Ptc Therapeutics, Inc. Q1 FY2026 Earnings Call

Ladies and gentlemen, thank you for standing by. Welcome to PTC Therapeutics' First Quarter 2026 Earnings Conference Call. Today's conference is being recorded. I would now like to turn the call over to Ellen Cavaleri, Head of Investor Relations. Please go ahead.

Good afternoon, and thank you for joining us to discuss PTC Therapeutics' First Quarter 2026 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 and 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 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 today. We are off to a terrific start to 2026. We had a record quarter of product revenue, led by the continued strong momentum of the Sephience launch as well as contributions from our mature products. First quarter total revenue was $273 million, including $226 million of product revenue. With this revenue performance, we are raising our 2026 full-year product revenue guidance to $750 million to $850 million, with expected total revenue of $1.08 billion to $1.18 billion. I'll begin by providing an update on the Sephience global launch. In the first quarter, the launch continued at a strong pace, with all signs indicating sustained growth and breadth of uptake. First quarter Sephience global revenue was $125 million, representing 36% quarter-over-quarter growth with U.S. revenue of $112 million. As of March 31, we had 1,244 commercial patients globally. And in the U.S., we surpassed the 1,500 patient start mark in the quarter with a consistent cadence of prescription starts averaging 140 per month over the past few months. We see this robust cadence of U.S. starts continuing for the foreseeable future. In addition to the sustained momentum in the U.S., growth is accelerating internationally through both commercial access and paid early access programs. We had our first Sephience sale in Japan in late March, ahead of schedule and remain on plan to have commercial sales in up to 30 countries by year-end. I'm incredibly proud of the execution of our global teams. Within nine months, we have gained marketing authorization in the U.S., Europe, Japan, Brazil and several other countries and are well positioned to serve the global addressable market of over 58,000 children and adults with PKU, making Sephience a blockbuster rare disease product. We continue to see broad adoption across age groups, disease severities and treatment histories, including treatment-naive patients and those who have not responded to existing therapies. We are also seeing rapid penetration into centers of excellence in the U.S., with now over 90% of centers having prescribed Sephience. Persistence remains strong, supported by high refill rates, underscoring the long-term commercial opportunity. Feedback from patients, their families and health care providers continues to be positive. We have seen social media reports of meaningful reductions in phenylalanine and the ability to liberalize diet and enjoy certain foods for the first time. We also continue to gather, present and publish real-world evidence on success of diet liberalization as well as effects on other aspects of disease, including mood and cognition. I'm also pleased to report that our manuscript describing Sephience's novel differentiated dual mechanism of action has been accepted for publication. This manuscript nicely details how the dual mechanism of action supports the ability of Sephience to provide greater benefit to those who have a response to BH4, as well as the potential for Sephience to deliver benefit to those individuals with more severe mutations not responsive to BH4, typically associated with classical PKU. Based on Sephience's highly differentiated efficacy and safety profile, the strong start to the launch as well as our ability to maintain momentum in the U.S. and accelerate growth globally, we remain confident in the $2 billion-plus global commercial opportunity for Sephience. Turning to the votoplam Huntington's disease program. Last week, we reported positive top line results from the 24-month interim analysis of the PIVOT-HD long-term extension study. At 24 months, votoplam demonstrated dose-dependent slowing of disease progression on cUHDRS with an average slowing of 52% relative to a matched natural history cohort at the 10-milligram dose level in participants with Stage 2 disease. In addition, the safety profile continues to be favorable across doses and disease stages. These data support that the significant dose-dependent HTT lowering observed in the 12-month PIVOT-HD study are manifesting in dose-dependent clinical benefit over long-term treatment. In addition, the interim study results give us increased confidence for the success of the now enrolling global Phase III INVEST-HD study funded and led by our partner, Novartis. INVEST-HD has a target enrollment of approximately 770 individuals with early symptomatic disease who will be randomized 3 to 2 to receive votoplam 10 milligrams or placebo. The study also includes an interim analysis. The PTC and Novartis teams are still reviewing the data from the Phase II long-term extension interim readout and will discuss potential plans to meet with regulatory authorities. For vatiquinone, we had a Type C meeting with FDA in April to discuss the design of a new trial to provide additional data to support NDA resubmission. Based both on written comments and meeting discussion, we are moving forward with an open-label study with a matched natural history control group from the robust FACOMS disease registry. The study will have a target enrollment of approximately 120 individuals with Friedreich's ataxia from age 7 to 21. The primary endpoint will be a change in mFARS from baseline to 24 months. We look forward to initiating this study within the next few months and believe the design of the study, along with our learnings from previous studies, significantly increases the probability of success. Turning to our earlier-stage pipeline. In the second quarter, we expect to initiate the Phase I study of PTC612, our oral NLRP3 inhibitor. While the majority of the study will be conducted in healthy volunteers, we will look to include a dosing cohort of individuals with elevated inflammatory biomarkers to enable an early assessment of PK/PD. As we have discussed, PTC612 benchmarks favorably to other NLRP3 inhibitors in terms of potency. We expect to develop PTC612 for inflammatory lung disorders, where there is overlap between the NLRP3 inflammasome and disease pathology. We also continue to make good progress on our other pipeline programs, including our wholly owned MSH3 oral splicing program for HD and DM1. The MSH3 program for HD could complement the HTT reduction approach of the votoplam program as well as be particularly suited to target the juvenile HD population. We are also making good progress on several programs from our Inflammation and Ferroptosis platform, including our Phase II-ready PTC844 DHODH program, ferroptosis Parkinson's disease program and NRF2 activator program. Overall, we're off to a great start in 2026. We look forward to the sustained momentum of the Sephience global launch over the course of 2026 and continued favorable developments in our R&D portfolio. Our strong cash position enables us to continue to support all current programs, as well as to look for accretive business development opportunities that can leverage the strength of our global rare disease commercial engine to accelerate short- and intermediate-term growth. I will now turn the call over to Eric to provide a commercial update, including more details on the Sephience launch. Eric?

