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 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. Good evening, everyone. My name is Susie 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 CASGEVY revenue of $116 million and JOURNAVX's 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 CASGEVY, growing JOURNAVX, both in prescriptions and revenue, and advancing the emerging renal franchise, starting with Pove 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, ALYFTREK is a next generation 2.0 CFTR modulator and is the fifth approved CF therapy in our portfolio. ALYFTREK 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 ALYFTREK phase III trial, this one in two- to five-year-olds. All patients in this study were on TRIKAFTA and switched to ALYFTREK on entry into the study. ALYFTREK was safe and well tolerated, and the sweat chloride data showed a mean reduction of 9.6 mmol from a TRIKAFTA baseline. Importantly, 65% of these ALYFTREK patients achieved levels of sweat chloride below the normal or carrier level of 30 mmol 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 ALYFTREK in the two- to five-year-old age group in the first half of this year. As we continue to march down to younger age groups, I'm also pleased to share that the ALYFTREK one- to two-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, VX-828 is the most efficacious corrector we have ever studied in vitro and advanced to studies in patients. The VX-828 proof of concept study is on track to complete enrollment and dosing in the first half of 2026. VX-581, another corrector from this 3.0 class, is currently in a phase I healthy volunteer study. 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 I/II study of VX-522 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+ 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. Povetacicept, 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 1 million people in Asia. We see Pove'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, Pove's biophysical characteristics enable a differentiated profile. Pove 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, pove has delivered substantial reductions in proteinuria and stabilization in GFR, supported by significant reductions in Gd-IgA1 and hematuria. As importantly, povetacicept's meaningful advantages in dosing. Povetacicept 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. Pove's progressing through the BLA regulatory pathway, where FDA's granted breakthrough therapy designation as well as rolling review. We used a 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 2025. 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 Pove 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 Zai and Ono for these markets, as we did in IgAN. Membranous nephropathy, like IgAN, carries significant morbidity and lacks disease-modifying therapies. Accordingly, pove has FDA Fast Track and EMA PRIME designations and was recently granted Orphan Drug Designation in the U.S. The OLYMPUS phase II/III adaptive study of pove in membranous is enrolling and dosing patients. I'm pleased to share we remain on track to complete the phase II portion of this study and advance to phase III 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 pove's potential as a pipeline and a product with our plans in generalized myasthenia gravis. The rationale to study pove myasthenia is compelling. First, it's 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, pove 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 pove'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 pove in myasthenia in the first half of 2026. Now, returning back to renal and inaxaplin 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 inaxaplin 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. accelerated approval thereafter. Finally, in the Amplified study of inaxaplin 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 VX-407, 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. VX-407 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 II proof of concept study is up and running, and we expect to complete enrollment this year. This study will evaluate the effect of VX-407 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 CASGEVY, we remain on track to file for U.S. approval in patients ages five 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 JOURNAVX in acute pain, a pair of single-arm JOURNAVX phase IV 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, JOURNAVX 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 JOURNAVX 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 suzetrigine 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. Thanks, Reshma. The focus of the commercial organization in 2025 was to drive multiple successful launches, fueled by clear strategic intent, disciplined execution, and targeted investments. We launched ALYFTREK in the U.S. and Europe, built momentum behind the launch of CASGEVY in the U.S., Europe, and the Middle East, and successfully executed on the first year of launch for JOURNAVX here in the U.S. We're pleased with the progress we're making to diversify our revenue growth and treat patients in four diseases around the world. 