PTC Therapeutics Q4 2023 Earnings Call Transcript

Quartr
Provided by Quartr
February 29, 2024

There are 15 speakers on the call.

Operator

Good day, and thank you for standing by. Welcome to PTC 4th Quarter 2023 Financial Results. At this time, all participants are in a listen only mode. After the speakers' presentation, there will be a question and answer 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.

Speaker 1

Good afternoon, and thank you for joining us today to discuss PTC Therapeutics' Q4 and full year 2023 corporate update and financial results. I'm joined today by our Chief Executive Officer, Doctor. Matthew Klein our Chief Business Officer, Eric Powells our Chief Commercial Officer, Kiley 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.

Speaker 1

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 ks 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 Claring. Matt?

Speaker 2

Thank you, Ron. Good afternoon and thank you all for joining today's call. I'm pleased to share our Q4 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 4th quarter revenue of 307,000,000 dollars and full year 2023 revenue of $938,000,000 representing 34% growth over 2022. Our DMD franchise revenue totaled $143,000,000 in the quarter $611,000,000 for the full year.

Speaker 2

Eric and Kiley 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 sepia tarant 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.

Speaker 2

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 nazepam. As I have previously emphasized, through our efforts to focus our R and 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.

Speaker 2

I will begin with our cepataren program for the treatment of children and adults with PKU. We remain on schedule to submit the NAA for cikataren to the EMA in the Q1 of this year and to submit the NDA in the United States no later than the Q3 of this year. As we continue to collect data from the open label extension study following the Phase 3 APHINITY trial, we continue to see durability of cepiaterin treatment effect and the ability of patients on cepataren 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 sepia tariff to fill the persistent unmet medical need of the majority of the 58,000 PKU patients worldwide. Moving to our vatipinone program for Friedreich ataxia.

Speaker 2

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 ataxia patient registry using analyses similar to those provided to FDA by Reata as part of the Cyclaris 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 etiquinone fill the significant remaining unmet need for pediatric and adolescent FA patients.

Speaker 2

In other regulatory updates, we remain on track to submit the BLA for ABSTAZA to the FDA in March and are also scheduled to meet with FDA in March to discuss the contents of the potential NDA resubmission for Translarna. Turning to our ongoing clinical trials, we expect to share interim 12 month results from the PIV HD trial of PTC-five eighteen in HD patients in the Q2 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 huntingtin 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's registration directed trial of etreloxostat in ALS patients in the Q4 of this year.

Speaker 2

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 Kiley to discuss our commercial performance. Eric?

Speaker 3

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 of products in more mature markets such as the U. S. 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.

Speaker 3

In the Q4, we delivered $155,000,000 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 Q4 for both Translarna and Emflaza, delivering an impressive $143,000,000 in net revenue, which is 25% growth compared to the Q4 of 2022, with a strong full year performance of $611,000,000 For Translarna, we achieved $75,000,000 in revenue this quarter with annual sales of $356,000,000 dollars 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 7 new countries last year as part of our ongoing expansion geographically around the world.

Speaker 3

Now turning to Emflaza. Quarterly net revenue was $67,000,000 with $255,000,000 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.

Speaker 3

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 co pay 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 2 to 5 year old DMD patients, which continues into 2026.

Speaker 3

And we are also leveraging patient advocacy in support of the benefits and value of Emflaza. Now, I will ask Kiley to update the progress of our current and future new product launches. Kiley? Thanks, Eric.

Speaker 4

Let me begin with UPSTASA, the 1st and only approved gene therapy infused directly into the brain, where we continue to see transformative results. In October, we presented UPTHASA 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.

Speaker 4

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 Q1.

Speaker 4

As previously discussed, we are updating our total revenue guidance following the CH and P opinion for Translarna. With growth continuing across the portfolio for EVRIZI, ABSTAYZA, 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 $600,000,000 to $680,000,000 We continue to plan for our global launch of sepiaterin. Feedback from the PKU community is extremely positive and there is a widespread recognition amongst metabolic specialists, geneticists and dietitians of the potential of sepiaterin 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 cepiaterin as we saw for numerous patients in the APHINITY trial as well as classical PKU patients. More importantly, continue to see durability of treatment effect and the ability for patients on sepiateran to increase their dietary protein intake beyond the recommended daily allowance, while still maintaining control of fee levels in the long term extension study.

