VX1.DEVX1.DEXETRA
Loading
Operator: Good day, and welcome to the Vertex Pharmaceuticals Incorporated Fourth Quarter 2025 Earnings Call. All participants will be in a listen-only mode. 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.
Susie Lisa: Good evening, everyone. My name is Susie Lisa, and as Senior Vice President of, I would 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, 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 will now turn the call over to Reshma.
Reshma Kewalramani: 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 '25 results included KASJEVY revenue of $116,000,000 and Gernamix revenue of $60,000,000 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 Kashyabi, growing Jurnavics both in prescriptions and revenue, and advancing the emerging renal franchise starting with POBI 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 will focus my R&D comments tonight on cystic fibrosis and the renal franchise.
Reshma Kewalramani: Beginning with cystic fibrosis, Elliptrex is a next-generation 2.0 CFTR modulator and is the fifth approved CF therapy in our portfolio. Aliftrex 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 Elephtrak Phase 3 trial, this one in two- to five-year-olds. All patients in this study were on TRIKAFTA and switched to ElefTrex on entry into the study. A Liftrec 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 AlifTrac 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 AlifTrex in the two- to five-year-old age group in the first half of this year. And as we continue the march down to younger age groups, I am also pleased to share that the AlifTrek one- to two-year-old study has already initiated and enrollment and dosing are underway.
Reshma Kewalramani: Turning now to our next wave of CFTR modulators, or NextGen 3.0 medicines. In this class, VX 828 is the most efficacious corrector we have ever studied in vitro and advanced studies in patients. The VX 828 proof-of-concept study is on track to complete enrollment and dosing in 2026. VX 581, another corrector from this 3.0 class, is currently in a Phase 1 healthy volunteer study. And beyond these two assets, we are advancing additional CF regimens. Shifting to the VX 522 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 VX-1522 is on track for readout in the second half of this year. And we are not 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 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.
Reshma Kewalramani: 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. Povatacept, a dual BAFF/APRIL inhibitor, is the most advanced asset in our renal pipeline, with the first expected indication in IgA 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 BAFF/APRIL inhibition as key to interdicting the underlying cause of IgA nephropathy, because this is a disease driven by B cells, and BAFF and APRIL are the key cytokines that play distinct roles in B cell proliferation, differentiation, and survival. In addition to mechanism of action, Povi's biophysical characteristics enable a differentiated profile. Povy 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 2, Povi has delivered substantial reductions in proteinuria and stabilization in GFR, supported by significant reductions in Gd-IgA1 and hematuria. As importantly, Povi's meaningful advantages in dosing. Povi 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. Povi is progressing through the BLA regulatory pathway where FDA has 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 '25. We remain on track to complete the BLA submission in the first half of this year, if the Phase 3 interim analysis results are supportive.
Reshma Kewalramani: Switching to Povi in 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 partnered with Zai 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 membranous 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.
Reshma Kewalramani: 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-in-a-product with our plans in generalized myasthenia gravis. The rationale to study Povi in myasthenia is compelling. First, it is a serious disease with high morbidity. Second, there are approximately 175,000 patients with myasthenia in the U.S. 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, Povi is dosed chronically and does not require cycling on and off. Lastly, recent human clinical pharmacology results provide strong evidence for dual BAFF/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 are on track to initiate a proof-of-concept Phase 2 dose-ranging study of Povi in myasthenia in 2026.
Reshma Kewalramani: Now returning back to renal and enaxaplin 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 enaxaplan milestones.
Operator: First,
Reshma Kewalramani: 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. Accelerated Approval thereafter. Finally, in the AMPLIFIED study of enaxaplin 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.
Reshma Kewalramani: The last program in renal to cover tonight is VX 407, which is being studied in a Phase 2 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 VX 407 Phase 2 proof-of-concept study is up and running, and we expect to complete enrollment this year. This study will evaluate the effect of VX407 on height-adjusted total kidney volume, an important efficacy measure given that it is an FDA-accepted surrogate endpoint in ADPKD.
Reshma Kewalramani: I will close with two quick updates on a couple of other R&D programs. For KASJEVY, we remain on track to file for U.S. approval in patients ages five to eleven 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 Gernavix in acute pain, a pair of single-arm Gernavix 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 arthroscopic procedures. In both studies, Gervix 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 Gernavix 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 sicetralgene Phase 3 studies in patients with diabetic peripheral neuropathy remain on track to complete enrollment by the end of this year. With that, I will turn the call over to Duncan to review the commercial highlights.
Operator: Thanks, Reshma. The focus of the commercial
Duncan McKechnie: organization in 2025 was to drive multiple successful launches fueled by clear strategic intent, disciplined execution, and targeted investments. We launched a lift truck in the U.S. and Europe, built momentum behind the launch of Kasjevi in the U.S., Europe, and the Middle East, and successfully executed on the first year of launch for Genavix here in the U.S. We are pleased with the progress we are making to diversify our revenue growth and treat patients in four diseases around the world.
