Q2 2022 PTC Therapeutics Inc Earnings Call

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[music].

Good day, and thank you for standing by.

Congrats on the quarter.

Thank you.

Yeah.

Good day and thank you for standing by welcome to the PTC second quarter 2022 financial results and corporate update conference call at.

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

After the speaker's presentation, there will be a question and answer session to ask a question you will need to press star one on your telephone.

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

Welcome to the PTC Second Quarter 2022 Financial, Results and Corporate Update conference call.

Can you give us a sense, just, now having a couple more months of looking at the upstairs commercial markets under your belt on the potential cadence of kind of revenue recognition that you anticipate maybe this year?

And we'll take our next question from Danielle Brill from Raymond James.

I would now like to hand, the conference over to your speaker today.

Your line is open.

Kylie Okeefe senior Vice President head of global commercial and corporate strategy. Please go ahead.

Hey, guys, this is Alex on for Danielle.

At this time, all participants are in a listen-only

And even if you give a little more color into, you know, how you anticipate the launch going into next year, that'd be helpful.

Just wanted to.

Good afternoon, and thank you for joining us today to discuss the PTC Therapeutics second quarter 2022, corporate update and financial results.

Thanks.

I'm joined today by our Chief Executive Officer, Stuart Peltz, our Chief operating Officer, Matthew Klein, Our Chief Business Officer, Eric Pals, and our Chief Financial Officer Emily Hill.

After the speaker's presentation, there will be a question and answer session. To ask a question, you will need to press star 11 on your telephone. Please be advised that today's conference is being recorded.

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

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

Which contains our forward looking statements our actual results could materially differ from these forward looking statements as such statements are subject to risks that can materially and adversely affect our business and results of operations.

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, and quarterly report on Form 10-Q.

<unk> 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.

I would now like to hand the conference over to your speaker today, Kylie O'Keefe, Senior Vice President, Head of Global Commercial and Corporate Strategy.

Yeah, great.

Please go ahead.

Hey, thanks, Raju.

Touch back on trans in the U. S. and the read through.

Thanks, Gary.

Good afternoon, everyone and thanks for joining us today.

Good afternoon and thank you for joining us today to discuss the PTC Therapeutics, second quarter 2022 corporate update and financial results.

And kind of how you're looking at the agency considering.

Im excited to share that.

Current quarter 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.

But to be a transformational year for the company.

Today's call will include forward-looking statements based on our current expectations. Please take a moment to review the slide posted on our Investor Relations website, in conjunction with the call, which contains our forward-looking statements.

Obviously, you know, our goal is to, you know, bring, up data to all the AADC deficient patients.

Their apparent tolerance for some looks like data set flexibility and.

Listen that PTC is.

To discover and develop innovative therapies and bring them to patients with rare disorders.

So to create significant value.

All of our stakeholders.

We've been very successful in pursuit of this mission.

Our actual results could materially differ from these forward-looking statements, as such statements are subject to risk that can materially and adversely affect our business and results of operation.

And, you know, maybe just a little bit of color is, you know, while we recently just got the approval, you then have to do a bit of work to be able to go that into other places.

Do you think that are you reading through to this that you're.

Good day.

The future has a better.

Marketed products seven development programs.

So, that's being worked on right now.

Several scientific platform.

And then we're going to be working on or have been working on also market access in different, places as well.

To generate future product.

Continue to build a robust pipeline of potential new therapies.

Steady state will deliver a new product.

For the year.

We made important progress in the second quarter towards achieving our ambitious goals for 2022.

So, we're pretty well positioned for the commercial launch.

Due to strong revenue growth and to advance towards multiple clinical milestones.

I'd like to highlight several particularly significant achievements in the quarter.

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 and quarterly report on Form 10-Q filed with the Securities and Exchange Commission as well as the company's other SEC filings.

We'll be using both the commercial launch in terms of bringing drugs to patients as well as expanded access program to the patients as well.

Or do you think it stands on its own, or are you not considering that there are different divisions at play here?

Let me begin with our strong revenue growth in the quarter.

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.

You know, I think I.

Sure.

We achieved a $166 million in total revenue with a 42% increase over the second quarter. In 2021. This is quite remarkable and puts us in good position.

With that, let me pass the call over to our CEO, Stuart Pauwels.

Stuart?

And so, we feel like that, you know, we're in a good position.

But like we said, we already have one extended access patient that has had the surgery and is a commercial patient.

The preparation for launch has a lot of work has gone into and there's, you know, a number of key success factors, which is accelerating disease education, patient identification, and then preparation of the surgical center.

To achieve our full year revenue targets.

And then making sure that the key positions are engaged and then working with the patient advocacy groups and payer engagement.

Between 700 $750 million.

We've been working hard on that.

The DMD franchise is expected to continue its strong growth trajectory throughout the remainder of 2022.

The first country, obviously, that we're going into in Europe is going to be Germany, followed by other international markets, in particular, where we can do expanded access programs.

And so, if you think about it, patient identification has been a key focus of us for the launch preparation.

We also reported top line results of 741.

We're going to important step forward for Translarna.

And this goes on, you know, really forever and even post-approval.

February four one demonstrated a statistically significant benefit for translarna in nonsense mutation DMD patients.

So, I think, you know, at the end of the day, I think we've shown a strong track record in launching rare drugs.

The team is quite, experienced, a broad global commercial footprint to get into, you know, over 50 countries.

A number of relevant outcome in the broad incentive <unk> population.

Based on these results.

Plan to require conversion of the EU conditional authorization.

<unk> marketing authorization.

So, we're pretty confident that this is a significant opportunity for the FDA to launch.

In addition to the EU, we look forward to discussing these results.

It takes a path forward for approval with the FDA and other international markets.

Great, thanks Stu.

In addition, these results.

Reinforcing our strong value proposition with payers in the EU and international markets.

And that will go into these results in more detail shortly.

We recently announced the marketing authorization for <unk>.

And then just on a question on clinical trial enrollment, can you give, us a sense of where you are with the affinity trial on enrollment, as well as it looked like the MITE-E trial's first quarter 23 readout, as well as obviously the face-to-face study.

So by the European Commission.

Yeah.

Approval expands our product portfolio.

<unk> commercialized products.

Did you say for the PKU trial, right?

The PKU trial, and then I just saw on the press release that I think the MITE-E trial, is now a one Q23 readout.

Third gene therapy ever marketed.

Third market with gene therapy directly administered into the brain.

Yeah, sure.

Our goal at PTC as the breakup fee.

The fourth quarter.

<unk> deficient patients.

Family as quickly as possible.

Yeah, so we're pretty excited, obviously, about the PKU trial. We think that, you know, our drug has substantial benefit over Kuvan.

And so, you know, we're pretty excited about that.

Well pause for commercial launch and our plans for Mercury.

Three of $3 5 million.

This reflects.

Section of valuable data and takes into account the ultra orphan ADC patient population with a small budget impact to players from this onetime durable treatment.

Pricing of our stages based on multiple factors, including that the disease is highly morbid.

Hello.

High unmet medical need.

ADC depreciate, thank you with no standard of care.

Lastly, favorably substantial value.

Patients with transformative clinical results and durable effect with up to 10 years of follow up.

We have already treated our first patients on commercial drug through the early access program in France, and then Eric will go into that in more detail shortly.

Let me switch gears to a risky as we continue to achieve strong uptake across all regions.

The FDA recently approved the supplemental NDA or <unk> for pre symptomatic infants with SMA under two months away.

The approval was based on interim efficacy and safety data from the Rainbow study in Newport.

That pre symptomatic babies.

It was already achieved key milestones such as sitting standing and walking.

After 12 months of treatment similar to that seen in.

Normal babies.

Turning now to our oncology program with <unk> previously known as <unk>, where we.

Recently announced encouraging preliminary safety and efficacy results from our phase <unk> study in <unk> or <unk>.

The vast Leo Mariani sarcoma patients at a podium presentation at Astro.

Based on these preliminary results PTC initiated the sunrise element of it.

Well controlled registration directed study of the efficacy and safety of <unk> and <unk> in patients with advanced Allen.

PTC has a broad and deep pipeline across a range of diseases and we eagerly anticipate an import results with several registration directed study during the next six to 12 months.

We believe the positive results from these trials could be transformational for PTC.

Thank you for you is clearly having an exciting year and execute on all of what we set out to achieve in the first half of 'twenty.

I don't know if you heard what I said before, but I think that.

Two which is truly remarkable with that let me hand, it over to Matt for <unk>.

Thanks, Kylie, and good afternoon, everyone, and thanks for joining us today.

Matt, you wanted to talk a little bit about where we are on that.

You know, I think we're hopeful that.

Development update Matt.

Yeah, sure, Raj.

Thanks.

I'm excited to share PTC's second quarter results, in what I expect to be a transformational year for the company.

All three of these trials are global trials leveraging our global development, infrastructure.

Look, we did study 41 with a well done study. That demonstrated functional benefit in a broad population.

Sure and then our teams continued to execute on our May 2022 governments, we are working tirelessly to deliver on our mission to bring innovative therapies to patients around the world.

Our mission at PTC is to discover and develop innovative therapies, and bring them to patients with rare disorders, and in doing so, to create significant value for all of our stakeholders.

And for PKU, the sites are up, running, enrolling, and we're on track for results by the end of 2022.

We've been very successful in pursuit of this mission. Today, PTC has five marketed products, seven development programs, and several scientific platforms which should generate future products.

Similarly, as we updated on the PIVOT-HT study, we're getting sites up around the world and enrolling that trial with data by the end of 2022 and results by the end of 2022. Similarly, as we updated on the PIVOT-HT study, we're getting sites up around the world and enrolling that trial with data by the end of 2022 on the 12-week portion.

We continue to build a robust pipeline of potential new therapies, that at steady state will deliver a new product every two to three years.

And then on MITE-E, we moved the data front to one quarter to first quarter, 2023. That's mainly due to the COVID-related delays.

Of the shed muscular dystrophy patient.

Beginning with Translarna as Steve mentioned, we recently announced the positive results from study <unk> one in patients with nonsense mutation DMD.

With the, you know, the broad population in the population.

As a reminder, <unk> one was designed as a global trial with a 72 week placebo controlled phase followed by a 72 week open label extension fee, which is still ongoing.

Topline results from study <unk>, one demonstrated a statistically significant effect of trains Laura on six minute walk distance and the overall ITT population of 359 boy. This.

Demonstrated statistically significant.

In the 6 minute walk that, but also in.

This is the first disease modifying therapy to demonstrate a statistically significant functional benefit in a placebo controlled trial.

In addition, a statistically significant benefit of trends Laurent I was also demonstrated in the North Star ambulatory assessment and the 10 meter run walk enforced their spend timed function test in the ITT population.

The North and time function test.

So, I think that itself, and that's if you think about it, that I think the 1st example.

With a, you know, with a.

A drug that actually show.

These results are not only statistically significant but provides evidence of clinically meaningful benefit as they represent a 20% to 25% slowing of disease progression and a known unilaterally progressive and fatal disease.

This year in a pooled analysis of the over 700 boys enrolled in our three placebo controlled trials one a trial 37, 2020 and <unk> 41.

As a highly statistically significant benefit across a range of functional assessments.

While the study <unk> one M. ITT population results did not achieve significant we believe a significant result in the ITT population, which was the prespecified population along with evidence of real World long term benefit generated from the stride registry position us to request conversion from the EU.

New conditional marketing authorization of transport up to standard marketing authorization. In addition, we plan to meet with the FDA to discuss the potential for an NDA in the U S.

Turning now to our gene therapy following.

Following on the approval what stays in the year. We are now focusing efforts on submission of our BLA to the FDA, which is planned for the fourth quarter of this year.

