Vertex Pharmaceuticals Incorporated

Good day and welcome to the Vertex Pharmaceuticals third quarter of 2025 earnings call. All participants will be in a listen-only mode. Should you need assistance, please signal a conference specialist 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, ma'am.

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 third quarter 2025 financial results conference call on tonight's call making prepared remarks we have dr reishma kewal ramani vertex's ceo and president duncan mckechnie chief commercial officer and charlie wagner chief operating and financial 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 delivered strong performance across the board in Q3, with $3.08 billion in revenue reflecting double-digit growth versus Q3 2024. As we continue to extend our leadership in CF, we're also diversifying our revenue base by product and by geography with the growing global momentum of Cascevi and the broad uptake of Jernavix in acute pain across a wide range of prescribers, pain types, and settings of care. Concurrently, we are forward planning for the fourth vertical of Vertex's growth, centered on renal diseases and povitacicept in multiple indications, starting with POVI in immunoglobulin A nephropathy or IGAN. Moving to the pipeline and starting with CF. Our longstanding goals in CF have been threefold. One, bring forward a medicine that can treat CF patients who make some amount of CFTR protein. Two, bring forward a medicine that restores CFTR function to normal levels as measured by sweat chloride and to do so from as early in life as possible so patients have the potential to live a long and healthy life like people who carry just one CF allele. And three, Bring forward a medicine for the last 5% of CF patients who do not make any CFTR protein at all. We are making progress on all three fronts. First, Oliftric treats more mutations than Trikafta. The number of patients newly eligible for a CFTR modulator that treats the underlying cause of their disease is approximately 400 more patients in the U.S. and approximately 4,000 more patients in the EU than Trikafta. In total, 95% of all patients are eligible or will be eligible for LiftTrek as we make our way to lower age groups. Second, LiftTrek, which launched in the U.S. late last year and is launching in Europe now, has seen a strong response from patients and physicians who are excited for a once-daily medicine that can bring sweat chloride levels down in patients ages 6 plus to the lowest levels achieved of any CFTR modulator in this age group. Two additional points to make on sweat chloride. We recently completed the pivotal study for Trikafta for the 1- to 2-year-old patient population, and the results are remarkable. The study's primary endpoint was safety, and the data were consistent with the established safety profile of this medicine. The secondary endpoint was reduction in sweat chloride. The baseline sweat chloride was about 100 millimoles per liter. And over the course of the 24-week study, there was a mean reduction of more than 70 millimoles per liter from baseline through week 24. Furthermore... Nearly 70% of patients in the study achieved levels of sweat chloride below the 30 millimole per liter threshold, the level considered normal. This magnitude of sweat chloride improvement is unprecedented and the largest reduction we have seen with any CFTR modulator in any population to date. We are on track to make global regulatory submissions for Trikafta in this population of 1 to 2-year-olds in the first half of 2026. Additionally, as we serially innovate, we continue to develop new CFTR regimens with the aim of reaching our longstanding objective of bringing the majority of patients of any age with CF to normal levels of sweat chloride. As I just discussed with the Trikafta 1-2 year old study, we are already there in our youngest patients. And in our ELIFTREC phase 3 study of 60-11 year olds, more than 50% of patients got to normal levels of sweat chloride. VX828, our next-gen 3.0 CFTR corrector, is the most efficacious we have ever studied in vitro to enter the clinic. I am pleased to share we have now initiated the CF cohort in the VX828 study. And third, regarding our final goal, VX522, which we're developing for the 5,000 or so patients who cannot benefit from our CFTR modulators, we have resumed enrollment and dosing in the MAD portion of that Phase 1-2 study. Moving then to pain. In acute pain, during the quarter, we completed enrollment in two phase four trials evaluating Jernavix, initiated preoperatively and as part of multimodal approaches to acute pain management. The interim analysis for one study will be shared at a medical conference later this week. And top line results for Jernavix show safety and efficacy consistent with the pivotal program, accompanied by substantial reductions in opioid use following aesthetic or reconstructive procedures, with approximately 90% of participants being opioid-free, compared to less than 10% after similar procedures, per the literature. In neuropathic pain, the first DPN Phase III study is well underway, and we have completed work that sets up the initiation of the second DPN Phase III study later