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've 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. Focusing now on ALYFTREK. The rollout in the U.S. and Europe continues to progress well. The vast majority of treatment-naive patients in countries where we have reimbursement are already on ALYFTREK. We also see continued ongoing transitions from TRIKAFTA to ALYFTREK, and the majority of ALYFTREK scripts continue to come from switches. ALYFTREK'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 ALYFTREK in key countries, for example, England, Ireland, Germany, Denmark, and Norway. We also recently announced reimbursement for ALYFTREK 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 geographically 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 ALYFTREK globally, treating younger patients, expanding to additional geographies, securing access for patients, and maintaining our comprehensive patient support programs. Turning now to CASGEVY, 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 quarter four 2025 results, where CASGEVY had 111 new patient initiations, 37 patients with first cell collections, and 30 patients receiving infusions, driving $54 million in quarterly revenue. We also reached some notable reimbursement agreements for CASGEVY in quarter four 2025. In the U.S., more than 30 states have joined the CMS Cell and Gene Therapy Access Model, and there is now approximately 90% access for both Medicaid and commercial CASGEVY patients, with the remainder having case-by-case access. In Europe, all countries in the U.K. are now providing reimbursed access, and a recent landmark coverage decision by the Italian reimbursement body represents about 5,000 eligible TDT patients, half of Europe's beta thalassemia population. We anticipate seeing continued quarter-to-quarter variability in CASGEVY 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're 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 CASGEVY's multibillion-dollar potential. Moving to pain. I'm pleased to report that JOURNAVX achieved our 2025 launch objectives of, firstly, 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 JOURNAVX. More than 550,000 JOURNAVX prescriptions were filled in 2025, with a roughly 50/50 split between hospital and retail channels. There were as many prescriptions written in the fourth quarter of 2025 as there were in the prior three quarters cumulatively. Although I would note that quarter four 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 JOURNAVX in 2025, including orthopedic surgeons, general surgeons, anesthesiologists, pain specialists, dentists, and general practitioners. Over 200 million 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. JOURNAVX 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 JOURNAVX in their treatment journey as an effective, well-tolerated non-opioid option for moderate to severe acute pain. Looking ahead, given the strong adoption of JOURNAVX by hospitals and physicians and the progress we've made in securing payer coverage, we plan to double the size of our field force in quarter two. 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 JOURNAVX 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 normalizes 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 JOURNAVX gross to net will ultimately settle at levels comparable to other branded medicines. We're 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 multi-billion-dollar franchise for Vertex. Turning now to our emerging renal business. We are partnering with and investing in the nephrology community for the long term, and povetacicept 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 scale of our CF business, and we're seeking to bring the best elements of our success in CF to these kidney disease areas. These best practices include an 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 their 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. Povetacicept'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, Pove 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 nephrologists, who highlight the importance of payer access and preference for an auto-injector versus prefilled syringe in their treatment decisions. This market research with nephrologists reinforces what we've seen in the biologic 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 povetacicept's launch last year by building a commercial team for renal and engaging payers to ensure broad access. We're 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're also developing a comprehensive 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, multiple renal diseases. I'll now turn the call over to Charlie for our financial results and outlook. Thanks, Duncan. I'm 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 management. In the fourth quarter, total revenue reached $3.2 billion, a 10% increase compared to Q4 2024. For the full year, total revenue was $12 billion, 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 ALYFTREK, 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 KAFTRIO in established markets and contributions from ALYFTREK in countries where reimbursed, partly offset by the previously communicated $200 million decline in Russia sales for the year. CASGEVY achieved $54 million in revenue in Q4 and $116 million for the full year 2025, and during Q4, demonstrated continued momentum in patient initiations and first cell collections. JOURNAVX delivered $27 