I would like to now share encourage young adult 19 study I havent noticed that for the treatment of COVID-19.

For, you know, for the treating the underlying cause of disease.

Where we're seeing in an ITT population.

The fight 19 study was designed as a double blind placebo controlled 28 day study of hospitalized COVID-19 patients.

Statistically significant.

Results in multiple.

As a reminder, in voter Scott is an oral small molecule that targets the cellular enzyme die hydro or take the hydrology for DHA, the H by targeting a cellular enzyme rather than a viral protein and bonus that is less likely to illicit drug resistance, which is particularly important as the COVID-19 virus.

In multiple endpoints and everything favored.

<unk> community.

Translined versus placebo and so I think.

Given the changing nature of the pandemic to the outpatient setting we concluded enrollment in the fight study early with 189 subjects enrolled in order to review the data collected to date and make an informed decision on next steps.

That data, along with the results.

From study, oh, 7 or 14.

Across all randomized subjects, there was a trend towards a bonus that benefit across several disease relevant endpoints, including duration of hospitalization and time to reduction of fever.

That that really shows.

That you're seeing clinical benefit and you don't have to rely on.

A biomarker that hasn't shown.

In our view, haven't yet shown is predictive of.

Notably when examining the cohort of patients enrolled within five days of infection. There was a clear benefit of a bonus that treatment on time to respiratory improvement duration of hospitalization.

Of, of, of clinical benefits, so I think.

We're in a pretty good position from a clinical perspective.

And then the data that goes along with it was 7 and 0, and ACT-EMD.

And then the STRIVE registry that translates for people what is, you know, in a way, when you do clinical endpoints, the goal of clinical endpoints is to predict outcomes for patients, right?

And in this case, we also have that data to show the regulatory bodies where you see that in the STRIVE registry, we saw greater than five years in preservation or regulation, two years or so of preservation, of being able to get off the ground, and really strong preservation of pulmonary function.

Those are really the hardest, you know, when you're a patient, what do you care about?

And if you're showing improvement in those, I mean, the drug is showing clinical benefits.

Can you still ambulate?

Can you still get off the ground?

The resolution and coffee.

And can you, you know, what do DMV patients die of, which is pulmonary and cardiac function?

So we think we have a strong case there.

As an example median time to respiratory improvement study primary endpoint was 28 days in the placebo group and only 10 days and the <unk> group with a P value of less than 0.05 <unk>.

Great.

Thanks so much.

These findings are particularly important as they suggest a clear potential term bonus that early treatment of Colgate and the inpatient or outpatient setting where the majority of cases are now manage.

Thank you.

We plan to complete the remaining data analyses and we will then formulate a strategy for next steps in advancing both the stat for the treatment of COVID-19.

Over the course of the second quarter, we continued to make progress across our other platform and expect results from several of our ongoing registration directed trial in the next six to 12 months.

We made important progress in the second quarter, towards achieving our ambitious goals for 2022.

We continue to achieve strong revenue growth, and to advance towards multiple clinical milestones.

Starting with our ongoing registration directed affinity phase III trial of PTC 93 in patients with PKU, we remain on target to share results by year end 2022.

The affinity trial is a six week placebo controlled study with a primary endpoint of reduction in blood phenylalanine levels.

Enrich the randomized study population for likely responders. The study includes a run in phase during which potential subjects are treated with 93 for two weeks and only those demonstrating response to PTC 93 treatment are randomized.

Following completion of the six week placebo controlled study all subjects will be eligible to enroll in a long term extension study.

Turning to the bio E platform, we have three ongoing registration directed trial, two with particular knowledge and mitochondrial disease associated seizures ataxia and one with PTC.

These children with mitochondrial disease and seizures are quite ill.

These children with mitochondrial disease and seizures are quite ill. In fact, when there's not a pandemic going on, seasonal colds and flus can easily put them in the hospital and even can be fatal events.

And so, there's been a lot of caution on the part of parents and physicians to get the kids into the study site.

In patients with ALS.

So, that's caused a little bit of delay in getting the trial to the enrollment target, but we're now on target to have results, as we said, in the first quarter 2023.

Due to COVID-19 related delays in enrollment we now expect to have results from the 90 trial of <unk> in patients with mitochondrial disease associated seizures in the first quarter of 2023.

That's helpful.

Thanks.

Thank you.

As we have previously shared the move out to a global trial of the <unk> ataxia patients is fully enrolled and we continue to expect results in the second quarter of 2023.

And we'll take our next question from Kristen Kluska from Cancer Fitzgerald.

Enrollment is ongoing in the Cardinal global placebo controlled trial of PTC <unk> ALS patient.

Your line is open.

Hi.

The Cardinal trial with a six month placebo controlled study with a target enrollment of approximately 258 subjects.

Good afternoon.

Thanks for taking my questions, and congrats on the Upstaza launch.

So, given that you have three registrational trials where we're expecting data through, the second quarter of next year and the Upstaza PLA guided for the fourth quarter, could you talk about some of the commercial readiness steps you're taking towards juggling these potential filings and beyond, should they be successful?

Next will be randomized two to one to receive PTC 857 or placebo.

The primary endpoint of the study is change in the <unk> at FRS score from baseline to six months with secondary endpoint, capturing other aspects of disease morbidity and mortality risk.

Yeah, sure.

Finally, I want to provide an update on our PTC five Huntington's disease program from our splicing platform.

<unk> is ongoing in our phase III pivotal <unk> study, our global placebo controlled study of PTC five in HD patients.

The study will consist of two parts and initial 12 week placebo controlled phase focused on PTC 508, pharmacology at Pharmacodynamic effects.

Led by a nine months placebo controlled portion during which we will collect blood CSS and radiographic biomarker data.

The study will initially include two dose levels five milligrams and 10 milligrams with the potential to study a third.

We anticipate data from the 12 week portion of the study by the end of this year.

We are very excited about our continued progress across our development programs and look forward to sharing results from several of our studies in the near future I will now hand, the call over to Eric to discuss our commercial portfolio Eric.

I'd like to highlight several particularly significant achievements in the quarter.

And I am showing no further questions at this time.

And I'd like to turn the conference back over to Stuart Peltz for any closing remarks.

That's great.

Well, look, I want to thank you all for joining us today.

I think what you can see from, we've been having really, you know, a great year, made significant progress this year, and have been delivering on a number of key milestones.

Thanks, Matt.

This is a very exciting time for PTC and in particular for our global customer facing teams commercializing a diversified portfolio of products that address high unmet needs for patients with rare diseases.

We have achieved another very strong quarter.

Let me begin with our strong revenue growth in the quarter, in which we achieved $166 million in total revenue with a 42% increase over the second quarter in 2021. This is quite remarkable and puts us in a good position, to achieve our full-year revenue target of between $700 and $750 million. The DMD franchise is expected to continue a strong growth trajectory throughout the remainder, of 2022.

And we are thrilled to add a fifth commercial product to our portfolio with the recent approval of upstate and to bring much needed treatment.

<unk> deficiency patients.

Our DMD franchise continues to be a key revenue driver.

As we continue to expand our global footprint that will also support the future growth from the pipeline.

Let me begin with this data and our.

We also reported top-line results of Study 41, which was an important step forward for, translinase. In Study 041, we demonstrated a statistically significant benefit for translinase in NASA, mutation DMD patients across a number of relevant functional outcomes in the broad intent-to-treat study population. Based on these results, we plan to request conversion of the EU conditional authorization, to a standard marketing authorization.

Let me start a little bit where, obviously, just the way the structure of the, team is, it's such that each team is moving forward on that.

And I think that the positive results from study 041 demonstrating the benefits to non-submutation DMV patients really adds and demonstrates that translinase benefits of the patient and adds to the totality of evidence of translinase.

So, in terms of juggling, we don't really juggle.

And so the other important point is that, and what we've talked about, particularly in the questions that you've asked, is that we have a number of registration directed studies that are ongoing that we look forward to sharing those results with you in the near future.

Each team has, in each of the registration-directed programs, each team is doing their work to get ready for both launch and regulatory track.

So we're excited and happy at PTC to continue on this mission of discovering and developing these innovative therapies for rare disorder patients.

Ongoing launch preparations.

So thanks for joining today, and we look forward to our next conversation with an update.

In addition to the EU, we look forward to discussing these results and a potential path, forward for approval with the FDA and other international markets.

So, it isn't like we have to wait for one versus the other.

Operator Thank you.

We are very excited about the recent approval in Europe and our team is actively executing on all strategic initiatives supported the launch.

Every team, every one of those has their own team that is moving forward.

We are off to a great start and have treated our first commercial patient this quarter under the French early access program.

In addition, these results will reinforce our strong value propositions with payers, in the EU and international markets.

And I think we have a pretty strong track record in moving those forward.

Matt will go into these results in more detail shortly.

Treatment Center readiness is well on track as well as further preparation for surgeries carried out European centers.

We recently announced the marketing authorization for Abstaza by the European Commission. This approval expands our product portfolio to five commercialized products. Abstaza is the third gene therapy ever marketed and the first marketed gene therapy directly, administered into the brain.

And the team is pretty experienced in that.

So, I think we'll be able to, you know, be able to move all of them as things move forward, and I think with the global footprint that we have gives us really the capability to be able to, you know, knock on wood, all goes well, that we'll be able to launch all of them, and each one, you know, as it progresses and gets approved both in Europe as well as in the United States.

Patient identification.

Our goal at PCC is to bring Abstaza to AADC-deficient patients and their families as quickly as, possible.

Two increased salary.

And we anticipate treating additional commercial patients.

Coming launch in Germany.

We are also focused globally on markets that have early access program.

Such as France, Italy, and other via cross border healthcare.

The FCC price is expected to be in the range of <unk> 3 million to $3 5 million.

We are well poised for commercial launch and our planned commercial price is between $3, and $3.5 million. This reflects the exceptional value of Abstaza and takes into account the ultra-orphan AADC, patient population with a small budget impact to payers from this one-time durable treatment. Pricing of Abstaza is based on multiple factors, including that the disease is highly morbid, and fatal and the higher medical needs of AADC-deficient patients with no standard of care. Lastly, Abstaza brings substantial value to patients with transformative clinical results, and durable effects with up to 10 years of follow-up.

Which factors in our projection of future pricing negotiations in key European markets.

We are confident that the durable efficacy and safety data, we haven't paid for over 10 years of patient experience with the data will support HCA dossier submissions for reimbursement as the <unk>.

First and only treatment approved for ADC deficiency patients 18 months and older.

We have guided to $20 million to $40 million in revenue from upstate them.

We have already treated our first patient on commercial drugs through the Early Access, Program in France and Eric will go into this in more detail shortly.

Let me switch gears to AVRISI as we continue to achieve strong updates across all regions. The FDA recently approved the supplemental NDA of AVRISI for pre-symptomatic infants, with SMA under two months of age. The approval is based on interim efficacy and safety data from the Rainbow Fish Study, in New Orleans, which showed that pre-symptomatic babies treated with AVRISI achieved key milestones such as sitting, standing, and walking after 12 months of treatment, similar to that seen in normal babies.

Turning now to DMD.

Global DMD franchise continues to deliver robust revenue across all regions.

Turning now to our oncology program with Unetzaline, previously known as PPP-596. We recently announced encouraging preliminary safety and efficacy results from our Phase, 1B study in Unetzaline, our tubulin binding agent, in advanced leomyoid sarcoma patients at a podium presentation at AFSCME.

Based on these preliminary results, PTC initiated the Sunrise LMS Study, a placebo-controlled, registration-directed study of the efficacy and safety of unethylene and decarboxyne in patients with advanced LMS.

Our second quarter revenue for the DMD franchise with $134 million.

