Ptc Therapeutics, Inc. Q3 FY2025 Earnings Call

Thank you for joining us. Welcome to PTC Therapeutics Third Quarter 2025 Earnings Conference Call. Today's call is being recorded. I will now hand over the call to Ellen Cavaleri, Head of Investor Relations. Please proceed.

Good afternoon, and thank you for joining us to discuss PTC Therapeutics' Third Quarter 2025 Corporate Update and Financial Results. I'm joined today by our Chief Executive Officer, Dr. Matthew Klein; our Chief Business Officer, Eric Pauwels; and our Chief Financial Officer, Pierre Gravier. Today's call will include forward-looking statements based on our current expectations. These statements are subject to certain risks and uncertainties, and actual results may differ materially. Please review the slide posted on our Investor Relations website in conjunction with the call, which contains information about our forward-looking statements, our most recent quarterly report on Form 10-Q and annual report on Form 10-K filed with the SEC as well as our other SEC filings for a detailed description of applicable risks and uncertainties that could cause our actual performance and results to differ materially from those expressed or implied in these forward-looking statements. Additionally, 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. I will now pass the call over to our CEO, Dr. Matthew Klein.

Thank you all for joining the call today. I'm excited to share our outstanding third quarter results. The highlight of the quarter was the initiation of the Sephience global launch in Europe and the United States. As we have discussed, we expect Sephience to be the foundational product for PTC's sustainable growth and near-term path to profitability. Overall, third quarter revenue totaled $211 million, which includes the first revenue from the Sephience launch as well as continued contributions from our DMD franchise. With this strong quarter performance, we are narrowing our 2025 full-year revenue guidance to $750 million to $800 million, the upper end of the initial revenue guidance range. The Sephience launch is off to a great start. As of September 30, Sephience generated $19.6 million in revenue. This includes $14.4 million in the U.S. and $5.2 million ex-U.S. We have seen a great deal of enthusiasm upon launch with 521 patient start forms received from U.S. centers as of September 30. We have received start forms for patients of all ages, including adults, all disease severities, including classical PKU and various treatment histories, including patient switches, previous treatment failures, and treatment-naive patients. While these are still early days, the fact that we are seeing demand from all key patient segments underscores the significant unmet need for PKU patients and the potential for Sephience to become the standard of care, providing a safe and effective therapy for both classical and nonclassical PKU patients. While we are presenting results today through September 30, the results for the month of October show sustained momentum. We are encouraged by the strong initial numbers and broad interest from the physician and patient communities. To sustain broad uptake, our teams are continuing to gather data to help reinforce the highly differentiated Sephience profile. At the International Metabolism Meeting in September, we presented the results from the AMPLIFY head-to-head study comparing phenylalanine lowering between Sephience and BH4. In this crossover study, Sephience treatment resulted in an average of 70% greater reduction in phenylalanine levels compared to BH4, demonstrating once again the robust and clinically differentiated benefits Sephience can provide. Additional presentations at the conference highlighted Sephience benefits on cognitive function and diet liberalization, including in the most severe patients with classical PKU or BH4 non-responsive mutations. We are also finalizing a publication on the Sephience mechanism of action, including in vitro, in vivo, and clinical efficacy data in the most severe PKU mutations, supporting the potential ability of Sephience to provide a safe, well-tolerated, and efficacious therapy for the full spectrum of PKU patients. Eric will provide additional details on the launch. I will now briefly provide an update on the development and regulatory status of our other programs. Starting with the votoplam Huntington's disease program, a meeting with FDA is planned for the fourth quarter to align on the study design for the next efficacy study as well as to discuss the data package that could potentially support an accelerated approval application. For the vatiquinone Friedreich's ataxia program, we are planning to meet with FDA this quarter to discuss potential next steps for the program. And for Translarna, the NDA remains under FDA review. Finally, we remain in a very strong financial position, ending the third quarter with approximately $1.68 billion in cash. As we have discussed, this enables us to reach cash flow breakeven as well as participate in strategic business development activities to complement our R&D and commercial portfolios. Additionally, as the company continues to build for future success, we will be hosting an R&D Day on Tuesday, December 2nd, to share progress on our research programs, including those from our splicing platform. I will now turn the call over to Eric to discuss details of the Sephience launch and our commercial performance.

