Good day and thank you for standing by. Welcome to PTC Second Quarter 2024 Financial Results Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Ron Aldridge, Senior Director of Investor Relations..

Good afternoon and thank you for joining us today to discuss PTC Therapeutics second quarter 2024 corporate update and financial results. I'm joined today by our Chief Executive Officer, Dr. Matthew Klein, our Chief Business Officer, Eric Pauwels; our Chief Commercial Officer, Kylie O'Keefe; and our Chief Financial Officer, Pierre Gravier.

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.

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 quarterly report on Form 10-Q and annual report on Form 10-K filed with the Securities and Exchange Commission as well as the company's other SEC filings. We will disclose certain non-GAAP information during this call.

Information regarding our use of GAAP to non-GAAP financial measures and a reconciliation of GAAP to non-GAAP are available in today's earnings release. With that, let me pass the call over to our CEO, Dr. Matthew Klein.

Matt?.

Thank you, Jane. Good afternoon and thank you all for joining the call. I'm pleased to share with you our second quarter 2024 financial results and to provide an update on the progress of our development programs. As we have discussed, our focus for 2024 is on execution.

As we complete the first half of the year, I'm pleased to report that our teams have executed across all areas with solid revenue performance, on schedule regulatory submission and effective management of our operating expenses. We had a very busy and productive second quarter, and I'll review some of the highlights.

Starting with commercial performance, we had another great quarter across the portfolio. Second quarter revenue totaled $187 million including DMD franchise revenue of $118 million. Based on this consistent solid performance, we are updating 2024 total revenue guidance to $700 million to $750 million.

In addition to strong revenue, we also continue to effectively manage our operating expenses and will thus maintain the 2024 OpEx guidance previously provided. In the second quarter, we also completed the sale of our gene therapy manufacturing business in Hopewell, New Jersey.

As part of this transaction, PTC received an upfront cash payment of $27.5 million. In addition to the cash consideration, this transaction reduces expenses associated with operation of the facility, including employee costs. I'll now discuss the great progress our teams made across our development portfolio.

As we shared last week, we submitted the NDA for sepiapterin for the treatment of PKU to the FDA. This is an important step towards our planned global launch of sepiapterin in 2025 as we bring the potential new standard of care to PKU patients around the globe.

The sepiapterin NDA includes significant and clinically meaningful evidence of efficacy from the Phase III APHINITY study as well as data from the open label extension study demonstrating durability of the sepiapterin care and treatment benefit as well as C. Tolerance. Recent data from the C.

Tolerance sub study indicates that approximately 60% of subjects are able to increase their daily protein intake beyond the recommended daily allowance while still maintaining control of Phe levels. These data support that sepiapterin can provide significant benefit to PKU patients of all age groups and severity subtypes, including classical PKU.

We plan to submit marketing authorization applications for sepiapterin in Japan and Brazil as well as several additional countries in 2024 to support the global launch. Kylie will provide more details on our ongoing launch preparation. In July of plan, we also resubmitted the NDA for Translarna.

As discussed with the FDA, the submission is based on the results of Study 41 in which significant benefit was recorded across key endpoints in the ICT population as well as on the long-term evidence of meaningful treatment benefit from these drivers.

In the second quarter, we also shared the positive results from the 12-month interim data readout of the PIVOT-HD study of PTC518 in Huntington's disease patients.

The 12-month data demonstrated durable dose dependent lowering of mutant HCP protein in blood cells, reaching 42% of the 10 milligram dose level, along with dose dependent lowering of mutant Huntington protein in the CSF at levels similar to the blood in Stage 2 patients.

In addition, at 12 months, there was dose dependent favorable clinical effect on key disease measurements, including the total motor score and the CUHDSR. Importantly, the interim results also demonstrated PTC518 to be safe and well tolerated.

This combination of biomarker and clinical effect along with favorable safety position PTC518 as one of the most promising, if not the most promising therapy in development for Huntington's disease. We are in the process of preparing a meeting request to discuss with FDA the potential for accelerated approval based on the PIVOT-HD study results.

In addition, we have begun work on the design of the Phase III efficacy trial of PCC518, which can serve as a confirmatory study in the context of an accelerated approval or as a registration trial.

We look forward to continuing to advance PTP518 to the over 130,000 symptomatic Huntington's disease patients worldwide who desperately need a safe and effective disease modifying therapy. As we move into the second half of 2024, we remain on schedule for our planned regulatory and clinical milestones.