million in sales in the fourth quarter and $60 million for the full year, with substantial growth in quarterly prescriptions since its launch in Q1 of 2025. Note that JOURNAVX 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. Turning to operating expenses, Q4 2025 combined non-GAAP, R&D, acquired IPR&D and SG&A expenses totaled $1.4 billion, 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 $56.5 million of IPR&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 $5.1 billion, 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 JOURNAVX 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 $1.3 billion, up 24% year-over-year, delivering $5.03 of earnings per share, up 26% versus the prior year. Full- year 2025 non-GAAP net income of $4.7 billion resulted in $18.40 of EPS. Vertex ended 2025 with $12.3 billion 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 4.8 million shares for roughly $2 billion. This reflects our ongoing commitment to returning value to shareholders while maintaining the flexibility to act on growth opportunities. Let me now turn to guidance for 2026. We expect full- year 2026 total company revenue to be in the range of $12.95 billion-$13.1 billion, representing 8%-9% growth versus the prior year. This outlook anticipates continued solid performance from our CF franchise and a $500 million or greater revenue contribution from non-CF products, including greater volumes of patient infusions for CASGEVY and a ramp of JOURNAVX prescriptions. 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 $5.65 billion-$5.75 billion as we continue to invest in our late-stage clinical pipeline and commercial build outs in support of new launches and revenue diversification, particularly for genetics in acute pain and for renal. We anticipate our non-GAAP effective tax rate to be in the range of 19.5%-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'll now ask Susie to begin the Q&A period. We will now begin the question- and- answer session. To ask a question, you may press star then one on your touchtone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. Our first question will come from Cory Kasimov with Evercore ISI. Please go ahead. Great. Good afternoon. Thanks for taking my question. Probably not surprising that it's on pove. Curious how you view the risk of potential hypogammaglobulinemia adverse events and how this could ultimately impact the label, if at all. Thank you. Cory, this is Reshma. Let me take that one. On hypogammaglobulinemia, that's to say, low IgG levels. The way BAFF/APRIL inhibitors work, you're going to see a decrease in IgG. It's part and parcel of the mechanism of action. But the important question you're asking is, what does that mean, if anything, on safety? So the data that we've shown is RUBY-3, the 80 mg RUBY-3 cohort that we showed at ASN in November. What you see there is there were actually no SAEs, none of infection. It doesn't matter what IgG level you look at, there were simply none. That's good news. There was a single patient with IgG levels of less than 300 mg. 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 limit range, so let's say, around 700 mg. When I look at that, I don't really see anything there. 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. I hope that helps. Very helpful. Yeah, very helpful. Thank you, Reshma. You bet. The next question will come from Salveen Richter with Goldman Sachs. Please go ahead. Good afternoon. Thanks for taking my question. With regard to the guidance here, is there any way you could help us understand what's baked into the guide for the CF component relative to ALYFTREK and TRIKAFTA? And on ALYFTREK 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. Salveen, I'm going to split that question and ask Charlie to go first on the guide, and then I'll ask Duncan to comment on the market dynamics that led to the Aly numbers we shared. Yes, Salveen, no, no additional color on the guidance. Obviously, total revenue guidance of $1.295 billion-$1.301 billion, so 8%-9% for the year. Within that, a contribution, a non-CF contribution of $500 million or more. Within CF, we're not going to break it down further in terms of Aly versus other products. Maybe Duncan can comment on the dynamics in Aly that we're seeing right now. Sure. Thanks for the question, Salveen. So I'd say the fourth quarter was buoyed by the international launch. So we, as you know, secured reimbursement in Europe, in countries like the U.K., 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. Next question, sir. Thank you. The next question will come from Geoff Meacham with Citibank. Please go ahead. Hey, guys. Thanks for the question. Just have a couple. The first one, you guys seem really excited about pove's potential as well as the renal space. I guess the question is, is there work to do on the payer side when you think about access and reimbursement and, and maybe cost benefit? When you look historically, rare renal hasn't been a category where you get higher realized value, but obviously a new MOA can help that. Then just a follow-up on Aly. Is there more interest in the US in, in using sweat chloride as a disease biomarker? And, and you mentioned the European launch. I mean, how would you characterize maybe the awareness and willingness to switch, to, to Aly compared to the