Thanks, Matt. To start, we are very proud of our commercial team's performance as they continue to execute on the launch of Sephience with excellence. Our outstanding performance in the first quarter reached our highest level of product revenue in the history of the company and has laid the foundation for continued success in 2026. The global launch of Sephience continues to accelerate, driven by continued strong growth in the U.S. and growing contributions internationally. First quarter Sephience revenue was $125 million, including $112 million in the U.S. and $13 million internationally, representing 36% growth from the fourth quarter of 2025. We continue to see growth with new prescriptions in all PKU patient segments, irrespective of age and severity and are seeing the rapid adoption of Sephience as we expand our global footprint with our experienced teams. Since the initial launches in the U.S. and Germany last summer and as of March 31, 2026, our commercial operations have generated over 2,200 prescriptions worldwide. In the first quarter, we continue to see momentum in the U.S. in terms of new patient starts and low discontinuation rates. As Matt mentioned, uptake in the U.S. continues to be broad with over 90% of U.S. PKU centers of excellence prescribing Sephience. We are also seeing broad adoption across the full spectrum of disease severities, including classical patients. We continue to see new patients with various treatment histories, including treatment-naive adults, past treatment failures and patient switches. Refill rates remain strong and discontinuation rates remain low in the low double digits, reinforcing our confidence in the sustained launch momentum. U.S. payer dynamics for Sephience remain favorable. Most commercial and government provider policies are in place, covering over two-thirds of the U.S. population with limited restrictions and flexible criteria for reauthorization. The AMPLIFY head-to-head data demonstrating superior clinical benefits of Sephience versus BH4 continues to strengthen the value proposition with payers, further supporting broad access in the U.S. and ongoing pricing and reimbursement discussions in Europe. Our Sephience launch momentum continues to build globally with the launch in Japan, which has progressed ahead of plan. We had our first commercial patients and revenue recorded in Q1, which was earlier than expected, and we are very pleased with the positive feedback from Japanese health care providers and patients in the early stages of the launch. We also secured Sephience regulatory approval in Brazil, where our local team is fully engaged in creating awareness for access via named patient programs while we finalize pricing in the second half of the year. In Germany, we're seeing good progress, with centers of excellence accelerating new patient starts, including adults, while we finalize pricing and reimbursement this summer. In other European markets, health technology assessment dossiers are being actively reviewed with paid early access programs already in place, while pricing and negotiations advance in France, Italy, Spain and other key European markets. While the U.S. remains a key near-term growth driver, we expect international revenue to continue to ramp with commercial patients in up to 30 countries by year-end. Sephience represents a significant global commercial opportunity long term. Its differentiated efficacy and safety profile and dual mechanism of action support broad adoption and positions Sephience as a potential standard of care, which gives us confidence to achieve multi-billion peak revenue. Going forward, as the Sephience business grows and diversifies globally, the launch metrics we provide will include only global revenue and the number of active patients on Sephience treatment worldwide. We believe these metrics will best illustrate the long-term trajectory of Sephience growth. Now turning to our DMD franchise. We delivered solid first quarter performance despite significant headwinds. Translarna revenue was driven by a large government purchase order in Brazil, and we continue to support nonsense mutation DMD patients on therapy across Europe. In the U.S., Emflaza generated $22 million in quarterly revenue despite multi-generic erosion, supported by strong brand loyalty and high-touch patient services. Our experienced global commercial team have successfully executed multiple rare disease product launches for over a decade. Looking ahead, we are confident in our ability to drive strong performance and continued growth in building Sephience into a blockbuster brand for PTC. With that, I will now turn the call over to Pierre for a financial update. Pierre?

