Q4 2021 PTC Therapeutics Inc Earnings Call

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

[music].

Operator: Today's conference is scheduled to begin shortly. Please continue to stand by. Thank you for your patience. [music] [inaudible] Thank you very much, thank you very much, thank you very Thank you very much, thank you very Music, Good day and thank you for standing by. Welcome to the PTC fourth quarter and full year 2021 financial results conference call. At this time, all participants are in a listen-only mode.

Good day, and thank you for standing by and.

Welcome to <unk> two the P. T C fourth quarter and full year 2021 financial results Conference call.

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

Operator: After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star then 1 on your telephone keypad. Please be advised today's conference may be recorded. If you require operator assistance during the call, please press star then zero.

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 one on your telephone keypad.

Please be advised today's conference maybe recorded.

If you require operator assistance during the call. Please press Star then zero.

Operator: I'd now like to hand the conference over to your host today, Kylie O'Keefe, Senior Vice President of Global Commercial and Corporate Strategy. Please go ahead. Good afternoon, and thank you for joining us today to discuss the PTC Therapeutics fourth quarter and full year 2021 corporate update and financial results. I am joined today by our Chief Executive Officer Stuart Peltz, our Chief Operating Officer Matthew Klein, our Chief Business Officer Eric Pauwels, and our Chief Financial Officer Emily Hill.

I'd now like to hand, the conference over to your host today highly okeefe senior Vice President of global commercial and corporate strategy. Please go ahead.

Good afternoon, and thank you for joining us today to discuss the PTC therapeutics fourth quarter and full year 2021, corporate update and financial results.

I'm joined today by our Chief Executive Officer Stuart Peltz.

Keep operating officer, Matthew Klein, our Chief Business Officer, Eric Palace, and our Chief Financial Officer Emily Hill.

Operator: Today's call will include forward-looking statements based on current expectations. Please take a moment to review the slide posted on our investor website in conjunction with the call, which contains our forward-looking statement. Our actual results could materially differ from these forward-looking statements, as such statements are subject to risks that can materially and adversely affect our business and results of operations.

Today's call will include forward looking statements based on current expectations.

Please take a mine that turvy, the slide posted on our Investor website in conjunction with the call which contains our forward looking statements.

Our actual results could materially differ from these forward looking statements as.

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

Kylie O'Keefe: For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent annual report on Form 10-K, filed with the Securities and Exchange Commission, as well as the company's other SEC files. 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, let me pass the call over to our CEO, Stuart Peltz. Stuart?

For a detailed description of applicable risks and uncertainties. We encourage you to review the company's most recent 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 let me pass the call over to our CEO Stuart Peltz.

Thanks, Gary.

Stuart Peltz: Thanks, Kylie. I'm excited to share with you today the significant progress in 2021. Over the last few decades, we have advanced innovative therapies from ideas and discovery to commercializing and distributing them to patients around the globe. These efforts have positioned us to continue to grow to an enduring, innovative biopharmaceutical company with substantial revenue. Our vision is to build our pipe, such that at steady state, we can commercialize a new product every two to three years.

I'm excited to share with you today the significant progress in 2021.

Over the last few decades, we have advanced innovative therapy from ideas and discovery to commercialize them in distributing that to patients around the globe.

These efforts have positioned us to continue to grow to an enduring innovative biopharmaceutical company with substantial revenue.

Our vision is to build our pipeline such that at steady state. We can commercialize a new product every two to three years. This will allow us to continue to create value for all of our stakeholders.

Stuart Peltz: This will allow us to continue to create value for all of our stakeholders. Executing on our strategy over the last few years has led us to having a robust pipeline with five registration-directed studies on going, and we anticipate results from many of them this year. Along with the growth of our pipeline, I'm pleased to report that the commercial engine has performed exceedingly well.

Executing on our strategy over the last few years has led us to having a robust pipeline with five registration directed studies ongoing and we anticipate results for many of them this year.

Along with the growth of our pipeline I'm pleased to report that the commercial engine has performed exceedingly well.

Stuart Peltz: We have reached $539 million in total revenue in 2021. The Duchenne muscular dystrophy franchise continued to grow, contributing $423 million in net product, These products demonstrate robust growth years after approval. And we expect this growth to continue based on the treatment benefit, maintaining treatment compliance and continuing with geographic expansion. Our goal is to bring transliners to non-substantiation to shed muscular dystrophy voice globally. And we see continued geographic opportunity in regions like Asia-Pacific, Central and Eastern Europe, Middle East and North Africa, and Latin America.

We have reached $539 million in total revenue in 2021.

To send muscular dystrophy franchise continued to grow contributing $423 million.

Net product revenue.

These products demonstrate robust growth years after approval.

We expect this growth to continue based on the treatment benefit maintaining treatment compliance and continuing with geographic expansion.

Our goal is to bring translarna to nonsense mutation Duchenne muscular dystrophy boys globally, and we should continue with geographic opportunity.

Regions like Asia Pacific Central and Eastern Europe , Middle East, North Africa, and Latin America.

Stuart Peltz: In addition, with the potential of successful results of study 041 mid-year, we look forward to pursuing the registration path to bring TransLarna to patients in the United States. We anticipate that the commercial team will execute flawlessly and will have a stellar year.

With the potential of a successful result of study O. Four one mid year, we look forward to pursuing the registration path to bring <unk> to patients in the United States.

We anticipate that the commercial team.

Can flawlessly and we will have a stellar year based on that we're confident that we'll continue to have a strong and growing revenue base and our revenue guidance for 2022.

Stuart Peltz: Based on this, we're confident that we'll continue to have a strong and growing revenue. And our revenue guidance for 2022 is between $700 and $750 million, with $475 to $495 million from the Duchenne Muscular Dystrophy Franchise. In addition to the DMV franchise, RISD has shown remarkable growth in 2021, just over a year after launch. Overithy has now approved in 72 countries capturing over 20% of the SMA market in the United States and is now the number one prescribed disease-modifying therapy in the SMA. We also see continued growth in the ex-United States market with approximately 30% market share in Germany. This rapid and sustained uptake demonstrates the appeal of an effective orally bioavailable therapy.

700, and $750 million with $475 million to $495 million from the Duchenne muscular dystrophy franchise.

In addition to the DMD franchise.

Wednesday has shown remarkable growth in 2021 just over a year after launch.

It is now approved in 72 countries, capturing over 20% of the market.

The United States and is now the number one prescribed disease modifying therapy.

Alright.

We also see continued growth in ex United States market with approximately 30% market share in Germany.

Rapid and sustained uptick demonstrates the appeal of an effective orally by available therapies.

Stuart Peltz: Tixettian Ray Lieber, I'm not well-positioned, for successful commercial launches in 2022. Both therapies receive Category 1 pricing in Brazil, and this Category 1 designation allows pricing in line with international markets. Eric will go into more detail on this later in the call. In addition to PTC's commercial success, we're excited about the progress across our robust pipeline. By the end of 2022, we expect to have initiated three additional registration directed studies and a potential approval in Europe for PTC-AADC, our first gene therapy, As alluded to previously, we have a number of results expected in 2022 and we believe this will be a transformative year for PTC.

The second way Libra are now well positioned for a successful commercial launches in 2022.

Both therapies received category one pricing in Brazil, and this category one designation allows pricing in line with international markets, Eric will go into more detail on this later in the call.

In addition to Ptc's commercial success.

Cited about the progress across our robust pipeline by.

By the end of 2022 we expect to have initiated three additional registration directed studies and a potential approval in Europe for PTC a D C. Our first gene therapy.

As alluded to previously we have a number of results expected in 2022, and we believe this will be a transformative year for PTC, let me share a few highlights.

Stuart Peltz: Let me share a few highlights, from our Bio-E platform, results from our Registration Directive, Mighty Ease Trials, are expected in the fourth quarter for a particular known in minor congerial disease associated C. From our metabolic platform, the registration directed PTC 93 affinity trial for PKU is expected to be completed by the end of this year. As a reminder, there is substantial alumni medical need remaining in PKU, and with newborn screening, well-defined centers of excellence, and a clear path to registration, we're extremely excited about this program.

From our via replay phone results from our registration directed.

Trial are expected in the fourth quarter for particular known mitochondrial disease associated seizures.

From a metabolic platform.

Registration directed since you've seen 19, three affinity trial for PKU is expected to be completed by the end of this year. As a reminder, there is there is substantial unmet medical need remaining in PKU and with newborn screening well defined centers of excellence and a clear plan.

The registration where it is.

We are excited about this program.

Stuart Peltz: We're moving forward with the next compound from our splicing platform, PTC 518, for the treatment of Huntington's disease. As a reminder, the Phase I Healthy Volunteer Study demonstrated that PTC-51A reduced HTTP mRNA and protein levels to the target level of the 50% reduction. PTC 508 was also measured in the PSF, demonstrating that it crosses the blood-brain barrier and has no e-plug.

We're moving forward with the next compound from our splicing platform <unk> 518 for the treatment of Huntington's disease.

As a reminder, the phase one healthy volunteer study demonstrated that PTC five ordinary reduced H T T mrna and protein levels to that.

Target level of 30 for the 50% reduction.

PVC pipe coordinate we've also measured in the CSF demonstrating that it crosses the blood brain barrier and has no. Your flocks. The phase two study of the PTC popcorn to eat in Arlington disease patients is initiating this quarter, we know about the Huntington's disease community is eager for progress.

Stuart Peltz: The Phase 2 study of the PCC 518 in Huntington's Disease patients is initiating this quarter. We know that the Huntington's Disease community is eager for progress. We made significant achievements in 2021 despite the ongoing COVID-19 pandemic. I'm proud of the continued hard work of our people.

Yes.

Stuart Peltz: We've shown true dedication to our goal of bringing therapies to pay. PTC has consistently delivered results across research, development and commercial business. And we're well-positioned to continue deliver both short and long-term value to our stakes. I'll now turn it over to Matt for more on our development programs. Matt.

We made significant achievements in 2021.

The ongoing COVID-19 pandemic I'm proud of the continued hard work of our people who have shown true dedication to our goal of bringing therapies to patients PTC has consistently delivered results across research.

Element in commercial booth.

And we're well positioned to continue to deliver both short and long term value to our stakeholders.

Now I'll turn it over to Matt for more on our development program Matt.

Matt Klein: Thanks Stu. We made tremendous progress across our broad development pipeline in 2021, and I'm happy to provide some key updates on the team's progress. I'll start with our bio. Our first compound in the BioE platform is the Kikwin, which targets the enzyme 15-lipoxy, Key Regulator of the Inflammation and Oxidative Stress Underpinning a Number of CNS Diseases. As Stu highlighted, we have two ongoing registration-directed trials. David Trial, and the Move F8 Trial.