Duncan McKechnie: In cystic fibrosis, our goal has been to help patients get to carrier or normal levels of CFTR function as measured by sweat chloride. We have made incredible progress against this goal for patients with all mutations, all age ranges, and all geographies. We now have five approved CFTR modulators, a decade plus of real-world evidence, over 77,000 patients on one of our CF therapies, and access agreements in over 60 countries across six continents. We continue to drive growth from new patients, new launches, new geographies, and new reimbursement agreements, all supported by an underlying 3% annual increase in the CF population over the last five years.
Duncan McKechnie: Focusing now on Elephtrak. The rollout in the U.S. and Europe continues to progress well. The vast majority of treatment-naïve patients in countries where we have reimbursement are already on AlifTrex. We also see continued ongoing transitions from TRIKAFTA to AlifTrex and the majority of AlifTrek scripts continue to come from switches. ElefTrex’s improved sweat chloride profile and once-daily dosing versus TRIKAFTA are resonating with the clinical community, even as we observe strong patient loyalty to TRIKAFTA. In Europe, we have already secured reimbursed access for ElefTrek in key countries, for example, England, Ireland, Germany, Denmark, and Norway. We also recently announced reimbursement for Eleftrac in Australia, New Zealand, and Italy, the latter enabling access for 1,500 patients to a CFTR modulator for the first time. Additionally, we continue to make excellent progress expanding geographic reach with meaningful contributions in 2025 from Brazil and Turkey. Overall, 2025 was another year of strong execution and growth in CF, and we will continue these efforts into 2026. Key drivers of growth for CF in 2026 include continuing the launch of AlifTrek globally, treating younger patients, expanding to additional geographies, securing access for patients, and maintaining our comprehensive patient support programs.
Duncan McKechnie: Turning now to Kashyvi. Where we successfully moved from a foundational year in 2024 to a year of building significant momentum in 2025. You can see the evidence of this acceleration in our excellent Q4 2025 results, where Casjevi had 111 new patient initiations, 37 patients with first cell collections, and 30 patients receiving infusions, driving $54,000,000 in quarterly revenue. We also reached some notable reimbursement agreements for KASJEVY in Q4 2025. In the U.S., more than 30 states have joined the CMS Cell and Gene Therapy Access Model. There is now approximately 90% access for both Medicaid and commercial KASJEVY patients with the remainder having case-by-case access. In Europe, all countries in the UK are now providing reimbursed access, and a recent landmark coverage decision by the Italian reimbursed body represents about 5,000 eligible TDT patients, half of Europe's beta thalassemia population. We anticipate seeing continued quarter-to-quarter variability in JEVY infusions in 2026 based on the duration of the patient journey and given the fact that patients themselves dictate when they wish to receive their infusion. We anticipate this will smooth out in 2027 and beyond as the number of patients at all stages of the treatment journey continues to build. Overall, we are very encouraged by the robust flow of patients in the U.S., in Europe, and the Middle East moving from referral to cell collection and infusion as we drive towards realizing KASJEVY's multibillion-dollar potential.
Duncan McKechnie: Moving to pain. I am pleased to report that Genavix achieved our 2025 launch objectives of first securing broad payer access, secondly, ensuring extensive hospital adoption, and thirdly, creating a broad prescriber base across both the hospital and retail segments. This launch strategy was designed to create a strong long-term foundation for years of growth with Genavix. More than 550,000 Genavix prescriptions were filled in 2025, with a roughly 50/50 split between hospital and retail channels. There were as many prescriptions written in 2025 as there were in the prior three quarters cumulatively. Although I would note that Q4 revenue growth does not yet fully reflect this strong prescription growth given the continued utilization of our patient support programs. Importantly, more than 35,000 physicians wrote prescriptions for Genavix in 2025, including orthopedic surgeons, general surgeons, anesthesiologists, pain specialists, dentists, and general practitioners. Over 200,000,000 lives now have access across all three national PBMs. In addition, 21 states now provide unrestricted access for Medicaid recipients without prior authorization or step-edit requirements. Genavix has also been incorporated into formularies, order sets, and/or discharge protocols across more than 950 hospitals and over 100 integrated delivery networks, a significant accomplishment in a short period of time and an indicator of the unmet need in this space. Perhaps most importantly, we estimate that about 420,000 Americans benefited from the inclusion of in their treatment journey as an effective, well-tolerated non-opioid option for moderate to severe acute pain.
