Vertex Pharmaceuticals Incorporated

Good day and welcome to the Vertex Pharmaceuticals first quarter 2026 earnings call. All participants will be in a listen-only mode. Should you need assistance, please signal conference specialists by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. Please note this event is being recorded. I would now like to turn the conference over to Ms. Susie Lisa. Please go ahead.

Good evening, all. My name is Susie Lisa, and as the Senior Vice President of Investor Relations, it is my pleasure to welcome you to our first quarter 2026 Financial Results Conference Call. On tonight's call, making prepared remarks, we have Dr. Reshma Kewalramani, Vertex's CEO and President, Charlie Wagner, Chief Operating Officer and Chief Financial Officer, and Duncan McKechnie, Chief Commercial Officer. We recommend that you access the webcast slides as you listen to this call. The call is being recorded and a replay will be available on our website. We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission. These statements, including without limitation, those regarding Vertex's marketed medicines for cystic fibrosis, sickle cell disease, beta thalassemia, and moderate to severe acute pain, our pipeline, and Vertex's future financial performance, are based on management's current assumptions. Actual outcomes and events could differ materially. I would also note that select financial results and guidance that we will review on the call this evening are presented on a non-GAAP basis. I'll now turn the call over to Reshma.

Thanks, Susie. Good evening, all, and thank you for joining us on the call today. Vertex is off to a terrific start in 2026, which we see as a year defined by execution. Q1 revenue growth was strong across the portfolio as we reach more patients with more products and delivered total product revenue of $2.99 billion, reflecting 8% growth year-on-year. Importantly, we achieved key commercial milestones for each of the newer products since launch through end of Q1. Aliftrek exceeded $1 billion in cumulative revenue. More than 500 people have initiated their Kastjevi treatment journey. and over 1 million prescriptions have been written for Jurnavix. Another highlight in Q1 was that products from the new disease areas, namely Kastchevy and Jurnavix, drove approximately 25% of total product revenue growth. Execution in R&D was equally strong, with multiple regulatory submissions recently completed and more anticipated, combined with rapid progress across clinical trials and important advancement in research. Let me spotlight a few accomplishments. First on POVI, the interim analysis results from the Phase III Rainier study in IGAN on efficacy and safety from top to bottom were sparkling and further fueled our enthusiasm for POVI as a potentially best-in-class Baf-April inhibitor. I was exceptionally pleased with the rapidity and quality of the recently submitted BLA filing for POBI in IGAN. Indeed, at 27 days from database lock to regulatory submission, this was the fastest submission in Vertex history. Equally notable is the urgency with which the POVI primary membranous nephropathy and the POVI myasthenia gravis programs are advancing. In membranous, the Phase II study has been fully enrolled and the Phase III program has already initiated. In addition, the Phase II proof-of-concept myasthenia gravis trial is underway. Second on Kastjevi, I'm also very pleased with the rapidity and quality of this SBLA submission for Kastjevi in 5 to 11-year-olds with sickle cell disease or beta thalassemia. The Kastjevi filing has been granted a Commissioner's National Priority Voucher, reflecting the importance of treating this younger age group before some of the most serious complications of the disease can begin. Overall, Vertex continues to extend its leadership in CF drive growth with new product launches while building out our next disease area franchise in nephrology, accelerate programs in mid and late stage development, and advance the earlier stage R&D pipeline. Tonight, I'll limit my R&D comments to CF, as well as the pipeline programs with the most significant New information to share. Certain renal programs, povine myasthenia gravis, and zamylocell in type 1 diabetes. Starting with CF, four quick R&D updates for this quarter. We recently reached a significant milestone in the U.S. with label expansions for both Olivtrek and Trikafta. With this expansion, patients with a clinical diagnosis of CF who have at least one variant in the CFTR gene that is responsive based on clinical and or in vitro data are now covered by the Eliftrek and Trikafta labels, reinforcing the impact of these medicines regardless of the location of the variant in the CFTR protein. This is a significant expansion of eligibility that reflects decades of investment, effort, and a relentless pursuit of the science. It is also a great example of innovation, using results from clinical trials complemented by in vitro data to expand the benefit of vertex CFTR modulators to about 95% of people with CF, including those with rare and even N of 1 genotypes. As we expand the Oliftrec and Trikafta labels to additional mutations, we're also expanding the labels to younger patients. We will soon submit for approval for Oliftrec in patients 2 to 5 years of age, where you may recall our pivotal trial demonstrated a remarkable 65% of children reaching normal levels of CFTR function. and we also plan to submit for Trikafta in children 1 to 2 years of age in the near term. In addition, we continue to advance our next-generation 3.0 CFTR modulators, including VX828, which is currently in the study of patients with CF. We are on track to complete the study and share results in the second half of this year. Following closely behind VX828 in the family of next-gen 3.0 are VX581 and VX272. both of which are currently in the clinic in Phase 1 Healthy Volunteer Studies. As we have consistently said, if it is possible to do better in CF, we're committed to being the ones who do so. And finally, on VX522, the mRNA therapy we've been developing for people who produce no CFTR protein and therefore cannot benefit from our modulators. We previously disclosed tolerability issues in this program. Despite actions we have taken in the trial to overcome these issues, we have not been able to do so. and as such, we have chosen to discontinue the program. Given this early termination, we will not be able to assess the efficacy or full safety of VX522. We will be working with sites to close out the study in the coming weeks. Moving on to our renal franchise, which continues to make quick progress and is rapidly establishing itself as Vertex's fourth franchise along CF, heme, and pain. In total, we have four programs in mid- and late-stage development in renal, POVI and IGAN, POVI in primary membranous