Good morning, everyone. Thank you so much for joining us. It's my pleasure to introduce Vertex Pharmaceuticals, and with us we have Reshma Kewalramani, who's President and CEO of the company. Reshma, thank you for being here. You bet. Maybe to start here, a high-level overview on the company. Help us understand where Vertex stands today in terms of your core cystic fibrosis and emerging pain and kidney autoimmune franchises, the key pipeline priorities, and the outlook and strategy for the company as we head into the end of the decade. Sure thing. Sounds good. First of all, it's very nice to be here with you, Salveen. I know we're the last fireside chat, so it's good to see those of you in the room. I've described 2026 and for the next six, 12, 18 months as a year period of time for Vertex. That's an execution-rich period, and that's exactly how the first part of this year has played out. I expect the H2 of this year and as we go forward, it's going to be about expanding and extending our leadership in CF. You know that we now have medicines that can get up to 95% of people with cystic fibrosis, and we continue to expand geographically as reimbursements come out outside the U.S. and lower in age groups. For our last 5,000 or so patients, we're working on a nucleic acid therapy approach. You know that the approach we had started with is not going to be the one that goes forward. In CF, we're looking forward to all of that work and potentially bringing the next in-class molecules, although it is getting awfully difficult to beat the medicines we have. I know I said that when we were working on ALYFTREK when TRIKAFTA was available, but it's even more so to try and beat ALYFTREK with something else. Nonetheless, we have three programs in that area, VX-828, VX-271, and VX-522 as those next-gen programs. Moving on to pain. JOURNAVX is now about a year into its launch. There were more than 500,000 scripts written last year. We're expecting to more than three times that this year, and of course, with that comes commensurate increases in revenue. The hematology franchise with CASGEVY is growing nicely, and I like the momentum there. It's a long patient journey, so we have line of sight to the number of patients who've been in the doses that are ready to be administered. I like what I see there. Of course, POVI. It was at this conference last year, I think Salveen was the first to recognize that the fourth vertical of Vertex was about to be created. Fast-forward a year, just last week, we learned from the FDA that the filing for accelerated approval has been accepted, therefore the PDUFA date for POVI and IgAN is set at November 30th. As we look through the end of the decade then, it's certainly about these programs and driving them to their full potential as we complete the launches or get them launched in the example of POVI. It's a lot about moving forward rapidly the phase III programs. I'll just name them, and we can certainly talk about whichever ones are of interest. The type 1 diabetes program, the cell-based therapy, that's in phase III. There's a DPN, diabetic peripheral neuropathy study in phase III, inaxaplin is in phase III for something called APOL1-mediated kidney disease, and POVI in both IgAN and membranous nephropathy are also in phase III. Of course, there's a whole pipeline behind that. Then as we look at the balance sheet, it continues to grow. We really like the way we're allocating capital largely to innovation. As the company grows and the balance sheet grows, we'll also do more stock buybacks, and you should expect more of the same from us on that front. That probably takes us through at least 2030. Yeah. Perfect. Maybe on the balance sheet side here. How does BD play a role here in terms of de-risk by BD like you did with Alpine? Yeah. Also, how are you thinking about dividends going forward? Yeah. Maybe three things to say on that front. The first is, if you look at our pipeline, about 60% of our clinical stage pipeline comes from internal innovation, and a full 40% comes from external innovation. We've been active in both for quite some time. Maybe the second thing to point out is the Alpine acquisition looked really good to us as we were going through the process, and boy, am I excited. The more we peel the onion, the better and better it looks. The Seattle site is extremely productive. Some really great people who came to us from Alpine. I think you're going to see some medicines that come into the clinic in the near future that are from our site in Seattle. The last thing to say is I really do think the strategy around investing in innovation is the right one for us. As I look into my crystal ball, I don't see dividends in my crystal ball from where I sit today. Perfect. Starting with the