Thanks, Matt. We are very pleased with the early momentum of the Sephience global launch. Our seasoned customer-facing teams are off to a strong start, leveraging their years of preparation and experience and delivering across all fronts. We are excited to simultaneously launch Sephience in the U.S. and Europe following regulatory approvals, and we are actively preparing for the upcoming launch in Japan following MAA approval anticipated in Q4. As of September 30th, Sephience global revenue reached $19.6 million and 341 patients on commercial therapy, driven by robust performances in both the U.S. and Germany. Following FDA approval on July 28th, our U.S. team made the first Sephience shipments to patients approximately 2 weeks afterwards. Through the end of the third quarter, our PTC Cares teams received 521 patient start forms from 141 unique prescribers. The response thus far from U.S. health care providers has been overwhelmingly positive with a high willingness to prescribe Sephience to a wide range of PKU patients, including switches, poorly controlled or failed therapy, and treatment-naive individuals as well as to children and adults. Many of these health care providers have shared their observations of the rapid benefits of Phe lowering and improved patient outcomes and indicated their intent to continue to prescribe Sephience to a broad spectrum of PKU patients. U.S. payer engagement continues to be positive. And our market access and medical affairs teams have met with more than 35 payers covering approximately 250 million lives. U.S. payers continue to recognize the highly differentiated profile and strong value proposition of Sephience. We have seen initially favorable payer policies that maintain broad access with coverage that includes prior authorizations to the label, with no or limited step edits and refills for 6 to 12 months. Although we are still in the early stages of the launch, we have seen a favorably higher commercial payer ratio and expect this payer mix to stabilize at 65-35 as Medicaid and Medicare plans finalize their policies in Q4. Likewise, the launch in Germany is off to a great start as we quickly converted compassionate use program patients that were on Sephience prior to EMEA approval onto commercial therapy. We have also received prescriptions for new patients from Germany and additional EU countries on a named patient basis and are preparing health technology assessment dossiers to secure pricing and reimbursement across many international markets with early access programs. Throughout Europe and other key markets, we see similar dynamics with health care providers prescribing Sephience to a broad range of PKU patients. Along with the positive feedback from health care providers, we have also seen a highly engaged response from the PKU patient community worldwide. Social media serves as a powerful platform to see firsthand patients' experiences with Sephience and is also a strong channel for patient-to-patient communication. Instagram and other channels, including stories and posts from patients who have started Sephience, some who are even tasting new foods for the first time. The excitement for Sephience is equally tangible at PKU community events such as the NPKUA Annual Gathering in September, where many PKU patients shared their desire for new treatment options. Our customer-facing teams continue to lead medical education programs at key congresses such as ICIEM and ESPKU in September, featuring roundtables, scientific exchanges, and investigator meetings in the U.S., Europe, and Japan, highlighting the strong clinical data of Sephience. As Matt mentioned, these activities featured new Sephience data, including long-term results from the APHENITY extension study and new data from the head-to-head study, further supporting the differentiated efficacy of Sephience. Additionally, data were presented in Japanese patients showing robust Phe lowering and safety results consistent with the global PKU population. We continue to expand the global launch with our experienced teams in key international markets. We recently received approval for Sephience in Canada, and we anticipate regulatory approval in Japan and Brazil later this year. As we have previously discussed, we will continue to maintain a narrow pricing corridor throughout this early stage of the launch. Now turning to our established portfolio, we continue to defend our DMD franchise by maintaining patients on Translarna across the majority of European markets, leveraging Article 117 and fostering brand loyalty for Emflaza with targeted programs for health care providers and DMD patients in the U.S. despite multiple generic entries. In summary, the early global rollout of Sephience is off to a great start. We are very pleased with the early results in the quarter with the U.S. being our main engine for product growth, supplemented by other key international markets that we expect to bring on board over the next 12 months. With that, I will now turn the call over to Pierre for a financial update.

