Q1 2021 PTC Therapeutics Inc Earnings Call

Ladies and gentlemen, todays conference is scheduled to begin shortly please continue to standby. Thank you for your patience.

Operator: Ladies and gentlemen, today's conference is scheduled to begin shortly. Please continue to stand by. Thank you for your patience. BF-WATCH TV 2021

Unknown Speaker: Thank you for watching! Copyright 2019 Mooji Media Ltd. All Rights Reserved. No part of this recording may be reproduced without Mooji Media Ltd.'s express consent. Ladies and gentlemen, thank you for sitting in this class.

Operator: Ladies and gentlemen, thank you for sitting by, and welcome to the PTC First Quarter 2021 Financial Results Conference Call. At this time, all participants are in a listen-only 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, then 1 on your telephone. Please be advised that today's conference is being recorded. If you require any further assistance, please press star then zero. I would now like to hand the conference over to your host, Tali O'Keefe, Senior Vice President, Commercial and Corporate Strategy. Please go ahead.

Kylie: Good afternoon, and thank you for joining us today to discuss the PTC Therapeutics First 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, 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.

[music].

Kylie: Our actual results could materially differ from these forward-looking statements, as any and all such risks 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 website.

Kylie: and our most recent quarterly report on Form 10-Q and our 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?

Ladies and gentlemen, thank you Christine and.

And welcome to the P. T C first quarter 2021 the financial results conference call. At this time all participants are in a listen only mode. After the speaker's presentation there'll be a question and answer session to ask the question. During the session you would need the press Star then one on your telephone please be advised of todays conferences.

Unknown Executive: Thanks, Kylie, and thank you for joining us today. As this quarter marks the year since the COVID pandemic, we reflect on the incredible fortitude and determination of our employees, patients, and stakeholders during this challenging time. I'm incredibly proud of PTC's success and continued growth despite the pandemic, which I believe is a testament to our people and their resilience to adapt as circumstances evolve. Our passion for our mission remains to provide innovative treatments to patients with debilitating rare diseases that have few or no treatment options.

Being recorded if you don't acquire any further assistance. Please press Star then zero I would now like the hand the conference over to your host.

Oh, Keith Senior Vice President commercial and corporate strategy. Please go ahead.

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

And that's how our Chief Development Officer, Matthew Klein, our Chief business Officer, Eric pounds, and our Chief Financial Officer Emily Hill.

Unknown Executive: I'm pleased to report that PTC is emerging from this challenging time as an even stronger company. At PTC, we have always taken our environmental, social, and governance initiatives very seriously, and as we continue to grow, this has not changed. We pride ourselves on our culture.

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 coal which contains our forward looking statements.

Our actual results could materially differ from these forward looking statements as any and such risks can materially and adversely affect our business and results of operations.

Unknown Executive: We were also honored to have recently received Gallup's Don Clifton Strength-Based Culture Award, which reflects our ongoing deep commitment to our employees, as they are a key ingredient to our success. PTC received this award alongside Accenture and the Atlantic School System. Let me now speak to the strong performance this quarter. We outperformed revenue projections, delivered on a number of key objectives, and are making substantial progress towards our upcoming milestone in 2021. But first, let's focus on the DMV franchise.

For a detailed description of the applicable risks and uncertainties. We encourage you to review the company's most recent quarterly report on form 10-Q, and our 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.

Unknown Executive: The franchise continues to see robust growth with one of our strongest quarters ever in commercial revenue. TransLondon and Plaza saw a substantial 32% growth in revenues compared to the first quarter of 2020. This is quite incredible, considering TransLino was launched in 2014 and it was in 2017, and we expect strong growth to continue into the future. The commercial team continues to deliver impressive growth and has been working hard to bring these treatments to patients around the world.

With that let me the pass the call over to ask the EI Stuart Peltz Stuart.

Thanks, Scott and me.

And thank you for joining us today.

This quarter marks a year and to the COVID-19 pandemic, we reflect on the incredible fortitude and determination of our employees patients and stakeholders. During this challenging time.

I'm incredibly proud of the PTC success and.

Continued growth despite the pandemic, which I believe is a testament to our people the resilience to adapt the circumstances evolve.

Our passing per our mission remains to provide innovative treatments to patients with debilitating rare diseases.

There are no treatment options.

Unknown Executive: Now let's move to a very important point. The first at-home treatment for spinal muscular atrophy, RISD, has continued to see strong uptake in the U.S., with 1,600 SMA patients now on treatment. This represents a remarkable 15% market share in a short period of time post-approval, and we expect this growth to continue.

I'm pleased to report the PTC as the emerging from this challenging time and even stronger company.

And PTC, we have always taken our environmental social and governance initiatives very seriously and is it.

Continue to grow this is not true we pride ourselves on our culture. We were also honored to have recently received Gallup Stan flipped and strength the cultural award.

Unknown Executive: We were pleased to report that ARISI received EMA approval and had its first EU sale the following day. This shows the pent-up need for a convenient, orally-bioavailable, effective therapy for SMA patients. The first EU sale triggered a $20 million milestone from our partner, Roche. We expect additional ex-U.S. growth as European markets secure pricing and reimbursement. A Japanese approval is also expected before the end of this year.

Reflects our ongoing commitment to our employees as they are a key ingredient to our success.

And you see received this award alongside of Accenture, and the Atlanta School system.

Let me now speak to the strong performance this quarter, we outperformed revenue projections and delivered on the number of key objectives and are making substantial progress towards our upcoming milestones in 2021.

First let's focus on the DMD franchise the <unk>.

Unknown Executive: The success we established at RISD provides a roadmap for future oral small molecule splicing therapeutics. The roadmap guided us in our development of PTC 518 for Huntington's disease, or HD, which I will now return to. In our recent Huntington's disease deep dive, we demonstrated that the splicing platform has proven to be a robust engine to identify therapeutic candidates for a number of key diseases, including SMA and HD. We also demonstrated that PTC 518 is an orally bioavailable small molecule that penetrates the blood-brain barrier selectively, titratable, and not EFLA. Preclinically, it not only uniformly lowers HTT across all sections of the brain but also reduces mRNA and protein levels uniformly in the periphery.

<unk> continues to see robust growth with one of our strongest quarters ever and commercial revenue.

Translarna and and Plaza saw substantial 32% growth and revenues compared to the first quarter of 2020.

This is quite incredible considering the trim, Florida was launched in 2014 and it was from 2017 and where.

The fact strong growth to continue into the future.

The commercial team continues to deliver impressive growth and have been working hard to bring these treatments to patients around the world.

Now, let's move to of room.

The fourth at hold true for spinal muscular atrophy.

Originally of continues to see strong uptake and the U S with 1600 SMA patients now on treatment.

This represents a remarkable 50% market share in the short period of time post approval and we expect this growth to continue.

Unknown Executive: Most importantly, the preliminary results from the Phase I clinical trials were quite profound. In healthy volunteers, we achieved the desired dose-dependent lowering of HTT mRNA beyond the targeted 30 to 50 percent, even with a single dose. We also demonstrated that in the completed SAD and MAD cohorts, TTC 518 was found to be well-tolerated with no safety bias. Rarely are you able to demonstrate you're on target in a phase one trial in the Healthy Volunteers. And analogous to the EBRSI program, this puts us in a unique position.

We were pleased to report that of risky received EMA approval and they had the first EU sales of the following day. This shows the pent up need for a convenient orally bio available effective therapy for SMA patients. The first one your sales triggered a $20 million milestone from our partner Roche.

And we expect additional ex U S growth of European market secure pricing and reimbursement of Japanese approval was also expected before the end of this year.

The success, we have established.

Unknown Executive: We're extremely pleased with the progress to date and look forward to sharing additional results and next steps as the study progresses. Based on the mechanism of action and the pharmaceutical properties of PGC 518, we believe it has the potential to become the treatment of choice and the First Disease Modifying Therapy for Huntington's Disease. I now want to touch on our PKU program.

Rupee provides the roadmap for future oral small molecule splicing therapeutics.

The roadmap guides us and our development of the PTC part of one eight for Huntington's disease, or HD, which all of them now returns.

And a recent Huntington disease deep dive, we demonstrated that the splicing platform has proven to be of robust engine to identify therapeutic candidate for a number of key diseases, including SMA and HD.

Unknown Executive: As a reminder, a small phase two head-to-head responder study was previously performed with PTC 923. The results demonstrated that PTC 923 showed a two-fold greater reduction of phenylalanine levels in blood relative to crude blood. Importantly, the results also show that 50% more patients responded to PTC 923 as compared to QVET, including patients with classical PKU. We will start a registrational trial evaluating PTC 923 and PKU called Affinity mid this year, and we expect to have results by the end of 2020. There is an estimated global prevalence of 58,000 PKU patients, and the vast majority are not well addressed by current therapy.

We also demonstrated the PTC 518 is an orally bio available small molecule the penetrates the blood brain barrier and selective type of tradable and not eat blocks.

Pre clinically and not only uniformly lowered the HPT across all sections of the brain, but also reduce the MRE mrna and protein levels uniformly in the periphery.

Most importantly, the preliminary results from the phase one clinical trial, we're quite per pounds.

In healthy volunteers, we achieved that the value of dose and the lowering of H T. T M R&D beyond the targeted 30% to 50% even with the single zone.

We also demonstrated that and the completed and safety and Emma.

The cohorts PTC five one day was found to be well tolerated with no safety volume.

Rarely are you able to demonstrate you are on target and the phase one trial and the healthy volunteer and analogous to the of rupee program.

Unknown Executive: We see potential for PTC 923 as a clinically differentiated therapy to address this high-occupancy medical need. With newborn screening and established centers of excellence, we see this as an exciting program. Let me next turn to our BioE project.

It's us and the unique position.

We're extremely pleased with the progress to date and look forward to share and additional results and next steps as the study progresses.

Based on the mechanism of action and the pharmaceutical properties of PTC part of one eight we believe and it has the potential to emerge as the treatment of choice.

Unknown Executive: The BioE platform is a key component of our diversified pipeline because of its novel approach to targeting disorders of oxidative stress and inflammation. As a reminder, we have initiated two registrational trials with patiquine. The first compound from the BioE platform, one for mitochondrial epilepsy and one for free drink attachment, through its targeted BASA actions at the ends on 15 Leboxage, Ticuinone reduces the oxidative stress pathology that underpins mitochondrial epilepsy and free drink attack.

First disease modifying therapy for Huntington's disease.

I now want to touch on our PKU program and the.

A reminder of small phase two responders.

The responder study was previously performed with PTC and 92, three and the results demonstrated the PTC and 93 show the twofold greater reduction of NOL and lean levels and blood relative to COVID-19 importantly, the results also show the 50% more patients responded and <unk>.

Unknown Executive: Moving on to our gene therapy platform, we have some updates to share on PTC AADC. Due to the inability to complete its pre-approval inspections, because of COVID-related delays, the CHMP has requested a clock stop in the MAA approval process to allow for completion of these inspections. As a result of this clock stop, we now anticipate receiving the CHFP opinion in the third quarter of 2021. In addition, due to further COVID-related delays to complete the third cannula surgery, we now anticipate the BLA submission to be delayed by at least.

92, and three as compared to cool day, including patients with classical PKU.

We will start of the Registrational trial evaluating the PTC and 93 and PKU called the affinity mid this year and we expect to have results by the end of 2022.

There is an estimate of the global prevalence of 58000, PKU patients and the vast majority of not well addressed by current therapies.

Unknown Executive: Let's now turn to PTC299 and COVID-19. As a reminder, PTC299 is an oral small molecule with a dual mechanism of action that demonstrates both antiviral and anti-inflammatory effects. PTC 299 inhibits SARS-CoV-2 viral replication and calms the cytokine storm.