cystic fibrosis franchise here, how do you view the long-term trajectory? Speak to the extent of market share remaining or any additional growth levers. In cystic fibrosis, I'm going to round a little bit, but there are around 100,000, 107,000 people around the globe. The vast majority of patients who can be on medicine are on medicine. As I think about the medium-term growth and the near and medium-term growth, it's going to be about getting to additional countries. There are countries, think Turkey, think Brazil, that aren't yet at the place or just getting to the place where reimbursement has come through. That's going to get us more patients to be on medicine and more growth. We're still working on the lower age groups. KALYDECO is six months old. The TRIKAFTA medicine, we're soon going to file for the one to two-year-olds. For ALYFTREK, we're filing, just getting ready to file for two to five-year-olds. That brings more patients into the fold, that brings more growth. Lastly, in the more medium to long term, it's the last 5,000 patients. For that, we are going to need a nucleic acid therapy. We're working through both the delivery, which frankly has been the greater obstacle, and then the payload. That's where we are with CF. Of your existing franchise here, can you talk to what proportion of patients you think will transfer to ALYFTREK and over what time frame, and what factors are moderating conversions, given I think it has about 15% share of the franchise currently? That's about right. ALYFTREK now cumulatively has hit over $1 billion in revenue, and it was launched right about January of 2025. That's a program that's picking up momentum. The key attributes for ALYFTREK are, one, it's once-a-day dosing. You'll remember TRIKAFTA is twice-a-day dosing. It actually is interesting. It's turned out to be more important than perhaps I'd even given it credit for, especially in our younger patients, for daily dosing is a real benefit. The second is that it's approved for even more mutations than TRIKAFTA, there are more patients with the ultra-rare mutations that can access a drug that treats the underlying cause of their disease. Lastly, a benefit for all is that in head-to-head studies versus TRIKAFTA, the ALYFTREK molecule had even greater reductions in sweat chloride. Those are the attributes. If you think about the conversion, in the U.S., the label is such that there is additional monitoring a patient needs to go through if they start a new medicine, whatever the new medicine is, if it's ALYFTREK or TRIKAFTA. For the conversions, that counts as a new medicine. There's additional monitoring. In Europe, the label is just plain different, and it does not have this additional monitoring. If you look in Europe, if you look at certain Nordic countries, for example, it's more than 70% of the CF patients have converted to ALYFTREK from TRIKAFTA. I think as the years go by, I continue to expect that the majority of patients are going to choose to be on the medicine that has the best profile, and that is ALYFTREK. I do think the majority are going to switch to ALYFTREK. We've never forced switching in the past, we don't intend to do so here, I think patients and physicians will choose ALYFTREK over the next period of time. How are you positioning your next-gen correctors, your 3.0s, versus your existing franchise as you think about the future and any timelines you can give us here? Yep. The next wave are the three that I named VX-828, VX-271, and VX-582. The first of that next wave, we should be able to see some patient results in the H2 of this year. That's VX-8 28, and f or VX-271 and VX-582, they're a little bit behind 828 to w hat we're looking for. Our long-term goal has been to bring the vast majority of patients to below carrier. That number is 30 mmol. Where we are today with ALYFTREK, we have 2/3 of patients who start medicine early in life already getting to that goal. More than 90% of patients are at a sweat chloride of less than 60. That's the diagnostic threshold, and more than 2/3 are less than 30. One of the interesting things in CF today is to think about, is there more room to get even better? When you look at the sweat chloride values and you think about the median, when we talk about median of less than 60 or median of less than 30, there's a normal distribution around that, as you would expect. When we plot the lower age groups who are on ALYFTREK and you look at their median, less than 30, and you look at the distribution, you plot carriers, so those who are the parents of children with disease who are essentially free of disease, they are now overlapping. Our young kids who are taking ALYFTREK on their distribution of sweat chloride, and you look at normals, we are near overlapping. That's a