PTC Therapeutics - Q4 2023

Transcript

Operator (participant)

Good day and thank you for standing by. Welcome to PTC Fourth Quarter 2023 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 a message advising your hand is raised. To withdraw your question, press star one one again. Please note that today's conference is being recorded. I would now like to pass the call over to the Senior Director of Investor Relations, Ron Aldridge.

Ron Aldridge (Senior Director of Investor Relations)

Good afternoon, and thank you for joining us today to discuss PTC Therapeutics' fourth quarter and full year 2023 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 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. Good afternoon, and thank you all for joining today's call. I'm pleased to share our fourth quarter and full year 2023 results and to provide an update on the progress of our pipeline programs as we move into what will be an exciting 2024 with a number of potential significant milestones. As we closed out 2023, we had another solid quarter of commercial performance, with total fourth quarter revenue of $307 million and full year 2023 revenue of $938 million, representing 34% growth over 2022. Our DMD franchise revenue totaled $143 million in the quarter and $611 million for the full year. Eric and Kylie will provide additional detail on our commercial performance shortly. Our revenue performance reflects the continued outstanding work of our global customer-facing teams and our successful efforts in geographic expansion.

With this infrastructure and track record of execution, I remain confident in our team's ability to succeed with our next product launches, including sepiapterin for the treatment of PKU. Most of you are aware, in January, we received the negative opinion from the CHMP on the continued conditional marketing authorization for Translarna in the EU. This opinion is expected to be ratified by the EC in late March or early April. Importantly, Translarna remains on the market until ratification occurs. In addition, we continue to commercialize Translarna in several regions outside of the EU where independent authorizations exist. While we are, of course, disappointed in the CHMP opinion and the potential impact it has on patients in Europe, PTC is well positioned to withstand this outcome.

As I have previously emphasized, through our efforts to focus our R&D portfolio, right-size the organization, and strengthen our balance sheet, we have a solid foundation for building the company forward and continuing to deliver on our goal of discovering, developing, and commercializing transformative therapies for patients. As we look forward to 2024, we have a number of important potential regulatory and clinical milestones for a number of our programs. I will begin with our sepiapterin program for the treatment of children and adults with PKU. We remain on schedule to submit the MAA for sepiapterin to the EMA in the first quarter of this year and to submit the NDA in the United States no later than the third quarter of this year.

As we continue to collect data from the Open Label Extension study following the Phase III APHINITY study, we continue to see durability of sepiapterin treatment effect and the ability of patients on sepiapterin to tolerate increases in dietary protein intake beyond the recommended daily allowance. This liberalization of diet is incredibly meaningful to patients and further supports the potential of sepiapterin to fill the persistent unmet medical need of the majority of the 58,000 PKU patients worldwide. Moving to our vatiquinone program for Friedreich's ataxia, we had a Type C meeting with the FDA earlier this quarter. Based on discussions with FDA, we now have a path to potential NDA filing based on the placebo-controlled results of the MOVE-FA study in combination with long-term Open Label Extension data currently being collected.

The Open Label data will be compared to a natural history population from the robust Friedreich's ataxia patient registry using analyses similar to those provided to FDA by Reata as part of the Skyclarys NDA. Based on the time needed to collect sufficient long-term Open Label data, we expect to be able to submit an NDA in late 2024. We are very excited about the potential of vatiquinone to fill the significant remaining unmet need for pediatric and adolescent FA patients. In other regulatory updates, we remain on track to submit the BLA for Upstaza to the FDA in March and are also scheduled to meet with FDA in March to discuss the contents of a potential NDA resubmission for Translarna.

Turning to our ongoing clinical trials, we expect to share interim 12-month results from the PIVOT-HD trial of PTC518 in HD patients in the second quarter of this year from the initial cohort of subjects on whom we reported data last summer. The 12-month results will include additional safety and tolerability data as well as biomarker data, including CSF Huntington protein levels, NfL levels in the blood and in the CSF, and volumetric changes on MRI. We will also be sharing data from the clinical outcome measures collected as part of the study.

Finally, we expect to share top-line results from the CARDINAL registration-directed trial of utreloxostat in ALS patients in the fourth quarter of this year. In closing, we are well positioned for an exciting 2024. We have the team, the capital, and the strategy that position us to execute on the many impactful opportunities that lie ahead. I will now turn the call over to Eric and Kylie to discuss our commercial performance. Eric?

Eric Pauwels (CBO)

Thanks, Matt. Our global customer-facing team has delivered yet another strong quarter, continuing the significant momentum we have built. We see ongoing growth from our portfolio products in more mature markets such as the US and EU, and also new markets where we have invested in geographic expansion in Latin America, the Middle East, North Africa, and the Commonwealth of Independent States, where there has been robust year-over-year growth. In the fourth quarter, we delivered $155 million of revenue for PTC-marketed products, which represents 22% growth year-over-year. For the DMD franchise, we closed out the year with a strong fourth quarter for both Translarna and Emflaza, delivering an impressive $143 million in net revenue, which is 25% growth compared to the fourth quarter of 2022, with a strong full-year performance of $611 million.

