million for the third quarter of 2021, a 17% increase over the third quarter of 2020.

Emily Luisa Hill: This revenue includes $115.6 in net product.

Emily Luisa Hill: and 23.1 in Royalty and Collaboration Revenue. The strong growth of the DMV...

Emily Luisa Hill: TransVarna Net Product Sales 67.2 million

It's reasonable to assume we may have data.

Emily Luisa Hill: compared to 43.4 million in the third quarter of 2020.

Probably data next year. Thanks.

Yeah, maybe I'll start and then I'll pass it on.

Matt you might remember that we you know we did a let's.

The phase one study, where we really did a 15 and 30 milligram and we saw.

And the 30 milligram up to 60 or 65% of the RNA.

That was reduced.

We would anticipate that.

Instead, he states the protein levels lets go down as well.

Matt: And as we learned from that first placebo control phase about the relationship between dose, so PKPD in terms of hunting mRNA and protein reduction in patients, we'll have the opportunity to titrate that dose if, in fact, there are any differences between what we observed in Phase I and what we observed in HD patients. In terms of design and data, you alluded to the 12-week placebo control phase. We said that we are looking to start that study before the end of the year.

Number.

I think what we'd be initially targeting is what we've said is the 30% to 50% of that to be able to get to that and the way we're thinking about this as well as probably.

Also thinking about taking advantage of some of them are the fact that we see a bit higher.

<unk> seen this year, so that gives us an opportunity to actually looked at a range of fruit.

Of doses, so Matt maybe I'll pass on to you.

Thinking on that.

Yeah, absolutely so.

Hey.

30 milligram dose was the dose that we used for the protein cohort as Steve said, it's really guide us to.

Matt: Those subjects will then roll over to a long-term extension where we'll be focusing on measuring changes in important biomarkers of disease, including the reduction in Huntington mRNA protein in the blood as well as in the CSF, and look at other important biomarkers of disease, including NFL, as well as volumetric changes on MRI. In terms of time into data, I think we'll have more. We will have more detailed information on time to results once we get the trial started, so we can give you more information on that in the future.

65% mrna and novel protein reduction.

We said all along we've been using the input some phase one which was the.

Blood mrna and protein reduction as well as plasma exposure in CSF exposure to come up with a range of dose levels that would put us into that 5% to 23.

30% to 50% range, which we believe will be somewhere target doses somewhere between five and 20.

We generally don't give out all the details of the.

Design until the protocol is up and running and we're ready to start. So we will have more specific information on that as we get closer but needless to say we will.

Matt: So sorry, just to clarify, Matt, would you would you intend to provide data after?

Matt: Do you want to share data after the placebo-controlled portion of the trial, or would you wait until the one-year crossover period completes?

We'll be leveraging the titrate the ability of the molecule and as we learn from that first placebo controlled phase.

The relationship between dose PK PD in terms of hunting Huntington mrna and protein reduction in patients will have the opportunity to titrate that dose. If in fact, there is any differences between what we observed in phase one and what we observed in HD patients.

Matt: I expect we'll share the data after the placebo control phase because that first part of the study is very important in terms of establishing the PK-PK relationship in Huntington's disease patients and will be very important in informing the dose level after the efficacy trial, whether that's done as a phase three, or we're able to take advantage of the accelerated approval pathway as post-marketing. So we do believe that this data set is very important.

In terms of the design and data.

Although the.

12 week placebo control phase.

We're looking at well plan to start that study before the end of the year. The subjects will then roll over into a long term extension, where we'll be focusing on measurable changes in important biomarkers of disease, including the reduction in Huntington mrna and protein in the blood as well as in the CSF and look at other important biomarkers of disease, including.

Danielle Brill: Okay, that makes sense. Thank you so much for clarifying.

Tazeen Ahmad: Thank you. Our next question comes from Tazeen Ahmad with Bank of America. Your line is open.

So as well as volumetric changes on MRI.

Tazeen Ahmad: Hi, good afternoon. Thanks for taking my questions. A question for you, Stu. How are you thinking about the TransLarna franchise in Europe? Specifically, given that it's a relatively mature product now, where do you see most of the new uptake coming from these days?

In terms of timing to data I think we'll have more.

More detailed information on time to our results once we get the trial started so we can give you more information on that in the future.

So sorry, just to clarify Matt would you would you intend to provide data after the placebo controlled portion or would you wait.

Tazeen Ahmad: And then I have a couple of follow-up questions. Yeah, sure.

Until the one year of crossover complete.

Unknown Executive: Yeah, sure. I think you're still seeing growth, which is predominantly new patients and geographic expansion which we're continuing to do, and it's been going quite well. Eric, why don't you go through what your team has been doing? [inaudible] Yeah, yeah, thanks, yeah, thanks, too.

Yes, I expect we will share the data after the placebo controlled phase because that first part of this study is very important in terms of establishing the PK PD relationship and Huntington's disease patients that will be very important.

The dose level for the efficacy trial, whether that's done is that a fair.

It is three or we're able to take advantage of the accelerated approval pathway as post marketing. So we do believe that that is that's very important.

Okay. It makes sense. Thank you so much for clarifying.

Eric: I'm sorry, can you hear me okay? Yeah, hi, Eric. Okay. Yeah. Hi, Tazeen. How are you?

Thank you. Our next question comes from <unk> with Bank of America. Your line is open.

Eric: Sorry, I'm having a few connection problems here. So, Tazeen, yeah. You know... Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah,

Hi, good afternoon, thanks for taking my questions.

A question for you still how are you thinking about.

The trends are in our franchise.

Europe.

Specifically given that it's a relatively mature product now where do you see most of the new uptake coming from these days and then I have a couple of follow up thanks.

Eric: So right now, a lot of our growth that we've seen this quarter has continued to come from

Yeah sure so.

I think youre seeing still growth.

Was it predominantly.

A new patient and geographic expansion, which will continue to do and it's been quite it's been growing quite well.

Eric: of the main markets. We're seeing very high compliance. We're also implementing a lot of dose adjustments as patients are getting, you know, older and heavier. And we're seeing growth in many of the main markets where we have been quite mature and have launched the product over these 5-6-7 years. But we're also seeing growth in other parts of Europe and in international markets. As I mentioned during the call, we have recently launched in Russia. And very quickly, we were able to get centralized reimbursement in Russia. And also, very quickly, a significant order came in for a group of patients. So that dynamic is quite interesting.

Eric wants to go through with the team has been good.

Sure.

Yeah, Yeah, yeah. Thanks Bruce.

I'm sorry can you hear me okay.

Yeah, Hi, Eric.

Yeah, Hi, this is dean how are you sorry, I'm, having a little connection problems here so to say.

Right now a lot of our growth that we've seen in the quarter as continues to come from a lot of the main markets. We're seeing very high compliance. We're also implementing a lot of dose adjustments as patients are getting.

Get older and heavier than.

And we're seeing growth in many of the main markets, where we have been quite mature.

We have launched the product over at least 567 years, but we're also seeing growth in other parts of Europe and other international markets as I mentioned.

During the call.

We have recently launched in Russia.

And very quickly we were able to get a centralized reimbursement in Russia and also very quickly a significant order came in for a group of patients. So that dynamic is quite interesting is it similar to Brazil. So.

unknown: [inaudible]

unknown: that we are seeing new patients that are coming in from areas in Central and Eastern Europe and Latin America and many others, many other areas. So the collective around Europe and internationally is extremely important.

Is there a large orders for a number of patients, which creates a little bit of lumpy revenues quarter over quarter, but what we see continued growth with trade in Florida is that patients are staying on drug for long periods of time.

unknown: And some of the tough pairs, even some pairs that we've had to fight with for a number of years, have

There are dosing with the Doc.

Dose there is long.

There are patients that we are seeing new patients that are coming in.

unknown: And then the number of less restrictions that are going on right now in terms of patients who go non-ambulatory, so physicians are making, if you will, a sort of risk-benefit decision before taking patients who are not off-drug before going non-ambulatory. So, if I had to actually look at it collectively...

In areas in central and Eastern Europe, and Latin America, and many others, but many other areas. So the collective route in Europe and international is extremely important and in some of the top players even some payers that we've had to fight with for a number of years have opened up and signed new agreements. So even smaller countries like that.

Otherwise in Finland.

