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

Good afternoon, and thank you for joining us today to discuss PTC Therapeutics First Quarter 2024 Corporate Update and Financial Results. I'm joined today by our Chief Executive Officer, Dr. Matthew Klein, our Chief Business Officer, Eric Pauwels; our Chief Commercial Officer, Kylie O'Keefe; and our Chief Financial Officer, Pierre Gravier.

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

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

For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent quarterly report on Form 10-Q and annual report on Form 10-K filed with the Securities and Exchange Commission as well as the company's other SEC filings. .

We will disclose certain non-GAAP information during this call. Information regarding our use of GAAP to non-GAAP financial measures and a reconciliation of GAAP to non-GAAP are available in today's earnings release. .

With that, let me pass the call over to our CEO, Dr. Matthew Klein.

Matt?.

Thank you, Jane. Good afternoon, and thank you all for joining the call. I'm pleased to share with you our first quarter 2024 financial results and to provide an update on the progress of our development programs.

As we have discussed, 2024 will be a year of execution for PTC, with a number of important and value-inflecting milestones throughout the year..

We are off to a great start with strong revenue and achievement of all of the planned first quarter regulatory and clinical milestones. .

Starting with commercial performance. We had a great quarter driven by execution across the entire commercial portfolio. First quarter revenue totaled $210 million and DMD franchise revenue was $161 million.

The first quarter DMD revenue resulted from our team's efforts to ensure that we optimize revenue during the time that Translarna remains authorized in Europe. At this time, the European Commission has not yet adopted the CHMP opinion to withdraw Translarna authorization. And thus, we will continue to commercialize Translarna across Europe.

Eric and Kylie will provide additional details on our commercial performance shortly. .

We had a number of important regulatory achievements in the first quarter. As planned, we submitted the marketing authorization application for sepiapterin to the EMA and we remain on schedule to submit the NDA for sepiapterin no later than the third quarter.

The European MAA submission is an important step towards our planned global launch of sepiapterin as we bring a potential new standard of care to PKU patients around the globe.

As emphasized recently by Lisa Milberg, the Executive Director of the National PKU Alliance, the vast majority of PKU patients are not served by the currently available PKU therapies, and there is a great deal of enthusiasm in the PKU community for sepiapterin based on the data generated to date, including the reported patient experience in diet liberalization.

.

In the first quarter, we also submitted the BLA first data, and we aligned with the FDA on an NDA resubmission for Translarna and an NDA submission for vatiquinone for treatment of Friedreich ataxia.

The NDA resubmission for Translarna will be based on the placebo-controlled results from Study 41 and data from the STRIDE registry which confirmed long-term benefits of Translarna and slowing time to loss of ambulation. We expect to submit the NDA in mid-2024.

The vatiquinone NDA will include results from the 72-week placebo-controlled portion of the MOVE-FA trial, along with data from those trials long-term open-label extension. We expect to submit this NDA in late 2024..

Turning to our development programs. We plan to share interim results from the PIVOT-HD study of PTC518 in Huntington's disease patients in the second quarter. This data update will include 12-month biomarker and clinical results from the initial cohort of approximately 30 subjects on whom we shared data last summer.

Specifically, we will share data on blood Huntington protein lowering, CSF mutant Huntington protein lowering, volumetric MRI changes and SL levels as well as data on several clinical scores including the total motor score, total functional capacity and CUHDRS.

These 12-month data will allow us to understand the longer-term safety and tolerability profile of PTC518 as well as to identify favorable early signals of CNS activity on disease biomarkers for clinical endpoints..

The second quarter update will also include 12-week results for a larger number of Stage 2 and Stage 3 subjects, including blood Huntington protein changes. .

Lastly, we completed enrollment in the CardinALS registration-directed trial of utreloxastat in ALS patients and remain on schedule to report top line results in the fourth quarter of this year.

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

Given the recent changes in the therapeutic landscape for ALS, positive results from the CardinALS study could enable utreloxastat to address the significant unmet need of ALS patients. .

In closing, I am proud of our team's execution in the first quarter. We achieved all of our planned objectives and remain on schedule to achieve the many important expected milestones in 2024. .