Thank you, Eric. I will now share the financial highlights of our first quarter of 2026. Beginning with top line results, total product and royalty revenue for the first quarter was $273 million and total net product revenue across the commercial portfolio was $226 million compared to $153 million for the first quarter of 2025, representing 47% growth. First quarter 2026 product revenue includes Sephience net product revenue of $125 million and DMD franchise revenue of $81 million. Translarna net product revenue was $59 million, including a large one-time government purchase order. And Emflaza net product revenue was $22 million. For Evrysdi, Roche achieved first quarter global revenue of approximately USD 585 million, resulting in royalty revenue of $47 million. As a reminder, we continue to report Evrysdi royalty revenue in our financial statements. However, there are no cash proceeds to PTC. For the first quarter of 2026, non-GAAP R&D expense was $90 million, excluding $11 million in non-cash, stock-based compensation expense compared to $100 million for the first quarter of 2025, excluding $9 million in non-cash, stock-based compensation expense. Non-GAAP SG&A expense was $74 million for the first quarter of 2026, excluding $12 million in non-cash, stock-based compensation expense compared to $72 million for the first quarter of 2025, excluding $9 million in non-cash, stock-based compensation expense. Cash, cash equivalents and marketable securities totaled $1.89 billion as of March 31, 2026, compared to $1.95 billion as of December 31, 2025. Our strong financial position supports continued development of our commercial and R&D portfolios and preserves flexibility for strategic and disciplined business development to further enhance long-term growth. And I will now turn the call over to the operator for Q&A.

Our first question coming from the line of Kristen Kluska with Cantor Fitzgerald.

Congrats on the record quarter for the company. Now that you have a couple of quarters under your belt for Sephience, I was hoping you can give us a little bit more color and clarity about patterns that are emerging in the real world around making sure that patients and physicians are working conservatively in measuring Phe and slowly increasing the protein uptake and how that's been resonating in terms of compliance, long-term utilization and also how these patients that are staying on therapy, is it entirely driven by diet liberalization? Or are there in other instances, other factors that are playing a key role?