Speaker 4

In addition, we have heard from patient advocacy groups around the world that PKU patients are excited as they've been waiting for a therapy that combines efficacy through both fee reduction and improved fee tolerance with tolerability. Both the physician and patient excitement continues to give us the confidence that we can reach over $1,000,000,000 opportunity and we look forward to taking a step closer to realizing this upon our first global approval. In conclusion, the strong 4th quarter rounds out what was a strong 2023 for our commercial team. 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 cepiaterin for success in 2024 and beyond. I will now turn the call over to Pierre for a financial update.

Speaker 4

Pierre?

Speaker 5

Thank you, Kylie. I'll now share the financial highlights of our Q4 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 Q4 was 307,000,000 dollars This consisted of DMD franchise revenue of $143,000,000 and other revenue of 164,000,000 dollars Starting with the DMD franchise.

Speaker 5

Translarna net product revenue in the quarter was 75,000,000 dollars while Emflaza net product revenue of $67,000,000 Moving to EBRISD. 4th quarter global revenue of CHF354 million, which equates to about US400 $1,000,000 was achieved by Roche, earning royalty revenue of US51 $1,000,000 for PTC. We also earned a $100,000,000 milestone for every year achieving more than US1.5 billion dollars 20.23. Our total revenue for full year 2023 was 938,000,000 dollars or year over year growth of 34%. This included DMD revenue of 611,000,000 dollars which represented 21% year over year growth.

Speaker 5

EBITDA royalties for the year grew 49% to $169,000,000 year over year. Non GAAP R and D expense was $113,000,000 for the Q4 of 2023, excluding $8,000,000 in non cash stock based composition expense, compared to $175,000,000 for the Q4 of 2022, excluding $14,000,000 in non cash stock based compensation expense. The year over year reduction in R and D expenses reflects the strategic portfolio prioritization as the company continues to focus its resources on its differentiated high potential R and D programs. Non GAAP SG and A expense was $68,000,000 for the Q4 of 2023, excluding $8,000,000 in non cash stock based compensation expense compared to $79,000,000 for the Q4 of 2022, excluding $13,000,000 in non cash stock based compensation expense. This expense reduction reflects lower operating costs as a result of the reduction in the workforce.

Speaker 5

We're maintaining our guidance we provided in January for GAAP R and D and SG and A expense of between $740,000,000 835,000,000 dollars We are also maintaining our guidance for non GAAP R and D and SG and A expense of between €660,000,000 755,000,000 including expected R and D expense milestone payments of up to €65,000,000 and excluding estimated non cash stock based compensation expense of €80,000,000 Cash, cash equivalents and marketable securities totaled approximately EUR 877,000,000 as of December 31, 2023, compared to $411,000,000 as of December 31, 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 ceclaptery launch. And I will now turn the call over to the operator for Q and A. Operator?

Operator

Thank you so much. Our first question is from Sami Corwin with William Blair. Please proceed.

Speaker 6

Hi. This is Brooke Shuster on for Sami. Thanks for taking our question. We were wondering if you could provide more details on the transition of sales of forces and resources for Translarna with the removal of the EU market? And if there will be any effect on the SG and A outlook for 2024?

Speaker 2

Okay. Thank you very much, Brook, for the question. As we talked about previously, obviously, we still have marketing trends in the Q1 in Europe until the ratification of the CHF T opinion occurs. And then it will be a very rapid transition of that infrastructure to get ready for the sepiateran launch. As we discussed, we'll be submitting the MAA for sepiaxin in the Q1.