Shown that they're willing to pay.

unknown: TransLarna is a combination of good patient compliance, dosage adjustments, geographic expansion, and particularly in key markets. And this quarter, clearly Russia and our main markets have really driven TransLarna in what is probably one of our strongest revenue quarters to date. Okay.

Which have been more restrictive in the pop.

And then there are there's obviously a lot of the label expansions that have occurred.

We had a label expansions for children.

Youre getting a two year and really broadening the number of eligible patients.

And then there are a number of less restrictions that are going on right now in terms of patients who go non ambulatory. So physicians are making if you will.

Sort of risk benefit decision before taking patients who are not off drug before non ambulatory. So if I had to actually look at it collectively it is a combination of good patient compliance dosage adjustments geographic expansion and particularly in key markets and this quarter.

Tazeen Ahmad: Okay, that was super detailed, and thank you for that. So, related to what you just said, the guidance and sales that you introduced today, would you say that's coming more from confidence in TransLarna or from uptake for MFLAZA? And then my last question, probably for Emily here, is can you just talk to us about your expense estimates? It looks like they're going lower relative to last year, and why is that? Thanks.

Clearly, Russia and our main market have really driven translarna in what is probably one of our strongest revenue quarter to date.

Okay that was super detailed and thank you for that so really related to what you just said.

The guidance in sales that you introduced today would you say that's coming more from confidence in trans larena or from uptake for <unk> Plaza and then my last question probably for Emily here is.

Can you just talk to us about your expense estimates it looks like they're falling lower relative to last year and why is that.

Unknown Executive: Sure. Okay. So, obviously, there's a lot of confidence, both TransLondon and Plaza, and they both have been growing it. So Eric, do you want to talk a little bit about the growth of both of those two?

Sure Okay. So.

Obviously, there's a lot of confidence in.

Both trends, London Plaza and they both have been growing it. So Eric you want to talk a little bit about growth of both of those two.

Eric: Yeah, absolutely. I mean, we saw 22% core growth within PLAZA.

Yeah, absolutely I mean, we saw 22%.

Emily Luisa Hill: Continued geographic expansion, particularly in Russia, has been

Quarter over quarter growth with some plaza.

Eric: I earnt $1,000,000 in the quarter.

$47 million in the quarter, we've seen that.

unknown: We've seen that as, again, a combination of different things, but primarily, again, very high compliance. We've also been working on dose adjustments, and we minimized dropouts.

Emily Luisa Hill: Year-over-year MFLAZA revenue is also up this quarter, with net product revenue of $4.2 billion.

Yeah, again, a combination of different things, but primarily again very high compliance.

Emily Luisa Hill: 37.1 million, compared to over 38.5 million in the third quarter of 2020.

Emily Luisa Hill: This has primarily been driven by better compliance and new prescriptions starting. Due to this strong performance, we have raised revenue guidance for the DMD franchise to $400 to $420 million, from $370 to $390 million. Turning now to Evrizdi, where our partner Roche has reported year-to-date revenue of 396 million Swiss francs, resulting in 33.3 million in year-to-date royalties to PTC. Royalties to PTC for the third quarter were $13.1 million. As a reminder, PTC also retains sales-based cash milestones, and the $10 million milestone payment for the first commercial sale in Japan was received by PTC.

Emily Luisa Hill: Non-GAAP R&D expenses were $117.8 million for the third quarter of 2021, excluding $13 million in non-cash stock-based compensation expenses, compared to $83.8 million for the third quarter of 2020, excluding $9.2 million in non-cash stock-based compensation expenses.

Emily Luisa Hill: Non-GAAP SG&A expenses were $56.4 million.

Emily Luisa Hill: 2020, excluding $7.6 million in non-cash stock-based compensation. We have lowered and narrowed the range of our non-GAAP R&D and SG&A expense for the full year 2021 to $715 to $735 million, from $725 to $755 million. Cash, cash equivalents, and marketable securities totaled $867.9 million as of September 30, 2021, compared to $1.1 billion as of December 31, 2020.

Emily Luisa Hill: for the third quarter of 2021, excluding $12.8 million in non-

Emily Luisa Hill: I will now turn the call over to the operator for Q&A.

Operator: Thank you. As a reminder, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key.

Emily Luisa Hill: Non-cash, stock-based compensation expense

We've been also working on dose adjustment.

Emily Luisa Hill: Compared to $50.3 million for the third quarter,

Eric William Joseph: Please stand by while we compile the Q&A roster. Our first question comes from Eric Joseph with JP Morgan. Your line is open. Hi, good afternoon. This is Hannah on for Eric. Thanks for taking the question.

Hannah Temiloluwa Adeoye: PTC 299, the FITE-19 COVID-19 study, just wondering if you're able to talk about powering assumptions for your primary endpoint of time-to-respiratory improvement and maybe what some of the entry criteria are as it relates to prior vaccine exposure or COVID-19 seropositivity. Sure. Okay, I'll start with the...

We've minimized dropouts, but we've also seen a lot of new patients from.

Eric: But we've also seen a lot of new patients that have gone on to EMPLASA. Not only new patients who are naive, but many patients who are switching based on a number of key publications and scientific data now, and, of course, the experience that we've generated that shows that EMPLASA is superior to prednisone. So we see a lot of those tailwinds of EMPLASA continuing as the base of patients grows with EMPLASA. For TransLerna, I think we are equally confident based on the things that I mentioned.

Unknown Executive: The Oral Splicing, I think that's the splicing one, and the platform is what we've been talking about in terms of the splicing that, you know, it's really quite interesting that we, you know, we've been able to build an informatics program that allows us to identify But we've always been interested in the ability to be able to produce the expression of these using our technologies so that we can So I think that it's being used quite well.

Unknown Executive: In the case of 299 and Site 19, I'll pass that over to either Matt or Kylie on that one. I have a question about the FITE-19 trial code. As you mentioned, our primary endpoint in that trial is Time to Sustain Respiratory Improvement, which is defined as an oxygen saturation of 94% on remair, which is sustained until discharge from the hospital or the end of the study, which is day 28. Basically, the powering assumptions here were based on an estimation of median time to respiratory improvement in the placebo group, which we've taken, which is based on existing data, which was roughly 11 days, and then we had a hypothesized treatment effect, and then basically looked at a hazard ratio of about 1.38, you know, a two-sided type one error, which got us to our sample size of 380 subjects, which we believe In terms of your question regarding the vaccination, we don't have any criteria that include or exclude that previous vaccination, or nothing that relates to seropositive.

That have gone to a plaza not only new patients who are naive, but many patients who are switching based on a number of key publications and scientific data now and of course the experience that we've generated that shows that in plaza.

Unknown Executive: Okay, great. Thanks for taking the question.

Superior to prednisone, so we see a lot of those tailwind to the plaza continuing at the base of patients is growing within plaza per trans learn I think we're equally confident based on the things that I mentioned.

Danielle Catherine Brill Bongero: Thank you. The next question comes from Danielle Brew with Raymond James. Your line is open. Hi guys. Good afternoon. Thanks so much for the questions. I guess first on the doses for Phase 2, the 518 study. I'm presuming 30 mg will be one of the two doses you're thinking of using. Are you contemplating going higher or lower for the second dose? And then do you think it's reasonable to assume we may have data, 12-week data next year? Yeah, maybe I'll start in the...

Unknown Executive: Yeah, maybe I'll start and then I'll pass it on to Matt. You might remember that we did a phase one study where we did a 15 and 30 milligram dose, and we saw in the 30 milligram dose up to 65% of the RNA that was reduced, and we would anticipate that at steady state, the protein levels would go down as numbers. I think what we'd be initially targeting is what we've said is the 30 to 50 percent of that to be able to get to that, and the way we're thinking about this as well as probably also thinking about taking advantage of some of the fact that we see a bit higher levels in the CFF so that gives us really an opportunity to actually look at a range of doses. So Matt, maybe I'll pass on to you to give the thinking Yeah, absolutely.

Matt: Okay, that makes sense. Thank you so much for clarifying. Our next question comes from Tazeen Ahmad with Bank of America. Your line is open. Hi, good afternoon. Thanks for taking my questions. I have a question for you, Stu. How are you thinking about the TransLarna franchise in Europe? Specifically, given that it's a relatively mature product now, where do you see most of the new uptake coming from these days? And then I have a couple of follow-ups. Thanks.