I will now turn the call over to Eric and Kylie to discuss our commercial performance.

Eric?.

Thanks, Matt. Our global customer-facing team has kicked off 2024 on a strong footing and has delivered $178 million in revenue for our 5 marketed products. Our team is focused on growth as well as diversification within our current commercial portfolio and on executing launch preparations for Upstaza in the U.S. and for sepiapterin globally.

Our global DMD franchise had a robust quarter, while our geographic expansion continues to progress in Latin America and the Middle East and North Africa, and our future growth markets in the Asia Pacific region. .

We delivered revenue of $161 million, which resulted from our strategies to continue to maximize Translarna revenue in Europe and to successfully protect the Emflaza business in the U.S. For Translarna, we achieved $104 million in revenue this quarter.

The team continued to work to ensure that Translarna patients in Europe continue to receive treatment. Evaluations of local country pathways and named patient sales for continued access to treatment are ongoing. .

Now turning to Emflaza. Quarterly net revenue was $57 million, which reflects our strategy to protect the brand in the face of initial generic entry. Robust Emflaza sales were driven by continued brand loyalty from health care providers and patients with a significant number of new patient starts on Emflaza. .

We continue to work closely with health care providers, payers, specialty pharmacies and advocacy groups to reinforce the benefits and the value of Emflaza while reemphasizing our exclusivity for 2- to 5-year-old DMD patients. .

Now I will ask Kylie to update the progress of our current and future new product launches.

Kylie?.

Thanks, Eric. We continue to plan for our global launch of sepiapterin following the recent submission of the MAA in the EU and the planned NDA submission to the FDA later this year as well as additional regulatory submissions in Brazil and Japan in 2024.

As Lisa Milberg, the Executive Director of the National PKU Alliance recently stated, there is a significant unmet need for PKU patients. There is widespread recognition amongst metabolic specialists, geneticist, dieticians and PKU patients of the potential of sepiapterin to meet these significant unmet needs..

As we saw from numerous patients in the AFFINITY trial, classical PKU patients as well as those unresponsive to and fully controlled on Kuvan could potentially do significantly better on sepiapterin.

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 phenylalanine levels in the ongoing affinity long-term extension study. .

PKU patient advocacy groups around the world have shared that PKU patients have been waiting for a therapy like sepiapterin that combines efficacy through reduction and a potential ability to liberalize their incredibly burdensome fee restricted diet to improve their quality of life.

We continue to believe in the potential $1 billion plus global opportunity. .

Now turning to Upstaza. The first and only approved gene therapy infused directly into the brain where we continue to see transformative results. As Matt mentioned, we submitted our BLA to the FDA in March and launch preparations in the U.S.

are well underway, and the customer-facing team is incredibly excited to bring this much needed treatment to AADC patients in the U.S..

In Europe, we treated new patients in France and the U.K. as well as treating new cross-border patients in the quarter.

In February, data from the GT-002 study was presented at the IAS PMD Congress that showed significant uptake of CSF, HVA and F-Dopa up to 8 weeks after administration of Upstaza, translating into dopamine production and improvements in common symptoms such as hypotonia.

Globally, patient identification, treatment center readiness and access and reimbursement discussions continue to advance as we prepare for additional filings and regulatory approvals. .

Moving to Tegsedi and Waylivra in Latin America. We continue to make excellent progress across this franchise with growth in both patients identified and patients treated across the region. In Brazil, we completed delivery of the new group purchase order for Waylivra, and anticipate receiving a group purchase order for Tegsedi shortly.

Our strategy for geographical expansion continues with additional regulatory filings planned and approvals anticipated for both products. .

In conclusion, coming off a robust first quarter, we have set a strong trajectory for 2024 and are well positioned to continue to deliver and diversify our portfolio across our geographies as well as to execute our global launch strategies for sepiapterin and Upstaza. I will now turn the call over to Pierre for a financial update.

Pierre?.

Thank you, Kylie. I'll now share the financial highlights of our first quarter of 2024. Please refer to the earnings press release issued this afternoon for additional details. Beginning with top line results. Total revenue for the first quarter was $210 million, including DMD franchise revenue of $161 million. .