The potential for PTC and 93 as of clinically differentiated therapy to address this high unmet medical need.

With newborn screening and establish centers of excellence, we see this as an exciting program.

Let me next turn to our bio E platform the <unk>.

<unk> platform is the key component of our diversified pipeline because of its novel approach to targeting disorder of oxidative stress and the inflammation. As a reminder, we have initiated two registrational trials of particular note. The first compound from the buyer of your platform one for mitochondrial epilepsy and one for Friedrich of taxi.

Unknown Executive: PTC 299 functions by targeting a cellular enzyme, dihydroorytase dehydrogenase, or DHODase. The advantages of targeting the cellular end... [inaudible] We are currently running a Phase 2-3 registrational trial consisting of two stages. We expect enrollment to be completed for the full trial in the second quarter of 2021. We're proud to continue to deliver across our global commercial program and our robust development pipeline, which currently includes three ongoing registrational trials and one additional to be initiated in mid-2021.

Through its targeted base the action at the end of 15 lipoxygenase.

The one known reduces the oxidative stress pathology the lender.

The pits mitochondrial epilepsy and Friedrich ataxia.

Moving on to our gene therapy platform, we have some updates to share on PTC AGC due to the inability to complete the preapproval inspection because of COVID-19 related delays.

Unknown Executive: We are in a great financial position with a strong cash balance and a number of upcoming milestones to look forward to in the remainder of the year. With that, I'll turn the call over to Matt, who will further discuss our clinical progress.

<unk> request of the clock stop and the MAA approval process to allow for completion of these inspection.

As a result of the clock stop we now anticipate receiving the <unk> opinion and the third quarter of 2021.

In addition, due to further COVID-19 related delays the complete the third tenure of the surgery. We now anticipate the BLA submission to be delayed by at least the quarter.

Matt: Thanks, Stu. I would like to start by emphasizing the consistent progress our development teams have made despite the ongoing challenges of the pandemic. We are very proud of the success that we have had in advancing programs on all of our scientific platforms. And I'm pleased to share our most recent program. First, I'll begin with our validated supply chain.

Let's now turn to PTC to nine nine and COVID-19 is the reminder, PTC 299, and there is an oral small molecule with the dual mechanism of action the demonstrates book of anti viral and anti inflammatory effects.

PTC 299 inhibits Sars COVID-19, two viral replication and pumps the cytokine storm.

PTC 299 book just by targeting the cellular enzyme.

Matt: As Stu mentioned, we remain enthusiastic about the potential of PTC518 to deliver a meaningful benefit to Huntington's Disease patients. PTC 518's broad brain biodistribution and lack of heat flux from the CNS are key differentiating properties and reflect PTC's experience in developing selective, specific, and broadly biodistributed oral small molecule splicing drugs. The PTC 518 Phase 1 Healthy Volunteer Study is ongoing. As we shared in a deep dive last month, data from the SAD and first two MAD cohorts demonstrated dose-dependent reduction of Huntington mRNA. These are the key objectives of the Phase 1 study. In addition, we achieved a desired 30 to 50% reduction in HTT mRNA at the lowest MAD dose.

The hydro <unk> dehydrogenase or D zone.

The advantage of targeting the cellular and instead of a viral protein because that is less likely to illicit drug resistance, which is particularly important as the virus continues the mutual and we are.

Currently running the phase two three registrational trial, consisting of two stages, we expect enrollment to be completed for the full trial and the second quarter of 2021.

We're proud to continue to deliver across our global commercial program and our robust development pipeline. The currently include three ongoing Registrational trial, and one additional could be initiated and mid 2021.

We are and the great financial position with the strong cash balance and the number of upcoming milestone. The look forward two and the remainder of the year with that I'll turn the call the call over to Matt.

For the discuss our clinical progress and Matt.

Thanks, Dan and I would like to start by emphasizing the consistent progress our development teams have made despite the ongoing challenges of the pandemic.

Matt: Furthermore, we observed that the long half-life of PTC518 resulted in sustained reductions in HTT mRNA levels up to 72 hours after cessation of dosing. We look forward to sharing additional data, including pharmacology data from the CSS Sampling Cohort, once available. Turning to our BioE platform, enrollment is ongoing in our two vitiquinone registrational trials in mitochondrial epilepsy and phagocorticoid cataracts. As a reminder, the Mitochondrial Epilepsy Trial, the MITEI study, is a global placebo-controlled trial enrolling approximately 60 children with inherited mitochondrial disease and associated refractory seizures.

And I'm very proud of the success <unk> had and advancing programs from all of our scientific platforms and I'm pleased to share our most recent program updates.

First I'll begin with our validate and splicing platform.

As Stuart mentioned, we remain enthusiastic about the potential of PTC, five women and deliver a meaningful benefit to huntington's disease patients.

PTC five many broad, bringing bio distribution and lack of eplex in the CNS are key differentiating properties and reflect PTC experience and developing selective specific and broadly bio distributed oral small molecule splicing drugs.

The PTC 508 phase one healthy volunteer study is ongoing as we shared and the deep dive of last month's data from the safety and first to any of the cohorts demonstrated dose dependent reduction of Huntington mrna. The key objectives of the phase one study.

Matt: The primary endpoint is the reduction in observable motor seizures following six months of treatment. The MOVE-EPI trial, our Phase III study in pediatric and adult predrug ataxia patients, is also a global placebo-controlled trial. The primary endpoint of this study is improvement in the modified FAR score, and the key secondary endpoint is improvement in activities of daily living, as assessed by the FAABL scale.

In addition, we achieved the desired target of 50% reduction and HPT mrna and the lowest and <unk>.

Cohort.

Furthermore, we observed that the long half life of PTC five.

Resulted in sustained reduction and HGT mrna levels up to 72 hours after cessation of dose.

Matt: As we have discussed previously, this endpoint strategy was developed in consultation with both the FDA and the FDA. We expect to have data readouts from the MITEI study in Q3 2022 and from the MOVE-FA study in 2021. We have completed the Phase 1 study of PTC 857, the next compound from our BioWeek platform, and expect to have data available later this quarter. PTC 857 is a second-generation 15-lipoxygenase inhibitor being developed for neurodegenerative disorders characterized by pathology of the 15-lipoxygenase response pathway.

And we look forward to sharing additional data, including pharmacology data from the CSF sampling cohort once available.

Turning to our bio E platform enrollment is ongoing and our two particularly non registrational trials and mitochondrial epilepsy. Thanks, Richard the tax.

As a reminder, the mitochondrial epilepsy trial the mining study as the global placebo controlled trial enrolling approximately 60 children with inherited mitochondrial disease and associated refractory seizures.

The primary endpoint is the reduction in observable motor seizures, following six months of true.

The move ethane trial, our phase III study in pediatrics, and adult project and taxation and also our global placebo controlled trial.

Matt: Turning to our PKU program, we are excited about the potential for PTC 923 to meet the persistent unmet medical need for PKU. PTC 923 is an orally administered precursor of BH4, the cofactor of the phenylalanine hydroxylase enzyme that is affected in PKU. PTC 923 readily crosses the cell membrane and, as Stu mentioned, demonstrated significant effects in reducing phenylalanine levels in a Phase II trial, including in even the most severe classical PKU. We are on schedule to initiate our Global Phase III Placebo Control Trial, the AFFINITY trial, in mid-2021.

The primary endpoint in the study is improvement and the modified Fars score and the key secondary endpoint is improvement and activities of daily living as assessed by the FAA ADL scale.

As we have discussed previously and point strategy was developed in consultation with both of the FTA and means.

We expect to have data readouts from the <unk> study and Q3 2022 and from the move that base study from 2023.

And we've completed the phase one study of PTC eight <unk>. The next compound from lab on the platform and expect to have data available later this quarter.

Matt: Next, I'd like to provide an update on our AADC deficiency gene therapy. As Stu mentioned, due to an inability to complete pre-approval inspections because of COVID-related delays, the CHMP has requested a clock stop in the MAA approval process to allow for completion of these inspections.

PTC five seven and the second generation 15, lipoxygenase inhibitor being developed for Neurodegenerative disorders characterized by pathology of the 15 lipoxygenase response pathway.

Matt: As a result of this clock stop, we now anticipate receiving the CHMP opinion in the third quarter of 2020. In addition, the third planned surgery with the commercial cannula has been delayed, and we now anticipate DLA submission to be delayed at least one quarter. Nonetheless, our teams are continuing their global commercial launch efforts, which Eric will describe in more detail. Finally, I want to share the continued progress in our FITE-19 trial of PTP299 and COVID-19.

Turning to our PKU program, we are excited about the potential for PTC, 19th and <unk> to meet the persistent unmet medical need of PKU.

PTC 93, and an orally administered precursor of the each for the co factor of the standard alanine hydroxylase enzyme that is affected and PK.

PTC and ITC readily crosses the sale of members and as Steve mentioned and demonstrated significant effects and reducing phenylalanine levels and of phase II trial, including and even the most severe classical PKU patients. We are on schedule to initiate a global phase III placebo controlled trial the affinity trial in mid 2000 and.

Matt: You have completed stage one of this registrational trial and are currently enrolling stage two. Despite the great strides in the development of COVID-19 vaccines, there remains a need for effective COVID-19 treatments as we face new challenges due to virus variants, uneven vaccine distribution, and vaccine hesitancy. We expect to have data from Fight 19 in the second half of 2020.

'twenty one.

Next I'd like to provide and update on our ADC deficiency gene therapy program as Steve mentioned due to an inability to complete preapproval inspections because of COVID-19 related delays the.

<unk> has requested a clock stops in the.

And a approval process to allow for completion of these and sketch.

As a result of the clock stop we now anticipate receiving the CH and key opinion in the third quarter of 2021.

Eric: As you can see, we continue to make progress in advancing our robust and diverse development pipeline. I will now hand the call over to Eric for an update on our commercial execution this quarter. Thanks, Matt.

In addition, the third plant surgery with the commercial cannula has been delayed and we now anticipate DLA submission to be delayed at least one quarter.

Eric: I'm proud of the remarkable growth of our global D&D commercial franchise. The continued focus on Executing with Excellence from our customer-facing team was instrumental in delivering one of the most successful quarters for commercial revenue to date. We've seen incredible growth in our DMV franchise, with Inflaza leading the way at 58% and Translarna at 15% growth. Our total DMV franchise grew 32% compared to Q1 2020. We have seen incredible growth in our DMV franchise within Plaza, leading the way at 58% and TransLana at 15%.

Nonetheless, our teams are continuing and a global commercial launch efforts, which Eric will describe in more detail.

Finally, I wanted to share the continued progress and our fight 19 trial of <unk> hundred 99, and COVID-19 the.

Completed stage one of the Registrational trial and are currently enrolling stage two.

Despite the great strides and the development of COVID-19 vaccines and it remains the need for effective COVID-19 therapies as we face new challenges due to the virus very uneven vaccine distribution and vaccine hesitancy.

We expect to have data from the <unk> 19, and the second half of 2021.

As you can see and we continue to make progress and advancing our robust and diverse development types.

And then I'll hand, the call over to Erik for an update from our commercial execution this quarter.

Eric.

Thanks, Matt I'm proud of the remarkable growth of our global DMD commercial franchise.

Eric: Our total DMV franchise grew 32% compared to Q1 2020. The sustained in-place growth is primarily driven from new patient starts, a reduction in patient assistance, and bridge programs. Maintaining high levels of compliance and lower treatment discontinuations is the largest base of DMV patients globally. As a reminder, Inflaza is the first and only FDA-approved treatment for all EMD patients ages 2 years and older.

The continued focus on executing with excellence from our customer facing team was instrumental in delivering one of the most successful quarters for commercial revenue to date.