U.S.? Thanks. All right, Geoff, I'm going to ask Duncan to comment on both, but we'll take it in two parts. Let's do Aly first, Duncan. How do folks, how does the community think about sweat chloride, U.S. versus ex-U.S.? How do you see the uptake? And then let's get to pove. Geoff, you are absolutely right to detect a ton of enthusiasm in our voice on pove. It's not just about pove and IgAN, but it's pove in membranous nephropathy and in myasthenia gravis. And it is getting close to the time where we think we're going to have the results to share and close to the time where we think we're going to be able to file. So enthusiasm is certainly building internally. Duncan, on the pove question, it was about reimbursement and how you're seeing that. Yeah. So Aly first? Yeah. Thanks for the question, Geoff. 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, as you know, 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've always seen more rapid uptake in naive patients, and as per the prepared remarks, there are, for example, 1,500 naive patients in Italy that have just been reimbursed for a 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, povetacicept 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 last year. We've, 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're at with our engagements with payers so far, and where those will go in the future. The next question will come from Tazeen Ahmad with Bank of America. Please go ahead. Hi, guys. Good afternoon. Thanks for taking my question. With relation to pove, can we talk about what you're expecting to show on proteinuria? Like, what results do you think would provide, in your mind, medically, clinically differentiated data versus competitors? Thanks. Sure. Magnitude of proteinuria response. I think we've talked about this before, but in every study that we've 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's 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's very similarly designed in the inclusion and exclusion criteria, the proteinuria threshold, the GFR threshold for entry. It's the same exact dose, 80 mg, and the endpoint is exactly the same. In RUBY-3, the 36-week proteinuria data was a 56% reduction in proteinuria. I think it's important to also note that the proteinuria reduction is something that I believe will have. I think you could think of it as compounding effect over time. Even a little bit more improvement in proteinuria, better proteinuria reduction, is gonna be important because these patients are gonna be on the medicine 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 II, that would be incredibly important, very meaningful from a clinical perspective. Okay, thanks, Reshma. Yeah. The next question will come from Evan Seigerman with BMO Capital Markets. Please go ahead. Hi, guys. Thank you so much for taking my question. I'd love for you to expand on the rationale to study pove in gMG. Just seems to be a more crowded, a rare disease. I'd love for you to just touch on what differentiates this asset, what you saw potentially kind of, you know, in earlier studies, and how you think it would compare to both, assets that have been approved and are under investigation for the indication. Yeah, sure thing, Evan. I'll repeat a couple of things I said in my prepared remarks. It's 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, that is how this disease happens. It's 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're not taking the treatment, obviously, if you're not on the medicine, what happens is the autoantibodies come back, and that can lead to the disease returning. Now, what I'm about to tell you next is cross-study comparison, so you have to take it with a grain of salt. But there's been a study in China, China-based study, using a wild type TACI. And using a wild type TACI, if you do a side-by-side comparison of what's called the myasthenia gravis ADL score, that's the endpoint, it is remarkable what the wild type TACI, this is the wild type TACI, was able to accomplish. Again, these are cross-study comparisons, so take it with a grain of salt. But what that wild type TACI tells me is that by mechanism of action, it is something to really hold close. So then you translate that to Pove. Pove is not a wild type TACI. Pove is this engineered fusion protein, better potency, better binding affinity, better pharmacokinetics, better tissue distribution. So I look at the wild type TACI, and then I think about what pove could bring to the table, and that's the reason I'm so excited about this. I think this is going to be a really important indication for pove. First things first, we got to get through phase II. That study should be up and running shortly. That is a dose-ranging study, so we're gonna study 80 mg and 240 mg, and then we can take it from there and go to pivotal development. But it is one of the ones that I'm excited about. The next question will come from Michael Yee with UBS. Please go ahead. Hello. Thank you. Two questions. First, on Pove, 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's a chronic drug, that could be something to think about? And then I don't think anyone's asked on AMKD, but obviously you have a very potent drug there, and that data could be in about a year or so. I just wanted to think about how you expect those results to play