PTC Therapeutics - Q2 2024

Transcript

Operator (participant)

Good day, and thank you for standing by. Welcome to the PTC Therapeutics Second Quarter 2024 Financial Results. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one, one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one, one again. 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 Aalbers, Senior Director of Investor Relations.

Ron Aalbers (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 Strategy 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 information about 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, Matthew Klein. Matt?

Matthew Klein (CEO)

Thank you, Ron, and thank you all for joining the call. I'm pleased to share 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 submissions, 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-$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 a 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 3 AFFINITY study, as well as data from the open label extension study, demonstrating durability of the sepiapterin treatment benefit, as well as Phe tolerance. Recent data from the Phe tolerance sub-study indicate 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, as planned, we also resubmitted the NDA for Translarna. As discussed with the FDA, the submission is based on the results of Study 041, in which significant benefit was recorded across key endpoints in the IPT population, as well as on the long-term evidence of meaningful treatment benefit from the STRIDE trials. In the second quarter, we also shared the positive results from the 12-month interim data readout of the PIVOT-HD study of PTC-518 in Huntington's disease patients. The 12-month data demonstrated durable dose-dependent lowering of mutant huntingtin protein in blood cells, reaching 42% at the 10 mg dose level, along with dose-dependent lowering of mutant huntingtin protein in the CSF at levels similar to the blood in phase 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 cUHDRS scale. Importantly, the interim results also demonstrated PTC-518 to be safe and well-tolerated. This combination of biomarker and clinical effects, along with favorable safety, position PTC-518 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 3 efficacy trial of PTC-518, which could serve as a confirmatory study in the context of an accelerated approval or as a registration trial.

We look forward to continuing to advance PTC-518 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 retinitis pigmentosa, 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 from the MOVE-FA study, along with confirmatory evidence from 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 from the registration-directed CARDINAL trial of Utreloxastat in ALS patients in the fourth quarter. Utreloxastat is the first compound being developed for ALS that specifically targets ferroptosis, a pathway of oxidative 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 CARDINAL study could enable Utreloxastat to address the significant unmet needs of ALS patients.

In closing, I am 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 2024. I will now turn the call over to Eric and Kylie to discuss our commercial performance. Eric?

Eric Pauwels (Chief Business Officer)

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 healthcare 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 third quarter.

As Matt mentioned, we have resubmitted the NDA for Translarna in the US, 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 copays 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 here today. Now, I will hand it over to Kylie to update the progress of our current and future new product launches. Kylie?

Kylie O'Keefe (Chief Strategy Officer)

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 E.U. 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 APHINITY 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 AFFINITY 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 Phe 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 dieticians 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 a target regulatory action date of November thirteen, twenty twenty-four. Launch preparations in the US 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 LATAM, 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 discussions. 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 a 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-$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?

Pierre Gravier (CFO)

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. From Emflaza, net product revenue in the quarter was $70 million, while Translarna, 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. Non-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 $117 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 Roche Pharma and exercised one of its put options in exchange for $250 million in cash, less royalties received. Cash, cash equivalents, and marketable securities total $1.09 billion as of June 30, 2024, compared to $877 million as of 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?

Operator (participant)

... Thank you. At this time, we will conduct a question and answer session. As a reminder, to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Kristen Kluska from Cantor Fitzgerald. Your line is now open.

Kristen Kluska (Senior Equilty Analyst)

Hi, everyone. Good afternoon. Congrats on a great quarter, and thanks for taking my question. The first one I had 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?

Matthew Klein (CEO)

Kristen, thanks very much for the question. So, you know, 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 huntingtin 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 huntingtin protein. The goal of huntingtin lowering is to decrease that protein that is causing the disease. And of course, there's a broad scientific literature substantiating that lowering huntingtin protein, mutant huntingtin protein, is likely to result in clinical benefit.

In the development of PTC-518, we really followed the playbook established by Evrysdi for the development of a both safe and effective oral silencing agent for a whole-brain disease like Huntington's disease. Therefore, in the development, it was incredibly important to ensure that we're lowering huntingtin protein so that we can have the desired therapeutic effect one would expect when reducing the cause of a 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 selective for the huntingtin target, that 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. This is something that has been seen in the 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, in Huntington's disease, over the shorter period of time of 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? The fact that we've not seen any evidence of treatment-related NfL spikes, and we continue to observe that PTC-518 has been safe and well-tolerated in the PIVOT-HD study, is an incredibly important finding for patients.

Then to also say that we're having a desired biomarker effect of lowering Huntingtin protein in the blood, we're seeing lowering of Huntingtin 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 one would hope for disease-modifying therapy. But importantly, we're also having the safety that will be incredibly important for a successful therapy.

Kristen Kluska (Senior Equilty Analyst)

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.

Matthew Klein (CEO)

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.

Kylie O'Keefe (Chief Strategy Officer)

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 treatment centers of excellence. As you noted, we're also very close to the PKU community, understanding where the unmet medical need is and where these patients exist. 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 and formal pricing and reimbursement. So across the board, I think we're looking at a relatively fast and rapid uptake… Thanks, everyone.