wonderful milestone to achieve. We're there with 2/3 of our patients. What are we looking for? We're looking to get even more patients to under 30. That's the North Star that we're following. In that carrier population, is there any benefit to going even lower? That is an absolutely excellent question. It does not appear to be the case that even lower is better. To be fair, we don't have a lot of data in the even lower. We're just getting patients now. It's really the wave of ALYFTREK that's gotten large numbers of patients to less than 30. TRIKAFTA got patients to less than 60. We're exploring this, and I do think you're going to need exceptionally long-term data. You're going to need data over 5, 10, 15, 20 years. Because if you look at model data from ALYFTREK or TRIKAFTA as an example, this is model data. Patients are living to more than 70 years of age. We're getting to these points of very good survival. The key question is, but can we get your protein function, your CFTR protein function, to essentially carry your levels? That's what we're trying for. I don't know that there's any additional benefit beyond getting you to less than 30. If you look at the less than 60 and the less than 30, now you're sort of maximizing benefit. Maybe there's a little bit more between less than 60 and less than 30, but I don't think there's even more under 30. I think that's the goal, get our patients to less than 30. Finally on this topic, there is a competitor schema that's developing assets in cystic fibrosis targeting NBD1 under the belief that it would lead to increased efficacy of CF1 over Vertex's assets, namely TRIKAFTA and that first data set this summer. Describe the work you've done to understand this target and why you believe your assets have reached the ceiling here in FEV1 or overall, the saturation of the protein. We've been working in CF for so long and have data all the way back to KALYDECO and have data that looks at sweat chloride levels and ppFEV1 lung function, we have an enormously large data set for this rare disease population. What I can tell you is that there's a good correlation between sweat chloride and ppFEV1 up to a point. After that, you don't get more ppFEV1 benefit. It is for that reason, I don't think it has anything to do with which drug you use, a potentiator, a corrector, or something that binds to a different location like an NBD1 that drives additional ppFEV1. It does appear to be an asymptote of lung function improvement. Maybe the easy way to think about it is these medicines don't reverse the damage already done. What they do is prevent further damage. We have reached an asymptote of that with where we are today. If you ask me, do I think that there's going to be improvement in ppFEV1, regardless of mechanism, after you are at the levels of ALYFTREK, TRIKAFTA? I don't think so. You can see that in the ALYFTREK to TRIKAFTA comparison. Turning to POVI. This drug is going to enter a market with two currently approved drugs. One area POVI differentiated versus the other drugs in IgAN is by its presentation as a low volume subcutaneous auto-injector delivered once every four weeks at home. Right. You've got that delivery profile benefit, there are also clinical profile benefits that you pointed to. Maybe help us understand how you go in and take that dominant position. Absolutely. I actually think, Salveen, what you pointed out with regard to presentation or what others might call administration, I actually think that's going to be the key feature of these medicines. I'll tell you a little bit about the safety and efficacy, one thing that's clear is the patient's not going to get the benefit if they don't take the medicine. This medicine is chronic lifelong therapy. It is a biologic, it's an injectable. The ability, the Vertex medicine is once monthly. It's subcutaneous, small volume, 0.46 mls in an auto-injector. None of the emerging medicines have that profile. I think that that feature is going to be amongst the most important once these medicines come out. On safety and efficacy, the big thing to say in my view as I've looked at the data, I believe POVI is best in class based on the following features. When you look at the proteinuria reduction, that's protein in your urine, hematuria reduction, and improvements in Gd-IgA1. Gd-IgA1 is a dynamic marker. All those measures look best in class. When you look at the safety profile, quite favorable, you put that together with the dosing and administration elements we were talking about, I believe POVI is best in class and is poised to be the medicine that most doctors and patients will want to take. Boy, am I excited to get this out into the hands of patients and doctors because it happens to be Vertex's first biologic, and it happens to be