PTC has a broad and deep pipeline across a range of diseases, and we eagerly anticipate, important results with several registration-directed studies during the next 6 to 12 months. We believe the positive results from these trials could be transformational for PTC.

Our implied net product revenue for the second quarter was 57 million, which represents 16% growth over the second quarter last year.

Ongoing execution by our broader team drove new patient starts continued favorable access.

Hi, compliance and appropriate way.

Dosing for DMD patients in the United States.

Poor trend BARDA, we achieved 77 million in net product revenue for the second quarter, which represents a 46% increase over the second quarter of 2021, driven by growth in all regions.

As a reminder, we can have large group purchase orders, which can create lumpiness due to uneven government buying pattern.

Overall trends larger revenue continues to be globally diversified and robust in all key markets.

We continue to make good progress with regulatory approval and pricing and reimbursement.

Our newer markets Eastern Europe , the Middle East and Latin America.

We are also continuing to expand our presence in additional markets in Asia Pacific as this region continues to be of strategic importance.

Potential future revenue growth for PTC.

We are in a strong position to achieve the 2022 DMD revenue guidance of 475 million to $495 million.

In Latin America, our team continued to strengthen the tech study and will lever franchise.

In Brazil, following the innovative drug classification protect study.

Steve The first purchase order from the Ministry of Health.

Was delivered in the second quarter.

This is an important milestone for <unk> patients awaiting treatment.

Furthermore, patient identification continues to be strong and we anticipate additional group purchase orders over the course of the year.

Finally discussions progressed with contact the National Commission for the incorporation of technologies for inclusion of test study.

The essential drug list, which simplifies access.

Four we libre, we now have patients.

On treatment for FCS in Latin America.

And patient identification continues to progress well.

As a reminder, last December we submitted an application to NBC in Brazil for approval of Libre for the treatment of FPL.

If approved we believe <unk> will be the first crew.

Treatment for FPL in Brazil, and this will mark the first approval globally for this indication.

We anticipate a decision in the second half of 2022.

PTC is clearly having an exciting year and has executed on all of what we set out to, achieve in the first half of 2022, which is truly remarkable.

Does that help you?

This concludes today's conference call.

In conclusion, our customer facing teams globally have had an extremely successful first half of the year.

And we will be focused on capitalizing on the momentum built and our non sort of stayed here for the remainder of the year.

With that, let me hand it over to Matt for a development update.

Yes.

Thank you for your participation, and you may now disconnect.

Now, let me turn the call over to Alan for a financial update I'm already.

Matt?

Thank you.

Everyone have a wonderful day.

Thanks, Sir and the first half of 2022, and we saw continued strong revenue growth and progress in advancing our pipeline across multiple platforms.

Thanks, Stu.

Appreciate that.

Thank you for joining us.

Given current market conditions in the biotech space, we are particularly pleased that the royalty monetization preference team combined with our strong continued revenue growth allowed our strong capital structure to fund the further advancement of our pipeline.

I'm proud to share that our team has continued to execute on our many 2022 goals.

And I know in the past you've made a lot of synergies with your splicing platform as it relates to BRISD, and then, of course, the work you're doing in Huntington's disease, but now that there's been a lot of commercial experience here, wondering if your views have at all changed, confidence increase, or anything that you could really take away from the commercial experience.

The press release issued earlier this afternoon summarizes the details of our second quarter 2022 financial results.

I will take a few minutes now to review these financial results.

Please refer to the press release for additional detail.

Beginning with top line results total revenues were $166 million for the second quarter of 2022.

We are working tirelessly to deliver on our mission to bring innovative therapies to patients, around the world.

Yeah, I think, you know, from our point of view, we're really pleased with the splicing platform and the commercial prospects of it.

Obviously, the nice aspect of these molecules is that they're orally bioavailable, that, you know, especially for neurodegenerative diseases, the fact is that they get to every part of the brain, and therefore, if they could change, you know, the structure of the brain, they could change the structure of the brain.

We think oral, in these cases, oral is probably the best way to go.

A 42% increase over the second quarter of 2021.

This was driven primarily by net product revenue from DMD franchise on $134 million and that brings the royalty revenue of 22 million.

So, you're not driving the bus blindly.

Our total revenues in the first half of 2022 has an impressive $314 million.

And as Steve said, we are on track to achieve our 2022 total revenue guidance of $700 million to $750 million.

Apart from that continued net product revenue, we also anticipate a $50 million milestone payment from Roche, but annual RMC sales reached $750 million.

In addition, we have guided to $20 million to $40 million in revenue from upstate.

Beginning with transLARNA, as Stu mentioned, we recently announced the positive results, from Study041 in patients with non-sense mutation DMD. As a reminder, Study041 was designed as a global trial with a 72-week placebo-controlled, extension phase, followed by a 72-week open-label extension phase, which is still ongoing. Top-line results from Study041 demonstrated a statistically significant effect of transLARNA, on 6-minute walk distance in the overall ITT population of 359 boys.

This is the first disease-modifying DMD therapy to demonstrate a statistically significant, functional benefit in a placebo-controlled trial.

Turning now to our DMD franchise, Translarna net product revenues were $77 million representing year over year growth of 46% compared to the second quarter of 2021.

In addition, a statistically significant benefit of transLARNA was also demonstrated, in the North Star ambulatory assessment and the 10-meter run-walk and 4-stair ascend timed function test in the ITT population. These results are not only statistically significant, but provide evidence of clinically meaningful, benefit as they represent a 20 to 25 percent slowing of disease progression in a known unilaterally progressive and fatal disease.

In addition, in a pooled analysis of the over 700 boys enrolled in our three placebo-controlled, transLARNA trials, Study07, Study20, and Study41, there is a highly statistically significant benefit across a range of functional assessments.

Plaza net product revenues of $57 million or 16% growth year over year.

Moving now to have risky our partner Roche reported 2022 year to date sales of approximately 500 million Swiss francs.

Which translated into second quarter royalty revenue for PTC of 22 million.

As a reminder, PTC retains approximately 57% of <unk> royalties.

Royalty pharma, receiving the remaining 43% up to a cumulative total of $1 3 billion.

After which PTC received 100% of that brings deep biopsies.

non-GAAP R&D expenses were 144 million for the second quarter of 2022, excluding $14 million in noncash stock based compensation expense.

$412 million for the second quarter of 2021, excluding $13 million in noncash stock based compensation expense.

Over year increase in R&D expenses reflects additional investment in research programs and the advancement of the clinical pipeline.

non-GAAP SG&A expenses were 66 million for the second quarter of 2022, excluding $14 million in noncash stock based compensation expense.

Compared to $57 million for the second quarter of 2021, excluding $12 million in noncash stock based compensation expense.

You're actually, you know, you have a pretty good look into saying what is, you know, based on this exposure level, you're getting this effect on splicing.

Cash cash equivalence and marketable securities totaled approximately $506 million as of June 32022.

$773 million as of December 31, 2021.

I'd now like to turn the call over to the operator for questions and answers.

Operator.

And we think that's really important.

Thank you.

And then you can measure the level of the drug and therefore know that, you know, in the CFS as well, to know the exposure level that you're getting within the brain as well.

So, you get a lot of information that lets you make good decisions at the same time.

And as a reminder to ask a question. Please press star one one please standby will be compile the Q&A roster.

And our first question will come from Eric Joseph from Jpmorgan. Your line is now open.

Hi, good evening and congrats on the quarter and thanks for taking the questions a couple from us on Translarna.

First yes.

Wondering if you could just sort of unpack a little bit the geographic mix.

This quarter and the extent to which you you saw some large group purchase orders that we.

That may have driven the performance and perhaps that we should be sort of backing out and thinking about the sales trajectory of the second half.

Lately is there any material FX impact that we should also be.

Considering and then secondly, as it relates to requesting.

The transition to standard authorizing marketing authorization in the EU.

Can you just sort of.

Provide a little more granularity on the timelines, both requesting that change and sort of what that recycling might look like.

Yes.

Yes fair.

The.

The core.

I mean the question, yes, I think we've had.

I think because of the great quarter.

Growth.

Both gross loan early.

<unk>.

Good.

And there was growth throughout.

All geographies.

But maybe maybe.

Eric you want to talk a little bit about it.

Yes.

Sure.

Where there could be different.

And we are the <unk>.

Where we saw the growth.

Yes, thanks for the question.

You have certainly seen robust growth across all geographies.

And as you know trade, Florida.

Our product has international markets and we have large group purchase orders that can be sometimes a little on timely but in this quarter, we actually saw large orders.

Across all geographies and in particular, it was very robust in Europe .

And what we what we see with revenue. This year is we never really guide to quarters.

Yes.

Right now what we're doing is we're really focusing on.

Growth in all key markets. Our guidance continues to be 475 to 495. So the growth is actually continuing across different markets and that's really because of new product new patients.

We've continued to see really high compliance.

We've added.

We've had programs that would also include dose adjustments for patients. So we're really doing very well in terms of preserving the base and broadened the base, but also through geographic expansion.

We have new markets that are also significantly contribute so.

So essentially we are seeing that robust growth across the global and diversified markets that we have right now.

Okay.

Great.

Sure.

Yes.

I will say one thing and then I'll pass it to.

I think what's important.

I think you can see we've continued to grow.

Our business quite well and I think we're going to continue to do that.

We are reiterating the 750.

No Im sorry.

I'm comfortable with that we will talk a little bit about that sir.

Okay.

Yes, absolutely.

Eric with your question around.

And then, obviously, from a commercial perspective, when you, you know, the fact that this is the case is a standard sort of commercial program where you have, where you know that you could show everyone what the dose is, what the right, what the right level is.

FX I think obviously.

Therefore, you know, with the clinical data on hand, I think this is a really nice commercial product to move forward with.

We've spent a lot of time now perfecting the splicing platform where it's really honed and efficient.

And the perspective that the state that we are reiterating our guidance and so while we do see an impact across the U S dollar to the euro.

So, we think this is going to be a platform that's going to add multiple programs that ultimately will get the commercial for multiple drugs.

We think it's going to be an exciting, I mean, I think it's really an exciting platform.

Okay.

Thank you, Stu.

We continue to see a red box and globally diversified portfolio across a number of different geographies.

While we are seeing an impact we remain confident in our business.

And its geographic diversity allows us to remain confident and reiterate guidance.

Your question please.

Two housekeeping timeline, Matt you want to take that one.

While the Study041 MITT population results did not achieve significance, we believe the, significant results in the ITT population, which was the pre-specified population, along with evidence of real-world long-term benefit generated from the STRIDE registry, position us to request conversion from the EU conditional marketing authorization of transLARNA to standard marketing authorization.

Thanks for the question, Kristen.

In addition, we plan to meet with the FDA to discuss the potential for an NDA in the, U.S.

Yes sure. Thanks for the question Eric So just as a reminder, steady at four one.

Turning now to our gene therapy platform, following on the approval of apstaza in the, EU, we are now focusing efforts on submission of a BLA to the FDA, which is planned for the fourth quarter of this year.

Thank you.

Was part of our commitment to following the conditional marketing authorization from the EMA and really the idea here was to conduct studies 41 to provide comprehensive evidence in support of the benefit risk of trends, Florida, and it's that generation of comprehensive evidence, which really triggers our ability.

I would like to now share encouraging results from our FITE-19 study of imvodastat for the, treatment of COVID-19. The FITE-19 study was designed as a double-blind, placebo-controlled, 28-day study of hospitalized, COVID-19 patients.

As a reminder, Imvotastat is an oral small molecule that targets the cellular enzyme, dihydroorotate dehydrogenase, or DHODH. By targeting a cellular enzyme rather than a viable protein, Imvotastat is less likely, to elicit drug resistance, which is particularly important as the COVID-19 virus continues to mutate.