Operator (participant)

Thank you. Our next question comes from the line of Eric Joseph of JPMorgan. Go ahead, Eric.

Eric Joseph (Analyst)

Thank you, and good evening. A couple 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 do you hope to have a meeting with FDA for a type B or type C meeting on a, you know, potential registration path? And also wondering or 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 kinda 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.

Matthew Klein (CEO)

Thanks for the questions, Eric. Maybe I'll go in reverse order, start with 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 gonna 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 Friedreich ataxia study done many years ago in adult patients. We had previously done that long-term analysis, but 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 buy-in, 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 contents and structure of the NDA, and we will share our data when we have it from those open-label studies that go into the NDA.

On your second question regarding PTC-518 and the regulatory path, with the results from the interim results from PIVOT-HD, as we've talked about, we are moving forward on two fronts. One is to have a discussion with the agency regarding the potential for huntingtin 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 the revenue and the components and how we think about that, let me turn that over to Pat.

Kylie O'Keefe (Chief Strategy Officer)

Perfect. Thanks, Pat. Yeah, 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-$750 million for 2024. 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-$750 million, the majority of the revenue is coming from PTC marketed products.

Eric Joseph (Analyst)

Okay, great. Thanks for taking the questions.

Operator (participant)

Thank you. All right, our next question comes from the line of Kelly Shi from Jefferies. Your line is now open.

Kelly Shi (Analyst)

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 US, 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, for US approval? Thank you.

Matthew Klein (CEO)

Thanks very much, Kelly, for the question. So on the European Translarna front, we submitted our request for reexamination. We did that in early July. And as you know, the calendar for reexamination is set. It's typically a 120-day process of the day of notification. We have 60 days to submit what is known as the grounds for reexamination, which is our briefing document 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 rapporteurs, which is another component of the reexamination process. And our grounds for reexamination are focusing on the evidence of benefit in Study 41.

And we've also been able to address some of the concerns that were raised 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 against loss of ambulation is well supported and it 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 a 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. I'll point out that this is, as I mentioned in the comments, what we really focused on in our discussions with FDA was the evidence of significant benefit from Study 41 in the overall IPT population, not only on the primary endpoint of 6-minute walk distance, but all of the other key endpoints, including North Star and time function test. 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. Those discussions with FDA were really to align on two things. One, what would be the structure and data package of the NDA?

What would be needed in terms of additional analyses that would allow us to be reviewing the package? So we believe we've been able to address all of the agency's concerns. Their most recent feedback to us prior to submitting the NDA was 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 US, for whom there remains a significant unmet need.

Kristen Kluska (Senior Equilty Analyst)

Thank you very much.

Operator (participant)

Thank you. The question from our next participant is going to come from the line of Sami Corwin from William Blair. Your line is now open.

Sami Corwin (Analyst)

Hi, this is Brooke Schuster on for Sami. 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 for efficiency, and if you expect this readout to be at a medical conference or a company event?

Matthew Klein (CEO)

Sure. Thanks for the question, Brooke. So as we've talked about, the CARDINAL ALS study is a registration-driven 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-R, such that if we're positive and we achieve 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. It's a double-blind, placebo-controlled study, randomization 2-to-1 of utreloxastat to placebo.

We included an eight-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 group is one that is 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.

Operator (participant)

All right, thank you. Our next question comes from the line of Brian Abrahams from RBC Capital Markets. Your line is now open.

Brian Abrahams (Analyst)

Hi, this is Joe on for Brian. Thank you 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 accelerated 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.

Matthew Klein (CEO)

Thanks, Joe. I think the only marker that's really been shown to correlate reliably with potential clinical benefit is huntingtin lowering. And the rationale for huntingtin lowering to be a surrogate endpoint that's likely to predict clinical benefit is based on several things. First, just basic principles. Huntington's disease is a monogenic disorder caused by a mutation in the huntingtin gene that leads to a production of a disease-causing toxic mutant huntingtin 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 huntingtin protein, it's been reported in a range of 10%-50%. That's been associated with clear phenotypic benefit.

There's also been an epidemiologic study, which has demonstrated that, so an experiment that Mother Nature did, that if you are born with a single nucleotide polymorphism in the promoter for the huntingtin gene and make about 50% less huntingtin 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 huntingtin protein is likely to result in clinical benefit. And not only is it lowering of huntingtin protein, it's lowering huntingtin protein in that range I mentioned, of, as has been shown between 10% and 50%.

And so that when we now move to the clinical data, the type of data we've collected for the HD, to be able to show that we are lowering Huntingtin 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 readout was a relatively small data set, but we're clearly seeing dose-dependent lowering of Huntingtin protein in the blood, in the CSF, and dose-dependent benefit on the clinical endpoints that we've collected thus far. Thank you, Matt.

Operator (participant)

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

Joseph Thome (Managing Director and Senior Analyst)

Hi there. Good afternoon. Congrats on the progress, and thank you for taking our questions. Maybe the first one, just to 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 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 3? Thank you.