We made tremendous progress across our broad development pipeline in 2021, and I'm happy to provide some key updates on <unk> progress.

Start with our biotech at.

Our first compound from the bio E platform as the kikwit, which targets the enzyme 15 lipoxygenase, a key regulator of the inflammation and oxidative stress underpinning a number of CNS diseases.

As Steve highlighted we have two ongoing registration directed trials in particular.

The trial and then move FAA trial.

Matt Klein: MIMI-TRIAL is a placebo-controlled study of the tiquidone in patients with mitochondrial disease-associated seizures. This study will enroll approximately 60 patients from study sites in North America, Europe, Australia, and Asia. The study includes a 28-day observational phase to ensure subjects are having a minimum number of observable motor seizures, followed by a 24-week placebo-controlled phase, during which subjects are randomized to receive either the tiquinone or placebo. The primary endpoint of the trial is a reduction in observable motor seizures, with secondary endpoints assessing different aspects of seizure pathology as well as overall disease morbid, We expect results from this study in the fourth quarter of 2022. Second Registration Director, Trial of the Tiquet Move F A, is being conducted in patients with C-Direct Attacks.

Miami trial is a placebo controlled study of particularly in patients with mitochondrial disease associated seizures.

Eddie will enroll approximately 60 patients from study sites in North America, Europe , Australia and Asia.

The study includes a 28 day observational phase to ensure subjects are having a minimum number of observable motor seizures, followed by a 24 week placebo controlled phase during which subjects are randomized to receive either <unk> or placebo.

The primary endpoint of the trial is the reduction in observable motor seizures with secondary endpoints assessing different aspects of seizure pathology as well as overall disease market.

We expect results from this study in the fourth quarter of 2022.

The second registration directed trial in particular move assay is being conducted in patients with <unk> ataxia move assay is a randomized placebo controlled 72 week trial with the primary end point being change in a modified fars disease rating scale with the key secondary endpoint being improvement in activities of daily.

Matt Klein: MOVE-FA is a randomized, placebo-controlled, 72-week trial with the primary endpoint being change in the modified FARS disease rating scale, with the key secondary endpoint being improvement in activities of daily living, as assessed by the Friedreich Ataxia ADL. The trial is fully enrolled and we expect results in the second quarter of 2023. The second compound from the BioWeek platform, PTC857, also targets 15-lipoxygenase and is a potent inhibitor of ferriptosis, a recently described cell death pathway demonstrated to be key to neurodegenerative disease pathology, and the first indication for PTC 8x7 to the ALF.

Living as assessed by the <unk> ataxia ABL.

The trial is fully enrolled and we expect results in the second quarter of 2023.

Our second compound from the biome platform PTC seven also targets 15, lipoxygenase and as a potent inhibitor of fab Ptosis. Ah recently described sell desktop way demonstrated to be key neurodegenerative disease pathology.

The first indication for PTC Kevin.

Matt Klein: This is the first indication for PTC 8x7 to the ALF. With the successful completion of the Phase 1 Healthy Volunteer Study, we are planning to initiate the Cardinals Phase 2 trial in the second quarter of this year. This Global Registration Directed Trial is a 24-week placebo-controlled study with change in ALS-FRS scale as the primary endpoint. We'll provide more details on the trial as we move closer to initiation. Turning the actual amount of balls.

Yes.

With the successful completion of the phase one healthy volunteer study, we are planning to initiate the Cardinal phase III trial in the second quarter of this year.

This global registration directed trial is a 24 week placebo controlled study with change in ALS FRS scale as the primary endpoint we.

We will provide more details on that trial as we move closer to initiation.

Turning now to our metabolic platform, we initiated the affinity phase III clinical trial for PTC 93 in PKU patients in 2021 and are expecting trial results by the end of 2022.

Matt Klein: We initiated the Affinity Phase III clinical trial for PTC923 and PKU patients in 2021 and are expecting trial results by the end of 2022. As a reminder, Affinity is a double-blind, placebo-controlled trial that includes a run-in phase to identify PTC923 responders who will then be randomized to receive either PTC923 or placebo for six weeks. The ability to identify and enroll only responders to PTC-923 significantly enriches our primary analysis popular, As with previous approved therapies for PKUs, the primary endpoint of the affinity trial is a reduction of blood fennel health.

As a reminder, affinity is a double blind placebo controlled trial that includes a running.

Two identify PTC 93, responders, who will then be randomized to receive either.

Why two three or placebo for six weeks.

The ability to identify and enroll only responders to <unk> 93 significantly enriching our primary analysis population.

As with previous approved therapies for PKU. The primary endpoints of the affinity trial is a reduction of blood panel.

Turning now to PTC 518 from our siphoned platform, we remain on schedule to initiate the phase II Kenneth HD study in patients with Huntington's disease this quarter.

Matt Klein: Turning now to PTC 518 from our splicing platform, we remain on schedule to initiate the phase two PIVOT HD study in patients with Huntington's disease this quarter. The PIVOT-HC study will consist of two parts, an initial 12-week placebo-controlled phase focused on PTC 518 pharmacology and pharmacodynamics, and the PIVOT-HC study will consist of two parts, an initial 12-week placebo-controlled phase focused on PTC 518 pharmacology and, followed by a nine-month placebo-controlled phase focused on PTC508 biomarkers. The study will initially include two dose levels of PTC 500, five milligrams in 10 minutes.

The pivot HD study will consist of two parts and initial 12 week placebo controlled phase focused on PTC five eight pharmacology and Pharmacodynamic effect, followed by a nine months placebo controlled phase focus on PTC five with a biomarker.

The study will initially include two dose levels of PTC 505 milligrams in Canada.

Matt Klein: The third grossing group may be added based on initial form of ecology and biomarker data, leveraging the titrate ability, PTC 518. The primary objectives of the Phase 2 study are to demonstrate safety, pharmacology, and evidence of HTT mRNA and protein lowering in HD patients. In addition, you will collect CSF, Plasma, and CNS Radiographic Biomark, which could provide meaningful evidence of PTC 518 treatment. As we have previously discussed, we have carefully selected the study population based on extensive review of the existing HD natural history data, to ensure that we have a population that is neither too early nor too advanced in terms of disease progression to allow for the best opportunity to demonstrate treatment effects.

A third dosing group may be added based on initial pharmacology and biomarker data leveraging the titrate ability.

Right.

The primary objectives of the phase II study are to demonstrate safety pharmacology and evidence of HTC mrna and protein lowering HD patients.

In addition, you will collect CSF plasma and CNS radiographic biomarker.

Which can provide meaningful evidence of PTC <unk> treatment effect.

As we have previously discussed we are carefully select the study population based on extensive review the existing HD natural history data to ensure that we have a population that is neither too early or too advanced in terms of disease progression to allow for the best opportunity to demonstrate treatment effect.

Matt Klein: I am proud of our development team's efforts and accomplishments in 2021, and look forward to providing updates on the numerous milestones that we anticipate this year. I will now turn the call over to Eric for an update on our commercial progress, Eric. Thanks, Matt.

I am proud of our development team's efforts and accomplishments in 2021 and look forward to providing updates on the numerous milestones that we anticipate this year.

I will now turn the call over to Erik for an update on our commercial progress Eric.

Eric.

Eric Pauwels: It is exciting to see the great progress of our late-stage clinical pipeline, and our global customer-facing team is well-poised to leverage our expertise and footprint to bring these treatments to patients. Our team has delivered another excellent quarter worldwide building on the significant momentum created during the year and closing out what has been the strongest year for PTC commercial success. Our global DMV franchise continues to grow across existing main markets and via new geographic expansions.

Thanks, Matt.

Fighting to see the great progress of our late stage clinical pipeline and our global customer facing teams well poised to leverage our expertise and footprint to bring these treatments to patients.

Our team has delivered another excellent quarter worldwide.

On the significant momentum created during the year and closing out what has been the strongest year for PTC commercial success.

Our global DMD franchise continues to grow across existing main markets add via new geographic expansion.

Eric Pauwels: We delivered on key milestones for our products in Latin America, where we are actively commercializing a portfolio of three innovative rare disease products. And importantly, we are well positioned to execute on our potential launch of the PTC AADC gene therapy in Europe and other international markets this year, thanks to our DMV franchise. Our 2021 revenue for the franchise was $423 million, which is an impressive 28% growth over 2020. The foundation of the Implaza business continues to be solid.

We delivered on key milestones for our product in Latin America.

Where we are actively commercializing a portfolio of three innovative rare disease products and importantly, we are well positioned to execute on our preclinical launch of the PTC a agency gene therapy in Europe and other international markets. This year.

Turning to our DMD franchise.

Our 2021 revenue for the franchise with $423 million, which is an impressive 28% growth over 2020.

Eric Pauwels: Our 2021 Implaza franchise sale, was 187 million and impressive 35% growth over 2020. Operational excellence drove new patient start. More Favorable Access, Continued High Compliance, Appropriate Weight-Based Dosing, and Lower Treatment Discontinuation. Now, turning to TransLarder.

The foundation of the Plaza business continues to be solid.

Our 2021 and Plaza franchise sales.

180, 187 million and an impressive 35% growth over 2020.

Operational excellence drove new patient starts.

More favorable access continued high compliance appropriate weight based dosing and lower treatment discontinuation.

Now turning to tread, Florida.

Eric Pauwels: We achieved 236 million in 2021 net revenue, a remarkable 23% growth over 2020. The growth was due to ongoing expansion of the patient base. High Compliance, as well as Continued Geographic Expansion. While Russia was the key driver of the growth, we also continue to see growth in our main markets in Europe. In Brazil, we successfully secured a group purchase order for Tranflarna for both you and existing non-set depotions and depotions with the first part of that order delivered into semifinals. Now turning to take study in white labor.

We achieved $236 million in 2021 net revenue a remarkable 23% growth over 2020.

The growth was due to ongoing expansion of the patient base.

Hi, compliance as well as continued geographic expansion.

While Russia was the key driver of the growth. We also continued to see growth in our main markets in Europe .

In Brazil, we could.

We secured a group purchase order for trim, Florida for both new and existing nonsense mutation DMD patients with the first part of that order delivered in December .

Now turning to take steady and why Libra.

Eric Pauwels: The Latin American team is delivered on significant milestones for both franchises throughout 2021, following the waiver approval in the third quarter. We were excited to announce that we successfully received Category 1 Innovation Classification from CMED, the drug market regulation chamber in Brazil. CMED price categorization is the first critical step in getting pricing and reimbursement in Brazil.