Given the changing nature of the pandemic to the outpatient setting, we concluded enrollment, of the Pfizer-BioNTech study early, with 189 subjects enrolled, in order to review the data collected to date and make an informed decision on next steps. Across all randomized subjects, there was a trend towards Imvotastat benefit across, several disease-relevant endpoints, including duration of hospitalization and time to reduction of fever. Notably, when examining the cohort of patients enrolled within five days of infection, there, was a clear benefit of Imvotastat treatment on time to respiratory improvement, duration of hospitalization, dyspnea resolution, and cough relief.

As an example, median time to respiratory improvement, the study primary endpoint, was, 28 days in the placebo group and only 10 days in the Imvotastat group, with a p-value of less than 0.05. These findings are particularly important as they suggest a clear potential for Imvotastat, in the early treatment of COVID in the inpatient or outpatient setting, where the majority of cases are now managed.

We plan to complete the remaining data analyses and will then formulate a strategy for next, steps in advancing Imvotastat for the treatment of COVID-19.

Over the course of the second quarter, we continue to make progress across our other, platforms and expect results from several of our ongoing registration-directed trials in the next 6 to 12 months.

Starting with our ongoing registration-directed AFFINITY Phase 3 trial of PTC923 in patients, with PKU, we remain on target to share results by year-end 2022. The AFFINITY trial is a 6-week placebo-controlled study with a primary endpoint of reduction, in blood phenylalanine levels. To enrich the randomized study population for likely responders, the study includes, a run-in phase during which potential subjects are treated with 923 for 2 weeks and only those demonstrating response to PTC923 treatment are randomized. Following completion of the 6-week placebo-controlled study, all subjects will be eligible to enroll, in a long-term extension study.

Our next question will, come from Joe Thome from Cowen.

To.

Both from a conversion and to convert the conditional to the standard marketing authorization. So obviously, we're very excited about the results which were.

Collected in the ITT population of 359 boys and when you think about comprehensive evidence. When you think about 359 Boise is the largest data package in a single trial for CMV and the statistically significant results on functional endpoints, including walk us into Northstar.

Clearly believe that we have that comprehensive evidence. This is mark the benefit of trends volume and then of course the safety collected in this study at a long term safety package collecting not only through our clinical trials, but also in our long term registry again informs a favorable safety aspects of the drug and then finally, we also have generated over the past several years.

Or is the stride data, which provides long term real world evidence of benefit and tread water in the way of loss of ambulation of roughly $5. Four years. So I have lots of pulmonary function of one eight years, which are really important given that those are the two key mortgage transitions in the disease. So when you put the study.

<unk> one data together with the stride data. We believe we have the comprehensive data that warrants conversion from the conditional marketing authorization as a standard.

This happens mechanically is as we've said before we are due to provide the data by the end of Q3, but we will submit a type two variation.

The CHP or DMA, which basically request that conversion this will initiate a process.

In Europe that will unfold over the course of several months, where they will be back and forth. They may have questions about the data so hard to say exactly what the time will be from initiation of that process in September story, and how we think it will be several months, but clearly much shorter than what we're anticipating a typical MAA submission.

Okay, Great. That's very helpful. Thanks for taking the questions.

Thank you.

Your line is now open.

And we will take our next question from Rajiv Prasad from William Blair. Your line is now open.

Hi there.

Good evening and thank you for taking my question.

Thanks for taking the question congrats on the quarter can you give us some sense just now having a couple more.

Months of looking at the Upstage commercial markets under your belt on the potential cadence of kind of revenue recognition that you anticipate maybe this year.

Even if you could give a little more color into how you anticipate the launch going into next year that'd be helpful. Thanks.

Maybe one on the mitochondrial epilepsy patients.

Great Hey, Thanks Rosy.

Yes.

Obviously.

Our goal is to.

Bring up phases.

Appreciate it.

And maybe just a little bit of color.

<unk>.

While we while we recently got the approval you Ben.

How could do a bit of work to be able to go to other places. So that screening is being worked on right now and we're going to be working on or have been working on also market access to a different place.

So we're pretty well positioned.

For the commercial launch will be using both <unk>.

The commercial launch.

In terms of premium drove the pacing as well as expanded access program.

The patients as well.

And so.

We feel like we're in a good position, but like we said we already have one experience extended access space.

Very good.

Yes.

Okay.

The surgery.

In commercial cases.

The preparation.

<unk> launched a lot of work has gone into it.

A number of key success factors.

Accelerating.

<unk> patient identification and then preparation of the surgical center, and then making sure that.

The key the key for this year.

In case, and then working with the patient advocacy groups in Asia, we've been working.

Hard on that the first country, obviously well before.

And Europe is Germany, followed by other international market.

In particular, we continue expanded access program.

And so if you think about our patient identification as well.

What's kind of your updated thinking in terms of how many patients are out there and is it relatively straightforward to identify them?

A key focus of our preparation.

This goes on really forever.

Even post approval.

I think at the end of the day I think we've shown.

Our strong track record in launching a drug.

<unk> is quite experienced.

<unk> global commercial footprint to get resolved.

Over 50 countries, so we're pretty confident.

This is <unk>.

A significant opportunity.

Quarterly upticks awash.

Turning to the BioE platform, we have 3 ongoing registration-directed trials, 2 with Pitiquidone, in mitochondrial disease-associated seizures of predipataxia and 1 with PTC857 in patients with ALS. Due to COVID-19-related delays in enrollment, we now expect to have results from the MIGHTY, trial of Pitiquidone in patients with mitochondrial disease-associated seizures in the first quarter of 2023.

Great. Thanks, and then just on a question on clinical trial enrollment can you give us a sense of where you are with the affinity trial.

As we have previously shared, the MOVE-FA global trial of Pitiquidone in predipataxia, patients is fully enrolled, and we continue to expect results in the second quarter of, 2023.

Enrollment is ongoing in the Cardinals Global Placebo-Controlled Trial of PTC857 in ALS, patients. The Cardinals trial is a 6-month placebo-controlled study with a target enrollment of approximately, 258 subjects. Subjects will be randomized 2-to-1 to receive PTC 857 or placebo.

The primary endpoint of the study is change in the ALS FRS score from baseline to 6 months, with secondary endpoints capturing other aspects of disease morbidity and mortality risk.

Finally, I want to provide an update on our PTC 518 Huntington's Disease Program from, our splicing platform.

On enrollment as well as it looked like the Mic E trial, the first quarter of 2003 readout.

Research is ongoing in our Phase II Pivot HD study, a global placebo-controlled study, of PTC 518 in HD patients. This study will consist of two parts, an initial 12-week placebo-controlled phase focused on, PTC 518 pharmacology and pharmacodynamic effects, followed by a 9-month placebo-controlled portion during which we will collect blood, CSS, and radiographic biomarker data. The study will initially include two dose levels, 5 milligrams and 10 milligrams, with, the potential to study a third dose.

We anticipate data from the 12-week portion of the study by the end of this year.

As well as obviously the phase <unk> study.

Yes.

Did you say.

For the PKU trial right.

Particularly in your trial and then I just saw on the press release that I think.

Details of <unk> readout.

Yes, sure fourth quarter.

We are very excited about our continued progress across our development program and look forward, to sharing results from several of our studies in the near future.

Yes, so we're pretty excited obviously about the PK trial.

Yeah.

Our drug has.

I will now hand the call over to Eric to discuss our commercial portfolio.

Eric?

So a benefit there.

And so.

We're pretty excited about that you wanted to talk a little bit about.

Thanks, Matt.

This is a very exciting time for PTC and, in particular, for our global customer-facing, teams, commercializing a diversified portfolio of products that address high unmet needs for patients with rare diseases.

We have achieved another very strong quarter, and we are thrilled to add a fifth commercial, product to our portfolio with the recent approval of Absaza and to bring much-needed treatment to AADC deficiency patients.

Our DMV franchise continues to be a key revenue driver as we continue to expand our global, footprint that will also support the future growth from the pipeline.

Where we are on that.

Yes sure Raj.

All three of these trials are global trials, leveraging our global development infrastructure for PKU the sites are up running enrolling.

We are on track for it results by the end of 2022.

Similarly, as we updated both Kimberly as we updated our pivotal <unk> study were getting sites up around the world in enrolling that trial with the data by the end of 2022, our results by the end of 2022.

Similarly, as we updated both temporary as we updated our pivotal <unk> study were getting sites up around the world in enrolling that trial with the data by the end of 2022 on the 12 week portion and then our Navy we move the data to one quarter to first quarter of 2023, Thats, mainly due to the COVID-19 related delays.

Children mitochondrial diseases seizures are quite ill children mitochondrial diseases seizures are quite ill and factor in there is not a pandemic going on seasonal colds includes can easily put them in the hospital. It can be fatal events and so theres been a lot of caution on the part of parents and physicians to get the kids into the store.

Eddie sites, so thats caused a little bit of delay.

And given the trial to the enrollment target, but for now on target to have results as we said in the first quarter of 2023.

That's helpful. Thanks.

Okay.

Thank you.

And we will take our next question from Kristen <unk> from Cantor Fitzgerald. Your line is open.

Let me begin with Absaza and our ongoing launch preparation.

Hi, good afternoon, Thanks for taking my questions and congrats on the phase of launch so given that you have three registrational trials, where we're expecting data through the second quarter of next year and the updated BLA guidance for the fourth quarter could you talk about some of the commercial readiness steps youre taking.

We are very excited about the recent approval in Europe, and our team is actively executing, on all strategic initiatives supporting the launch.

We are off to a good start and have treated our first commercial patients this quarter, under the French Early Access Program.

Treatment center readiness is well on track, as well as further preparation for surgeries, carried out at key European centers.

Patient identification is continuing to accelerate, and we anticipate treating additional commercial, patients with the upcoming launch in Germany.

Towards juggling these potential filings and beyond should they be successful.

We are also focused globally on markets that have early access programs, such as France, Italy, and others via cross-border healthcare.

The Absaza price is expected to be in the range of $3 million to $3.5 million, which, factors in our projections of future pricing negotiations in key European markets.

Yes sure.

We are confident that the durable efficacy and safety data we have obtained from over, 10 years of patient experience with Absaza will support HTA dose-case submissions for reimbursement as the first and only treatment approved for AADC deficiency patients 18 months and older.

We have guided to $20 to $40 million in revenue from AUSPESA.

Let me start a little bit we're obviously.

Turning now to DMV.

Our global DMV franchise continues to deliver robust revenue across all regions. Our second quarter revenue for the DMV franchise was $134 million.

Our MPLAZA net product revenue for the second quarter was $57 million, which represents 16% growth over the second quarter last year. Ongoing execution by our MPLAZA team drove new patient starts, continued favorable access, high compliance, and appropriate weight-based dosing for DMV patients in the United States.

For TransLarna, we achieved $77 million in net product revenue for the second quarter, which represents a 46% increase over the second quarter of 2021, driven by growth in all regions. As a reminder, we can have large group purchase orders, which can create luckiness due to uneven government buying patterns.

Just the way the structure of the team is such that each team is moving forward on that so.

Overall, TransLarna revenue continues to be globally diversified and robust in all key markets.

Furthermore, patient identification continues to be strong, and we anticipate additional group purchase orders over the course of the year.

We continue to make good progress with regulatory approval and pricing and reimbursement in our newer markets in Eastern Europe, the Middle East, and Latin America.

Finally, discussions progressed with CONITECH, the National Commission for the Incorporation of Technology, for inclusion of TxEDI in the essential drug list, which simplifies access.

We are also continuing to expand our presence in additional markets in Asia Pacific, as this region continues to be of strategic importance for potential future revenue growth for PTC.