Duncan McKechnie: Looking ahead, given the strong adoption of Genavix by hospitals and physicians, and the progress we have made in securing payer coverage, we plan to double the size of our field force in Q2. We will also continue with a range of consumer engagement activities to drive meaningful prescription and revenue growth in 2026. This includes the recent launch of our first Vertex connected TV campaign in January, which we are piloting in select markets. In 2026, we expect to more than triple the number of Genavix prescriptions compared to the approximately 550,000 written in 2025. As we work to finalize access and gain coverage with additional payers, including Medicare Part D plans, we have made the strategic decision to maintain the patient support program for those patients not covered by their insurance. As this PSP program sunsets and gross-to-net in late 2026, early 2027, we expect prescription growth to increasingly drive meaningful revenue growth, especially in the latter half of the year. Our expectation is that Genavix gross-to-net will ultimately settle at levels comparable to other branded medicines. We are excited to continue to drive a transformation in the management of the 80 million Americans with moderate to severe acute pain each year by offering a safe and effective non-opioid treatment option and to build another multibillion-dollar franchise for Vertex.
Duncan McKechnie: Turning now to our emerging renal business. We are partnering with and investing in the nephrology community for the long term, and povitacept is the first in a series of potentially transformative medicines that tackle the underlying cause of several renal diseases: IgAN, PMN, AMKD, and ADPKD. We anticipate that the renal franchise will ultimately rival the of our CF business, and we are seeking to bring the best elements of our success in CF to these kidney disease areas. These best practices include intense focus on the patient, an unrelenting commitment to serial innovation in R&D, a clear high-science sell to specialist physicians, and disciplined execution in securing reimbursed access here in the U.S. and around the world. We will also offer comprehensive patient support programs for eligible patients to remove access challenges and enable them to more seamlessly obtain the medicine that HCPs prescribe. We believe our experience, focus, and capabilities equip us to win in renal and deliver substantial value to both patients and healthcare providers.
Duncan McKechnie: Povatacept's potential best-in-class profile enables us to clearly distinguish it within the IgA nephropathy landscape, setting it apart from other therapies. As Reshma detailed, Povi is an engineered fusion protein designed specifically to address B cell–mediated autoimmune diseases with a strong clinical profile that is further supported by an easy-to-use small-volume auto-injector administered at home every four weeks. The importance of this insight has been borne out in our recent research with nephrology who highlight the importance of payer access and for an auto-injector versus prefilled syringe in their treatment decisions. This market research with nephrologists reinforces what we have seen in the biologics space many times over. Commercial excellence combined with patient convenience and ease of use of the medicine are critical drivers of market share. We began preparing for povitacept's launch last year by building a commercial team for renal and engaging payers to ensure broad access. We are completing the staffing of our teams, and the first contingent of our field team is already trained and actively engaging customers and providing disease education. As noted above, we are also developing a renal patient support program based on our decade plus of experience supporting cystic fibrosis patients. In summary, each of our commercialization areas reflects a clear strategic intent and an ambitious approach to both established and future launches. Our 2025 performance positions the portfolio for continued revenue growth, deeper market penetration, and most importantly, broader patient impact across cystic fibrosis, hematological disorders, moderate to severe acute pain, and potentially, in the future, renal diseases. I will now turn the call over to Charlie for our financial results and outlook.
Operator: Thanks, Duncan.
Charlie Wagner: I am pleased to share the details of Vertex's strong financial performance in the fourth quarter and for the full year 2025, which stands as a testament to our market leadership, the strength of our product portfolio, and our disciplined approach to investment and operational. In the fourth quarter, total revenue reached $3,200,000,000, a 10% increase compared to Q4 2024. For the full year, total revenue was $12,000,000,000, an increase of 9% versus 2024. These results reflect our consistent commercial execution, durable CF franchise strength, and expansion into new, high-value disease areas. Our cystic fibrosis therapies remain the foundation of our revenue and cash flow with full year 2025 growth of 7% globally. CF revenue in the U.S. grew 11% year over year, largely due to pediatric uptake, ongoing strength in TRIKAFTA and ELEFTREC, higher realized net prices, and a modest benefit from channel inventory in the fourth quarter. Internationally, CF revenue grew 2% year over year, reflecting the ongoing penetration of Calf Trio in established markets and contributions from AlifTrek in countries where reimbursed, partly offset by the previously communicated $200,000,000 decline in Russia sales for the year.
Charlie Wagner: Kaschevy achieved $54,000,000 in revenue in Q4 and $116,000,000 for the full year 2025, and during Q4 demonstrated continued momentum in patient and first cell collections. Dronavix delivered $27,000,000 in sales in the fourth quarter and $60,000,000 for the full year, with substantial growth in quarterly prescriptions since its launch in 2025. Note that Gernavix gross-to-net was significantly impacted by our patient support program in 2025, and that impact will diminish over the course of 2026. Our increasingly diversified commercial portfolio, now spanning four disease areas, is driving new revenue streams and adding to our near- and long-term growth profile. Our fourth quarter gross margin of 85.7% reflects this product mix as well as investment in manufacturing optimization for our diversifying portfolio. I would add that Q4 gross margin is a reasonable proxy for what to expect in 2026.
