Hi, everyone. I'm Ellen Maura, one of the biotech analysts here at Barclays. Very excited to have Vertex here with us, to discuss a lot of exciting news this week, with the povetacicept phase III amongst a lot else going on in the pipeline. Joining us is Miroslava and Susie Lisa from the Investor Relations team. Thank you both so much for joining us. Maybe to kick it off before we jump right into pove after. You know, we've seen Vertex shift from being a cystic fibrosis biotech to a more diversified story across several verticals. Could you walk us through the strategy behind the efforts you've made so far and what's coming on the horizon? Sure. Thanks, Ellen, and thanks for having us very much. Yeah, it's a really exciting time. We have long been proud of the work we've done in cystic fibrosis, but have also long had the goal to diversify our revenue base as well as the patient groups that we can address. I think are very pleased with the progress that we have been making, all while maintaining the utmost diligence and care towards that CF patient community and continuing to move the bar forward there in terms of our ongoing ALYFTREK launch now, which is our fifth commercialized medicine, as well as having a next-gen 3.0 family of therapies already in the clinic, and we can talk more about that if there's time. We're very pleased with the progress that we have made with our ongoing launches in CASGEVY for sickle cell disease and beta thalassemia, as well as for JOURNAVX in acute pain, to the point where we have built really strong foundations for these products in terms of the patient outreach and support, the commercial capabilities, as well as the clinical data to support these transformative therapies, and have said for 2026, right. That it would expect those two products combined to do over $500 million in revenue and have established strong basis for their growth. I give an additional targets for JOURNAVX, I think excitingly to more than triple the number of prescriptions in 2026 versus 2025, and revenue growth should outpace that on a year-over-year basis. I think as we'll get into the pove data, what we are really excited about is we feel that this exciting phase III data from the interim analysis firmly establishes our vision for renal ultimately to rival the size of our cystic fibrosis franchise. There are three therapy, three phase III ongoing programs in the renal franchise as well as an exciting phase II for autosomal dominant polycystic kidney disease. I think just an exciting time in renal medicine overall, and we look to be a thought leader there in expanding that. Beyond that, all the while, we've remained very true and disciplined to our R&D strategy with our identified sandbox diseases where they're serious diseases. We understand the causal human biology. There are validated markers. There are efficient pathways for both clinical and regulatory progress as well as specialty commercial infrastructure. I think sticking true to that discipline and then just the focus on R&D, the outsized investment that we maintain, that's what enables us to continue to diversify away from CF all while maintaining a strong outlook for growth there. Great. Yeah, certainly a lot going on beyond cystic fibrosis. Turning to the pove data, you know, outside of just, you know, the top line proteinuria result, which I think a lot of investors were focused on, what are the other important data points that you think people should be focused on coming out of that release? Yeah. I think there's a lot. Bear with me. I'll try and keep it quick. I think we were very excited by the overall what feels to us like best in class profile from an efficacy standpoint. Keep in mind too, that we feel we definitively have an advantage from a patient administration and dosing standpoint where we have the lowest dose of 0.46 mL in an at-home auto-injector, and it's once monthly versus peers are either higher dose and/or weekly injections that are required. We also feel that we will have best in class from commercial capability standpoint as well. There are actually a lot of similarities between the CF and renal markets and the nephrology community, and we're excited for that. In terms of the key data highlights, UPCR certainly does grab everyone's attention, and that's where we saw a 52% reduction at 36 weeks. I think that's important because some of the peers have had primary endpoint measurements at 40 weeks, and you continue to see improvement over time. Seeing that type of reduction at 36 weeks is important. From Gd-IgA1 on the secondary objectives, two endpoints there, one on Gd-IgA1 with a 77% reduction, as well as an 85% resolution for patients' hematuria, an 85% rate of resolution. Those two were at 36 weeks. Again, some of the peers are measuring secondary endpoints at 48 weeks, so even more potential for differentiation. I think another key highlight, particularly in physicians' minds, is the fact that 42% of our patients got to the KDIGO recommended guidelines of a UPCR less than 0.5 grams per gram. That also compares quite favorably. This is very much a real-world population, right? We're the most recent of the IgAN studies. We enrolled the fastest. We also had the highest rates of background therapy. Nearly everyone was on ACEs and ARBs, and more than 65% of patients were on SGLT2 inhibitors. We also saw that the average duration from time of diagnosis, biopsy diagnosis to enrolling in the study was three point eight years, right? It very much is a