The Latin American team has delivered on significant milestones for both franchises throughout 2021.

Following the way Libre approval in the third quarter.

Eric Pauwels: Category 1 classification is given to innovative, That provides greater efficacy than current standards of care and allows for pricing in line with international markets. Tech Steady also received Category 1 pricing in Q4 2020. Categorization of both products' innovative treatments are key milestones towards optimizing the long-term value in Latin America. Additionally, in December, we submitted an application to NVISA, for approval of Waylivra in the treatment of FPL. If approved, Waylivra will be the first approved treatment for FPL in Brazil, and this will mark the first globally approved product for this indication.

We were excited to announce that we successfully received category one innovation classification from CMS that drug market regulation chamber in Brazil.

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

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

The study also receive category one pricing in Q4 2021.

Categorization of both products with innovative treatments are key milestones towards optimizing the long term value in Latin America.

Additionally in December we submitted an application to anything so.

For approval of Libre in the treatment of <unk> L. If approved with Libra will be the first approved treatment for FBL FPL in Brazil, and this will mark the first globally.

Other product for this indication.

Eric Pauwels: This application has been submitted under the rare disease pathway, and we anticipate it a decision in the second half of 2022. I will now touch on the preparation for PTC's first gene therapy launch for PTC AADC I will now touch on the preparation for PTC AADC's first gene therapy launch for PTC, I am very confident that our team is well prepared to execute on the potential launch of PTC AADC, which we anticipate will occur in Europe shortly after final approval.

This application has been submitted under the rare disease pathway and we anticipate a decision in the second half of 2022.

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

Cool.

I am very confident that our team is well prepared to execute on the potential launch of <unk>.

The agency, which we anticipate will occur in Europe . Shortly after final approval.

Eric Pauwels: PTC's efforts to accelerate patient screening and Identification Activities in Enriched High-Risk Populations continue to progress well. Significant progress has been made with the identification and preparation of expert pediatric neurological centers of excellence and advancing medical education throughout the European Union and other key markets to ensure treatment center readiness at the time of launch. We remain focused on identifying patients globally in markets where gene therapies are accessible and reimbursed. Now, let me turn the call over to Emily for a financial update. Emily: I'm sorry, I'm sorry, I'm sorry. Thanks, Eric.

Ptc's efforts to accelerate patient screening and.

And identification activity in enriched high risk populations continue.

<unk> continues to progress well.

Significant advancement has been made with the identification and preparation of expert pediatric neurological centers of excellence and advanced Medical education grew up in European Union and other key markets to ensure treatment center readiness at the time of launch.

We remain focused on identifying patients globally in markets, where gene therapies are accessible and reimbursed.

Now, let me turn the call over to Emily for a financial update.

All right.

Emily Hill: In 2021, we continue to see strong commercial growth and achievements across our pipeline. We have worked position PTC to deliver on a number of planned, value-creating milestones in 2022. The press release issued earlier this afternoon summarizes the details of our fourth quarter and year-end 2021 financial results.

Thanks, Zach and 2021, we continue to see strong commercial growth and achievements across our pipeline.

We have worked to position PTC to deliver on a number of planned value creating milestones in 2022.

The press release issued earlier this afternoon summarizes the details of our fourth quarter and year end 2021 financial results.

Emily Hill: I will take a few minutes now to review those financial results and our 2022 guidance. Please refer to the press release for any additional details. Let me begin with our top line results. We reported 538.6 million in total revenue for the fully year 2021, compared to 380.8 million for the fully year 2020. Revenue growth was primarily driven by our global DMD franchise, with total franchise revenue of $423 million as compared to $331 million in 2020. TransLarna Net Product Revenues were $236 million for the year, compared with $191.9 million for the full year 2020, for a year-over-year growth of 23%.

I will take a few minutes now to review the financial results and our 2022 guidance. Please.

Please refer to the press release for any additional details.

Emily Hill: From FAVA, net product revenues were $187 million for 2021, compared to $139 million for the full year 2020. We recorded $109.7 million in collaboration and loyalty revenue for the full year 2021, as compared to $47.4 million in the full year 2020. This increase was due to an increase in a RISD royalty revenue and three milestone payments. In 2021, we recognized royalty revenue of $54.6 million compared to $4.8 million in 2020. We achieved milestones in 2021 of 20 million for the first commercial sale in the EU. 10 million for the first commercial sale in Japan, and the 25 million sales-based milestone for reaching 500 million and six.

Let me begin with our topline results.

$538 6 million in total revenue for the full year 2021, compared to $380 8 million for the full year 2020.

Revenue growth was primarily driven by our global DMD franchise with total franchise revenue of $423 million as compared to $331 million in 2020.

Trends are in our net product revenues were $236 million for the year compared with $191 9 million for the full year 2023 year over year growth of 23%.

From father net product revenues were $187 million for 2021.

Compared to $139 million for the full year 2020.

We recorded $109 7 million in collaboration and royalty revenue for the full year 2021.

As compared to $47 4 million in the full year 2020.

This increase was due to an increase in <unk> royalty revenue and three milestone payments.

In 2021, we recognized royalty revenue of $54 6 million compared to $4 8 million in 2020.

We achieved milestones in 2021 of 20 million for the first commercial sale in the EU.

$10 million for the first commercial sale in Japan, and the $25 million sales based milestone reaching $500 million in SAP.

Turning now to 2022, our total revenue guidance of 700 $715 million, which includes expected revenue contributions from all of our approved commercial products and projected revenue sales.

Emily Hill: Turning now to 2022, our total revenue guidance is $700 to $750 million, which includes expected revenue contributions from all of our approved commercial products and projected revenue sales, for PTC AAGC. Also included in our guidance is an anticipated sales-based milestone from Roche of $50 million, which would be reached upon $750 million in annualized sales of Everest. There is the possibility of an additional 100 million milestone payment if sales of a VRZXC'd $1.5 billion in 2022.

PTC ADC.

Also included in our guidance is an anticipated sales based milestone from Roche of $50 million, which would be reached <unk> $750 million in annualized sales of that risky.

There is the possibility of an additional $100 million milestone payment it sounds that the prestige <unk>, one 5 billion in 2020 kit.

Emily Hill: However, this potential milestone is not included in our 2022 guidance and remains potential upset. As a reminder, PTC retains 100% of all milestone payments and 57% of royalties under our agreement with royalty farmers, 100% of the royalties from EBRSDI will be retained by PTC once we reach the cap of $1.3 billion. Non-GAP R&D expenses were $487.1 million for the full year 2021, excluding $53.6 million in non-tash stock-based compensation, compared to $438.9 million for the full year 2020, excluding $38.7 million in non-cash stock-based compensation expense. Non-GAAP SG&A expenses were $235.9 million for the full year 2021, excluding $49.9 million in non-cash stock-based compensation expense compared to $213.6 million for the full year 2020, excluding $31.6 million in non-cash stock-based compensation expense.

However, this potential milestone is not included in our 2022 guidance and remains potential upside.

As a reminder, PTC retains 100% of all milestone payments and 57% of royalties under our agreement with royalty pharma.

100% of the royalties from Everest he will be retained by PTC. Once we reach the one 3 billion.

non-GAAP R&D expenses were $487 1 million for the full year 2021, excluding $53 6 million of noncash stock based compensation expense.

Compared to $438 9 million for the full year 2020.

Excluding $38 7 million in noncash stock based compensation expense.

non-GAAP SG&A expenses were $235 9 million for the full year 2021.

Excluding $49 9 million in noncash stock based compensation expense compared to $213 6 million for the full year 2020, excluding $31 6 million in noncash stock based compensation expense.

Operator: We anticipate non-GAAP R&D and SG&A expense for the full year 2020 to be between $800 and $850 million, excluding approximately $115 million in estimated non-cash stock-based compensation expense. Cash, Cash Equivalents, and Marketable Securities totaled $773.4 million as of December 31, 2021, compared to $1.1 billion as of December 31, 2020. I will now hand the call over to the operator to start our question and answer session. Operator. As a reminder, if you'd like to ask a question at this time, please press the star, then the number one key on your touchtone telephone. To withdraw your question, press the pound key.

We anticipate non-GAAP R&D and SG&A expense for the full year 2020 to be between 808 hundred $50 million, excluding approximately 115 million in estimated noncash stock based compensation expense.

Cash cash equivalents and marketable securities totaled $773 4 million as of December 31, 2021.

<unk> to $1 1 billion as of December 31, 2020.

I will now hand, the call over to the operator to start our question and answer session.

Greater.

As a reminder, if you'd like to ask a question at this time. Please press. The Star then the number one key on your Touchtone telephone to withdraw your question press the pound key.

Alethea Young: Our first question comes from Alethea Young with Cantor. Hey guys, thanks for taking my question and congrats on all the progress that you've made so far. It's exciting. Next 12 months. Maybe just like one and then maybe a little quick one throw in there.

Our first question comes from Olivia Young with Cantor.

Hey, guys. Thanks for taking my question and congrats on all the progress that you've made so far it's exciting next 12 months.

Maybe just like one and then maybe a little quick one throw in there can you just maybe frame for us I know, Germany might be the first market for ADC. Just is there any more color you can give about like how many patients do you kind of think might be there. How we should think about kind of a contribution of Europe and then the second part of that question is just in the United States can you just give us a refresher on where you are exactly.

Alethea Young: Can you just maybe frame for us? I know, you know, Germany may be the first market for ADC. Just is there any more color you can give about like how many patients you kind of think might be there? How we should think about kind of contribution of Europe?

Stuart Peltz: And then the second part of that question is just in the United States. Can you just give us a refresher on where you are exactly with, you know, kind of getting to the finish line and have any kind of new other matters or concerns, you know, kind of popped up? Thank you. Yeah, sure. Yes. Thanks, Alicia.

And you know kind of getting to the finish line and have anything kind of new other matters of concern in our kind of popped up thank you.

Stuart Peltz: Thanks for the questions. I think, yeah, so we've been working hard to identify patients, develop sites, centers of excellence, so that on approval, we're ready to be moving forward. And I think, you know, as you've probably seen in some of the clips that we have, this is clearly a transformational drug. Maybe, Eric, why don't you talk a little bit about where we are in terms of getting ready for the launch, and then Matt could talk a little bit about the trial question. Yeah, absolutely, Alicia.

Yeah sure. Thanks, Alicia Thanks for the.

The questions.

Yes, so we've been working hard to identify patients developed sites.

Centres of excellence.

That on approval, we're ready to go.

Moving forward as I think you probably have seen in some of the.

The clips that we have this clearly a transformational drugs maybe.

Maybe Eric why don't you talk a little bit about where we are in terms of getting.