Matt: So, the 30 milligram dose was the dose that we used for the protein cohort, as Stu said, which really got us to and the 65% mRNA and model protein reduction. And again, as Keith said all along, we've been using the inputs from phase one, which was. Blood mRNA and Protein Reduction as well as Plasma Exposure and CSF Exposure to come up with a range of dose levels that would put us in that 5 to 20, sorry, 30 to 50 percent range, which we believe will be somewhere, target doses, somewhere between 5 and 20.

Matt: And as we learn from that first placebo control phase about the relationship between dose PKPD in terms of hunting mRNA and protein reduction in patients, we'll have the opportunity to titrate that dose if, in fact, there are any differences between what we observed in Phase I and what we observed in HD patients. In terms of design and data, you alluded to the 12-week placebo control phase. We say that we are looking to start that study before the end of the year.

Matt: Those subjects will then roll over to a long-term extension where we'll be focusing on measuring changes in important biomarkers of disease, including the reduction in Huntington mRNA and protein in the blood, as well as in the CSF, and look at other important biomarkers, including NFL as well as volumetric changes on MRI. In terms of time to data, I think we'll have more. We will have more detailed information on time to results once we get the trial started, so we can give you more information on that in the future.

Matt: So, sorry, just to clarify, Matt, would you intend to provide data after the placebo-controlled portion, or would you wait until the one-year crossover completes?

Danielle Brill: I expect we'll share the data after the placebo control phase because that first part of the study is very important in terms of establishing the PK-PK relationship in Huntington's disease patients and will be very important in informing the dose level after the efficacy trial, whether that's done as a phase 3 or we're able to take advantage of the accelerated approval pathway as a post-marketing. So we do believe that this data set is very important. We'll share it with you.

Eric: And we're looking forward to continued geographic expansion. Keep in mind, all the work that we did over the last probably year, year and a half to expand in many of these markets is paying off. And we've continued those investments in Asia Pacific and also in other places in Latin America, and we expect those to continue to provide us growth. So overall, I think we're very confident.

We're looking forward to continued geographic expansion keep in mind all of the work that we did over the last probably a year year and a half to expand in many of these markets is paying off and we continue those investments in Asia Pacific and also in other places in Latin America, and we expect those to continue to provide us growth. So overall I think we are.

Very confident.

Okay.

No.

And then this is Emily to Zane when it comes to your Opex question.

Alicia Young: Thank you. The next question comes from Alicia Young with Cantor Fitzgerald.

Tazeen Ahmad: Yeah, sure. I think you're still seeing growth, which is predominantly new patients and geographic expansion, which we're continuing to do, and it's been quite, it's been going quite well.

Helpful. Thank you.

Thank you. Our next question comes from Alicia Young with Cantor Fitzgerald.

Nina: Hi, thanks for taking our questions and congrats on all the progress. This is Nina on behalf of Aletheia.

Your line is open hi.

Hi, Thanks for taking our questions and congrats on all the progress this is neena on for Alethia.

Nina: We are wondering what gives you confidence in the MI-E readout in the third quarter of 2022? And how do you think of risk for that trial? And also another one. We are curious how you were planning to update us on the FDA.

We're wondering what gives you confidence and then might E readout in the third quarter of 2022, and how do you think for that trial.

Unknown Executive: Eric, why don't you go through what your team has been doing? Unknown Attendee. Unknown Speaker. Yes, sure. Yeah, yeah, thank you.

And also another one.

We were curious how you're planning to update us on the FDA feedback for the phase two PTC 508 trial next year. Thanks.

unknown: Please send in FDA feedback for the Phase 2 PTC518 trial next year.

Matt: Sure. There might be. Matt, you want to go through that? Yeah, absolutely.

Sure there might be Matt do you want to go through that.

Eric: I'm sorry, can you hear me okay? Yeah, hi, Eric. Okay. Yeah. Hi, Tazeen. How are you? Sorry, I'm having a little connection problems here. So, Tazeen, yeah.

Yeah, absolutely that's our sort of might be trial is the.

Matt: That's our Mighty Trial is the Registration-Directed Trial in Children with Mitochondrial Disease-Associated Seizures. And as we've talked a bit about before, this is a highly morbid and severe symptom of mitochondrial disease that occurs across many different disease subtypes. And so the trial, this Phase 2-3 trial, is really constructed based on a number of mechanistic data as well as previous clinical data we have in the treatment of mitochondrial disease children with seizures who have a variety of different genotypes and phenotypes.

Registration directed for island children with mitochondrial disease associated seizures, and we will see.

Talk a bit about before this is a highly morbid.

Severe symptomatic.

That occurs across many different disease subtypes and so the trial.

<unk> phase III trial is really constructed based upon a number of mechanistic.

Data as well as previous clinical data, we have in the treatment of mitochondrial disease children with seizures, who have a variety of different genotype and phenotype.

Matt: And so, what we've been able to demonstrate in our previous studies is that we are able to reduce seizure frequency, reduce the occurrence and arrest the occurrence of status epilepticus, which is the condition of continued seizures in one specific subtype of mitochondrial epilepsy. And we have also been able to demonstrate that we can reduce disease-related hospitalizations in that cohort. The children, on average, had 52 days in the hospital over the course of a year. That was reduced to zero days in the hospital the following two and three years on therapy.

And so what we've been able to demonstrate our previous studies is that we are able to reduce seizure frequency reduce.

The occurrence and arrest the occurrence of status epilepticus, which is the condition of continued seizures in one specific subtype of mitochondrial epilepsy, we've been able to demonstrate that we can reduce disease related hospitalization in that cohort. The children on averaged 52 days in the hospital over the course.

The year over year that was reduced to zero days in the hospital following two or three years on therapy and in that cohort. We were also able to demonstrate and mortality benefit. So when we looked across not only that one subtype again across all the different subtypes of treated and you've been able to demonstrate that we're able to affect seizure frequency and tissue related.

Matt: And in that cohort, we were also able to demonstrate a mortality benefit. So when we looked across not only that one subtype, but across all the different subtypes we've treated, we were able to demonstrate that we're able to affect seizure frequency and seizure-related morbidity in these children. And again, the fact that the ticrinone target, the 15-lipoxygenase enzyme, and the oxidative stress response pathway that is common to the disease pathology regardless of the underlying genotype and phenotype gives us further confidence that we're able to demonstrate the treatment benefit across the whole family of mitochondrial disorders, again, independent of the specific mutation.

These children and again, the fact that particularly our targets.

<unk> 15, lipoxygenase enzyme and the oxidative stress response pathway that is common to the disease pathology, regardless of the underlying genotype phenotype is what gives us further confidence that we are able to demonstrate the treatment benefit across the whole family of my apologize disorders, Okay independent of the specific mutation.

Eric: Right now, a lot of our growth that we've seen in

Operator: Transcripts provided by Transcription Outsourcing, LLC.

Operator: We're seeing very high compliance. We're also implementing a lot of dose adjustments.

Eric: for more information., and we are seeing growth in many of the main markets where we have been quite mature and have launched the product for at least 5, 6, 7 years. But we are also seeing growth in other parts of Europe and in international markets. As I mentioned during the call, we recently launched in Russia, and very quickly, we were able to get centralized reimbursement in Russia.

Eric: and also, very quickly, a significant order came in for a group of patients, so that dynamic is quite interesting.

Operator: Transcripts provided by Transcription Outsourcing, LLC.

Eric: It's their large orders for a number of patients, which creates a little bit of a lumpy.

So that trials enrolling 60 children it centers around the world, we've been able to work closely with our global network.

And close relationships with patient conditions around the world that we've been able to develop over the course of many years.

Eric: Revenues Quarter Over Quarter, but what we see continued growth with TransLarna is that patients are staying on drugs for long periods of time. They're adjusting with the dose. There is long, there are patients.

We are moving forward with enrollment in that trial and as we said expecting the data data and results in the third quarter of 2022.

Eric: that we are seeing new patients that are coming in from areas in Central and Eastern Europe and Latin America and many others, many other areas.

Eric: Collective action around Europe and internationally is extremely important.

I missed the second part of your question. If you could just repeat it related to that trial.

unknown: Just how do you think about the risks for that trial? Yeah, so I obviously

Just how do you think about risks for that child.