For Relivra, we now have patients on treatment for STL in Latin America, and patient identification continues to progress well. As a reminder, last December, we submitted an application to MDF in Brazil for approval of Relivra for the treatment of STL. If approved, Relivra will be the first approved treatment for STL in Brazil, and this will mark the first approval globally for this indication. We anticipate a decision in the second half of 2022.

We are in a strong position to achieve the 2022 DMV revenue guidance of $475 million to $495 million.

In conclusion, our customer safety teams globally have had an extremely successful first half of the year, and we will be focused on capitalizing on the momentum built and the launch of Abstasia for the remainder of the year.

In Latin America, our team continues to strengthen the TxEDI and will leave our franchise.

In Brazil, following the innovative drug classification for TxEDI, we received the first group purchase order from the Ministry of Health, which was delivered in the second quarter. This was an important milestone for our HHGTR patients awaiting treatment.

The geography.

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

We don't really juggling therapies team has.

In each of the registration directed.

Sure.

Program each team is doing.

Emily?

Thanks, Eric.

In the first half of 2022, we saw continued strong revenue growth and progress in advancing our pipeline across multiple platforms.

Where we.

Given current market conditions in the biotech space, we are particularly pleased that the royalty monetization for EBRSI, combined with our strong continued revenue growth, allows a strong capital structure to fund the further advancement of our pipeline.

Work to get ready for launch and regulatory.

The press release issued earlier this afternoon summarizes the details of our second quarter 2022 financial results.

I will take a few minutes now to review these financial results.

Please refer to the press release for additional details.

Beginning with top line results, total revenues were $166 million for the second quarter of 2022, a 42% increase over the second quarter of 2021. This was driven primarily by net product revenue from DMD franchise of $134 million and EBRSI royalty revenue of $22 million.

Our total revenue from the first half of 2022 is an impressive $314 million, and as Stu said, we are on track to achieve our 2022 total revenue guidance of $700 to $750 million. Apart from our continued net product revenue, we also anticipate a $50 million milestone payment from Roche when annual EBRSI sales reach $750 million.

Correct. So we go it isn't like we have to wait for one versus the other a routine every every one of those factors.

In addition, we have guided to $20 to $40 million in revenue from Upstaza.

Turning now to a DMD franchise, Transmarna net product revenues were $77 million, representing year-over-year growth of 46% compared to the second quarter of 2021.

And Plaza had net product revenues of $57 million, or 16% growth year-over-year.

Moving now to EBRSI, our partner Roche reported 2022 year-to-date sales of approximately $500 million Swiss francs, which translated into second quarter royalty revenue for PTC of $22 million. As a reminder, PTC retains approximately 57% of EBRSI royalties, with Royalty Pharma receiving the remaining 43% up to a cumulative total of $1.3 billion, after which PTC receives 100% of EBRSI royalties.

Non-GAAP R&D expenses were $144 million for the second quarter of 2022, excluding $14 million in non-cash stock-based compensation expense, compared to $112 million for the second quarter of 2021, excluding $13 million in non-cash stock-based compensation expense.

The year-over-year increase in R&D expenses reflects additional investment in research programs and advancement of the clinical pipeline. Non-GAAP SG&A expenses were $66 million for the second quarter of 2022, excluding $14 million in non-cash, stock-based compensation expense, compared to $57 million for the second quarter of 2021, excluding $12 million in non-cash, stock-based compensation expense.

Cash, cash equivalents, and marketable securities totaled approximately $506 million as of June 30, 2022, compared to $773 million as of December 31, 2021.

I'd now like to turn the call over to the operator for questions and answers.

Operator?

That is moving forward and I think we have a pretty strong track record.

And moving those forward from the team.

So I think we'll be able to.

To be able to move all of them.

Move forward and I think the global footprint.

That we have gives us really the capability.

Variable.

Knock on wood all goes well.

We'll be able to launch all of them.

And each one.

Progressive.

And.

So if approved both in Europe as well.

Yes.

Does that help you.

Yes. Thank you appreciate that and I know in the past you've made a lot of synergies with your splicing platform as it relates to Bruce D. And then of course, the work Youre doing in Huntington's disease, but now there's been a lot of commercial experience here wondering if your views have changed confidence increase.

Or anything that you could really take away from the commercial experience relative to this platform.

Yes.

From our point of view.

We're really pleased with.

The splicing platform in the commercial.

But obviously the nice aspect of.

Of these molecules is that they are orally bio available.

Especially from Europe .

Diseases.

Okay.

The fast moving business to every part of the freight and therefore that could treat every aspect of the disease, we think Oro.

In these cases oral is probably the best way to go you could probably traded you could you know you can utilize.

PD markers in the blood.

But where you are in terms of what goes through your goodwill.

The effect of either increasing or decreasing the amount.

Protein like we've done with.

With the.

PTC five eight.

So could you actually put your you're not driving the blindly youre actually.

You'll have a pretty good look into say what.

Based on this.

Exposure level youre getting the effect on pricing and we think that's really important and then you can measure the level of the drug.

And therefore know that.

In the CSF as well to know the exposure levels.

The block within the brain as well.

Get a lot of information that likes to make good decisions.

Got it.

And then obviously from a commercial perspective.

The fact that this is the case that the standard sort of commercial program.

You have.

No.

So everyone knows what the doses with the right.

What's the right level therefore.

With the clinical data.

I think this is a really nice commercial products and move forward with we've spent a lot of time now perfecting the splicing platform.

Where it's really homed in those spaces. So we think this is going to be.

A platform that's going to add multiple.

So.

Multiple programs that ultimately, we'll get the commercial for multiple drug flu season is going to be.

We are excited.

I mean, I think that's really an exciting new platform.

Thank you.

Okay. Thank you Sue.

Thanks for the question Chris.

Yes.

Thank you. Our next question will come from Joe Thome from Cowen. Your line is now open.

And as a reminder, to ask a question, please press star 11.

Hi, there good evening and thank you for taking my question, maybe one on the mitochondrial epilepsy patients.

Please stand by while we compile the Q&A roster.

It's kind of your updated thinking in terms of how many patients are out there and is it relatively straightforward to identify them and then as youre looking at sort of the.

And then as you're looking at sort of the presentation, are there any variabilities in the type of seizures that these patients experience?

Presentation are there any variability in the type of seizures that these patients experience. Thank you.

Thank you.

And our first question will come from Eric Joseph from J.P. Morgan.

Yes.

Hi, Matt.

Yes, hi.

You want to take that? Yeah, absolutely.

Hi, Matt you want to take that.

Yes, absolutely Joe Thanks, Thanks for the question.

Your line is now open.

Joe, thanks for the question.

So when you talk about seizures in mitochondrial disease.

Highly morbid common components of these disorders, so roughly 30% to 50% of kidney disease.

Relatedly, is there any material FX impact that we should also be considering?

So just when you talk about seizures and mitochondrial disease, it's a highly morbid and common, component of these disorders. So roughly 30 to 50% of kids with mitochondrial disease have seizures as part of their disease. And the vast majority of these seizures tend to be refractory to typical anti-epileptic therapies.

These have seizures as part of their disease and the vast majority of these seizures tend to be refractory to typical anti epileptic therapies. The simple reason that most traditional anti epileptic therapies increase as part of their benefit increased oxidative stress, which is actually which is actually the pathology under modest seniors and children.

The simple reason that most traditional anti-epileptic therapies increase as part of their benefit, they increase oxidative stress, which is actually the pathology underlying seizures in children with mitochondrial disease.

So in many ways, both of these make them worse.

So in many ways traditional therapy based on worse, obviously that particular targets the underlying pathways that underpin the oxidative stress mediated seniors and children. We estimate there are about 20000.

Obviously, the method of the Tick-B-Nose targets the underlying energetic pathways that underpin the oxidative stress mediated seizures in these children.

We estimate there are about 20,000 patients worldwide with mitochondrial disease-associated, seizures.

Patients worldwide with mitochondrial disease associated seizures, and as you pointed out we've seen this week there is some variability there.

And as you pointed out within this group, there is some variability.

They have variability in the number of seizures, and as you alluded to as well, Joe, there's actually a lot of variability in the types of seizures.

There are a number of seizures, and obviously you alluded to as well Joe as I saw the variability in the types of seizures.

They could be motor, they could be myoclonic, they could be tonic, they could be chronic.

Making the motor they could be.

And then most of these children actually have a composite picture with many different seizure subtypes.

Myocardial uptake of the tonic clonic.

Most of these children actually have a positive picture with many different features subtitled started taking the purposes of the clinical trial, we're focusing on observable motor seizures as the primary endpoint because those are obviously, one observable that too quantifiable, which is obviously an important aspect of being able to measure treatment effect and in fact the.

Obviously, for the purposes of the clinical trial, we're focusing on observable motor seizures as the primary endpoint because those are obviously one, observable, and then two, quantifiable, which is obviously an important aspect of being able to measure treatment effects.

And in fact, the study design of focusing on the observable motor seizures, having observational learning phase, and the overall structure mimics the previous trials and the things like Lennox-Castell interface.

The study design of.

Focusing on several motor seizures, having observed observation a lot of cases and the overall structure of index.

<unk> trials done in things like life Sciences analytics, castellan showcase, which is seasonal very well established study design for pediatric epilepsy syndromes.

We're just using a very well-established study design for pediatric epilepsy syndromes.

Perfect and then maybe just to follow up on that is there.

Perfect.

Separation from placebo in terms of production.

And maybe just to follow up on that, is there a separation from placebo in terms of, reduction in number of major motor seizures that you're looking for in order to go forward with the submission or conversation with the FDA?

Number of major motor seizures that Youre looking for in order to go forward with a submission of our conversation with the FDA.

Yes.

Yes. So we powered the study for a delta of about 40% were estimating placebo to have a decrease of about 10% and that's just based on what's been observed in previous pediatric epilepsy syndromes and then we are targeting approximately 50% reduction in theaters in the treatment group.

So, we powered the study for a delta of about 40%.

We're estimating placebo to have a decrease of about 10%, and that's just based on what's, been observed in previous pediatric epilepsy syndromes. And then we are targeting approximately 50% reduction in seizures in the treatment group.

That's a median reduction.

Median reduction in a way that changes calculated as I mentioned, there is that 2008, a run in period, where we establish a baseline seizure frequency and then the measured in monthly frequency over the course of the six months placebo controlled phase.

And the way that the, change is calculated is, as I mentioned, there's that 28-day learning period where we establish a baseline seizure frequency, and then we measure the monthly frequency over the course of the six-month placebo-controlled phase.

I think while we're targeting a delta of 40% in terms of difference between treatment and placebo, I would point out that in these children, given how severe their seizures are, how highly morbid these seizures are, and how they're related to other morbid aspects of disease like aspiration and pneumonia, and in some cases, status epilepticus and death, even an observed decrease of 20% to 25% would be clinically meaningful for these patients.

While we are targeting a delta of 40% in terms of difference between treatment and placebo I would point out that in these children given how severe their seizures are highly morbid. These figures are and how they related to other morbid aspects of disease like aspiration pneumonia in some cases.

That is very helpful.

Thank you very much.

Thank you.

Status epilepticus in depth, even observe decrease of 20% to 25% will be clinically meaningful for these patients.

Got it very helpful. Thank you very much.

Thank you.

And we'll take our next question from Tazeen Ahmad from Bank of America.

And we will take our next question from causing Ahmad from Bank of America. Your line is now open.

Your, line is now open.

And then secondly, as it relates to requesting the transition to standard marketing authorization in the EU, can you just sort of provide a little more granularity on the timeline for requesting that change and sort of what that recycle might look like?

Hey, guys.