For Translarna, we achieved $75 million in revenue this quarter with annual sales of $356 million, which is a robust 23% growth over the same annual period last year. I'm very proud of the team's efforts and determination these last few months, as they have worked tirelessly to ensure that every single Translarna patient in Europe continues to receive treatment until the ratification of the CHMP opinion, and we are actively evaluating local country options for ongoing access to treatment. Additionally, we continue to diversify our Translarna franchise globally as we brought this treatment to patients in seven new countries last year as part of our ongoing expansion geographically around the world. Now turning to Emflaza. Quarterly net revenue was $67 million, with $255 million of net revenue in 2023, which is a 17% growth over 2022.

The team has implemented a multi-pronged strategy to ensure that we protect our Emflaza business in anticipation of loss of exclusivity in Q1 this year. Our U.S. team continues to engage with healthcare professionals by providing meaningful clinical differentiation compared to prednisone, and have implemented other strategies to ensure Emflaza brand loyalty for new and existing patients. We continue to support DMD patients and their caregivers with outstanding service from our PTC CARES teams by enhancing customer experience, providing easier access to treatment, facilitating copay assistance, and improving adherence for patients in the U.S. PTC is also partnering with our specialty pharmacies and contracting with targeted payers to dispense the Emflaza brand.

We continue to communicate and support our exclusivity for two-five-year-old DMD patients, which continues into 2026, and we are also leveraging patient advocacy in support of the benefits and value of Emflaza. Now, I will ask Kylie to update the progress of our current and future new product launches. Kylie?

Kylie O'Keefe (CCO)

Thanks, Eric. Let me begin with Upstaza, the first and only approved gene therapy infused directly into the brain, where we continue to see transformative results. In October, we presented Upstaza data at the CNS conference showing cognitive improvement and continued increase in long-term motor milestones. Our rollout across Europe continues to progress with new patients treated in the quarter. Furthermore, we are continuing the global expansion of the franchise with additional regulatory filings in Asia-Pacific countries and have recently received regulatory approval in Israel, where the team is working actively to treat our first patient. Globally, patient identification, treatment center readiness, and access and reimbursement discussions continue to advance. Moving to Tegsedi and Waylivra in Latin America. We closed out the year with robust growth for both Tegsedi and Waylivra, more than doubling our revenue in the region.

Patient identification is robust, and the number of patients on treatment continues to grow across the region, including first-time revenue in new countries. In Brazil, we received a new group purchase order for Waylivra, which is in recognition of the increased number of patients that rely on these life-changing treatments. We anticipate fulfilling this group purchase order in the first quarter. As previously discussed, we are updating our total revenue guidance following the CHMP opinion for Translarna. With growth continuing across the portfolio for Evrysdi, Upstaza, Tegsedi, and Waylivra, our efforts to protect the Emflaza business and expected Translarna revenue in geographies outside of Europe, we are updating our annual total revenue guidance to $600 million-$680 million. We continue to plan for our global launch of sepiapterin.

Feedback from the PKU community is extremely positive, and there is a widespread recognition among metabolic specialists, geneticists, and dietitians of the potential of sepiapterin to meet the significant unmet needs for many of their PKU patients. Not just patients who have been unresponsive to Kuvan, but also those who are poorly controlled on this drug and could potentially do significantly better on sepiapterin, as we saw for numerous patients in the APHENITY Trial, as well as classical PKU patients. More importantly, we continue to see durability of treatment effect and the ability for patients on sepiapterin to increase their dietary protein intake beyond the recommended daily allowance while still maintaining control of Phe levels in the long-term extension study.

In addition, we have heard from patient advocacy groups around the world that PKU patients are excited as they have been waiting for a therapy that combines efficacy through both Phe reduction and improved Phe tolerance with tolerability. Both the physician and patient excitement continues to give us the confidence that we can reach over a billion-dollar opportunity, and we look forward to taking a step closer to realizing this upon our first global approval. In conclusion, the strong fourth quarter rounds out what was a strong 2023 for our commercial teams. Our team is well positioned to continue to execute across all our commercial products and across all geographies, together with building out the foundation for Sepiapterin for success in 2024 and beyond. 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 fourth quarter of our full year 2023. Please refer to the earnings press release issued this afternoon for additional details. Beginning with top-line results, total revenue for the fourth quarter was $307 million. This consisted of DMD franchise revenue of $143 million and other revenue of $164 million. Starting with the DMD franchise, Translarna net product revenue in the quarter was $75 million, while Emflaza net product revenue of $67 million.

Moving to Evrysdi, fourth quarter global revenue of CHF 354 million, which equates to about $400 million, was achieved by Roche, earning royalty revenue of $51 million for PTC. We also earned a $100 million milestone for Evrysdi achieving more than $1.5 billion in 2023 sales. Our total revenue for full year 2023 was $938 million for year-over-year growth of 34%. This included DMD revenue of $611 million, which represented 21% year-over-year growth. Evrysdi royalties for the year grew 49% to $169 million year-over-year.

Non-GAAP R&D expense was $113 million for the fourth quarter of 2023, excluding $8 million in non-cash stock-based compensation expense, compared to $175 million for the fourth quarter of 2022, excluding $14 million in non-cash stock-based compensation expense. The year-over-year reduction in R&D expenses reflects the strategic portfolio prioritization as the company continues to focus its resources on its differentiated, high-potential R&D programs. Non-GAAP SG&A expense was $68 million for the fourth quarter of 2023, excluding $8 million in non-cash stock-based compensation expense, compared to $79 million for the fourth quarter of 2022, excluding $13 million in non-cash stock-based compensation expense. This expense reduction reflects lower employee costs as a result of the reduction in the workforce.