Charlie Wagner: Turning to operating expenses, Q4 2025 combined non-GAAP R&D, acquired IPR&D, and SG&A expenses totaled $1,400,000,000, up 5% year over year, and reflect our strategic investments in product launches, principally in pain, and late-stage pipeline programs. Fourth quarter non-GAAP operating expenses included $56,500,000 of AIPR&D expense, or approximately $0.22 per share. This fourth quarter BD activity included an exclusive global license agreement with WuXi Biologics to develop and commercialize a tri-specific T cell engager for B cell–mediated autoimmune diseases. This asset is currently in preclinical development. For the full year, combined non-GAAP R&D, acquired IPR&D, and SG&A expenses totaled $5,100,000,000, consistent with our previous guidance. Excluding acquired IPR&D, the increase versus prior year was primarily driven by the acceleration of late-stage clinical programs in renal medicine and ongoing expansion of commercial and marketing activities to support the launch of Gernavix and upcoming launches in renal. The fourth quarter 2025 non-GAAP effective tax rate was 13.5%, reflecting increased utilization of one-time tax credits, and our full year 2025 non-GAAP effective tax rate was 17.3%. Q4 2025 non-GAAP net income was $1,300,000,000, up 24% year over year, delivering $5.30 of earnings per share, up 26% versus the prior year. Full year 2025 non-GAAP net income of $4,700,000,000 resulted in $18.40 of EPS. Vertex ended 2025 with $12,300,000,000 in cash, cash equivalents, and marketable securities. Our strong balance sheet positions us to continue investments in both internal and external innovation. During 2025, we increased our repurchase activity, buying approximately 4,800,000 shares for roughly $2,000,000,000. This reflects our ongoing commitment to returning value to shareholders while maintaining the flexibility to act on growth opportunities.
Charlie Wagner: Let me now turn to guidance for 2026. We expect full year 2026 total company revenue to be in the range of $12,950,000,000 to $13,100,000,000, representing 8% to 9% growth versus the prior year. This outlook anticipates continued solid performance from our CF franchise and a $500,000,000 or greater revenue contribution from non-CF products, including greater volumes of patient infusions for CasGevi and a ramp of Gernavix. In Q1 2026, we anticipate year-over-year total revenue growth of approximately 7% with growth accelerating thereafter and building towards our full year guidance. Additionally, we expect combined non-GAAP operating expenses to be in the range of $5,650,000,000 to $5,750,000,000 as we continue to invest in our late-stage clinical pipeline and commercial buildouts in support of new launches and revenue diversification, particularly for generics in acute pain, and for renal. We anticipate our non-GAAP effective tax rate to be in the range of 19.5% to 20.5% for 2026, as we do not expect a repeat of the one-time tax benefits we experienced in 2025. In addition, based on our understanding of current rules, we do not expect a material impact from tariffs given our diversified supply chain and large U.S. manufacturing presence, but this outlook is subject to change. In summary, 2025 was a year of very strong performance, continued execution on our commercial priorities and clinical programs, and further strengthening of our robust financial foundation. As we turn to 2026 and beyond, Vertex remains well positioned to continue expanding our impact for patients, investors, and all stakeholders. We look forward to updating you on our progress on future calls, and I will now ask Susie to begin the Q&A period.
Operator: We will now begin the question and answer session. To ask a question, you may press star then 1 on your touch-tone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. And to withdraw your question, press star then 2. And our first question will come from Cory Kasnov with Evercore ISI. Please go ahead. Great. Good afternoon. Thanks for taking my question. Probably not surprising that it is on Povi.
Cory Kasnov: Curious how you view the risk of potential hypogamma adverse events and how this could ultimately impact the label, if at all? Thank you.
Operator: Cory, this is Reshma. Let me take that one.
Reshma Kewalramani: On hypogammaglobulinemia, that is to say low IgG levels, the way BAFF/APRIL inhibitors work, you are going to see dips in IgG. It is part and parcel of the mechanism of action. But the important question you are asking is, what does that mean, if anything, on safety? So the data that we have shown is RUBY-3, the 80 mg RUBI-3 cohort that we showed at ASN in November. What you see there is there were actually no SAEs, none of infection. It does not matter what IgG level you look at. There were simply none. That is good news. There was a single patient with IgG levels of less than 300 milligrams. That was a threshold we used. It was not associated with any serious infection, and there was no severe infection either. And on average, when you look at the IgG levels from the RUBY-3 IgAN study, the average value was within the normal range. So let us say around 700 mgs. So when I look at that, I do not really see anything there. And I think that when you look at the overall benefit-risk including IgG levels, but look at everything as a whole, it looks really very good.
Operator: I hope that helps. Very helpful.
Cory Kasnov: Yeah. Very helpful. Thank you, Reshma.
Operator: You bet. The next question will come from Salveen Richter with Goldman Sachs. Please go ahead.