real-world population, that high background therapy and still seeing that level of improvement on there, I think is really significant. The other big piece of news is that we announced that we'll submit our complete rolling submission by the end of this month. I think that's beating expectations by about a full quarter for most. We have used a priority review voucher. After the FDA has two months to accept the filing, consider and hopefully accept the filing, then it'll be a six-month review from there. I think those are the key highlights. Yeah. If others come up, we can bring them up later. Yeah. I think that's particularly compelling, particularly the proportion of patients that got below 0.5 grams. Yeah Given that is in the guidelines now, in terms of this, where patients should be going. Exactly. I think that's an interesting comparison from an efficacy perspective. Considering the patient baselines, which I think you appropriately called out, seems to be a more real-world patient population. A question that we're getting a lot of is on safety. Yep. Maybe if we could talk about that. I mean, you have the potential to be more potent, but with the immune system, that also comes with the potential risk of some more, you know, like infection risk. Can you talk through what was actually seen in the study and how you're thinking about the safety here? Yeah. We were quite pleased with the overall safety results, and it's a very, very clean profile. I think perhaps to start that the vast majority of adverse events were mild or moderate, and that there were no SAEs that were deemed related to pove, and no SAEs that were inherent in that, right? None due to infection. We can also confirm that there were no discontinuations related to infection, and there were no opportunistic or unusual infections either. Most of that we included in our release, that the greater than 10% rate were upper respiratory tract infections, nasopharyngitis, and injection site reactions, right? So all very common. I think a very favorable profile, and we're excited to move forward. A question that we got has been on hypogamma. I guess what can you say on what was seen here and when we can expect to learn more about that? Yeah. Thanks for the question. I think there has been a lot of discussion around this, and it's very I think in general, everyone cautions from cross-trial comparisons, right? Particularly when it comes to issues like infection, I think it's even more fraught with peril. There are very different definitions across the industry in terms of definitions of what the thresholds were for hypo IgG as well as what counted as a case of it. For us, in the RAINIER study, any patient who went below a level of 300 milligrams per deciliter, that was then deemed to be monitored. If the patient went below 150, then treatment was discontinued or would be discontinued. We have told you there are no discontinuations through the interim analysis group. In order to maintain study integrity, we're not disclosing the number of that below 300 number or numbers. We have told you all the information on infections because the so what of hypo IgG is infection, and you're just not seeing it as we went through previously. I would say similar question, we did disclose that there was evidence of ADAs, but the so what there is on efficacy. As we mentioned and discussed, right, I think very, very good efficacy even with all of the background therapy. In addition, we provided a forest plot in the press release that shows you excellent results across every subgroup, including by race as well as by region. You don't see any of the outliers perhaps you've seen in other studies. I think, both on hypo IgG as well as in ADAs, I know investors always want more disclosures, but we feel that we've given the consequences, the answers to the potential consequences of those, and there's nothing there. That makes sense. In terms of pove, what I think is interesting is that this could be a pipeline and a product and have applications in a number of other conditions. Can we talk through that and sort of the rationale you see in PMN, myasthenia gravis, and the timelines for those? Yeah. In primary membranous nephropathy, I think very much akin to thinking about IgAN in terms of that patient population. IgAN is a little bit larger, right, 330,000 patients in U.S. and Europe, and PMN is slightly smaller. We're in an ongoing phase II, phase III study. There is no interim analysis or accelerated approval pathway here. It's a 104-week study, but we're underway and excited to keep progressing. I do think as physicians are considering their choices, the thought of having to learn and be fully immersed in one therapy to treat a broader array of their patients is a potential advantage we could have. For myasthenia gravis, we said that we'll initiate a phase II study in the first half of this year. I think if you're looking for a poster child for a B-cell-mediated disease, that's probably myasthenia gravis. You have seen data out of China that looks quite compelling, and I think the rationale just makes all the sense in the world, and that's why we're moving forward and excited for that. There could be additional indications beyond those three that we have discussed. Makes sense. How should we think about kind of the commercial opportunity for each of these, considering unmet need, patient population, but also the competitive landscape? Yeah. I think in, let's maybe just start with IgAN, that there is a clear