You'll be ready for the launch of a math could talk a little bit about the trial question.

Eric Pauwels: We have been very excited with the progress that we've been making in terms of patient finding. We've expanded a lot of our activity. Screening Programs in many of those countries in Europe. We do anticipate the first country to launch will be Germany.

Yeah, absolutely yeah, we have been very excited with the progress that we've been making in terms of patient finding.

We've expanded a lot of our activity screening programs in many of those countries in Europe , we do anticipate the first country to launch will be Germany.

Eric Pauwels: And of course, we'll have free pricing for a period of time and we hope to treat as many ADC patients. But we will also be exploring early access programs that are currently available to these treatments. So clearly there are a number of European countries and international markets that following the European approval, we will be able to begin to access and begin to discuss the value proposition.

And of course, we will have free pricing for a period of time and we hope to treat as many agency patients, but we will also be exploring early access programs that are currently available to it.

These treatments. So clearly there are a number of European countries and international market.

Following the.

European approval.

We will be able to begin to access and begin to discuss the value proposition.

Eric Pauwels: Our focus has really been to prepare sites of centers of excellence and patient identification and the majority of our efforts have really paid off. We've been seeing new patients coming in quarter on quarter, the disease and educational programs that we have in the testing that we've been doing has been giving us much higher yields, particularly in those enriched populations. [inaudible] So the sequence will be a typical kind of European sequence with Germany, a number of key early access markets, and then international markets that follow, following the first launch, from the U.S. [inaudible] Yes, so I leave this matter. I can take that question.

Our focus has really been to prepare sites or centers of excellence and patient identification and the majority of our efforts have really paid off we have been seeing.

New patients coming in quarter on quarter, the disease and educational programs that we have of the testing that we've been doing has been giving us much higher yields, particularly in those enrich populations. So the sequence will fit will be a typical kind of European sequence with Germany, a number of key early access markets and then <unk>.

National markets that follow following the first launch in Germany.

And then the U S.

Matt Klein: So first, as you pointed out, we expect to be moving forward in Europe and expect an opinion now in April of 2022. There was some additional manufacturing biological data that the CHMP had asked for when the process of collecting that data will have that anybody had to disquiet or put us in a position for the opinion in April. We're in a process of getting ready to meet with the FDA to align on the submission package and obviously we're going to avail ourselves in the future.

Yes.

If not I'll I can take that question so.

As you pointed out we expect to be moving forward in Europe , and we expect an opinion now in April of 2022, there was some additional manufacturing biological data that they see HMT ASP or we're in the process of collecting that data we'll have that in by the end of this quarter and put us in a position to the <unk>.

And in April .

We are in a process of getting ready to meet with the FDA to align on the submission package and obviously, we are going to avail ourselves of the new bioanalytical data, we're generating in support of the MAA.

Matt Klein: New Bioanalytical Data We're Generating in Support of the MAA, and so we'll be including that along with the data we have from the county-level treatment cases, and with that we plan to submit the BLA in the second quarter of the year. Awesome.

So including that along with the data we have from the carryover treatment cases, and with that we plan to submit the BLA in the second quarter of this year.

Awesome. Thank you.

Matt Klein: Thank you. Our next question comes from Joseph Dome with Cowan. Thank you very much for taking more questions and congrats on the progress because there are a couple more on AADC. In terms of the label itself, do you anticipate any sort of guidance on age group or patient size, either in the U.S. or a European label, and then we need to talk about reimbursement. I know for what this may cost, other cities kind of pay for performance models.

Our next question comes from Joseph Thome with Cowen.

Hi, there thank.

Joseph Dome: Are you debating various ways to get this reimbursed? Great, yeah. So, Matt, you want to take the first one?

Thank you very much for taking our questions and congrats on the progress.

More on ADC.

In terms of the label itself do you anticipate any sort of guidance on age group or patient size.

Either in the U S or European label, and then you talk about reimbursement.

Sure.

<unk> cost others have used kind of pay for performance models are you debating various ways to get to three members.

Right Yeah.

So Matt do you want to take the first one.

Matt Klein: Yeah, absolutely. I think what's really impressive, Joe, about this, the package for ADC is the consistent demonstration of treatment effect across patients of all pediatric age groups, even into early adulthood. So what we really have is a body of data demonstrating not only an important biomarker response in the early months following treatment, but then significant improvement in motor function, achievement of motor milestones. We have children who are unable to move at all and can now walk.

Yeah, absolutely I think what's really impressive Joe about the package for a period is the consistent demonstration of treatment effect across patients. So all pediatric age groups even into early adulthood. So what we really have is a body of data demonstrating not only.

An important biomarker response in the early months following treatment and significant improvement in motor function and achievement of motor milestones. We had chosen who are unable to move at all and can now walk. So it's really an impressive clinical package that has been demonstrated in patients of all different age groups and part of that is because adcs.

Matt Klein: So it's really an impressive clinical package that has been demonstrated in patients of all different age groups. And part of that is because AADC is not a neurodegenerative disease, rather all of the networks and and coordination that would be needed for motor function remain in place. What's missing is dopamine. And so with the provision of the gene therapy, the dopamine can now be produced, and all of those coordinated movements and such can happen.

Not a neurodegenerative disorder.

All of the networks and.

And.

Coordination that would be needed for motor function remain in place, what's missing is dopamine and so with the provision of the gene therapy. The dopamine cannot be produced and all of those coordinated movements and such can happen and I bring that up because that's the reason why we wouldn't expect that to necessarily be a treatment effect difference based on age.

Matt Klein: And I bring that up because that's the reason why we wouldn't expect there to necessarily be a treatment effect difference based on age. While younger patients certainly do well, we're seeing impressive results in all different age groups. So at this point, really, the package includes that breadth of age. And, you know, we can't comment whether there'd be any restrictions in age at this point.

While younger patients certainly do well, we're seeing impressive results at all different age groups. So at this point willing to package includes that breadth of age.

We can't comment whether.

Stuart Peltz: And again, we're putting forward a data package that's really strong in terms of treatment effect across all the ages that we treat. And in terms of reimbursement, let me just say that, first of all, I think, you know, from a payer perspective, I'd say we have a really strong package where we have really five years of clinical data, five years of follow-up after that. We show all the patients actually responding.

Maybe any restrictions in Asia at this point.

So all of the data package, that's really strong in terms of treatment effect across all of the agents that we train.

Yes.

And in terms of reimbursement, let me just say that first of all I think from a percent perspective.

We have a really strong pack is where we have really five years of clinical data five years of follow up after that we show all of the patients actually risk.

Responding it's transformative.

Stuart Peltz: It's transformative where you see, you know, younger children being able to go from being floppy babies to walking. And then there's biomarker data demonstrating that dopamine is made continuous for long periods of time. So from a payer's perspective, I think the package is actually quite strong. It's obviously also a ultra-rare patient population. And so we expect that it'll have really small budget impact with it. And if you look at another ultra-orphan product, such as the Orchard Gene Therapy for MLD, that was priced at three and a half million dollars. And that's about twice as big, as the, as, as AADC.

Younger children being able to go from being sloppy payments to sort of walked in.

And then there's biomarker data demonstrating that the dopamine.

<unk>.

Concern was for long periods of time, so from a payer's perspective, I think the package is actually quite strong and it's obviously also a ultra rare patient population.

And so we expect it will have really small.

And the impact with it.

If you look at another.

Ultra orphan products such as well.

The Orchard gene therapy for MLG that.

It was priced at three and a half.

Millions of dollars and that's about twice as big.

As the.

D C. So I think you know we think the pack, but the package is incredibly strong a highly valuable product. So I think we're excited about this and so.

Eric Joseph: So I think, you know, we think the pack, but the package is incredibly strong, highly valuable product. So I think we're excited about this. And so, you know, on approval, we'll talk more about the pricing, but we think it's a highly valuable product. Great, thank you very much. Our next question comes from Eric Joseph with J.P. Morgan. Hi, good afternoon.

An approval will talk more about the pricing, but we think it is a highly valuable product.

Great. Thank you very much.

Our next question comes from Eric Joseph with JP Morgan.

Eric Joseph: Thanks for taking the questions. A few on TransLerna from us. First, Vivek, Eric, can you kind of speak to the brand's exposure to Russia and whether you see any impact in being able to access that market from sort of the rising geopolitical tensions with Ukraine? Is your top line guidance at risk at all on the lower end without Russia or sales in Russia? And then looking longer term, I guess, given all the experience, commercial exposure and D&D, what, if any, are the avenues to extend the market exclusivities in TransLana and in Plaza beyond their current terms? How should investors be thinking of any additional R&D or BD activity within D&D to backfill the franchise? Thanks.

Hi, good afternoon, thanks for taking the questions.

A few on Translarna from Us first.

Okay.

Maybe Eric can you kind of speak to the brand's exposure.

Two Russia, and whether you see any impact.

Being able to access that market.

Why is he.

Geopolitical tensions with that with Ukraine.

Is your topline guidance at risk at all.

Lower end without Russia sales into Asia.

And then looking longer term.

I guess given all the experienced commercial exposure in DMD, what if any are the avenues, which then the market exclusivity to Translarna and plaza beyond their current terms.

Should investors be thinking here.

Additional R&D or BD activity within.

DMD that tobacco.

Thanks.

Stuart Peltz: Yes, sure, so, in terms of... [inaudible] You know, you're, you're between Russia and Ukraine, it's obviously a highly valuable, volatile situation and will, Closely, watch, the rest of the, The Geopolitical Tensions, and as the situation unfolds, we'll plan accordingly in how to adjust the business. But we've always had puts and takes within our guidance. So as such, we're not changing the guidance as a consequence of that. We'll need to learn more, obviously, about what the sanctions, and if they'll affect things like medical. So that's time only to tell someone about that.

Yes sure so.

In terms of.

Obviously, it's unfortunate.

What's occurring.

Europe .

Between Russia.

Ukraine is obviously a highly volume volatility.

What's your where you said there will be closely watching.

Russ.

The geopolitical tensions.

Understood.

As the situation unfolds, we'll plan accordingly, and how to adjust the business, but we will always have puts and takes within our guidance so as such.

We're not changing the guidance is the consequence of that when we get to learn more obviously about.

What the sanctions and the look back.

<unk>.

Things like medical so thats time always tell somewhat above that.

Eric Pauwels: Then the second question was... Commercial Exposure and how, in terms of what we're doing with Tech Study and WayLead for the long run. Oh, Eric, no, it was more about, sorry, sorry, more about d&d IP runway, any strategies to extend it, and whether you're doing a useful investment.

The second question was.

Commercial.