We are in the process of preparing the NDA submission for Vatiquinone for the treatment of Friedreich ataxia, which we expect to submit by the end of the year.

This submission will be based on the findings of significant treatment benefit in pediatric and young adult patients on the Upright Stability subscale of the mFARS disease rating scale in the MOVE FA study along with confirmatory evidence in the long-term open label portion of the trial.

As we have previously discussed, the Upright Stability Scale is the most sensitive and relevant portion of the mFARS for pediatric and young adult ambulatory patients and has been shown to be predictive of risk of long-term loss of ambulation.

Importantly, Vatiquinone also has a strong safety profile, including in children under age 16 for whom there are no approved FA therapies. Finally, we remain on schedule to share top line results in the registration directed CARDINALS trial of utreloxastat in ALS patients in the fourth quarter.

Utreloxastat is the first compound being developed for ALS that specifically targets paraptosis, a pathway of oxadata stress and cell death demonstrated to be highly relevant to ALS pathology.

Given the recent changes in the ALS therapeutic landscape, positive results from the CARDINALS study could enable utreloxastat to address the significant unmet need of ALS patients. In closing, I'm proud of our team's continued execution.

We accomplished all of our objectives and remain on schedule to achieve the many milestones we have set for the remainder of 2022. I'll now turn the call over to Eric and Kylie to discuss our commercial performance.

Eric?.

Thanks, Matt. Our global customer facing team had a strong first half of the year, delivering $133 million in revenue in Q2 across our five marketed products. Our global DMD franchise had a solid quarter during which we delivered $118 million.

We continue to actively commercialize Translarna in all European markets and in other international markets as our geographic expansion continues to progress further.

Our commercial teams are working closely with health care providers to ensure that patients continue to have access to treatment in Europe for as long as Translarna remains authorized pending the reexamination and ratification processes.

In Brazil, we signed a new group purchase order with the Ministry of Health and delivered 50% of this order in the second quarter, with the remainder of the order delivered in the Q3. As Matt mentioned, we have resubmitted the NDA for Translarna in the U.S.

and the team is well positioned to bring this important treatment to nonsense mutation DMD patients pending FDA approval. Now turning to EMFLAZA. Second quarter net revenue was $47 million. We continue to work closely with healthcare providers, payers and specialty pharmacies to dispense the brand.

We are leveraging PTC Cares patient programs, providing personalized services and support to each patient with insurance co pays and timely shipments from specialty pharmacies.

These efforts continue to reinforce the benefits of EMFLAZA for a significant number of new patient starts and maintaining existing patients on treatment, all of which are key revenue drivers for the brand year to date. Now, I will hand it over to Kylie to update the progress of our current and future new product launches.

Kylie?.

Thanks, Eric. We are extremely excited about the upcoming global launch of sepiapterin. As Matt mentioned, we have filed our NDA in the U.S., which is an important step in bringing sepiapterin to children and adults with PKU. In addition, in May, we received validation of our EU MAA filing and review is ongoing.

Further submissions are planned in several additional countries in 2024, including Brazil and Japan, which alongside the U.S. and Europe are considerable value drivers for the global launch.

The sepiapterin data package supports clear differentiation versus current therapies and includes data from the Phase III AFFINITY trial, where 84% of the subjects achieved Phe control in accordance with treatment guidelines of less than 360 micromolar per liter and 22% of subjects had normalization of Phe levels.

It also includes data from the APHINITY open label extension study, which provides evidence of subjects being able to achieve protein intake above the age adjusted recommended daily allowance for unaffected individual people, while still maintaining fee levels less than 360 micromolar per liter.

The ability to liberalize the diet is an important factor for physicians, payers and patients alike and will drive uptake. We've been planning for our launch of sepiapterin for several years and preparations are going very well.

We've been working closely with geneticists, pediatric metabolic specialists and dietitians to understand the needs of the PKU patients and to build a strong relationship with the PKU community. Our teams have a deep understanding of the PKU prescribers and their prescribing habits, as well as how to reach them.

Unlike other rare diseases, PKU patients are identified through newborn screening and managed by well-defined PKU treatment centers. We have mapped these key treatment centers globally and the key opinion leaders and treating physicians within each treatment center.

In addition, we have an established rare disease global infrastructure with a footprint in over 50 countries. Our experienced teams understand the complexities of rare disease, as well as the regulatory and payer landscape in each of the different regions and countries.