We've seen incredible growth in our DMD franchise with employers of leading the way of 58% and trends Lorna at 15% growth.

Our total DMD franchise grew 32% compared to Q1 2020.

We have seen incredible growth and our DMD franchise with employers of leading the way at 58% and trends lineup at 15% growth.

Eric: Importantly, with multiple publications of EMPLAZA's real-world data, we continue to support clinically differentiated benefits over prednisone. Additionally, including the recent switch data presented at MDA and AAM, we continue to see strong new prescription growth from patients seeking switches from their health care providers. TransLana's strong performance is driven by growth due to ongoing expansion of the patient-based NT market, continued high compliance and broader access in existing geography, as well as continued geographic expansion.

Our total DMD franchise grew 32% compared to Q1 2020.

The sustained and Plaza growth is primarily driven from new patient starts a reduction and patient assistance and bridge programs.

Maintaining high levels of compliance and lower treatment discontinuation of the largest base of DMD patients globally.

As a reminder, and plaza is the first and only FDA approved treatment for all DMD patients aged two years and older.

Eric: Following approval in the fourth quarter of 2020, we are pleased to announce that the Russian Federation has approved a plan to financially support all eligible ambulatory nonsense mutation D&D children in Russia with Translana. We also look forward to continued expansion into additional geographies in Central and Eastern Europe, Latin America, the Middle East, and Asia Pacific. Despite ongoing administrative challenges in Brazil driven by COVID-19 and leadership changes in the Ministry of Health, we continue to see increases in newly diagnosed DMV patients and are working towards securing a group purchase order for TransLarna in the second half of 2021 to meet the needs of new and existing DMV patients. Now, turning to tech study and why Libra.

And late with multiple publications of the clauses of real World data, we continue to support clinically differentiated benefits over pregnant zone.

Including the recent switch data presented at the NDA and.

We continue and see strong new prescription growth from patients seeking switches from their health care providers.

Try and Florida, the strong performance was driven by growth and ongoing expansion of the patient base in key markets continued high compliance and broader access and existing geography as well as continued geographic expansion.

Following the approval in the fourth quarter of 2020, we are pleased to announce that the Russian Federation has approved the plan to financially support all eligible ambulatory nonsense mutation DMD children in Russia with Translarna.

We also look forward to continued expansion into additional geographies and central and eastern Europe.

Eric: The team continues to make progress with disease awareness and patient identification in Latin America for our patients, despite the ongoing COVID-19 challenges in the region. In Brazil, we continue to explore avenues for pricing of TegCeti, and during this process, we continue to provide medical education, genetic testing, and patient program support to make TegCeti available in certain countries within Latin America through early access programs. We are pleased that we now have some of the first patients benefiting from the treatment with Vailibra in Latin America through Early Access Pathways and are making progress in Brazil, as we anticipate and in visa approval in Q3.

And America.

The middle East and Asia Pacific.

Despite ongoing administrative challenges and Brazil, driven by COVID-19, and leadership changes in the Ministry of Health, we continue to see increases and newly diagnosed <unk> patients and are working towards securing the group purchase order for trends Lauder and the second half of 2021 the need.

The needs of new and existing DMD patients.

Now turning to Chegg study and widely breath.

The team continues to make progress with disease awareness and patient identification and Latin America for our patients. Despite the ongoing COVID-19 challenges and the region.

And in Brazil, we continue to explore avenues for pricing of TEG study and during this process will continue to provide medical education genetic testing and patient program support to make Chegg study available in.

Eric: Moving on to AEDC. As a reminder, PTC-AADC is a transformative gene therapy that has the potential to produce meaningful changes in AADC deficiency patients. PTC has had a continued focus on preparing for a gene therapy launch for patients with AIDS and deficiencies.

And in certain countries within Latin America through early access programs.

Emily: to oppose Europe shortly after final EMEA approval. PTC continues to execute on-the-patient screening activities with over 100 at-home and saliva-based genetic testing programs in over 20 countries initiated in enriched high-risk populations. We aim to identify more than 300 patients globally by launch, and we remain confident with this goal. In addition to patient identification, the team has a continued focus on identifying and preparing expert pediatric neurosurgical centers of expertise, which is underway through the U.S., the European Union, and Latin America, as well as continued disease awareness and educational activities.

We are pleased that we now have some of the first patients benefiting from the treatment with why Libre and Latin America to early access pathway and are making progress and Brazil, as we anticipate and and visa approval in Q3.

Moving onto the AGC.

As a reminder, PTC ADP as a transformative gene therapy.

Has the potential to produce meaningful changes and the ADC deficiency patients.

PTC has had a continued focus on preparing for our gene therapy loss for patients with the agency efficiency, which is now expected to occur and Europe. Shortly after final EMEA approval.

PTC continues to execute on the patient screening activities with over 100 at home and.

And saliva based genetic testing programs and over two country initiated and rich high risk population.

Emily: PTC generated one of our strongest quarterly revenues ever, and I continue to have pride in our customer-facing team and their ability to execute against their strategic priorities. I will now turn the call over to Emily for a financial update.

And we aim to identify more than 300 patients globally and bylaws and we remain confident with this call.

In addition to patient identification and the team Hasnt continued focus on identification and preparation of expert pediatric neurosurgical centers of excellence, which is underway and the U S.

Emily: Thanks, Eric. In the first quarter of 2021, we saw strong continued revenue growth and progress across multiple platforms of our pie. In addition, given current marketing conditions, we are proud to have strategically and proactively strengthened our balance sheet last year through the Royalty Monetization Deal. This, combined with our impressive revenue growth, puts us in a strong cash position to continue to advance our diverse pipeline. We are executing on a number of fronts to deliver on many potentially value-creating milestones this year for long-term growth. The press release issued earlier this afternoon summarizes the details of our first quarter 2021 financial results. I'll take a few minutes now to review these financial results. Please refer to the press release for additional details.

Of the European Union.

And Latin America, as well as continued disease awareness and educational activities.

PTC generated one of our strongest quarterly revenues ever and I continue to have pride and our customer facing team and their ability to execute against our strategic priorities.

I'll now turn the call over to Emily for a financial update and light.

Thanks, Eric and the first quarter of 2021, we saw strong continued revenue growth and progress across multiple platforms of our pipeline and the.

Addition, given current market conditions, we are proud to have strategically and proactively strengthened our balance sheet last year through the royalty monetization and beyond.

This combined with our impressive revenue growth puts us and a strong cash position to continue to advance our diverse pipeline.

We are executing on a number of fronts to deliver on many potentially value, creating milestones this year for long term growth.

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

Take a few minutes now to review the financial results. Please refer to the press release for additional details.

Emily: Beginning with the top line results, revenues were $117.9 million for the first quarter of 2021, a 73% increase over the first quarter of 2020. This was driven primarily by net product revenue from the DMV franchise of $90 million, Collaboration revenue of $20 million from the EU First Commercial Sale Milestone Payment for EBRSI, and Royalty revenue of $6.7 million. Turning first to our DMD franchise,

Beginning with the top line results revenues were $117 9 million for the first quarter of 2021 of.

73% increase over the first quarter of 2020.

This was driven primarily by net product revenue from the DMD franchise of 90 million collaboration revenue of $20 million from the EU first commercial sale of milestone payment forever and fee and the royalty revenue of $6 7 million.

Turning first to our DMD franchise.

Emily: TransLarna net product revenues were $46.5 million, compared to $40.5 million for the first quarter of 2020. From PLAZA, we reported net product revenues of $43.5 million, as compared to $27.5 million in the first quarter of 2020. Moving now to a br, our partners Roche reported 2021 year-to-date sales of approximately 80 million Swiss francs. As a reminder, PTC retains approximately 57% of Eversi royalty. Until Royalty Pharma receives a return of $1.3 billion, after which 100% of the royalties revert back to PTC. Also, in our royalty monetization deal, we earned sales-based cash milestones that we fully retained. One milestone this quarter was related to the first European commercial sale, with a $20 million payment triggered when this occurred.

And sorry, and on net product revenues were $46 5 million compared to $40 5 million for the first quarter of 2020.

From the Plaza, we reported net product revenue of $43 5 million as compared to $27 5 million and the first quarter of 2020.

Moving now to of Brinci.

Our partners Roche reported 2021 year to date sales of approximately 80 million Swiss francs.

As a reminder, PTC retains approximately 57% of the risky Bryan and <unk>.

<unk> royalty pharma receives the return of one 3 billion after which of 100% of the royalties revert back to PTC.

Also and a royalty monetization deal we earn sales base cash milestones that we fully redeemed.

One milestone this quarter was related to the first European commercial sale with the $20 million payment triggered by Mr. Kurt.

Operator: The Royalty Monetization Transaction not only transformed our balance sheet by bringing forward future cash flow to a current $650 million cash asset, while still allowing PTC to maintain the majority of the royal stream, along with future potential growth as the royal stream could become the preferred global SMA therapy worldwide. Non-GAAP R&D expenses were $120.8 million for the first quarter of 2021, excluding $13.7 million in non-cash stock-based compensation expense, compared to $81.9 million for the first quarter of 2020, excluding $8.2 million in non-cash stock-based compensation expense.

The royalty monetization transaction not only transformed our balance sheet by bringing forward future cash flow through of current 650 non cash asset.

Still allowing PTC the maintain the majority of the Royal stream, along with the future potential growth and separately the could become the preferred global SMA therapy worldwide.

Non-GAAP R&D expenses were 128 million from the first quarter of 2021, excluding $13 7 million of noncash stock based compensation expense.

Compared to $81 9 million for the first quarter of 2020, excluding $8 2 million of noncash stock based compensation expense.

Operator: The year-over-year increase in R&D expenses reflects increases in spending due to advancing the gene therapy, catabolic, and BioE platforms, MPTC 299 and COVID-19, as well as increased investment in research programs and advancement of our clinical pipeline. Non-GAAP SGNA expenses were 49.1 million for the first quarter of 2021, excluding $12 million in non-cash stock-based compensation expense, compared to $51.2 million for the first quarter of 2020, excluding $7 million in non-cash stock-based compensation. Cash, cash equivalents, and marketable securities totaled approximately $988.4 million as of March 31, 2021, compared to $1.1 billion as of December 31, 20 I will now turn the call over to the operator for Q&A. Operator?

The year over year increase and R&D expenses reflect increases in spending 80 to advancing the gene therapy and a bar.

And bio E platform.

And PTC 299, and COVID-19, as well as increased investment and research programs, and then and of our clinical pipeline.

Non-GAAP SG&A expenses were $49 1 million for the first quarter of 2021, excluding 12 million and noncash stock based compensation expense compared to $51 2 million for the first quarter of 2020, excluding $7 million and noncash stock based compensation expense.

Cash cash equivalents in marketable securities totaled approximately $988 4 million as of March 31, 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.

Thank you.

Operator: Thank you. As a reminder, to ask a question, you will need to press star then one on your telephone.

The reminder to ask the question you would need the press Star then one on your telephone to book.

Operator: On the phone, to withdraw your question, please press the pound key. Please stand by while we compile the Q&A.

All of your question. Please press the pound key please standby, while we compile the Q&A roster.

Operator: Please stand by while we compile the Q&A roster. Our first question comes from the line of Eric Joseph with JPEG.

Our first question comes from the line of Eric Joseph.

Eric William Joseph: With JP Morgan, your line is now open. Hi, good evening, and thanks for taking the questions. Just a couple from us, primarily on PTC 518 for Huntington's. First, how should we be thinking about the timing of the next updates with the Healthcare Volunteer Study, specifically the analyses on protein change in the periphery and also drug exposure in the CSS. Will you be looking at exposure to MS-DSF in more than one or simply one cohort and will that be sufficient to inform dose selection in a patient study?

