Vertex Pharmaceuticals Incorporated

Good day and welcome to the Vertex Pharmaceuticals first quarter 2025 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. To ask a question, you may press star then one on your touchtone phone. And to withdraw your question, please press star then two. Please note this event is being recorded. I would now like to turn the conference over to Ms. Suzy Lisa. Please go ahead, ma'am.

Good evening, all. My name is Suzy Lisa, and as the Senior Vice President of Investor Relations, it is my pleasure to welcome you to our first quarter 2025 Financial Results Conference Call. On tonight's call, making prepared remarks, we have Dr. Reshma Kewalramani, Vertex's CEO and President, Stuart Arbuckle, Chief Operating Officer, Charlie Wagner, Chief Financial Officer, and Duncan McKechnie, SVP, North America Commercial Operations, and come July 1, 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, are pipelined 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 will now turn the call over to Reshma.

Thanks, Susie. Good evening, all, and thank you for joining us on the call today. Continuing the momentum from 2024, we've kicked off 25 with another quarter of strong performance across the board, growing and diversifying revenue as we execute on multiple launches, accelerating programs in pivotal development, and advancing the R&D pipeline. We continue to reach more patients with more products and delivered 2.77 billion in revenue in the first quarter, representing 3% growth versus Q1, 2024. This year, we are keenly focused on commercialization and we are pleased with the early launch dynamics and physician and patient feedback on Olivtrec, our fifth CF medicine, and Jurnavix, the first oral non-opioid for moderate to severe acute pain in more than two decades, both of which were approved in the U.S. in just the last few months. With these approvals and the continued global launch of Casgevi, our gene-edited therapy for sickle cell disease and beta-thalassemia, we are significantly expanding the number of patients we serve. We are also sharply focused on advancing the four programs currently in pivotal development. Sucetragine in diabetic peripheral neuropathy, Zamylocell in type 1 diabetes, Enaxiplin in APOL1-mediated kidney disease, and POVI in IgA nephropathy. Importantly, three of these phase three programs are on track to complete enrollment of the interim analysis cohort or the full study this year, setting up a series of potential filings in 2026. And as we approach the one-year anniversary of the acquisition of Alpine Immune Sciences, I wanted to highlight two big recent povitacicep-related milestones. First, we completed enrollment in the interim analysis cohort in the Phase III Rainier IGAN trial. And second, we reached agreement with the FDA to advance POVI to pivotal development in a second indication, primary membranous nephropathy. This is a notable milestone as POVI continues to deliver on its promise as a pipeline and a product with best-in-class potential. The start of the POVI membranous study will also mark our fifth program in pivotal development. Tonight, I'll limit my R&D comments on the pipeline programs with the most significant new information to share, specifically CF, pain, type 1 diabetes, and the kidney programs, starting with CF. Following our December U.S. approval of a lift track, we have gained MHRA approval in the U.K. and a positive CHMP opinion in the E.U. As a result, we expect potential approval from the European Commission for a lift track in the second half of this year, along with potential approvals in Canada, Australia and Switzerland. These approvals are in addition to the European Commission's early April approval of CAF TRIO for rare mutations, which followed similar approvals for Trikafta rare mutations in the U.S. and Canada late last year, adding hundreds of additional eligible patients in North America and thousands in Europe. These approvals are a direct result of the team's decades-long, painstaking work to establish and verify the hypothesis that the three unique binding sites of our CFTR modulators results in overall protein stabilization and have the potential to transform the lives of nearly 95% of patients with CF. Stuart will share more on the U.S. Electrek launch shortly. Next on the horizon for our CF small molecule program is the NextGen or NG3.0 CFTR regimen. With this program, we seek to reach our longstanding goal of bringing most, if not all, patients with CF to normal levels of CFTR function. The backbone of this NG3.0 combination is VX828, the most efficacious CFTR corrector that we have ever studied in vitro. It is completing Phase 1 development and we remain on track to initiate a study with VX828 in patients with CF before the end of this year. For the ongoing Phase 1-2 study of VX522 for the approximately 5,000 or so patients, who cannot benefit from our CFTR modulators, we have recently implemented a temporary pause to the study as we assess a tolerability issue. Given that this remains an active clinical trial, we won't be providing any additional details at this time so as to maintain study integrity. We will update you when we know more. Moving next to the pain programs. First, the Phase III study of sucetragine in diabetic peripheral neuropathy, a chronic peripheral neuropathic pain condition that affects over 2 million Americans annually, is well underway with ongoing enrollment and dosing. As a reminder, sucetragine has fast-track designation for peripheral neuropathic pain and breakthrough designation for diabetic peripheral neuropathy. Next, I'm very pleased to share that the study of oral VX993, another NAV1.8 inhibitor, in acute pain post-bunionectomy is on track to complete this quarter, and we expect to report results from this trial in the second half of this year. VX993 has fast-track designation for acute pain in both the oral and IV formulations. Lastly, we continue to make solid progress with additional NAV1.8 inhibitors beyond VX993, as well as in our NAV1.7 pain signal inhibitor program that may be used alone or in combination with NAV1.8 inhibitors. Transitioning now to type 1 diabetes. Zamyla Cell remains on track to complete enrollment and dosing of its pivotal study this quarter, positioning us for global regulatory submissions in 2026, if the data are supportive. Recall, we expect about 60,000 severe type 1 diabetics who may potentially benefit from this first Zamyla Cell submission. Based on the high unmet need in T1D and the transformative nature of this therapy, Zamyla Cell has multiple global regulatory designations, including RMAT and FastTrack in the US, Prime in the EU, and the Innovation Passport in the UK. In our other T1D work, following the recent data from VX264 or the Cells Plus Device Program, we have returned this approach to the research stage. We continue to make preclinical progress on our other approaches to cloak the VX880 cells from the immune system. These cells have already demonstrated transformative efficacy. These approaches include alternative immunosuppressive regimens and gene editing to make hypoimmune islet cells. And we look forward to updating you as these programs advance. Finally, a few updates on our kidney portfolio, which now has clinical stage programs in four renal diseases, IgA nephropathy, AMKD, membranous nephropathy, and ADPKD, or autosomal dominant polycystic kidney disease. Starting with povitacicept, a potential best-in-class dual antagonist of the BAF and APRIL cytokines, which play a key role in the pathogenesis of B-cell-mediated autoimmune diseases. First, in IGAN, as mentioned earlier, I am very pleased to share that we have completed enrollment in the interim analysis cohort of the Rainier Phase III trial. Once this cohort completes 36 weeks of treatment, we will conduct the interim analysis, and if positive, it will support filing in the first half of 2026 for potential accelerated approval in the U.S. In addition, our program to support the launch of POVI with a subcutaneous auto-injector for monthly at-home administration is well underway. And for full approval, we are making strong progress towards our goal of enrolling the complete cohort of 480 patients, in whom we will assess eGFR through week 104. Second, based on the positive results from the Ruby 3 basket study, we have reached agreement with the FDA to advance POVI to pivotal development in membranous nephropathy. Beginning in the second half of this year, we are planning to initiate a single Phase 2-3 adaptive study of POVI versus standard of care with the primary endpoint of complete remission at week 72. Next, two highlights on enaxiplin for APOL1-mediated kidney disease, or AMKD. First, we remain on track to complete enrollment in the interim analysis cohort of the AMPLITUDE pivotal trial this year. AMPLITUDE is a study of primary AMKD, that is to say, patients with two ApoL1 variants and no additional renal-related comorbidities. After completing enrollment, when this cohort reaches 48 weeks of treatment, we will conduct an interim analysis. If positive, we will be poised to file for potential accelerated approval in the U.S. Second, based on the positive proof-of-concept results of inoxiplin in primary AMKD, the momentum in the Phase III study, and interest from the community, we recently initiated the amplified study. Amplified is a Phase II proof-of-concept study of enoxiplin in patients with AMKD and other comorbidities, including type 2 diabetes. This study is enrolling and dosing patients. To close on our kidney pipeline, a few comments on VX407 in autosomal dominant polycystic kidney disease or ADPKD. VX407 is a first-in-class small molecule protein folding corrector that is designed to target the underlying cause of ADPKD by restoring PC1 protein function, thereby reducing total kidney volume and preventing progression to kidney failure. As a reminder, by way of its mechanism of action, VX407 addresses up to 10% of ADPKD patients. And, as in CF, we will seek to expand the eligible patient population with serial innovation over time. We have completed the Phase 1 trial of VX407 and the PK and safety are supportive of advancement. The Phase 2 proof-of-concept study is designed as a 52-week, single-arm study of 24 patients that will evaluate the efficacy of VX407 as measured by the height-adjusted total kidney volume, and we are on track to initiate this study in the second half of this year. For five years now, at the end of my remarks, I've turned the call over to Stuart. I'll do so for the final time tonight. Let me acknowledge and thank Stuart once again for the incredible run at Vertex and wish him the very best in retirement. With that, I'll now turn the call over to Stuart and Duncan for a commercial update.