out, and given you have a more heterogeneous population rather than just FSGS, do you expect essentially the same results from the phase II? Thank you. Yeah. Mike, let me take the AMKD results first, and I'll come back to pove and ADA. So in AMKD, when I was listening to Duncan talk about AMKD, ADPKD, pove and IgAN, pove, remember this, it really is a substantial renal franchise that's emerging. I do expect that the bottom line, I do expect that our results from the AMKD phase III AMPLITUDE Study will be very similar to what we saw in the phase II AMKD study. Recall, though, Mike, that the readout, the primary endpoint for the phase III study is GFR slope. Of course, we're going to measure proteinuria, but you'll recall that the FDA pathway to accelerated approval for AMKD is based on 48-week GFR. So, there's that difference. And if you ask me, "Well, why do you think that?" Even though the group that we studied in phase II was something we called FSGS, which is a histologic diagnosis, it's what you see on biopsy. The group that we studied in phase III is AMKD, 2 APOL1 alleles. They are the same disease. It's just whether or not the patient with 2 APOL1 alleles, depressed renal function and proteinuria, was sent to get a biopsy or not sent to get a biopsy. If you don't go to get a biopsy, you will never be able to see FSGS because that's simply a histological diagnosis. So net net, I expect the results to be in line with phase II. And I will reaffirm the timelines for data sharing, tail end of this year, beginning of next. On Pove and ADA and NAb, just to set the stage, and I know you know this, in biologics, ADAs, anti-drug antibodies, are to be expected. If it doesn't 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 a antibody that causes safety, but based on how this particular drug works, I don't have concerns in that domain. So it's 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 ASN in November, I don't expect that to be something of consequence. ADA, that is. The next question will come from Ellie Merle with Barclays. Please go ahead. Hey, it's Ellie. Thanks for taking my question. Just on JOURNAVX, how do you see the mix between retail and the 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. Duncan, do you want to take that one? Yeah, sure. 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're a commercial patient, whether they're a Medicare patient or a Medicaid patient, and indeed, whether they are going through our patient support program or whether they're a self-pay patient. So there are a number of dynamics in terms of how this sort of prescription- From William Pickering with Bernstein. Please go ahead. Hi, thank you for taking my question. I was wondering, this is a pove one. If you could discuss how you expect the baseline GFR to impact the observed effect size. I think your phase II patients had an average GFR about 10 mL higher than the competitor phase II or phase III trials. And so, if we were to see a phase III baseline for pove that's more similar to those competitor trials, just wondering directionally, which way, if at all, that would influence effect size. Thank you. Yeah. Well, I think you're asking about what the impact of baseline GFR could be on proteinuria. Did I understand that correctly? Yeah, that's, that's right. Okay. In general, when you're in the range of proteinuria where we're studying, so you have to be somewhere between 30, and I think the entry criteria is, like, 30-90 or something like that. When you're not at the very tail end, close to dialysis, so what we would call a burnt-out kidney, in the range that we're studying, it shouldn't have any great impact on proteinuria. When you have a burnt-out kidney, proteinuria could seemingly decrease because you don't have any renal function left. But in the range that we're talking about, it should be fine. There's no real big impact there. 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 pove. Just recognizing there's 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 the degree of patients on SGLT2 inhibitors, that might impact proteinuria response to povetacicept. 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 UPCR reductions from both the 80 mg and 240 mg doses from RUBY-3, just to get to a higher end? I'm just wondering if there's any reason 240 might have conferred lesser activity mechanistically. Thanks. Okay. On the differences between phase II, RUBY-3, and the phase III RAINIER, I think the most important one is that the phase II study was not placebo-controlled. The phase III study, obviously, is placebo-controlled. In all the other dimensions, inclusion, exclusion criteria, the dose of the study, the endpoint, they're 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's 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% and 5%. I think that's about right. So I think that's the big one. I don't have baseline characteristics, Brian, to share with you from the RAINIER study. Obviously, we'll have that for you when we share the results. I think there was another question about 80 mg and 240 mg. We did not study 240 mg any further after RUBY-2, and all of the 240 mg data that we had we shared with you at the ASN, and it did look, on average, about the same as 80 mg. Thanks so much. Yeah, you bet. The next question will come from Terence