our first medicine in renal disease, and that's a wonderful place for a nephrologist like myself. Do you think that Otsuka and Vera having eGFR data out that versus you will impact that uptake curve? The eGFR data has an interesting context point to make, and that is the FDA, the U.S. regulatory agency, has asked all companies who are going through the accelerated approval pathway to not share GFR because the study, the phase III study is ongoing, because all of these are accelerated approvals. Once your phase III study is complete, of course, you can share the GFR. One important thing is that the phase III study has to be complete. One of the programs has completed their study, which is why they shared data. The other two programs have not completed their phase III study, which is why, the Vertex program, for example, won't be sharing GFR data. I think that it's well known in the kidney community, and it is the reason for the agency, the FDA, accepting proteinuria as the accelerated approval endpoint, that proteinuria is very related to stabilization of GFR, and that ultimately leads to delay of dialysis, transplantation, or death, which is the real goal. I think that's very, very familiar, and it is indeed the renal community that worked for many years, I'd say decades, with the FDA for proteinuria to be an accelerated endpoint. I think that's well understood. I don't think it's a big surprise that when you have, like you do with the POVI medicine, good reductions in proteinuria, you're going to get stabilization in GFR when that GFR is known. I'll also say the agency has asked all of the companies to share GFR data with them. They will make a decision about whether they're comfortable with what they're seeing before they provide the accelerated approval. I see that as very helpful to know, and I don't see it as a big surprise. I think it's an expected outcome when you have good reductions in proteinuria, that you get stabilizations in GFR. Speak to your confidence here about this drug, moving forward and translating into- Yeah -the follow-on indications and for myasthenia gravis in particular- Yeah. -where would this be positioned in that landscape? Sure. In IgA nephropathy, it's a 52% improvement in proteinuria change from baseline. It's some 83% on hematuria, and it's some 77% on Gd-IgA1. Those are really good numbers. On the next program, therefore the next approval, just given where it is in its cycle, I believe will be in membranous nephropathy, another kidney disease. There, the study is a phase II/III adaptively designed study. The phase II portion of it has completed its enrollment, and we're now in the phase III portion of it. That one is a traditional approval, a 104-week, what's called remission. It's a combination of proteinuria and GFR. I do think that'll be the second POVI indication. Third, we are prosecuting an indication called wAIHA. It was in one of the basis studies that the company we acquired, Alpine, had initiated. It's warm autoimmune hemolytic anemia. I think we'll have some updates for you this summer, early fall. The next one after that, which is in phase II study, is myasthenia. To your question of where do we position it in myasthenia? There's been some real advancements in this disease where, when you look at the endpoints, there have been substantial improvements. One of the difficulties, though, is that some of these medicines have to be cycled on and cycled off. In the cycled-off period, that's for safety reasons. In the cycle-off period, you can imagine autoantibodies returning and damage continuing until you can get back to the on period. What I expect with a drug like POVI, and there's another example of a BAFF/APRIL inhibitor that has done a study in China that has shown remarkable benefits. You have to look and do comparisons, which have all of the challenges and have all the same, the benefit was remarkable. One of the reasons I think it has that kind of benefit is because it's a medicine you can take continuously. You don't have this cycle on, cycle off matter to work through. I think about POVI compared to that BAFF/APRIL. That's a wild-type medicine. POVI was specifically engineered to have better binding affinity, better potency, better tissue distribution, and that's what gives me a lot of enthusiasm and confidence for the POVI program in myasthenia. That one's in phase II. It's about 40 people. We're studying two doses. I do think we will have something important to look at in the coming months. Great. Inaxaplin. You'll have data, phase II data in APOL1-mediated kidney disease- Yeah -with modest proteinuria and diabetes in the H2. Help us understand or frame for us how to think about this data set- Yep -recognizing we saw some data from Maze as well. Yep. Sure