Thanks very much, Reshma. I'll focus my comments tonight on the CF franchise, including the launch of Eliftrek and the continuing global launch of Casgevi, building on the foundation we established in 2024. I'll then turn it over to Duncan to provide an update on the US launch of Genavix in acute pain. Starting with CF, with our existing portfolio of CF medicines, Kalydeco, Orkambi, Symdeco and Trikafta, we have continued to grow the number of eligible patients taking our CFTR modulators. As expected, we also continue to make regulatory and reimbursement progress that enables us to expand to younger patients. Kalydeco is now approved down to one-month-olds. Patients with rare mutations. Trikafta recently secured US and EMA approvals to expand the label for additional mutations, which means that the triple combination is now approved for mutations present in nearly 95% of all CF patients in our core markets. and patients in new geographies such as Brazil. In addition, as a result of better patient care, including the availability of our CFTR modulators, people with CF are now living longer than ever before. Now turning to the Oliftrec launch, our fifth CFTR modulator approved to treat the underlying cause of CF. In phase three studies when compared head to head with Trikafta, Oliftrec demonstrated non-inferiority on lung function and further improvements in CFTR function as measured by sweat chloride. Oliftrec was also approved by the FDA for an additional 31 mutations not covered by the Trikafta label and offers the convenience of once daily dosing. Recall too that a LiftTrac carries a meaningfully lower royalty burden for Vertex and extends our composition of matter pattern protection from 2037 for Trikafta into 2039 for a LiftTrac. We're pleased with the early US launch progress and we're seeing uptake in all of the patient groups eligible for a LiftTrac. Those naive to CFTR modulators or with newly approved rare mutations where we have seen the fastest initial uptake. patients who've discontinued one of our other CFTR modulators and patients switching from Trikafta who seek greater improvement in CFTR function and or the convenience of once daily dosing. Oliftrec prescriptions are off to a strong start as patients and physicians familiarize themselves with the Oliftrec clinical data including statistically significant lower sweat chloride than Trikafta the liver monitoring requirements when initiating therapy, and the convenience of once-daily dosing. We continue to expect the majority of patients in the US who are currently on CFTR modulator therapy will switch to a Lyftrec over time. We also look forward to launching a Lyftrec later this year in the UK and other countries pending ongoing regulatory approvals. Transitioning now to Caschevy. are transformative, one-time treatment for patients with sickle cell disease and beta-thalassemia. Since regulatory approvals in late 2023 and early 2024, the rollout of Casgevi is progressing as we expected and gathering momentum across all regions. ATC activations and patient initiations continue to increase. as we now have more than 65 authorized treatment centers, nearing our goal to activate approximately 75 total ATCs globally. We're also encouraged to see many ATCs have now collected cells from multiple patients. As to specifics on the other important marker of our progress, since launch approximately 90 patients have now had their first cell collections, meaning they have begun the patient treatment journey. Encouragingly, more than twice that number of patients has been referred by their physicians to ATCs to initiate the treatment process. And in Q1, 8 patients completed their treatment journey and received their infusions of Casgivy edited cells. With regard to access and reimbursement, we continue to make progress on the Kastjevi payer front. In the US, formal commercial coverage is either in place or provided through single case agreements. For Medicaid patients, who represent about 45% of total patients, the majority of states have joined the CMMI demonstration project for cell and gene therapy access model, enabling fertility coverage for these patients and providing an alternative, seamless approach for ATCs and states to the existing case-by-case coverage and state agreements. In Europe, we have now secured reimbursed access for both sickle cell disease and beta thalassemia patients in England, Wales, Denmark, Austria and Luxembourg. And in the Middle East, we have reimbursement in Bahrain, Saudi Arabia, and recently added coverage in the majority of Emirates in the UAE. The interest in Kastjevi continues to be incredibly high in the sickle cell disease and beta thalassemia patient and physician communities globally, and uptake is accelerating as access and reimbursement are secured and familiarity with the process for collecting cells and infusing this truly transformative treatment grows. The impact of Kastjevi is best captured by the real-world feedback from patients, caregivers and physicians. It's been inspiring to hear that Kastievi patients now feel able to live their lives in ways they never have before, whether that means having the energy to play with their kids, taking up snowboarding without fear that the cold might bring on a pain crisis, or investing in their education and careers, given expectations now for a longer and healthier life. It is a privilege to be part of their journey. I'll close my comments today by saying what a true honour it has been to serve patients, employees and shareholders, as the Chief Commercial Officer and Chief Operating Officer at Vertex. The company has never been better positioned from a scientific, commercial, financial or people perspective, and I look forward to following its continued success, including with Duncan as the new Chief Commercial Officer. I'll now hand over to Duncan to provide an update on the latest chapter in our commercial diversification with the exciting launch of Genavix in moderate to severe acute pain.