Hey, guys. Good afternoon, and thank you for taking my questions.

Steve I just wanted to get your thoughts on how youre viewing the opportunity for <unk> and co.

Thanks.

Good afternoon, and thank you for taking my questions.

Number one I guess, it's a little bit outside of what we've all become you still expecting from PTC in terms of areas of focus.

Hey, Eric.

And then also I think people kind of your comment is becoming more endemic now and there are a number of oral anti virals available.

To hear your thoughts on where you think Andrew Matt Needham.

And then secondly, just going back to your study can you clarify if you met the primary endpoint and what additional analyses would you expect to conduct before you make a decision on what to do with the product X.

Yeah.

Thanks for the call.

Stu, I just wanted to, get your thoughts on how you're viewing the opportunity for InvotoStat, you know, in COVID.

Yes.

So.

Obviously, we started the.

Early on as we were learning about Covid.

And the way too.

I mean, the question.

The best way to look at it became relatively clear.

You bet.

It was obviously a.

<unk> evolved.

Seeing where well even in hospitals in order to see effect.

Things that affected both.

The viral viral load.

Look at it early.

<unk> have been patients who have come in much later, it's much harder.

So in effect on something thats going to affect the viral load so.

That sort of something that we've learned and actually it turns out to be a relatively difficult.

To be able to guess who is the best.

Sites in order to move forward to it Nonetheless I think.

What we've decided to do is look.

At the study early with 180 subjects, who were enrolled in order to review the data collected in Jamaica.

The decision because it was taking a long time in order to.

In order to complete the trial and we felt we'd be better off looking now and seeing what would be the best way to do it.

Across all subjects.

There was a trend toward components that benefit across.

<unk>.

In several disease relevant endpoints.

Including duration of hospitalization time.

Definitely the vessels.

When examining the patients that were enrolled five days of infection. There was a statistically significant benefit of <unk> treatment on time.

Respiratory.

Improvement duration of hospital basis.

The lucent cost per lead.

For example, the median hospitalization leg.

In the placebo group was 28 days 10 days.

That group.

So I think the credit.

Pretty clear that the.

It was particularly important as they are.

Suggest a clear potential for <unk> to work.

And early treatment cohort, which is I think what people expect.

Sure.

And clearly I think one of the better ways to do this is in the outpatient setting.

I think the majority of the cases are now areas.

So we're considering what's the best way to do they outpaced that.

And to think about.

What's the best strategy, whether we work with someone else to get but what.

With these.

The <unk> compounds that inhibit COVID-19, what's.

What's the best way.

We get applications, Firstly I think there still is.

Need.

For sure.

Four four drugs I mean, clearly I think what we've shown here for Keith.

Clearly a proof of principle that this would be good.

Intriguing cohort to the next question, though has been.

This and other viruses that come up with it because let me remind you of cellular targeting therefore.

Good.

The low mutation rate and you could see some of the other drug whether you are or excuse me that resistance.

But this.

So I think there's a need for additional drugs out there. So we'll just have to consider the best way to move this forward and to your point about it.

Number one, I guess, it's a little bit outside of, you know, what we've all become used to, expecting from PTC in terms of areas of focus.

Something that we normally would.

I think youre right. This is normally a position.

One area that would go into large indications.

There was a real need for treatment for.

So there was the pandemic.

We thought it was important to us.

And we knew that.

Just because the way it works in the row.

So th controlling.

The logo permitting.

We learned that you need to notebooks surpluses for viral replication.

And that the <unk> pathway.

Most of those work isn't enough.

For viral replication, but this is a potentially good target.

So we thought that this was an important.

Sure.

No problem.

Around the world that we'd like to be part of this loosen the possible. So that's why we did that.

Okay. Thank you for the color.

Yes.

Thank you.

And we'll take our next question from Misha <unk> Gandhi from <unk> Securities. Your line is now open.

Hi, and thanks for taking my question and congrats on the quarter.

Alex on for Robyn.

What type of cadence, we want them to know for news flow and should we expect to see around the trends on our filing at the launch prep in the U S.

And then also, I think people kind of view, COVID as becoming more endemic now, and there are a number of oral antivirals available.

And what kind of communication can we expect and then also can you remind us about your manufacturing capabilities and capacity to support launches in both the EU and U S. Thanks.

I'd love to hear your thoughts on where you think the undermat need is.

Manufacturing.

What are you referring to.

Just in general.

Do you anticipate any sort of supply chain.

Ashish.

And regarding complying with gene therapy products for an ultra orphan therapy in our global markets.

Sure.

Yeah, I think we've had a – I think we've – I think this is a great quarter where we saw growth of both TransLarna and SLASA quite good.

And then secondly, just going back to your study, can you clarify if you met the primary endpoint, and what additional analyses would you expect to conduct before you make a decision on what to do with the product next?

And, you know, and there was growth throughout all geographies.

So I think.

Obviously, we're excited about the trends La arena will be wherever you have an end of phase two meeting and talking with the FDA I think we will have news flow.

We continue to see a really high compliance.

Thanks.

We've added – you know, we've added programs that would also include dose adjustments for patients.

Talk more clearly.

In the phase III that will then give clarity on that.

Amit do you want to talk a little bit about mix.

Yeah.

So, you know, obviously, we started this early on as we were learning about COVID, and the way to, what are the best ways to look at it.

Yes, absolutely.

So we're really doing very well in terms of preserving the base and growing the base but also through geographic expansion.

It became relatively clear that, you know, that it was obviously an evolving scene where, well, even in hospitals, in order to see effects of things that affected both the viral load, you had to look at it early, versus having patients who come in much later, it's much harder to see an effect on something that's going to affect the viral load.

So, that's sort of something that was learned.

We have new markets that are also significantly contributing.

In terms of Europe , I think we've talked quite a bit about the timeline, we expect to submit a type two variation by the end of <unk>.

So essentially, we're seeing that robust growth across the global and diversified markets that we have.

Unknown Speaker Right.

September to request the conversion from conditional standard in the U S. As you add the plan will be to meet with the FDA.

And actually, it turns out to be a relatively difficult to be able to guess where's the best sites in order to move forward to it.

Lay out all of the data from <unk> 41, as well as the totality of data, which strongly supports the benefit of Trans Laura 10, being able to share. The fact that we have statistically significant data in dnb on functional endpoints, which Corey.

Nonetheless, I think what we decided to do is look at the study early when 189 subjects were enrolled in order to review the data collected and to make an informed decision, because it was taking a long time in order to complete the trial.

Therapy, that's targeting the underlying mechanism of disease will be the first.

It would be able to share that along with the totality of data that we've collected in the stride registry demonstrated long term safety and benefit as we've previously talked about so once we have that meeting with the agency and they gave a lot of that on the path to an NDA will obviously move forward.

Obviously it.

And we'll share updates as appropriate.

Thanks Harlan.

And then for <unk>.

For supply chain and manufacturing.

Work is two pronged.

Small molecule passing on the gene therapy path.

Small molecule path or something of that with you.

We've been doing now for almost 20 years, we have a strong supply.

A manufacturer or supply chain group.

That's been capable of.

Making sure we can manufacture.

Supplied to either clinical or commercial products.

Multiple ones.

I think they're very good evidence of it.

We've been able to move forward it can handle multiple programs.

And they've shown to be capable of doing that obviously in.

In gene therapy.

Well site.

Close to three 300000 square foot facility.

Oh for gene therapy manufacturing and plus we have with both.

Massachusetts.

Yes.

Manufacturer as well as the other.

Steve.

So square feet for commercial manufacturing as well, so I think we're well suited and capable.

And we have a team.

Experienced people who've now.

They have under their belt.

Approvals.

An approval.

Getting therapy right really over a third one that's been <unk>.

<unk>.

So I think we are in the clinic.

And Bayer.

And.

So we've been.

So we clearly have a state of the art facility.

They'll be able to do gene therapy manufacturing and in fact, we've also built out.

In the sense of small.

<unk> with working with.

Other companies the breeder protects the capacity.

That we can make a business out of <unk>.

Manufacturers. So I think we're in pretty good shape, both in the manufacturing of <unk>.

Gene therapy, as well as small molecule.

And then I'll say one thing and then I'll pass it to Kylie.

Thanks for taking the question.

Okay.

Thank you.

And we thought we'd be better off looking now and seeing what would be the best way to do it.

And we will take our next question from Brian Abrahams from RBC capital markets. Your line is open.

So, across all subjects, there was a trend towards the most benefit across that in several of these, relevant endpoints, including duration of hospitalization and time to defer the lessons.

But when examining the patients that were enrolled five days of infection, there was a statistically significant benefit of involving that treatment on time to respiratory improvement, duration of hospitalization, dyspnea, resolution, and cough relief. You know, for example, median hospitalization length in the placebo group was 28 days, 10 days on Imbodacet group.

So, I think it's pretty clear that it was particularly important as they suggest a clear potential for Imbodacet to work in early treatment in COVID, which is, I think, what people expect.

Hi, This is Steve on for Brian Thanks for taking my question.

And clearly, I think one of the better ways to do this is in the outpatient setting, where I think the majority of the cases are now managed.

So we're considering what's the best way to do the outpatient and to think about what's the best strategy, whether we work with someone but with the DH or DH compounds that inhibit COVID-19, what's the best way to get that patient?

Personally, I think there still is a need for additional drugs.

<unk> learned I'm curious, whether you see any impact of the recent news that FDA may consider accelerated approval for DMD gene therapy on the path forward for trends learner, maybe as a related question can you share whether any additional subgroup analysis.

I mean, because clearly, I think what we've shown here for DH or DH is clearly a proof of principle that this would be good in treating COVID-19.

The next question, though, is then this and other viruses that come up with it, because let me remind you, it's a cellular target, and therefore, we think it would be good, you know, in terms of low mutation rate.

And you could see some of the other drugs, whether they are seen as resistant or additional flashbacks.

So I think there's a need for additional drugs out there.

From study 101, but maybe didn't present, yet might help that application and maybe how many.

Subgroup analysis performed thanks.

Sure.

I think what's important is, you know, I think you can see we continue to grow our business quite well.

So we'll just have to consider the best way to move this forward.

And I think we're going to continue to do that.

And to your point about it's something that we normally wouldn't do, I think you're right, this isn't normally a position, an area that we would call in a large indication.

Hum.

We were reiterating that the 700 to 750 million.

But, you know, there was a real need for treatment for COVID.

So.

It was a pandemic.

And we thought it was important to – and we knew that just because the way it works and the role of DH or DH in controlling, the novel pyrimidine synthesis, where we learned that you need the novel synthesis for viral replication, and that the salvage pathway was what most cells work on, isn't enough, and you need this for viral replication, that this is a potentially good target.

I think you know.

And so we thought that this was important enough of a disease and COVID enough problems around the world that we'd like to be part of the solution as possible.

For in terms of.

A couple of quarters.

In terms of the gene therapy.

So I think, you know, we're comfortable with that.

So that's why we did that.

First of all is limited to the patient population up.

Possibly but they're kind of in it.

Okay.

I think the <unk> lineup.

Thank you for the color.

And the trials or for that matter, a public key foundational treatment, but a sense of the care for Duchenne muscular dystrophy.

I think I've shown the Wildcat <unk> ratings and benefits that looks rather to a broad range of patients.

And I think there are always going to be.

Use.

For that.

I have a little bit different view in terms of the gene therapy with <unk>.

The gene therapy, with the highest dose small patient numbers.

With.

Benefits yet.

Australia is up with a drug that.

You cant withdraw a reverse the therapy once treated places aren't capable of getting other treatments.

That would be interesting with the FCA in terms of thinking about and I think there's a number of key questions or issues that are yet to be a threat.