All of this will enable us to have a rapid and highly targeted focus on key customers and stakeholders at launch, and reinforces our belief in the potential $1 billion plus global opportunity. Turning to Upstaza.

In May, we announced that the FDA had accepted the BLA and granted priority review with the target regulatory action date of November 13, 2024. Launch preparations in the U.S. are well underway. Globally, access and reimbursement discussions advance, as we continue to treat patients in Europe through access and cross border healthcare.

In addition, we secured approval in Taiwan and are preparing for additional filings and regulatory approvals globally. Moving to TEGSEDI and WAYLIVRA in Latin America. We continue to make good progress across these franchises with growth in both patients identified and treated across the region.

Our geographical expansion continues with the recent approval of TEGSEDI in Mexico, following which we have initiated reimbursement discussion. In Brazil, we received a new group purchase order for TEGSEDI, of which 50% was delivered in the second quarter, and we anticipate delivering the remainder in the Third quarter.

Additionally, for WAYLIVRA, in the second quarter, we delivered 50% of the new group purchase order. In conclusion, coming off a robust first half of the year, as Matt mentioned, we are updating our guidance with a 2024 total revenue guidance of $700 million to $750 million.

We have set a strong trajectory for 2024 and continue to deliver and diversify our portfolio across our geographies, as well as to prepare for a successful global launch of sepiapterin in 2025. I will now turn the call over to Pierre for a financial update.

Pierre?.

Thank you, Kylie. I'll now share the financial highlights of our second quarter of 2024. Please refer to the earnings press release issued this afternoon for additional details. Beginning with top line results, total revenue for the second quarter was $187 million including DMD franchise revenue of $118 million.

Translarna net product revenue in the quarter was $70 million while EMFLAZA net product revenue of $47 million. Moving to Evrysdi. Second quarter global revenue of approximately $535 million was achieved by Roche, resulting in royalty revenue of $53 million for PTC.

No- GAAP R&D expense was $123 million for the second quarter of 2024, excluding $9 million in non-cash stock based compensation expense compared to $170 million for the second quarter of 2023, excluding $16 million in non-cash stock-based compensation expense.

The year-over-year reduction in R&D expenses reflects our strategic portfolio prioritization as the company continues to focus its resources on its differentiated high potential programs.

Non-GAAP SG&A expense was $60 million for the second quarter of 2024, excluding $10 million in non-cash stock based compensation expense compared to $75 million for the second quarter of 2023, excluding $14 million in non-cash stock based compensation expense.

In the second quarter, PTC amended its agreement with Royalty Pharma and exercised one of its put options in exchange for $250 million in cash last royalties received. Cash, cash equivalents and marketable securities totaled $1.09 billion as of June 30, 2024 compared to $877 million December 31, 2023.

Our strong balance sheet provides PTC with the resources to execute on our strategy and to achieve our milestones over the next several years, including the anticipated sepiapterin launch. And I will now turn the call over to the operator for Q&A.

Operator?.

Thank you. [Operator Instructions]. Our first question comes from the line of Kristen Kluska from Cantor Fitzgerald. Your line is now open..

Hi, everyone. Good afternoon. Congrats on a great quarter and thanks for taking my questions. The first one I have was on Huntington’s disease, obviously looking at the field, we've seen a lot of data recently but one thing that stood out is your approach seems to be one of the only ones where you're not seeing an increase in NFL through the therapy.

Obviously, it's a prognostic biomarker of neurodegeneration, but other drugs have been shown to make it worse.

So a question we've been getting is, do we have a sense of how dangerous it is when NFL increases via drug targeting? And then second, is this a really important consideration for physicians on safety?.

Kristen, thanks very much for the question. So the goal here is to develop a therapy, a disease modifying therapy for patients with Huntington's disease that is both effective and safe. So the safety of the product during development is of incredible importance. When we talk about Huntington lowering as a therapeutic strategy, it makes a lot of sense.

It's well understood. Huntington's disease is a monogenic disease caused by the production of a toxic mutant Huntington protein.

The goal of Huntington lowering is to decrease that protein that is causing the disease and, of course, there's a broad scientific literature substantiating that lowering mutant Huntington mutant protein is likely to result in clinical benefit.

In the development of PTC518, we really followed the playbook established by Rare Disease [ph] for the development of a both safe and effective oral slicing agent for a whole brain disease like Huntington's disease.