Thank you, Stuart. It has been a privilege to know you for over 35 years and work with you at Vertex for the last 12. I wish you every happiness in your retirement. Genavix received FDA approval on January 30th and has been available at retailers since mid-March. Although it's early days, we are seeing a strong reception for a novel, non-opioid option for the treatment of moderate to severe acute pain. We're pleased with the early launch, including broad retail pharmacy stocking, progress of reimbursement discussions and payer coverage, P&T committee reviews, the breadth of usage to date, and media coverage. To give you a sense of Genavix's progress thus far, I'll detail several key elements of our launch plan. One, let me start with retail pharmacy stocking, which is crucial given the acute nature of pain. By mid-March, Genavix was available at approximately 33,000 pharmacy locations, including nearly every location for the three largest pharmacy chains in the country, as well as over a dozen regional chains nationwide. Two, I'm also happy to report that we've made rapid progress with payers, which is a testament to their appreciation for the Genavix clinical profile and the importance of a novel non-opioid option in the treatment of acute pain. As of May 1st, across commercial and government payers, 94 million lives already have covered access to Genavix and 42 million have unrestricted access without the need to complete prior authorisations or step edits. With commercial payers, our negotiations continue to progress favourably. We've recently reached a formal coverage agreement with one of the large national pharmacy benefit managers to make Genavix available to their customers, collectively representing 22 million commercial lives. In Medicare, we continue to engage with Medicare plans to secure off-cycle coverage in 2025 and 2026 coverage in line with Medicare bid cycle timing. For Medicaid patients, 10 state Medicaid plans are now providing unrestricted access to Genavix, meaning no prior authorization or step edit requirements, and co-pays as low as $3 to $5, as is common practice for Medicaid. We expect that coverage across commercial, Medicare and Medicaid payers will expand through 2025. Three, a key area of focus is hospital P&T committees. As a reminder, we are prioritising approximately 2,000 hospitals, many of which ladder up to 150 healthcare systems or integrated delivery networks. More than a third of these target healthcare systems have already taken steps to initiate P&T reviews of Genavix, and some have already added it onto their formulary. Turning to patients, our patient support programs are working as designed. to provide a smooth and positive patient experience so that eligible patients who are prescribed Genavix for their acute pain get access to the medicine for an interim period while payer coverage decisions are made. Five, shifting to the policy landscape, we are encouraged by the continued momentum and interest by federal and state policymakers to provide equal access to non-opioids. The critical need for non-opioid options was underscored by the presentation of new research at the American Academy of Pain Medicine in April. Our health economics analysis indicates that replacing just 25% of current acute pain prescriptions for opioids with non-opioids, like Genavix, could deliver annual cost savings of $4.5 billion to the healthcare system and could prevent up to 260,000 cases of opioid use disorder and approximately 9,000 overdose deaths over the next 15 years. With respect to state legislation, to date, nearly 35 states have already either enacted or proposed legislation to support the use of non-opioids. At the federal level, I'll highlight the No Pain Act, which in January began providing an add-on payment for non-opioids used in Medicare patients in the hospital outpatient or ambulatory surgery center settings. We continue to expect Genavix to be added near term to the list of medicines approved for this add-on payment. Lastly, an important indicator of our launch progress and a reflection of the unmet need in moderate to severe acute pain is that more than 20,000 prescriptions were successfully filled for Genavix as of April the 18th. While it is early days in the launch, we are very encouraged by the breadth of physician types writing prescriptions for Genavix, as well as the wide range of pain types being treated, which is aligned with Genavix's broad label. We continue to execute on the opportunity to transform the treatment of pain, while also creating another multi-billion dollar franchise for Vertex. To conclude, we are in a new era of commercial diversification at Vertex, and we look forward to bringing our transformative therapies to more and more patients and to keeping you updated on our progress. I'll now turn the call over to Charlie to review the financials.