Starting with the DMD franchise. Translarna net product revenue in the quarter was $104 million, while Emflaza net product revenue of $57 million. .

Moving to Evrysdi. First quarter global revenue of about USD 400 million was achieved by Roche, earning royalty revenue of $31 million for PTC.

Non-GAAP R&D expense was $107 million for the first quarter of 2024, excluding $9 million in noncash stock-based composition expense compared to $180 million for the first quarter of 2023, excluding $15 million in noncash stock-based compensation expense.

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

Non-GAAP SG&A expense was $64 million for the first quarter of 2024, excluding $9 million in noncash stock-based compensation expense, compared to $73 million for the first quarter of 2023, excluding $14 million in noncash stock-based compensation expense.

This expense reduction reflects lower employee costs as a result of the reduction in the workforce. Cash, cash equivalents and marketable securities totaled $885 million of March 31, 2024, compared to $877 million of December 31, 2023.

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. And I will now turn the call over to the operator for Q&A.

Operator?.

[Operator Instructions] Our first question comes from the line of Kristen Kluska with Cantor Fitzgerald. .

On PKU, I know you've gone at length multiple times with us talking about specific segments of where the highest unmet need remains. But I'm wondering, initially, if you think there's a specific market segment where you'll see uptake being the strongest.

So one thing we weren't initiating that our [indiscernible], for example, is a really critical market. .

Kristen, thank you very much for the question. We have talked a lot about how the strong data set both from AFFINITY as well as from the long-term extension, including the tolerance data really position us well to address all of those key market segments.

And that's why we really see this as such a large opportunity and we talked about it was being a $1 billion-plus opportunity. I'll let Kylie go into a little bit more detail about what we see as sort of the initial segments that we're positioned to penetrate. .

Yes. Thanks, Matt, and thanks, Christian, for the question. I think as Matt highlighted, there truly is an opportunity across all the different segments. And I think in the near term, immediately post launch, I think we are going to be looking at a number of key segments to penetrate quickly.

I think one of the opportunities, as we've talked about in the past is therapy naive, so that includes patients that have classical PKU, high unmet medical need, also those that have previously failed on Kuvan and those that are poorly controlled. .

And I think we've also talked about Kristen in the past, as KOLs have highlighted. We have Ania Muntau highlight this on the deep dive we did last year.

But since then, we've heard a number of other KOLs also highlight this, the importance of even those on Kuvan that could have a deeper reduction in Phe levels because that really means something to patients and their ability to be able to deepen that Phe reduction allows them to look at potentially liberalizing their diet, and that's truly important.

So it's hard to sort of pinpoint a particular segment, but we will be looking at sort of those key segments in the near term, and that's why we believe we're able to achieve the $1 billion. .

Okay.

And I remember at your deep dive, you had a nice map that talked about some of the key regions and where there's already patients identified that either don't respond to one of the available therapies or for whatever other reasons, they were available, but I'm wondering what work you've done around Europe as well as Japan and Brazil as you think about those filings and upcoming decisions?.

Yes, absolutely. We've done consistent work across all the different regions. As we've talked about, we have existing commercial infrastructure in place and those teams are ready to go. So they're out there.

They're visiting the treatment centers of excellence, they're getting to know the patient communities and upon launch, they'll be ready to execute upon those patient segments. So we have similar information that's being collected across all of the different markets. And that's what we're also collecting.

But in addition to that, there's a substantial market pull. So there's people coming to PTC gearing up and wanting the drug. So it's coming from both directions. .

Our next question comes from the line of Eric Joseph with JPMorgan. .

Just picking up on your opening comments on the pending European Commission decision for Translarna. I guess we were expecting a potential update earlier in the month.

Do you have any visibility as to when the EC might come to with his decision? And whether they're perhaps reconsidering CHMP's recommendation in light of perhaps regulatory progress with FDA? And then maybe just following up on that.

If Translarna remains authorized, how should we be thinking about sequential performance in the second quarter to the extent you saw sort of advanced pull-through last quarter?.