We're maintaining our guidance we provided in January for GAAP R&D and SG&A expense of between $740 million-$835 million. We are also maintaining our guidance for non-GAAP R&D and SG&A expense of between $660 million-$755 million, including expected R&D expense milestone payments of up to $65 million and excluding estimated non-cash stock-based compensation expense of $80 million. Cash, cash equivalents, and marketable securities total approximately $877 million as of December 31st, 2023, compared to $411 million as of December 31st, 2022. The 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. I will now turn the call over to the operator for Q&A. Operator?

Operator (participant)

Thank you so much. As a reminder, to press star one one to get in the queue and to remove yourself, press star one one again. One moment while I compile the Q&A roster. Our first question is from Sammy Corwin with William Blair. Please proceed.

Brooke Schuster (Biotech Equity Research Associate)

Hi, this is Brooke Schuster on for Sammy. Thanks for taking our question. We were wondering if you could provide more details on the transition of sales force and resources for Translarna with the removal of the EU market, and if there would be any effect on the SD&A outlook for 2024.

Matthew Klein (CEO)

Okay. Thank you very much, Brooke, for the question. As we talked about previously, obviously, we still are marketing Translarna in the first quarter in Europe until the ratification of the CHMP opinion occurs, and then it'll be a very rapid transition of that infrastructure to get ready for the Sepiapterin launch, as we discussed where we'll be submitting the MAA for Sepiapterin in the first quarter. And that infrastructure that we built will be well-positioned for what we plan to be a successful launch of Sepiapterin in Europe. So the OpEx guidance that we've given for the year incorporates what we plan to have today. It also already accounts for what we're going to need tomorrow for the Sepiapterin launch and any other product launches that we have upcoming.

Brooke Schuster (Biotech Equity Research Associate)

Thank you.

Operator (participant)

Thank you. One moment for our next question, please. It comes from the line of Kristen Kluska with Cantor Fitzgerald. Please proceed.

Rick Miller (Equity Research Associate)

Hi, this is Rick Miller on for Kristen. Thanks for taking our questions. Maybe on FA for vatiquinone, can you speak to anything on kind of the ongoing regulatory strategy in the U.S. versus Europe with the two guided regulatory interactions? Do you plan on making similar arguments around the data and MOVE-FA to the different regulatory bodies, or could there be sort of different strategies when it comes to the FDA and EMA based on what they're looking for? Any color here could be helpful. Thank you.

Matthew Klein (CEO)

Yeah, sure, Rick. As we shared on the call, we were very pleased to announce that we had a very productive discussion with the FDA regarding the Friedreich's Ataxia program earlier in the first quarter. Based on those discussions, we now have a path to NDA submission, we believe, late in the year. It was an extensive discussion regarding the clear evidence of benefit in the MOVE-FA placebo-controlled study, particularly an upright stability scale, which is now clearly recognized as the most applicable part of the entire mFARS score for assessing ambulatory pediatric, adolescent, and young adult patients that made up the majority of the population in the MOVE-FA study.

So after that discussion, it was agreed that we have the ability to potentially submit an NDA based on MOVE-FA, along with confirmatory evidence from the long-term open label extension portion of MOVE-FA, comparing those data to natural history data, very much like Reata did for the Skyclarys NDA. So this idea that we're combining solid, reliable, strong evidence of clinical benefit in the MOVE-FA study, along with confirmatory evidence from the open label portion of that study. So we're very excited to be able to provide that update.

Rick Miller (Equity Research Associate)

Okay. Thank you.

Operator (participant)

Thank you so much. One moment for our next question, please. It's from the line of Kelly Xie with Jefferies. Please proceed.

Alex Yuen (Managing Director and Head of China ECM and Syndicate)

Hi, this is Yuen for Kelly. Thanks very much for taking the question. First question on Emflaza. Have you seen any patient switching from Emflaza to generic? And I know that you cannot speak for patient, but if patient were to switch or were not to switch, do you know what could be the reason driving patient decision, please? I have a follow-up question, please.

Matthew Klein (CEO)

Yep. Thank you very much for the call-up. Kylie, do you want to comment on what we've the Emflaza revenue projections and potential impact of generic?

Kylie O'Keefe (CCO)

Yeah, absolutely. Thank you very much for the question. As we've said in the past, we've obviously had the fact that loss of exclusivity has been on the horizon, and we've been preparing for this. The team has a number of strategies in place to do everything they can to protect the business. Obviously, Eric outlined a number of these in the prepared remarks. I think from that perspective, we've talked about contracting with specialty pharmacies. We've talked about contracting with payers, a number of initiatives highlighting clinical differentiation to prednisone, ensuring brand loyalty through our patient PTC CARES team.

And a number of these programs are in place to ensure that we can protect the business upon the loss of exclusivity. From that perspective, I think it's too early to say if we're seeing switches. There's nothing that we've seen so far. I think what we have seen and understand through speaking to both physicians and patients in the community is that there is a strong brand loyalty to Emflaza. There's a number of programs in place to ensure that brand loyalty. So from our perspective, we've done everything we can to maintain that business, and our revenue guidance is projecting that as well.