Speaker 2

And that infrastructure that we built will be well positioned for a successful what we're planning to be a successful launch of CPACERAN in Europe. So the OpEx guidance that we've given for the year incorporates what we plan to have today and also already accounts for what we're going to need tomorrow for the Cputamate launch and any other product launches that we have

Speaker 6

Thank you.

Operator

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

Speaker 7

Hi, this is Rick Miller on for Kristen. Thanks for taking our questions. Maybe on FA for vatiguino, can you speak to anything on kind of the ongoing regulatory strategy in the U. S. Versus Europe with 2 guided regulatory interactions, if 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 you're looking for?

Speaker 7

Any color here could be helpful. Thank you.

Speaker 2

Yes, 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 ataxia program earlier in the Q1. Based on those discussions, we now have a path to NDA submission, we believe late in the year. It was a sense of discussion regarding the clear evidence of benefit in the move FA placebo controlled study, particularly in 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 essentially 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 Breyada did to the Vyclaris at the end.

Speaker 2

So it's like they were combining solid, reliable, strong evidence of clinical benefit in the MOUVE FA study along with confirmatory evidence from the open label portion of that study. So we're very excited to go provide that update. Okay. Thank you.

Operator

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

Speaker 8

Hi, this is Yun 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 speak sorry, were to switch or were not to switch, do you know what could be the reason driving patient decision, please?

Speaker 8

And I have a follow-up question, please.

Speaker 2

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

Speaker 4

Yes, absolutely. So 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 take the business. And obviously, Eric outlined a number of these in the prepared remarks.

Speaker 4

So I think from that perspective, we've talked about contracting with specialty pharmacies, we've talked about contracting with payers, number of initiatives highlighting clinical differentiation to prednisone, ensuring brand loyalty through our patient PTC CAS 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. And 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.

Speaker 4

And so from our perspective, we've done everything we can to maintain that business and our revenue guidance is projecting that as well.

Speaker 8

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.

Speaker 2

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 collected so far in the TIVID HD study from 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 6 months worth of safety data. So that's obviously very encouraging because as we 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.

Speaker 2

So we look forward to being able to share now with the FDA the 6 month data they'd like to see to miss the partial clinical hold, which we will expect to do as we get those data in the coming months. Great. Thank you.

Operator

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

Speaker 9

Yes, thank you. I just wanted to touch on vatiguino 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? Were they Was any new data from the open label extension discussed?

Speaker 9

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 seem to want a confirmatory study, if you proceed with an NDA submission here that would be for full approval or accelerated approval?

Speaker 2

Thanks. Yes. 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 you were looking at, the ambulatory patients, the only sensitive portion of that scale is the Upright Stability Scale.

Speaker 2

Now over the past couple of years, there have been several publications and there's also been an FDA funded study looking at pediatric Friedreichotaxia patients. All of these studies have shown clearly that if you want to assess the treatment effect in a young adolescent, ambulance 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 mPARS. It was really only on upright stability that you see disease progression in that population over 70 2 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 the study they 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 uprights stability scale.

Speaker 2

So I think those data and that understanding along with the supportive evidence on the fatigue scale, which has also statistical significance is well recognized as the most burdensome symptom for FA patients and 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 new 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.

Speaker 2

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 that they study and fill what is still a significant unmet need for pediatric and adolescent Friedipotaxis 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.

Speaker 9

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 data?

Speaker 2

Yes. So we expect those open label data to be collected over the next several months and would expect then to complete the analysis once they collect all the data. We'll also be doing a analysis of the original study. As you know, we've previously shown that in the long term follow-up from the initial patiquinone study, we had a highly significant benefit when comparing those patients treated for 24 months versus age stage and natural history match. We'll be updating that analysis as well and including that as a source of confirmatory evidence.

Speaker 2

To the exact sequencing of having the data share in the FDA and updating the Street. We'll certainly keep the Street posted as we move towards the NDA, including a pre NDA meeting.

Speaker 9

Okay, great. Thanks for taking the questions.

Operator

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

Speaker 10

Thanks for taking my questions. For Translarna, are you aware of any it come from Brazil? And then I have a follow-up.