Thanks very much for the question, Eric. You highlighted the obvious, right? With the CHMP opinion in January, typically, it would be 67 days following that opinion that the European Commission would adopt that opinion and Translarna would have been withdrawn. That has not happened.

We remain fully authorized as we talked about as some business as usual in terms of commercializing Translarna in Europe. We have been notified by the commission that they would be leading this week to discuss the matter in a live meeting. Obviously, we're in a little bit of a -- a lot of an unprecedented situation here.

But considering that Translarna has a strong data record of efficacy and safety and considering the significant unmet medical need for nonsense mutation patients in Europe with Translarna be withdrawn..

The tremendous outcome from the patient and the physician community, it may not be that surprising that the commission is looking at this very closely. Obviously, we'll wait further update until we hear, we'll continue again to make sure Translarna available to as many patients as possible.

And our team are working to do that, and we look forward to the opportunity to continue to bring the therapy to patients as long as we can..

In terms of your second question, which was on what we see in terms of impact to revenue, look, the revenue performance in the first quarter was expected based on what we've talked about, based on the fact that we said for Translarna in Europe, it would be business as usual while it was authorized.

As Eric mentioned on the call, we had a number of strategies in place in the U.S. to protect the brand and protect Emflaza and protect that business. Those strategies will continue. The efforts for Translarna will continue through this quarter and if there is a need to update our revenue guidance we will. .

Next question comes from the line of Kelly Shi with Jefferies. .

I'm so curious for the ALS trial, you mentioned the MOA of utreloxastat is through inhibiting proptosis, wonder what kind of a genetic biomarker associated with proptosis in ALS patients? And do you expect more prominent treatment outcome in a subgroup of ALS patients?.

Kelly, thank you very much for the question. Theraposis is a pathway of a relatively recently described pathway as inflammation, cell stress and cell death that is increasingly being linked to neurodegenerative diseases, including ALS.

And what is important about this is it's not related to any specific genetic talk about what really a common response pathway in ALS. And that's why our trial with utreloxastat enrolled both genetic and idiopathic ALS patients.

So this is one advantage of this approach is that we're targeting objectively common to any genetic or nongenetic cause of ALS. .

Our next question comes from the line of Sami Corwin with William Blair. .

I was wondering if you could provide any additional color on how much the EU contributed to Translarna revenue this quarter? And then have you heard any feedback from U.S.

physicians, patients, et cetera, on their perception of the Translarna and the [indiscernible] data and kind of with their view of what the commercial potential might be in the U.S.?.

Thank you very much for the questions. I'll just make a brief comment, and then I'll turn it over to Kylie to give a little bit more detail. Certainly, on your second question, there's given the unmet need for noncompletion of DMD patients in the U.S.

and what's known about Translarna in a number of patients have been on Translarna for years, there's a great amount of anticipation for the potential availability of Translarna with an FDA approval. .

And similarly for vatiquinone for pediatric patients, there's a significant remaining unmet need and it's not well appreciated in the physician expert community as well as the patient community that the data that we've collected by FDA demonstrating that important significant effect in upgrade stability and what that means in terms of delaying time loss of ambulation is incredibly meaningful for patients and therefore, there really is a significant amount of interest for vatiquinone [indiscernible].

Kylie, I'll turn it over to you for more color on revenue. .

Yes. Thanks, Matt, and thanks, for the question. I think starting with your first question, Sami, around the contribution from European revenue for Translarna, it's pretty consistent with the first quarter of last year.

We've shared that it represents around 45% of total revenue, and it's pretty consistent when you look at Q1 of this year to Q1 of last year. So as Matt said earlier in his comments, the plan going into the quarter was to continue to ensure patients have access to Translarna while it remains in the market.

And I think the team has done an incredible job in executing upon that plan. So contribution is about consistent..

Jumping to your second question around Translarna in the U.S. and perception there and also vatiquinone in FA. I think what Matt said is absolutely accurate. I think starting with Translarna, there's still nothing available for nonsense mutation DMD patients. And so there's a high unmet medical need there.

And then when you look at FA, there's nothing available for pediatric patients. And I think physicians are starting to get to understand how SKYCLARYS fits into the marketplace in the older patients. And there's still a place for vatiquinone in those older patients as well..