nephropathy, inoxiplin in AMKD, and VX407 in ADPKD. Tonight, I'll cover the first three programs, starting with POVI and IGAN. Recall, POVI's differentiated potential best-in-class profile stems from its specific design as an engineered tachyfusion protein with binding affinity, potency, and PK properties that deliver optimal dual BAFAPRIL inhibition. The dual inhibition and engineering advantage is evident in both the interim analysis data of the Rainier study, where we saw rapid, deep, and sustained improvement in proteinuria, a favorable safety profile, and consistency across all subgroups, as well as in three key patient dosing benefits, once-monthly dosing, small volume, and subcutaneous administration via an autoinjector. Overall, the Phase III interim analysis data represent a home run in terms of study design, execution, and the results, with POVI achieving statistically significant and clinically meaningful results across all primary and secondary endpoints. Patients in this trial received excellent standard of care, with high rates of background medicines, including the highest rates of SGLT2s seen in any IGAN study. Baseline characteristics were well matched to real-world IGAM patients in terms of age, renal function, and degree of pertinuria. In addition, as a measure of study quality, it's important to look at discontinuations. In this study, treatment discontinuations were low and trial discontinuations were even lower at a rate of 1.5% in the placebo group and 0.8% in the POVI group. To replay the top-line primary and secondary efficacy results, for the primary endpoint, POVI achieved a 52% reduction from baseline in proteinuria as measured by 24-hour UPCR. That's a 49.8% reduction versus placebo. For the first secondary endpoint, POVI treatment led to a 77.4% reduction from baseline in serum GDIGA1 levels. That's a 79.3% reduction versus placebo. For the second secondary endpoint of those patients with hematuria at baseline, 85.1% of POVI-treated patients achieved hematuria resolution, which is a 61.7% reduction versus placebo. In addition, 42.2% of patients reached the exploratory endpoint of 24-hour UPCR of less than 0.5 grams per gram, an important clinical threshold. These are remarkable results. and particularly noteworthy considering that at the time of the interim analysis, patients had received just 36 weeks of POVI treatment. On safety, POVI was generally safe and well tolerated. The majority of adverse events were mild to moderate, and there were no serious adverse events related to POVI. Importantly, in terms of infections, most were mild to moderate. The rate of SAEs of infection was low, at 0.5%, observed in both the placebo and POVI groups. There were no opportunistic infections and no discontinuations related to POVI overall, including no discontinuations due to infections. Lastly, on anti-drug antibodies or ADAs, ADAs were observed as expected with biologics, but had no impact on POVI's efficacy or risk profile. We look forward to sharing more details of the interim analysis results and anticipate doing so at upcoming medical meetings this fall. Shifting to POVI and primary membranous nephropathy, I am pleased to share we have completed enrollment of the Phase 2 portion of the Olympus Phase 2-3 study and have already initiated the Phase 3 portion ahead of our previously announced mid-2026 goal. And finally on POVI, as part of its pipeline and a product potential for B-cell mediated diseases beyond renal, I'm also pleased to share that the phase two proof of concept study of POVI in generalized myasthenia is underway. This is a 30 patient study of people with GMG evaluating both the 80 and 240 milligram dose for 12 weeks with the primary endpoints of safety and the percent change from baseline in IgG at week 12. The rationale for studying POVI in myasthenia is compelling. It's a serious B-cell mediated disease with high morbidity affecting approximately 175,000 people in the U.S. and Europe. There is high unmet need as current therapies have meaningful limitations. which means there's room for improved efficacy, a better benefit-risk profile, and more patient-friendly dosing and administration, which we have discussed in the context of IGAN as being critically important when considering a chronic biologics market. We believe POVI's mechanism of action, striking at the heart of autoantibody production with an engineered protein format, provides best-in-class promise in myasthenia, and we are excited to develop this opportunity. Shifting back to renal to finish up with enoxaplin in APOL1-mediated kidney disease, or AMKD. First on amplitude, the pivotal phase 3 study of primary AMKD, that is to say patients with two APOL1 variants, pertinuric kidney disease, and no other renal-related comorbidities. We are on track to conduct the interim analysis, which occurs after 48 weeks of treatment, and to share data from this cohort in early 2027. If positive, we will be poised to file for potential accelerated approval in the U.S. thereafter. Second, on Amplified, our Phase IIb study of enaxiplin in separate populations. patients with 2-APOL1 variants, modest pertinuria, and no other kidney disease, and patients with 2-APOL1 variants, moderate to severe pertinuria, and a second disease, type 2 diabetes, that could impact the kidney. These two populations are not being studied in amplitude. We recently completed enrollment in the amplified study, which is a study of 13 weeks in duration. Given the clear differences in these populations, we made the decision early on to study them in separate trials. Emerging data in the field confirmed the wisdom of this decision. We are excited to learn from the amplified study and look forward to sharing results in the second half of this year. Finally, on type 1 diabetes, a reminder that Zamylocell has very strong clinical results to date, as detailed in last year's New England Journal of Medicine. Among patients who received a full dose and had at least one year of follow-up, 10 out of 12 patients were insulin-free. These results are unprecedented and are particularly noteworthy given that these patients are those with 20-plus years of type 1 diabetes, undetectable endogenous insulin production at baseline, taking 40-plus units of exogenous insulin per day, and with two or more severe hypoglycemic events per year despite best available care. You may recall that in the second half of last year, we paused dosing of the Phase 1-2-3 study in order to conduct a manufacturing analysis, which we have now completed. I am pleased to report that dosing in the study has resumed and multiple patients have been dosed. With dosing now restarted, we will update you in the coming months on the revised timelines for study completion and regulatory filings. With that, I'll turn the call over to Duncan for a commercial update.