J P. Morgan your line is now open.

Hi, good evening and thanks for taking the questions.

Just a couple from us primarily on PTC five weighted for Huntington's.

First is how we should be thinking about the timing of the next updates and I'll, let Stuart.

And specifically the analyses.

Protein change and the periphery and.

And also drug exposure of the CSS.

Will you be looking at.

The exposure in the CSF and more than one or simply one cohort and.

Will that be sufficient to absorb.

The dose selection and a patient study and then secondly, I guess looking at.

Eric William Joseph: And then secondly, I guess coming away from some of the presentations from EnrollHB at AAN, are you thinking any differently, or how has your thinking evolved in terms of, I guess, the feasibility of establishing or kind of looking for the Therapeutic Benefit Approval Concept of the Phase 1 Huntington Patient Study. Yeah, thanks, Eric. Thanks for the question.

We had coming away from some of the presentations from the enrollees.

And.

Are you thinking any differently or how has your thinking evolved in terms of.

I guess.

Feasibility of.

Establishing or kind of looking for.

Therapeutic benefit of proof of concept and the phase one.

Huntington study okay.

Yeah.

Eric Thanks for the.

Unknown Executive: And so we're, you know, in the process of completing the additional cohorts. And as we've said, that will include a food effect, the multiple ascending dose, and the treatment, so that we get the CSS and protein analysis. And then, so we'll be getting that relatively soon. And then we look forward to sharing this information when it becomes available. And so that's working well.

On the question and so we're.

And the process.

And the additional cohorts and as we've said that will include.

A full the fact of multiple of <unk>.

Sending dose.

The the.

Treatment and so that we've got the.

TSS and wellness call protein analysis and then.

So we'll be getting that relatively soon and then we look forward to share this information when it becomes available.

And so that's working well so in terms of.

Unknown Executive: So in terms of the update, in terms of how we're thinking, and we do think the exposure will be good enough. You've got to remember, we have a lot of results demonstrating that, you know, what we see in the blood is what we see in the brain, and what we see in the blood is equal to the equivalent that we make to the CSF. And so we, and that, you know, I remind you that that's really important.

Of the update in terms of how we're thinking of.

And we do think the exposure will be well enough and you've got to remember we have.

A lot of results demonstrating the what we've seen and blood is what we've seen in the breakdown of what we see and.

And blood is equal to the equivalent of them, we meant to the CSF and so and the.

I'll remind you that that's really a major advantage.

Unknown Executive: BAM, in terms of being able to define what the drug levels are and be able to do that. So we have a lot of data on that. So we're, you know, obviously excited to have seen the results that we've seen in terms of lowering the target even with a single dose. And so we're going to be completing that.

In terms of.

In terms of of.

Being able to.

I'll be able to define what the the drug levels are and be able to do that so we are of a lot of data on that so were obviously were excited to of seeing the results that we've seen in terms of the lowering of the targets even with the single dose.

And so we're going to complete the best.

Unknown Executive: So in terms of the questions, in terms of what we are thinking in terms of the results based on that, and we think that the question there is more on the issue really, you know, at the end of the day, what we think in terms of what we saw in the Roche data, it seems to be a real issue in terms of the, we think it's a toxicity on the, and so do they, by the way, in terms of the issue, in terms of the reason that it went wrong was that it's been, we think it's an ASO specific problem that we think is due to toxicity as well as insufficient, and I think the hydrocephalus that was observed with the Roche drug was also seen with Spinraza, which are both ASOs. I can remind you that the Roche drug they had four times the volume and about 10 times remodeled. ASO.

So in terms of the the questions in terms of what we.

Thinking in terms of the.

The results based on that and we think that the question. There was more on the use of really at the end of the day, what we think in terms of what we saw on the Roche data it seems to be the real issue in terms of the rethink of the toxicity on the.

And so of the bank probably the way in terms of the the show in terms of the.

The reason that it went wrong with the students.

We think it's and so specific problems that we think is due to toxicity as well as and sufficient keep bringing up penetration and I think the hydrocephalus that was observed.

With the Roche drug was also see what's been roz of what's on both.

I can remind you that's the sort.

And then the Roche drugs. They had four times of the volume of about 10 times the amount of them okay.

So and so I'm not surprised that they are seeing the hydrocephalus and I think thats probably.

Unknown Executive: I'm not surprised that they're seeing the hydrocephalus, and I think that's probably interfering as well with penetration. And I think this is consistent with what Roche has reported. So from our point of view, I really don't wanna make an argument that this is a statement about the ability to actually alter that. We're pretty confident that you could, that our drug affects splicing, and reduces the level of HTT, and there's a plethora of data that shows that reducing the HTT levels is critical for elongating or preventing the effect of the disease from occurring, and we You know, I want to remind everyone that Huntington disease is a monogenetic disease, and it's the consequence of the mutant Huntington protein. So it's not like it could be from something else.

And appearing as well and with the penetration.

And I think this is consistent with what Roche has reported.

And from our point of view.

I really don't one making the argument that this is the statement about the ability to actually all three of them were pretty confident that you could that our drug effects of twice and reduces the level of HPT and there's a plethora of data that shows that reducing the HPT levels is critical for us.

And.

And J P and the programming.

And the effects of the disease to occur and we've seen that both with <unk> and <unk>.

Patients, who have lower levels of of that of.

Of that.

I want to remind everyone the huntington diseases of monogenetic disease.

And that's the consequence of the Huntington protein. So it's not like it could be from something out and we definitely think that both HPT and the RNA and the protein and the best targets of.

Unknown Executive: And we definitely think that both HTT and the RNA and the protein are the best targets for that. And there are plenty of case studies showing in animal models that lowering wild-type HTT is well tolerated, and that lowering mutant Huntington disease by 50% has demonstrated clinical benefits. So the fact that we have an orally bioavailable... That is, that gets to every tissue where you can control the precise level of the drug within the brain really is a promising small molecule with broad tissue distribution.

And fourth and there's.

Plenty of case studies showing both in animal models, what we're and wild type of UCT is well tolerated and that lower and mutant Huntington disease.

By 50% of its demonstrated clinical benefit so.

The fact that we have and orally bio available of trial since the <unk>.

Yes. The every tissue that you can control of the precise level of the drug within the range really is the promising small molecule with broad tissue distribution.

Unknown Executive: It's not in flux, and we think this really, we think, has the potential to be the best in class for this treatment. Does that help you, Eric? I'm sorry, I was on mute there. You know, that's very helpful. Thanks for taking the question.

It's not the blocks and we think this is really we think has the potential of these the best in class for this treatment.

Good day of healthier.

I'm, sorry, I was on mute there.

That's very helpful. Thanks for taking the questions great.

Alright.

Thank you. Our next question comes from the line of Alicia Yap with Cantor Fitzgerald. Your line is now open.

Operator: Thank you. Our next question comes from the line of Alethea Young with Cantor Fitzgerald. Your line is now open. Hi, thanks for taking my question. This is Naina on from.

Hi, Thanks for taking my question. This is neena on from UBS.

Unknown Attendee: So we were wondering, what are the remaining steps to filing in the U.S. for AADC beyond the one-queue delay? And do you think the delay is potentially longer?

So we're wondering.

What are the remaining steps to filing and in the U S for ADP.

On the the <unk> delay related to COVID-19 and and do you think the delay is potentially longer the two corner.

Unknown Executive: Sure. Thanks for the question.

Sure.

Unknown Executive: So ADC, I think, is obviously a really exciting product and has shown really transformational results in being able to take people who are developmentally rested, kids who are, and being able to actually see those developmental, being able to be seen in terms of being able to ultimately sit and stand and walk. So we're really pretty excited about that. Matt, do you want to talk a little bit about the steps that we'll be taking?

Thanks for the question the ADC.

I think it is.

It was obviously a really exciting.

The product and.

And as shown really transformational results in the April and being able to take.

People, who have developed and the rest of the kids, who are and being able to actually see those developmental.

And Oh.

Being able to be seen in terms of being able to ultimately.

And standard work, so we're really pretty excited about that.

And that you want to talk a little bit above the steps that will.

Matt: Yeah, absolutely. So just a few comments made on the call as well, as everyone knows we had submitted the M&A.

Yes, absolutely.

And the comments, you made and the call as well.

And the ZIP line as we have submitted the MAA to the EMA and Thats moving solid and we've now been asked to take the clock stop by the EMA.

Matt: As everyone knows, we have submitted the EMA to the EMA, and that's moving forward, and we've now been asked to take a clock stop by the EMA so that they can complete the pre-approval inspections. So just want to remind everyone that that's moving forward, and we now expect to have that opinion in the third quarter.

So that takes and complete the pre approval inspections.

So just wondering what level of that's moving forward and we now expect to have that opinion and the third quarter.

Matt: So the BLA, as we've talked about, really one of the key gating factors was their desire for us, the agency's desire for us to demonstrate some experience with our specific gene therapy product with a specific cannula we intend to use commercially, which is the SmartPool cannula. Now, of note, that cannula has been marked in the EU, which is why it was not an issue. The cannula was not an issue in the MAA process.

And the BLA as we've talked about.

One of the key gating factors was their desire for us the agency of desire for us to demonstrate some experience with our specific gene therapy products with a specific cash flow, we intend to use commercially which is the smartphone.

Of note that calculus and see.

And Mark in the EU, which is why it was not an issue.

And the kind of it was not an issue and the MAA process on.

Matt: On the FDA side, the cannula has been 510K cleared for a number of CNS procedures. It's been used in gene therapy procedures before, but just not specifically for the administration of our gene therapy product. And I think, as we've talked about before, the way the gene therapy product is administered is through complex stereotactic surgery. So what the surgeons do is, before the procedure, they get a Google map that basically tells them how to get from the outside world safely into the containment where we provide a direct infusion of the gene therapy product. The cannula is that piece of equipment that follows the path and instills the gene therapy into the exact place.

On the FDA side, the cannula has been 500 10-K cleared for.

For a number of CNS procedures and its been using gene therapy procedures before but just not specifically to the administration of our gene therapy product and I think as we've talked about before of the way the gene therapy product is administered as two of our complex stereotactic surgery. So what the surgeons do is before the procedure and they get a Google map that basically tells them how.

And to get from the outside world safely instead of the team and where we provide a direct infusion of the gene therapy product.

The calculus that piece of equipment that follows the path and instill the gene therapy engine of the exact place. So we've done two of the procedures already.

Matt: So we've already done two of the procedures already, as we previously reported. Those procedures went well. We had a third scheduled, and that's been delayed. And our plan, as we've discussed before, is to complete that third procedure. And then, obviously, we'll take the data online, make sure everything else is in place with the agency, and look to move forward with that.

As we previously reported those procedures went well we had a third of scheduled and that's been delayed and our plan as we've discussed before is to complete the third procedure and then obviously, we'll take the data line make sure everything else is in place of the agency and look to consolidate at that point.

Yeah.

Thank you that was helpful.

Yes.

Thank you. Our next question comes from the line of Robyn <unk> with true of Securities. Your line is now open.

Operator: Thank you. Our next question comes from the line of Robyn Karnauskas with True Securities. Your line is now open.

Robyn Kay Shelton Karnauskas: Hi guys, thanks for taking my question. I guess first...

Hi, guys. Thanks for taking my question.

I guess first just to follow up on expectations for Huntington data I had two questions. So you set the bar low for what we could learn from the CSS and you said it will be getting that the CSF data. Shortly can you just sort of give us a little bit more color updated thought on how we should view that data. So we don't.

Unknown Executive: To follow up on expectations for Huntington data, I had two questions. You set the bar low for what we could learn from the CSF, and you said that we'll be getting that CSF data shortly. Can you just sort of give us a little bit more color, updated thoughts on how we should view that data so we don't, you know,

Over expect too much.