Exposure and how in terms of what we're doing with Tech February we broke the long run.

Eric.

It was more about sorry, sorry city with more about <unk>.

AMD IP runway and he says this extended and whether you're doing additional investment segment.

Eric Pauwels: Yeah, Eric, you want to talk a little bit about that? Yeah, sure, you know, and Eric, I would just say, just on the Russia situation, we're watching that closely, but, you know, we have a very important and dedicated team in Russia on the ground that will ensure the continuity of product. We have patients on TransLarna, and as you know, they received TransLarna already. So we're watching that very, very, very closely, and we don't think there's going to be an overall impact to the overall revenue guidance that Emily and Stuart provided.

Eric you up a little bit about that.

Yes sure.

And Eric I would just say just on the Russia situation, we're watching that closely but we have a very important and dedicated team in Russia on the ground that will ensure the continuity of product.

We have patients on trends, Florida as they were.

C Translarna already so we're watching that very very closely and we don't think that's going to be an overall impact to.

So the overall revenue guidance that Emily and Stuart provided on.

Eric Pauwels: You know, on the IP situation, we know that the IP will, loss of exclusivity for Implaza will be in 2024, but we have a number of different programs that we're actually working on at this stage that look at various ways to capture the patient, hold the patient, because we've been providing exceptional service around Implaza, and we don't know at this point in time that there's going to be the kind of rapid erosion. We have a feeling that we're going to be able to maintain a number of these patients.

On the IP situation, we know that the IP loss of exclusivity for employers will be in 2024, but we have a number of different programs that we're actually working on at this stage that look at various ways to capture the patient home patient because we've been providing exceptional service around and Plaza and we don't we don't know it.

At this point in time.

There's going to be the kind of rapid erosion, we have a feeling that we're going to be able to maintain a number of these patients and we have a number of key programs.

Eric Pauwels: And we have a number of key programs, both in terms of model to distribution and patient capturing and retainment for Implaza. For TransLarna, we obviously have extended patent protection that goes beyond well into 2029 and potentially beyond.

Both in terms of model to distribution and patient capturing and retained for a plaza.

For Translarna, we obviously have extended patent protection that goes beyond.

Into 2029 and potentially beyond.

Eric Pauwels: You know, our goal is to continue to innovate. And of course, with the upcoming results, hopefully vote for one, we could also have a nice runway in the US with TransLarna potential approval and the FDA. So, and that would give us an additional amount of runway.

Our goal is to continue to innovate and of course with the upcoming results hopefully both for one we could also have a nice runway in the U S.

With the trends Lauren a potential approval and the FDA, so and that would give us some additional amount of runway. So we have dedicated teams that are working on.

Eric Joseph: So we have dedicated teams that are working on all aspects around the IP for both products. And, you know, I have to say that we're really doing a lot at the patient level to ensure that we're capturing and making that the best experience. I hope that answers your question. It does, thanks.

All aspects around the IP.

For both products and.

I have to say that we're really doing a lot at the patient level to ensure that we're capturing and making up the best experience.

If that answers your question.

Eric Joseph: If I could sneak in one more related to EBRSDI. As we're looking toward the potential label expansion for the pre-symptomatic population based on the Rainbow Fish Study, can you just maybe describe how you and Roche are thinking about the market opportunity there and its competitive positioning? Are there any particular geographies that might be more receptive to EBRSDI over Zolgensma or Spinraza in the pre-symptomatic patient population?

It does thanks, if I could sneak in one more.

Related to a rosy.

As were looking.

Toward the.

Central label expansion recent somatic population based on the Rainbow fish study.

Can you just maybe describe how you and Roche is thinking about the market opportunity there.

Competitively.

<unk> positioning.

Are there any particular geographies that might be more receptive to <unk> Uber.

So, it's all judgment or spin rather than the patient somatic fish population.

Stuart Peltz: Yeah, I think, you know, as you alluded to, we recently announced some results from the Rainbow Fish Study where we evaluated both the safety and efficacy of RISD and pre-symptomatic SMA babies from birth to six weeks of age. And we saw that an overwhelming number, about 80% of the pre-symptomatic infants, that were treated for at least 12 months achieved the motor milestone, such as Sidney Rowley, probably Sam, and Walking Independently. In a sense, similarly to what normal health, So it's really quite exciting.

Yes, I think I assume.

As you as you alluded to we recently announced some results from the radio to study were <unk>.

Both the safety and efficacy.

Or is the pre symptomatic SMA babies.

Birth to six weeks of age.

We saw that overwhelming number about 80% of the pre symptomatic infants.

We're treating it with them.

Dennis.

For at least 12 months achieved the motor milestones.

Let's just say the rolling crawling standing.

And walking independently.

Similarly too.

What.

Normal healthy babies, so it's really quite a bit.

Stuart Peltz: And that we, you know, we put an SNDA in for that, so that these kids could get that. And I think... First of all, I think, you know, obviously, in places in particular where they're doing, in Europe does a fair amount more of this in terms of identification of newborn screening and filing. We, you know, we think in those countries that would make it available.

And that we put in that sense.

Yes.

So that these kids to get that.

And I think.

First of all I think obviously in places in particular, where they're doing in Europe .

They're much more of this in terms of identification, though.

Newborn screening and finally.

We've taken those countries.

Make it available.

Stuart Peltz: And so the trick here is, you know, really to be the first to do that, and you'll be able to do, I think, one of the major advantages that you could have in the whole treatment for pre-symptomatic babies who have SMA. So I think we think that's a really big advantage. And that will, all over, all over the world, we think it's something that people will want to take and could take, not only during the early stage but throughout their life, and its efficacy over the long term has a major advantage. Okay, great.

And so the trick here is really to be so.

First to be able to do that.

I think one major advantages that you can do with the whole treatment for a pre symptomatic babies, who have SMA. So I think.

I think that's a real major damage.

Well in all over all over the world, which is something that people will.

I wanted to take it could take.

Not only during the early stage, but throughout.

The life and death.

Its efficacy over the long term is a major advantage.

Okay, great. Thanks for taking my questions.

Eric Joseph: Thanks for taking the questions. Our next question comes from Raju Prasad with William Blair. Thanks for taking the question. I just want to get your thoughts on some of the clinical holds that we've seen in some of the PKU programs, and maybe, you know, how that impacts or how you are looking at the commercial market, you know, kind of in the long term for 923, given, given kind of a gene therapy holdups, Yeah, so I think that's, you know, obviously, that's an interesting uh points you've seen where we've seen it in two different trials with two different viral vectors um having issues as a consequence of in terms of the viral vectors that they both have been put on hold. And so that's sort of, you know, with the team therapy and, you know, the, that consequences of that. You know, could be for large quantities of the enzymes that were produced.

Our next question comes from Raju Prasad with William Blair.

Thanks for taking the question.

Want to get your thoughts on some of the.

Clinical hold that we've seen in some of the PKU programs.

And maybe.

How that impacts or how you are looking at the commercial market.

No kind of in the long term for 923 given given.

Kind of a gene therapy holdups.

Yeah. So I think that's obviously.

That's an interesting.

Points, you've seen where we've seen it in two different trials with two different viral vectors.

Having.

Issues as a consequence of.

In terms of the viral vectors that people have been.

Put on hold.

And so that's sort of what to do.

<unk> therapy.

The exact consequences of that.

It could be for large quantities of <unk>.

Of the enzymes that were produced its unknown really but again the advantage that we have is that it's an orally bio available molecule.

Stuart Peltz: It's unknown really but again, the advantage that we have is that it's enormous, by Available Knowledge, and that I think that's a real major advantage for us that you could take, that read it taken orally, we know that that you can do this without this sort of issue. So we think obviously, that's a real advantage to us as you think of it compared to what we're trying to do in terms of our gene therapy. So we think there's a real advantage in terms of our molecule which we think has a real advantage there.

And that.

I think that's a real major advantage for us that you could take that.

Rather it taken orally, we know that.

You can do this without sort of issues. So we think obviously.

Sure.

That's a real advantage to us.

Picked up there compared to what we're trying to do in terms of our gene therapy. So we think there's a real advantage in terms of our molecule.

Which we think has a real live.

Vantage there, but also when you think about it in terms of.

Stuart Peltz: But also when you think about it in terms of targeted gene therapy and the strategy that we we've taken which is really goes directly to the tissue that we need to get the gene therapy at and to do relatively low levels I think it's a major advantage, for what we're doing in terms of gene therapy. And that's one of the reasons why we took this approach. We didn't want to have a systemic use concentrations at the very beginning and have to be able to spend more time understanding and to be able really to go into low levels that first move into gene therapy that way. So I think, It's, you know, clearly in the PKU, there's been no really proof of concept in PKU yet.

Targeted gene therapy in the strategy.

We've taken which is there.

Really goes directly to the tissue that we need to get the gene therapy.

And to do relatively low levels I think is a major advantage for what we're doing.

In terms of the gene therapy, and that's one of the reasons why we took this approach we didn't want to have the stomach huge concentrations.

At the very beginning and be able to spend more time understanding and there'll be able really to go into low levels, but first move into gene therapy that way so I think.

It's <unk>.

Clearly in the PKU. This then.

No really proof of concept in PKU, yet so I think there's obviously a need for an oral therapy.

Stuart Peltz: So I think there's obviously a need for an oral therapy. Great, and then on AADC, I know in previous quarters, you've kind of talked about number of patients that have been identified. You know, at this point, is there, do you have a sense of number of patients that have been identified in EMA territories versus the U.S. and kind of how you're looking at, I think someone else asked about kind of country by country, but how you're looking at the launch just given where you've identified patients so far. Thanks.

Great and then on ADC and I know in previous quarters, you've kind of talked about number of patients that have been identified.

At this point is there do you have a sense of.

Number of patients.

That had been identified an EAA territories versus.

The U S and kind of how youre looking at think someone else asked about kind of country by country, but how are you looking at the launch just given where you've identified patients so far thanks.

Stuart Peltz: Yeah, no, I think, you know, I understand. You know, we've been obviously really been working hard in terms of identification. We said we've identified about 300 patients worldwide. We haven't broken it out, but I think we're in a pretty good position to be able to on approval, be able to, you know, rapidly bring patients, you know, be able to perform this, get center of excellences up in terms of being able to do, So we think we're in a good position to keep going, and I think at the end of the day, we're making very good progress, in terms of finding patients.

No I think I understand.

Obviously really been working hard in terms of the Densification, we separately identified.

300 patients worldwide, we haven't broken it out, but I think we're in a pretty good position to be able to on approval.

Able to.

Rapidly bring patients.

Be able to perform this gift center of excellence is up in terms of being able to do.