Thanks very much, Reshma. I'll start with CF, which continues to perform very well. Year-over-year revenue growth was 6% globally, balanced nicely between U.S. growth of 5% and international growth of 8% in Q1. Global growth reflects continued Eliftrek uptake as its once-daily dosing and improved sweat chloride profile continue to resonate with the clinical and patient communities. As mentioned, Eliftrek has now surpassed $1 billion in cumulative global revenue since its approval in the US in late December 2024 and Europe in July 2025. Outside the US, we have signed reimbursement agreements in 11 countries for Eliftrek in Q1 alone, building on the access generated in the second half of last year. The tremendous scientific and regulatory achievements represented by the label expansions for Eliftrek and Trikafta also represent a meaningful incremental commercial opportunity of approximately 800 people in CF who are newly eligible in the US. This broad labeling is one of several key CF growth drivers for the remainder of 2026, along with the global rollout of a lift track, treating younger patients, and expanding into additional geographies. We have worked closely with the CF population for two decades and remain focused on continuing to serve the CF community and expand our leadership across all genotypes, age groups, and geographies. Shifting to heme, the rollout of CasGevi continues to gather momentum across all three regions, and I'm pleased to highlight another significant commercial milestone since launch. Over 500 patients have now initiated the CasGevi treatment journey. Hundreds have had their first cell collection, and many patients have had their cells edited and are ready for infusion. During the first quarter, we delivered $43 million in CasGevi revenue. Importantly, we worked on securing a pricing agreement for Casgevi in Germany in Q1 and are currently working through the implementation steps. This is a historic moment and we're excited that German patients with sickle cell disease and TDT may soon be benefiting from long-term access to Casgevi at a sustainable price. Overall, we are very encouraged by the robust flow of patients in the US, in Europe, and the Middle East moving from referral to cell collection and infusion. First quarter revenue reflects expected variability quarter to quarter as patients choose the timing for their infusion that suits them best. For the full year 2026, the Casgevi outlook is very promising, as we have built our ATC network, secured reimbursements, and now have many patients at all stages of the treatment journey. We therefore have very strong visibility to revenue for the rest of 2026, for Casgevi to contribute meaningfully to our $500 million plus revenue goal for non-CF products this year, and towards Casgevi's ultimate multi-billion dollar potential. For genavics in moderate to severe acute pain, prescriptions, prescribers and awareness all continue to build. More than 350,000 prescriptions were filled in the quarter compared to approximately 550,000 in all of 2025, which was in line with our expectations. We also surpassed the milestone of over a million Genavix prescriptions written since launch. Prescriptions this quarter were once again split roughly 50-50 between the hospital and retail channels and generated $29 million in revenue, also in line with our expectations. Overall, prescription growth remains strong, although quarter one revenue reflects some normal inventory destocking. We remain on track to more than triple the 550,000 prescriptions for 2025 and for revenue growth to significantly exceed prescription growth. I'll now outline some of the key drivers of our continued growth and expected success for Genavix in 2026. Firstly, physician and patient clinical experiences on Genavix continue to be excellent, which provides a great foundation for continued growth. We also continue to see outstanding breadth of physician uptake, as well as Genavix additions to hospital and IDN formularies, protocols and order sets. Secondly, we continue to make good progress in the payer space, with 240 million lives now covered. In addition to the big three commercial PBMs, I'm delighted to announce that we've reached an agreement with the first of the big four Medicare Part D plans to start covering Genavix, effective as of May 1st. Given the multiple and well-documented challenges that opioids present seniors, this is welcome news, and we're in discussions with the remaining Medicare Part D plans, as well as the smaller regional plans. Thirdly, we have completed doubling the size of our field force to 300 representatives, slightly ahead of plan. As we've communicated before, Genavix is highly promotionally responsive and we're excited about the impact of this new field team on Genavix growth. Lastly, we also continue to execute multiple initiatives to drive awareness, growth, and provide new mechanisms for patient access, including the launch of Vertex's first direct-to-patient telehealth platform, Informed Pain Care. This platform is accessible from Genavix.com and provides appropriate and independent telehealth evaluations for non-surgical acute pain patients, if eligible. We're also pleased that Genavix was recently added to the list of non-opioid medicines eligible for separate payment under the No Pain Act, effective retroactively to January 23rd. In summary, with the increased size of our field organization, our continued progress in securing payer and hospital coverage, as well as strong gains in formulary status, we remain confident we will triple prescriptions for Genavix in 2026. In addition, our strong reimbursement progress continues to position us to taper our patient support program over the course of 2026 and enter 2027 with a normalized gross-to-net. We continue to expect Genavix to contribute meaningfully to the $500 million plus we expect in revenue outside CF this year. I'll conclude with an update on the commercial initiatives for our emerging renal business. We're investing in the nephrology community for the long term, and povitacicept is the first in a series of potentially transformative medicines that tackle the underlying cause of four serious renal diseases, namely IGAN, PMN, AMKD, and ADPKD. We were thrilled with the interim analysis results of the Rainier Phase III study, with excellent results across the board in efficacy, safety, across all subgroups, and in the areas of greatest interest to nephrologists and patients. The results create a superb foundation for the commercial launch of a potentially best-in-class medicine. Our goal for povitacicept is to be physicians' first choice for their IGAN patients, given POVI's compelling trifecta of differentiated efficacy results, well-tolerated profile, and patient-centric administration characteristics due to its low-volume, monthly dosing via sub-Q auto-injector. Based on our market research and discussions with nephrologists, plus feedback from our field team engagements, we know nephrologists are looking for treatments in IGAN that meaningfully and rapidly reduce proteinuria in the patients they treat, as they see proteinuria as the key indicator of where the patient is headed clinically. Nephrologists also seek a favorable tolerability profile, and both physicians and patients communicate to us the need for a seamless treatment experience, which includes everything from access to patient support to monthly dosing, size of dose, and administration in an auto-injector. We believe that uniquely, POVI has the clinical profile and that Vertex has the capabilities to meet all of these needs. Our renal field force will be specialty-sized and large enough to cover nephrologists who see approximately 80% of US IGAN patients. We will target key facilities that represent a combination of renal centers of excellence, glomerular disease clinics, and key high-volume private practices. Our payer conversations are proceeding well in a US market where approximately 70% of patients have commercial coverage. We have a proven track record in securing broad and rapid access for our medicines and plan to establish the same for POVI and IGAN. And lastly, we know that the quality of the patient support provided is critical in the biologic space. With that in mind, Vertex programs to support POVI patients will enable speed to therapy and personalized support through the treatment journey, delivering a seamless experience of onboarding for patients and physicians alike. POVI in IGAN is the first component of our emerging renal franchise. We're excited to bring it to nephrologists and their patients. Based upon our work with them, we know they're excited to try it as well. We believe POVI delivers exactly what nephrologists are looking for in IGAN, and just as we've done for over a decade in CF, POVI's success will be driven by a field force delivering a high science cell fueled by a potentially best-in-class product broad reimbursement, and robust and high-quality patient programs. We are very excited to begin building our fourth commercial pillar and creating another multi-billion dollar franchise at Vertex. I'll now turn the call over to Charlie to review the financials.