Kristen, thanks for the questions. We are incredibly excited about the continued launch momentum we're seeing. We think we're in a stage now of consistent growth in the U.S. and of acceleration ex-U.S., which is what's going to make this such a valuable product for us. As a global launch, this is exactly what we've been working for and exactly as we expected. In terms of dynamics now a couple of quarters in, in general, we are seeing a consistent theme of breadth of uptake across all patient segments, including those naive patients who many thought were lost to follow-up. It was really just a matter of being able to offer them a safe and potentially effective therapy, full age range from babies up to octogenarians, and broad uptake across centers of excellence in the U.S. as well as outside the U.S. In terms of people staying on drug, it's a combination of factors. Of course, the ability for individuals on the drug to liberalize their diet and try foods for the first time is incredibly impactful and motivating not only for those individuals to stay on drug, but it is also continuing to increase the enthusiasm and desire of others to get on drug. We have worked very hard with the centers where dietitians are on staff; they are an important part of PKU management even when an individual is not on therapy. The approach is making sure that when someone gets on the drug there is first evidence of Phe lowering and getting into that range where you can liberalize diet and then proceeding slowly so that we're set up for success. We are also hearing a lot about other benefits that have been important for patients. For many prescribers and patients, it is not necessarily about a number. It's about being able to liberalize diet. Others are saying they just feel better: improved anxiety, improved cognition, less brain fog. Those are impactful things that patients report. As Eric mentioned, and as I did as well, these are things that we're codifying now in real-world evidence papers as well as presentations. We have a number of them coming up at the SSIEM in September, talking about all these different ways in which benefit is provided to patients and supporting persistent demand and high adherence, which remains very high.

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

I have a couple. So when you talk about the cadence of around 140 new start forms, you've been careful to make sure you say this is consistent. So, do you expect this trend to continue? Or do you think this could accelerate, especially in the U.S. over the course of the coming year? And then can you also comment on discontinuation? So, you've talked about that a little bit, but for patients who are discontinuing, what's the main reason?

Tazeen, thanks for the questions. In terms of the start forms, when we talk about the consistency of about 140 per month, that's referring to the cadence since the later parts of 2025. As expected coming into the new year around the holidays, there was a bit of a decrease. That's a seasonal effect. We had one of the strongest months in March and we're seeing continued momentum into April. We think that the 140 probably represents a reasonable run rate for the foreseeable future, knowing there will be ups and downs and typical dynamics one sees in an early launch. We believe that's a solid number, and we're excited about adding those starts to an already substantial base of patients who are maintained on the drug, which is a key to driving the revenue opportunity over time. I'll make a brief comment about discontinuations and then turn it over to Eric for a bit more color. As he mentioned on the call, we're in the low double digits at this point in the launch. We're starting to approach steady state. What's really encouraging is that the earliest individuals put on Sephience tended to be those not on a therapy, the more challenging patients, therapy-naive adults. To have this kind of adherence rate in the context of the most challenging patients coming on first is obviously encouraging for the strength and growth of the launch over time. Eric, do you want to provide a little more color on what we're seeing?

Yes. Thanks for the question. In the very first phase of the launch, we would call that an accelerated phase. The vast majority of these patients were those who had failed or were poorly controlled on previous treatments. What we're seeing now is that even that hard-to-treat group has benefited really well, and we have low double-digit discontinuations. The amount of discontinuations for clinical reasons in terms of efficacy or safety is very low. Some reasons are because patients don't respond or safety reasons, but these are a small minority. The other reasons are patient choice, which could be a variety of factors. Overall, considering the number of patients that have come in, we're building a very large base. As Matt said, it's an accelerated but robust cadence. As we build that base, we'll sustain momentum, continue to grow refill rates, and work diligently to keep discontinuations very low.

Our next question coming from the line of Ben Burnett with Wells Fargo.

I wanted to ask about what you're seeing in terms of average weight or average price. And as you add Japan and some of these ex-U.S. territories to the mix, would you foresee any changes to the long-term average price estimate?