On the protein levels, which everyone's really interested in seeing should we expect a difference and kind of a delay and the lowering of protein and like we should be expected of the rest of the person level and not be lowered as much as the RNA because of the delay or should we expect it to be similar if and true it's working that way and then lastly, I just had a question on PTC.

Transcription by CastingWords: Transcription by CastingWords

Unknown Executive: RNA because of delay, or should we expect them to be similar if and when it's working that way? And then lastly, I just had a question on PTC 293 so you talk a lot about how you know that compares to Kuvan, but what about how it compares to Palanzik, and do you think you'd be able to use this drug without the diet? Are you incorporating that into your affinity trial? Thanks Thanks for the questions.

And three can you talk a lot about how that compares to two van and.

What about how it compares to the policy and do you think you'd be able to use the strategy without the diet.

Are you incorporating that into your affinity trial.

Hello, and thanks, Rob and thanks for the question just so the.

Unknown Executive: Yes, so the yeah, we think that the look we've done a lot of work on this and we know the drug is is capable of passing the blood-brain barrier gets into all Aspects of the brain and all tissue types gets into the CSF. We've seen that in the non-human primates Where we saw equal amounts. So what we're what we'll do is is in the clinical trial We'll and we know what by the way what we've seen before that the amount that we saw in the blood is what we saw in in the CSF that the same levels were observed of The free drug within that both in the non-human primates rats other molecules other that we looked at So we're we're we're we're feel pretty comfortable about that And so that will be coming up And so that you know, so that's that's one I think it will do one dose that we think should be sufficient to answer the question That particular question and then in terms of the RNA and protein levels, you know What will what we're doing is to you know as part of the cohorts is to look and see the levels of proteins and since the way that Anticipated may not be a perfect one-to-one in the sense of that You're not yet at steady state at 14 days, but we're expecting to see reduction within that and within that time So we're gonna you know, we'll know the levels based on that Base and we'll be able to calculate what percent we think we have in terms of reduction So we'll be pretty confident that we'll be, I would make the point, I know there's been a lot of discussion about the protein but if you think about it, you make protein from the RNA and as the RNA level goes down, you're seeing, you know, you're going to get, it's pretty proportional to the level of RNA reduction that you see, you see the production of the protein. There's a pretty good correlation.

Yes, we think that the.

And you look we've done a lot of work on this and we know the drug is capable of passing of the blood brain barrier gets into all aspects of the the.

And the brain and all of tissue types gets into the CSF, we've seen that and the non human primates, where.

And where we saw equal amount. So what we're what we'll do is as and the clinical trial and we think it will be sufficient we will.

And we know by the way of what we've seen before but the amount.

Of that we saw in the blood is what we saw and the CSF. The same levels were observed of the free drug within that both in the non human primates brand suffered from all the other.

Other that we looked at so we're we're we're feel pretty comfortable about that and.

And so that will be coming up.

And so that so that's one and I think it will do one dose that predict should be sufficient to answer the question.

And that particular question and then in terms of the RNA and protein levels.

And what we're doing as true as part of the cohorts is to look and see the levels of protein and since the <unk>.

And the anticipated it may not be of perfect one to one and the sense of that youre not yet at steady state of 14 days, but we're expecting to see production within the atmos within that time, so we're going to.

We'll know the the levels based on that.

And we'll be able to calculate what percentage you think would have in terms of the reduction so it will be pretty confident that will be good.

And so I wouldn't make the point I know there from a lot of discussion about the protein, but if you think commodity you make protein from the RNA and the RNA level goes down.

We're seeing growth.

It's pretty proportional to the level of or the reduction that you see youll see the.

Production of the proteins and Stuart pretty good correlation of there's no regulation that we've observed is that as you reduce the level of our day youll see the protein synthesis. So.

Unknown Executive: There's no regulation that we've observed that as you reduce the level of RNA, you see increased protein synthesis. So, it's, we're pretty confident that the level when you see a reduction of the RNA, and you'll also see a reduction within the protein in that. So, we're very comfortable. That's what we've seen throughout all our work when we've looked at the reduction of both RNA and protein within the animal models that we've tested. So we're very comfortable with that.

We're pretty confident that the level when you see a reduction of the holiday and that you'll also see a reduction within the protein.

And so we're very comfortable and that's what we've seen.

The throughout all of our work when we've looked at the reduction of both power and the protein within the animal models that test and so we're very comfortable with the.

Unknown Executive: And then with 9.2.3, you know, obviously, we think we're excited about it that it actually targets more patients. So, it's more active in a greater number of patients as well as it actually causes a lower level, and we think that's true both with PUVEN as well as PALIN-Z. So, we're pretty sure that this is going to be, you know, the fact that it's an oral molecule, that it's quite active, that we've seen it perform well against Cruvan in the Phase 2 trial. We feel pretty comfortable that this is going to be quite helpful to these patients. Matt, do you want to add anything to that?

And then with 92 three.

Obviously, we think we're excited about the deficit did actually targets.

More patients so it's more active and the greater number of patients as well as the impacts that causes the lower level and we think thats true both with proven and as well as pilot and see so we're pretty we think that this is Don and the fact that it's an oral molecules and.

And that it's quite active that we've seen at the.

And performed well with this group and in the in the phase two.

So we feel pretty comfortable that this is going to be quite helpful to these patients and that humana and and listening to that.

Matt: Yeah, so I would just say that, you know, in the Phase 2 study that we referenced, that was a head-to-head comparison with KUVAN, and part of the reason, the clear reason for the superior effect is really bioavailability. PKU treatment requires activating the phenylalanine hydroxylase enzyme, which is dysfunctional in the disease. And PTC 923 is a precursor to BH4, which is the cofactor for the enzyme. And giving that precursor allows it to effectively cross plasma membranes and get into the cell, where it's readily activated into BH4.

Yes, so I would just say that and.

And the phase II study, which we referenced that with the head to head comparison with.

And with <unk> and and part of the reason the clear reasons sort of the superior of effect is really bioavailability.

And the PKU treatment requires activating the technology and hydroxylase enzyme which is.

Dysfunctional and the disease and PK PTC 19 three.

Is a precursor.

<unk> four which is the co packer for the enzyme and giving the precursor of allows it to effectively cross plasma.

Plasma and brains get into the cell, where it's readily activated into the range for whereas Alternatively Kuban itself is actually poorly absorbed at the highly LIFO phobic molecule and much of the BH too that's formed from Kuban goes on to either just getting screened by the kidneys and with only a small amount of getting it.

Matt: Whereas, alternatively, CuVan itself is actually poorly absorbed because it's a highly lipophobic molecule. And much of the BH2 that's formed from CuVan goes on to either just get excreted by the kidneys with only a small amount getting into the cell. So, this is really a story of superior bioavailability and, therefore, much superior action seen in the Phase 2 study, including activity in the classical PKU patients, which in our study had an almost 200..., reduction of 200 points in fetal alanine in the Now, you also brought up Palenzik. We didn't do a head-to-head comparison of Palenzik.

Sales. So this is really the story of superior bioavailability, and therefore, a much superior actions.

The superior accuracy and the phase II study, including activity in the classical PKU patients, which in our study had all and almost 200.

Reduction of 200 points of set of our need and the in the classical PKU patients, where there was really no reduction seen in the coup and treating patients with.

And the classical PKU and now you had also by the talent, we didn't do a head to head comparison of talent Zeke and Wild policy has shown efficacy and some patients. Obviously, it's one of the there are safety and Tolerability concerns and also takes time per policy to sort of effective LNG requires you to have and epinephrine auto injector.

Matt: And while Palenzik has shown efficacy in some patients, obviously, it's well known there are safety and tolerability concerns. It also takes time for Palenzik to be fully effective. Palenzik requires you to have an FNF and an auto-injector in case of anaphylaxis risk. So there really is a tolerability concern, which may be in part attributable to its, you know, lack of universal uptake. It's also not used by kids, which is obviously an important part of the population.

And the case of anaphylaxis risks so.

And the Tolerability concerns, which may be in part attributable to its tools and the lack of universal uptake. It's also.

Not used by kids, which obviously is an important part of the the population. So we think when you look at the existing PKU.

Matt: So we think when you look at the existing BKU marketplaces, there's still a large amount of medical need because the current therapies aren't addressing it. In terms of the diet question, that's not something we're looking at explicitly in the study, but obviously, we're focused, as the agency likes you to do, to make sure those diets are controlled so you don't have any co-founding factors in a placebo But obviously, we expect with an efficacious therapy that diet.

Market places to sort of large unmet medical need and really because of the current therapies are the adjusted in terms of the diet question and that's not something we're looking at it explicitly in the study, but obviously with the we're focused as the agency likes it and you make sure those die of controlled so you don't have any tactical sat and factors and a placebo controlled study.

But obviously, we expect with the efficacious therapy that could be loosen.

Operator: Thank you. Our next question comes from the line of Brian Abrahams with RBC Capital Markets. Your line is now open.

Great. Thank you.

Thank you. Our next question comes from the line of Brian Abrahams with RBC capital markets. Your line is now open.

Brian Corey Abrahams: Hey there, thanks so much for taking my questions. Two questions for me, I guess first on the evolving Huntington's space. Have you guys assayed ventricular volumes in non-human primates or done any analyses of cellular protein or RNA expression, either ones that maybe you have done preclinically or clinically or can do, to maybe help disentangle any potential off-target ASO construct inflammatory response versus maybe some adverse effect of lowering HTT itself? And then secondly, uninflaza obviously showed a strong quarter-over-quarter growth in sales.

Hey, there. Thanks, so much for taking my questions two questions from me I guess first on the evolving Huntington's space have you guys assayed ventricular volumes in non human primates or done any analyses of cellular protein or RNA expression.

Either one thing and maybe have done pre clinically or clinically or can do.

To maybe help disentangle.

Any potential off target ASO construct inflammatory response versus maybe some.

The adverse effect of lowering HGT itself, and then secondly unemployed.

Obviously, you showed a strong quarter over quarter of growth and sales just wondering if you could maybe break that down a little bit in terms of how much of that.

Brian Corey Abrahams: Just wondering if you could maybe break that down a little bit in terms of how much of that was demand-based or if there were any other changes in ordering patterns, gross to net, or inventory that may have also factored in. Thanks.

It was demand based or were there any other changes and.

Ordering patterns of gross to net of inventory that may have also factored in.

Unknown Executive: Yeah, yeah, thanks, Brian, for the question. Just to remind everybody, right, it's the oral nature of this and being able to catch it through without any increase in the CSF, and so when we measure, we didn't see any hydrocephalus in the non-human primate, so in terms of disentangling, I think that's a really good point that our drug, in terms of the non-human primate data So I think, again, it's pretty clear to us that we think the effect is really almost a toxic effect of the oligonucleotide. That's our point of view on this.

Yes.

Yes, Thanks, Brian for the question.

Just.

And remind everybody right.

The old nature of this and being able to get.

Through without any increase and the CSF and so when we measured.

We didn't see any hypothetical in the non human primate. So there was there in terms of disentangled and I think that's a really good point.

Our drug in terms of the non human primate data, we have not seen the MD of.

Of what Youre seeing so I think it's again, it's pretty clear to us that we say pizza.

And the effect is really almost of the toxic effects of the oligonucleotide, that's our point of view on this.

And.

Again, the from our point of view of the.

Eric: Again, from our point of view, just the fact that it's an orally bioavailable molecule, I think there are two issues: the toxic effect and then the distribution. It just doesn't get everywhere, and that's just not the case with an oral bioavailable molecule. Just like we saw for SMA, how well it was able to distribute throughout the body and throughout the brain tissues, we see the same thing, and we built that in to PTC 518. And not only did we build that in, we also built in that it was an efflux, and that really allowed us to see the level of what we see in the blood is equal to the brain, which gives us a lot of confidence.