unmet need, right? There's 330,000 of these patients who are diagnosed today really with no good options. You heard physicians describe them as kind of just waiting to see how and when and how fast they'll progress. To have a disease modifying therapy that can stave off the need for dialysis or transplant and ideally death, right? That is, I think, obviously compelling to patients, physicians, and to payers as well, because all of those options are expensive ones. There are, I think about 4,000 nephrologists treat 80% of these diagnosed patients in the U.S. We've had ongoing conversations with them with payers about access since the middle of last year and continue to have those conversations. We have built out sort of the initial phase of our sales force, and now with this data, we'll look to complete that. Vast majority of the ones we have hired have nephrology experience in the community. Again, we've been in nephrology for a long time with our inaxaplin study. I think definitely as we saw at ASN last November, a real excitement and buzz about the innovation that Vertex is bringing to the renal community. Not the least of which is helped by the fact that our CEO is a trained transplant nephrologist, so that certainly helps. PMN, similarly, I think no real disease-modifying therapies. In myasthenia gravis, we view the opportunity as some of the existing therapies. The drawback there is that they need to be cycled on and off, whereas we don't see that need, given the mechanism with povet, but we need to do the trials and move forward from there. Makes sense. I guess in terms of inaxaplin, you have some exciting data either late this year or early next year. Let's talk about that opportunity and what you're looking to see in the phase III program. Yes, sure. This is a disease that has no existing therapies, nothing that addresses the underlying cause of disease. We think that the cause is the APOL1 mutations that people inherit, that ultimately there is a second trigger, but they drive pore formation in the kidneys that ultimately results with the progression of kidney disease and rapid progression to kidney failure. What we're developing there is our molecule is inaxaplin. It's in phase II phase III pivotal development, and we expect to read out the interim results from this trial late this year or early next year. The goal is reduction in proteinuria, and we will also look at eGFR slope versus placebo. Those are the endpoints. It is clear we need to show stabilization of eGFR versus placebo as a pathway to file for accelerated approval. What gives you confidence that you'll be able to see the stabilization in eGFR slope? Yeah. It's a great question. AMKD, this is really the first trial for this population. Obviously, we are the first to study this disease. What gives us confidence is these patients, based on all the literature and everything we know about them, they progress twice as fast to renal failure and to dialysis than their peers who don't have the APOL1 alleles. Based on all of the everything we know about the patients and the progression of disease, there is reason to be optimistic that the curves can separate even at one year. I'd also mention in our phase II study, which we published in New England Journal, that even just at 13 weeks, right, you saw a 47.6% reduction in UPCR. We're hopeful with that sort of speed and depth of reduction that that can lead to the endpoint in eGFR. I think admittedly, 48 weeks typically would be a short timeframe for eGFR, but we're optimistic. Great. Turning to the cystic fibrosis business, maybe just the latest that you're seeing in terms of ALYFTREK uptake. We saw, you know, some decent growth in the fourth quarter. How should we think about the trajectory over 2026? Yeah. We would expect a continuation of the same solid trends in terms of ALYFTREK and conversions from TRIKAFTA to ALYFTREK. I would say that virtually all new patients are initiating on ALYFTREK, given the lower sweat chloride that you can see with it, as well as the once-daily dosing convenience, as well as the fact that that means only one fatty meal a day and patients have appeal there. We're also excited by the ongoing launches and reimbursed access in Europe. For instance, just given the derivation of the disease, you actually see more of the rare mutations in Europe than you do in the U.S. We gave an example on the fourth quarter call that there are now 1,500 patients with access for the first time in Italy, given their rare mutations that can be addressed by ALYFTREK. There's also no incremental liver monitoring anywhere outside the U.S., so that's helpful for uptake outside the U.S. too. I think continued good progress and a focus on the messaging around lower sweat chloride is better, and ALYFTREK gets you there, right? We also just published or released top-line data from our study in ALYFTREK, where you see in the 12+ population, right, about 30% of patients are getting to diagnostic levels. In the six to 11, I think it's about 53%, and by the time you get to two to five, which is the one we just released, you're getting to north of 60% of patients getting below the diagnostic threshold. These are kids who will essentially be asymptomatic of their CF, and we've begun a study in one to two-year-olds with ALYFTREK. That will continue the momentum. We've talked about growth overall in CF from younger patients, additional geographies, additional patients with the rare mutations, and then the underlying population