Ben, we said at the beginning we expected average weight to be around 45 kilos and our studies showed we'd be somewhere in the 45 to 50 range. I think we're very much in that ballpark. International dynamics play into that as well. We have some adults who came on, and the average age globally is around 17, but there are different mixes by region. We're seeing very young patients put on first, especially in some early access programs where there's a preference to get infants on drug because of the concern for neurodevelopmental protective effects. In an early access scheme, those factors can lead to earlier treatment ahead of formal pricing and reimbursement. Overall, we're still in the ballpark we expected and we'll continue to watch that dynamic as the launch plays out.

Our next question coming from the line of Eliana Merle with Barclays.

Just a follow-up question on how to think about the ex-U.S. opportunity and the near and long term for Sephience. Specifically, how should we think about pricing for Sephience and then how should we think about the cadence of ex-U.S. sales over the course of the year?

Thanks, Eliana. We've always been intent on maintaining a rigid pricing corridor that went into our launch strategy. I'll let Eric detail how we're seeing price globally and the cadence of contribution ex-U.S.

The international business will be an important future contributor to revenues, but the U.S. will still be the main driver this year. Each country that comes on, up to the 30 countries we anticipate, will be incrementally important, but the U.S. remains the main driver for this year. Japan got off to an early start and we've been able to maintain pricing and reimbursement there; we locked that down in Q1 and it will be locked for the next 10 years during orphan exclusivity. We have HTA assessments and dossiers in Europe and pricing and reimbursement discussions being finalized towards the second half of this year and early next year. The U.S. will be the near-term driver of revenue and will continue to play a very important role; however, over time each country will add incremental revenue and patients which will be important for the long term.

Our next question coming from the line of Brian Cheng with JPMorgan Chase.

Can you hear me?

Yes.

Congrats on the quarter. Matt, you sounded very confident in the 140 patient start forms per month run rate continuing and you see growth accelerating in your prepared remarks. You mentioned over 90% of the centers have now prescribed Sephience. So, what is holding back the remaining 10% of the centers? Is it just a matter of reaching out to those doctors and increasing the touch points? Or is there something else that we should also consider?

Thanks, Brian. We are very bullish on the opportunity in the U.S. and globally. This is a true global launch, and adding approximately 140 starts per month on top of an already strong base supports the promising revenue potential. We are incredibly excited. After the second full quarter of this rare disease launch, the fact that we have prescriptions from over 90% of the centers is incredible progress, thanks to our market development and relationships with centers. These tend to be the larger centers. I'll let Eric talk about the center dynamics, but I want to emphasize we're proud to have that degree of penetration at this early part of the launch. Eric?

This is a very strong penetration. The centers leading prescriptions are the larger metropolitan Tier 1 centers that have already written many prescriptions and continue to drive the cadence, particularly for new starts. Those centers also have many patients on therapy, so we're working to get new starts and maintain many of these patients with high refill rates and low discontinuations. The remaining approximately 10% are typically late adopters and are often smaller centers. We call on all of them, and in many cases they're not staffed adequately and not as proactive with patients. The bulk of prescriptions come from the larger centers, which are working very hard and providing robust cadence.

Our next question coming from the line of Judah Frommer with Morgan Stanley.

Congrats on the progress here. Two quick ones for us. First, on the guidance update, can you separate out that one-time Translarna order from the rest of the guidance raise? And then on vatiquinone, any indication within that meeting or written feedback as to how prior data would be treated, specifically subcomponents of the mFARS? Or should we think about this as kind of starting from scratch in a late-stage trial?