Therefore, in the development, it was incredibly important to ensure that we're lowering Huntington protein so that we can have the desired therapeutic effect one would expect for reducing the cause of the disease, but at the same time, wanting to make sure that we're doing so safely and that involves making sure that we have a molecule that is specific and is selected for the Huntington target, and it gets into the brain, gets to all regions of the brain because Huntington's disease is a whole brain disease and so when we look at these markers of safety like NFL, we're asking, are we seeing some harm to nerve cells, because the way that nerve cell injury can present itself is through NFL spikes and this is something that has been seen in development of a number of therapies, and it's the reason why, as you pointed out, NFL could be thought of as a marker of clinical benefit, but more importantly, Huntington's disease, over the shorter period of time on a clinical trial, it's really acknowledged to be more important as a marker of safety.

Are we delivering therapeutic benefit without causing spikes that show that we may also be causing harm? So the fact that we've not seen any evidence of treatment related NFL spikes and we continue to observe that PTC518 one has been safe and well tolerated in the PIVOT-HD study is an incredibly important finding for patients and then to also say that we're having a desired biomarker effect of lowering Huntington protein in the blood, we're seeing lowering of Huntington protein in CSF, and importantly, as we reported, we're seeing early evidence of clinical benefit on key disease scales like total motor score and CUHDRS tell us that so far we're seeing that we're having the desired therapeutic benefit, while we hope for disease modifying therapy, but importantly, also having the safety that will be incredibly important for a successful therapy..

Thanks for that, Matt. And then if I may ask a second question, just on PKU. I think when we think about rare disease launches, the uptake curve is always different depending on this disease.

So how would you think about this one for maybe call it the first two years? You already have a really good sense of where the patients are that you've identified that either don't respond or don't take standard of care. Thank you again..

Yeah. Absolutely. And as Kylie mentioned in her comments, we've been preparing for several years now for a successful launch. I'll let Kylie talk about how we expect the ramp to be..

Yeah. Absolutely. Thanks, Kristen. As Matt said and as I mentioned in my prepared remarks, we've been preparing for this launch for a number of years now and it's been going really well.

We have a focus across all of the different important prescribers as well as the ancillary physicians that are relevant to this disease in the key treatments and is of excellence and as you noted, we're also very close to the PKU community understanding where the unmet medical need is and where these patients exist and so as you said, this is not your traditional rare disease launch in the sense that patients are identified through newborn screening at birth and well known treatment centers of excellence and so that coupled with our expertise and our preparation means that we are expecting a fast uptake particularly in the U.S.

where it's one market we're able to move fast with pricing and reimbursement, and then outside of the U.S., we'll look to each market that has named patient programs and early access programs to move quickly in those markets as well while we progress with regulatory submissions, informal pricing and reimbursement.

So across the board, I think we're looking at a relatively fast and rapid uptake..

Thanks everyone..

Thank you. Our next question comes from the line of Eric Joseph – J.P. Morgan. Go ahead, Eric..

Thank you and good evening. A couple of questions from us.

First on top line guidance, I'm wondering if you could unpack that a little bit for what's anticipated in terms of net product sales marketed by PTC? Secondly, on PTC518 in Huntington's, wondering if you could give us a sense of when you hope to have a meeting with FDA for a Type B or Type C meeting on a potential registration path and also wondering how you think about the merits of breakthrough therapy designation for this indication and whether that's something you intend to pursue with the compound? Then finally on Vatiquinone, what's left to kind of get over the line for that submission in Friedreich ataxia? I believe data from the open label extension portion of Move FA was part of that.

Have you viewed additional follow-up from that study? Is that something you plan to share with the street? Thanks very much..

Thanks for the questions, Derek. Maybe I'll go in reverse order, so I'll repeat the third one first. So the Vatiquinone NDA is coming along. We expect the submission to happen before the end of the year.

As I mentioned in my comments, that's going to be based on the 72-week placebo controlled data from MOVE FA where we had significant effect on upright stability and a number of other relevant disease measures as well as long-term open label data, both from MOVE FA as well as the long term extension data from the earlier of Friedreich ataxia study than many years ago in adult patients.

We had previously done that long-term analysis that was published showing significant benefit over a 24-month period. At the FDA's request, we are going to repeat that analysis with newer natural history match data, and so we provided a statistical analysis plan to the FDA for their buyout and then we'll do that analysis.

We're still waiting for the final long-term extension data for MOVE FA to be collected. Those data will be collected the data -- collection will be completed shortly, and then we'll be able to move forward with that long term analysis and get the whole package together for submission.