The just the fact of its an orally bio available molecules out of gifts.

It's just I think the stewardship of the toxic effects of them the distribution of it just doesn't get everywhere and that's just not the case within the rule of biodiesel molecule just like we saw for SMA.

Well.

And was able to distribute throughout the body and throughout the brain tissue and received the same thing and we've built that in two of PTC five one day and.

Not really because we build that and we've also built the that it was the <unk> flux and other really allowed us to see the level of what we see in the blood was equal to the brain, which.

It gives us a lot of confidence when we measure of what Youre seeing the blood just like we did previously with the Bruce do you know whats getting it to the break so I think there's lots of reasons for us.

Eric: When we measure what we see in the blood, just like we did previously with the RISD, we know what's getting into the brain. So I think there are lots of reasons for us to think that we, in a sense, as you said, disentangle one issue from the other. So we're pretty confident that it's not really a question of, is it the right target? We're very certain that it is the right target. It's a monogenetic disease, and we think that reducing this into the toxic form of that, there's evidence that shows that is indeed what you want to do. So in terms of the plot or breakdown, Eric, do you want to talk a little bit about that? Yeah, sure.

And the sense as you said disentangled one issue from the other so we're pretty confident that that's true.

It's not really a question and it gives us the right target, we're really sort.

And that that's the right amount of genetic disease and.

And the tickets.

You know the reducing the toxic form of that aside from just looks robust.

Even the fees what you wanted to you so in terms of of the <unk>.

The breakdown.

Eric do you want to talk a little bit of Opex.

Yeah sure Yeah, Brian we had an excellent quarter for DMD franchise, all around I mean, it was one of our strongest quarters commercially.

Eric: Yeah, Brian, we had an excellent quarter for the DMD franchise all around. I mean, it was one of our strongest quarters commercially. And Inflaza led the way with almost 60% growth year over year. Now, to your specific question about Inflaza. The base of patients that we've been able to accrue, that we started to build in 2020, has been very, very strong. We've really minimized a number of key dropouts. Patients have been benefiting from treatment longer.

And then plaza led the way with almost 60% growth year over year.

And floods and to your specific question about and Plaza.

The base of patients that we've been able to accrue that we started to build and 2020 has been very very strong we've really minimized the number of key dropout.

Patients.

Had been benefiting on treatment longer there's been lower discontinuation and the extremely high compliance we've had thresholds of well over 90% of compliance and refills and that's incredible but once we also seen us back and back in the last quarter, we saw that that new prescriptions really continued with its mold.

Eric: There have been lower discontinuations and extremely high compliance. We've had thresholds of well over 90% compliance and refills, and that's incredible. What we've also seen is back in the last quarter, we saw that new prescriptions really continued with their momentum. New prescription growth has been some of the best, and so we have had some of our best months in Q1 in terms of new prescription growth. Our market access teams have been working, and our commercial teams have been working very, very hard to, if you will, bring down the time from the time of new prescriptions to the time when there's a commercial fill.

Rentals and new prescription growth has been some of the best and so we have and have had some of our best months.

In Q1 in terms of new prescription growth and our market access teams have been working and our commercial teams have been working very very hard to if you will bring down the time from the time of new prescription.

And to the time of where Theres a commercial Phil so we've been able to reduce that time on patient assistance programs as well.

Eric: So we've been able to reduce that time on patient assistance programs, as well as bridge programs, which are technically free of charge type programs, and we've been able to reduce that time. And we're also seeing a sort of fundamental change with many of the plans right now that have, over the last years, have had restrictions on emplaza that have removed those, which has helped as well. So it's a combination of a strong base, as well as continued new prescription growth, and the time that we get from the time we get a prescription to the time it gets filled. And we continue to see that these kinds of tailwinds will continue throughout 2021. That's really helpful. Thanks, Eric, and thanks, too. Sure.

British programs, which are technically free of charge type programs and we've been able to reduce that time and we're also seeing sort of fundamental change with many of the plans right now that are.

Over the last years of had restrictions on implausible that and remove those which has helped as well. So it's a combination of a strong base as well as continued new prescription growth and the time that we get from the time, we get a prescription to the time it gets filled and we.

We continue to see that these kind of tailwind will continue throughout 2021.

That's really helpful. Thanks, Eric and thanks to share.

Operator: Thank you. Our next question comes from the line of Danielle Brill with Raymond James.

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

Danielle Brill: Hi guys, good evening. Thanks so much for the questions. Stu, I know you talked a lot about how you think the toxicity that Roche is seeing in their Huntington's program is ASL-related. But given that we can't completely rule out the potential role of wild-type Huntington or the possibility of maybe a narrow therapeutic window, I'm just curious if this has impacted your thoughts on the development strategy for 518 at all.

Hey, guys. Good evening, thanks, so much for net questions and.

And I know you talked a lot about how do you think the toxicity that ratio of staying and they're Huntington's program and its AD sales related.

But given that we can't completely rule out that the.

And the potential role of wild type Huntington and or the possibility of maybe.

The and narrow therapeutic window and I'm just curious if this has impacted your thoughts on the development strategy for $5 eight at all.

Unknown Executive: I think the way we think about, yeah, I mean, we've had a lot of discussions about that. And the way we, what we think about this is that HD is a monogenetic disease, right? And, and, and, and it's the consequence of the mutant honeydew, right? So, from our view, that makes it the best Target.

And I haven't got the follow up.

Sure Yeah. So.

I think the way we think about.

We've had a lot of discussion on that and the way we.

What do you think about that.

And that HD is as of <unk>.

On the genetic disease right.

And it's the consequence of the new tonnage right. So.

So from our view of that makes it the best targets from the question of how much can you lowered and do the wild type Huntington and there is data already out there that shows from both animal models that you can reduce it substantially.

Unknown Executive: And from the question of how much you can lower and do the wild-type Huntington's, there is data already out there that shows from both animal models that you can reduce it substantially, you know, 50% for sure. And then certainly, the reduction of mutant HTT has also been shown to actually elongate the time when a patient shows a disease effect. So I think there's plenty of data out there.

50% for sure and then.

The the rig.

Ducks and the <unk>.

The T. T also has been shown to.

Excellent and elongate the time.

We're of patients so it shows.

The effect, so I think there's plenty of data out there and then.

Unknown Executive: And then I think the most likely hypothesis is, and that's what we said, the toxic effects, that you've seen this not only in Tumminericin but also in Spinraza. And now you have... 10 times the amount of the oligonucleotides, as well as four times the volume. So you're already creating.

And I think the the most likely hypothesis and the sense of what we said the <unk>.

So the effect that you've seen this not only in.

And Tom and they're seeing but also and spin raws.

10 times, the amount of the oligonucleotide as well as four times the volume so you already creating an issue of it.

Unknown Executive: So let's, okay, so that's, I think, the most likely hypothesis. But let's take the other point of view, which the other question is: we already know that illegal nucleotides show a disproportionate decrease in animals. You see, more in one part of the brain than the other. So you already have a disproportionate part, and then you're measuring, you're trying to make those levels of measurement using the mutant Huntington and the CSF, which I'm not sure we know exactly what that means. So you already know you have an issue.

Okay. So that's I think the most likely hypothesis, but let's take the other point of view, it's the <unk>.

Other question is we already know the illegal nucleotide share with disproportionate lowering.

And the animals to see more and one part of the brain and the other products.

And I already have a disproportionate part and then youre measuring youre trying to make those levels of measurement using the mutant Huntington and the CSF, which I'm not sure we know exactly what that means so you're already.

No you have an issue there youre not getting everything and you may hit maybe lets take your point, let's say, it's true he might be oversee the as the consequence of particular areas best of the hypothesis that you really bring it down too much and one spot and not enough.

Unknown Executive: You're not hitting everything. You may hit maybe, you know, let's take your point. Let's say it's true. You might be overhitting as a consequence of a particular error.

Unknown Executive: That's the hypothesis. If you're really bringing down too much in one spot and not enough in another, that's not a problem when you have a small molecule that gets distributed equally around the brain, and you can titrate it, you can get to every part of the brain tissue, and the levels are highly controlled, and we've shown that to be the case. So from my point of view, no matter which sort of hypothesis you take, it's still a consequence of the oligonucleotide.

And the Melbourne, that's not a problem with the.

When you have the small molecule that GAAP.

The gets distributed equally equally around the brand and you can titrate that you can get to every part of the the brain tissue and the level of or how do we control and we've shown that the synergies would be the case.

So from my point of view, no matter, which sort of hypothesis take it is still a consequence of albeit with the nuclear side. It seems to me that the most promising reason the and even Roche said this themselves is that the oligonucleotide is the real problem, but even if you take the other lease likely hypothesis.

Unknown Executive: Seems to me that the most promising reason that, and even Ro said this themselves, is that the oligonucleotide is the real problem. But even if you, let's take the other least likely hypothesis, it's probably against, it's probably then, it still doesn't distribute very well, and therefore it's probably a problem of too much in one place and not enough in another. You would see that with an orally bioavailable small molecule. So, I think...

It's probably again, it's probably then it still doesn't distribute very well and therefore, it is probably a problem of too much in one place and not enough and the northern and you would see that with the orally bio available small molecule.

So I think I.

Unknown Executive: I think for us, it's reinforced our belief in the importance of the advantages of an orally bioavailable small molecule. And it's something that we've been talking about, PTC 518, and it's not only its, you know, obviously the biological distribution. So when we put all this together, and we really do believe it's likely to just high levels of an allelical nucleotide, which we know, by the way, that humans don't like, and high levels can cause problems.

I think for us it's reinforced our belief.

And the importance of the advantages of an orally bio available small molecule and that's something that we've been talking about PTC by the one way business not only its obviously of the bio distribution. So when we put all of this together and.

We really do believe it's likely to just high levels of.

And <unk>, which we know about the weighted.

The humans don't like and high levels can close pulpwood and so I think we're pretty much.

Unknown Executive: So I think we're pretty much very confident in the progress that we've made thus far. We're not seeing any volumetric, any differences, you know, when we've looked at animal models. So in terms of the volume within the ventricles, we feel pretty good that we're in a pretty good spot that we have the potential to be the best in class.

Very confident and the progress that we've made thus far we're not seeing the volumetric.

Any differences when we booked and animal models. So in terms of the the volume.

And within the venture closed so we feel pretty good that.

We're in a pretty good spot you have the.

The potential best in class.

Okay. Thanks, that's actually really helpful. And then just quickly I was wondering if you could comment on where things stand with the frequency of taxi of gene therapy program can you remind us when you're expecting to enter the clinic with that asset. Thank you yes.

Unknown Executive: Okay, thanks. That's actually really helpful. And then, just quickly, I was wondering if you could comment on where things stand with the Friedrich's Ataxia Gene Therapy Program. Can you remind us when you're expecting to enter the clinic with that asset? Thank you. Yeah, yeah.

Unknown Executive: Yeah, thanks for that. So yeah, we're excited about that program. We have had, as we've talked about, some delays as a consequence of COVID, but the progress keeps going on, and we expect the first human dosing really before the year ends. You know, our goal is, and what we're doing now is just completing some of the gating items in the preclinical stage ahead of moving into the clinic, and that's going on now, and we've already begun some startup activities, So we're really working on the fastest path to bring that in so that we can get the first human dose.

Thanks for that and so we're excited about of that program.

We have had as we've talked about some some delays as a consequence of COVID-19, but with the <unk>.

<unk> keeps going on and we expect the first human dosing really before.

And the year and so our goal is.

And what we're doing now is just completing.

