Vertex Pharmaceuticals Incorporated

Good day and welcome to the Vertex Pharmaceuticals fourth 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. 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, everyone. My name is Suzy Lisa, and as Senior Vice President of Investor Relations, I'd like to welcome you to our fourth quarter and full year 2025 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.

Thank you, Susie. Good evening, all, and thank you for joining us on the call today. 2025 was marked by excellent progress across the business, disciplined commercial execution in CF and the new product launches, meaningful pipeline progress, and robust financial performance. Fourth quarter results wrapped up another strong year, with 10% total revenue growth, and for the full year 2025, total revenue growth was 9%. As we executed on our plans for commercial diversification, full year 2025 results included cash chevy revenue of $116 million and dynamics revenue of $60 million in the eight months since launch. Building on the momentum of our Q4 and full-year 2025 results, in 2026, we are focused on increasing the number of patients we serve and further diversifying our revenue base. 2026 priorities include expanding leadership in CF, accelerating adoption of Keschevi, growing Jernavix both in prescriptions and revenue, and advancing the emerging renal franchise, starting with POVI in IGAN. We are entering an exciting period, and Vertex is well-positioned to deliver on the significant opportunities in front of us and drive sustained growth over the long term by combining commercial execution with serial innovation and rapidly advancing the pipeline across multiple serious disease areas. With that overview, I'll focus my R&D comments tonight on cystic fibrosis and the renal franchise. Beginning with cystic fibrosis, Oliftrec is a next-generation 2.0 CFTR modulator and is the fifth approved CF therapy in our portfolio. Oliftrec brings many important benefits for patients, once daily dosing, regulatory approval in additional mutations, and the best CFTR protein function restoration in our CF portfolio. As continued evidence of this, I am pleased to share the top-line results from the recently completed Oliftrec Phase III trial, this one in 2- to 5-year-olds. All patients in this study were on Trikafta and switched to Oliftrec on entry into the study. Oliftrec was safe and well-tolerated. and the sweat chloride data showed a mean reduction of 9.6 millimoles from a Trikafta baseline. Importantly, 65% of these Olivtrec patients achieved levels of sweat chloride below the normal or carrier level of 30 millimoles when treated through 24 weeks. This compares to 37.5% of patients at normal levels of sweat chloride at baseline on Trikafta. This magnitude of sweat chloride reduction is unprecedented for this age group in cystic fibrosis. We are on track to initiate global regulatory submissions for Oliftrec in the 2- to 5-year-old age group in the first half of this year. And as we continue the march down to younger age groups, I'm also pleased to share that the Oliftrec 1- to 2-year-old study has already initiated and enrollment and dosing are underway. Turning now to our next wave of CFTR modulators or next-gen 3.0 medicines. In this class, VX828 is the most efficacious corrector we have ever studied in vitro and advanced to studies in patients. The VX828 proof-of-concept study is on track to complete enrollment and dosing in the first half of 2026. VX581, another corrector from this 3.0 class, is currently in a Phase I healthy volume tier study. And beyond these two assets, we're advancing additional CF regimens. Shifting to the VX522 program, for the approximately 5,000 patients who do not make any CFTR protein and therefore cannot benefit from our CFTR modulators, our Phase 1-2 study of VX522 is on track for readout in the second half of this year. And we aren't stopping there. We are poised to continue to expand our CF leadership position, driven by more than 20 years of serial innovation, an enduring goal that if it is possible to do better for our CF patients, we are committed to doing so, an unmatched 200,000-plus patient years of real-world data, and a proven ability to extend the benefits of our medicines to the youngest patients. Moving next to our renal pipeline, which is emerging as our fourth vertical, alongside CF, heme, and pain, as a key engine for Vertex's next decade of growth. Povatacicept, a dual bath April inhibitor, is the most advanced asset in our renal pipeline, with the first expected indication in IgE nephropathy, or IGAN. IGAN is a progressive kidney disease with high unmet need that affects 330,000 people in the U.S. and Europe, and more than a million people in Asia. We see POVI's dual BAF-APRIL inhibition as key to interdicting the underlying cause of IgA nephropathy because this is a disease driven by B-cells, and BAF and APRIL are the key cytokines that play distinct roles in B-cell proliferation, differentiation, and survival. In addition to a mechanism of action, POVI's biophysical characteristics enable a differentiated profile. POVI was specifically engineered to achieve improvements in binding affinity, potency, pharmacokinetics, and tissue distribution. This protein engineering translates to two key areas of downstream advantage. First, in terms of efficacy, through Phase II, POVI has delivered substantial reductions in proteinuria and stabilization in GFR, supported by significant reductions in