this month. Transitioning now to the kidney portfolio, renal medicine is experiencing a renaissance in drug development, and Vertex seeks to be a leader in the field. With our differentiated R&D approach, grounded and causal human biology, validated targets, and biomarkers that translate, we have a broad portfolio of innovative therapies with transformative potential for patients with serious kidney diseases. Our clinical pipeline has first-in-class or best-in-class assets for four kidney diseases, three of which are already in or approaching pivotal development. VX407 for autosomal dominant polycystic kidney disease or ADPKD, enaxiplin for APOL1-mediated kidney disease or AMKD, POVI for IGAN, and POVI for primary membranous nephropathy. starting with VX407 for ADPKD, where the Phase II proof-of-concept study was initiated earlier this quarter. Recall there are approximately 300,000 patients with ADPKD in the U.S. and Europe. These patients have limited treatment options and no approved therapies that treat the underlying cause of this disease. We believe that up to 10% of patients with ADPKD may be eligible for treatment with VX407, a first-in-class small molecule protein folding corrector. VX407 is designed to target the root cause of ADPKD by restoring PC1 protein function. This Phase II proof-of-concept study is a single-arm trial of 24 patients that evaluates the effect of VX407 on on height-adjusted total kidney volume. The second kidney program to highlight is Anaxipline for primary AMKD, a disease that affects 150,000 patients in the U.S. and EU. Enrollment in the interim analysis cohort of the Amplitude Pivotal Study has completed. The patients in this cohort are now being treated for 48 weeks, after which we will conduct the interim analysis, and if positive, we will be poised to submit for potential accelerated approval in the U.S. Additionally, we are running the Amplified Study, which is a Phase II proof-of-concept study of enaxiplin in patients with AMKD with moderate pertinence. or patients with AMKD and diabetes, populations not being studied in the Amplitude trial. Amplified is on track to complete enrollment by the end of this year. Now turning to povitacicept. The lead and first indication for POVI is IGAN, a disease impacting more than 300,000 diagnosed patients in the U.S. and Europe and over 1 million patients globally. There are four points to highlight in this program. First, we completed enrollment of the interim analysis cohort of the Rainier Phase III trial earlier this year. Second, the FDA has granted POVI breakthrough therapy designation and rolling review for our BLA. Third, we have completed the studies to support the launch of POVI for at-home self-administration with a subcutaneous autoinjector. Lastly, the new news I'm very pleased to share tonight, is that we have completed full enrollment in the Rainier Phase III trial. The trial enrolled approximately 600 patients in approximately 15 months, the fastest of any contemporary Phase III study in IGAM, and is a testament to the significant opportunity ahead for POVI. Here's the outlook when you put these four major milestones together. With the rolling review that the FDA has granted, we will begin our submission for potential accelerated approval before the end of this year. Once the interim analysis cohort completes 36 weeks of treatment, assuming the results are positive, we will complete our BLA submission for potential accelerated approval in the U.S. in the first half of 2026. We have used a priority review voucher, and thus, we have certainty that POVI's BLA in the IGAN indication will receive an expedited priority review in the U.S. That is, a six-month review versus a traditional 10-month review. Next, and consistent with this pipeline and product potential, we are pleased to have initiated the pivotal study for the second potential renal indication for POVI in primary membranous nephropathy. There are approximately 150,000 patients with membranous nephropathy in the U.S. and Europe and nearly 500,000 globally. Today, there are no approved therapies that treat the underlying cause of this disease, leaving a significant patient population with high unmet need. POVI was recently granted fast-track designation by the FDA in membranous nephropathy, and our Phase II-III Adaptive Study Olympus is now underway. One final note in R&D regarding Zamylocell in type 1 diabetes. While we have completed enrollment in the pivotal trial for T1D, we have temporarily postponed completion of dosing while we work through an internal manufacturing analysis. As this is an ongoing, pivotal trial, it is critical to maintain study integrity, and so we won't be providing any additional detail. I look forward to updating you once dosing is complete. In closing, Vertex now has seven commercialized medicines, five programs in Phase 3 development, and an exciting earlier stage R&D pipeline. Accordingly, as we drive to achieve our R&D milestones, we're executing on the concurrent work of getting our approved medicines to more patients around the globe and preparing for additional near-term potential launches. To tell you more about our commercial efforts, I'll now turn over the call to Duncan.