Alex Yuen (Managing Director and Head of China ECM and Syndicate)

Okay. Great. And then on the Huntington's disease program, has the FDA given you specific guidance in terms of criteria and timeline to lift the clinical hold, please? Thank you very much.

Matthew Klein (CEO)

Yes. Yes. As we previously shared, we had a very productive discussion with the agency in the fall of last year where they shared that this data we've collected so far in the PIVOT-HD study through 12 weeks should be sufficient to allow conduct of that study for 12 weeks' duration. And if we wanted to be able to do the full protocol of 12 months, that they would like to see six months' worth of safety data. So that's obviously very encouraging because, as we've shared last June, there's very strong evidence of safety and tolerability thus far with no evidence of NfL spikes seen and also no treatment-related serious adverse events.

The profile continues to be safe as we continue to collect more data. So we look forward to being able to share now with the FDA the 6-month data they'd like to see to lift the partial clinical hold, which we will expect to do as we get those data in the coming months.

Alex Yuen (Managing Director and Head of China ECM and Syndicate)

Great. Thank you.

Operator (participant)

Thank you. One moment for our next question. It's from the line of Eric Joseph with JPMorgan. Please proceed.

Eric Joseph (VP and Branch Manager of Chase Private Client Branch)

Yeah. Thank you. I just wanted to touch on Vatiquinone and FA. It's nice to see that opportunity back on the table. Can you just talk a bit more about sort of what has got FDA a little more constructive? Was any new data from the open label extension discussed, or is it more about just sort of getting them on board with upright stability as a key functional endpoint? And just kind of looking back on your commentary where they previously seemed to want a confirmatory study, if you proceed with an NDA submission here, that would be for full approval or accelerated approval? Thanks.

Kylie O'Keefe (CCO)

Yeah. Thanks for the question, Eric. So the discussion with the agency really focused on the upright stability scale. I think as we've talked about when we started the MOVE-FA study, what wasn't quite appreciated was that for the population we were looking at, ambulatory patients, the only sensitive portion of that scale is the upright stability scale. Now, over the past couple of years, there have been several publications, and there's also been an FDA-funded study looking at pediatric Friedreich's patients. All of these studies have shown clearly that if you want to assess the treatment effect in a young adolescent ambulant patient population, that the upright stability is the only way to do it.

In fact, if you even look at the placebo data in our trial, you see that the placebo group barely changed on any of the other parts of the mFARS. It was really only on upright stability that you see disease progression in that population over 72 weeks. And so when you are able to show those data and talk about those data and provide evidence to the agency, including evidence from a study they've funded, it becomes very clear that while the primary endpoint itself in mFARS didn't hit, we demonstrated significant benefit on the only thing you possibly could show significant benefit on disease progression, and that's the upright stability scale.

So I think those data and that understanding, along with the supportive evidence on the fatigue scale, which has also statistical significance and is well recognized as the most burdensome symptom for FA patients in some correlation with walk tests, all of that together, I think, was very helpful in having a constructive discussion with the agency and being able to talk about a path forward to NDA based on the MOVE-FA data. We have not done the analysis yet of the open label data. Those weren't shared. We'll obviously prepare an analysis plan for those data and share with the agency ahead of doing those analyses.

In terms of this being accelerated or full approval, we're still having those discussions at this point. But what we're most excited about, obviously, is being able to have the potential to submit an NDA based on the MOVE-FA study and still what is still a significant unmet need for pediatric and adolescent Friedreich's ataxia patients, and also to be able to have a therapy that would provide benefit to ambulatory patients who are young adults or in adult age as well.

Eric Joseph (VP and Branch Manager of Chase Private Client Branch)

Okay. Appreciate the commentary there. Maybe just on the sequencing of the Open Label Extension analysis and showing those data with FDA, I guess, will you be updating the street with those data ahead of further interactions with the agency?

Matthew Klein (CEO)

Yes. We expect those open label data to be collected over the next several months and would expect then to complete the analyses once we collect all the data. We'll also be doing an analysis of the original study. As you know, we've previously shown that in the long-term follow-up from the initial vatiquinone study, we had a highly significant benefit when comparing those patients treated for 24 months versus an age stage and natural history match. We'll be updating that analysis as well and including that as a source of confirmatory evidence. To the exact sequencing of having the data shared with the FDA and updating the Street, we'll certainly keep the Street posted as we move towards the NDA, including a pre-NDA meeting.

Eric Joseph (VP and Branch Manager of Chase Private Client Branch)

Okay. Great. Thanks for taking the questions.

Operator (participant)

Thank you. One moment for our next question, please. And it's from Jeff Hung with Morgan Stanley. Please proceed.

Jeff Hung (Equity Research Analyst and Biotechnology)

Thanks for taking my questions. For Translarna, are you aware of any communication between the EMA and the Brazilian Health Regulatory Agency after the recent EMA decision given their data-sharing agreement? Roughly, how much of your data will come from Brazil? And then I have a follow-up.

Matthew Klein (CEO)

Yeah, Jeff. We're not aware of any correspondence. I think Brazil has traditionally been quite independent, and we expect that to continue to be the case. And indications we've had is that they will continue to act independently in making their assessment of the benefit of Translarna.