Thanks, Duncan. As Reshman noted, Vertex's Q1 2026 results demonstrate our consistent strong performance and attractive growth profile. First quarter 2026 total revenue increased 8% year-over-year to $2.99 billion. CF global revenue increased 6% year-over-year, and new disease areas also contributed, with Casgevi delivering $43 million and Jernavix $29 million in Q1 sales, representing about 25% of total year-over-year growth for the quarter. By region, U.S. revenue growth of 7% year-over-year was driven by continued steady performance in CF and growing contributions from Kasjevi and Jurnavix. International revenue grew 9% year-over-year, driven by continued CF expansion, an increasing contribution from Kasjevi, and, as anticipated, a benefit from year-over-year changes in foreign exchange. First quarter 2026 combined non-GAAP R&D, acquired IPR&D, and SG&A expenses were $1.29 billion, an increase of 5% compared to $1.23 billion in the first quarter of 2025. Within total OpEx, non-GAAP R&D expenses were down 2% year-over-year, partly driven by the timing and mix of certain clinical trial expenses. In addition, certain POVI manufacturing expenses were included in R&D in 2025 and are now recorded in cost of sales following the positive interim analysis data. Non-GAAP SG&A expenses increased 30% year-over-year, driven primarily by commercial investments, with roughly 40% attributable to gernavics and pain and approximately one-third to renal launch programs. We also recorded $1 million in IPR&D expense in the quarter versus $20 million in the first quarter of 2025. First quarter 2026 non-GAAP operating income was $1.31 billion compared to $1.18 billion in non-GAAP operating income in the first quarter of 2025. First quarter 2026 non-GAAP effective tax rate was 19.6%. First quarter of 2026 non-GAAP net income was $1.1 billion, an increase of $93 million compared to the first quarter of 2025, primarily due to increased product revenue partially offset by increased operating and income tax expenses in the first quarter of 2026. First quarter 2026 non-GAAP earnings per share were $4.47 compared to $4.06 in the first quarter of 2025, reflecting our strong revenue growth and disciplined expense management. We ended the quarter with $13 billion in cash and investments after deploying approximately $344 million to repurchase more than 741,000 shares in the first quarter. this activity reflects our ongoing commitment to returning value to shareholders while maintaining the flexibility to act on strategic growth opportunities overall our priorities for cash deployment remain unchanged with a primary focus on investing in innovation Now switching to guidance. We are reiterating our 2026 total revenue guidance of $12.95 to $13.1 billion, representing growth of 8% to 9%. This outlook reflects continued solid performance from the CF franchise, driven by the Oliftrec launch, expansion into younger patient groups, incremental patients from the label expansion, and geographic expansion. We continue to have high confidence in our outlook for revenue of $500 million or more from non-CF products, driven by growing Casgevi infusions, where we have good line of sight given the length of the patient journey and a meaningful ramp in Gernavix prescriptions and revenue as gross-to-net normalizes through the second half of the year. Lastly, our revenue outlook continues to include an expected impact from foreign exchange net of our hedging program. Our outlook for full-year gross margin remains at just under 86%, reflecting the growing non-CF product mix impact and ongoing investments in manufacturing network and process development for various products. We are also reiterating our combined non-GAAP operating expense guidance of $5.65 to $5.75 billion, reflecting continued investment in our late-stage clinical pipeline and commercial infrastructure and activities for new launches and revenue diversification. We also continue to expect our non-GAAP effective tax rate to be in the range of 19.5% to 20.5% for the full year 2026. On the subject of tariffs, we do not expect any material impact to the income statement in 2026. We continue to evaluate the details of recent announcements and the potential applicability to Vertex. In summary, Q1 2026 was a very strong start to the year. Financial results are on track, commercial launches and diversification are gaining momentum, and we continue with targeted investment, both in innovation and commercialization, as the pipeline is advancing across our multiple disease areas. Our increasingly diversified commercial portfolio, now spanning three disease areas and soon to be four, with the establishment of the renal franchise, is driving new revenue streams and adding to our near and long-term growth profile. Vertex is well positioned to continue expanding its impact for patients, investors, and all stakeholders. These and other anticipated milestones of continued progress in multiple disease areas are detailed on slide 17. We look forward to updating you on our progress on future calls. I'll now ask Susie to begin the Q&A period.