So across the board, we've seen very positive feedback. Physicians are very well versed on Translarna in the U.S. As that said, there's a number of patients that are on the drug. And then as we're engaging with the community on FA, there's positive feedback coming there, too. .

Our next question come from the line of Joseph Thome with TD Cowen. .

Maybe on the Huntington study. Looks like maybe this might be the first time we're really committing to some of those functional measures, the TMS, TFC and CUHDRS.

Maybe what are your expectations for efficacy on those points, the follow-up time that we're seeing in the Q2 data, going to be long enough to show benefit on these measures, do you think? Or how should we interpret those data when we see them?.

Maybe second question, just on the AADC gene therapy.

Can you talk a little bit about reimbursement progress in Europe? And maybe what are you learning there that you can apply to the U.S.?.

Thanks for the question, Joe. We are very much looking forward to the HC data readout later in the second quarter. As we talked about, this will be our opportunity to share 12-month data from that initial group of patients on whom we share 12-week data last summer.

And this will allow us to, for the first time, get a glimpse at CNS biomarker effect, including Huntington protein levels in the CSF, NFL levels, brain volumes, and as you pointed out, clinical scales, looking at the total motor score, and total functional capacity. .

I think from our standpoint, a home run on the data would be to be able to see continued safety and tolerability after 12 months and then be able to see some signal of CNS activity, whether that's on biomarkers or on any of the clinical scales.

And given the small number of patients, I think we're really looking for a signal or a trend here, given the duration of 12 months. And then we said this is approximately 30 patients. And so that's how we're really looking at success here.

Safety tolerability is our signal either on biomarker and/or clinical scores that we're having CNS activity, I think patients. And let me turn it over to Kylie to give some more color on AEC reimbursement and how that's setting the stage for the U.S. .

Yes, absolutely. So we continue to see progress with pricing and reimbursement negotiations across Europe, and we've continued to have favorable agreements come into place and we'll be shortly treating patients in those additional countries. As we talked about in the quarter, we treated additional patients in France, in the U.K.

and additional patients in -- through cross-border health care. And so that's continued success in this space. If you talk about learnings and how we sort of think to the U.S.

market, I think one of the things that we've walked away with from some of these discussions is there's a recognition of high unmet need in AADC and with the absence of standard of care from a disease-modifying point of view, there are no treatments available..

There's a recognition of an ultra-orphan condition and therefore, small budget impact and a recognition of the transformative results that come with the treatment of Upstaza. And so put together, this allows us to be able to move forward with favorable pricing and reimbursement negotiations. And we do expect that to carry across into the U.S.

upon launch. .

Our next question will come from the line of Brian Abrahams with RBC. .

This is John for Brian.

So back on Translarna, can you talk more about the buying pattern you're seeing for Translarna in Europe in recent weeks? If European Commission does decide to follow CHMP opinion, are you seeing anything on the ground that might suggest that withdrawal from the channels may be more gradual or on the orphan side, even more rapid than you're expecting?.

Yes. Thanks for the question, Joe. Look, we are seeing, as I said, really business as usual. Their prescriptions and numbers are really unchanged here. And it goes without saying that the patients and the physicians want to take advantage of every day that Translarna is on the market, and we expect that fully to continue to be the case.

Our teams, as Kylie pointed out, are focused on ensuring that happens. So we're ensuring that patients can access to therapy.

Of course, we've also been working in the background to put mechanisms in place to leverage mechanisms that might be available on a country-by-country basis to continue to provide Translarna in the event that the EC Commission adopts the opinion of Translarna job. .

Got it. If I could squeeze one more.

Are you scheduled to meet with the FDA regarding [indiscernible] anytime soon? Just wondering if you will get a visibility on whether you can file in parallel to the carcinogen study or not?.

Yes. We had -- Joe, we had the pre-NDA meeting last year with the agency last fall, and it was very clear that every other part of the package is there and in place, that safety efficacy data would support our NDA and support approval on review. And the one outstanding matter was the completion of that carcinogenic study.