So I'm very curious to see how buyer both the accelerated approval path, where he is in the teens.

Gene therapies, where there isn't critical data.

And the notion of <unk>.

Just circling biomarkers that in this case.

Welcome to necessarily predict functional benefit.

Yes.

How you can.

How you can bring back the patients when they can't get other other chemotherapies as a consequence of that.

I personally am skeptical of that pathway right now in gene therapy.

In terms of the $74 one I see.

The fact that we are in the ITT population.

As well as we've told you than the three to 400 analysis.

The improvement is statistically significant from the ITT population is a three to 460 <unk> statistically significant with the North star as well as the time quotes.

<unk>.

And also.

<unk>.

10% worse than me, but we have a broad range.

Of analyses not to mention also the pool Atlas.

Statistical significance overall.

Uh huh.

When you pull all of that together was appointed.

Two P.

P value both with six minute walk.

Northstar.

So I think.

The strong data demonstrating.

Then in study 41 in the combination with <unk>.

With the other trial seven.

In fact PMT.

The strong <unk>.

So that and then you could thanks.

Thanks.

Really when you think about we could show that there is a 20%.

Improvement is the consequence of treatment with <unk>.

When you think about translating that to date to two what does it really meeting the patient from a functional perspective, when you look at the stride registry and menu.

And when you see the stride registry.

And see that.

See greater than five years presentation evaluation, almost two years in terms of preservation of being there to get off the ground.

Actually a strong presence in Asia.

Pulmonary function.

How you could where in this very interesting position, where we have so much data that shows you. The results you get into the clinical trial, what does that mean from a real clinical practice.

With a long term five years of data.

During those presentations of escalation putting off the floor pulmonary function.

No.

The results mean for a patient.

So we're pretty excited about that.

<unk>.

Maybe you could also be other the other interesting.

Analysis recruiters like what's the North Star as you know, it's a number of different.

Functional.

It shows that you measure if you go to North Star.

Score, but nonetheless.

What we also do on top of looking at that data we see.

Not only to work what does it do.

How well did it preserve.

Those funds right because over time, they lose function. So we saw when looking at this.

To reduce the risk by more than 30% 40%.

On February <unk>, so that's equivalent to perhaps daily saving one or two functions in these kids as a consequence of that so thats.

That's again another Great example.

Preservation of function.

So.

So I think thats really really sort of important so.

At the end of the day.

The most important thing I think we have all of this is that if we got a positive.

Result.

In the EMEA.

ITT population the whole population.

<unk> of patients.

Really every group and it was a large enough studies to be able to see this year. So I think all in all all of those results really isolate.

<unk> strong study.

Menstruating.

Sure as long as the effectiveness.

You want to talk a little bit about that.

Okay.

Thank you.

Does that help great. Thanks for that color, yes, yes. Thanks.

Thank you.

And we will take our next question from Colin Bristow from UBS. Your line is open.

And we'll take our next question from Nishant Gandhi from Truist Securities.

Your line is now open.

Hi.

Thanks for taking the question.

Hi, This is Ian on for Connie.

I can, go up on a quarter.

Congrats on the quarter and thanks for taking my question.

This is Alex on for Robin.

We have one question on PBC 80.

Finding youll ask so as you are getting a call the filing will be expected in the fourth quarter. So could you. Please give us some more color on the details for the company. If there is anything to be down beforehand.

Comprehensive launch experiences for the FDA filing.

And how can you have any further discussions with FDA. Thank you.

Yes, sure Mark do you want to take that.

Yeah, absolutely.

Yes, absolutely.

So Eric, with your question around.

What type of cadence we wanted to know for news flow should we expect to see around the transfer on the filing and the launch prep in the U.S.?

Thank you Leon for the question. So as we said all along we would work hard to get the MAA across line. Obviously, we're incredibly excited about the approval in the U S is to say this is Troy trailblazing in a number of ways and now we're focusing the efforts on the BLA submission as we set our plan is to meet with the agency and we have not done that.

I think obviously, you know, in the perspective that Stu said, we are reiterating our guidance and so while we do see an impact across the US dollar to the Euro, we continue to see a robust and globally diversified portfolio across a number of different geographies.

And, you know, what kind of communication can we expect?

So while we are seeing an impact, we remain confident in our business.

And then also, can you remind us about, your manufacturing capabilities and capacity to support launches in both the EU and the U.S.?

And it's geographic diversity allows us to remain confident and reiterate guidance.

And then your question.

Thanks.

To how the timeline.

Manufacturing for what are you referring to?

Matt, you want to take that 1?

Just in general?

Yeah, sure.

Do you anticipate any sort of supply chain issues regarding supplying the gene therapy, products for an ultra-orphan therapy in the global market?

Yet to align on a package.

And make sure that we have all of that is needed for the submission of the BLA.

Thanks for the question, Eric.

Sure.

And then based on the timing of that meeting we believe we'll be in a position to submit the BLA in the fourth quarter of this year.

So just as a reminder, study for 1.

Was part of our commitment to following the condition marketing authorization from the, and really the idea here was to conduct study 41 to provide comprehensive evidence.

In support of the benefit risk of transmortem, it's that generation of comprehensive evidence, which really triggers our ability to.

Believe that obviously has gone through the experience in Europe , and being able to achieve an approval puts us in a very strong position. Obviously, we have the clinical data that.

Go from a conversion to convert the conditional to the standard marketing authorization.

So, I think, obviously, we're excited about the TransLion, we'll be having an end-of-phase, 2 meeting and talking with the FDA.

It's actually Dave about data all those key components for approval, obviously, we've been able to provide in Europe , and we look forward to be able to provide those to the FD.

So, obviously, we're very excited about the results, which were collected in the population of 359 boys.

As part of our BLA submission.

Thank you.

Thank you.

And when you think about comprehensive evidence, and you think about 359 boys is the largest.

I think we'll have news flow as we talk and get more clarity, I mean, end-of-phase 3 meeting, that will then give clarity on that.

And we'll take our next question from Gena Wang from Barclays. Your line is now open.

Data package in a single trial for.

Matt, do you want to talk a little bit about next steps?

Hi, and thank you so much for taking my question. This is Shawn for Gina.

Yeah.

I have two questions Tom I wanted to start with.

And the statistically significant results on functional endpoints, including walk distance North star, we clearly believe that we have that comprehensive evidence.

Absolutely.

<unk> four and <unk>.

This is more at the benefit of transline.

So, in terms of Europe, I think we've talked quite a bit about the timeline we expect to, submit a type 2 variation by the end of September to request a conversion from conditional standard in the U.S. to U.S.

You mentioned before you have identified 300 patients globally.

And then, of course, the safety collected in this study and a long term safety package collected not only through our clinical trials, but also in a long term registry again, informs the favorable safety aspect of the drug.

How many of them are addressable can be treated based on the EU label.

Please can you break down the patient numbers by country or region and how many of them have already access.

Yeah.

Yes, Thanks Lou.

And then finally, we also have generated over the past several years, the stride data.

The plan will be to meet with the FDA, lay out all of the data from 041, as well as the, totality of data, which strongly supports the benefit of TransLion and being able to share the fact that we have statistically significant data in DMD on functional endpoints, which for a therapy that's targeting the underlying mechanism of disease will be a first.

Good.

Thanks for your.

Which provides long term real world evidence of benefit and trans water in the way of loss of emulation of probably 5.4 years.

A question obviously.

Maybe talk a little bit.

About <unk> deficiency.

So I lost a pulmonary function of 1.8 years, which are really.

Obviously, a very severe disease.

These are patients lacking the motor milestones.

Lack of dopamine production so.

Important given that those are the 2 key morbid transitions in the disease.

The vast majority of these patients.

We've identified really do fall.

Under the Theyre missing major milestones.

So, when you put the study for 1 data together with the stride data, we believe we have the comprehensive data that warrants conversion from the condition.

And so our label is.

Really we have the breadth of the label.

Very broad so we will.

Authorization to standard the way this happens mechanically.

We're pleasantly surprised by that.

Is, as we said before, we are due to provide the data by the end of Q3.

And so.

And this was an important point.

We were able to get that so thats going to be probably translates to a higher number.

That we will submit a type 2 variation.

Okay.

Patients.

But.

We'll get treated.

We have 300 patients, but we just have been identified and will continue to.

To identify patients.

Continue to do that we haven't broken them out.

From a close.

Place to place.

But what we're going to certainly what we do is while we have 300 patients we certainly have.

And we havent broken those out.

Specific countries as well we've found the location said I think we're going to be pretty busy.

Oh.

Throughout 2022 and beyond.

We already have patients that have been reaching out into the Germen center they get treated.

Also as scheduled.

Expanded access patients so as well.

From a move.

As we do that I think Thats I think thats doing really quite well, we look at the opportunity as.

A greater than.

$1 billion.

So, we really look forward to being able to share that along with the totality of data, that we've collected in the STRIDE registry demonstrating long-term safety and benefit as we've previously talked about.

Opportunity overall overall, what we've said is that the revenues will.

So, once we have that meeting with the agency and again, alignment on the path to it, NDA, will obviously move forward, and obviously, we will share updates as appropriate.

And then for supply chain, for supply chain and manufacturing, you know, we work – there's, two problems.

It will be this year, we've guided to.

Between 20, and $40 million and we think that will continue to grow.

There's the small molecule path and the machine therapy path.

The small molecule path is something that we've been doing now for almost 20 years. We have a strong supply chain – you know, manufacturing and supply chain group that's, been capable of making sure we can manufacture and supply to either clinical or commercial products, multiple ones at the same time.

As a.

I think they're very good at it, and it's – we've been able to move forward.

We lined up all the patient continue.

And we will get all of it.

Of the surgical failures.

So I think we're well.

We're pretty excited over the next couple of years.

Getting all the patients we have.

To continue.

Would you buy more and more patients to treat.

It can handle multiple programs, and they've shown to be capable of doing this.

Thank you very much.

May I ask a second question Andre.

Yeah, a little bit to Huntington your.

Obviously, in gene therapy, we have the Hopewell site, which is, you know, close to 300,000, square foot facility for gene therapy manufacturing.

Chemo to HD trial.

Wondering what kind of data.

And plus, we have a site in Massachusetts that – with NBL that we can manufacture, as well, another 15,000 or so square feet for commercial manufacturing as well.

We should expect by year end.

So I think we're well-suited and capable of – and we have a team of experienced people, who now, you know, have the – have under their belt approval – an approval in gene therapy, right, really only a third one that's been commercially valued.

So I think we're in a pretty good position there, and so we've been – so we're – you, know, we clearly have a state-of-the-art facility to be able to do gene therapy manufacturing.

And in fact, we've also built out, in a sense, a small CRO in working with other companies, that we have excess capacity that we can make a business out of making plasmids and manufacturing.

Sure like Nurofen them on data.

Besides biomarkers what type of order.

So I think we're in pretty good shape, both in the manufacturing of – in gene therapy, as well as small molecules.

Points, you will show by year end, such as any like imaging radar light.

Cayman venture coal volume.

Thank you for taking the question.

Yeah. So.

Remember that the trial.

It really has two parts one is the 12 week trial.

Thank you.

Look the first part of this is really to say what we saw in healthy volunteers.

We see in.

And we'll take our next question from Brian Abrams from RBC Capital Markets.

102 spaces right. So.

So clearly.

A placebo controlled trial.

We're the first 12 weeks would focus on the pharma front.

Mycology Pharmacodynamic effects.

And then the second is more on Biomarkers and clinical endpoints right. So the first 12 weeks will provide the important results.

Between relationship with dose exposure HPT mrna and protein reduction in the blood.

Right.

We think that's important to us.

Is it the same or different.

What the PK looks like in the CSF.