We will now begin the question and answer session. To ask a question, you may press star then 1 on your touchtone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then 2. And our first question for today will come from Jessica Fye with JP Morgan. Please go ahead.

Hey, guys. Good afternoon. Thanks for taking my question. So you've talked about Reno one day rivaling the cystic fibrosis business in size. Can you speak to what needs to play out from here to realize that vision? And among your renal assets, which you see having the greatest long-term revenue potential? Thank you.

Hi, Jess. This is Reshma. I guess as a nephrologist at the company, maybe I can take this. And Duncan, please feel free to add. So, Jess, what we're talking about in our emerging renal franchise is four assets, COVID, four diseases, three assets, POVI for IGAM, POVI for membranous, enaxiplin for AMKD, and what we call VX407 in ADPKD. The reason I think that this has the potential to be as big, if not larger, than CF is that the diseases that these medicines treat are rare diseases, But they are common rare diseases, and when you add them all up together, they are well into the hundreds of thousands of patients. For example, we talk about 150,000 or so patients with IGAN in North America and Europe, 100,000 patients with membranous in the same geographies. For AMKD, that's another 150,000 or so patients. with the amplitude population not including the amplified population, which adds another 100,000, and 80 PKDs, about 300,000 patients. Of course, the first medicine that we're studying, DX407, can treat about 10% of that 300,000. So one, while each one is a rare disease, they are common rare diseases, and when you add it together, we're at hundreds of thousands of patients in just the Western world. The second is that in renal medicine, unfortunately, the outcome of these diseases is a relentless decline in renal function and a movement then to death, dialysis, and transplantation. Obviously, those are enormous burdens for society. I don't need to say much more about death, but dialysis in particular is exceptionally expensive. And while it allows you to live, it is a very, very difficult life and life expectancy is like very serious cancers like pancreatic cancer. And then last of that block, when we look at the emerging results For POVI, for example, in IGAN and membranous, you can look at the phase two. And for IGAN, you can certainly look at the phase three interim analysis results. As I said on the call, they are sparkling from top to bottom, safety, efficacy. These are the kind of medicine that can bring transformative value. When I think about AMKD, same thing. You look at the phase two results that we published in the New England Journal, 47.6% reduction in pertinuria is a very big deal. And when we think about ADPKD, no human results yet. But when you look at the mechanism of action. This is to say to properly fold the misfolded PC1 and what we see preclinically, another one where we think transformative effect. That's why we believe this is another vertical that can rival, if not crest, CF. Best renal asset. That's a tough one, Jess. I'm going to focus my attention for the here and now on POBE. It just looks sparkling. You can call it near-term bias because we just looked at the phase three results.

Thank you. The next question will come from Salveen Richter with Goldman Sachs. Please go ahead.

Good afternoon. Could you discuss the read-through from Mesa's recent data to the enaxiplin program? And also, could you just speak for that program, whether there were enrollment considerations to enrich for patients with larger APOL1 contribution to CKD, especially in the non-FSGS patients? Thank you.

Yeah. Hey, good afternoon, Salveen. On the maize data, you know we don't like commenting on other companies' assets and results. But I'll simply say at the top line, the Vertex results were 47.6% reduction in proteinuria as published in the New England. And my recollection is the maize data is 35.6% at the top line. Going below that is difficult because we're talking about groups of two and three patients with or without diabetes and such, and I just don't think you can make very much when you're down to two or three patients. What I will say is I'm very happy about the decision we made early on to not mix a heterogeneous group and to focus our program on those with heavy pertinuria, 2A4L1 alleles, and reduced kidney function, and not study those who have a comorbid condition like diabetes. Instead, what we did is study those people in a separate trial called Amplify, along with a group of patients with lower pertinuria. That trial has done enrollment, and I do expect to have results in the second half of this year.

The next question will come from Brian Abrams with RBC Capital Markets. Please go ahead.

Hey, guys. Thanks so much for taking my question. With the POVI launch not too far off, what do you think you'll need to convey to KOLs and community physicians to convince them of Hovitaciceps differentiation and overcome first mover advantage by competitors? Thanks.

You bet, Brian. Let me ask Duncan to take that. He's been spending a lot of time with nephrologists both in academic institutions and centers of excellence as well as in the community. Duncan.