Salveen Richter: Good afternoon. Thanks for taking my question. With regard
Salveen Jaswal Richter: to the guidance here, is there any way you could help us understand what is baked into the guide for the CF component relative to Alevtrex and and on Alevtrek in particular, you had a strong quarter. So walk us through the contributing factors here as we think of the trajectory for 2026? Thank you. I will be happy to split that question and ask
Reshma Kewalramani: Charlie to go first on the guide, and then I will ask Duncan to comment on the market dynamics that led to the Ali numbers we shared.
Operator: Yes. So I mean, additional color on the guidance.
Charles F. Wagner: Obviously, total revenue guidance of $12.095 to $13.01. So 8% to 9% for the year. Within that, a contribution, a non-CF contribution of $500,000,000 or more. Within CF, we are not going to break it down further in terms of Ali versus other products. Maybe Duncan could comment on the dynamics in Ali that we are seeing right now. Sure. Thanks for the question, Salveen. So I would say the fourth quarter was buoyed by the international launch
Duncan McKechnie: so we, as you know, secured reimbursement in Europe, in countries like the UK, Germany, Denmark, Ireland, Norway, in 2025. So that really helped drive some of the numbers that we saw in the latter part of 2025, and we expect that to continue obviously into 2026.
Reshma Kewalramani: Next question,
Operator: Thank you. The next question will come from Geoff Meacham with Citibank. Please go ahead.
Geoffrey Christopher Meacham: Hey, guys. Thanks for the question. Just have a couple. First one, you guys seem really excited about Povi's potential as well as the renal space. Guess the question is, is there work to do on the payer side when you think about access and reimbursement and maybe cost-benefit? When you look historically, Reshma, renal has not been a category where you get higher realized value, but obviously,
Geoffrey Christopher Meacham: a new MOA can help that. Then just a follow-up on Ali. Is there more interest in the U.S. in using sweat chloride as a disease biomarker? And you mentioned the European launch. I mean, would you characterize
Geoffrey Christopher Meacham: maybe the awareness and willingness to switch
Geoffrey Christopher Meacham: to Ali compared to the U.S.? Thanks.
Reshma Kewalramani: Alright. Jeff, I am going to ask Duncan to comment on both, but we will take it in two parts. Let us do Ali first. Duncan, how do folks, how do the community think about sweat chloride U.S. versus ex-U.S.? How do you see the uptake? And then let us get to Povi. Jeff, you are absolutely right to detect a a of enthusiasm in our voice on Povi. It is not just about Povi in IgAN, but it is Povi in membranous and in myasthenia. And it is getting close to the time where we think we are going to have the results to share and close to the time where think we are going to be able to file. So enthusiasm is certainly building internally. Ducking on the Povi question, it was about reimbursement and how you are seeing that.
Duncan McKechnie: Yep. So Ali first. Yeah. Thanks for the question, Jeff. So as far as the interest in sweat chloride is concerned, in general terms from a physician level, the level of sort of understanding and interest in the connection between sweat chloride and CFTR function is by and large similar in the U.S. to Europe. There are no major differences in that regard. In terms of your question about willingness to switch, there are some different dynamics with regard to the labeling between the U.S. and Europe, meaning that there are fewer liver function and liver monitoring requirements in Europe. So that has an impact on the dynamic. The other comment I would make as well is we always see more rapid uptake in naïve patients, and as per the prepared remarks, there are, for example, 1,000–1,500 naïve patients in Italy that have just been reimbursed for CFTR modulator for the first time ever, so we would anticipate rapid uptake in that particular patient population. On the first part actually of your question, povitacet and our engagements with payers and the payer community, I would make just a couple of comments. Firstly, we started engaging with the payers in July. We have, at this point, had 74 engagements with multiple payers that cover over 210 million lives. And I would say those conversations are going extremely well. They are very well educated on IgAN, and they are very interested in the products that are coming to the market. So we feel really good about where we are at with our engagements with payers so far and where those will go in the future.
Operator: The next question will come from Tazeen Ahmad with Bank of America. Please go ahead.
Tazeen Ahmad: Hi, guys. Good afternoon. Thanks for taking my question.
Reshma Kewalramani: With relation to Povi, can we talk about what you are expecting to show on proteinuria? Like what results do you think would provide your mind
Tazeen Ahmad: medically, clinically differentiated data versus competitors? Thanks.
Reshma Kewalramani: Sure. Magnitude of proteinuria response, I think we have talked about this before, but in every study that we have done, the depth of proteinuria response, the greater the depth, the better it is in terms of long-term outcomes, long-term outcomes being defined as death, dialysis, or time to transplantation. In this particular interim analysis, I would point you to the RUBY-3 80 mg IgAN results. I think it is the best analog to look at to sort of get a sense for what we could see from the RAINIER trial. I say that because it is very similarly designed in the inclusion and criteria. The proteinuria threshold, the GFR thresholds for entry, it is the same exact dose, 80 milligrams, and the endpoint is exactly same. And in RUBY-3, the 36-week proteinuria data was 56% reduction in proteinuria. I think it is important to also note that the proteinuria reduction is something that I believe will have, think you could think of it as compounding effect over time. Even a little bit more improvement in proteinuria, better proteinuria reduction, is going to be important because these patients are going to be on the for their whole life. It takes something like 20 years for a person to develop end-stage renal disease from when they start having their GFR drop or proteinuria starts to become heavy. So over that course of time, improvements in proteinuria could really be very important. So if we see something like we saw in RUBY-3 Phase 2, that would be incredibly important. Very meaningful from a clinical perspective. Thanks, Krishna. Yeah. See you next.