We do plan a pre NDA meeting with the agency, as we always do to review the content and structure of the FDA, and we will share data when we had it from those open label studies that go into the NDA.

On your second question regarding PTC518 and the regulatory path, with the results from the interim results from PIVOT-HD, as we talked about, we are moving forward on two fronts.

One is to have a discussion with the agency regarding the potential for Huntington lowering to serve as a surrogate endpoint likely to predict clinical benefit that could allow us to access the accelerated approval pathway and also a separate interaction to discuss our endpoint strategy, for the efficacy trial, which we've said would either be a registration study or in the context of potential accelerated approval could be a confirmatory trial.

We expect to have both of those interactions in the second half of this year.

We're also, of course, looking at the other pathways that exist including Fast Track and Breakthrough, but our priority right now is to have the key interactions around the potential for surrogate endpoint pathways as well as alignment on an endpoint strategy for the efficacy study.

In terms of more detail on unpacking revenue and the components and how we think about that, let me turn that over to Kylie..

Perfect. Thanks, Matt.

Yes, so Eric, on your question around just unpacking revenue a little bit, I think one of the things that we're really happy to share is that we're updating guidance from the previous guidance to the $700 million to $750 million for 202, and this is driven by the fact that originally the low side scenario had assumed that with a negative CHMP opinion that Translarna European revenue would come out from Q2 onwards and while this is not the case because of the EC bouncing it back, we've been able to maintain it throughout 2024 and this has driven substantial upside for PTC and this has also driven the updated guidance.

In regards to your question around PTC marketed products of the $700 million to $750 million the majority of the revenue is coming from PTC marketed products..

Okay, great. Thanks for taking the questions..

Our next question comes from the line of Kelly Shi from Jefferies. Your line is now open..

Thank you for taking my questions.

So curious on the regulatory front of Translarna in Europe, could you share what's the most current status of Translarna? And what are the timeline of next steps if you have a new update, newer update after last call? And also, in the U.S., any other color you would be able to share on the discussion with the regulatory agency after the NDA submission to FDA? And how are you thinking about the risk of U.S.

approval? Thank you..

Thanks very much, Kelly, for the question. On the European Translarna front, we submitted our request for reexamination. We did that in early July and then, as you know, the calendar for reexamination is set.

It's typically a 120-day process from the day of notification, we have 60 days to submit what is known as the grounds for reexamination, which is our briefing documents supporting, our reexamination request and then within 60 days after that submission, we would receive an updated opinion.

So we're on that timeline and we're still awaiting the assignment of new repertoires, which is another component of the reexamination process and our ground three examination are focusing on the evidence of benefit in Study 41 and we've also been able to address some of the concerns that were made during the most recent review process and so therefore, we're able to say we can address concerns particularly around the reliability of the STRIDE analysis and we're able to show that the evidence of multi-year protection as loss of ambulation is well supported and can be reliably attributed to Translarna treatment benefit in the long term.

Turning to the FDA, we resubmitted the NDA at the end of July. The resubmission process typically takes six months from submission to regulatory action. We expect to hear within 30 days of submission from the agency as to whether or not they'll accept the filing. So it's a slightly different timeline since it is a resubmission.

As we previously shared, we had two separate meetings with the FDA to align, on the package, for submission and I'll point out that this is, as I mentioned in the comment, what we really focused on in our discussions with FDA was the evidence of significant benefit from Study 41 in the overall ITT population, not only on the primary and from a 6sixa-minute walk distance, but all of the other key endpoints, including North Star and time function test and then that evidence of benefit from Study 41 will be confirmed, or the confirmatory evidence, is from the long-term data we have in the STRIDE registry.

So those discussions with FDA were really to align on two things. One, what would be the structure and data package of the NDA and what would be needed in terms of additional analysis that would allow us to be reviewable package. So we believe we've been able to address all the agency's concerns.

Their most recent feedback to us prior to submitting the NDA is that they believe any remaining questions they may have would be a matter of review. So we look forward, to the review process and of course, as always, look forward to bringing the Translarna to boys and young men with nonsense mutation DMD in the U.S.

for whom there remains a significant unmet need..

Thank you very much..

Thank you. Our next question is going to come from the line of Samantha Corwin from William Blair. Your line is now open..

Hi. This is Brooke Shuster on for Sammy. Thanks for taking our question. We were wondering if you could provide, some more color you expect for the upcoming ALS trial readout, like the bar of the for efficiency and if you expect this readout to be at a medical conference or a company event..