Judah, on guidance: we entered the year confident in the growth trajectory and strength of the Sephience launch and believed the vast majority of product revenue would come from Sephience. There is uncertainty in the mature products, specifically the DMD franchise. Translarna business in Europe is hard to predict long-term without a license. We can face variability from government purchase orders in countries like Brazil or Russia. On Emflaza, we are already seeing Q1 reflect erosion with multiple generics in the market and expect continued erosion. We increased guidance based on the overall performance of the quarter. As the year progresses and we understand trajectories for mature products and future government orders, we'll update guidance as appropriate. On vatiquinone: we were encouraged by FDA suggesting that additional data to support NDA resubmission could come from a natural history controlled study. The safety profile of vatiquinone is favorable and well established, and there's no need for a placebo-controlled study to identify new safety signals. The MOVE-FA data provide a signal of efficacy. We view the proposed study as a way to obtain additional data that will support the existing data set of safety and signs of benefit, particularly in younger patients. Endpoint selection depends on study duration. The natural history of FA in young individuals is well characterized in publications. Over shorter periods, about 12 to 18 months, the upright stability subscale is likely the most sensitive component of mFARS to capture progression and treatment benefit. With a 24-month study, literature shows that other components of mFARS capture progression, and we saw this in MOVE-FA: at 18 to 24 months, upper limb and lower limb measures began to contribute. So endpoint selection is a function of population and study duration, and we believe 24 months is appropriate for capturing the relevant components.

This is Jarwei on for Jeff with Citigroup. Our next question is coming up.

Maybe just thinking about the ex-U.S. opportunity. A two-parter: first, can you help paint the picture for how the early Japan launch pattern has looked? Have you seen a similar uptick pattern from the early days of the U.S. initial launch? And secondly, given the U.S. has had success using social media to gain awareness among patients, can we expect similar success in other geographies given different patient-to-physician dynamics? Third, given vatiquinone's open-label study plans, how sensitive is mFARS to potential protocol deviations or data?

Jarwei, let me take the third one first and the second one second, then I'll turn it over to Eric for Japan dynamics. On sensitivity of mFARS and using a natural history comparator: FDA has well-thought-out guidance if you're using a natural history comparator group as a control. The agency has used FACOMS in the past to support regulatory decision-making and held it out as a model registry with high-quality data that characterizes and captures disease progression. We have set up the treatment portion of the study to match many dynamics in the natural history registry, including timing of assessments. In selecting a natural history cohort from the registry, we will ensure they have appropriate endpoint information at key time points: baseline, 12 months, and 24 months. These are built into the protocol and statistical analysis plan to make the comparison as robust as possible. The FA community has developed a robust and rigorously collected protocolized natural history registry for the key endpoints relevant to clinical trials. Regarding social media and global dynamics: social media is global and there are well-aggregated patient communities that communicate internationally. Information flows from the U.S. to other countries and there are communities in other countries that share information via social media and other channels. Let me turn it over to Eric to talk about Japan dynamics and add anything about social media.

Our Japanese launch is off to a great start and ahead of schedule. We received approval in December and have been profiling centers; in Q1 we finalized pricing and reimbursement, which is locked in now with no price decreases for the next 10 years due to orphan exclusivity and no referencing. That's important for a sustained business. In early stages of the launch in Japan, we see similarities to the U.S.: patients seeking treatment who failed or were uncontrolled on prior therapies, and we are also seeing adults and naive patients come in. So far, we're seeing accelerated dynamics similar to the U.S. in Japan as well.

Our next question coming from the line of Brian Abrahams with RBC Capital Markets.

This is Kevin on for Brian. Maybe just on Sephience and payer dynamics: can you talk about the types of step edits you are seeing or anticipated at this point? And what percentage of prescriptions are currently facing prior authorization delays, and how do you see that evolving?

Thanks, Kevin. Eric, do you want to take those payer dynamics and any challenges in authorization?