Brian, good afternoon. So one comment before we dive into your answer. I just made the point that obviously this is a huge market opportunity with about 160,000 patients. In the US, it's five times bigger than CF, for example. And the vast majority, about 75% of those patients, are nowhere near the Cadego guideline goal in terms of proteinuria. So the opportunity is significant. We've been engaging through market research and other mechanisms with many nephrologists. And essentially, they tell us they're looking for a product that significantly impacts proteinuria. We'll come back to that. is well-tolerated and is easy for patients to use. And we believe that povitacet uniquely meets those needs. We think it has the sort of winning trifecta of incredible clinical effects As you heard in the prepared remarks, things like the rapid, deep, and sustained reduction in proteinuria, as well as GDIGA1 and hematuria, it has a supremely favorable tolerability profile and very attractive dosing and administration. So, as you know, it's once a month, it's a small volume dose, and it's delivered by an auto-injector. So we think we have an incredible product, as we saw in the clinical data. We also know from our market research that those nephrologists that distinguish between BAF April and April alone, the vast majority of them prefer dual inhibition with BAF. and April. And in our patient market research, the vast majority of patients prefer monthly dosing over weekly dosing. In fact, eight times more patients prefer monthly dosing to weekly dosing. So in terms of the profile of the product, matched against the needs of the physicians and patients, we think we have a best-in-class asset on our hands. And I would also add on the commercial capability side, We know how to execute a high science cell. We know how to secure rapid, deep, and broad reimbursement. And we know how to build patient support programs, which are incredibly important in the biologic space, as we have done for the last 12, 13 years or so in cystic fibrosis. So We're feeling really good about the profile of provitacicept. We are getting ready for launch, and we're going to be ready to go the day the FDA give us regulatory approval.

The next question will come from Jeff Meacham with Citi. Please go ahead.

Good afternoon, guys. Thanks so much for the question. I have two quick ones. So on pain and on 993 in particular, You know, as you guys have got commercial experience with your Navix, are there settings where an IV modality is perhaps a better fit in the clinical practice? I imagine that's maybe the hospital setting in the Cuba one to obviously get your perspective. And then on POVI, you know, congrats on the quick filing in IGAN, but looking beyond PMN and You know, is it worth it to do a basket study? Are there other autoimmune indications that make, you know, sort of that you could have the most differentiation for POVI and then maybe have the highest probability of success? Thank you.

Hey, Jeff, this is Reshma. On the pain portfolio and whether or not an IV medicine would be helpful, I think it would be helpful to have an IV medicine. And what we're really looking to do here, and the reason we have not only sucetragine or genavix, but 993 and additional NAV18s, but very importantly, NAV17s, is to make sure that we have the best medicine, whether it's PO or IV, and that formulatability into IV is one of the features that we're looking at and are interested in. Switching then to POVI and where we see things go, IGAN is already done in terms of the interim analysis and filing. Membranous phase three is already underway. Myasthenia phase two is underway. There are some additional B-cell mediated diseases that we are thinking about, and I do think a basket study is a very efficient way of evaluating those conditions through phase two development. I won't say much more about exactly which conditions, but suffice it to say, There are some B-cell mediated conditions, autoantibodies are important, where we think POVI would fit nicely. And I do think that going about this by way of basket studies and efficient phase 2, 3s are the right way to go. You'll be hearing us talk more about POVI and our immunology portfolio in the coming months and in the coming time. But I like your idea.

Thank you, Rachel.

And the next question will come from Corey Kasimov with Evercore ISI. Please go ahead.

Hey, good afternoon, guys. Thanks for taking my question. I wanted to follow up on Salvin's question on anoxiplin. And when you think about the pending data from Amplified looking at AMKD patients with moderate proteinuria or diabetes, What's needed in this population for a clinically meaningful benefit to justify advancement in this patient segment? Thank you.

Corey, I would say that generally speaking in renal medicine, we've been thinking about double-digit improvements as being valuable. By that, I don't mean 10% or 11%. I would say if we can show 30% improvement, you know, some number between 20 and 40%, 25 and 50%, some substantial double-digit improvement in proteinuria on top of standard of care, of course. So on top of ACEs, ARBs, ERBs, et cetera. That would be meaningful. And we'll be able to see how we fare shortly. The enrollment's done. It's a 12-week study. So we'll be able to tell you the results in the near term.

That's very helpful. Thank you, Reshma.

You bet. The next question will come from Kyle Yee with UBS. Please go ahead.

Hey, this is Mike Yee from UBS. Povey, do you believe that you're, on the efficacy standpoint, that your differentiation on EGFR will be able to come through over 9, 12, or 24 months versus, say, Otsuka, which I think is presenting their EGFR nine-month data, I think, next month, and then their two-year data coming up. And so I just wanted to think about where you would start to see differentiation for yours in a read-through to their data that they're going to present. And then on the safety component for Povey, Reshma, can you talk a little bit about the hypogamma globulinemia, and I think there are some questions around whether 150 or 300 matters, and the noise within the assay, and the timing of the measurement, and why you don't think that would be any issue here for POBE. Thanks.

Yeah. Start with safety and the question on hypogamma globulinemia, and then we'll go to efficacy. the results are really terrific. Because POVI and any medicine that works on April or back April, in essence, is modulating B cells, you do need to think about the safety profile. And in the safety profile, the domain to think about is infection. So specifically, what we focused on and what I was very pleased to see is we can get this level of efficacy on pertinuria, on hematuria, on GDIGA1, on getting down to these very low levels, less than 0.5 grams per gram, which is the important clinical threshold, we can get down to those levels with a very favorable safety profile. So on infection, most of the infections are mild to moderate, think upper respiratory infections. There's no opportunistic infections, no uncommon infections. The SAEs of infection are low and balanced. It's exactly 0.5% in the placebo group and the same exact number in the POVI-treated group. So that looks really nice. With regard to the actual immunoglobulin levels, and let's focus on IgG, the IGG levels of less than 300 or 150 or 200. Some people use 400. These thresholds are important because that's how people set up their trials and that's how the trials may have certain actions taken. You are correct. Each trial defines a different threshold. You measure it a different number of times. Some people measure it monthly like us. Other people measure it quarterly. Some people require multiple measurements to call it less than that threshold. Others require a simple one level. So it's not very easy at all to cross-compare. The important thing, though, Michael, if you're asking me, hey, is there anything there that gives you concern? None at all. The important thing to look at is the infections, and the infections look very balanced between these groups. On efficacy, you ask about GFR, which is the regulatory enabling endpoint, right? So the regulators have said, Pertinuria is acceptable at nine months for accelerated approval, but they are looking for two-year GFR for full approval. Note, however, GFR is actually not the hard endpoint in renal medicine. The hard endpoint is death, dialysis, or transplantation. That's what we're really trying to avoid. It's just that that endpoint takes a long time, and so the acceptable regulatory enabling endpoint for full approval is GFR. The reason I think that the pertinuria is so important is when you think about that hard endpoint of death, dialysis, and transplantation, which takes years to develop, the thing that most proximally reflects that is pertinuria. And what I would do is think about pertinuria, okay, if I got one point of pertinuria improvement more than any other medicine, two points, five points, ten points, I'll count that over years. And you start to see why pertinuria is so very important. The agency has said very clearly that we're not allowed to share GFR, but they've equally said that they need to see GFR to provide accelerated approval. So what I would say is any medicine in IGAM that gets accelerated approval has the pertinuria that we've already shared and has GFR that the agency finds comforting.