Sure. Thanks for the questions, Brooks. So as we've talked about the CARDINAL ALS study is a registration direct study of utreloxastat in ALS patients.

This study was designed to be a six-month placebo controlled study with an endpoint strategy that being the primary endpoint of the ALSFRS scale, such that if it were positive and we achieved statistical significance on the primary endpoint, it would support an NDA submission in the United States.

This is a study that was designed, leveraging the learnings made from other products that have been tested in ALS patients. Double-blind placebo controlled study, randomization 2:1 of utreloxastat to placebo.

We included 8-week run-in in order to determine the baseline rate of progression, which again has been done in many previous ALS trials so that we ensure that the primary analysis is one that's moving at an appropriate disease rate so that we can practically record a treatment benefit.

So I would define success here as a statistically significant primary endpoint because that would then allow us to move forward with NDA submission. We said that we expect to have top-line results in the fourth quarter. We expect that we'll share those results on a public call as we typically do when we have top line data..

Our next question comes from the line of Brian Abraham from RBC Capital Markets. Your line is now open..

Hi, this is Joe on for Brian. Thanks for taking our question.

So going back to Huntington's, when looking at your and other developers' data collectively, which biomarker other than HTT lowering do you think has shown the best translatability to clinical benefits and support accelerator approval? And I guess along these lines, have you had a chance to look at the correlation between HTT knockdown levels to functional measures at individual levels for your data? Thank you..

Thanks, Joe. I think the only marker that's really been shown to correlate reliably with potential clinical benefit is Huntington lowering and the rationale for Huntington lowering to be a surrogate endpoint that's likely, to predict clinical benefit is based on several things. First, just basic principles.

Huntington disease is a monogenetic disorder caused by a mutation in the Huntington gene that leads to a production of a disease causing toxic mutant Huntington protein and, thus, it stands to reason if you could lower the disease causing protein, you're likely to have benefit and that's been studied.

It's been studied extensively in a number of preclinical models, and they all demonstrate that if you could lower Huntington protein, it's been reported in a range of 10% to 50%. That's been associated with clear phenotypic benefit.

There's also been an epidemiologic study, which has demonstrated that, sort of an experiment by [Indecipherable] and if you are born with a single nuclear polymorphism and the promoter for the Huntington gene and the about 50% less mutant Huntington protein, you have an almost 10-year delay in onset of disease and a slower disease progression.

So when you put that scientific package together, the evidence is strong that lowering Huntington protein is likely to result in clinical benefit and not only is it lowering the Huntington protein, it's lowering Huntington protein in that range I mentioned that it's been shown between 10% and 50%, and so that when we now move to the clinical data and the type of data we collected in PIVOT-HD to be able to show that we are lowering Huntington protein at that level that has been associated with benefit.

That's really the support and evidence that we'll use in our discussion with the agency around a potential accelerated approval path. We've not looked specifically at correlation thus far.

As you recall, the PIVOT-HD beat out was a relatively small dataset, but we're clearly seeing dose dependent lowering of Huntington protein in the blood, in the CSF and dose dependent benefit on the clinical endpoints that we've collected thus far..

Thank you, Matt. Thank you. Our next question comes from the line of Joseph Thome of TD Cowen. Your line is now open..

Hi there. Good afternoon. Congrats on the progress and thank you for taking our questions. Maybe the first one, just a follow-up on the ALS trial.

I guess, do you believe there's been any change in what the FDA wants to see for a pivotal package for ALS given the experience with the Amylyx compound? And then maybe second on Huntington's, I know we're waiting on more data for the in the first half of next year, the full data set from PIVOT.

Is there anything in that data set that you'd like to see before launching a Phase III? Thank you..

Thanks for the questions, Joe.

On ALS, we worked closely with the agency to ensure that we had designed the CARDINAL study and that we were analyzing the data and had the right endpoints that would be consistent with what they would want to see in terms of those approval package and so what we have in terms of our study design, the statistical analysis plan, how we're approaching the analysis for the primary endpoint and one important point here is something that you just see really likes to see and understand is not only the change on the continuous variable of the ALSFRS scale, but also incorporating any deaths that might occur in the time to death as a second component of looking at primary treatment effect.

Therefore, I can say that we have certainly taken all of their advice and believe that we designed the study and our analyses to be consistent with exactly the type of package they would want to see for approval, which is quite the system to look at these have always been.