Operator: Question will come from Evan Seigerman with BMO Capital Markets. Please go ahead.
Evan David Seigerman: Hi, guys. Thank you so much for taking my question. I would love for you to expand on the rationale to study Povi in gMG. Just seems to be a more crowded rare disease. I would love for you to just touch on differentiates this asset, what you saw potentially kind of in earlier studies, and how you think it would compare to both assets that have been approved and are under investigation for the indication? Yep. Sure thing, Evan.
Reshma Kewalramani: I will repeat a couple of things I said in my prepared remarks. It is a sizable population, right, nearing 200,000 patients in the U.S. and Europe. It is clearly, like, one of the best examples of a B cell–mediated disease. That is how this disease happens. It is autoantibodies largely against the acetylcholine receptor. And the available treatments have some real limitations. One of the big limitations is for some of the treatments, you have to cycle on and cycle off. During the time where you cycle off the treatment, where you are not taking the treatment, obviously, if you are not on the medicine, what happens is the autoantibodies come back and that can lead to the disease returning. Now what I am about to tell you next is cross-study comparisons, so you have to take it with a grain of salt. But there has been a study in China, China-based study, using a wild-type tacky. And using a wild-type tacky, if you do a side-by-side comparison of what is called the myasthenia gravis ADL score, that is the endpoint, it is remarkable what the wild-type PELI test is that this is the wild-type tacky, was able to accomplish. Again, these are cross-study comparisons, so take it with a grain of salt. But what that wild-type tacky tells me is that by mechanism of action, it is something to really hold close. So then you translate that to Povi. Povi is not a wild-type tacky. Povi is this engineered fusion protein. Better potency, better binding affinity, better pharmacokinetics, better tissue distribution. So I look at the wild-type tacky, and then I think about what Povi could bring to the table. And that is the reason I am so excited about this. I think this is going to be a really important indication for Povi. First things first, we have to get through Phase 2. That study should be up and running shortly. That is a dose-ranging study, so we are going to study 80 and 240. Then we can take it from there and go to pivotal development. But it is one of the ones that I am excited about.
Operator: The next question will come from Michael Yee with UBS. Please go ahead. Hello. Thank you. Two questions. First on Ovi, can you remind us how to think about what rates of ADA are possible, either absolute rates or neutralizing rates? And do you expect that to be of any material number given it is a chronic drug that could be something to think about? And then I do not think anyone has asked on AMKD, but obviously you have a very potent drug there and that data could be in about a year or so. And just wanted to think about how you expect those results to play out and, given you have a more population rather than just FSGS, expect essentially the same results from the Phase 2? Thank you. Yeah. Mike, let me
Reshma Kewalramani: take the AMKD results first, and I will come back to Povi and ADA. So in AMKD, when I was listening to Duncan talk about AMKD, ADPKD, Povi in IgAN, Povi remembrance, it really is a renal franchise that is emerging. The bottom line, I do expect that our results from the AMKD Phase 3 AMPLITUDE study will be very similar to what we saw in the Phase 2 AMKD study. Recall, though, Mike, that the readout, the primary endpoint for the Phase 3 study is GFR slope. Of course, we are going to measure proteinuria, but you will recall that the FDA pathway to Accelerated Approval for ANKD is based on 48-week GFR. So there is that difference. And if you ask me, well, why do you think that? Even though the group that we studied in Phase 2 was something we called FSGS, which is a histologic diagnosis. It is what you see on biopsy. The and the group that we studied in Phase 3 is AMKD, two APOL1 allele. They are the same disease. It is just whether or not the patient with two APOL1 alleles, depressed renal function, and proteinuria was sent to get a biopsy or not sent to get a biopsy. If you do not go to get a biopsy, you will never be able to see FSG because that is simply a histological diagnosis. So net-net, I expect the results to be in line with Phase 2. And I will reaffirm the timelines for data sharing, tail end of this year, beginning of next.
Reshma Kewalramani: On Povi and ADA and NAb, just to set this stage, and I know you know this, in biologics, ADAs—anti-drug antibodies—are to be expected. If it does not have a consequence on efficacy—so you would know that by neutralizing antibodies, you would see it on the endpoint of interest, in this case proteinuria—it is not something to be concerned about. And, of course, on the other side, it could be an antibody that causes safety, but based on how this particular drug works, I do not have concerns in that domain. So it is really about a specific subset of anti-drug antibodies, neutralizing antibodies, that have an impact on outcomes. Based on everything that we saw in RUBY-3 that we shared with you in November, I do not expect that to be something of consequence.