Jeff Hung (Equity Research Analyst and Biotechnology)

Okay. Thanks. And then for the sepi after an NDA submission, what other data might be needed beyond the tox data? Could the FDA look for clinical data versus Kuvan and classical PKU patients, or have they ever asked you or said about running a head-to-head study against Kuvan? Thanks.

Matthew Klein (CEO)

Yep. So as we previously talked about, the only outstanding or the only gating item for the NDA submission was the completion of the mouse study. We started that as expected in December. Now that we have visibility to those timelines, we look forward to discussing being able to possibly submit the NDA sooner than the third quarter. So we'll obviously look forward to those discussions. In terms of comparison to Kuvan, I think that's something we've never been asked for. In fact, what we've been able to show FDA and other regulatory authorities as well is that we had the phase two study, which was a head-to-head comparison of Kuvan, which showed statistically significant benefit of sepiapterin over Kuvan.

And then, of course, the APHENITY study where we had that number of patients, 27 patients who came in the study on Kuvan, who then washed out of it, and then we had a 50%, roughly 50% greater lowering of phenylalanine once those patients switched over to sepiapterin, again clearly demonstrating that we're able to provide significant greater benefit to these patients. And then, of course, the evidence in the classical PKU patients in the APHENITY study with a mean reduction of 69% in the placebo-controlled portion,

I think, is again very supportive of the potential for sepiapterin to provide benefit to the full spectrum of PKU patients, that being of all ages and all degrees of severity, and also reinforcing that if patients have demonstrated responsiveness to BH4 in the past, so we can certainly expect a much greater response once they're put on sepiapterin.

Jeff Hung (Equity Research Analyst and Biotechnology)

Great. Thanks so much.

Operator (participant)

Thank you. One moment for our next question, please. It's from the line of Brian Abrahams with RBC Capital Markets. Please proceed.

Brian Abrahams (Managing Director and Global Sector Head of Healthcare Research)

Hey. Good afternoon. Thank you for taking my questions. On the 518 Huntington's program, I guess two questions. First, I'm curious how your views have evolved on whether there could be a potential path for accelerated approval for that drug based on NfL and/or brain volume. And then secondly, I know there's an additional cohort of patients that you guys were enrolling, the ones that weren't presented last year and included early stage III patients. Just wondering where you're at with that cohort, if we might see interim results from less than 12 months' timeframe in the second quarter as well, and your latest thoughts on moving to a 20-mg dose. Thanks.

Matthew Klein (CEO)

Thank you very much, Brian, for the questions. So on your first question, look, I think it's very clear that FDA as a whole and the neurology division in particular has been looking at the accelerated approval path as one that is rational for neurodegenerative diseases where it's typically many years and very, very large study needed to register clinically meaningful effects. So to be able to have a biomarker that is likely to predict clinical effect makes perfect sense.

So you can have an accelerated approval, get patients immediate access to a therapy while you collect that longer-term data. Obviously, if it makes sense for neurodegenerative disease in general, it certainly makes sense for a disease like Huntington's disease, which, of course, is an indolent disease. And the efforts of the study will necessarily need to be large and long.

In terms of potential biomarkers for HD, we think there are several, as you mentioned, both NfL and brain volume. Certainly, in a disease of inflammation-oxidative stress, to be able to show a benefit on a marker of inflammation-oxidative stress like NfL certainly should be likely to predict clinical benefit. Similarly, for something like brain volume where the pathogenesis of disease is cell injury, cell death, loss of brain volume, and then symptoms that present itself in ultimate clinical neurodegeneration, and if you could slow that process, a brain atrophy, that certainly suggests you should be able to influence the progression of disease. We see those both as potential biomarkers. Of course, it's going to be a matter of having the data, having the discussions with the agency because we'd be the first ones through that portal.

But I definitely think that the agency is showing openness to leveraging the accelerated approval pathway in the case of diseases like HD. And we certainly would look to avail ourselves of that opportunity. In terms of your second question, the Phase III enrollment has gone quite well. In fact, overall enrollment really picked up after we shared the June data. We're able to reassure both the patient community and the physician community that you can develop a drug for HTT lowering that is safe and well-tolerated and has the necessary biodistribution and pharmacodynamic effect necessary for therapeutic benefit. So we've seen excellent enrollment. And we will be sharing, in addition to the 12-month data in the second quarter, interim data from 12 weeks on the other Phase II patients as well as some of the Phase III patients.

So we look forward to sharing all of those data with you all in the second quarter. Your third question regarding the 20-milligram dose, our view remains as it was when we talked about it in June. I think what we're seeing with the 10-milligram dose and the preferential distribution to the CNS with a 1:1.5 ratio of plasma and a CSF exposure, that we very much believe that 10 milligrams is probably the dose that we need.

So right now, we're committed to moving forward with 5 milligrams and 10 milligrams and learning more about it. Of course, we do have that opportunity to titrate up to 20 milligrams if need be. But right now, we believe that we may very well be sitting with dose levels that are the right ones to safely achieve the desired lowering of Huntington proteins that can provide clinical benefit to patients.

Brian Abrahams (Managing Director and Global Sector Head of Healthcare Research)

Thanks so much, Matt.

Operator (participant)

Thank you so much. One moment for our next question, please. It's from the line of Peyton Bonsack with TD Cowen. Please proceed.