Do that so we think we're in a good position to keep going and I think.

At the end of the day.

We're making very good progress.

Stuart Peltz: And I think we'll continue to find patients in particular on approval in the fact. And even now we're seeing that the quicker uptake in terms of patient numbers as a consequence of people beginning to understand that there'll be a treatment board. We've seen this time and time again with older orphan diseases that as treatments begin to come on board, you find more and more patients. We've seen this time. We've seen this time. We've seen this time. We've seen this time. We've seen this time. We've seen this time. We've seen this time.

In terms of finding patients and I think we'll continue to find patients.

In particular on the approval and the fact and even now we're seeing just a quicker uptake in terms of patient numbers as a consequence of people beginning to understand that there'll be a treatment for it and we've seen this time and time again.

With.

Ultra orphan diseases that is treatments begin to come on board.

More and more pensions and theres more and more patients than you thought there would be.

Stuart Peltz: And there's more and more patients than you thought there would be as a consequence of that because there's now a treatment for these patients and physicians begin to look at them carefully. So we think we're well positioned, to be able to do, you know, to be able to not only have identified a number of patients, but get them treated for next year, this year on the, based on the approval. Thank you.

As a consequence of that the group is now a treatment for these patients and physicians begin to look at them carefully. So we think we're well positioned.

To be able to do.

Not only have been identified a number of patients.

Treatment for next year.

Of this year on the base on the approval.

Thank you.

Brian Abrahams: Our next question comes from Brian Abrahams with RBC Capital Market. Hey there, thanks very much for taking my questions and congrats on all the progress. Couple of quick ones on PKU.

Our next question comes from Brian Abrahams with RBC capital markets.

Hey, there thanks very much for taking my questions and congrats on all the progress.

Couple of quick ones on PKU.

Brian Abrahams: For 9-2-3, I'm curious, what are the key parameters that you're gonna be looking for in the affinity study, particularly the lead-in portion, to guide who's gonna optimally respond to 9-2-3 and how it's gonna be used in the real world? I'm curious if you envision this being used primarily in classical patients or some COVID non-responders, or perhaps more broadly in order to get more patients to be able to normalize their diet. And then my second question is also on 9-2-3.

92, three I'm curious what the key parameters that youre going to be looking for in the affinity study, particularly the lead in portion to guide who's going to optimally respond to 92, three and how it is going to be used in the real world and I'm curious if you envision this being used primarily in classical patients or some kuban non responders or.

With perhaps more broadly in order to get more patients to be able to normalize their diet.

And then my second question also on <unk> can you remind us where you are on the chronic tox studies, and maybe any similarities or differences to what preclinical signals had been observed with with Kuban in at comparable doses.

Brian Abrahams: Can you remind us where you are in the chronic tox studies and maybe any similarities or differences to what preclinical signals have been observed with Kuvan at comparable doses? Thanks. Sure. Oh, Matt, you want to take that? Sure. Hi Brian.

Sure.

Matt do you want to take that.

Matt Klein: So, your first question regarding the trial. Now, as a reminder, there was a phase two trial done with PTC 923 comparing it head-to-head with QVAN, where we demonstrated that it was a crossover study, so all subjects got treated with both 923 and QVAN, and we were able to demonstrate that 50% more patients responded to PTC 923 than to QVAN. And when you looked at the subjects who had a response to both 923 and QVAN, there was actually an over 200 greater micromole per liter reduction in phenylalanine in the 923 patients relative to QVAN.

Yeah sure Hi, Brian So your first question regarding the trial.

And just as a reminder, there was a phase III trial done with PTC <unk> comparing it head to head with Kuban, where we demonstrated that it was a crossover study all subjects treated with both <unk> and we've been able to demonstrate that 50% more patients responded to PTC.

Then to Kuban and when you looked at the subjects, who had a response to both 903 and Kuban there was actually an over 200.

Greater micro multiple lead a reduction in federal in the 93 patients relative to crude that so we're seeing that 93, they want to deliver benefit to more patients, including the classical T. K.

Matt Klein: So, we're saying that 923 is able to deliver benefit to more patients, including the classical PKU patients, and those are those with baseline levels of phenylalanine greater than or equal to 1,200 micromoles per liter. And when there was a signal of effect with QVAN, 923 had a much stronger response.

PKU patients.

Those with a baseline levels of phenylalanine is greater than or equal to 1200 microbiology the leader.

And when there was the signal effects with satellite with Kuban 93, It had a much stronger response. So that's what gives us a great deal of confidence that we can address the still.

Matt Klein: So, that's what gives us a great deal of confidence that we can address the still need for an effective therapy in the PKU marketplace. As we move forward to the phase three trial, we believe this 923 will be able to provide benefit for all patients of all ages. So, this study includes pediatric and adult populations and has this running phase where basically all potential subjects who pass screening will receive therapy with 923 for two weeks and will ask a simple question. Is there a market reduction in fentanyl levels following treatment with 93?

Need for an effective therapy in the PTC in the PKU marketplace as we move forward to the phase III trial, we believe is.

93, we'll be able to provide benefit for all patients of all ages. So this is this study includes pediatric and adult populations and has this learning phase where basically all potential subjects, who passed screening will be C therapy with 93 for two weeks and will ask a simple question.

Matt Klein: If the answer is yes, those subjects will then get randomized to receive a 93-hour placebo for the six-week placebo control phase, and the primary endpoint of that placebo control phase is reduction in fentanyl levels, in 19 through the elephant placebo. So again, based on the mechanism, based on the data we have to date, we expect to be able to provide benefit in all populations and all genotypes and degrees of severity, even those classical BKG patients, where we already been able to record the benefit in the series to study.

Is there a market reduction in selling all phenylalanine levels following treatment with 93, if the answer is yes. Those subjects will then get randomized to routine.

93 outsourcing opened six week placebo control phase on the primary endpoint is a placebo controlled phase is reduction in phenylalanine levels.

Relative to placebo. So again based on the mechanism based on the data we have to date, we expect to be able to provide benefiting all populations and all genotype and degrees of today, even those classical PKU patients, where we already are being able to record for <unk>.

In the phase two study.

Matt Klein: [inaudible] In terms of the chronic tox, we have completed all the necessary tox work needed to allow for not only, obviously, the six-week placebo control phase, which is the primary efficacy study or formal basis for the efficacy component of NMDA, pending the data, but also for the long-term safety component, which long-term open label safety portion of the study into which all patients will roll over once they complete the placebo control phase. So, those studies have been completed and we're able to now move forward with the full trial, the six-week placebo control phase, and the open label extension. Thanks so much, Matt.

In terms of the chronic tox, we have completed all the necessary Tox work can you do to allow for not only obviously the six week placebo controlled phase, which is the primary efficacy study of our form the basis for the efficacy component of NBA <unk>.

Ending the data, but also for the long term safety component, which long term open label safety portion of the study in which all patients will rollover once they complete the placebo control phase. So those those studies are complete and we're able to now move forward with the full trial.

A six week placebo control phase and the open label extension.

Thanks, so much Matt.

Dina Wang: Our next question comes from Dina Wang with Barclays David Lebowitz, David Lebowitz, David Lebowitz, David Lebowitz, Thank you for taking my questions. I just have one regarding TransLana confirmatory study 041 data in mid-2022. Could you provide different scenarios of the outcome and its impact to TransLana launch in Europe market? Yes, sure. Amin.

Our next question comes from Gena Wang with Barclays.

Thank you for taking my questions I just have one regarding Translarna confirmatory study.

One data in mid 2022.

Could you provide different scenarios.

The outcome and its impact to Translarna launch in <unk>.

Hi.

Market.

Yes sure.

Yes.

Stuart Peltz: They're just going to remind everybody. What we've done is there's study 041 that will be done. In the middle of this year, we're pretty excited about O41 because I think that we were able to utilize all the learnings that we had from the, you know, from the clinical trials that were performed to really be able to define what's the, you know, run to the right endpoints, what's the right patient population that we can study.

So just to remind everybody.

What we've done is there's study old 41 that will be done.

In the middle of this year, we're pretty excited about Oh 41, because I think that we were able to utilize all the learnings that we've had.

From the from the clinical trials that were performed really to be able to define what's the rather the right endpoints, what's the right pace.

<unk> population that we can study.

Stuart Peltz: And so I think we're in a really good position to be able to, yeah, define and show that TRANSLON is working and to use the right patient population and to use the right endpoints. Matt, do you want to talk a little bit about the details of how we're moving forward?

And so I think we're in a really good position to be able to.

Be able to defy the.

Show that Transcanada is working and to use the right patient population.

Is the right endpoints, so Matt you want to talk a little bit about the details of how we're moving forward.

Matt Klein: So, as you mentioned, we really were in a position, Gina, to leverage all of our learnings from the previous study. I think there's always previous studies, there's always the case, the key is really understanding the right patient population, the appropriate inclusion criteria, the appropriate endpoint, and the appropriate duration. And I think we have all of those coming to bear in this study. The primary analysis group is a population of seven to 16-year-olds, with a baseline six-minute walk distance greater than or equal to 300 meters and a standard supine time of greater than or equal to five seconds.

Yes sure so.

As you mentioned, we really were in a position to leverage all of our learnings from the previous study I think theres always previous studies is always the case. The key is really understanding the writing patient population the appropriate inclusion criteria the appropriate endpoint and the appropriate.

The appropriate duration I think we have all of those coming to bear in this study the primary analysis population.

Plus 7% to 16 year olds with.

With a baseline six minute walk distance.

Greater than or equal to 300 meters stand at some point in time are greater than equal five seconds of note. When we look at the previous studies when we look at our previous system setting those seven seven in 'twenty and we look at this group in those studies, we saw that we had.

Matt Klein: Of note, when we look at the previous studies, when we look at our previous two studies, study 07 and 020, and we look at this group in those studies, we saw that we had a markedly significant effect. For example, in study 07, there was a difference of 46 meters greater walk distance in treating relative to placebo. In 020, it was 43 meters greater walk distance relative to placebo.

Markedly significant affect for example, the ink.

In studying all of a sudden the there was a difference of 46 meters.

46% greater than walk distance in treating relative to placebo in <unk> 'twenty.

43 meters.

Relatives quite a few minutes later walk greater distance relative to placebo and those are getting close to the market. The statistically significant so now to be able to design a study with that exact goldilocks population is the primary analysis population is what gives us confidence in the design of the study.

Matt Klein: And those, again, both were markedly statistically significant. So, now to be able to design this study with that exact Goldilocks population as the primary analysis population is what gives us confidence in the design of the study. And as you mentioned, we expect to have results of this study in mid-year. We believe, obviously, that with a positive study, we'll be in a position to go to the FDA and be able to submit an NDA and make transalumnia available to kids in the U.S. In Europe, well, obviously, this is a component of the conditional marketing authorization.