growth, which has averaged 3% over the past five years, due in large part to the survival benefit that you're seeing from our meds. Makes sense. As you think about long-term and lifecycle management, any thoughts on NBD1? Sure. NBD1, we know the CFTR protein intimately well. I've been studying it for 20 years. NBD1 is a known binding site on the protein for many years. It's been in the literature, I think over a decade. We are looking at NBD1, we've disclosed, but that the binding sites that we've used for our five commercialized medicines have been different ones. As I mentioned, as we're getting close to now, you know, almost 2/3 of two to five-year-olds getting to carrier levels of sweat chloride, I think we are happy with the binding sites that we have chosen. We'll continue to look to try and improve until we can get virtually all patients to those carrier levels. I don't know that there's anything particularly unique, particularly given the breadth that we're seeing in terms of over 300 rare mutations, et cetera, about NBD1. We are continuing to look to move forward. We have a next gen 3.0 family of therapies, one of which is in patients, one of which is in healthy volunteers. We'll look to continue to raise the bar and we'll see what others can do in terms of data middle of this year, I believe, which is on top of TRIKAFTA, which is our therapy. As I said, we'll see and we continue to move the bar forward. It's a long pathway from proof of concept, if that's what you see, to finding a molecule. A combination therapy is inherently difficult and then the head-to-head studies, and then just getting it down into the younger patients. It took us a decade to get into the one-month-olds from initial approval. Yeah. Makes sense. That's helpful context. Turning to JOURNAVX, you said you expect scripts to triple this year, which is certainly impressive growth. This is a program that I think investors should be paying more attention to. Maybe talk through some of the investments in the sales force that you've made and what's driving some of this script growth. Yeah. On JOURNAVX, we are very pleased with the momentum, frankly, entering 2026. We came into 2026 having secured the last remaining commercial PBM for access to for coverage to JOURNAVX. We are at over 200 million covered lives. That's 67% of all covered lives in the U.S. As you remember, Ellen, we had 550,000 scripts written for JOURNAVX in 2025 in year one, which was pretty broad across the hospital, the retail segment and different specialties. 35,000 physicians writing prescriptions. We were very pleased with the momentum going into 2026, and we feel strongly that now is the right time to double down and invest further behind the launch. We are doubling the sales force from 150 to 300 reps. These reps will be active in the field in the second quarter, and the goal for them will be to go broader and deeper with accessing physicians and driving adoption of JOURNAVX. In addition to that, we are also increasing our marketing investments, so things like direct to consumer, where we are launching advertising across connected TV, or Hulu, Paramount Plus, and the like. We have a campaign with basketball star Hall of Famer Jayson Tatum. We're out there, we're promoting heavily, and we expect that to increase over the course of 2026. As coverage broadens, the gross-to-net we are realizing on JOURNAVX will improve over 2026. That will result in more revenue and higher revenue growth, as Susie mentioned, relative to the script growth. One other thing I'd add is Miro touched on is two phase four studies that we're excited about. One we just published was presented last week in aesthetic and reconstructive procedures. We'll have one next month in arthroscopic and laparoscopic orthopedic procedures, but showing really tremendous patient satisfaction as well as high rates of patients being opioid-free in the 14 days post-treatment. I think in the aesthetic one, it was 90% of patients were opioid-free, and typically in that patient group, you see only 10% of patients are opioid-free, according to the literature. We look forward to similar results in the orthopedic one. I think that will also help continue to fuel the momentum. Yeah, we've certainly heard very positive feedback from physicians in the aesthetic setting, as well, so exciting data. As we head into 2027 and potential phase III data for DPN, sort of remind us of the timelines and the trial design there and what gives you confidence in potential success. Because this certainly would dramatically, in my view, expand the market opportunity given. The duration of the script would be much longer as a chronic type of pain. Yes, we are well underway with our two phase III trials in diabetic peripheral neuropathy. We expect to complete enrollment in both trials by year-end, and that would set us up for results in 2027. We feel very good about the progress of this program. There's 2.5 million patients with diabetic peripheral neuropathy in the U.S. who have significant unmet need. The current available treatments are either not well tolerated, I would say, or just don't provide sufficient relief. We think we have a lot to offer here with JOURNAVX, but we'll have to read out the results and see how it plays out. They're 12-week studies with two weeks of follow-up. Is that right? Yes. Great. Well, a lot to look forward to. I think we're at time, but thank you both so much for joining us, and appreciate the time today. Thanks very much for having us.