Thanks, Eric. I'll now share the financial highlights of our third quarter of 2025. Beginning with top line results. Total revenue for the third quarter was $211 million. Starting with Sephience, net product revenue in the quarter was $19.6 million as of September 30. DMD franchise revenue for the quarter was $86 million with Translarna net product revenue of $51 million and Emflaza net product revenue of $35 million. For Evrysdi, Roche achieved third quarter global revenue of approximately USD 532 million, resulting in royalty revenue of $71 million for PTC. For the third quarter of 2025, non-GAAP R&D expense was $91 million, excluding $9 million in noncash stock-based compensation expense compared to $152 million for the third quarter of 2024, excluding $9 million in noncash stock-based compensation expense. Non-GAAP SG&A expense was $74 million for the third quarter of 2025, excluding $10 million in noncash stock-based compensation expense compared to $63 million for the third quarter of 2024, excluding $10 million in noncash stock-based compensation expense. Cash, cash equivalents, and marketable securities totaled $1,688 million as of September 30, 2025, compared to $1,140 million as of December 31, 2024. The third quarter cash balance reflects the previously announced purchase of 90% of our Sephience annual global net sales payment obligation of 8% to 12% owed to former Censa shareholders for approximately $225 million upfront and future sales-based milestone payments. Given the significant Sephience revenue opportunity, we expect meaningful value creation based on the transaction terms. We remain well capitalized to reach cash flow breakeven and profitability as well as pursue business development opportunities that will further enhance our commercial portfolio and expand our innovative pipeline. I will now turn the call over to the operator for Q&A.

Our first question comes from Kristen Kluska with Cantor Fitzgerald.

Congrats on an amazing start for Sephience really exciting to see that. I wanted to ask what's going to give you confidence that beyond this really strong out-of-the-gate launch, you're going to see maintained durability and that patients will be on therapy for a while.

Kristen, thank you for the question. We're also very excited about the start and are seeing a lot of what we anticipated. The highly differentiated profile of Sephience is showing uptake across all segments, including patients who have previously been on therapies, therapy-naive individuals, and even adults thought to be difficult to reach. We're consistently hearing positive feedback from physicians and the patient community regarding the response. On social media, patients are sharing experiences of being able to eat foods like hamburgers and pizza for the first time. We also have feedback from doctors about how some of the more severe patients they prioritized are responding well. One physician who was initially skeptical about Sephience's role with classical and more severe patients recently mentioned her conversion and her eagerness to try it with all her patients, which reflects a growing trend among physicians. There's broad interest in trying Sephience, and initial feedback indicates that patients are responding positively by reducing Phe levels and expanding their diets. Although it’s still early—just a few weeks post-launch—what we've observed so far is promising. We will continue to monitor the situation as it develops. In our clinical studies, we saw response rates of up to 75% among patients across the spectrum, indicating our potential to assist a wide range of patients. Ultimately, as you’ve pointed out in your research notes, patients want lower Phe levels and dietary flexibility, which will be crucial for their continued adherence to the therapy.

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

Congrats from me as well on a really strong launch out of the gate. Matt, maybe I wanted to ask you a couple of questions. So can you just talk to me about what magnitude of Phe reduction are doctors and payers looking for in order to keep a patient on treatment beyond the trial period? Maybe related to that as well, what's your expectation for the percentage of patients that are going to stay on treatment following this initial trial? And how are you thinking about guiding the Street on that particular dynamic as well?