Flynn with Morgan Stanley. Please go ahead. Hi. Thanks for taking the question. Maybe two for me. First one, unsurprisingly, on pove. I was wondering, Reshma, if you can comment at all about the blinded serious infection data you're seeing from the RAINIER study at this point. And then the second one was on the WuXi deal. I know you mentioned you're developing this TCE for B cell-mediated autoimmune conditions. Just wondering how you think about differentiation there on the portfolio in terms of where you might carve out those indications relative to pove. Thank you. Yeah. Yeah. On the data for RAINIER, as you may know, there's 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 DSMB. They have not asked us to change anything in the study, and they've given the study clean bills of health as it goes through. Maybe that's the most helpful thing I can say to you with regard to what the ongoing data is. With regard to WuXi and indications, we specifically didn't share, so I'm gonna keep that information under wraps for a little bit longer. I will say that the idea of having a medicine like povet pipelining a product from multiple B cell-mediated diseases is exciting, and our interest in serial innovation stands. You put those two together, it's probably unsurprising to you that we're interested in these kind of tri-specific engagers, because they would work for a variety of diseases, not just the ones that we've talked about, IgAN, membranous, myasthenia, but other B cell-mediated diseases that we're interested in. But I'll keep the specifics under wraps for a little longer. The next question will come from Debjit Chattopadhyay with Guggenheim. Please go ahead. Hi, this is Morrison for Debjit. Thanks for taking our questions. I have two about pove. First, looking at the RUBY-3 UPCR data, povetacicept had a much larger standard error than atacicept or sibeprenlimab did in their comparable studies. Any comment on what may have caused this variability? Second, atacicept and sibeprenlimab phase III studies showed very different placebo rates in their UPCR interim analyses. What's your assumption for the placebo rate in the RAINIER interim? Yeah. I don't 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 the number of trials and is a real IgAN expert, offered that his idea was 0%-5% for placebo. I think that's 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 their data. I don't know that I have anything particularly helpful to say. As you know, the standard error is impacted by sample size. So I don't know exactly which data sets you're looking at, but that's one thing I would look at. And it also matters what lab tests you use, whether you're using 24-hour urine or you're using spot urine. So I could offer multiple explanations, but unfortunately, I haven't looked at the data you're looking at. But if you send it to Susie, I'm happy to look after the call. Thanks. And just to be specific, the 0%-5%, is that increase or decrease, given that in the competitor phase III studies, one of them showed a placebo increase and the other showed a decrease in UPCR? I was thinking about proteinuria, the placebo group potentially having proteinuria improvement of somewhere between 0%-5%. Obviously, if the proteinuria in the placebo group, if there was more proteinuria, it would be incrementally beneficial to pove because it is a comparison versus placebo. But of course, the placebo's equal opportunity could go up or down. We'll take one more question, Lisa. Thank you so much. You bet. The next question will come from Phil Nadeau with TD Cowen. Please go ahead. Good afternoon. Thanks for taking our question. We want to ask about the $500 million guidance for products outside of CF. First, could you give us some sense of the breakdown between CASGEVY and JOURNAVX 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 CASGEVY infusions, CASGEVY self-harvest that are happening, visibility from PBMs on JOURNAVX? Can you give us some sense of where you're seeing to put that number out there? Thanks. I'll ask you to take that one. Sure. Yeah. So the guidance includes a contribution outside from non-CF products of $500 million 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 won't break it down further in terms of CASGEVY or JOURNAVX, but you will see the CASGEVY and JOURNAVX results in our quarterly reporting after it's occurred. So you'll have a sense of where the contribution is coming from. You know, with CASGEVY, we had a strong year with over 300 or so patients initiating, 150 or so having first cell collections, and given the length of the patient journey, that gives us great visibility into the year. So we're very confident that CASGEVY will ramp up nicely compared to 2025. And then similarly, you've seen our previous commentary about JOURNAVX prescriptions tripling in 2026 compared to 2025. With greater access in 2026 versus 2025, the revenue conversion on those prescriptions will be greater as well. 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. That's helpful. Thank you. Thanks, Jeff. If you could wrap it up for us, please. 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 1-877-344-7529 or 1-412-317-0088, using replay access code 10206104. Again, that replay access code is 10206104. Thank you for today. Thank you for participating today. You may now disconnect.