Yes, so I think obviously in constructing the trial, we leveraged our many years of experience in doing trials in children with mitochondrial disease I think when you talk about mitochondrial diseases. One of the biggest challenge in St. Drug development is a heterogeneity in disease not only heterogeneity in genotype, but also heterogeneity in genotype peanuts.

unknown: Yes, I think, obviously, in constructing this trial, we leveraged our many years of experience in doing trials in children with mitochondrial disease, and I think when you talk about mitochondrial disease, one of the biggest challenges in drug development is the heterogeneity of not only heterogeneity and genotype but also heterogeneity and the genotype-phenotype relationship. And so we took that into careful consideration in designing this trial. And to overcome that, we are again pleased that we're focused on a symptom that's common to all of these different subtypes.

Type relationship and so we took that into careful consideration in designing this trial and to overcome that we again.

Eric: And some of the tough pairs, even some pairs that we've had to fight with for a number of years, have

Eric: Opened up and signed new agreements. So even smaller countries like the Netherlands and Finland have shown that they're willing now to pay, which has been more restrictive in the past. And then there's obviously a lot of label expansion.

Eric: that have occurred. We have label expansions for children at the beginning of two years, really broadening the number of eligible patients.

Eric: And then the number of less restrictions that are going on right now in terms of patients who

We are pleased that we're focused on a symptom that is common to all of these different subtypes. So we don't have to worry about different constellation of symptoms. We know that all the children in the trial had the symptoms theaters and we're also employing a strategy that has been used in several successful approval trials for pediatric epilepsy syndrome, that's utilizing a running phase II.

unknown: So we don't have to worry about different constellations of symptoms. We know that all the children in the trial have symptoms and seizures, and we're also employing a strategy that's been used in several successful approval trials for pediatric epilepsy syndromes. That's utilizing a run-in phase to ensure a minimum frequency of seizures, and then having the subsequent parallel arm only enroll those children who meet that threshold. In addition, we're stratifying the randomization for the most common subtypes to ensure balance across both the placental and the control group. And we think all of those are very good measures at addressing what we know could be potential risks in the design of that trial.

Sure a minimum frequency of seizures, and then having subsequent parallel arm only enrolling those children.

Operator: https://www.patreon.com

That threshold.

<unk> to account for any heterogeneity that might still come into play where stratify randomization code. The most common subtype. So we ensure balance across both the placebo and the control group.

Operator: Let's look at it collectively.

I think all of those are very good measures.

By addressing what we know could be potential risks in the design of that trial.

unknown: Got it. Thank you. And I guess for the second question, just how do you

Got it thank you.

And I guess for the second question just how do you plan on updating us on the FDA feedback for the phase two trial for PTC 518 next year.

unknown: Question: just how do you plan on updating us on FDA feedback for the phase two trial for PTC 518 next year?

Eric: [inaudible] Okay, that was super.

Tazeen Ahmad: Okay, that was super detailed, and thank you for that.

Tazeen Ahmad: The confidence in sales that you introduced today, would you say that's coming more from confidence in TransLarna or from uptake for MFLA?

So I think what we'll be doing this.

Emily Luisa Hill: And then my last question, probably for Emily here, is, can you just tell us a little bit about the work that you've been doing in the last couple of years?

Obviously once we initiate the trial will be telling you.

Operator: Transcription by CastingWords

Unknown Executive: Sure, okay, so obviously there's a lot of confidence, both Trans London and Plaza, and they both have been growing it. So Eric, you want to talk a little bit about the growth of those two?

Well, we'll look to grow we will let everyone know and also after we.

We get the results after the 12 weeks, where you would actually talked about that as well.

unknown: Okay, thank you. That was helpful.

Eric: Yeah, absolutely. I mean, we saw 22%.

Unknown Attendee: Thank you. Our next question comes from Raju Prasad with William Blair. Your line is open.

Eric: I mean, we've got $47 million in the quarter. We've seen that.

Okay. Thank you that was helpful.

Eric: and again, a combination of different things, but primarily again, very high compliance. We've also been working on dose adjustments.

No.

Thank you. Our next question comes from Rajiv Prasad with William Blair. Your line is open.

Unknown Executive: Thanks for taking the question. I know you guys recently opened the gene therapy facility. Can you talk a little bit about your plans for scaling it up with, obviously, the ADT program, as well as some of the follow-on gene therapy programs, kind of getting a sense of, you know, what type of scale you'll have and GMP compliance and things of that nature? Yeah, sure.

Thanks for taking the question I know you guys recently opened the gene therapy facility and can you talk a little bit about your plans with scaling it up with.

They do see program as well as some of the follow on gene therapy program, just kind of getting a sense of what type of scale youll have in GMP.

Compliance and things of that nature.

Yeah sure in terms of compliance and if the if a fully operating facility we have.

We have about 220000 square feet of both suites.

Where we can.

Grow.

Repair.

Unknown Executive: In terms of compliance, and it's a fully operating facility, we had, you know, we have about 220,000 square feet of both. We've been doing a lot of the preparation of our own plasmids in-house, but also preparation of all the viral vector that's required to do that. And we have all of the manufacturing capabilities to do that in-house, as well as all the quality and analytical equipment to be able to perform those as well.

<unk> vector as well as the ability to do both TMT.

Eric: We've minimized dropouts, but we've also seen a lot of new patients that have gone on to EMPLASA, not only new patients who are naive but many patients who are switching.

Eric: Based on a number of publications and scientific data now, and, of course, the experience that

Eric: TransLerna is a new program that we've just generated that shows that emploza is superior to prednisone. So we see a lot of those tailwinds of emploza continuing as the base of patients grows with emploza. For TransLerna, I think we are equally confident based on the things that I mentioned, and we're looking forward to continued geographic expansion. Keep in mind, all the work that we did over the last probably year, year and a half to expand in many of these markets is paying off, and we've continued to do that.

Operator: https://www.patreon.com

Alicia Young: Hi, thanks for taking our questions and congrats on all the progress. This is Nenon for Aletheia.

Emily Luisa Hill: And then this is Emily Tazeen. When it comes to your OPEX question, I think it's really just a result of 2021 being a full year impact of COVID versus 2020. So obviously, we greatly reduced our travel expenses, and then Eric's team has very successfully transitioned to holding most of their physician seminars and consortiums virtually. Helpful, thank you. Thank you. Our next question comes from Alicia Young with Cant

Plasmids as well in that matter and so we built the team is now fully capable of not only.

Preparation of our own plasma in house, but also preparation.

Overall, the bulk of viral vector that's required to do that and we have all of the manufacturing capabilities to do that in house as.

As well as all the.

Quality and analytical.

We're able to perform those as well so that's all.

Unknown Executive: So that's all being done, and we've been doing it for our other programs that are going on, like what we've talked about for FA, as well as for Angelman Syndrome and others as well. So the team's capable of doing that both in a GMP manner, can do it from 30 liters to a 1,000-liter facility, and make the plasmids as well. We've also been, as I said, and I think I've talked about in the past, We'll be doing it for external, potential external customers. We don't anticipate yet that we'll be, you know, it'll take a little bit of time to be fully functional.

Being done and we've been doing this for our other programs that are going on.

Like what we've talked about for <unk> as well as for.

Angelman syndrome, and others as well.

The team is capable of doing that both synergy.

You can do it from 30 liters to 1000 liter facility.

Well, we've also been as I said and I think I've talked about in the past.

We'll be doing it.

Matt: Registration-Directed Trial in Children with Mitochondrial Disease-Associated Seizures. And as we talked a bit about before, this is a highly morbid and severe symptom of mitochondrial disease that occurs across many different other disease subtypes.

No.

Unknown Executive: Sure. There might be some, Matt. Would you want to go through that?

Potential external customers, we don't anticipate yet will be.

Matt: Absolutely. That's what our Mighty Trial is the...

It will take a little bit time to be fully functional and probably use some of.

Unknown Executive: And so we'll use some of the extra space we have to be able to bring in potential customers, especially with classes where, you know, in a sense, we'll be able to bring in not only work through that but also be able to bring in revenue as well. So the system itself is now all set up, the site is all up and running, capable of making both plasmids and DNA. And we've been making both vectors as well as plasmids now, and we're confident we can do this. And so we're going to be doing, fulfilling all the needs we have as we grow and do more and more, and then also be able to have some customers on the outside. Great

Yeah.

Extra space, we have to be able to bring in court.

Bring in potential customers and especially with Plaza.

And our sense of opening up.