Yes, absolutely. Thanks for the question, Tazeen. I'll give an initial response, and I'll ask Eric to provide a little bit of color. On your first question, regarding magnitude of response, we're hearing different things from different folks, right? We're hearing that for some patients, certainly those that are more severe who have never had a therapy that they could tolerate or respond to, that 15% Phe reduction could be meaningful for them, like a 20% Phe reduction. Others say we're going to look for maybe a 30% Phe reduction, which is what we used in the trial and others say it's not really a number. Are patients feeling better? And one of the exciting pieces of data we reported at the International Metabolism Meeting in Japan is that we are able to see in the clinical study that patients' cognitive function, executive function and mood are improving. That's another aspect of benefit that is not as easy to quantify, but it's another example of the kind of things that physicians would be looking for in addition to quantifiable reductions in phenylalanine. Patients report they can liberalize their diet in this overall sense that they're feeling better. So I think it's going to be a combination of factors. And again, I'll ask Eric to comment a little bit on what we're hearing in terms of the dynamics in terms of payer requests and things like that. In terms of expectations for patients to stay on it, look, it's early. It's also too early, to your third question, to provide specific guidance as we get further into the launch, we will be able to do that. But again, we've fallen back a bit on the clinical trial data which shows that we have anywhere between a 66% to 75% response rate, looking at 15% or 30% as a threshold for Phe reduction with very good adherence given the safety, the tolerability, and the ease of administration of the drug. So again, that's why we're so excited about being able to see early starts from all segments of the population because our experience has been that patients regardless of their age, regardless of their severity or previous treatment history, once they get on the therapy, it's a low burden to take and the vast majority of patients report having some benefit. Eric, do you want to provide a little bit more color on what we're hearing in terms of defining responders and staying on therapy?

Thank you, Matt and Tazeen, for the question. We are experiencing a very swift response from these centers of excellence. While it's still early, we are pleased with our interactions with payers and the adoption of Sephience by physicians. The clinical data we shared, including the APHENITY long-term extension and AMPLIFY data, has been utilized by both physicians and payers. We are witnessing a robust efficacy that manifests within days, which is important for both patients and physicians. The safety profile has been outstanding, and the ease of a once-daily oral administration is favorable for physicians. Currently, we have encountered no major barriers or significant restrictions to access Sephience from payers. Our teams have been collaborating effectively with payers, now covering over 250 million lives, and the clinical data along with the value proposition is clearly influencing these policies. Although it is still early, these policies are favorable, and we are observing physicians not only initiating prescriptions but also seeing a positive trend in refills this October.

Our next question comes from Brian Abrahams with RBC Capital Markets.

Congratulations on the launch. Could you discuss the timeline from when a new start form is submitted to when a patient receives a prescription and gains access to the drug? Additionally, how should we consider the patients who have start forms but are not yet on Sephience? Should we anticipate those patients to begin treatment in the fourth quarter?

Yes. Thanks for the question, Brian. I think, again, so far, things have been moving through quite well. Eric can give a little bit more detail, but I just want to give a particular mention to our PTC Cares team, which is our team of case managers who are incredibly experienced and provide a white glove service. Again, they were with us through all the Emflaza days, they're battle-tested through that and are really at the front lines now working with the patients, working with the physicians' offices, working with nurse practitioners, who are writing a lot of the prescriptions to really get the start forms and then quickly get those start forms processed and shepherd them through the system so we can get these patients on drug as quickly as possible. Eric, do you want to provide some detail on the timelines?

Yes. It's still early, just a few weeks in, but we are pleasantly surprised that several commercial payers have already established very favorable policies. This has significantly accelerated the process from the time of PSF to actual fill. We need to monitor any potential denials or restrictions, but so far, we haven't encountered any significant issues. Any denials we have seen are minor, and we're addressing them through medical necessity documentation. Our PTC Cares team has extensive experience managing these situations for the past 8.5 years in DMD and is resolving them rapidly. Currently, the time from PSF to fill varies by plan; for commercial plans, it could take just days, while on average it's around 2 to 4 weeks. We expect that government plans like Medicare and Medicaid will take longer to finalize their policies. However, we are already seeing reimbursements for patients on Medicare, Medicaid, and Tricare.

Our next question comes from Brian Cheng with JPMorgan.

I just want to pass on my congrats here as well. Just on the 521 start form number, how should we think about the rate of start forms that are coming in? I think earlier, you said that October, you're seeing sustained momentum. Can you provide just more color on that comment? Is that specifically referring to the pace of uptick in start forms or access with payers? What is the momentum specifically based on?