Speaker 2

Yes, Jeff. We're not aware of any core finance. I think Brazil has traditionally been quite independent. 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 TRAN-1.

Speaker 10

Okay. Thanks. And then for the CEPI after an NDA submission, what other data might be needed to be on the tox data? Could the FDA look for clinical data versus Kuvan in classical PKU patients? Or have they ever asked you or sensed about running a

Speaker 11

head to head study against Kuvan? Thanks.

Speaker 2

Yes. So as we previously talked about the only outstanding or the only gating item for the NDA submission was the completion of the MAU study. We started that as expected in December. Now that we have visibility into those timelines, we look forward to discussing being able to possibly submit the NDA sooner than the Q3. So obviously, look forward to those discussions.

Speaker 2

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 that we had the Phase 2 study, which was a head to head comparison of KUVAN, which showed statistically significant benefit of cikitarin over Kugan. And then of course, the AFFINITY study where we had that number of patients, 27 patients who came in the study on Kugan, we then washed out of it and then we had a 50% roughly 50% greater lower than phenylalanine once those patients switched over to sepiaotaren, 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 APHINITY study with a knee reduction of 69% of the placebo controlled portion, I think is again very supportive of the potential for cepiaterin to provide benefit to the full spectrum of PKU patients, that being of all ages and all degrees of severity and also reinforcing that patients have demonstrated responsiveness to be H4 in the past. So we can certainly expect a much greater response once this put on superior care.

Speaker 10

Great. Thanks so much.

Operator

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

Speaker 10

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 3 patients.

Speaker 10

Just wondering where you're at with that cohort, if we might see interim results from less than 12 months timeframe in the Q2 as well and your latest thoughts on moving to a 20 milligram dose? Thanks.

Speaker 2

Thank you very much, Brian, for the question. 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 they'd 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 who need a drug access to therapy while you collect that longer term data. Obviously, if it makes sense for neurodegenerative disease in general, certainly makes sense for a disease like Huntington's disease, which of course is an indolent disease and the efficacy study will necessarily need to be large and long.

Speaker 2

In terms of potential biomarkers for HD, we think there's several, as we mentioned, both NfL and brain volume, certainly in an 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. And similarly for something like brain volume, whether the pathogenesis disease is cell injury, cell death, loss of brain volume and then symptoms that present itself and ultimate clinical neurodegeneration, you saw that process a brain atrophy that certainly suggests you should be able to influence the progression of disease. So 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 agencies as 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.

Speaker 2

In terms of your second question, that's the Phase 3 enrollment has gone quite well. In fact, overall enrollment really picked up after we shared the June data and we're able to reassure both the patient community and the physician community that you can develop a drug for Huntington's lower and that is safe and well tolerated and have the necessary bio distribution 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 Q2 interim data from 12 weeks on the other Stage II patients as well as some of the Stage II patients. So we look forward to sharing all of those data with you all in the Q2. Your third question regarding the 20 milligram dose, our view remains as it was when we talked about it in gene.

Speaker 2

I think what we're seeing with the 10 milligram dose and the preferential distribution to the CNS with a 1 to 1.5 ratio of plasma to 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 learn 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 be better in order to be sitting at dose levels that are the right ones to safely achieve the desired volume of Huntington proteins that can provide clinical benefit to patients.

Speaker 10

Thanks so much, Matt.

Operator

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

Speaker 11

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?

Speaker 11

And do you expect I know you mentioned earlier that there was a new crossheader between the two agencies, but

Speaker 2

do you expect the recent EU decision would have any implications here? Thanks. Yes. Thank you for the questions. So as you mentioned, we're up for reauthorization of Brazil.

Speaker 2

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 that are not influenced by the CHMP decision. I'd say that we're seeing similar things in the UK 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.

Speaker 11

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 national history like external cohort group will look like with the FDA or is that still ongoing?

Speaker 2

So, Dana, I think you're talking about for Friedreich ataxia?

Speaker 11

Yes, sorry for betchaquinone. Yes.