Tazeen Ahmad: 80 is that is.
Operator: The next question will come from Io Muir with Barclays. Please go ahead.
Eliana Merle: Hey, it is Elly. Thanks for taking my
Reshma Kewalramani: just on TERNAVEX, how do you see the mix between retail and
Eliana Rachel Merle: hospital setting evolving over the course of the year? And how should we think about how that mix could impact gross-to-net as well as treatment duration? Thanks.
Reshma Kewalramani: Duncan, do you want to take that one?
Operator: Yeah. Sure.
Duncan McKechnie: So as far as the mix is concerned, I would say that we did see it evolve over the course of 2025. We concluded the year at around about 50/50 between retail prescriptions and hospital prescriptions. And I would say that in the future, we anticipate that that will move more towards the retail space proportionally compared to where it is right now. In terms of the impact on gross-to-net, there are a number of dynamics to that. Obviously, the length of the prescription in hospital is usually shorter than the duration of the prescription in retail. But it also depends on the type of patient, for example, whether they are a commercial patient, whether they are a patient or a Medicaid patient, and indeed whether they are going through our patient support program, or whether they are a self-pay patient. There are a number of dynamics in terms of how this sort of prescription balance affects gross-to-net.
Operator: Your next question will come from William Pickering with Bernstein. Please go ahead.
William Pickering: Hi, thank you for taking my question. I was wondering—this is a Povi one—if you could discuss how you expect the baseline GFR to impact the observed effect size. I think your Phase 2 patients had an average GFR about 10 mL higher than the competitor Phase 2 or Phase 3 trials. And so if we were to see a Phase 3 baseline for Povi that is more similar to those competitor trials,
Operator: just wondering directionally which way, if at all, that would influence effect size?
William Pickering: Thank you.
Reshma Kewalramani: Yeah. Well, I think you are asking about what the impact of baseline GFR could be on proteinuria. Did I understand that correctly?
Charles F. Wagner: Yeah. That is right.
Reshma Kewalramani: Okay. In general, when you are in the range of proteinuria where we are studying—so you have to be somewhere between 30, and I think the entry criteria is, like, 30 to 90 or something like that—when you are not at the very tail end close to dial—so what we would call a burnt-out kidney—in the range that we are studying, it should not have any great impact on proteinuria. When you have a burnt-out kidney, proteinuria could seemingly decrease because you do not have any renal function left. But in the range that we are talking about, it should be fine. It does no real big impact there.
Operator: Thank you. I hope that helps. Yeah. Your next question will come from Brian Abrahams with RBC Capital Markets. Please go ahead. Hey, good afternoon, and thanks so much for taking my question. Another one on Povi. Just recognizing there are similar inclusion/exclusion criteria between RUBY-3 and RAINIER. I was just wondering if there were any differences such as proportion of patients from China or their degree of patients on SGLT2 inhibitors that might impact proteinuria response to povitacicept. And then also, is there any reason as we sort of think about a proxy for the potential magnitude of what we might see not to include the blend of UCPR reductions from both the 80 and 240 mg doses from RUBY-3, just to, I guess, get to a higher end? I am just wondering if there is any reason 240 might have conferred lesser activity mechanistically. Thanks.
Eliana Merle: Okay.
Reshma Kewalramani: On the differences between Phase 2 RUBY-3 and the Phase 3 RAINIER, I think the most important one is that the Phase 2 study was not placebo-controlled. The Phase 3 study, obviously, is placebo-controlled. In all the other dimensions— inclusion criteria, the dose of the study, the endpoint—there are either exactly the same or very, very similar. The difference is the placebo arm. So you do have to think about that. And at the ASN event, there was a question to one of the thought leaders who has worked in this space for a long time about, well, what do you think the placebo protein response could be over this period? And they said between 0–5%. I think that is about right. So I think that is the big one. I do not have baseline characteristics, Brian, to share with you from the RAINIER study. Obviously, we will have that for you when we share the results. I think there was another question about 80 and 240. We did not study 240 any further. After RUBY-2 and all of the 240 data that we had, we shared with you at the ASN, and it did look on average about the same as 80 milligrams.
Brian Abrahams: Thanks so much.
Reshma Kewalramani: Yep. You bet.
Operator: The next question will come from Terence C. Flynn with Morgan Stanley. Please go ahead.
Terence C. Flynn: Hi, thanks for taking the question. Maybe two for me. First one, unsurprisingly on Povi. I was wondering, Reshma, if you can comment at all about the blinded serious data you are seeing from the RAINIER study at this point. And then the second one was on the WuXi deal. I know you mentioned you are developing this TCE for B cell–mediated autoimmune conditions. Wondering how you think about differentiation there on the portfolio in terms of where you might carve out those indications relative to Povi? Thank you.