Matt: And so the trial, this Phase 2-3 trial, is really constructed based on a number of mechanistic data as well as previous clinical data we have in the treatment of mitochondrial disease children with seizures who have a variety of different genotypes and phenotypes. And so what we've been able to demonstrate in our previous studies is that we are able to reduce seizure frequency, reduce the occurrence, and arrest the occurrence of status epilepticus, which is the condition of continued seizures.

Matt: In one specific subtype of mitochondrial epilepsy, we've been able to demonstrate that we can reduce disease-related hospitalizations. In that cohort, the children, on average, had 52 days in the hospital over the course of a year. That was reduced to zero days in the hospital following two and three years on therapy.

Bring them not only.

Matt: And in that cohort, we were also able to demonstrate mortality benefits. So when we looked across not only that one subtype, but again, across all the different subtypes we've treated, we were able to demonstrate that we're able to affect seizure frequency and seizure-related morbidity in these children. And again, the fact that the Tick-Borne Target, the 15-life oxygenase enzyme, and the oxidative stress response pathway that is common to the disease pathology regardless of the underlying genotype and phenotype gives us further confidence that we're able to demonstrate the treatment benefit across the whole family of mitochondrial disorders, again, independent of the specific mutation.

Work through that but also being able to.

Bring in revenue as well so the system itself is now.

The site is all up and running capable of making both plasma from DNA.

And we've been making both vectors as well as plasma now and we're confident we can do this and so we're going to be doing.

So all of the needs, we have as we grow into more and more.

And then also being able to have some customers on the outside.

Unknown Executive: And with regard to affinity, I may have missed this, but do you have a sense of the number of patients that you're going to try and enroll in the arms? And just given kind of the penetration of generic Kuvan into the market, just wondering if you think the delta that you've seen in phase two, if you recapitulate that, do you think that'll be enough to convert most patients over, or do you think that you'll need kind of a bigger effect, or you're going to go into Kuvan failures? Just kind of curious to know the strategy based on what you may see in the registration trial. Thanks.

Great and with regards to affinity I may have missed this but do you have a sense of the number of patients that you're trying to enroll in the arms and just given kind of the.

The penetration of generic Kuban into the market.

Nina: Just how do you think about the risks for that trial? Yeah, so I obviously

Just wondering if you think the delta that you've seen kind of the phase III recapitulate that you think that'll be enough to.

Matt: Yes, I think obviously, in constructing this trial, we leveraged our many years of experience in doing trials in children with mitochondrial disease, and I think when you talk about mitochondrial disease, one of the biggest challenges in drug development is the heterogeneity of not only heterogeneity and genotype but also heterogeneity and the genotype-phenotype relationship. And so we took that into careful consideration in designing this trial. And to overcome that, we are, again, pleased that we're focused on a symptom that's common to all of these different subtypes.

Matt: So we don't have to worry about different constellations of symptoms. We know that all the children in the trial have symptoms and seizures, and we're also employing a strategy that has been used in several successful approval trials for pediatric epilepsy syndromes. That's utilizing a run-in phase to ensure a minimum frequency of seizures, and then having a subsequent parallel arm, only enrolling those children who meet that threshold. In addition, to account for any heterogeneity that might still come into play, we're stratifying the randomization for the most common subtypes so we ensure balance across both the placental and the control group. And we think all those are very good measures at addressing what we know could be potential risks in the design of that trial.

Convert most patients over or do you think that youll need kind of a bigger effect or you kind of go into Kuban failures, just kind of curious another strategy based on.

Nina: Got it. Thank you. And, for the second question, just how do you plan on updating us on FDA feedback for the phase two trial for PTC 518 next year?

What you may see in the registration trial.

Unknown Executive: Yeah, so I think that's an excellent point and that while there are a large number of patients, there are patients that have been on QVAN and have failed or have never shown any improvement on it. So there are a large number of patients where QVAN doesn't work. Adieu.

Yeah, no. So I think that's an excellent point that while there is a large number of patients both patients.

Unknown Executive: So I think what we'll be doing is, obviously, once we initiate the trial, we'll be telling you, we'll let everyone know, and also after we get the results after 12 weeks, we will actually talk about that as well.

That had been on programming.

And failed or have never shown any.

Improvement on it so there's a large number of patients.

We are proven doesn't.

Do well.

Unknown Executive: Wow. So, we don't think even with the generic that it's going to be a problem to be able to bring in enough patients to do this. We're targeting about 80 patients for the primary analysis cohort. You know, obviously, just to remind everyone, we'll have a run-in for that, so we'll know people will be responsive to it, so it's already set up, I think, for a high chance of success. We've enriched the study population of patients who respond to it, and just to remind everybody, we had done a previous trial. And I think it's obviously better we view this as really quite a significant opportunity.

Nina: Okay, thank you. That was great.

For patients. So we don't think even with the generic that it's going to be a problem to bring it in.

Operator: Thank you. Our next question comes from Raju Prasad with William Blair. Your line is open.

To be able to bring in enough patients to do this we're targeting about 80 patients for the primary analysis cohort.

Obviously, just to remind everyone will have a run in for that so we'll know people will.

Responsive to it so it's already set up I think for a high chance of success.

We've been rich the study population.

Patients who are.

Unknown Executive: Yeah, sure. In terms of compliance, it's a fully operational facility. We have about 220,000 square feet of both. [inaudible] [inaudible] on, like what we've talked about for FA, as well as for Angelman Syndrome and others as well. So the team's capable of doing that both in a GMP manner, can do it from 30 liters to 1,000 liters of facility, and make the plasmids as well. We've also been, as I said, and I think I've talked about in the past.

Who respond to that and just to remind everybody.

We had done a preview.

These two studies.

Directly comparing.

Kuban too.

Two two through our through our drug and so.

And I think what we've shown is that we see a higher number of <unk>.

So patients about 50% more responders and they had a greater effect.

Reducing phenylalanine.

And we saw.

Patients on <unk>, So we think.

Obviously, better we view this look really.

Quite a significant opportunity.

Unknown Executive: You know, really, if you think about it, it's a very well-defined patient population. There are newborn screening centers of excellence. The pathway to approval is well-known. It's a blood-based biomarker where you can measure phenylalanine and a large number of patients, many of them are in need of improvement by a better drug.

Really if you think about it's a very well defined patient population with newborn screening centers of excellence.

Uh huh.

The pathway to approval is well known.

Blood based biomarker, where you can bet your phenylalanine and a large number of patients.

And with many of them are need for improvement of our better.

Unknown Executive: So we're excited about this, and we think that there's obviously going to be increasing success because we have a run in the responder analysis, in the affinity study. So in our view, there is a very high amount of medical need in PKU, as the majority of patients remain untreated and are not well controlled, even though there are two commercial products that are available.

A better drug so we're excited about that.

Think that does obviously, we'll see increasing fits that bill.

Because we have a run in in the responder analysis.

On the affinity study.

Unknown Executive: We'll be doing it for external, potential external customers. We don't anticipate yet that we'll be, you know, it will take a little bit of time to be fully functional. And so we'll use some of the extra space we have to be able to bring in potential customers, especially with classes where, you know, in a sense, we'll be able to bring in not only work through that but also be able to bring in revenue as well.

In our view, there's a very high unmet medical need.

<unk>.

As the majority of patients remain untreated and are not well controlled control, even though there are two.

Commercial products that are available. So we think this is a significant opportunity.

Unknown Executive: So we think this is a significant opportunity. Great, thank you. Thank you. Our next question comes from Brian Abrams with Ardapital Markets. Your line is, Hi, this is Steve. I'm for Brian. Thanks for taking our call.

Great. Thank you.

Thank you. Our next question comes from Brian Abrams with our capital markets. Your line is open.

Hi, This is Steve on for Brian. Thanks for taking our question on 515 and building off an earlier question I'm curious can you speak a bit more on what you might have to show for safety. There. How long you might have to follow patients for a potential accelerated approval and if you looked at differences in transcriptome transcriptome or protium caused by five to 18 in preclinical models or clinical tissue.

Unknown Executive: So the system itself is now all, the site is all up and running, capable of making both plasmids and DNA. And we've been making both vectors as well as plasmids now, and we're confident we can do this. And so we're going to be fulfilling all the needs we have as we grow and do more and more. And then also be able to have some customers on the outside.

Brian Corey Abrahams: Thank you. Our next question comes from Brian Abrams with Arby's Capital Markets. Your line is open.