Payer dynamics have been as expected. Prior authorizations are typically in place based on the label, and most payers require PKU assessment and other requirements within the label; these are generally simple and easy to get through. The vast majority of commercial payers and government payers have already written their policies, and the coverage has been very favorable with very few limitations and few step edits. Many patients have documented histories, including prior use of Kuvan or Palynziq or evidence of prior failure, which helps move cases through. If step edits are required, they can typically be addressed with documentation in days to a few weeks. Time from prescription start form to dispense has improved because policies are in place. Regarding the split, we've historically said it's a little over two-thirds commercial and one-third government; that mix is holding well. In the last quarter we saw a slight tick up toward more commercial, and we anticipate around a 65% commercial to 35% government split.

Our next question coming from the line of Yifan Xu with Jefferies.

This is Yifan for Faisal. Congratulations on the quarter. Can you provide additional color on the PKU patient split? For the current quarter, what percentage of revenue contribution came from mild to moderate patients and what percentage from classic PKU patients? And for your $2 billion peak sales guidance, how is that split?

Yifan, we do not specifically collect whether a patient is classical, moderate, or mild. We have seen, from the beginning and continuing now, that up to one-third of patients are treatment-naive; those tend to be more classical patients who were never tried on other therapies. The remainder are patients who have tried and failed existing therapies or those switching from existing therapies. We're seeing more tried-and-failed patients as centers prioritized getting patients who were not on therapy into treatment earlier. Importantly, more severe patients are benefiting from Sephience as we expected. We have many patients showing significant reductions in Phe and the ability to liberalize diet. We see consistency of effect across moderate, classical, and mild patients, which is encouraging. We're doing a lot of work with the mechanism-of-action paper to support why that's the case, including the independent chaperone effect providing benefit in more severe mutations. We're also working with physicians on real-world evidence studies documenting responses including Phe reduction, diet liberalization, and other benefits like improvements in cognition and anxiety. I wouldn't limit the opportunity to $2 billion; we say $2 billion-plus and multi-billion. Eric, do you want to discuss how we think the splits and contributions can play out?

Contributions will be consistent with the U.S. as the main driver longer term, though international will be significant. There are 58,000 addressable patients worldwide, with two-thirds outside the U.S. We'll continue to work to maintain a narrow pricing corridor and secure access and reimbursement across countries. As we bring up to 30 countries online, we'll add international patients while continuing growth in the U.S. Getting new patients in and building and maintaining the base with services, education, and programs is critical. Minimizing discontinuation and maximizing adherence and compliance are priorities. This gives us confidence we can build a blockbuster brand across multiple countries and achieve a truly global launch.

Our next question coming from the line of Jacob Ormes with TD Cowen.

This is Jacob on for Joseph Thome at TD Cowen. I just wanted to ask regarding Sephience and the time it takes for patients to get on drug: do you have any insights on how that might differ based on geography?

Jacob, in the U.S. we're continuing to get folks on fairly quickly. Some take longer, some shorter, but on average we see rapid throughput. Eric, do you want to discuss global dynamics and why we plan to focus on global patients given the complexities?

It's complex because each country has its own system for access. In the U.S., dispenses can take a couple of weeks and in some cases a few days depending on insurance and policy. In Germany and Japan, once products are reimbursed and listed, it's often just a few days. In jurisdictions relying on named patient programs, the times can be days, weeks, or months. Each country is unique. The prescription is the most important metric because our teams work with providers to convert prescriptions into commercial therapy as quickly as possible. That's why global revenue and the number of active patients worldwide are important metrics to illustrate trajectory toward multi-billion status.

Our next question coming from the line of Luke Herrmann with Baird.

I had two questions. First on Sephience: is there any bolus of patients who haven't been able to get reimbursed yet that you think could be approved in the future? Second, on vatiquinone and the open-label study, how are you treating Skyclarys use? Do patients need to wash out and for how long? Any details would be helpful.

Luke, I'll take the second question first and then let Eric discuss payer dynamics. For vatiquinone, when using a natural history comparator, the treated patients must match the natural history cohort. Given there hasn't been extensive experience with individuals on Skyclarys for prolonged periods, we cannot allow concomitant long-term use of Skyclarys in the study as we need the natural history data to be comparable. There will be protocol provisions for those who were on Skyclarys for a short time and have washed out, but we can't permit concomitant or long-term Skyclarys use in the study because the natural history data do not capture that well. This is an example of the planning and alignment with FDA required when prospectively identifying a matched natural history cohort for resubmission. Eric, do you want to talk about payer dynamics and any areas of challenge?