Speaker 2

I think it's really a luxury. The Friedreich ataxia community has really been a model community in doing the necessary hard work of creating a robust patient registry. The FA, CLMS, the Back Home's 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 acknowledged this.

Speaker 2

I think the FDA publicly acknowledged the great work that the future the taxi community has done in building this registry. And obviously, that's something that's incredibly useful to drug developers like us, like Rayanna and others who can now leverage that natural history database to contextualize the long term beneficial effects of therapies. So 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 propensity score match with to ensure that we have an apples to apples comparison between the patients in move FA and vatipinone and the natural history patients. And 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.

Speaker 11

Great. Thank you so much for taking our questions.

Operator

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

Speaker 12

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

Speaker 2

Yes. Thanks, David. I think just for context, as we've talked about, the initial cephalteran development path was 505(2) which was a decision made by SENSA 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.

Speaker 2

That's more it's really not for a molecule like cevatran. Cevatran 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 need to 505(2) paradigm. It's a novel therapy that is and should be part of the 505b1 development pathway. As such, it's necessary then to provide a full slate of non clinical studies, including things like right pharmacology studies, toxicology studies, maternal fetal studies, all those types of juvenile toxicity, all of those studies then become necessary to be part of our program, all of which we'll have.

Speaker 2

And in terms of being ready to submit the NDA under 505(1) as we said, the only outstanding item is the mouse study, which I mentioned earlier on the call. So it's really a matter, I think it was probably not appropriately started in 505(2) pathway and it was really not appropriate where it belongs for novel differentiated therapy like supeteris 505(1).

Speaker 12

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

Speaker 2

Not at all. I think the one thing we could say is the 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've We including the cikataren 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.

Speaker 2

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

Speaker 12

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?

Speaker 2

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

Speaker 12

Got it. Thank you for taking my question.

Operator

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

Speaker 13

Thank you. I would just ask one more question regarding ventricino in FA. So, did 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?

Speaker 2

Yes. Thanks, Gena. They were not prescriptive. I think we've gone to them and they said that we would look to do a propensity analysis approach. Again, we're in a realm here of precedent.

Speaker 2

They recently approved an NDA for SCALCARIS based on a study, the placebo controlled study along with open label data compared to the FACOMS natural history data being season propensity score matching. So we have a lot we can follow here. And 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 likely be a mixed effects modeling to provide the appropriate longitudinal estimate treatment benefit relative to natural history.

Speaker 13

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

Speaker 2

From the open label registry?

Speaker 13

For SA?

Speaker 2

Yes, for the open label portion?

Speaker 5

Yes.

Speaker 2

No, there was no specifics there. There was nothing for certain. I think this is viewed as the in 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 that they study along with confirmatory evidence that we said will consist of me comparing the open label data to match with history showing that there is a benefit over a longer period of time from both WHOLE FA as well as I mentioned earlier to Eric's question also with data open label data with a natural history comparison from the 1st FA-seven 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 naturally.

Speaker 13

Okay. Thank you.

Operator

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

Speaker 2

Hi, good afternoon and thanks for taking our questions. I want to change gears for a moment and maybe ask about vutetrelostat 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 Pfizer treatment effects and or areas of differentiation versus the approved therapy, rozanruziva from Ameliq? And my second question is, under a scenario where Amlyx has a positive, PHOENIX comp confirmatory study for rodelirubrio, Can you maybe just comment on what your regulatory strategy might be? Should they get garnered full approval there following a positive confirmatory study?

Speaker 2

Thanks for taking our question. Yes. Thanks very much, Paul. And thanks for the question on the etreloxostat ALS program. This is a program we're very excited about given what's become very clear now is the link between ferroptosis and ALS.

Speaker 2

I think that that ferroptosis pathway is now seen as really important pathway in disease progression. And of course, your telotristat was developed to specifically target that pathway. We did a lot of the preclinical development work with eutelacastat benchmarking to adaravone, which is also another approved therapy for ALS that it has a much more sort of generic non specific effect on elements of oxidative stress in the ferroptosis pathway. And as we've talked about, we've been able to show 25 to 30 times the potency in the spinal astrocyte model. We've also been able to show important protective effects from bench edarafone and a number of other disease relevant preclinical test models.