Thanks, Duncan. Vertex's Q1 2025 results demonstrate our consistent, strong performance and attractive growth profile. First quarter 2025 total revenue increased 3% year-over-year to $2.77 billion. U.S. revenue growth of 9% year-over-year was driven by ongoing patient demand, higher net realized pricing, and the early launch of a lift track. As expected, ex-U.S. revenue in the quarter declined and was down 5% year on year. Recall that outside the U.S., Q1 2024 benefited from increased channel inventory due to the majority of Russia shipments occurring early in that year. In Q1 2025, Russia revenue was negatively impacted by the availability of an illegal copy product. Excluding the impact of the revenue decline in Russia, ex-USCF revenue growth would have increased in the low single digits. Included in Q1 total revenue was $14 million from Kastjevi and $10 million of collaboration revenue. First quarter 2025 combined non-GAAP R&D acquired IPR&D and SG&A expenses were $1.23 billion, an increase of 21% compared to $1.02 billion in the first quarter of 2024. The most significant increases in R&D and SG&A expenses versus prior year were due to rapid advancement of our broad pipeline, including clinical trials for IGAN, pain, and type 1 diabetes, as well as the build-out of commercial capabilities in pain. First quarter 2025 non-GAAP acquired IPR&D expenses were $20 million compared to $77 million in the first quarter of 2024. First quarter 2025 non-GAAP operating income was $1.18 billion compared to $1.34 billion in non-GAAP operating income in the first quarter of 2024. First quarter 2025 non-GAAP effective tax rate was 18.8%. First quarter 2025 non-GAAP earnings per share were $4.06 compared to $4.76 in the first quarter of 2024, primarily due to increased operating expenses as well as lower interest income. We ended the quarter with $11.4 billion in cash and investments after deploying approximately $425 million to repurchase more than 930,000 shares in the first quarter. Overall, our priorities for cash deployment remain unchanged. Now switching to guidance. Given the strong start and clear line of sight to the balance of the year, we are raising the low end of our 2025 total revenue guidance from $11.75 billion to to a revised range of $11.85 to $12 billion, representing growth of approximately 8% at the midpoint at current exchange rates. This outlook reflects our expectation for continued growth from our portfolio of CF medicines, including the ongoing launch of a lift-track in the U.S., followed by other regions later this year. We believe the illegal copy issue is isolated to Russia and is fully included in our outlook. Guidance also includes a continued ramp-up in Casgevi revenue as we treat more patients in geographies where we have secured regulatory approval and reimbursement. In addition, guidance reflects a revenue contribution from Gernavix primarily in the second half of 2025. As a reminder, we expect volumes will ramp ahead of revenue due to financial assistance programs that are designed to provide eligible patients with immediate access while we work to secure broad, sustainable payer coverage. Recently announced positive coverage decisions are included in our revenue guidance. As a result of these positive trends, and as implied in our guidance range, we expect growth to accelerate over the remainder of the year, delivering another strong year for Vertex in 2025. For combined non-GAAP R&D, acquired IP R&D expenses, and SG&A, there is no change to our guidance range of $4.9 to $5 billion for the full year 2025. Consistent with prior guidance, this includes approximately $100 million in projected IP R&D charges. We will continue to invest a majority of our operating expenses into R&D, given the momentum in our multiple mid- and late-stage clinical development programs with four and soon-to-be five Phase III studies ongoing and multiple Phase IIs. The planned increase in commercial costs in 2025 supports our increasingly diversified commercial portfolio, a full year of investments to support the launch of Dranavix and potential near-term launches. Given our differentiated business model and focus on specialty markets, we can make these targeted investments while maintaining attractive profitability and cash flow. We expect an immaterial cost impact from tariffs based on what we know today due to our low exposure to China and a geographically diverse supply chain. Additionally, much of our intellectual property is either in the U.S. or the U.K. Of course, given the dynamic nature of the tariff situation, including the potential for sector-specific tariffs, this outlook is subject to change. And finally on guidance, there is no change to our expected full-year 2025 non-GAAP effective tax rate in the range of 20.5% to 21.5%. In closing, Vertex yet again delivered strong results in line with our expectations in Q1 2025, growing and diversifying our revenue with the launch of two new products in the U.S., Eliftrek and Gernavix, continuing the global launch of Casjevi, and making significant pipeline progress across the portfolio. In addition, we now have five programs that are in Phase 3 or soon will be, and multiple additional programs with first-in-class and or best-in-class potential in the clinic in our early and mid-stage pipelines. 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. Before turning the call to Susie to begin the Q&A period, let me also add my thanks and congratulations to Stuart. Stuart is a talented executive and team player who has contributed enormously to Vertex. He's also a friend. As Stuart passes the baton, we look forward to welcoming Duncan to the executive team and to future earnings calls. I'll now ask Susie to begin the Q&A.