Comparing healthy in Huntington samples and does that hinted at any possible differences in safety.

Unknown Executive: Yeah. So we make a couple of points. One is obviously safety, which is usually dependent upon both how it does in patients as well as safety toxicology. See that I will say that these molecules are highly selective molecules. And I think we spend a lot, and I think that's really a differentiating factor for us.

Yes.

Unknown Attendee: Great. And with regards to affinity, I may have missed this, but do you have a sense of the number of patients that you're going to try and enroll in the arms and just given kind of the penetration of generic Kuvan into the market, just wondering if you think the delta that you've seen kind of phase two, if you recapitulate that, do you think that'll be enough to, you know, convert most patients over or do you think that you'll need kind of a bigger effect or, you know, you're going to go into Kuvan failures, just kind of curious to know the strategy based on, you know, what you may see in the registration trial?

So we.

I'll make a couple of points. One is obviously safety is usually dependent upon folks you know how it doesn't patients relative to something you talked about call. It.

I will say that these molecules.

Our highly selective molecule.

And I think we spend a lot of and I think that's really a differentiating factor for us. It's an orally bio available small molecule, where we really worked on that have selectivity and specificity.

Unknown Executive: It's an orally bioavailable small molecule that we really worked on to have selectivity and specificity of 518 so that it's very highly specific for HTT and for that particular U1 site. And so obviously, what we're going to do is we'll review the results. In terms of, you know, safety, we'll be following that. And what we're going to be doing is, in the placebo-controlled study, we'll review the results of the phase two study to see how patients do in terms of the levels of reduction within the blood of HTT RNA and protein and the levels that change within the CSS as well.

Oh God.

So that is very highly specific for.

H T T and for that particular, you one site.

Unknown Executive: Yeah, so I think that's an excellent point and that while there are a large number of patients, there are patients that have been on Cruven and have failed or have never shown any improvement on it. So there's a large number of patients where Cruven doesn't do well. So, we don't think, even with the generic, that it's going to be a problem to be able to bring in enough patients to do this.

And so obviously, what we're gonna do is we'll review the results.

In terms of the safety will be following that and what we're gonna be doing local people control that'd be well review the results from the phase two study.

Let's see how patients do in terms of the level of book.

Duction both the blood.

The club E T T auditing of protein in the levels of change within <unk>.

TSS as well and we'll be monitoring a number of others.

Unknown Executive: And we'll be monitoring a number of other biomarkers as well. And then to your question of potential accelerated approval, that's why we are actually going beyond the 12 weeks following that they transition on to an open-label study in which they'll be on for a total of 15 months, and that gives long-term safety as a consequence of that. So we think if there's a potential for an accelerated approval, what we're interested in is that we'll have not only the HTT RNA and protein levels but other biomarkers as well.

Unknown Executive: We're targeting about 80 patients for the primary analysis cohort. You know, obviously, just to remind everyone, we'll have a run-in for that, so we'll know people will be responsive to it, so it's already set up, I think, for a high chance of success.

Of other Biomarkers as well and then to your question a potential accelerated approval that's why we.

Why we're actually going beyond the 12.

<unk> weeks.

Unknown Executive: We've enriched the study population of patients who respond to it, and just to remind everybody, we had done a previous... And I think that's a really good example of how we can use these things to study, directly comparing Kuven to our drug. And I think what we've shown is that we see a higher number of patients, about 50% more, who responded to reducing phenylalanine than we saw with Kuven.

Following that as they transition on to an open label study for <unk>.

And we're still be on for a total of 15 months to make the long term.

Safety is a consequence of that so we think if theres a potential for an accelerated approval on what we're interested in that but we will have not only the looking at the.

H T T.

RNA and protein levels, but other biomarkers as well.

And so.

Unknown Executive: And so what we've found in the transcriptome, yeah, we looked in a lot of cells, and we saw that at concentrations I see, we see really only very few changes in gene expression or in alternative splicing.

What we found in the transcriptome, Yeah, we've looked at a lot of.

So can we see there.

Unknown Executive: So we think it's obviously better. We view this as really quite a significant opportunity. You know, really, if you think about it, it's a very well-defined patient population. There are newborn screening centers of excellence. You know, the pathway to approval is well known. It's a blood-based biomarker where you can measure phenylalanine.

That at the concentrations.

I see we see really only very few chain.

Changes in gene expression or an alternative or slightly so it's highly selective and specific.

Elaine: So it's highly selective and specific. Great Thanks for that. It was really helpful. I appreciate it. Thank you. Our next question comes from Elaine with Barclays. Hi, this is Sheldon from TINA. Thanks for taking our questions. We have maybe two questions. First, congrats on the promotion.

Great. Thanks for that really helpful. I appreciate it.

Thank you. Our next question comes from the Wang with Barclays. Your line is open.

Hi, This is Michel and Al Pacino. Thanks for taking my question well, we have maybe two questions. So first congrats on that.

Unknown Executive: And a large number of patients, many of them are in need of improvement on a better drug. So we're excited about this. And then we think that, obviously, we'll see increasing success because we have a run in the responder analysis, in the Affinity Study. So, in our view, there is a very high amount of medical need in PKU, you know, as the majority of patients remain untreated and are not well controlled, even though there are two commercial products that are available. So we think this is a significant opportunity.

On a good quarter.

Could you frame for us how long.

The Brazilian order and also the Russian launch contribution in Q3 number and.

And how should we think about the going forward run rate.

Huidong Wang: Thank you. Our next question comes from Huidong Wang with Barclays. Your line is open.

And the next question is about <unk>.

<unk> phase II trial have you got any feedback from FDA on what Biomarkers will be themes.

Good predictor of clinical benefits.

Unknown Executive: Yeah, sure. So, obviously, in terms of the FDA for Huntington's disease, we have not yet talked to them about the biomarkers. Clearly, it's important, we think, so we will be measuring the biomarkers of both RNA and protein in blood as well as, Unknown Speaker, Unknown Attendee, Unknown Attendee, Unknown Attendee, Unknown Attendee, [inaudible] In terms of lower levels delaying the progression of the disease, you're in a pretty good spot. Unknown Attendee, And that's coupled Preservation of Brain Volume, and others.

Thanks.

Yeah sure so.

Obviously in terms of.

V F D a R.

For Huntington's disease.

Given that you have talked to them on the Biomarkers clearly, it's important and we think so we will be measuring the biomarkers are both RNA and protein in blood as well with the changeover in Huntington protein in the CSF and then other biomarkers like neuro fill them out and then we'll be looking at the other.

Operator: Thank you. Our next question comes from Brian Abrams with Ard Capital Markets. Your line is open. Hi, this is Steve. I'm on behalf of Brian.

Your line is open.

MRI measurements and volumetric measurements as well.

Both kind of fell into the sea.

No Seth and plasma as well.

So I think you know that along.

Obviously, if you think about.

Huntington's disease.

Versus.

Alzheimer's as a monitor genetic disorder.

No. It was a gain of function and we know that.

Consequent so.

The H D T with the pag repeat.

Lower levels in this both animal data as well as natural history in clinical.

From patients that showed that reducing that improve the outcomes for patients.

I think you know.

Ever biomarker, where you could show a reduction of H D D.

Levels.

No.

Consequence of the season due to the H D D.

RNA and protein and lowering them back.

About level.

Really helps patients.

In terms of lower levels delays the progression of the disease.

You're in a pretty good spot to.

To be able to say.

That.

That you know you're hitting the <unk> in the sense that the GE lowering the levels of a protein and RNA and then the results of that should be better outcome. So I think that's pretty good arguments that were made.

Unknown Executive: And so while Brazil, you know, this year was hit relatively hard with COVID, the commercial team has been working tirelessly with the Ministry of Health to secure group purchase. We do expect one in the fourth quarter of this year, and maybe Eric, you want to talk a little bit about that.

And that coupled with looking at PFS and other biomarkers.

Preservation of rate volume and others, there's a package of information that we think would be important.

In terms of the growth.

Growth, Yes, I think Eric.

Erik already gave a little bit in saying that.

We're obviously you know the beauty of continuing to grow and have geographic expansion as well.

Things may be lumpy different.

Eric: Yeah, I think you have to characterize Russia in this quarter very similarly to what, perhaps,

Group there are ordering the different times that help at all with a little bit more.