And as I mentioned, we expect to have.

<unk> of this study in mid year.

We believe.

Obviously that was a positive study will be in a position to.

Go.

<unk> won't be able to submit an NDA in omni channel and the kids in the U S.

Europe . We're obviously this is a component of the conditional marketing authorization we.

Matt Klein: We feel that one of the more important considerations is the stride registry that we have where we've been able to, over the course of years, consistently demonstrate a significant benefit of transalumnia relative to loss of ambulation and loss of pulmonary function, which when you think about it, the clinical trials are really designed to give a picture of what you might be able to do for those significant events in the life of a DMV boy. We really use the six-minute walk test in a shorter period of time to try to say what we might be able to do in terms of preventing loss of ambulation.

We feel that one of the more important considerations as the stride registry that we have where we have been able to over the course of the years consistently demonstrate a significant benefit in terms of on a relative to loss of ambulation loss of pulmonary function, which when you think about it. The clinical trials are really designed to give a picture of what you might be able to do.

For those significant events in the life of a DMD boy, we really use the six minute walk test and a shorter period of time to try to say, what we might be able to do in terms of preventing loss of ambulation, so to be able to deal to continue to provide those data to the C. H N P, which we've been able to do and we just formed the basis of our annual renewal.

Matt Klein: So, to be able to continue to provide those data to CHMP, which we've been able to do, and which has formed the basis of our annual renewal of the conditional marketing authorization, other than showing in the most recent data cut a five-year difference in terms of loss of ambulation as well as the prevention of loss of pulmonary function, we believe is really a compelling part of the picture and I think will be an important component, remaining important component, of how the CHMP views transalumnia. So, I'm sorry, just follow up.

All of the conditional marketing authorization.

Showing in the most recent data.

A extension of it.

Five year difference in terms of loss of ambulation as well as the convention of loss of pulmonary function. We believe is really a compelling part of the picture and I think will be an important component remain important components of how you will see HMP views trademark.

Matt Klein: So if, you know, play devil's advocate, you know, if a child fails, what additional data you will need to provide to maintain TransLana on the market in Europe? Yeah, so I think that's what Matt was saying that we have a strived registry which has demonstrated years longer in terms of preventing loss of amulation, pulmonary function, being able to get off the ground. The data is really quite compelling. I think you've probably seen this as well in the publications that we've shared with you.

So sorry, just a follow up yes.

Uh huh.

Play Devil's advocate if trial for you what additional data you would need to provide to maintain translarna on the market in Europe .

Yes, so I think thats, what Matt was saying that we have described registry, which has demonstrated years longer in terms of.

Preventing loss of ambulation pulmonary function.

To get off the graph the data is really quite compelling I think you've probably seen this as well in and the publications that we've shared with you and we know that.

Matt Klein: And we know that... European, regulatory agents are very interested in that as well. So that would be a big piece of data that would, that we think, really demonstrate. Translonger's ability to prevent people from what really matters to DMV patients, which is maintaining motor functions.

European regulatory agencies are very interested in that as well so that would be a big piece of data that way.

That we think really demonstrates.

<unk> learned his ability to prevent people what really matters to DMD patients.

Maintaining motor function. So we think a lot of the renewal.

As we've talked about in the past.

<unk> been focused on the real world evidence from the strike data. So if if if like you said you wanted to play Devil's advocate if that were to happen. We believe that the strike data itself is strong enough.

That would work.

Keep it up.

The EU.

Marketplace for patients to get.

Okay. Thank you.

Danielle Brill: So we think a lot of the renewals, as we've talked about in the past, would have been focused on the real world evidence from the stride data. So if, if, like you said, you want to play devil of advocate, that where to happen, we believe that the stride data itself is strong enough, that would keep it on the EU, the EU marketplace for patients to get. Okay, thank you. Our next question comes from Danielle Brill with Raymond James. Hi guys, this is Alex Hung for Danielle.

Our next question comes from Danielle Brill with Raymond James.

Hey, guys. This is Alex on for Danielle Thanks for taking our question.

Danielle Brill: Thanks for taking our question. Could you remind us where the Angelin gene therapy program stands? Based on my notes, I'm looking at I think you were originally targeting 2021 for the IND filing. So we're just curious what needs to be done there to get that IND filed. Thanks. Yes, sure. Matt, you want to go through this a little bit? Yeah, absolutely. Hi, Alex.

Could you remind us where the engine one gene therapy program stands based on my notes I'm looking at I think you were originally targeting 2021 for the IND filing. So we're just curious what needs to be done there.

To get that IND filed.

Sure Matt you ought to go through this a little bit.

Matt Klein: We previously shared that we were in the process of completing the gating tox work to move the program into the clinic. We did have a number of delays related to COVID in terms of both its impact on our CDMOs and manufacturing CMOs as well as the global shortage of non-human primates. I'm happy to report that we are moving forward now and are continuing our work towards having the IND or CTA ready to get the program into the clinic. Kim and your future.

Yeah, absolutely Hi, Alex.

Obviously shared that we were in the process of completing the gating tox work to move the program into the into the clinic. We did have a number of delays related to COVID-19 in terms of both.

Packed on hours <unk> manufacturing Cmos as well as global shortage of non human primates are happy to report that we are moving forward now.

And are continuing our work towards having the IND or Cta ready to get that program into the clinic.

In the near future.

Great. Thanks, so much.

Matt Klein: [inaudible] Great, thanks so much. Our next question comes from Robin Karnaskis with Truist Security. Hi, thanks for taking my question. And again, congrats on all the progress. And you've got a lot reading out here.

Our next question comes from Robyn <unk> with <unk> Securities.

Robin Karnaskis: I just wanted, I actually had a question on MDS and the BioEats platform, that it's going to be coming into focus. Can you just talk a little bit more about the MI-EAT trial a little bit? I know you're enrolling patients that are, perhaps have a lot of seizures, you know, within 14 days of the run-in period within the last month. Like, what percentage of the population with MDS that you talk about kind of would fit that bucket?

Hi, Thanks for taking my question and again congrats on all the progress and you've got a lot reading out because here I just wanted I actually had a question on Mds and the bio E platform.

It's going to be coming into focus can you just talk a little bit more about.

They might eat trial, a little bit I know you are enrolling patients that are have to have a lot of things are you know what's unfortunate is the one and carrying it within the last month.

What percentage of the population with MBS and talk about kind of what's in that bucket.

Matt Klein: And can you help us understand, like, what are any of the risks with the placebo-controlled portion with the range of patients that you're enrolling and age? How variable is it that these patients have, like, a group of seizures and they stop and then they go on again? Just help us to understand.

Can you help us understand like what are any of the retrofits placebo controlled portion with a range of patients that you're enrolling in age.

Variable is it that these patients have like a group.

<unk> like that and then they go on again just help us understand.

Matt Klein: How to think about that study, and then the second question is just on, you know, the tapes, the terrible, a lot of mid-caps and platforms are on sale and thoughts on like, you know, your interest in doing M&A in this tape thing. So Matt, you want to take the.., in Mitochondrial Disease and Facial Seizures. Yeah, sure. Hi, Robin.

Trying to think about that study and then my second question is just on the take the terrible, but a lot of mid cap and platforms on cell and thoughts on like you know you're interested in doing M&A in the state.

So Matt you want to take the.

Okay.

We are mitochondrial disease.

Sure.

Yes sure.

Robin So b.

Matt Klein: So the, Mitochondrial disease associated seizures. Let's just talk a little bit about them for a second. So about 40 to 50% of all patients with mitochondrial disease have seizures as an important part of their pathology. And these seizures in mitochondrial disease patients tend to be refractory to traditional antiepileptics. That's because the energetic pathways that are disturbed in mitochondrial disease that cause these seizures are not addressed by the existing antiepileptic therapies.

Mitochondrial disease associated seizures.

Just talk a little bit about them for a second so about 40% to 50% of all patients with mitochondrial disease have seizures as an important part of that apology.

And these seizures in lot of countries patients tend to be refractory tradition to traditional anti epileptics, that's because the energetic pathways that are disturbed amount upon real disease that causes. These seizures are not addressed by the existing anti epileptic therapies in fact, many anti epileptic therapies exacerbate the energen.

Matt Klein: In fact, many antiepileptic therapies exacerbate the energetic defects that are causative of seizures in these patients. So whatever potential benefit they would have from the pure antiepileptic mechanisms of these drugs are offset by the exacerbation of the pathology-causing seizures. So it's a long way of saying these kids who have seizures have a lot of them. They're severe. They're a source of a high degree of morbidity, recurrent infections, and are typically a cause of early mortality in these patients.

<unk> set a causative of seizures in patients so whatever potential benefit that you would have from a pure anti epileptic mechanisms of these drugs are offset by the exacerbation of the pathology causes seizures.

A long way of saying these kids, who have seizures have a lot of them their severe hot source of a high degree of morbidity recurrent infections and are typically a cause of early mortality in these patients over the course of the development of the tick winnowing, we've studied particularly a number of different mitochondrial disease subtypes in the sub.

Matt Klein: Over the course of the development of the tiquinone, we've studied particularly a number of different mitochondrial disease subtypes, and these subtypes are the result of different mutations in the mitochondrial and nuclear genome responsible for mitochondrial structure and function.

Types of other results of different mutations in the mitochondrial and nuclear genome responsible for mitochondrial structure and function.

Matt Klein: And what we've seen across many different subtypes we've treated is that there's a consistent treatment effect with regards to seizure pathology, including the reduction of seizure frequency, the disruption of refractory status epilepticus, reduction in disease-related morbidity, as well in some cases where there's robust enough natural history data, we've been able to demonstrate a protective effect with regard to mortality. And so coming into the MITEI study, we really based this study on what we've seen to date in terms of effects on seizure, seizure-related morbidity and quality of life in mitochondrial disease patients of all different subtypes and all different ages.

And what we've seen across many different subtypes. We've treated is that theres, a consistent treatment effect with regards to see seizure pathology, including a reduction in seizure frequency the disruption of refractory status epilepticus reduction in disease related morbidity.

As well in some cases, where there is robust enough natural history data, we've been able to demonstrate a protective effect with regard to mortality and so coming into the Mighty study, we really base. This study on what we've seen to date in terms of effects on seizure seizure related more.

<unk> and quality of life and mitochondrial disease patients of all different subtypes and all different agents and so we developed. This this protocol is rarely a basket trial, where we focused not on specific genotype or mutation, but rather the common morbid symptoms drug resistance seizures.