Some of the gave you the items of the pre clinically.

Ahead of moving into equivalents and Thats.

That's going on now is that we forward it becomes and startup activities.

We're going to be looking to utilize our.

The global infrastructure of that we'd have the focus on sites and the U S and globally.

So we're in the we're really working on the fastest path to bring that in.

Bring that.

And so that we can get the first in humans of St.

Unknown Executive: Yep, it does. Thanks so much again for the questions.

Does that help.

Yeah. It does thanks, so much against the the question.

Yes.

Thank you. Our next question comes from the line of Joe Thome with Cowen and company. Your line is now open.

Operator: Thank you. Our next question comes from the line of Joe Thome with Cowan and Company. Your line is now open.

Joseph Patrick Schwartz: Hi there, thank you for taking my questions. First one, actually, both on Viticcanone, but the first one in the seizure disorder patients, is there a reduction in motor seizure frequency that you're looking for in that phase two, three versus placebo? And are there any efficacy measures that the FDA has kind of set out as a benchmark for this to be one pivotal study? And then, second, kind of following up on Friedrichotaxia gene therapy, are there patients that would benefit more specifically from a gene therapy approach versus vaticanone? Or how are you thinking about segmenting those two treatments?

And there. Thank you for taking my questions first one extra both on particular zone, but the first one in the seizure disorder patients is there a reduction in motor seizure frequency that youre looking for in that phase two three.

Versus placebo and is there are there been any efficacy measures of the FDA has kind of set out as a benchmark for this to be one one pivotal study and then second kind of following up on the Friedrich a taxi of gene therapy are.

Are there patients that would benefit more specifically from the gene therapy approach versus particularly known.

How are you thinking about segmenting those two therapies and the population. Thank you.

Unknown Executive: Those two therapies in the population. Yeah, I think those are, you know...

And I think those of you know thanks for those questions questions and.

Operator: Thank you. Yeah, I think those are, you know, thanks for those questions. Those are good questions. And so, just, I'll have Matt talk more about it, but it's obviously a, you know, we've seen reductions in seizures, and based on this, and we have long-term data on this, and patients who normally are in real trouble, we've seen survival as a consequence of this. But, and so, currently, it's a people-controlled study that's worldwide. Do you want to talk a little bit about how we thought of doing the trial match?

So just the.

I'll talk more about it but it's obviously a.

We've seen a reduction of seizures.

And based on this and we have long term data on this and patients who normally are in the real trouble.

Survival as a consequence of the book.

But and so we view of the.

Certainly there's lots of people controlled study, but worldwide do you want to talk a little bit of out.

How we thought of the doing the trial day.

Matt: Yeah, absolutely, thanks, and thanks Joe for the questions. So in terms of mitochondrial epilepsy, so that refers to that symptom of refractory seizures in kids with mitochondrial disease, and it turns out about 40 to 50% of patients with inherited mitochondrial disease also have seizures, and these seizures are typically refractory to existing anti-epileptic therapies, to the simple reason that existing anti-epileptic therapies don't target the energetic pathways that are causing seizures in the In fact, many of the seizure medications actually exacerbate oxidative stress and the underlying mitochondrial pathology.

Yeah, absolutely thanks Stuart.

And thanks, Joe for the question. So in terms of mitochondrial epilepsy. So that refers to the symptom of refractory seizures and kids of mitochondrial disease and it turns out of that.

<unk> 40, and 50% of of patients with inherited and other kinds of and he's also have seizures and the seizures are typically refractory to existing anti epileptic therapies for the simple reason of existing anti epileptic therapies don't target. The energetic pathways that are causing seizures in these kids and in fact, many of the seizure medications to actually.

Exacerbate oxidative stress and the underlying amount of kinds of mythology.

Matt: So, that further contributes to, you know, the problem that they have, whereas obviously vitiquinone targets those pathways. And what we've seen in both preclinical and more brilliant clinical studies is a significant effect on seizure frequency, as well as other seizure-related complications, like the occurrence of status epilepticus, and in one case series, we observed a marked reduction in disease-related hospitalizations and mortality risk, again, given that what we're targeting, the underlying energy disturbance in these kids, which is obviously manifest in seizures, but is also having other overall impact on the patients and their disease.

So that further contributes to the problem that they have whereas obviously the kick the known targets those pathways and and what we've seen and both preclinical and more importantly, the clinical studies of <unk>.

And in effect on the and seizure frequency as well as other seizure related complications and likely occur.

<unk> of status Epilepticus and in one case series, we observe the market and reduction in disease related hospitalizations and mortality risk.

And given that what we're targeting the underlying energy disturbance and these kids, which is obviously manifest the seizures and Theres also having other overall impact on the patients and their disease in terms of the specific seizure thresholds.

Matt: In terms of specific seizure threshold for our analysis, we looked at a target reduction of about 50%, which, you know, is typically regarded as being clinically meaningful, though I think most regulatory authorities we've discussed acknowledge that, given the incredible seizure burden in this disorder, that it's serious refractory, and the seizures are life-threatening, really, a significant improvement or significant reduction is really going to be looked at, maybe independent of And again, these are kids that sometimes have 50, 100, 150 seizures a day, which is, you know, a significant burden, and in one of our case series, we had a reduction, you know, from 120 to 150 seizures a day down to 20 to 30, which is obviously significant.

For our analysis, we looked at the target reduction of about 50%, which is typically regarded as being clinically meaningful I think most regulatory authorities. We've discussed acknowledge that given the incredible seizure burden and this disorder.

Series from the factory and the seniors are life threatening.

Really a significant improvement of significant introduction.

He is really going to be looked at may be independent of a specific number but in the context of the disease and and again. These are kids that have sometimes 50 of 100 <unk> hundred 60 seniors.

Day, which is the significant burden and.

One of our case series, we had a reduction.

From 120 of that 250 seizures, a day down to 20 to 30 of which is obviously significant.

In addition to the motor seizure frequency, which is the primary endpoint and will also be capturing other secondary endpoints looking at other aspects of the seizure activity and use of rescue meds and other aspects of morbidity that will help paint that fuller picture of of impact of the therapy.

Matt: In addition to motor seizure frequency, which is the primary endpoint, we'll also be capturing other secondary endpoints, looking at other aspects of seizure activity, use of rescue meds, and other aspects of morbidity that will help paint a fuller picture of the impact of the therapy, not only on disordered motor seizures but overall disease morbidity. In terms of pre-trophytaxia, you know, when you think about pre-trophytaxia, it's a whole body disease; it's a whole brain disease.

Not only in reserve of motor seizures, but overall disease morbidity in terms of accretion of the ataxia and when you think of I appreciate the taxi at the whole body diseases, the whole brain disease.

And while this is well known of the cerebellum as really one key aspect of the disease really ground zero for the ataxia, which is obviously and the name of the disease and a serious component of the neurological.

Technology, and so with our <unk> gene.

Gene therapy, and we're again taking of targeting approach just as an ADC and delivering the pretax and gene directly to the dentate nucleus and with the idea that we will be targeting a key aspect of the neurological aspect of disease that being said, it's still a whole brings me and the whole body of disease with peripheral neurological impact cardiac impact.

Matt: While this it's well known that the cerebellum is really one key aspect of the disease It's really ground zero for the ataxia, which is obviously in the name of the disease and a serious component of the neurological pathology and so with our FA gene therapy We're again taking a targeting approach just as an AADC and delivering the protaxin gene Directly to the dentate nucleus with the idea that we'll be targeting a key aspect of the neurological aspect of disease That being said it's still a whole brain disease and a whole body disease with peripheral neurological impact cardiac impact We're having a systemic therapy like the ticlinone can obviously be adjunctive to the direct cerebellar administration gene therapy So we really view this as as as complementary to each other and the ability to deliver benefit for all patients with treated conditions

And we're having a systemic therapy like particularly non Ken obviously, the adjunctive to the direct cerebellar administration of gene therapy. So we really view this as a complementary to each other and the ability to deliver benefit for all patients were treated and taxes.

Great. Thank you very much.

Thank you.

The next question comes from the line of Colin Bristow with UBS. Your line is now open.

Hey, good evening and congrats on the quarter of I think just a quick one from me on PTC.

Three can you walk us through your anticipated involvement timelines and then the timelines of subsequent data readout. Thanks.

Sure.

Operator: Thank you. Our next question comes from the line of Colin Bristow with UBS. Your line is now open.

But yes, that's one of the.

The beauty for non Q3 is that at the very short.

Colin Nigel Bristow: Hey, good evening. Congratulations on the quarter. I think just a quick one for me on PTC 923. Can you walk us through your anticipated enrollment timelines and then the timeline for subsequent data readouts? Thanks. Unknown Speaker Sure. But yeah, one of the beauties of 9 to 3 is that it's a very short time, you know, the time is about six weeks, I think, in terms of the measurements, looking at the anomalies of reduction. And so Matt, you want to go through a little bit of it.

The the time was one of about six weeks I think in terms of the measurements and sort of and we can depend on the island Inc.

A reduction.

And so back to one of the go through a little bit of the.

And the timelines.

Yeah, absolutely just to follow up on.

And again, thanks for the question Colin just to follow up on the <unk> comments on the designs of certain.

And when you look at it.

Doing the clinical trial and PKU and has many advantages one or do you have and endpoint of selling that set of all I mean reduction which is an objective metric it's a blood test.

Easy to measure.

Obviously, a bit different than traditional neurological diseases, where you have composite scales and things of that arent.

Readily administrator and.

<unk> assessed and moved quite quickly. So the study itself of really capturing efficacy as a six week placebo control phase and <unk>.

Unknown Speaker: Yeah, absolutely. Just to follow up. And again, thanks for the questions, Colin.

And we as well being.

And being able to follow the path of of obviously the previous successful clinical trials.

Matt: Thanks for the questions, Colin. Just to follow up on Sue's comments on the design, certainly when you look at doing a clinical trial in PKU, it has many advantages. One is that you have an endpoint of phenylalanine reduction, which is an objective metric. It's a blood test. It's easy to measure.

Okay and for example, where we know at the ideal way to set up. These trials is the first enroll patients in the two week running things, where we ensure that the responders to PTC 93, So all enrolled subjects, who meet criteria and will get treated with PTC and 90 day for two weeks and will then be able to establish the threshold, where we say that your risk.

Matt: Obviously, a bit different than traditional neurological diseases where you have composite scales and things that aren't readily administered or objectively assessed and move quite quickly. So the study itself for really capturing efficacy is a sick week for people control phase. Importantly, as well, we've been able to follow the path of obviously previous successful clinical trials with Huvan, for example, where we know that the ideal way to set up these trials is to first enroll patients in a two-week run-in phase where we ensure that they're responders to PTC 923. So all the enrolled subjects who meet criteria will get treated with PTC 93 for two weeks. And when then will we be able to establish a threshold where we say that you're a responder?

Ponder and if you're a responder and get randomized to receive either 93 of placebo for six weeks. So that upfront two week run and really allows us to knowingly and enrich the placebo controlled phase population with those who have already responded to non to sleep. So thats really obviously, a big advantage in terms of.

And increasing the probability of success of the clinical trial.

And when we do enrollment and we're gonna be enrolling obviously, a larger number of <unk>.

<unk>, we're targeting somewhere in the area.

160 to 100 and subjects globally.

And we expect from there to get it had at least 80% that will meet that enrichment threshold that would more than adequately power the.

Trial for success and given that this is a global disease their existing centers of excellence and quite frankly, they are able to leverage PTC existing global infrastructure and we are right now and working with our country teams to identify centers of excellence and be able to have patients at the ready to go and so we.