Reshma Kewalramani: Yeah. Yeah. On the data for RAINIER, as you may know, there is an independent data safety monitoring committee that monitors that study. And maybe the most helpful thing I can share is that they review the data in an ongoing fashion, and of course, they review blinded and unblinded data. They review everything because they are the DSM. They have not asked us to change anything in the study. And they have given the study a clean bill of health as it goes through. Maybe that is the most helpful thing I can say to you with regard to what the ongoing data is. With regard to WuXi and indication, we specifically did not share, so I am going to keep that information under wraps for a little bit longer. I will say that the idea of having a medicine like Povi, a pipeline-in-a-product for multiple B cell–mediated diseases, is exciting. And our interest in serial innovation stands. And you put those two together, it is probably unsurprising to you that we are interested in these kind of tri-specific engagers, because they would work for a variety of diseases, not just the ones that we talked about—IgAN, membranous, myasthenia—but other B cell–mediated diseases that we are interested in. But I will keep the specifics under wraps for a little longer.
Operator: Your next question will come from Debjit D. Pattijay with Guggenheim. Please go ahead. Hi. This is Morris on for Debjit. For taking our questions. I have two about Povi. First, looking at the RUBY-3 UPTR data, Povi had a much larger
Morris: standard error than the test receptors in their comparable studies. Any comment on what may have caused this variability? And, second, as I said, in cipaprevimab's Phase 3 studies showed very different placebo rates in their UPCR interim analysis. What is your assumption for the placebo rate in the RAINIER interim?
Reshma Kewalramani: Yeah. I do not have much more to add about the placebo rate other than what I said. When this question was asked at ASN, the physician who had been involved in a number of trials and is a real IgAN expert offered that his idea was 0% to 5% for placebo. I think that is probably about right, and that sounds right to me. So I would keep that. On the idea of standard error, I have not looked at, I have not looked at their data. I do not know that I have anything particularly helpful to say. As you know, the standard error is impacted by sample size, so I do not know exactly which datasets you are looking at, but that is one thing I would look at. And it also matters what lab tests you use, whether you are using 24-hour urine or you are using spot urine. So I could offer multiple explanations, but, unfortunately, I have not looked at the data looking at. But if you send it to Susie, I am happy to look after the call.
Morris: Thanks. And, just to be specific, the 0–5%, is that increase or decrease given that in the competitor Phase 3 study one of them showed a placebo increase and the other showed a decrease in UPCR?
Reshma Kewalramani: I was thinking about the placebo group potentially having proteinuria improvement of somewhere between 0% to 5%. Obviously, if the proteinuria in the placebo group—if there was more proteinuria—it would be incrementally beneficial to Povi because it is a comparison versus placebo. Of course, the placebo is equal opportunity, could go up or down. We will take one more question, thank you so much. You bet.
Operator: And the next question will come from Phil Nadeau with T.D. Cowen. Please go ahead. Good afternoon. Thanks for taking our question.
Philip Nadeau: Want to ask about the $500,000,000 guidance for products outside of CF. First, could you give us some sense of the breakdown between KESJEVRI and Genomics in that number? And then second, that is a big increase, a threefold increase over 2025 and an approximate doubling versus the Q4 run-rate. What gives you confidence in that level of growth? Is it KASJEVY infusions, KASJEVY self-harvest that are happening? Visibility from payers on Genrex? Can you give us some sense of what you are seeing to put that number out there? Thanks.
Reshma Kewalramani: I will ask you to take that one. Sure. Yes.
Charles F. Wagner: So the guidance includes a contribution from non-CF products of $500,000,000 or more. We do feel very confident about that number and have great line of sight to the year for some of the reasons that you touched on. I will not break it down further in terms of Kasjevi or Gernabix. But you will see the Kasjevi and Gernavix results in our quarterly reporting as it has occurred. So you will have a sense of where the contribution is coming from. With KASJEVY, we had a strong year with over—with 300 or so patients initiating, 150 or so having first cell collections. Given the length of the patient journey, that gives us great visibility into the year. So we are very confident that KASJEVY will ramp up nicely compared to 2025. And then similarly, you have seen our previous commentary about Jornavik's prescriptions tripling in 2026 compared to 2025. And with greater access in 2026 versus 2025, the revenue conversion on those prescriptions will be greater as well. So feeling confident about both. We have a nice trajectory heading into 2026 versus 2025, and look forward to reporting out on the results each quarter as we go forward.
Philip Nadeau: That is helpful. Thank you.
Eliana Merle: Thanks, Jeff. If you could wrap it up first, please.
Operator: Yes, ma’am. This concludes our question and answer session, as well as the conference call. Thank you for attending today's presentation. A replay of today's event will be available shortly after the call concludes by dialing 704-0529 or 8 using replay access code +1 000026104. Again, that replay access code is 10206104. Thank you for participating today. You may now disconnect.