Thanks, Charlie. Chuck, can you get us started, please?

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. If at any time your question has been addressed, and you would like to withdraw your question, please press star, then two. And at this time, we'll pause momentarily to assemble our roster. And the first question will come from Jeff Meacham with Citibank. Please go ahead.

Awesome. Afternoon, guys. Thanks for the question. Stuart, congrats again on the retirement. Duncan, looking forward to working together. I just had a couple of quick ones, one on a leaf tract on the launch. What's been the feedback on utilizing sweat chloride as a biomarker more in practice? I wasn't sure if the conversations that you guys are having with pulmonologists on switching from Trikafta is more related to the dosing differential or the sweat chloride or maybe a combination. And then just on Gernavix, to get an update, maybe give us a sense for how you're thinking about the chronic pain indications and the design of those studies. I know you haven't had full FDA discussions, but as you look at the prior data, you know, maybe give us a sense for, you know, where you are with implementing maybe more novel strategies for that study. Thank you.

Hey, Jeff, it's Rachel. Let me start with the gernavics and chronic pain work, and then I'll turn it over to Stuart to talk a lift track. Really no new news to report to you, Jeff. We're on track to have our end of phase two meeting with the FDA this summer. I really like the study designs the team has come up with. We've done a lot of work on innovating and optimizing the clinical trial designs. And I do expect that we'll have an update for you this summer. Separately, but on a related note, the DPN study, the diabetic peripheral neuropathy study with the X548 is well underway. Enrollment dosing in that study is going well. Stuart Oliftrek.

Yeah, Jeff, on Oliftrec, I would say sweat chloride is not routinely used in clinical practice to assess CFTR function, although it's well understood as a measure of CFTR function. But it's not something that's being increasingly adopted in clinical practice, despite the Oliftrec data. And in terms of what do people find compelling about the Oliftrec profile, I would say it's really the sum of parts. So it's firstly the fact that it's demonstrated in large, long, robust clinical trials that it's non-inferior to Trikafta, which as we all know sets a very high bar in terms of FEV1. And then it is the improvements in CFTR function that people have the potential to access as measured by sweat chloride. Then reinforcing that improved potential efficacy, it's the additional 31 mutations in the that the FDA granted us versus the Trikafta label. And then lastly, but still very importantly for CF patients, it's the once a day versus the twice a day for Trikafta. So I wouldn't say it's one thing more than the others. It's really that combination of benefits that I think people are finding attractive about the Oliftrec profile.

The next question will come from Jessica Fye with JP Morgan. Please go ahead.

Hey, guys. Good afternoon. Thanks for taking my questions, and Stuart, congrats again. First, when you – maybe for Charlie – when you said you expect immaterial impact from tariffs, just to confirm, is that from the current tariffs, or is that if biopharma-specific tariffs are implemented? And maybe just for our comfort, can you give us a little more detail on Vertex's manufacturing footprint, particularly for a lift track, Trikafta? and how you think about the company's potential exposure to tariffs if they are implemented. And then just separately on the CF business, can you recap how we should think about the impact of the Russia issue and just lapping last year's sales that included Russia? Is that impact largely contained to 1Q? Or if it also impacts 2Q in subsequent quarters, can you just quantify what that headwind is? Thank you. Carly?

Yeah, Jess, I'm going to start with the CF impact. Listen, the year's off to a great start, and it's very much in line with our internal expectations. We commented in the fourth quarter about this isolated issue in Russia, and it's worked out exactly as we expected. The impact in the first quarter is about $100 million, and for the full year, it's $200 million total. And so all of that is included in our current guidance, which as you know, is 8% growth at the midpoint, which implies acceleration over the balance of the year. So we feel really good about where we're at. We can talk more about some of the drivers. I'm going to move on to the second part of your question on tariffs. Given how dynamic the situation is, Jess, I have to limit my comments to what we know today. And so for tariffs that have been announced and are in effect, there is an immaterial impact to Vertex. We have, I think, a very well balanced global supply chain. We have minimal exposure to China. The vast majority of our drug product manufacturing for CF is in the United States, and most of our IP is concentrated in the U.S. and the U.K. So for those reasons, the impact is immaterial. Again, there are all sorts of different tariff concepts that are being discussed, including sector-specific tariffs Until we know more about what might be implemented, I can't really size the impact for you.

Thank you.

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

Thank you. Good afternoon. Just following up on Aleph Trek, could you just walk us through who the early adopters are, whether there seems to be a significant portion coming from a certain pool of patients And then on Joinivax, with regard to the commercial payers here, can you speak to the nuances with regard to tiered and preferred versus non-preferred status in your overall plan for positioning? Thank you.