We've mentioned that we expect that study to be done in June. We don't expect to have a formal meeting with the agency. We did say that we plan to contact them to discuss timing of the submission relative to the completion of that study.

We said that we still remain on track to submit in Q3, but we maybe bring that in a little early into Q2 based on that correspondence. But we don't expect that will be a formal meeting. .

Our next question comes from the line of Gena Wang with Barclays. .

I just have very quick questions. The first one is regarding Translarna Europe status. Based on your discussion with EMA, when do you expect Translarna will be withdrawn in Europe? And then second question is regarding sepiapterin in PKU. I think you mentioned that you wanted to target initial patient population that could be one part is a classic PKU.

Can you help us understand how our understanding that the sepiapterin is a precursor cofactor and across the PKU usually does not have any phenylalanine hydroxylase.

So basically does not have an enzyme like how would the sepiapterin will be helpful in classic PKU patient population?.

Thank you for the question, Gena. As we've discussed regarding your first question on the status of Translarna in Europe, the -- following the opinion in January, typically, the European Commission would have adopted that opinion within 67 days. Clearly, we're sitting here late in April in that adoption, the opinion has not occurred.

We had to notify that the commission was planning to meet this week to discuss the matter.

And I assume they're taking into consideration the current status in Europe, the lack of alternative therapies for patients with nonsense mutation DMD, the data which supports safety and efficacy of Translarna and the outpouring of support for the authorization remaining intact from the patient and physician community across Europe. .

So I think they're looking at the matter closely. We expect to have an update in the near future. And as we said, until that time, [indiscernible], using every day to continue to ensure that patients have access to Translarna. .

On your second question regarding classical PKU, I think there's sometimes a misunderstanding if the definition of classical PKU is basically patients, children and adults who at some point in their life have a documented phenylalanine level of greater than 1,200 micromolar per liter.

They're that going to be at any point in time or could they be lower, but they get a diet control. A very small number of those patients have what's called homozygous no mutation. That means they have on both on no mutation that prevents them from having phenylalanine hydroxylase enzyme. But that is a very small minority of patients. .

And therefore, the remainder of the classical PKU patients have functional enzyme. Obviously, it's severely affected by the mutation and has no function. Sepiapterin is, as you pointed a precursor of BH4, which is the cofactor for the enzyme.

It also has a second function, which is a chaperone function, which stabilizes the confirmation of the PAH enzyme. And therefore, we believe that's why we're seeing what we've seen in classical PKU patients in our studies, which is a significant fact..

In fact, in the AFFINITY trial in the subset of classical PKU patients, we had a mean phenylalanine reduction of 69%, that is actually a greater magnitude of production than was observed in the overall population. So certainly, signifying that sepiapterin can play an important role for these patients.

Similarly, as we've included -- we've seen patients going to the open label extension and participate in Phe tolerance protocol, we are seeing classical PKU patients that is defined as classical PKU patients being able to mineralize their diet and maintain control of phenylalanine.

So all of that really speaks to the importance of sepiapterin and a potentially really important role to have all patients with PKU, including those classical patients who are tend to be the most severe. .

Our next question comes from the line of Jeff Hung with Morgan Stanley. .

For sepiapterin, can you just remind us of the data that's collected in patients under 2 years old? And are there plans or time lines for starting that? And then given the meaningful effects on phenylalanine, like what would you give you confidence for results to translate into those younger patients?.

Thanks, Jeff. We did include patients under 2 in the AFFINITY study. Now they went through the initial run-in phase and we had patients who had a greater than 30% reduction in the run-in phase. But the regulatory authorities wanted those very young patients not to be randomized, but to go directly into the open-label extension study.

So we have patients who started in AFFINITY who were under 2, and we've actually had additional patients that we've enrolled directly into long-term extension. .

So we're getting data in a number of patients under the age of 2. And what we're seeing is exactly what we're seeing in patients over the age of 2. We're seeing safety and tolerability and also efficacy in terms of reducing phenylalanine.

So again, the data continues to support the potential benefit of sepiapterin in the full range of PKU patients, both classical and nonclassical and then patients of all ages. .

Our next question comes from the line of Joseph Schwartz with Leerink Partners. .