There have been very few limitations. Things are going as planned with U.S. payers. Very few patients are being denied, and if they are, it's not a hard denial—it's working through medical necessity. We do not have a large bolus of patients on patient assistance or bridge programs; if we do, we work to bridge them to commercial therapy in days or weeks. Time to dispense has become more efficient, with scripts filled in a matter of a couple of weeks or less. Reauthorizations have not been onerous and typically are for six to 12 months. Medical assessment, Phe lowering, and diet liberalization generally are sufficient for continued therapy. Overall, the vast majority of these patients are on treatment.

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

This is Jenny on for Joe. One on the longer-term PKU competitive setup with oral genotype-independent SLC approaches now in late-stage trials: how are you thinking about the parts of the PKU market where Sephience is most defensible long term? Is the differentiation around Phe lowering, diet liberalization, or physician comfort with the BH4 pathway? Relatedly, are there any patient segments where future oral competition could expand the treated pool rather than directly compete with Sephience?

Thanks, Jenny. While there are other therapies in late-stage development, we are not worried about a significant threat. We have a significant first-mover advantage and strong market penetration. The general view among prescribers is that new therapies would likely add on to Sephience rather than replace it. In PKU, combination approaches are common; patients are used to cocktails and mixing supplements. A future therapy could be added to Sephience to improve benefit, for example to enable more complete diet liberalization or additional Phe lowering in more severe cases. Of course, a small number of patients who do not respond to Sephience may try alternative drugs, but overall Sephience is becoming first-line therapy and the standard of care. Anything that comes later would likely be additive or aimed at those not served by Sephience.

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

I wanted to follow up on vatiquinone. Since the MOVE-FA study and the commercial availability of Skyclarys, has your understanding of FA natural history changed versus when previous studies were run? Second, on the cash balance and business development, what's the rate-limiting factor for additional business development?

Paul, thank you. On vatiquinone and FA natural history: the FACOMS registry has been incredibly well characterized and consistent. If you look over time, the rate of progression has been fairly consistent, roughly two to 2.5 points per year on mFARS. Components that contribute to that are a function of age and time. Even with an approved therapy, that natural history has remained consistent. In discussions with FDA about using FACOMS as a natural history comparator, that consistency, the robust data, the large number of patients and the completeness of the registry gave the agency comfort that efficacy could be substantiated using this design. Regarding cash balance and business development: we have positioned the company to support the Sephience launch, and the launch is proceeding as anticipated. We expect strong growth and a multibillion-dollar product opportunity. Friedreich's ataxia and the PIVOT-HD results are attractive future potential contributors later in the decade. We have capital and options. The limiting factor is finding the right fit for business development—assets that leverage our commercial infrastructure and are of the appropriate size and strategic fit. We remain excited about our R&D portfolio and opportunities across our platforms, including splicing and other programs outlined at R&D Day. The company is in a strong position financially and strategically, and we have the luxury to find the right opportunities to continue growing the top line in the short, intermediate and long term.

I'm showing no further questions in the queue at this time. I will now turn the call back over to the CEO, Dr. Matthew Klein, for any closing remarks.

Thank you all for joining the call this afternoon. We have worked very hard to build PTC into this position with a very strong launch for Sephience and a global opportunity that we are well positioned to capture. I'm incredibly proud of the team's performance. We are positioned to continue to grow in the U.S., accelerate growth outside the U.S., and realize the multi-billion-dollar opportunity, alongside advances in our R&D platform and a cash position that gives us flexibility to continue to drive value in the short and intermediate term. Thank you all again for joining the call.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation, and you may now disconnect.