Sure thing, Salvi. And let me flip that question and ask Stuart to comment on a lift track and the segments we've talked about. on the kinds of patients, and then I'll ask Duncan to give you a little bit more color and texture behind the Jurnavix launch in general, including where we are with Payers Steward.

Yeah, so we are seeing uptake from a lift track in all of the patient groups that we identified. There are those that are newly eligible for a CFTR modulator, people who are sort of truly naive, have never been on one previously, which includes the rare mutations that Trikafta was approved for and the additional mutations that a lift track was approved for. And perhaps not surprisingly, we're seeing the fastest uptake as a percentage of the total pool in that group. But we are also seeing patients who've discontinued coming back to a CFTR modulator now that a new option like a LIFTREC is available. And we are also seeing transitions primarily from Trikafta because that is where the lion's share of CF patients are. And on those transitions, we continue to expect the majority of patients will transition to a LIFTREC over time. So we're really seeing uptake in all three of those patient groups. The fastest, perhaps not surprisingly, in people who've never had a treatment option to treat the underlying cause of their disease before. Duncan.

Thank you, Stuart. So to provide you with a little bit of context to the overall launch of Genavix today, we are incredibly pleased with the early progress. Although it's early days, we're seeing tremendous receptivity to a novel non-opioid option for the treatment of moderate to severe acute pain. And over the last three months, we've made great progress in terms of broad retail pharmacy stocking, advancing discussions with payers, initiating P&T committee reviews, as well as broad usage of the product by physicians in multiple different pain settings and conditions in line with the label. To get to your question specifically with regard to tiers and preferred versus non-preferred, I would say there's an enormous number of payers in the U.S. with an enormous number of different plan designs. And even within the same payer, different tiers can mean different things. So what I would focus on are our goals in this area, and that is to ensure that we have payer coverage in line with label. to ensure that that coverage has as few restrictions as possible for physician prescribing and that we ensure the product is affordable for patients and that we get to all of those outcomes whilst ensuring, of course, that we're optimizing the long-term value for Vertex. And so in terms of the progress to date, of the three big PBMs in the U.S., we have one of those three big PBMs now are covering Genavix for a total of 94 million lives. And I can tell you that the progress that we're making is in line with those overall goals to minimize restrictions for physicians, maximize access for patients, and optimize long-term value for Vertex.

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

Hi, good afternoon. Thanks for taking my questions. I wanted to ask one, a couple actually, on Gernavix. You talk about, you know, the momentum that you've been seeing in the early innings of uptake. I'm just curious as to what the profile of the patients are that are the earliest onboarders, and where in the treatment regimen are these scripts being written? Are they being written for patients on their way home? Are they being written while in the hospital, for use in the hospital, or is there any other scenario that we're not thinking about? And as you think about the second half of the year, in terms of acceleration of recorded sales, would you expect to start to see that already in 2Q, or is most of that going to be back-end loaded towards the end of the year? Thanks.

All right, Duncan, can I ask you to comment on settings of care, types of pain on the one hand, and then a comment on the volume versus revenue that we've talked about?

Absolutely. So in terms of the settings of care that we're seeing at this point, we're seeing Genavix used in surgery settings, in non-surgery settings. So, for example, we're seeing it used in knee, hip, shoulder replacement, for example, all the way through to ankle sprains, fractured wrists, etc. So, we're seeing broad uptake of Genavix in line with its broad indication, and it's being used by a broad range of physicians, for example, orthopedic surgeons, plastics, general surgeons, anesthesiologists, and, of course, pain specialists, and perhaps Importantly, we're also seeing repeat use by physicians and we're seeing very, very positive feedback from physicians in terms of the clinical effect of Genavix to date. In terms of the recorded sales, I think we've always said that we would see volume ramp in the first half of the year and then revenue in the latter part of the year as we secure payer coverage and can thus pair back some of our patient support programs.

The next question will come from Evan Siegerman with BMO Capital Markets. Please go ahead.

Hi, guys. Thank you so much for taking my question. I really wanted to touch on the uptake of Casgevi and really what are some of the key hurdles that are accelerating, that are kind of preventing the acceleration of the uptake. Is it fertility issues, health system trust issues, involvement intensity of the procedure? You know, how can you really work to overcome those so we can see really this product hit its maximum potential?

Evan, let me ask Stuart to take that one.

Yeah, Evan, thanks for the question. So we did see acceleration in Tastjevi in the first quarter building on the foundation that we built in 2024. The things that I think are leading to that acceleration and that we expect to continue as we work through the balance of 2025 is firstly establishing authorized treatment centers. Obviously, we need to have those so that patients can get treated. securing access and reimbursement. We've done that in large part here in the U.S. in both commercial and government paid, and increasingly we are securing reimbursed access for sickle cell disease and beta thalassemia outside of the U.S., and we announced a number of those in my prepared remarks. We're also seeing centers get more familiar with the treatment process. Clearly, this is a very innovative medicine. This is a very innovative a new treatment process for them and their patients to consider. And as they get more experience with the process, then that's also encouraging them to treat more patients. And I mentioned again in my prepared remarks that we've seen a number of our authorized treatment centers have treated multiple patients now. So I think all of those things contribute to the acceleration we saw in the first quarter, and we expect that to continue through the balance of 2025 and beyond, and it's that which gives me confidence that Casgevy truly does have the potential to be a multi-billion dollar product for Vertex.