In terms of the HD question, in terms of timing of seeing more data and going on to Phase III, but we designed PIVOT-HD in the two different parts, Part A and Part B, to make sure that we were asking key questions key drug development questions at the right time.

The first 12 weeks were focused on pharmacology and pharmacodynamic effect saying, are we seeing the evidence of target engagement, evidence of the dose dependent lowering of Huntington protein we would want to see, are we seeing it at the magnitude we need to see to know that the dose of 5 mg and 10 mg are likely to be appropriate for efficacy? And are we seeing the CNS exposure? The answers to those were yes and yes.

As we move into the second part of the study, the none-month study, there we're asking the question, okay, at the dose levels we know we're having pharmacodynamic effects and adequate and excellent CNS exposure, are we starting to see changes in CNS biomarkers and clinical scale that give us confidence that over time we'll be able to register the efficacy necessary to have a therapy for patients with Huntington’s disease and so when we had the data readout with that first group of patients, the answer again was yes.

We saw what we needed to see in terms of biomarker effect, durability of Huntington lowering, early moving to clinical scales and then importantly continued safety and tolerability at the 5 mg and 10 mg dose levels. So for us, we really checked all of those gating boxes to move forward with Phase III.

So that's why we're go ahead to Phase III planning and continue to get aligned develop the study design, the endpoint strategy, get along with the regulatory studies and advance that study based on the data we have thus far..

Perfect. Thank you very much..

Thank you. Our next question comes from the line of Jeff Hung from Morgan Stanley. Your line is now open..

Hi.

Following the trends on our resubmitted NDA, can you just provide more color on how you're thinking about the market opportunity and overall patient dynamics in the U.S., sort of in comparison to what we've seen in the EU?.

Yes, sure. Thank you very much for the question. We as we've talked about, we've for a long time been ready to make Translarna available to boys and young adult nonsense mutation DMD in the U.S.

and the significant unmet medical need and need to be able to resubmit the NDA and have the opportunity to finally bring Translarna to boys and young men in the U.S. is will be a tremendous opportunity for us. Kylie joining us some more color on how we would think about and watch..

Yes, absolutely. Thanks very much for the question. So as Matt said, it's a high unmet medical need because there has been no other therapy for a targeted for nonsense mutation DMD.

So that this remains a high unmet medical need and our team has had over five years of experience of working embedded in the DMD community, working alongside the physicians, working alongside the patient advocacy groups and also has strong infrastructure set up for PTC cares to support the patients from start to finish throughout their treatment experience.

In addition to that, through our experience with EMFLAZA, we have thousands of DMD patients that have been genotyped and this allows us to move rapidly upon launch to understand where to go from for the nonsense mutation DMD patients and in addition to that, we also have a group of patients more than a 100 that are still on Translarna and have been on for over a decade on clinical trials and we'll be able to look to put them on commercial drug very quickly post approval.

So from a market dynamics perspective, we expect a very rapid uptake in this space..

Thank you. And I'm sorry, I forgot to mention this is Catherine on for Jeff. Just as a quick follow-up, have you received any early feedback from physicians in the U.S. that might be indicative of what demand or launch trajectory might look like there? Just curious. Thank you..

Yes, absolutely. Thanks, Catherine.

We have obviously received a lot of feedback and we've been working very closely with the DMD physicians and there's a huge amount of pull from those physicians and also from the patients because they've known about Translarna for a long period of time and PTC initiated the DMD space and they've been waiting to get access to that therapy and have struggled to understand why patients from all over the world can get access to Translarna, but patients in the U.S.

could not. and so we see the market opportunity in the U.S. larger than Europe, and I think from that perspective with both the physician and the patient pool and the market landscape dynamics we talked about earlier just reinforces my point around fast uptake..

Great. Thank you so much for the color..

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

Thank you. I have two questions. First, you will have several launches underway. Should we see a meaningful increase in SG&A in 2025 and beyond? And second question is regarding the Vatiquinone in Friedreich ataxia.

So the NDA in late 2024 and regarding the natural history data, when do you plan to share that data with investors?.

Thanks for the questions, Gina.

On the first question, as we've talked about, we have built, the infrastructure -- the global commercial infrastructure to support not only the existing therapies, but the potential therapies that are coming and so we have the infrastructure, we have the expertise across the board to launch several products and in fact, we're obviously quite proud to be in this situation where we've already submitted three new drug applications to BLA this year and potentially a fourth this year.