Thanks for the question, Brian. So there's not much more color we can provide because we are still very much in early days other than to say we've seen pretty consistent rates in the start forms and patients getting on drug. We'll continue to watch this as we head through the rest of the fourth quarter. Of course, there's Thanksgiving, there's Christmas, there's holidays and things, which may or may not affect the dynamics. But again, for now, things seem to be from the start until now, pretty consistent.

Our next question comes from Judah Frommer with Morgan Stanley.

Let me say congrats, too. So a couple on Sephience. I guess, first, just can you help us with the narrowing of the full-year guide? Is that solely tied to Sephience? Any other moving pieces you'd call out like the legacy portfolio coming in ahead this quarter? And second, I guess, just for those centers of excellence, I think you called out 104 of them. Can you talk maybe in numbers, how far you've penetrated those centers, what the opportunities left are within those?

Absolutely, Judah, thanks so much for the questions. Pierre, do you want to talk first briefly about guidance and what went into that? And then Eric, if you want to talk a little bit about the center of excellence and the high penetration rate we've seen?

Yes. On the guidance, I would say this is the upper end of our initial guidance, which highlights our confidence in our ability to execute on our launch and all our products. And the delta is really Emflaza. We always talked about the delta being Emflaza, and that's the main delta from the $750 million to the $800 million.

And to answer your question regarding the centers of excellence, so we have called on every center of excellence. There's 100% awareness of Sephience in each one of these centers, and we've received prescriptions from all of them. However, and what we're really interested in is how many of these centers have actually prescribed more than one. And we've seen about 2/3 of these centers having prescribed more than 1 prescription, and of course, there are some that are a little higher concentration than others. But overall, I think the centers of excellence are really bringing in patients at a nice cadence, and we're working with each one of them to increase the volume of patients to get on Sephience.

Our next question comes from Clara Dong with Jefferies.

Congratulations on a successful launch. Could you provide more details about the patient profile for new prescribers? Are you noticing any initial uptake that is more pronounced in one group compared to others? Additionally, I would like to hear your updated thoughts on the overall opportunity, considering the strong early momentum of the launch in the U.S.

Thank you, Clara, for your questions. It's still early, so it's challenging to provide specific numbers regarding the distribution across segments. However, it's important to note that we are seeing contributions from all groups. We have both treatment-naive patients and those switching from other therapies, including Palynziq. Our patient demographic spans a full age range, from as young as 2 to 3 months to as old as 79 years. This indicates that we have a wide variety of patients starting therapy. As we continue with the launch, we anticipate being able to provide more concrete metrics regarding penetration in each segment. The key takeaway is that we're successfully attracting patients from all possible segments, and the initial response has been strong. It's a bit early to offer revenue forecasts, but we've always regarded Sephience as a distinctly valuable rare disease therapy. Considering the market opportunity of 17,000 patients in the U.S., we view it similarly to a new, differentiated, safe, and well-tolerated therapy supported by strong data that can benefit the entire spectrum of those 17,000 patients.

Our next question comes from Paul Choi with Goldman Sachs.

Congrats on the early progress with the Sephience launch. I want to ask with regard to Europe, any additional coverage updates you could provide for both Germany and the other major markets there? And my second question is, as you think about sort of the outlook for '26, it looks like you guys are in a position to start generating leverage maybe ahead of Street expectations. Can you maybe just sort of comment on the trajectory of OpEx and just how you're thinking about it perhaps versus where consensus estimates are?

Yes. Absolutely. Thanks for the questions, Paul. Eric, do you want to take the first just about how dynamics are playing in Europe? And then Pierre, do you want to talk a little bit about how we're thinking about balance sheet?

Sure. Thanks for the question, Paul. In Germany, we are still in the free pricing period at this time. We will be assessing benefits and going through the MNOG process, which will take approximately another six months into 2026. This process will continue. Additionally, we have submitted HTA dossiers in most of Southern Europe. We are working in parallel with various mechanisms for early access and named patient programs that are offering prices equivalent to the German price. We have also opened markets in Southern, Central, and Eastern Europe, where those countries have their own mechanisms. We have received prescriptions in the Middle East and Latin America as well. We are navigating the named patient programs in each country, as they have specific rules. We are pleased with our progress so far. It's important to note that in Europe, this is generally a lengthy process, especially in Southern Europe, taking about six to twelve months from HTA assessment to final price negotiations.