Matt: And if you're a responder, you then get randomized to receive either 93 or placebo for six weeks. So that upfront two-week run-in really allows us to knowingly enrich the placebo-controlled population with those who have already responded to 93. So that's really, obviously, a big advantage in terms of increasing the probability of success of the clinical trial. So when we do enrollment, we're going to be enrolling, obviously, a larger number of subjects.

We expect to initiate the trial into 2021 and and roll it.

And in.

Rapid fashion and then get data.

And by the end of 2022.

Okay. That's super helpful. Thank you.

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

Matt: We're targeting somewhere in the area of, you know, 160 to 180 subjects globally, and we expect from there to get at least 80% that will meet that enrichment threshold. That would more than adequately power the trial for success. Again, given that this is a global disease, their existing centers of excellence, and quite frankly, we're able to leverage PTC's existing global infrastructure. And we're right now looking with our country teams to identify centers of excellence and be able to have patients that are ready to go. And so we expect to initiate the trial in 2021 and enroll it in a pretty rapid fashion and then get the data we're expecting by the end of 2020. Okay, that's super helpful. Thank you.

Hi, Thanks for taking all of my question. This is Sheldon and for Ciena.

The question on the 5000 <unk>.

Our Huntington's program.

So right now you are continuing dosing.

The healthy volunteers and what type of data do you need to determine the dose that would be of recommended for in patient testing and when do we expect to move into real patients.

And what type of patient population are you considering thanks.

Sure so.

And obviously, we're doing the.

The single ascending dose as well as the multiple ascending dose so.

I'm actually already pretty excited that we've also so we've already achieved the objectives that we've set out in terms of.

With the preliminary results that demonstrate to everyone that we can reach as measured in blood.

Operator: Thank you. Our next question comes from the line of Jayna Wang with Barclays. Your line is now open.

Even greater than 50% reduction.

The HTC.

Lower range based on the dose and what you saw that it was extremely it was well tight tradable.

Jayna Wang: Hi, thanks for taking our question. This is Sheldon Fujita.

You know we can determine the levels that we won the trajectory of that somewhere in the pretty good position here to be capable of defining the dose that leads to a reduction of the RMA, which we we're pretty confident about the steady state will lead to reduction of the protein. So we're in the process.

Sheldon Fujita: I have a question about the 518 Huntington's Program. So right now, you're continuing to dose healthy volunteers. And what type of data do you need to determine the dose that will be recommended for inpatient testing? And when do you expect to move into real patients? And what type of patient population are you considering? Thank you.

A complete you know doing a pretty thorough job to make sure completely and but just sort of cohorts that and of course.

The food effects the.

Finishing of the multiple ascending dose the CSF.

Measurements as well as complete the protein analysis. So that's what we'll have to go into.

Unknown Executive: So, you know, obviously, you know, we're doing I'm actually already pretty excited that we've already achieved the objective that we set out in terms of, with the preliminary results that we demonstrated to everyone, that we can reach, as measured in blood, an even greater than 50% reduction of HTC mRNA lowering based on the dose. And what you saw was that it was extremely, it was well titratable.

From there we will.

Probably we will have done what I really like about what we're doing and said that allows us the.

It should be have a very clear vision of a dose that we're giving them that gives us and exposure that we know the level of reduction of.

Hum.

R&D as a consequence of that so that we're not flying and any claim implying of here were going in and knowing exactly.

Unknown Executive: You know, we can determine the level that we wanted to get to. So we're in a pretty good position here to be capable of defining the dose that leads to reduction of the RNA, which we are pretty confident that a steady state will lead to reduction approaching. So we're in the process of, you know, doing a pretty thorough job to make sure we complete the additional cohorts that include the food effects, finishing up the multiple ascending dose, the CSF measurements, as well as complete the protein analysis. So that's what we'll have to go into, from there.

And what the dose and the exposure is that leads to the doctor the space due to the RNA. So we're pretty excited about that and then the next steps will do will be the show of the similar type of work.

If both levels of Paramount and Huntington's and.

And HD patients themselves, both the RNA and protein levels. As we also are beginning to think about the what is the trial for clinical benefit. So the future design wins will assess clinical benefit and and steep pace of.

And then and pop in.

Where possible, we're obviously want to enrich the patient population.

So that we've done the demonstrate the benefits and the reasonable timeframe with the reasonable sample size. So I think we're gonna be in the really great positions of the half.

Unknown Executive: Well, you know, and probably what we will have done, what I really like about what we're doing is that it allows us to actually have a very clear idea of a dose that we're giving that gives us an exposure that we know gives the level of reduction of Huntington RNA as a consequence of that. So that you know, we're not flying any plane blind here; we're going in knowing exactly what the dose and exposure is that leads to the reduction of HPT RNA. So we're pretty excited about that.

The right dose and then we're working hard to define.

What's the right.

Ah patient.

The right.

Set of patients and what will measure and so we can look at this analogous to the SMA story, where we've defined it and help rebuild.

And that we're on target to find the roadmap of growing into patients and then true.

But shows clinical benefit so that's our plan for now.

Got it thanks.

Thank you.

And our last question comes from the line of <unk> Prasad with William Blair. Your line is now open.

Unknown Executive: And then the next steps we'll do will be to show the similar type of work is both levels of mRNA and Huntington's disease in HD patients themselves, both the RNA and protein levels, as we also are beginning to think about what the trial that for clinical benefits will be. So in the future, we'll assess clinical benefits in HD patients. And then, in part, where possible, we obviously want to enrich the patient population.

Thanks for taking the question.

And 299, how are you thinking about.

The data.

Disclosure for that and.

How are you thinking about that program kind of in the context of increasing the vaccine distribution and some anti viral readouts expected in the near term.

Yeah, sure I think I would say.

And so a lot of efforts and put into the explanation of it we're really happy about that.

Unknown Executive: So that we demonstrate the benefits in a reasonable timeframe, with a reasonable sample size. So I think we're going to be in a really great position to have the right dose. And then we're working hard to find what's the right dose that shows clinical benefits. So that's our plan for now.

So right now that the fully vaccinated and.

Most of my team and the but having something that a text of the virus that's the small.

The treatment I think is still incredibly valuable and theres going to be.

Operator: Our last question comes from the line of Raju Prasad with William Blair. Your line is now open.

And number of people, who are not going to be vaccinated.

Unknown Attendee: Thanks for taking the question. On 299, how are you thinking about the data disclosure for that and

And this is.

Youre, probably seeing here, but you know what's going on and the other parts of the globe.

Continue.

Unknown Executive: How are you thinking about that program kind of in the context of, you know, increasing

The significant numbers of people have been COVID-19 and additional variants that come on.

Unknown Executive: In the context of increasing vaccine distribution and some antiviral readouts expected in the near term, yeah, sure.

And the advantage of both of the drug like PTC 299, where it hits, both sales and inhibits of Sars COVID-19, two viral replication and because.

Unknown Executive: I think, I think, so a lot of that was put into those explanations, and we're really happy about that. I can say right now that I'm fully vaccinated and I'm moving my team in, but having something that attacks the virus that's small, that's a treatment I think is still incredibly valuable. There are going to be a fair number of people who are not going to be vaccinated. I believe, and as you're probably seeing here, that you know what's going on in other parts of the world.

Of the mechanism of action also attenuates the sided story.

So the spread.

The bleed valuable drug for the treatment of.

Oh, sorry.

The COVID-19 book and also to the outpatient.

The treatment. So we think this is going to be and frankly, the other advantage of this is because of the targets.

Unknown Executive: There's going to be significant numbers of people having COVID. There will be additional variants that come on. And the advantage of both, of a drug like PTC-299, where it hits both things and inhibits SARS-CoV-2 viral replication, and because of its mechanism of action, also attenuates the cytosol.

I heard you or two dehydrofreeze of DHL D. H is the cellular inside and so.

But the interest accretion.

And also be less susceptible to variance of the virus.

Unknown Executive: So it's an incredibly valuable drug for the treatment of COVID-19, and also for outpatient treatment. So I think, you know, the anticipation is that it's going to also be less susceptible to variants of the virus, because it targets a cellular enzyme versus a viral one, so it would be more resistant to mutation. So we think that's actually good. We, I generally believe that we're, that this is going to be with us for quite some time.

We're going to be of cellular enzyme versus the viral one so it would be more resistant to.

The two mutation so we think that's actually a good week.

General and believes that the.

This is going to be with us for quite some time and so we're currently running of phase three Registrational trial as we said it from two stages.

We expect enrollment to be completed.

Unknown Executive: And so we're currently running a phase two, three registrational trial. As we said, it's in two stages where we expect enrollment to be completed in the second quarter of this year. And it's, you know, that the data from that should be not too far after that and should be in the second half. So that's our, and then we'll be able to look at the effect. So we're certainly quite hopeful and excited about perhaps having one of the first treatments for this disease. Great. Any, uh, sorry. So I was just going to say, obviously, we're going to go through rapid pathways for approval. Thanks.

And the second quarter of this year.

And it's you know that that the data from that should be not too far after that and should be and the second half of this year.

So that's all of it and we'll be able to book.

And the look at the effect. So we're certainly are quite hopeful and excited about.

And perhaps happening one of the firm.

And.

Therapies.

But the therapy for this disease.

Great and obviously.

No I was just because.

And obviously for rapid pathways for approval.

Yep.

Thanks, and any update an update of discussions regarding the trends of lot of the dystrophin study.

Unknown Executive: And any update on FDA discussions regarding the translunar dystrophin study? Yeah, so we're, as we said, we're working through this now. And, you know, once we complete some work that we need to do, then we'll be talking to them. So we're in the process of finishing that up so that we can then go and have a conversation with the FDA.

Yes.

And as we said we're working through the snow.

And.

And once we complete some work that we need to do.

And then we'll be talking to them. So we're in the process of finishing that up so that we can then go and type of conversation with.

The FDA.

Operator: This concludes today's question and answer session. I will now turn the call back to Stewart Peltz for his closing remarks.

Okay.

Thank you.

This concludes today's question and answer session I will now turn the call back to Stuart Peltz for closing remarks.

Unknown Executive: Okay, so... Look, I wanted to thank everyone for joining us today, and I think, as you've heard, PTC has really had an incredibly strong performance this quarter across, I think, all aspects of the company, from discovery to commercial and commercial revenue. The development team continues to execute across all the platforms, including the three registrational trials, which I think are really near-term value drivers. I'm also very excited to have recently shared the preliminary data from our PCC-5518 in one healthy volunteer trial for On Each Ine's Disease Program, and we're going to continue to provide updates as we complete the study.

Okay. So.

Look I wanted to thank everyone for joining us today, and I think as you've heard that PTC has really kind of the incredibly strong.

Our performance this quarter through I think all aspects of the company from discovery to.

Through the show and commercial revenue the development team continues to execute the extra.

Acute across all of the platforms.

<unk> the.

And three Registrational trial, which I think are really near term value drivers Ross of.

We're excited to have recently shared the preliminary data from a PTC $5 eight and quick one healthy volunteer trial for on each and disease program and we're kind of.

Can you.

Provide updates as we complete the study so.

Unknown Executive: So we're focused on translating the science into innovative therapies and really bringing them to patients to transform their lives, and the team is working hard toward this mission. And obviously, the patients are really waiting. So thank you for your time today, and that concludes our call.

We're focused on translating the signings since of the innovative therapies and all.

And really to bring it to patients the transform their lives and the team is working hard.

Towards this notion of.

And the patients are waiting.

Thank you for your time today.

And that concludes our the.

Operator: Ladies and gentlemen, this concludes today's conference call. Thank you for your participation.

Paul.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation you may now disconnect.

Operator: Thank you for your participation. You may now disconnect.

Unknown Speaker: © BF-WATCH TV 2021 ???

Yes.

[music].

And then.

[music].

And then.

And again.

And.

[music].