And so while Brazil, and this year was relatively hard with Covid.

unknown: For more information, please visit www.ISGlobal.org.

The commercial team has been working.

unknown: So that's correct, which creates the lumpiness. And while we don't necessarily provide a specific, you know, the size of the orders and the revenue of the orders that are within that,

Tirelessly with the minister of health to secure.

Eric Percher.

We do expect one in the fourth quarter of this year and maybe Eric you want to talk a little bit about the Russia.

Yeah Yeah.

I think the ACA characterized Russia in this quarter very similar to what perhaps four or five years ago was Brazil. So in these some of these countries.

unknown: For more information, please visit www.ISGlobal.org. The dynamic in this quarter was that Russia was a key driver of that growth, and its centralized reimbursement in that order is what helped us have one of our best quarters ever. And as Steve mentioned, we anticipate, and we're working tirelessly right now, we have an agreement in Brazil, and we anticipate filling that order for a large group of patients as well in the fourth quarter.

The government order or will provide access and reimbursement and will provide a single order for a very large number of patients or number of months. So that's correct creates the lumpiness and while we don't necessarily provide a specific.

The size of the orders and the revenue of the orders that within that quarter.

You can easily go back four or five years and start to look at where we've had some lumpy quarter, particularly when we started adding new patients in Brazil and <unk>.

Getting multiple orders or at least one or two orders a year.

Or a large group of patients.

The dynamic in this quarter was that Russia was a key driver of that growth isn't it centralized reimbursement in that order is what helped US I'll have one of our best quarters ever and as Steve mentioned.

We anticipate.

We're working tirelessly right now.

We have an agreement in Brazil, and we anticipate billings.

Filling that order for a large group of patients as well or in the fourth quarter. So it's very hard to predict.

unknown: So it's very hard to predict. These governments tend to have erratic buying patterns, and they do sometimes pick the number of patients and the number of months, which is not always predictable. So it's kind of hard to say what that would be in sort of long-term quarter-to-quarter forecasts.

Governments tend to have.

Erratic buying patterns and they do sometimes pick the number of patients and the number of bonds, which is not always predictable.

It's kind of hard to say what would that be in sort of long quarter quarter forecast, but what I'd like to emphasize is that on an annualized basis.

Eric: But what I'd like to emphasize is that on an annualized basis, you see translunar growth consistently, and we're seeing what Eric said before. So we opened up new areas in like Russia, but also Central and Eastern Europe, the Middle East, North Africa. We just got, you know, Latin America, and Asia Pacific we're working on. So on top of maintaining all the patients who've been on it, we've had incredible compliance. And there's just a continuous amount of data that we're adding too, like the stride data that Eric talked about, where kids are at five and a half years longer in terms of ambulation, better, better capabilities in terms of lung function if the data is becoming, is just so strong that patients are on for a long time. We keep those, we maintain them, and then we get more and more patients as we get geographic expansion.

Florida growing consistently.

And we're seeing like like what Eric said before so we opened up new areas in Russia, but also central and Eastern Europe Middle East North Africa, We just got.

In Latin America Asia Pacific, we're working on.

On top of maintaining all of the patients who've been honored with have incredible compliance.

And there's just continue with some amount of data that we're having to like the stride data that Eric talked about where kids are at five and a half years longer in terms of ambulation better better capabilities in terms of <unk>.

One function, it's David is becoming.

It was just so strong that is.

Patients around for a long time, we keep those we maintain them and then we're getting more and more patients as we get to geographic expansion.

unknown: Thank you. Our next question comes from the phone with Kelvin and Hello, good afternoon. Thank you for taking my questions. The first one, just on the AADC submissions in the U.S., can you just let us know sort of the cadence of interactions with the FDA, if there are any expected before the BLA submission? Have they signed off on the surgeries that have happened? And then second, just in the Friedrich ataxia study, can you just remind us a little bit how you arrived at that 72 endpoint? I know at six months, maybe I saw a little bit of a high placebo response in the prior study. So maybe what were the changes that were made in this pivotal study to potentially?

Got it thank you very much.

Thank you. Our next question comes from the phone.

Cowen and company.

Your line is open good afternoon. Thank you for taking my question.

The first one was just on the ADC submission in the U S.

Can you just let us know who is sort of the cadence of interactions with the FDA. If there are any.

Expected before the BLA submission and they signed off on the surgeries that have happened and then second just in the <unk> ataxia study can you just remind us a little bit how you arrived at that.

The 72 endpoint at six months, maybe some a little bit of a high placebo response in the.

Prior studies. So it's to me what were the changes that were made in this pivotal to potentially limit that the placebo response.

unknown: Transcripts provided by Transcription Outsourcing, LLC.

Yeah. Thanks for the question, Matt you want to take some of it.

Matt: Matt, you want to take some of this? Yeah, sure. So first, to the question about the DLA, as we talked about, we were going to complete the surgeries, collect the data, and then meet with the agency to align on the package, ensure everything's in place to make the submission. We have not had that interaction yet.

Yes sure.

Oh of course to the question about the the BLA as we've talked about we were going to complete the surgeries collect those data and then meet with the agency to rely on the package I'm sure everything is in place to make the submission.

We had not had that interaction yet we expect that we'll have any interaction be able to submit the BLA.

Matt: We expect that we'll have the interaction to be able to submit the DLA in the first quarter of 2022. In terms of the MOVE-FA study, as you alluded to, we have based a lot of this study on our previous Phase 2 trial of the tick-borne inflammatory cataxia, which had the six-week placebo control phase, followed by a long-term treatment duration where patients were treated for up to 24 months. But also, importantly, when we looked at the patients in our Phase 2 study, we found that over a two-year period, we were able to demonstrate an overall improvement in disease, that is, a reversal of disease progression.

The first quarter of 2022.

In terms of the move out based study.

Alluded to we have based a lot of this study on our previous phase II trial in particular on Ctrip ataxia, which had a six week placebo control phase followed by the long term treatment duration locations were treated up to 24 months importantly, we recorded a placebo effect in that six months, which prevented us achieving statistical significance.

That's comp if you look across for example, you can lay out his childhood that trials and stop at six months. They would not have hit their primary endpoint again because of a known placebo effect on that Fars outcome measure, but also importantly, what we looked at the patients in our phase II study, we found that over a two year period, we were able to demonstrate an overall.

Matt: And that really reinforced the important concept that, one, we're able to achieve a therapeutic benefit, and, two, that over longer treatments of time, you can actually see a meaningful impact. And so, when we put that together, along with the concern of a placebo effect, we believe that the 72-week study put us in a very strong position to not only have limited and perhaps no placebo effect that would impact our results, but, importantly, be able to reinforce the long-term potential benefit of the tick-borne therapy in freezer cataxia with regards to not only disease progression, as measured by the MFAR scale, but other of the key secondary endpoints that were collected in the study.

Maybe disease that is a reversal and disease progression and really reinforce the important concept that one we're able to achieve a therapeutic benefit to that over longer treatment to tie you can actually see a meaningful impact. So when we put that together along with the concern of a placebo effect. We believe that the 72 week study put us in a very strong.

<unk> position.

Not only have <unk>.

Ltd.

<unk> looks like that the impact on our results, but importantly be able to reinforce the long term potential benefit of <unk> therapy in Friedrich ataxia with regards not only disease progression as measured by the Empire sale, but other than the key secondary end points that will collect in the study.

Great. Thank you.

Matt: Great, thank you. Great, great. It's all right, right?

Alright.

No I'd just say I think we're look we're learning a lot in terms of a neuromuscular diseases, where youre not necessarily people seeing necessarily kits improve but you are stabilizing but youre going to need you need more time within the trial.

unknown: So I was just saying, I think we're learning a lot in terms of neuromuscular diseases where you're not necessarily seeing kids improve, but you're stabilizing that you're going to need more time within the trial to be able to get better clinical results. The Gene Therapy Facility is up and going. Are there any updates to the Phrygia Taxia Gene Therapy Program? Yeah, there are, yeah, that one was.

To be able to get better better clinical results.

Yeah, I don't think that makes a lot of sense.

And then just last quick one now that the gene therapy facility is up and going and we were on appreciate ataxia are there any updates to the predicted taxi gene therapy program win when we could maybe see that one to enter the clinic.