And in terms of OpEx trajectory, I will say a few things. Number one, as usual, we will provide 2026 guidance at JPMorgan. It's a bit early. However, you should expect OpEx to decline.

Our next question comes from Joon Lee with Truist Securities.

Congratulations on the strong launch. I was surprised to learn that you're seeing switches even from Palynziq. Is that an unusual occurrence? Are there any reasons why someone on Palynziq would consider BH4 or even Sephience? Are there individuals currently on Sephience who should really be using it? Also, how quickly could you launch in Japan following approval by year-end? Where do you envision the peak opportunity in Japan compared to the U.S. and EU? I believe you mentioned at least $1 billion in the U.S. and half that amount in the EU. I'm just curious about where Japan would fit into that comparison.

Jim, thanks so much for the questions. On your first question regarding Palynziq switches, look, we're just reporting what we're seeing and hearing from the field. Again, it's early days to say what's going to be a trend and not a trend. But what we have heard from KOLs, and I think several folks who've done KOL calls have shared similarly, the realization that the physicians and nurse practitioners and care teams have that Sephience can provide significant benefit to patients with severe mutations, including patients with GPV values of 0, which is the most severe genotypes, classical PKU patients. And for them, it's the question of can we give a once-a-day, well-tolerated oral therapy that can deliver significant reductions in phenylalanine and the ability to liberalize diet. And when you consider that opportunity with Sephience, that is something that physicians want to try, certainly considering the potential tolerability profile of Palynziq. But again, this is what we're hearing, and also, again, emphasizing that we're hearing that a number of physicians are saying their intent is to try all patients on Sephience knowing not every patient is going to respond. But certainly, given the fact that severe patients, classical PKU patients can respond, can have Phe lowering, can liberalize their diet and acquire a once-a-day oral well-tolerated profile of Sephience really makes that the attractive place to start. And then, Eric, do you want to talk a little bit about the timing of Japan launch and the dynamics there and pricing?

Japan is an important market for us and this will be our first approval, which we expect to receive before the end of the year. We anticipate a broad label for Sephience, similar to what we have in the U.S. and Europe. Currently, there are around 1,000 patients with PKU in Japan. While the market size is relatively small, it holds significant value. Both Kuvan and Palynziq are approved in this market, and we expect Sephience to be priced at a premium compared to them, based on our clinical data, which would result in higher pricing than in Germany and the U.S. Our experienced team is already in Japan, prepared to promote Sephience once we receive approval. We expect to engage in discussions over the next few months to finalize the pricing, aiming to complete negotiations by the first quarter, which would allow us to launch with full reimbursement. Japan is crucial to our overall strategy, and although we anticipate approvals in other regions, we intend to maintain a narrow pricing corridor, making Japan particularly appealing.

Our next question comes from Gena Wang with Barclays.

I also wanted to congratulate you on the impressive first quarter. Regarding price, I did some quick calculations. You delivered $19.6 million and treated 341 patients, which covers two months of the full quarter. If my calculations are correct, the net price is around $350,000. Is that the right calculation? Should we consider the net price as the appropriate benchmark? This is my first question. My second question is about the average time patients are on the drug right now. Have you observed any retention of patients so far? I know it's still early, but have all the patients been doing well on the drug? Lastly, could you clarify how you recognize revenue? Is it booked monthly, and do you record revenue once the patient review occurs each month?

Gena, thank you for your questions. Regarding your first point, I believe there may be some inaccuracies in your calculations. It's important to consider when we were able to actually launch the first drug, which was not at the time of approval. Different patients also start treatment at various times. I'll let Eric provide more details on our approach to gross to net at this stage. We've indicated that the weighted average cost of capital is around $490,000, with the average patient weighing approximately 45 kilograms. Currently, we are on track with these figures, which is expected but still in the early stages. Eric, would you like to share any insights on how we are approaching gross to net over time, as well as our revenue booking process?