Peyton Bonsack (Analyst)

Hi, guys. I guess for us, could you possibly elaborate on the reauthorization process for Translarna in Brazil and Russia and maybe the process for national assessment in the United Kingdom? It looks like in Brazil specifically, the renewal is up in April. Is that the case? And do you expect? I know you mentioned earlier that there wasn't any cross-checker between the two agencies. But do you expect the recent EU decision would have any implications here? Thanks.

Matthew Klein (CEO)

Yes. Thank you for the questions. So as you mentioned, we're up for reauthorization in Brazil. That process is ongoing. Every indication we have is that this will continue to be an independent assessment. They remain very interested in following their own assessment, the view of KOLs and others in Brazil, and are not influenced by the CHMP's decision. I'd say that we're seeing similar things in the U.K. where they also have said that they want to do their own independent national review and a national authorization. So the signals that we're getting very clearly is that there's a strong desire of countries to do their own assessment and not follow the lead of the CHMP.

Peyton Bonsack (Analyst)

Great. Thank you. And then I guess maybe just a quick follow-up question. When you're looking at the open label data, have you guys reached alignment with exactly what the natural history, like external cohort group, will look like with the FDA, or is that still ongoing?

Matthew Klein (CEO)

Pete, I see you're talking about for Friedreich's?

Peyton Bonsack (Analyst)

Yeah. Sorry for bad taco numbers.

Matthew Klein (CEO)

Yeah. I think there's really a luxury. The Friedreich's ataxia community has really been a model community in doing the necessary hard work of creating a robust patient registry. The FACOMS, the FACOMS Natural History Registry, is a robust repository of patient data that has several years' worth of data on things like the mFARS, including the upright stability scale. And this is something that Reata was able to leverage as part of their NDA, and we would look forward to doing the same. I think the FDA acknowledges this. I think the FDA has publicly acknowledged the great work that the Friedreich's ataxia community has done in building this registry.

And obviously, it's something that's incredibly useful to drug developers like us, like Reata and others, who can now leverage that natural history database to contextualize the long-term beneficial effects of therapies. I think there's no question that this is the registry. We will, as needed, develop a statistical analysis plan that precisely details how we'll do what will be a propensity score match to ensure that we have an apples-to-apples comparison between the patients in MOVE-FA, and particularly known, and the natural history patients. That should provide us the necessary natural history data needed or the long-term treatment data needed to provide that confirmatory evidence to the NDA.

Peyton Bonsack (Analyst)

Great. Thank you so much for taking our questions.

Operator (participant)

Thank you. One moment for our next question, please. It's from the line of David Lebowitz with Citi. Please proceed.

David Lebowitz (Senior Research Analyst of Biotechnology)

Thank you very much for taking my question. Could you compare the regulatory process for 505(b)(2) and 505(b)(1) and talk about how the data to this point for sepiapterin fits into the submission and what additional components or different ways of looking at the data might be required by the FDA?

Matthew Klein (CEO)

Yeah. Thanks, David. I think just for context, as we've talked about, the initial sepiapterin development path was 505(b)(2), which was a decision made by Censa when they were developing the compound. I think it was likely thought to be a path that would be maybe faster or less resource-intensive. But when we license the therapy, and it's very clear, it is not the appropriate path. It's really not for a molecule like sepiapterin. Sepiapterin has novel composition, novel mechanism of action, novel biodistribution, novel pharmacology, and clearly differentiated therapeutic benefit. So it doesn't fit into the sort of me-too-505(b)(2) paradigm. It's a novel therapy that is and should be part of the 505(b)(1) development pathway.

As such, it's necessary then to provide a full slate of non-clinical studies, including things like ADME pharmacology studies, toxicology studies, maternal-fetal studies, all those types of juvenile toxicity. All of those studies then become necessary to be part of that program, all of which we'll have. In terms of being ready to submit the NDA under 505(b)(1), as we said, the only outstanding item is the mouse study, which I mentioned earlier on the call. It's really a matter I think it was probably not appropriately started in the 505(b)(2) pathway. It was really not in where it belongs for a novel differentiated therapy like sepiapterin 505(b)(1).

David Lebowitz (Senior Research Analyst of Biotechnology)

Does the FDA require any type of head-to-head comparisons in this particular process?

Matthew Klein (CEO)

Not at all. I think the one thing we could say is, I think, we're in a situation that is precedented. There have been approved therapies for PKU. There's a well-established clinical trial design endpoint and what the FDA likes to see. And that's exactly what we follow, including the sepiapterin registration program looked a lot like the Kuvan program in terms of having a responder analysis to identify those that responded, then having a placebo-controlled study, and then having the necessary data to demonstrate durability and long-term safety, all of which we have.

I'd say the only difference in that program is the significantly greater responder rate, the significantly greater magnitude of treatment benefit. So those are the components of the data needed to support the NDA submissions, to support the efficacy. It's the evidence of effectiveness that are needed. It's the evidence of effectiveness that we have. We look forward to being able to submit that NDA as soon as possible.

David Lebowitz (Senior Research Analyst of Biotechnology)

Got it. And just jumping over to FA, have you received the minutes from the meeting yet? And what are the next steps in the process?