This is Jenny on for Joe. I was wondering if you could just talk a little bit more about the 4Q readout for ALS. I think you've said in the past that the study could be registrational.

Can you give us an idea of what regulators will be looking for to support that? And can you kind of give us some insight into what a clinically meaningful change in ALS functional rating scale would be?.

Thank you very much for the call, for the question rather. So we are designed the CardinALS study to be, as you said, registration direct, and this came from our feedback with FDA, both in terms of relation of the study being roughly 6-month study, placebo controlled and the endpoint strategy, having the primary endpoint being the ALSFRS scale.

We define success here as a statistically significant benefit on the primary endpoint, which on the ALSFRS scale, that has traditionally been the threshold for agency approval..

We powered the study to have what we believe would be a clinically meaningful effect, which is roughly 2.5 point difference between the treatment and the placebo group. And we designed the study to be well powered to detect that. So we believe if we're able to have statistical significance on the ALSFRS.

We also, of course, have secondary endpoints capturing other important aspects of the disease, including mortality, including respiratory function, where we, of course, will look for supportive data of that ALSFRS scale, we believe that will position us to advance for approval in the U.S. .

Our next question comes from the line of David Lebowitz with Citi. .

To this point, have you really significantly felt the presence of generic Emflaza or of a recently approved of [indiscernible]. .

David, thank you very much for the question. As we talked a bit about on the call, we put a lot of strategies in place to preserve the Emflaza market, even in the patient's competition. Let Kylie talk a little bit more about what we're seeing in terms of dynamics. .

Yes, absolutely. I think, David, the answer -- the quick answer to that is no. And I think that's a testament to the strategies that the team has put in place to protect the business. And as we said in the first quarter, they've been executing upon that.

I think what's really been a strong message for us is the continued new patient starts, and we've seen an incredibly large number of new patient starts in the first quarter. And I think that's a testament to the loyalty to Emflaza and the continued benefit seen by both patients and physicians. .

Next question comes from the line of Danielle Brill with Raymond James. .

I have 2 brief ones. First, to clarify on Translarna status in the EU. Is it possible that the delay in the EC ratification of the CHMP opinion is procedural? Or was this meeting this week specifically called because the EC is considering not ratifying the decision? And then on the second question is about [indiscernible] in the EMA.

I believe EMA feedback on the feasibility of a conditional approval was expected in 1Q.

Any updates on that front?.

Yes. Thanks, Danielle, for the questions. On your first question, the typical procedure is 67 days. Usually, this is done by writing. It's usually written agreement across the member states, and that then allows for the ratification by the EC.

That procedure, we know was a pause instead a live meeting was called for discussion, what the exact nature of that discussion was what motivated that discussion we can't say. What we can say is the typical EC adoption occurs within 67 days we're clearly beyond that time point. It's typically a written procedure. They're having a lot of meetings.

So there's a lot of things that are going on now that are really atypical..

What that means in terms of the ultimate EC decision, whether to adopt the opinion, then the matter back to the CHMP, whatever that the decide. We can't say what we can say is we're far beyond what we had expected and what was typically observed and the procedure has not gone according to what typically happens.

In terms of your question on vatiquinone, we had previously shared that we had got a feedback from the EMA from -- we have gone through the scientific advice procedure, they did not indicate that they thought that the move that Phase study could support conditional authorization at this time. We're looking forward to further discussions with them.

And of course, on the FDA side, we have a different experience where after we had a recent meeting with the FDA in Q1. We are moving forward with the NDA based on [indiscernible] open-label extension data book from the older study performed a few years back as well as from the MOVE-FA long-term open made extension. .

Our next question comes from the line of Tazeen Ahmad with Bank of America. .

One on FA. Can you just talk to us about the patient population, how different it might be in the U.S.

versus EU in terms of sizing? And then secondly, for Huntington, based on the conversations that you've been having so far with the agency, what's your level of confidence that a biomarker can be used at least as an end point, maybe not the sole endpoint? Is that topic has been brought up in recent discussions?.

Thank you very much for the questions, Tazeen. In terms of populations for FA, it's roughly similar sized population prevalence in the U.S. and in Europe.