GDIGA1 and hematuria. As importantly, POVI's meaningful advantages in dosing. POV is administered as a once-monthly, small-volume, subcutaneous dose delivered via an auto-injector, a noteworthy consideration in the chronic biologics market, where ease of use has repeatedly been shown to influence product choice. Toby's progressing through the BLA regulatory pathway where FDA's granted breakthrough therapy designation as well as rolling review. We used the priority review voucher to ensure an expedited timeline for regulatory review and initiated our rolling BLA submission by submitting the first module in December of 25. We remain on track to complete the BLA submission in the first half of this year if the Phase III interim analysis results are supportive. Switching to POVI and membranous nephropathy, a disease that affects approximately 150,000 patients in the U.S. and Europe and over 400,000 patients in Asia, where we've partnered with Zy and Ono for these markets, as we did in IGAN. Membranous nephropathy, like IGAN, carries significant morbidity and lacks disease-modifying therapies. Accordingly, POVI has FDA Fast-Track and EMA Prime designations and was recently granted Orphan Drug designation in the U.S. The Olympus Phase 2-3 Adaptive Study of POVI in Memberness is enrolling and dosing patients. I am pleased to share we remain on track to complete the Phase 2 portion of this study and advance to Phase 3 this summer. Before updating you on the two other renal programs in mid- and late-stage clinical development, let me shift focus briefly to neurology and POVI's potential as a pipeline and a product with our plans in generalized myasthenia gravis. The rationale to study POVI myasthenia is compelling. First, it's a serious disease with high morbidity. Second, there are approximately 175,000 patients with myasthenia in the US and Europe and an estimated 300,000 patients globally. Third, current therapies have limitations in terms of mechanism of action, specificity, or the need for cyclical administration. This need for cyclical administration is particularly challenging, as it can lead to disease relapse and progressive damage to neuromuscular junctions. In contrast, POBEs dose chronically and does not require cycling on and off. Lastly, recent human clinical pharmacology results provide strong evidence for dual BAF-APRIL inhibition as a transformative approach. Putting this all together, we believe POVI's mechanism of action and specifically engineered protein format provide best-in-class potential in myasthenia. I am pleased to share that we're on track to initiate a proof-of-concept Phase II dose-ranging study of POVI in myasthenia in the first half of 2026. Now, returning back to renal and enaxiplin for APOL1-mediated kidney disease, or AMKD, where we completed enrollment in the interim analysis cohort of the AMPLITUDE pivotal study last fall. We anticipate several key upcoming enaxiplin milestones. First, completing enrollment in the Amplitude full clinical trial cohort in the second half of this year. Second, results from the Amplitude interim analysis cohort either late this year or early next, and if the results are positive, to file for U.S. Accelerator approval thereafter. Finally, in the amplified study of enoxaplen in patients with AMKD and moderate proteinuria or patients with AMKD and type 2 diabetes, patient groups we did not study in amplitude, we expect results in mid-2026. The last program in renal to cover tonight is VX407, which is being studied in a Phase II proof-of-concept trial for autosomal dominant polycystic kidney disease, or ADPKD. This disease affects 300,000 patients in the U.S. and Europe with no available disease-modifying treatments. VX407 is a small molecule protein folding corrector that targets the underlying cause of disease in up to 10% of people with ADPKD. The VX407 Phase 2 proof of concept study is up and running, and we expect a complete enrollment this year. This study will evaluate the effect of VX407 on height-adjusted total kidney volume, an important efficacy outcome given that it's an FDA-accepted surrogate endpoint in ADPKD. I'll close with two quick updates on a couple of other R&D programs. For Kastjevi, we remain on track to file for U.S. approval in patients ages 5 to 11 in the first half of this year. Recall, this has been granted a Commissioner's National Priority Voucher, and thus, we expect an expedited review. For Jernavix in acute pain, a pair of single-arm Jernavix Phase 4 studies have been recently completed and will be presented at medical conferences this spring, one in aesthetics and reconstructive procedures and another in laparoscopic and arthroscopic procedures. In both studies, Jernavix was used as part of multimodal pain therapy. The first study in plastic surgery procedures showed approximately 90% of patients remained opioid-free versus less than 10% opioid-free rates in the literature with standard of care for similar procedures. In the second study, which included arthroscopic knee and shoulder procedures, As well as laparoscopic procedures, 76% of Genavix patients remained opioid-free versus less than 50% opioid-free rates in the literature with standard of care for similar procedures. And in chronic neuropathic pain, our two SucetraGene Phase III studies in patients with diabetic peripheral neuropathy remain on track to complete enrollment by the end of this year. With that, I'll turn the call over to Duncan to review the commercial highlights.