Yes, sure. I mean, first of all, we book revenue and we recognize revenue and we ship to our specialty pharmacies. We book our revenues immediately in Germany because we ship directly to pharmacies immediately after a prescription is written. There's very little inventory that's actually kept. It's usually just on demand as needed. So that's one thing. But importantly, around the gross to net, I think it will be important what drives that is, of course, in the U.S., our payer mix. And the payer mix right now is slightly more favorable to commercial. We anticipated that. That's generally the case with most orphan launches anyway because commercial plans tend to write their policies quicker, and we've had very favorable policies in the beginning. Now it's still early stages, and we're seeing that PKU patients in general and the PKU population is more skewed to commercial anyway. And so that's what's helping in terms of the favorability of gross to net. However, we also know that Medicare and Medicaid will be writing their plans and Tricare and a number of other government plans will be finalizing them over the next few weeks. We've guided that ultimately, when this stabilizes, this will be about a 65% to 35% patient mix, meaning 65% is commercial. We're tracking a little higher than that right now, but that's as expected.

And then, Eric, do you want to also comment on what we're seeing in terms of refill dynamics? As we said, it is early days, so it's really hard to see that. But...

So this is very early days. And interestingly enough, the vast majority of patients that we've seen both in Germany as well as in the U.S., the ones that were put on prescriptions in August or early September, we're seeing refills, the vast majority of them. And it's interesting more than not is that these physicians and the health care providers who have prescribed Sephience for the vast majority of them, these have been patients who have been the most challenging. So they're the ones who are poorly controlled, the ones who have failed on previous therapies. And so, when we look at that patient population and we see the results and very fairly good momentum in terms of refill rates, that gives us some real good confidence moving forward.

Our next question comes from Sami Corwin with William Blair.

I want to share my congrats as well on the strong launch. Matt, I know you said that the average weight is falling within the ballpark of 45 kilograms. But can you provide a bit more granularity on if you're seeing these initial patients are skewing more towards pediatric or adults? And then switching gears a little bit. Given the recent news from a competitor, how are you and Novartis thinking about the registrational trial for Huntington's disease? And what are you hoping to get out of that meeting with the FDA?

Yes. Thanks so much for the question, Sami. On your first question, we're seeing a good mix. As we said, we're seeing this full age spectrum. We've had infants all the way up to septuagenarians, which is pretty interesting. And also, I'd say on average, we're late adolescent and 17 years old, I think, is probably where we are in terms of an average. So again, things that we pretty much expected. And again, still early days. We'll know better as time moves on. In terms of HD, I mean, look, we all saw the news yesterday. Look, I mean, we have a very different therapy and a very different program. Votoplam is an oral small molecule. We've conducted a placebo-controlled study that has over 140 patients. We've been able to provide proof of target engagement and mechanism of action, dose-dependent effects, consistent safety profile in that large population and a protocol for the long-term extension that prespecified that we'll be doing a natural history comparison to determine treatment benefit over the long term. So we think we're in a kind of different context here. We expect that all patients will cross 24 months in the spring. We'll analyze those data. And then with Novartis, make a plan to go to FDA to talk about the potential for accelerated approval based on those data. The fourth-quarter meeting what we've talked about has 2 objectives, right? One is to talk about what a path to accelerated approval could look like, but then also to align on what that efficacy trial would look like, whether that's a Phase III approval trial or whether that would be done as a confirmatory study in the context of a potential accelerated approval. But again, I think we're in a very different framework with votoplam.

Our next question comes from Joe Schwartz with Leerink Partners.

Congrats on a strong launch. Can you quantify for us how the response rate for Sephience is tracking in the real world based on refills or any other metrics you have? I heard Eric mention you have good momentum in October with refills. It would be helpful to hear how the response rate is tracking relative to APHENITY in the real world.

Yes, Joe. I think it's too early for us to provide those numbers. We began with the first shipment of the drug in August, and it's really too soon now to offer any detailed information on that. As we progress further into the launch, we may gain a clearer understanding beyond what we've shared, which is that we're receiving very positive response rates and the commentary Eric provided on the refills so far, though we must keep in mind that it's all very early.