Clearly, in the -- in both territories, there's nothing indicated for patients under the age of 16, and we talked a lot about how the data from FA really supports the important treatment affecting that population with regard to delay in time of lots of ambulation..

And obviously, that has applicability beyond just the under 16-year-old patients, the effects we observed in our [indiscernible] of ambulatory patients with Friedreich ataxia. So population is roughly the same size.

We see an ability to fill the unmet need in the pediatric population, but also potentially have an important effect for all ambulatory patients regardless of their age. I believe your second question was on biomarker and HD as an endpoint.

Is that correct?.

That's right. .

So the -- we have not had discussions yet with the agency regarding biomarker accelerated pathways and biomarkers role in the endpoint strategy.

I think we've clearly seen that the agency, particularly the neurology division has been looking to leverage the accelerated approval pathway for neurodegenerative diseases like Huntington's disease, like Alzheimer's disease, we're collecting that definitive efficacy data in a Phase III trial takes many, many years.

I think the challenge we have in HD, of course, is there's no precedent yet for what that accelerated approval biomarker would be. We believe that the PIVOT-HD study offers several important biomarkers, including peripheral Huntington mRNA particularly with the systemically administered drug. .

And obviously, we talked a bit about the potential for NFL levels, which has been used in the case of the first in for ALS and then also things like Huntington protein and CSF.

So what we plan to do is collect data and begin to have discussions with the agency once we have data in hand of what a path using biomarker data or what would be as you asked, the role of biomarker data in establishing the efficacy of the therapy for Huntington's disease, but we think there certainly should be an appetite just based on the agency's recent activity.

.

Our next question comes from the line of Paul Choi with Goldman Sachs. .

I have 2, and my first is just with regard to the CardinALS trial and ALS. In the wake of the recent PHOENIX study results from Amylyx.

Have you either implemented or contemplated any study design changes or changes to the statistical plan just based on the recent PHOENIX results and just what your thoughts are there? And then second, just a follow-up also as well on HD and PTC518.

Can you maybe just comment on the -- with regard to your regulatory discussions just on the safety side for U.S. sites and any progress that may have been made there. .

Thank you very much for asking the question. Your first question regarding CardinALS. When we -- the FDA has been quite clear on what they want to see in terms of analytical approaches for the ALSFRS. They're very interested in understanding changes in score as a continuous variable.

They've also been interested in understanding mortality and the time to mortality.

And specifically, we talked about wanting to understand the difference in scores between treatment and placebo and then also implementing something called a joint rank test, which is a way of analyzing together both the change in ALSFRS score as well as patients who may have died and the information of their timing of death following enrollment..

So we've, of course, taken the agency's guidance to ensure that our analysis plan was consistent with what they want to see.

And that doesn't change with anything regarding as being expected and we work closely with the agency in designing the study to ensure that it would be registration directed and ensuring that we have the appropriate analysis plan so that when we get the results, if they're positive, that we'd be well positioned to advance the drug towards approval. .

Regarding your question on safety data from PIVOT-HD and discussions with the agency. As we prepare for the second quarter data disclosure, we will then have the safety data that the agency has asked to review in order to lift the partial hold. So we look forward to submitting those data to the agency when available.

Just as a reminder, they had asked us following the last data review of 12-week data to provide them a 6-month data on the sufficient number of subjects that would confirm what we've seen at 12 weeks..

Well, clearly, we're going to be in a position to provide the agency not only 6-month data, but 12-month data on a number of patients. And as we've shared, we're continuing to see the drug to be well tolerated.

So we look forward to putting that data package together, submitting it to the agency and hopefully to lifting a partial hold in the near future. .

And at this time, I'm showing no further questions. I'd like to hand the conference back to Dr. Matthew Klein for closing remarks. .

Thank you all for joining the call today. Clearly, we're very excited about the outstanding performance in the first quarter, both in terms of revenue and execution across all of our programs. We are well positioned to continue this success throughout the remainder of the year and look forward to updating you all as we move forward.

So thank you all and have a good evening. .

And this concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone, have a wonderful day..