The exposure, though the ratio between that and you might remember that we saw somewhere between the two and three to one.

In.

DSS to blood.

We wanted to see what it looks like.

In.

HPT patients.

<unk>.

Patients go on and we also wanted to look at HQ2 railroads neural element.

As well.

The first part of it is going to be the pharmacology blood T D.

Just wanted to confirm so by year end.

Fee owning PK and PD data in weeks.

But.

Are you going to collect that that are forthcoming internal reviewing.

I'm, sorry, I missed the last part of your <unk> parties.

For the first part of <unk>.

Just want to know you're focused on key PD that are you going to collect any of the biomarker data forward I can tunnels are you doing.

Yes.

Probably as not as we have everything wont be booking.

And.

And being able to monitor.

This is all relatively new there's never been an orally bio available drugs.

So right now we're trying to get to all the parameters correct in terms of.

Of knowing what the PK PD, what it looks like in terms of in patients in terms of what it's doing in the cells.

For protein and RNA.

Thank you very much.

Thank you.

Your line is open.

And we will take our next question from Danielle Brill from Raymond James Your line is open.

Hi, this is Steve Hunter, Brian.

Hey, guys. This is Alex on for Danielle just wanted to touch back on trend, Florida in the U S and the <unk>.

The rest of the read through.

And kind of how youre looking at the agency considering.

They are apparent tolerance for some let's say Dennis that flexibility in Duchenne do you think that there you're reading through to this that your train Florida future has.

It's better.

Do you think it stands on its own or are you not considering that there are different FDA divisions at play here.

Okay.

I think I I don't know if you heard what I said before but I think that.

I think we're hopeful that.

Look we did 741 was up a.

Well done study.

That's demonstrated functional benefit in a broad population of duchenne muscular dystrophy patients.

With the <unk>.

The broad population the ITT population.

<unk> demonstrated statistically significant.

The six minute walk test, but also the north star and time floats in test.

So I think that in itself.

Think about it I think the FERC for example, with.

For.

Okay.

A drug that actually show.

Treating the underlying cause of disease, where we're seeing in the ITT population.

Statistically significant.

Result in multiple.

In multiple endpoints and everything.

Our terrific.

<unk> versus <unk>.

Placebo, so I think that data along with the.

As a result.

From study <unk> seven.

14.

The.

That really shows that Youre seeing clinical benefit you don't have to rely on.

Our biomarker that hasn't so.

In our view hasnt, yet so it's predictable.

Of.

Clinical benefit so I think we're in a pretty good position from a clinical perspective, and then the data that goes along with it.

Oh.

And <unk> and then the stride registry.

Firstly for people what is in a way when you do clinical endpoints.

The goal of critical endpoints is for.

Perfect.

Outcome for patients right.

And in this case, we also have that data to show the regulatory bodies, where you see the.

<unk>.

In the stride registry, we saw greater than five years.

Preservation of regulation.

Two years or so of presentation of being able to get off the ground.

It really strong preservation of pulmonary function those are really the harvest in Europe Asia would you care about and there's.

Still ambulate can you still get off the ground and continue.

What is what are the DMD patient diode, which is pulmonary and cardiac function and if youre showing improvement in those sectors.

The drug is showing clinical benefit. So we think we have a strong space there.

Great. Thanks, so much.

Yes.

To the, which basically request that conversion, this will initiate a process.

Thank you.

I am showing no further questions at this time I would now like to turn the conference back over to Stuart Peltz for any closing remarks.

In Europe, that will unfold over the course of several months where there'll be back and forth.

Thanks for taking our question.

Great.

On TransLarna, I'm curious whether you see any impact of the recent news that FDA may, consider accelerated approval for DMD gene therapy on the path forward for TransLarna.

Maybe as a related question, can you share whether any additional subgroup analyses you, have performed from Study 101, but maybe didn't present yet, might help that application and maybe how many subgroup analyses you performed?

Thanks.

Well.

Sure.

So, you know, I think, you know, for in terms of a couple points, in terms of the gene therapy, I think, you know, first of all, it's limited to the patient population possibly that there has.

Look I want to thank you all for joining us today.

And I think that TransLarna, and in Swaziland for that matter, a public key foundational, treatments that are standard for care for Duchenne muscular dystrophy, that I think has shown the wide age range and benefits demonstrated in a broad range of patients.

And I think they're always going to be used for that.

You know, I have a little bit different view in terms of the gene therapy with, you know, the gene therapy with the high dose, small patient numbers, with, you know, benefit yet not demonstrated with a drug that you can't withdraw or reverse the therapy once treated and the patients aren't capable of getting other treatments.

I think what you could see from.

That is the interesting that the FDA, in terms of thinking that, and I think there's a number, of key questions and issues that are yet to be addressed.

So, I'm very curious to see how viable the accelerated approval pathway is in the gene, therapy where there isn't clinical data and the notion of using a different biomarker that in this case doesn't necessarily predict functional benefit.

How you can bring that to patients when they can't get other gene therapies as a consequence, of that.

We've been having really.

So, I personally am skeptical of that pathway right now in gene therapy.

In terms of the study 41, I think, you know, the fact that in the ITT population, as well, as we've told you in the 300 to 400 analysis, so you see improvement in statistically significance in the ITT population in the 300 to 400 that you saw statistically significant with the, North Star as well as the time function test.

A great year of significant progress this year.

And also in terms of time to 10% worsening.

So, we have a broad range of analyses, not to mention also the pooled analysis and the, statistical significance overall in when you pull all of that together with the .0002, P value both with six minute walk test, North Star, and time function test.

It had been delivering on a number of key milestones.

And we're proud of the approval of a phase, which I think is really growing breakthrough science and the milestone not only for PTC, but for the entire field of gene therapy and for the community and I think that the positive results from study <unk> demonstrated the benefits.

They may have questions about the data.

So, I think there's strong data demonstrating that in study 41 in the combination with the, other trials, the .007 and ACT-D and D, the strong results of that.

So it's hard to say exactly what the time will be from initiation of that process in September until the end.

And then you can, you know, what's next about, you know, really when you think about, we, can show that there's a 20% improvement as a consequence of treating with TransLARNA.

We think it will be several months, but clearly much shorter than 1 way to anticipate typical.

And that when you think about translating that to what does it really mean to patients, And then you, and when you see the site registry, and see that you see, you know, greater than five years preservation evaluation, almost two years in terms of preservation of being able to get off the ground, and actually a strong preservation of pulmonary function, it shows you how you could, you know, we're in this very interesting position where we have so much data that shows you the results you get in the clinical trial, what does that mean from a real clinical practice, with a long-term five years of data showing those preservations of exhalation, getting off the floor, and pulmonary function, you now know what that, what those results mean to a patient.

Okay, great.

So, you know, we're pretty excited about that.

Then you could also, the other interesting analysis we did is, like with the North Star, as you know, it's a number of different functional functions that you measure to get a North Star score, but not only, so what we also do on top of looking at that data, we say, not only what does it do, but how well did it preserve those functions, right?

Because, you know, over time they lose function.

So we saw when looking at this that you reduce the risk by more than 30 to 40% on several, tasks, so that's equivalent to perhaps saving one or two functions in these kids as a consequence of that.

So that's, again, another great example of preservation of function.

So I think that's really, really sort of important.

So if mutation.

So, you know, at the end of the day, the most important thing I think we have out of this, is that we got a positive result in the, you know, in the ITT population, that's the whole population of patients, so really every group, and it was a large enough study to be able to see this here, so I think all in all, all of those results really, I think, make this a very strong study demonstrating transliners' effectiveness.

Does that help?

The pace of.

Great.

Really adds.

And demonstrates.

That trend line of benefit to the patient.

So the totality of evidence both transponder.

Thanks for that, Culler.

Yes, yes, thanks.

So the other important point is that.

Thank you.

And we'll take our next question from Colin Bristow from UBS.

Your line is open.

And what we've talked about particularly in the question.

Hi.

This is Yihang.

I'm for Colin.

Congrats on the quarter, and thanks for taking our question.

Last is that we have a number of registration directed studies that are ongoing but we look forward to sharing those results with you in the near future.

So we have one question on the PPC-ABC-BLA filing U.S., so as you said in the call, the filing will be expected in the fourth quarter, so could you please give us some more color on the details, for example, if there's anything limited to be done beforehand, and how would you incorporate the video launch experiences for the FDA filing, and have you have any further discussions with FDA?

Thank you.

Great.

Matt, do you want to take that?

Yeah, absolutely.

Thank you, Lehan, for the question.

So, as we said all along, we would work hard to get the MAA across the line.

Obviously, we're incredibly excited about the approval in the EU.

That's very helpful.

As Stu said, this is really trailblazing in a number of ways.

I have two questions.

Thanks for taking the questions.

And now we're focused on the efforts on the BLA submission.

I want to start with the Abstaza for AADC.

We're excited and happy if you can do to continue on this mission of discovering and developing these innovative therapies.

As we said, our plan is to meet with the agency.

You mentioned before you have identified 300 patients globally.

We have not done that yet, to align on the package and make sure that we have all that is needed for the submission of the BLA.

So how many of them are addressable or can be treated based on the EU label?

And then based on the timing of that meeting, we believe we'll be in position to submit the BLA in the fourth quarter of this year.

Secondly, can you break down the patient numbers by country or region, and how many of them have early access?

We believe that, obviously, having gone through the experience in Europe and being able to achieve an approval, which is in a very strong position.

Yeah, thanks for your question.

Obviously, we have the clinical data, the necessary manufacturing data, non-clinical data, all those key components for approval.

Obviously, maybe talk a little bit about AADC deficiency. It's obviously a very severe disease where patients lack the motor milestones and lack dopamine production.

Obviously, we've been able to provide in Europe, and we look forward to be able to provide those to the FDA as part of our BLA submission.

So the vast majority of these patients that we've identified really do fall under the, you know, they're missing major milestones.

Thank you.

And so our label is really we have the breadth of the label that's very broad.

And we'll take our next question from Gina Wang from Barclays.

So we were pleasantly surprised by that.

Forward the certification.

Your line is now open.

And so this was an important point that we were able to get that.

Hey, thank you so much for taking my question.

So that's going to probably translate to a higher number of additional patients that will get treated.

This is Shuang for Gina.

And as I said, we have 300 patients that we have identified and will continue to identify patients and continue to do that.

Thanks for joining us today, and we look forward to.

We haven't broken them out from place to place.

But what we're going to certainly what we do is while we have 300 patients, we certainly have and we haven't broken them out by specific countries as well.

We found enough patients that I think we're going to be pretty busy treating them throughout 2022 and beyond.

<unk>.

We already have patients that have been reaching out into German centers to get treated.

Our next conversation with.

We also have scheduled paid expanded access patients as well.

So things from a move as we do this, I think that's doing really quite well.

We look at this opportunity as a greater than a billion dollar.

And the update.

Thank you. This concludes today's conference call. Thank you for your participation and you may now disconnect everyone have a wonderful day.

<unk> one one.

[music].

Yes.

[music].

Thank you.

Thank you, everyone, for joining us today.

And we'll take our next question from Raju Prasad from William Blair.

Even though you focused on PK PD data, are you going to collect any of the biomarker data for like internal reviewing?

Your, line is now open.

Yes, I, you know, probably as we have everything, we'll be looking and, and, and, and being able to monitor.

Thanks for taking the question.

And, you know, we were, you know, the question is, this is all relatively new.

There's never been.

And all of these bioavailable drugs, so right now we're trying to get to all the parameters.

Correct.

In terms of.

Of of knowing what the P. K. P. D. what it looks like in terms of.

In patients in terms of what it's doing in the cells.

For protein and not, I mean, thank you very much.