We're incredibly proud of the team's accomplishments in being able to do this and if those therapies are all approved, we have the team set ready to go and, we'll quickly get these therapies to the patients who desperately need them and so we don't expect any increases in SG& A with the infrastructure built and ready to go and scale with any number of new therapies that we convert to patients in the near future.

In terms of the Vatiquinone data, as I mentioned, we're still in the process of completing the collection of the long-term data for MOVE FA that will be compared to the natural history comparator. We've talked a lot about being in a fortunate situation with the FACOMS natural history registry.

Sarah and the FA team have done a model job in terms of building a natural history database that could be used for regulatory purposes.

We will be first doing the analysis of the data previously collected in the trial conducted several years ago in adults, and that'll be a 24-month, analysis of, analysis of -- analysis of the patient treated for 24 months relative to the appropriate matched natural history comparison and then of course, we'll be having the natural history comparator data from the long term open label extension from MOVE FA and we will look forward to sharing those data when they are available..

Our next question comes from the line of David Lebowitz from Citi. Your line is now open..

Thank you very much for taking my question. Given the operating spend, we'll have to start accounting for potential launches of additional products, mainly PKU.

Could you run us through what your assumptions would be and expectations, especially given those the convert that you do next year?.

Sure. So thanks for the question, David.

First, let me clarify that we have a convert, but that is up to 2026 and as I mentioned with the operating expenses and the level of OpEx we have now is at where it needs to be in anticipation of potential launches, as we talked about, I'm not sure if that answers your question?.

Thank you..

Thank you. Our next question comes from the line of Joseph Schwartz from Leerink Partners. Your line is now open..

Hi. It's Jenny on for Joe. Thanks for taking our question. We've heard from a couple of other sponsors that the FDA is not a fan of Huntington protein as a potential surrogate marker to support accelerated approval in Huntington's. Clearly, you guys disagree.

Why do you think that they might be thinking that way? And have you thought anything about other potential surrogate biomarkers that you guys might be able to use? Thanks..

Yeah. Thank you for the question. I'm not sure anyone could speak for what the FDA thinks or the FDA believes. I think where we certainly in Huntington's disease, we exist in a situation where no one has the opportunity to come before them and have a discussion around surrogate endpoints.

What we do know for sure is what the FDA publishes in their guidance and they have very clear guidance around what are the requirements for a surrogate endpoint and if you read their guidance regarding a surrogate, what's needed for surrogate endpoint that's likely to predict clinical benefits and therefore supporting accelerated approval application, what they would like to have is data, either scientific data that could be preclinical studies or clinical studies that show how a certain biomarker could be, shown to predict ultimate benefit and so in the case of mutant Huntington protein, the reason we believe that this is a worthwhile discussion is because there's a vast scientific literature clearly demonstrating that lowering Huntington's protein has been associated with benefits, both in preclinical models and in patients.

Furthermore, Huntington's disease provides a very unique situation for nerve degenerative disease in that it's monogenic, and we absolutely understand what the cause is a mutant the Huntington protein, and therefore, it's quite logical that if you can lower the amount of the disease causing protein, you should have benefit and, of course, that's been borne out in the scientific literature.

And then the other point of course that the FDA highlights in their guidance in terms of something they want to have in terms of discussion of a surrogate endpoint is not only having a biomarker that's likely to be a clinical benefit, but some scientific evidence that says what level of reduction or change in that biomarker is needed to have that clinical benefit and again, in the case of Huntington's disease, we have the advantage of knowing that the literature not only demonstrates that lowering Huntington's protein has an associated benefit, but it gives a range of 10% to 50% as being the necessary bar to achieve that cycling clinical benefit.

So I would say that, just reading the FDA guidance, the Huntington protein fits squarely within what the FDA themselves have written and published in terms of what they want to see, and that will be the basis of our conversations..

All right. Thank you..

Well, this concludes our question and answer session. I would now like to turn our call back over to CEO, Matthew Klein, for closing remarks..

Thank you all for joining the call today. I'm incredibly proud of our team's performance in the first half of the year. As we mentioned on the call, we achieved all of our milestones. We continue to execute on all fronts. We had three regulatory submissions. We have a strong balance sheet.

We're managing operating expenses effectively and we remain on schedule for a number of other important milestones in 2024. So we look forward to continue to share our progress along this path, and I wish you all a good evening. Thank you..

[Operator Closing Remarks]..