Thank you.

The next question will come from Tazeen Ahmed with Bank of America. Please go ahead.

Hi, good afternoon. I wanted to ask what your thoughts are, Reshma, on the read-through from this positive IGAM study that you provided the top line for recently onto the PMN study that you're currently running for POVI. And then secondly, on the CF pipeline, I just wanted to get a sense of what data you plan on showing in the second half of the year for 828, and what would be considered good data there. Thanks.

Okay. Let's do IGAN first. Nazeem, I see some data that are from the IGAN as very important. and positive for membranous because now we've studied hundreds of patients over a nine month period, which is additive information to the phase two results. So things like PK, PD, the reduction in proteinuria, I see all of that in terms of efficacy is important. Clearly, the auto antibody of interest is different. One is PLA2R. That's what we're looking for in membranous versus GDIGA1. So that has to play itself out. But in terms of those other parameters, I see that as really positive. The other variable that I see as very positive is on safety. The fact that there is such a favorable safety profile, I see as a positive. Of course, the IGAN study was in 80 milligrams, and in the membranous study, we're studying both 80 and 240 to pick one. Lastly, I feel very good about the way the study is being conducted. That is to say, low discontinuations in terms of study discontinuations and treatment discontinuations. And I also feel really good about the background therapies. Very important to look at as you think about doing these studies in contemporary practice. Switching now to CF. The 828 results are a CF cohort after we've completed the healthy volunteer study. And so what you should see is data from the single dose that's gone into the patient cohort. And you should expect to see sweat chloride results and safety results as well. It's a small cohort, so you shouldn't expect anything on PPFEV1. But the readout, the efficacy readout that we're looking for is sweat chloride. So you should expect us to share that.

The next question will come from Evan Segerman with BMO. Please go ahead.

Hi, guys. Thank you so much for taking my question. I want to expand a little bit on the discontinuation of VX522. Anything else you can share on the tolerability issues? And then looking ahead, do you plan to utilize another technology to help these patients that are not currently treatable with their current portfolio? Thank you.

Yeah. Good afternoon, Evan. On VX522, What I can tell you is that the tolerability issue that we have been monitoring and sharing with you now that the study is being discontinued has to do with lung inflammation, like an inflammatory response, probably in response to the LNP that's being used to deliver it. And I say that because this is not unusual in that regard. So with regard to what are we gonna do for our patients? I wanna be clear about the fact that our commitment to CF is absolute and steadfast. If there is any more that we can do for our patients in the 95% group, we're gonna be the ones who do it. And for our last 5,000 or so patients, we're going to work on that as well. I expect that the challenge is going to continue to be delivery. And in terms of modalities, we're going to have to go back to the drawing board on modalities. These last 5,000 are going to require some nucleic acid therapy, right? Because they simply don't make any protein. And so the big question is, not necessarily what the nucleic acid therapy is. We have some big ideas. There are ideas, and they're, I think, obvious. But how do you deliver it without having this lung irritation? And that's what we're going to be working on.

Great. Thank you. The next question will come from David Rissinger with LayerRank Partners. Please go ahead.

Yes. Thanks very much, and thanks for all the updates. My questions are on Jurnavix. Could you maybe help reconcile the $29 million in revenue in the first quarter with the volume of either prescriptions or pills? And then given that Jurnavix has PBM coverage for 240 million lives now, which is over two-thirds of the population, Does Genavix need to achieve more employer opt-ins and more tier two formulary positions for the gross to net to normalize? Thanks so much.

Duncan, do you want to take that one?

Sure. Good afternoon, David. So in terms of the first part of your question, I would say overall, by the way, we are extremely pleased with the progress on Genavix. We are fully on track in terms of our prescription numbers and our revenue numbers. In terms of reconciling quarter one dollars and volume, as I mentioned in the prepared remarks, we did see a small but relatively normal channel inventory destocking in quarter one, between quarter four, 25, and quarter one, 2026. It's also true that in that quarter, of course, Medicare Part D plans are resetting, which can lead to higher copays and more abandonment. And then also, we saw the traditional reduction in the number of elective surgeries in January, which were a little bit harder impacted this year because of the sort of fairly strong flu season. So overall, I would say that the quarter one performance was in line with our expectations. We are absolutely on track to more than triple the number of prescriptions that we delivered in 2025. And to answer the second part of your question, we have just achieved our 240 million lives covered, as you know. We're very happy with that. And actually, in an update since we finalized the script, you know that we've been working on four Medicare Part D plans And in the script, we communicated that we had secured coverage at one of those four plans. We've actually secured coverage at two of those four plans and are very close to securing coverage at a third of those plans or the third of those plans. And that coverage starts from between May 1st to July 1st. So I don't think we need to be focused on downstream plans, and employer plans. As we have said all along, as we secure the final pillars of access, the patient support program will taper down. Our gross-to-net will normalize by the end of the year, and you will see revenue significantly accelerate and accelerate faster than prescription growth as we go through the balance of the year.