Matthew Klein (CEO)

Yeah. So I think at this point where we are, we're still, as I mentioned, having some back and forth with the FDA regarding whether this could be an accelerated approval or a full approval. That's something that we look forward to getting written correspondence on in the near future. And I think for us right now, it's also moving forward in collecting all the open-label data and getting together the statistical analysis plans that can support the confirmatory evidence. And so that's what all our team is focused on right now.

David Lebowitz (Senior Research Analyst of Biotechnology)

Got it. Thank you for taking my question.

Operator (participant)

Thank you. One moment for our next question, please. It comes from the line of Gena Wang with Barclays. Please proceed.

Gena Wang (Managing Director and Biotech Equity Research)

Thank you. I would just ask one more question regarding vatiquinone and FA. So did the FDA suggest any specific statistical methodology to analyzing data since this will be comparing to the natural history data as well as open-label extension study?

Matthew Klein (CEO)

Yeah. Thanks, Gena. They were not prescriptive. I think we've gone to them, and they sort of said we would look to do a propensity analysis approach. Again, we're in a realm here of precedent. They recently approved an NDA for Skyclarys based on a placebo-controlled study along with open label data compared to the FACOMS natural history database using propensity score matching. So we have a lot we can follow here. But to be sure, we'll submit a statistical analysis plan that will fully detail our approach not only in the propensity model but also into what will likely be a mixed-effects modeling to provide the appropriate longitudinal estimate of treatment benefit relative to natural history.

Gena Wang (Managing Director and Biotech Equity Research)

Okay. And very quickly, did the FDA give guidance what type of data you need to hit in order to could be approvable?

Matthew Klein (CEO)

From the open label registry?

Gena Wang (Managing Director and Biotech Equity Research)

For FA.

Matthew Klein (CEO)

Yeah. For the open label portion?

Gena Wang (Managing Director and Biotech Equity Research)

Mm-hmm.

Matthew Klein (CEO)

Yeah. No, there was no specifics there. There was nothing prescriptive. I think this is viewed as within the regulatory framework, we have persuasive evidence of effectiveness. We would be putting together an NDA based on our ability to demonstrate persuasive evidence of effectiveness in the placebo-controlled portion of the MOVE-FA study along with confirmatory evidence that we said will consist of comparing the open label data to natural history, showing that there's a benefit over a longer period of time from both MOVE-FA

as well as I mentioned earlier to Eric's question also with open label data with the natural history comparison from the first FA study that was in a slightly different population that consisted mostly of adults, both ambulatory and non-ambulatory, where we've previously done these types of analyses to show significant long-term benefit relative to the natural history and natural history.

Gena Wang (Managing Director and Biotech Equity Research)

Okay. Thank you.

Operator (participant)

Thank you. One moment for our next question, please. It comes from the line of Paul Choi with Goldman Sachs. Please proceed.

Paul Choi (Biotechnology Analyst)

Hi. Good afternoon, and thanks for taking our question. I wanted to change gears for a moment and maybe ask about utreloxostat and ALS. And I was wondering if you could maybe ahead of the CARDINAL study reading out later this year sort of frame your thoughts on potential size of treatment effects and/or areas of differentiation versus the approved therapy Relyvrio from Amylyx. And my second question is, under a scenario where Amylyx has a positive Phoenix confirmatory study for Relyvrio, can you maybe just comment on what your regulatory strategy might be should they garner full approval there following a positive confirmatory study? Thanks for taking our questions.

Matthew Klein (CEO)

Yes. Thanks very much, Paul. Thanks for the question on the utreloxostat ALS program. This is a program we're very excited about given what's become very clear now as a link between ferroptosis and ALS. I think that ferroptosis pathway is now seen as really an important pathway in disease progression. And of course, utreloxostat was developed to specifically target that pathway. We did a lot of the preclinical development work with utreloxostat benchmarking to Relyvrio, which is also another approved therapy for ALS that has a much more sort of generic, nonspecific effect on elements of oxidative stress in the ferroptosis pathway. And as we've talked about, we've been able to show 25-30x the potency in the spinal astrocytes model.

We've also been able to show important protective effects when benchmarked against Relyvrio and a number of other disease-relevant preclinical test models. In terms of the study design, I think, again, we're in an element, as I mentioned with David's question in PKU, where there's clearly precedent for the design of an ALS study. And our discussions with the FDA were very constructive in ensuring that this is a protocol that could support registration if positive.

We designed the study with a two-to-one randomization with a treatment effect of roughly a 2.5 treatment difference between the treatment groups and the placebo groups, which gives us roughly 85% power to detect that difference. And I think that positions us very well to capture significant treatment benefit. I think the regulatory pathway doesn't change at all based on what happens with AMLEX's compound.

And obviously, the commercial opportunity and the differentiation will be based on the data, what we see on ALSFRS score, what potentially we could see in terms of pulmonary function, and also what we might see in terms of mortality. We call it the FDA has always been very keen at understanding both changes in ALSFRS and mortality risk. I think it's also become very well accepted in the ALS community that given the aggressiveness and the complexity of ALS, that this is probably not going to be a single therapy disease. I think it's probably going to require more than one. But again, I think the specifics are returning in terms of head-to-head comparison with AMLEX's compound is really going to be data-driven. And we look forward to seeing the results from the CARDINAL study.