Our next question comes from Peyton Bohnsack with TD Cowen.

Congratulations on the strong launch. I guess talking maybe about the Sephience launch in Brazil, assuming it's approved, can you kind of quantify the opportunity for us? And then maybe talk about any difference in patient population in terms of history of disease severity? And then what the steps are from a potential approval to a launch?

Sure, Peyton. As we said, we expect the Brazil authorization would come this quarter. We're still expecting it to come this quarter. I'll let Eric talk a little bit about the dynamics in Brazil and what happens between approval and how we get onto the market there.

Yes. I mean, Brazil will be an important market for us. I think there are a lot of differences in terms of how Brazil approaches PKU compared to perhaps the U.S. and Europe and other markets. I mean, there are certain states that do newborn screening, but not across the board. Patients are going to be likely diagnosed and they're going to be a little older in age. They're going to be adolescents in some places. But in terms of the process itself, we're first going to have registration. Obviously, we have a very experienced team in there that's been managing 4 rare disease products over the last 10 years. So they understand the dynamics, whether it's small molecules, DMD, metabolics with FCS, TEGSEDI, WAYLIVRA, all of that. So as we know right now, the experience of that team is first going to get after the registration, we'll get pricing from ANVISA-CMED. That will be referenced to the prices that will be currently available at the time, which will be Germany, Japan, and the U.S. and other markets, where we maintain a narrow pricing corridor. There will be a process afterwards by which once the product is approved, we already will be working with many of the key centers to ensure that patients are diagnosed and on to therapy. Some of these processes may include some judicialization. But for the most part, we believe that the opportunity will be very, very similar to other key markets. Certainly, the number of patients, well over 6,000 patients right now means that there is a significant opportunity. And then, of course, diagnosing new patients at younger ages will be another key area. But I would go back and say that Brazil is a very important market. Our experience there with rare disease means that we will be working very closely to bring this on board in likely in revenue in 2026.

Our next question comes from Luke Herrmann with Baird.

Congrats on the quarter and the Sephience launch progress. Just a follow-up on patient weight thus far. Given the commentary around trying new foods, do you think diet liberalization can be a tailwind to patient weight over time, particularly for those starting with poorly controlled disease?

Luke, thanks so much for the question. It's hard to say. I would say that not all PKU patients are many individual PKU have average typical weights for their height. They're not all underweight. In fact, we have patients who've had lifelong PKU who have much greater body weight than one would anticipate. In terms of diet liberalization, this is something we haven't thought about in terms of a tailwind. What we've been thinking a lot about with diet liberalization is making sure we are working very closely with the dietitians and nutritionists at the PKU centers so that we ensure that when patients do begin to liberalize their diet, they do so in a very steady, gradual way. And then it's being done very thoughtfully in terms of the diets and the nutrition quality of the foods being introduced into an individual's diet. So I think we're thinking of it more in terms of setting individuals up for success, the ability to liberalize their diet doing so in a gradual fashion, which is not such an easy thing sometimes, right? If you have an individual, a teenager, who is going to have a hamburger for the first time, they may want to have a hamburger for lunch and pizza for dinner. But this has to be done in a very thoughtful, managed way. And we've, again, worked very hard with the centers of excellence to ensure that there's protocols for diet liberalization so that we set all patients up for success so they can enjoy as much diet liberalization as possible and still maintain control of phenylalanine.

That concludes today's question-and-answer session. I'd like to turn the call back to Dr. Klein for closing remarks.

Thank you all again for joining the call today. We're excited about the performance for the quarter and the strong start to the Sephience launch. This really reflects a lot of work by our team over the past 2 years to get ready for this launch and really a strong desire to ensure that we could provide what we view as a very efficacious, safe, and well-tolerated therapy to as many individuals with PKU as possible. Thank you all again. We look forward to keeping you updated on the launch as we progress, and have a good evening.

This concludes today's conference call. Thank you for participating. You may now disconnect.