Yeah.

unknown: You know, obviously hit by COVID as well in terms of getting the animals completed. The long-term toxicology studies are ongoing, and we, as we said, we're still on track and expect to dose the first patient in the first half of 2022. So that's where we're at right now; obviously, the key here will be to demonstrate the safety of the gene therapy product and then the stereotactic surgical procedure that we'll be using within the pivotal trial. So that's the goal for those experiments, and it's ongoing, it's just we're looking forward to getting this going as rapidly as possible. Perfect, thank you, and congrats on the progress.

Yeah that one was.

You know, obviously hit by Covid as well in terms of getting the animals completed the long term toxicology studies are ongoing.

Because we said we were still on track and expect to dose the first.

In the first half of 2022.

So that's where we're at right now.

The key here will be.

Demonstrates safety of the gene therapy product and then.

If they are affected surgical procedure.

That will that will be using.

Within the pivotal trial. So that's the goal of those experiments.

Got it it's just.

We're looking forward to get this growing as rapidly as possible.

Karnauskas: Thank you. Our next question comes from Karnauskas. Hey guys, this is Kripp on for...

Perfect. Thank you and congrats on the progress.

Thanks, a lot.

Thank you. Our next question comes from Kornacki with Truth Securities. Your line is open.

Kripa: Hey guys, this is Kripa on behalf of Robyn. Thank you so much for squeezing me in, and congratulations on the progress this quarter. I had a question about the Huntington's program. So in deciding, you know, what you call the Goldilocks population for your study, you said that you looked at natural history databases. Firstly, how comfortable are you that, or what sort of feedback did you get from the FDA, if you've already talked to them about it, that a natural history study that you do yourself does not need to be part of the package?

Hey, guys. This is coupon for Robyn. Thank you so much for squeezing me in and congrats on the progress this quarter am I had a question about the Huntington's program. So in deciding what you call. The Goldilocks population for your study you said that you've looked at natural history database is firstly, how comfortable are you that or what.

Sort of feedback did you get from the FDA, if you've already talked to them about it. That's a natural history study do you do yourself does not need to be a part of the package.

And when we see data from the control part of the trial. The 12 week Park, what can we expect in terms of Readouts will it be safety and Huntington.

Huntington RNA and protein levels.

Levels are or do you think that is enough time to see a separation in some of the other biomarkers for example, like NFL. It. Thank you.

Yeah. Thanks for the question.

Kripa: Thanks for the question. In terms of the study of natural history, obviously, the HD community has a lot of natural history that helps us define where there's over, you know, in one database, there are over 20,000 patients that one could look at. It will help us define that. Obviously, within the trial that we're doing, we're doing a placebo control to compare within the first Unknown Speaker 12 weeks, and then it goes on. So we'll have that much information.

The.

For the study.

Study in natural history, obviously.

The B B H.

H D community has a lot of natural history that helps us.

Fine.

Where theres over on one database with over 20000 patients that one could look at.

It will help us define obviously within the trial that we're doing we're doing a placebo control to compare with the first.

12 weeks and then they would be.

Goes over so will have that much information so the.

The natural history, what were using what.

What is critical is really the help us inform the criteria.

All of which patients you can actually see a change in response right because what you need to you know and the goldilocks.

Unknown Executive: So the natural history, what we're using is, what is critical is really to help us inform the criteria for which patients you can actually see a change in response, right? Because what you need to, you know, and the gobilaxis, you know, as Matt has talked about, are not too early in the disease progression but have a higher risk of declining over the course of the trial. And therefore, Treatment versus that gives you the possibility of evil.

As Matt has talked.

About for some time now is like it's very much true in many of these types of diseases, where there.

The area, there's a time, where if they don't change you won't see a.

A change if that's not U swirl and then does it does.

What normally happens is if there.

So far down the line, it's very hard to see any changes to the too far gone very similar to how we invest in BMD. So we're trying to make sure we pick the right population, where theres a decline the decline isn't so.

Is that you can actually change the course of that.

unknown: And so we're hopeful that as we measure that, obviously, we'll be measuring the biomarkers, and we'll see the reduction in ctRNA and protein, that will be important, but we would also anticipate seeing changes in the CSF, as well as neural light changes, and we'll look at both the CSF and plasma and then, of course, monitoring the preservation of brain volume as assessed by MRI Imaging, so we think that package. It will be quite interesting, and so the short-term 12 weeks will allow us to get that, and the longer-term safety and pharmacology and pharmacodynamic measurements of all the others that will go on for a year, we think we'll be able to see something there in terms of the biomarkers.

That you would seek to you.

You would be able to measure what that difference. So the goldilocks population really helps to ensure that we're enrolling those subjects.

Not too early in the disease progression.

I have a higher <unk>.

Risk of declining over the course of the trial and therefore.

Treatment versus that gives you the possibility of feedback and so we're hopeful as we mentioned that obviously will bring back some of the biomarkers.

We'll see the reduction.

M protein.

It'll be important but we would also then anticipate many changes in the CSF.

Well with no light chain.

We will look in both the CSF and plasma and then of course.

The presentation of brain volume.

As assessed by MRI imaging, so we think that package.

It will be quite interesting and so the.

The short term 12 weeks will allow us to get that in the longer term.

Farmer pharmacology and Pharmacodynamic measurement.

All the others that will go on for the year, we think we'll be able to see something there in terms of the biomarkers.

unknown: Great, thank you. That was very helpful.

Great. Thank you that was very helpful. And then I had a quick follow up question on the PKU program.

unknown: And then I had a quick follow-up question on the PKU program. You know, Bandran has said that a lot of the PKU clinics are still not operating at full capacity. Do you see any, you know, any challenges in terms of being able to find enough patients for your pivotal trial, or are you seeing that it's easy to enroll?

Biomarin has helped that a lot of the PKU clinic are still not operating at full capacity and.

Do you see any.

Any challenges in terms of being able to find enough patients for the trial for your pivotal trial or are you, saying that you know it's it's.

It's easy to enroll.

So we just initiated the trial.

Unknown Executive: So, we just initiated the trial, so it's hard to give you any hard numbers of what we're looking at, but we think, and this we're doing is, you know, the good news, obviously, we have a global infrastructure, so we'll be able to get only sites not only in the U.S., but globally as well, and, you know, there's, we have a lot of investigators, And so, you know, obviously, that's what I think that's one of the things to make sure is that if you have an expanded number of investigators that will help pull through so that you can get those patients. And that's why we're doing that. So that's, we still expect the results, by the end of 2020.

Hard to give you any hard numbers of what we're looking at but we think we're.

We're doing this.

The good news, obviously, we have a global infrastructure, so it will be able to get.

Only in the U S, but global but globally as well.

We have a lot of investigators and so obviously, that's why I think that's one of the things to make sure that you're able to expand the number of investigators that will help pull through so that you can get those patients and that's why we're doing this so that we still.

Expect the result.

By the end of 2022.

Great. Thank you so much.

Unknown Executive: Thank you, and I'm showing no questions at this time. I'd like to turn the call back over to Stewart Peltz for closing remarks.

Thank you.

Thank you and I'm showing no questions at this time I would like to turn the call back over to Stuart Peltz for closing remarks.

Unknown Executive: Well, great. So, you know, thanks for joining us today. And I think, as you can see, we're continuing to build PGC into a revenue-generating company. And I'm proud that the PTC has made what we did this quarter. I think you can see we've delivered substantial continued year-over-year revenue growth and once again raised our DMD franchise 2021 revenue guidelines. This revenue growth, in addition to the continued advancement of our pipeline with the initiation of our fifth registration-directed trial in BKU. This progress really allows us to continue the mission that we have of delivering life-changing therapies to patients around the globe. So thanks for taking the time to listen, and thanks for your questions.

Well, great. So thanks for joining us today, and and I think as you can see we're continuing to build <unk> into a revenue generating company and I'm.

Proud that PTC has made.

What we've done this quarter I think you can see we've delivered substantial continued year over year revenue growth and once again, raising our DMD franchise 2021 revenue guidelines.

The revenue growth. In addition to the continued advancement of our pipeline.

The initiation of our.

Registration directed trial in PKU.

The progress this progress really allows us to continue.

The mission that we have and delivering life changing.

Our therapies to patients around the globe. So thanks for taking the time.

And thanks for your question.

This concludes today's conference call. Thank you for participating. You may now disconnect.

This concludes today's conference call. Thank you for participating you may now disconnect.

Q3 2021 PTC Therapeutics Inc Earnings Call

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