Thank you. The next question will come from Terrence Flynn with Morgan Stanley. Please go ahead.

Great. Thanks. Just two questions for me. I was just wondering if you can tell us if there's a defined percentage of FSGS patients in the amplitude phase three trial for Anaxaplan, if there's a cutoff or if it's just pretty much all comers and that mix will be dictated by who's enrolled. And then for a lift track, just curious to know if you're seeing anything different in terms of patient mix this quarter versus prior quarters in terms of the three different buckets that you guys have focused on. Thank you.

Terrence, I'll take your FSGS question for Phase 3 and ask the plan, and I'll turn it over to Duncan. I won't be able to share what the baseline characteristics look like because we haven't looked at those data and we don't know those data. But what I will tell you is that what's common in AMKD is because they tend to be heavily proteinuric, so we're talking about people who are coming in with proteinuria of 0.7 grams or more, they often tend to have a biopsy because that's a lot of proteinuria and people are trying to figure out whether there's an underlying identified cause So it wouldn't surprise me at all if many, maybe even the majority of patients in the AMKD phase three amplitude trial actually were known FSGS patients because a lot of these patients actually do get a biopsy. Not all of them, but it's not an uncommon act. So that would be my guess, but I don't have a formal answer for you. Fortunately, the IA enrollment is complete. The Full study enrollment will complete this year, and we fully expect to have results from the IA in early 2027. So we'll know the answer real soon. Duncan, a lift track characteristics, transition, new, yuck.

Yep, Terrence, thank you for the question. So yeah, I'm assuming the three categories you're talking about are the naive patients, the discontinued patients, and the transition patients. I would say that we see continued strong progress in all of those. Once we have both regulatory approval and reimbursement, we see the naive patients coming on first. Then we see the discontinuation patients coming on. And then finally, the transition patients are moving on to a lift track, indeed, exactly as we desire. So at this point, essentially, I would tell you that All new patients are going on to a Lyft rec. No one is going on to Trikafta. They're all going on to a Lyft rec. We see the discontinued patients largely moving on to a Lyft rec, and the vast majority, of course, of our patients now are transitions from Trikafta to a Lyft rec exactly as we would expect. So the three drivers, really, of a Lyft rec growth this year are continued uptake in the U.S., more European countries securing reimbursements, and the expanded labels, for example, the additional 800 patients that were recently included in the most recent labeling updates. So hopefully that answers your question, but we're seeing essentially a similar profile to that which we saw before, and super happy that we are well over a billion dollars on the lift track at this point.

One more question, please, Chuck.

And the next question will come from Ellie Mural with Barclays. Please go ahead.

an efficacy or safety perspective. And I guess as you think about the CF landscape broadly, how are you thinking about sort of the bar set by a lift track versus where you see room for incremental improvement? Thanks.

Elliot, we couldn't catch the first part of your question. Would you restart, please?

Sure. Sorry about that. Let me know if you can't hear me now. Just another question on a... You can hear me? Okay, good. Just on 828, just to follow up on the earlier question, I guess, what are you seeing as a bar for what you would want to see to bring this forward from an efficacy or safety perspective? And then just as you think about this cystic fibrosis landscape overall, how are you thinking about sort of the bar set by a lift track versus where you see room for improvement? Thank you.

Yeah. When we had Trikafta and were working to see what the ultimate need was, honestly, Ellie, it was a little bit easier to see. As amazing as Trikafta is, we could see that a once-daily medicine would be better for patients, and we could see that getting more CFTR protein function, that's to say more sweat chloride, more patients below the diagnostic threshold of 60 and the normal level of 30 would be advantageous. Now, fast forward to where we are today with the lift track. And genuinely, there is very little unmet need. And so it's going to take something special for us to advance. And that's why we're looking at VX828. We're looking at VX 581, and we're looking at VX272, because we want to really interrogate to see if there's more that we can bring to the table. And what I'm really saying in the event it's unclear is this. Today, 90% of people, if you start at a young age, which Ali is now approved down to six years old, and we're filing for two to five years old, 90% are less than 60. Two-thirds of our patients are at sweat chloride that's below normal. And this is with a once-a-day medicine. And now when you think about it, everyone has, Duncan, described all our new patients, all our young patients that are coming on to Allie, there's very little room for improvement here. So if it's possible, we're going to be the ones who do it, but it's getting really, really tough because we're already down to once a day, good-looking DDIs, excellent sweat chloride function with two-thirds normal. It's tough. So if we see it, we'll certainly let you know, but that's why we're being so particular and bringing these number of medicines forward to see if anything can be better than a lift tracker.

Great. I think we'll wrap there. Chuck, can you give the replay information?

Will do. This will conclude our question and answer session, as well as our conference call for today. The conference has now been concluded, and thank you for attending today's presentation. A replay of today's event will be available shortly after the call concludes by dialing 1-877-344-7529 or 1-412-7000. 317-0088 using replay access code 102-08-180. Thank you for your participation. You may now disconnect.