The next question will come from Michael Yee with Jefferies. Please go ahead.

Great, thanks. We had two questions on Payne. I guess a lot of Wall Street is looking at third-party data, actually the script data in total tracks with what you guys are talking about, but a lot of people are seeing it sort of decelerate week over week. So maybe could you just confirm or talk to what you see week over week, and are you seeing an acceleration? And don't pay too much attention to data there. And then on 993, we have historically talked about, or with David and Fred, about how that could have significantly better exposure than SUSY. So could you just tell us about the data coming up in acute pain in the second half, and how would you compare that to the acute pain data we've already seen and figure out what to do with that? Thanks.

Yeah. Hey, Mike. It's Reshma. I'll take your second question first on VX993, and then I'll turn it over to Duncan to tell you a little bit about Gernavix, the momentum, the data we see, and help you sort of think through the commonly available IMS data and the data that we see, which also includes hospital. On VX993, so the big news from my prepared remarks on this one is the phase two trial in acute pain post-bunionectomy is going to complete in the near term. And I do expect to be able to share results with you in the second half of this year. What we're looking for in this program, it is a more potent molecule. It is a molecule where we can dose higher. And so we're looking forward to exploring the full dose range of 993. And what we're really looking for here is two things. One is to have yet another safe and efficacious NAV 1.8 inhibitor. And we want that because we are looking for options for NAV1.7, which is making its way preclinically. Certainly, our NAV1.7 inhibitor, when it makes its way into the clinic, could be co-formulated with Gernavix. That's one possibility. And a different possibility is that we have additional options like VX993. So that's one thing we're looking for. And second is, of course, If it is possible to do better than Jurnavix on efficacy, boy, we're going to be the ones who do that. And 993 is the first option behind Jurnavix to tell us if that's possible. Clearly, that will require cross-study comparisons and the limits that come with that. But I'm really happy to see this program move as fast as it has and to share results when available. Duncan, can you say a few words about the momentum of the Genavix scripts and the data sources?

Yeah, thank you, Mike, for the question. So maybe just to step back briefly, quickly, our goals in 2025 are really focused on securing payer coverage for Genavix, as well as P&T wins, whilst providing, of course, a seamless experience for patients. And as you've seen from our prepared remarks. We're incredibly encouraged by the progress we're making with payers and in terms of P&T coverage as well. In terms of the prescription data, I would make a couple of points. Firstly, that the latest total prescription data ending the week of April the 25th, so Friday, April the 25th, is 25,000 prescriptions. But I suspect that in the data you're seeing, you're seeing the IMS retail data, which does not include usage in hospitals, where we are seeing, of course, uptake. So the total number we're giving you includes both the retail data as well as hospital usage. I would say also that we are incredibly early in the launch. And it is incredibly common to see variability week by week in prescription numbers. For example, actually last week's data showed the fastest growth in retail since Genavix became available. So overall, I think as the payer coverage improves and our formulary adoption increases in hospitals and as physicians get more experience with Genavix, we'll continue to see growth of the product. So overall, we're incredibly happy with the progress Happy with the 25,000 prescriptions to date and looking forward to seeing those numbers grow over time.

Thank you. The next question will come from Lisa Baco with Evercore ISI. Please go ahead.

Hi. Congratulations on the quarter and thanks for taking the question. I was wondering if you could just provide a little more granularity as a follow-up question to one of the earlier ones on Gernavix. In terms of the prescriptions, how many of those patients, you know, were kind of fully paying patients? What are gross to nets? And how do you anticipate that evolving as the year goes on? What should be the target gross to net, say, by the end of the year? And just then one on type 1 diabetes, if you could just give us a little bit of color on the product Zimicel, the 60K patients, who those patients are exactly. I know there's a certain blood type within that as well. Thank you.

Thanks so much, Lisa. Let me ask Charlie to comment on gross-to-net, and I'll come back and tell you a little bit about Zamylocel.

Yeah, Lisa, keep in mind that we're only reporting out first quarter results here, and the approval was only in the first quarter as well. So gross-to-net is impacted by our patient assistance program. That's going to have a significant impact early in the launch while we work to secure broad and sustainable access. As we gain access, the patient assistance programs will fall away, and gross-to-net will start to normalize over the balance of the year. So I'm not going to get any more specific than that, but as we exit 2025 and into 2026, we should be approaching something that's a bit more normalized.

And then, Lisa, on the ZamylaSalt program – You'll remember that this first program targets about 60,000 people in the U.S. and Canada and Europe that are the most severe of our type 1 diabetics. These are people who have very brittle diabetes, high highs in terms of sugar and low lows, and multiple SHEs or symptomatic hypoglycemic episodes. So this first filing that we're looking for, the enrollment and dosing should be done in the near term. I said by the end of the quarter. We'll set us up for that filing sometime next year. That is for about 60,000 patients. We're then looking to expand that not only in terms of the patient numbers that can be served, including immunosuppression, but also then moving to alternative immunosuppression, and then, of course, our gene-edited programs and other programs to cloak ourselves so that immunosuppression is not necessary. So that's sort of the trajectory that we're looking at. First filings, I expect, will start next year, and that's for about 60,000 patients. Those are the most severe of our T1D patients. Thanks.

The next question will come from Ellie Murrell with UBS. Please go ahead.