Matt Klein: So we developed this protocol as really a basket trial where we focused not on specific genotype or mutation, but on rather the common morbid symptoms of drug-resistant seizures, which is quite common in these patients. And so the study is set up with the run-in phase, as you mentioned, where we ensure that there's enough observable motor seizures so we have room to demonstrate benefits. Now, it turns out many of these patients do have those frequent seizures, again, because they're typically poorly controlled by the existing therapies that are available.

Which is quite common in these patients and so the study is set up with a run in phase as mentioned, where we ensure that there is enough observable motor seizures. So we have room to demonstrate benefit it turns out many of these patients do have those frequent seizures again, because they typically poorly controlled by the existing therapies that are available and if they have that.

Matt Klein: Then if they have that requisite number of seizures, observable motor seizures, over 28 days, which is, the number is actually six, they'll then get randomized to receive the tiquinone or placebo for six months, and the primary endpoint is the change in observable motor seizures on either the tiquinone or placebo relative to the number of seizures in that 28-day run-in phase. A study design that's been well instantiated and has been used for the approval of other, in other pediatric seizure syndromes.

The number of seizures observable seizures over 28 days, which is the number is actually six sale then get randomized to receive a ticket on a placebo for six months and the primary endpoint is the change in.

Observable motor seizures.

Either a particular placebo relative to the number of seizures in that 2008 gigawatt in phase <unk> study design, that's been well instantiated and that's been used for the approval of other in other pediatric seizure syndromes. We will importantly that'll include other secondary secondary endpoints assessing other aspects of senior pathology as well as disease morbidity.

Matt Klein: We will importantly, though, include other secondary, secondary endpoints assessing other aspects of seizure pathology, as well as disease morbidity, because, again, the tiquidone's not anti-epileptic. It's rather targeting a core mechanism of disease pathology. We're simply using the seizure measurement as a way of capturing and quantifying treatment effectiveness. So, just to make sure I covered all the points here, including many different disease subtypes. We are doing stratification in order to balance enrollment of some of the more common subtypes of disease, again, so we can balance out the.., balance out any particular mutation across both the treatment and placebo arms. And again, there's no particular age limit between zero and including all pediatric patients 18 years and younger.

Because again, particularly not anti epileptic, it's rather targeting a core mechanism of disease pathology were simply using the seizure measurement as a way of capturing quantifying treatment effect in these patients.

So just.

Just to make sure I covered all your points, including many different subtypes. We are we are doing stratification in order to balance enrollment of some of the more common subtypes of the disease again, so we can balance out the.

Yes.

<unk> out any particular mutation across both the treatment and placebo arms and pays no particular age limit between zero and we're including all pediatric patients 18 years and younger again, we're focusing just on them, having that requisite number of others.

The seizures.

Ron Aldridge: Again, we're focusing just on having that requisite number of observance. So, Ron, I think, was your question on what, you know, in this space, there's a fair amount of M&A, and you wanted us to comment on it, is that what you, was that the question? I think there's a, everyone asks this question because of the low valuations for a lot of SMICAPs, you know, like what people are interested in, or if they're, you know, if they're interested in acquiring certain platforms, it's sort of like gauging your interest given the tape and whether or not you think there's a high likelihood that we'll see more M&A in the back after the year. I think that's the key question we're all asking.

So Robert I think was your question.

Question on <unk>.

What.

This space there are a fair amount of M&A and you wanted us to comment on is that what you mean.

I think that everyone asked the question because of the low valuations for a lot of mid cap what people are interested or if there.

If they're interested in.

Wiring.

Certain platforms I'm, just sort of like gauging your interest given the tape and whether or not you think.

There's a high likelihood that we'll see more M&A in the back half of the year I think that's the key question. We're all asking every earnings call.

Stuart Peltz: I think, well, you know. You know, I guess my view on that a little bit. You know, M&A is always a complicated question on people's capabilities, on what their pipeline is like, what their commercial capabilities are. Could someone do it better?

Well you know.

I guess my view on that a little bit.

M&A is always a complicated.

Question on People's capabilities on what their pipeline is like what they are and commercial capabilities or could someone do it better.

Stuart Peltz: Do people want to, are they building or are they looking to, or is their goal to become acquired? So it's sort of hard to say. I mean, obviously there's a lot of interest, in treating these diseases. But it's hard for me to say there's gonna be more or less.

Do people want.

Are they building or are they looking to two.

Sure.

We're going to become acquired so it's sort of hard to say I mean, obviously, there's a lot of interest.

And <unk> contributing visas diseases.

But it's hard for me to say, but it would be more or less at this point.

Judah Frommer: I just think, you know, obviously there's still a lot of interest in these types of drugs. Okay, thank you. Our next question comes from Judah Frommer with Credit Suisse. Hi, thanks for taking the question. Just a couple on 508 as you kind of head toward beginning enrollment there.

Obviously, there's still a lot of interest from these types of drugs.

Got it okay. Thank you.

Our next question comes from Judah Frommer with credit Suisse.

Stuart Peltz: Just maybe any feedback from the sites as you get them set up on kind of receptivity to.., out of administration, maybe versus other. [inaudible] programs that are in the clinic, how important that is to pay.., and doctors, and also touch readability given, you know, lack of specificity toward mutants. And then also, you do have a functional endpoint in there as a secondary, kind of, how are you thinking about, you know, potential to show anything there given the length of the study?

Hi, Thanks for taking my question just a couple on a $5 eight as you kind of head towards beginning enrollment there just.

Maybe any feedback from the sites as you get them set up on kind of receptivity to.

Route of administration may be versus other Huntington Huntington the programs that are in the clinic, how important that is to.

Patients.

And doctors and also titrated ability.

Given lack of specificity towards mutant Huntington.

And then also you do have a functional end point and there is a secondary kind of how are you thinking about you know potential to show anything there given the length of the study.

Sure I think.

Stuart Peltz: Sure, I think. From the first part, I think, well, you know, obviously with the Orly Bioavailable Small Molecule, the right administration, the ease of giving it, it's just a huge advantage, right? I mean, the fact is that it's easy to take; you can do it at home.

From the first part I think.

Paul.

Obviously with the orally bio available small molecule.

The route of administration, the ease of giving that.

You should plan its right at me.

Hum.

Fact is when does it take you to do it at home.

Yes.

Stuart Peltz: But I think beyond that. The real advantage... And so what comes from that...you know that it gets distributed, you know, it passes the blood-brain barrier, it gets into the brain, it gets all over every tissue. You can measure the pharmacokinetics so you know the precise concentration of free drug that's both in the plasma, that's also in the CSF.

But I think beyond that.

The real advantage come from that.

No that gets distributed.

It passes the blood brain barrier gets into the brain that gets all over time.

Every tissue you can measure the pharmacokinetics are you more of a precise concentration of free drug that's both on the plasma. That's also in the CSF. So you know there's so much you know and then when you know that when you get into this.

Stuart Peltz: So you know, there's so much you know. And that when you know that when you get it into the CSF, you know the level that's within the whole brain. Then you can measure not only the level of reduction that occurs in the plasma, so you know there's a very good response as a consequence of that.

You know the level thats within the whole brain, then you could measure not only the.

The level of reduction that occurred minimal plasma. So you know there's a very good response as a consequence of that and then you know obviously.

Stuart Peltz: And then you know... As a consequence of that, you can see the effect on biomarkers like the HTT protein direct. So there's so much you could learn and you're confident of it's getting to the right place and that when you see it's in the right place, it's all over the brain so you know that it has an effect all over. So everyone's really happy about that. I think both sites, patients, physicians, are incredibly enthusiastic on learning that.

As a consequence of that you can see the effects on biomarkers like the HGT protein directly so.

The.

So much you could learn and your confidence.

It's getting to the right place and that when you see it in the right places, it's all over the bringing some know that.

In effect all over so everyone's really happy about that I think both types of patients physicians are incredibly enthusiastic.

On learning that and then from our point of view.

Stuart Peltz: And then from our point of view, what we put the package together to look at not only the reduction of HTT levels, but also to be able to look at biomarkers. NFL. PTT, MRI, volume within the brain, and changes that occur like that, and then see if, while it's not long enough, that you have outcomes.

We put the package together.

Look at the reduction of H T T levels.

But also to be able to look at Biomarkers.

MFL http MRI.

Within the brain.

Does that occur like that and then.

While it is not long enough that you have outcome measures, but then being able based on.

Stuart Peltz: But then to be able, based on, on what's been said by Novartis and others, that we're at least in a position for if it is possible to get accelerated approval to be able to do it on that, and then be able to do long-term trials as a consequence, for Outcome Measures for Clinical Benefit. So I think we're in a real good position to look at reduction of protein levels, reduction of CSF, of HCT in the CSF, the neurofilament, preservation of blood, brain volume. I think that's a pretty good path. David Lebowitz, David Lebowitz, David Lebowitz, That concludes today's question and answer session. I'd like to turn the call back to Dr. Stewart-Pelts for closing remarks. Okay, so.

Yes.

On what the what's been said.

By Novartis and others that were at least in our position.

It is possible to get accelerated approval to be able to do it on that and then be able to do long term.

<unk> as a consequence.

For outcome measures for clinical benefit so I think we're in a real good position.

Look at reduction of protein levels.

Reduction of CSF.

H D.

<unk>.

Yeah.

The neuro filament preservation of blood brain volume I think that's a pretty good package.

Great. Thanks.

That concludes today's question and answer session I would like to turn the call back to Dr. Stuart Peltz for closing remarks.

Okay. So.

<unk>.

Stuart Peltz: First of all, let me thank you, all for joining us today so that we can discuss the progress that we've made really up-to-date to 2021. I'm really proud of the team that really continues to execute on the goals as we continue to grow. And I think we've made significant progress across our research and development pipeline with many upcoming milestones in 2022. We're driven to bring these medicines to patients around the globe.

First of all let me thank you.

All four.

Joining us today, so that we can discuss the progress that we've made.

Really up to date to 2021, I'm really proud of the team.

That really continue to execute on the goals and we continue to grow and I think we've made.

And if it can progress across our research and development pipeline with many upcoming milestones in 2022.

We are driven to bring these medicines to patients around the globe as I anticipate that 2022 is going to be a real transformative year for us and.

And we look forward.

So the progress.

Progress on updates that will give you.

Stuart Peltz: And I anticipate that 2022 is going to be a real transformative year for us. And we look forward to the progress and updates that we'll get. So, thank you for joining. This concludes today's conference call. Thank you for participating. You may now disconnect. Google, © BF-WATCH TV 2021

So thank you for joining.

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

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