Matthew Klein (CEO)

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 an 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 the agency really likes to see and understand is not only the change on the continuous variable of the ALSFRS-R scale, but also incorporating any deaths that might occur in the time to, 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've designed this study and our analyses to be consistent with exactly the type of package they would want to see for approval, which is quite consistent to what their views have always been. In terms of the HD question, in terms of timing, seeing more data and going on to phase 3. Look, 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 effects, saying: Are we seeing the evidence of target engagement, evidence of the dose-dependent lowering of Huntingtin protein we would want to see?

Are we seeing it at the magnitude we need to see to know that the doses of 5 and 10 milligrams 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 nine-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 scales 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 Huntingtin lowering, early movement of clinical scales, and then importantly, continued safety and tolerability at the 5- and 10-milligram dose levels. So for us, we've really checked all of those gating boxes to move forward with phase 3. So that's why we're saying we're going to start the phase 3 planning and continue to get aligned, develop the study design, the endpoint strategy, get aligned with the regulatory authorities, and advance that study based on the data we have thus far.

Joseph Thome (Managing Director and Senior Analyst)

Perfect. Thank you very much.

Operator (participant)

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

Jeffrey Hung (Analyst)

Hi. Following the Translarna 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 E.U.?

Matthew Klein (CEO)

Yes, sure. Thank you very much for the question. As we've talked about, we've for a long time been ready to make Translarna available to boys and young men with nonsense mutation DMD in the US in a significant medical need, and to be able to resubmit the NDA and have the opportunity to finally bring Translarna to boys and young men in the US would be a tremendous opportunity for us. But Kylie, do you want to give some more color on how we would think about a launch?

Kylie O'Keefe (Chief Strategy Officer)

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

In addition to that, we also have a group of patients, more than 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 drugs very quickly, post-approval. From a market dynamics perspective, we expect a very rapid uptake in this space.

Jeffrey Hung (Analyst)

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 the launch structure might look like there? Just curious. Thank you.

Kylie O'Keefe (Chief Strategy Officer)

Yeah, 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 pull and the market landscape dynamics we talked about earlier, it just reinforces my point around fast uptake.

Jeffrey Hung (Analyst)

Great. Thank you so much for the color.

Kylie O'Keefe (Chief Strategy Officer)

Of course.

Operator (participant)

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

Gena Wang (Analyst)

Thank you. I have two questions. First, you know, 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?

Matthew Klein (CEO)

Thanks for the questions, Gena. 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, you know, we're obviously quite proud to be in this situation where we've already submitted 3 new drug applications or BLAs this year and potentially a fourth this year. And 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 move quickly to get these therapies to the patients who desperately need them.

And so we don't expect any increases in SG&A because the infrastructure is built and ready to go and scale with any number of new therapies that we can bring 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 from MOVE-FA that will be compared to the natural history comparator. We've talked a lot about being in the fortunate situation with the mFARS Natural History Registry. FARA and the FA community have done a marvelous job in terms of building a natural history database that could be used for regulatory purposes.

We'll 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 patients 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.

Operator (participant)

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

David Lebowitz (Senior Research Analyst)

Thank you very much for taking my question. Given could the operating spend will 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 there's the convert that's due next year?

Matthew Klein (CEO)

Sure. So thanks for the question, David. First, let me, let me clarify that, that we have a convertible, but that is up in 2026. And then as with the operating expenses and the level of OpEx we have now, is at where it needs to be in anticipation of potential launches, coming, as, as we talked about. I'm not sure if that answers your question or not?

David Lebowitz (Senior Research Analyst)

Thank you.

Operator (participant)

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

Joseph Schwartz (Senior Research Analyst)

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 Huntingtin 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.

Matthew Klein (CEO)

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 with Huntington's disease, we exist in a situation where no one's had the opportunity to come before them and have a discussion regarding 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 a surrogate endpoint that's likely to predict clinical benefits and therefore support an accelerated approval application, what they would like to have is data, either scientific data that could be from preclinical studies or clinical studies, that show how a certain biomarker could be shown to predict ultimate benefits.

And so in the case of mutant Huntingtin protein, the reason we believe that this is a worthwhile discussion is because there's a vast scientific literature clearly demonstrating that lowering Huntingtin protein has been associated with benefits, both in preclinical models and in patients. Furthermore, Huntington's disease provides a very unique situation for a neurodegenerative disease in that it's monogenic, and we absolutely understand what the cause is. A mutant Huntingtin 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 science of the 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 predict clinical benefit, but some scientific evidence that says what level of reduction or change in that biomarker is needed to have that clinical benefit. Again, in the case of Huntington's disease, we have the advantage of knowing that the literature not only demonstrates that lowering Huntingtin protein has been associated with benefit, but it gives a range of 10%-50% as being the necessary bar to achieve that likely clinical benefit.

So I would say that, you know, just reading the FDA guidance, the huntingtin protein sits squarely within what the FDA themselves have written and published in terms of what they want to see, and that'll be the basis of our conversations with them.

Operator (participant)

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.

Matthew Klein (CEO)

Thank you all for joining us on 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've achieved all of our milestones. We continue to execute on all fronts. We've 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. We look forward to continuing to share our progress along this path, and I wish you all a good evening. Thank you.

Operator (participant)

Thank you for participating in today's conference. This does conclude the program. You may now disconnect.