Hi, guys. Thanks for taking my question. For Gernavix, the retail pharmacy stocking, you mentioned stocking now in around 30,000 retail locations. Can you put this in the context relative to the total number of retail locations you hope to be stocked at? And then in terms of the mix of scripts being filled in the retail versus the hospital setting, how do you expect that to trend over the course of the year? And then just lastly, what's the average duration for the script that you're seeing for Journavix in terms of those that are being written so far? Thanks.

Sure thing. Duncan, all three are for you.

Okay. Thank you for the question, Ellie. So to take them in order, In terms of retail pharmacy stocking, it has always been a key part of our launch plan to ensure that Genavix is easily available for patients. Obviously, they are being treated for acute pain and need to be able to get the medicine rapidly. So at the point of retail stocking, we were in about 95% of retail locations across the U.S., Obviously, that number varies day by day depending on when Genavix has been used and prescribed and comes out of the pharmacy store. But overall, we're looking for broad coverage and thus easy access in retail for patients throughout the year. In terms of the retail and hospital setting, maybe to step back a little bit, you may remember that in the acute pain market, about 15% of patients are in the pure hospital setting, about 35% of treatment days in discharge, and about 50% are in retail. And we always communicated that we expected to see the initial prescriptions for Genavix focused heavily in the discharge setting as the hospital formularies get up to speed. And that essentially is exactly what we are seeing. That trend will, we think, persist for the rest of the year. And in terms of the average duration of a prescription in moderate to severe acute pain, it of course varies by setting of care as to whether someone's inpatient or whether they are outpatient or in the retail setting, and also by type of medicine, say an opioid versus an NSAID, but the average is about 14 days, and essentially that is what we're seeing, the prescription duration for Genavix at this point.

Chuck, we'll take two more questions, please.

Yes, ma'am. The next question will come from David Rissinger with Laring. Please go ahead.

Yes, thanks very much. So I'm just hoping to clarify, regarding the PBM with 22 million lives, are those within the 94 million figure or on top? And are they unrestricted or restricted lives? And then separately, just a higher level question, please, Reshma. How is Vertex engaging with Washington leadership to educate elected leadership about the importance of both proven medical science and biotechnology innovation to the United States. Thanks very much.

Yeah. Hey, David, thanks for the question. Let me take the second question first and then I'll turn it over to Duncan to tell you a little bit more about the lives covered. We are and have been engaged with DC as well as with state governments on all of our medicines, CF, Caschevy, Gernavix, as well as the pipeline. I found those meetings to be constructive. And as far as our ability to ensure that the programs are reviewed in a timely fashion, that we get feedback from regulators, and that we are able to speak with those providing coverage, that has also continued. It's been business as usual and nothing out of the ordinary for us. Duncan, over to you.

Thank you for the question. So yes, the 22 million lives that you're referring to are included in the total 94 million. And in general, those 22 million lives fall into our definition of unrestricted, where we're looking for either no prior authorizations or no step edits.

Last question, Jack?

The last question will come from Gina Wang with Barclays. Please go ahead.

Thank you for taking my questions. Maybe one regarding the VX522. I know you cannot comment too much, but for the temporary pause, was that due to the, so I don't know if you can give a little bit more color regarding what are the tolerability issue that raised? And then, yep, so that's the first question. And then second question is regarding the If we look at the first quarter revenue and when we compare to the other CF launch in the past, how do you see this compared to the past? And do you expect the trend to pick up in the next few quarters?

Yeah. Gina, let me take the question on 522, and then I'll ask Stuart to comment about the ElevTrak launch. Obviously, we have the great benefit of having Stuart here, who has been involved in every single CF launch, so he'll have good line of sight on that. I don't have much more to add, Gina. Because VX522 is an active program and because we want to maintain study integrity, I'll just leave it at the fact that the team is assessing a tolerability issue. And once we're able to say more, we certainly will. And I'll turn it over to Stuart to tell you about a lift track.

Yeah, Gina, I think it's a little bit difficult to compare a lift track to other of our CFDR modulator approvals. But for one main reason, if you think about Orkambi, when it was first approved, you know, it was approved for mutations, which accounted for approximately 50% of CF patients, where previously all we had was Kalydeco, which at the time I think was probably around 7% ish. of genotypes for all CF patients. And then if you think back to when Trikafta came along, Trikafta, you know, took us from the sort of the 50% to the, on its first approval, to almost 90%. So there was such a lot of newly eligible patients who had never had a treatment to treat the underlying cause of their disease. Oliftrec's slightly different to that, right? There are additional mutations. There are additional patients who are now eligible for a CFTL modulator with the approval of Oliftrec. I talked about the the 31 additional mutations here in the U.S., but that's really hundreds of patients, whereas for Orkambi and Trikafta, we were talking about, you know, thousands, if not tens of thousands of newly eligible patients. So I think it's really difficult to compare and contrast the approvals this early on. What I can tell you is we're seeing uptake in all the groups of patients that we anticipated. naive patients, those who are discontinued, and those who are already on a CFTR modulator. And so we're very pleased with the launch of a lift track today, and we look forward to keeping you updated over coming quarters.

Thank you. That will conclude. Chuck, if you could please relay the information.

Yes, ma'am. This concludes our question and answer session as well as our conference call for today. Thank you for attending today's presentation. A replay of today's event will be available shortly after the call concludes here by dialing 1-877-344-7529 or 1-412-317-0088 using replay access code 10196550. Thank you for your participation today. You may now disconnect.