Speaker 2

In terms of the study design, I think again, we're in an element, as mentioned with David's question in PKU, where there's clearly precedence 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 2: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 Amylaxis compound.

Speaker 2

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. Recall that the FDA has always been very keen in understanding both changes in ALS FRS and mortality risk. I think it's also become very well accepted in the ALS community given the aggressiveness and the complexity of ALS that this is probably not going to be single therapy disease. I think it's probably going to require more than 1. But again, I think the specifics are returning in terms of head to head comparison, while with amylaxis compounds really going to be data driven, we look forward to seeing the results from the CARDINAL study.

Speaker 2

Great. Thanks for that and taking our question.

Operator

Thank you. One moment for our next question please. And it's from the line of Daniel Grail with Raymond James. Please proceed.

Speaker 2

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

Speaker 2

Yes. Great questions. I think there's 2 separate issues. There's assay reliability and then assay sensitivity based on the population. Let me take that each in turn.

Speaker 2

We've worked very hard ensuring that we have robust assays that are accurate and precise. And I think one of the things we know very well about assays in clinical studies is 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 as these assay centers 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.

Speaker 2

So each time we run these analyses, we're doing them on as many samples as it 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 it's very early stage or pre symptomatic H2 patients, mutant Huntington protein is not detectable in a CSF because it's incredibly the concentration is incredibly low. We're talking about picomolar concentrations and maybe even lower.

Speaker 2

As we move into the Phase 2 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. Of course, the benefit now happens in Stage 3 patients is those are patients that, of course, are going to be a bit further in their progression and will be will likely have much higher baseline in Huntington protein levels that will make that sensitivity issue really not an issue.

Speaker 2

Thanks so much.

Operator

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

Speaker 14

Thanks so much for fitting me in. So I wanted to ask since it's been a while since Kuvan and Pegvalier were approved, I was wondering whether for ceptiaparin you've been able to establish with the FDA that data focused on fee lowering will be sufficient and that clinical outcomes assessments will be required for approval in PKU? And then I have a follow-up.

Speaker 2

Yes, Joe. Obviously, one of the most important things we did prior to commencing the Phase 2 study is to make sure we have full alignment on the study design, including the primary endpoint of fee reduction. I think traditionally, if you look at the FDA, when they have made a decision on approval based on something that doesn't change with time, it actually gives them confidence that they can understand that they can interpret your study results in a meaningful way. So we of course made sure that there was alignment on fee as the endpoint, fee 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 specifically significant and much greater magnitude than we've seen with previous oral therapies.

Speaker 2

So I think that it becomes very easy for them to see the not only statistically significant highly clinically meaningful benefit that we've been able to demonstrate in the ASCENDI trial. And of course, one of the elements of the pre NDA meeting was ensuring that we had the safety and efficacy data that's necessary to support that NDA submission and the answer was yes. Yes, we do.

Speaker 14

Okay. And then since strong patient advocacy seemed to be key for SKYCLARIS 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 LUTIQ 1?

Speaker 2

As I mentioned earlier, Joe, I think the Friedreich ataxia community led by the Friedreich 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 this therapy is developed and developed successfully for the treatment of Friedreich ataxia patients. I'm proud to say that we have partnered with Syrah since the beginning of the clinical development of petikwin ongoing 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. And quite frankly, the work that they help lead with the physician community and research community on demonstrating the importance of upright stability for pediatric and adolescent ambulatory patients. So I can probably say that they've been a part of ours and we think that's been an incredibly important part of the vatikinone journey and we think it will continue to be that partnership will continue to be an important part as we look forward to submit an NDA.

Speaker 3

Great. Thank you.

Operator

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

Speaker 2

I just want to thank everyone again for joining the call today. As we 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

And thank you all for participating. You may now disconnect.

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Earnings Conference Call
PTC Therapeutics Q4 2023
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