Paul Choi (Biotechnology Analyst)

Great. Thanks for that. Thank you for your questions.

Operator (participant)

Thank you. One moment for our next question, please. It's from the line of Danielle Brill with Raymond James. Please proceed.

Alex Sklar (Analyst)

Hey, guys. This is Alex from for Daniel. Just looking to Huntington's. Just kind of curious about what assay you're using for CSF mutant Huntington detection. Wondering if you expect to have similar issues that a recent competitor had and how reliable the results are in an early HD population. Thanks.

Matthew Klein (CEO)

Yeah. Great questions. I think there's two separate issues. There's assay reliability and then assay sensitivity based on the population. Let me take them each in turn. We've worked very hard ensuring that we have robust assays that are accurate and precise. I think one of the things we know very well about assays and clinical studies is it's not just the assay itself. There's making sure that you have care and sample acquisition, sample processing, sample storage, sample transport, and then ultimately sample analysis. Those are things that we pay very close attention on so that we minimize any confounding elements that could influence the assay results. We know the other part that's important as well is that these assays tend to work much better when you have a larger number of samples.

So something that we've been very thoughtful about is ensuring that we have batch samples. So each time we run these analyses, we're doing them on as many samples as makes sense at that time. So again, all things that we can do to try to reduce the variability and increase the fidelity of those assay results. You bring up another point that's very, very important, which is assay sensitivity based on disease stage. Now, it's well known that in very early stage or presymptomatic HD patients, mutant Huntington protein is not detectable in the CSF because the concentration is incredibly low. We're talking about picomolar concentrations and maybe even lower.

As we move into the stage II patients we have in the Huntington trial, of course, these are patients we believe there is detectable Huntington protein in the CSF. We've seen that so far. But of course, obviously, something we'll watch very carefully in those patients is where we are on that in terms of the limit of detection for the assay. But that's something we're very thoughtful about. And of course, the benefit now having the stage III patients is those are patients that, of course, are going to be a bit further in their progression and will likely have much higher baseline mutant Huntington protein levels that will make that sensitivity issue really not an issue. Thanks so much.

Operator (participant)

Thank you. One moment for our last question. It's from the line of Joseph Schwartz with Leerink Partners. Please proceed.

Joseph Schwartz (Managing Director and Senior Biotechnology Analyst)

Thanks so much for fitting me in. So I wanted to ask, since it's been a while since Kuvan and Pegvaliase were approved, I was wondering whether for sepiapterin, you've been able to establish with the FDA that data focused on Phe lowering will be sufficient and that clinical outcomes assessments won't be required for approval in PKU? And then I have a follow-up.

Matthew Klein (CEO)

Yeah, Joe. Obviously, one of the most important things we did prior to commencing the phase III study is to make sure we had full alignment on the study design, including the primary endpoint of Phe reduction. I think traditionally, if you look at the FDA, when they have made a decision on an approval based on something that doesn't change with time, it actually gives them confidence that they can interpret your study results in a meaningful way. So we, of course, made sure that there was alignment on Phe as the endpoint. Phe was the endpoint. And of course, we're very happy to have seen not only that we had a significant effect, but as I talked about earlier on the call,

results that are highly statistically significant and much greater magnitude than we've seen with previous oral therapies. I think that it becomes very easy for them to see not only the statistically significant, highly clinically meaningful benefit that we've been able to demonstrate in the APHENITY trial. Of course, one of the elements of the pre-NDA meeting was ensuring that we had the safety and efficacy data necessary to support that NDA submission. The answer was, yes, yes, we do.

Joseph Schwartz (Managing Director and Senior Biotechnology Analyst)

Okay. And then since strong patient advocacy seemed to be key for Skyclarys to get traction with the FDA, who wasn't on board with Reata being able to file at first, I was wondering if you could give us any insight into how much the FA patient or physician community has been lending support behind your effort to pursue a filing for vatiquinone?

Matthew Klein (CEO)

As I mentioned earlier, Joe, I think the Friedreich's ataxia community led by the Friedreich's Ataxia Research Alliance is really a model disease community in terms of aggregating the patients, the physicians, as well as industry and being able to really lead the charge in ensuring that those therapies developed and developed successfully for the treatment of Friedreich's ataxia patients. I'm proud to say that we have partnered with FARA since the beginning of the clinical development of vatiquinone going many years back. And we've been incredibly grateful for their partnership not only in helping us understand how to best design trials, their work in establishing a patient registry that will obviously be very important in us putting together a data package for our NDA.

Quite frankly, the work that they've helped lead with the physician community and research community on demonstrating the importance of upright stability for pediatric and adolescent ambulatory patients. So I can proudly say that they've been a partner of ours. And we think that's been an incredibly important part of the vatiquinone journey. And we think it will continue to be, that partnership will continue to be an important part as we move forward and look to submit an NDA. Great. Thank you.

Operator (participant)

Thank you. I would like to conclude the Q&A session now. I'll thank you all who participated and turn it back to the CEO, Dr. Matthew Klein, for additional comments.

Matthew Klein (CEO)

Well, I just want to thank everyone again for joining the call today. As we've discussed, we look forward to an exciting 2024 with a number of important and valuable potential milestones ahead. We look forward to sharing the journey with you all as we move forward. Thank you again.

Operator (participant)

Thank you all for participating. You may now disconnect.