thing. On inaxaplin and this disease, APOL1-mediated kidney disease, AMKD, there's two things to think about when you think about the Vertex program. The first is AMPLITUDE. That's the phase III study. We completed the enrollment of the accelerated approval cohort late last year, and I expect that we'll be able to see and share results early next year. That's AMPLITUDE. The key thing to know and remember about AMPLITUDE is that it's a study of two APOL1 mutations, reduced kidney function, and proteinuria. Let's call it primary AMKD. We specifically did not include people who had modest proteinuria. We specifically did not include people with a second kidney disease, think diabetes, because those are different populations based on all of the available evidence we have. I think those second and third populations that we discussed, modest proteinuria or diabetes, are worthy of study, but they are different. We studied them in AMPLIFY, a phase II-B study. It's a basket study. There's about 15-20 patients in each arm. The arm that has the modest proteinuria is separate from the arm that is the diabetic cohort. What we're going to be able to assess is whether or not inaxaplin works in those conditions. The modest proteinuria cohort is important but distinct from AMPLITUDE because it has lower levels of proteinuria. That means there's a certain dynamic range, and there's lower headroom to move. That's why we're studying it separately. The cohort that has diabetes, it is not clear, based on all of the available literature, if when you have two APOL1 alleles and you have diabetes, is the kidney disease driven by the diabetes? Is it driven by the APOL1 mutations or both? It's worthy of study, as I said, and therefore, we're studying it in this separate cohort. We are fully on track to see and share those data in the H2 of this year, so we'll know the answer to those questions shortly. For AMPLITUDE, maybe- Yeah -speak to the confidence and speak to the risks, but also, when you look at the phase II data that was- Yeah -published in the "New England Journal of Medicine" and kind of translate to the phase III. The phase II included only FSGS-confirmed- Yeah -disease, whereas that's not an inclusion criteria now. Help us kind of understand that. Now switching to AMPLITUDE, which is two APOL1 alleles, reduced GFR or renal function and proteinuria. Remember, this is a primary cohort. We studied in phase II the same thing, primary AMKD. That's the "New England Journal" publication that Salveen refers to. We saw a very impressive 47.6% reduction in proteinuria. That's really good. In that study, we chose to evaluate patients with something called FSGS. FSGS, or focal segmental glomerulosclerosis, is a histological diagnosis. You have to do a biopsy in order to know whether or not you have that. FSGS is so-called because that's what you see on biopsy. It's not to say that you don't have APOL1-mediated kidney disease if you don't have this diagnosis associated with you that says FSGS. It simply means we did not biopsy you. We chose to do the biopsy-proven FSGS because it was our first study in patients, and we wanted to make sure we knew exactly what disease you had, and we wanted to make sure we had a biopsy. The disease you have comes from having two APOL1 alleles. Therefore, when we went into phase III, we have two APOL1 alleles, reduced renal function, and proteinuria, same as the phase II study. We have patients in that cohort, in that phase III study, who actually have FSGS because their doctor decided they wanted to biopsy them. We also have patients who have all of those other characteristics, but their doctor did not decide to biopsy them. We see that as a homogeneous patient population. That's the population we've discussed with the FDA. That's the study that's in phase III, where the potential accelerated approval cohort or the interim analysis cohort will be available early next year. Great. Switching over to JOURNAVX. Yeah Your pain franchise here. You have guided that JOURNAVX prescriptions would triple in 2026. Help us understand what's driving the momentum and how to think of that growth outlook for 2027 and beyond. Yeah. Now switching to acute pain and JOURNAVX. JOURNAVX was launched about March of last year. We had the approval in January and drug in channel in March of last year. We had about 500,000+ prescriptions in calendar year 2025, we have guided to more than 3x-ing that this year. What I see in its use and as we go out and talk to physicians is broad use in accord with the label post-surgical. In the surgical domain, it's a lot of orthopedic surgery and a lot of general surgeries. In the non-surgical domain, it's things like fractures or use in wisdom teeth extraction, that kind of use. It's broad. It's 50% in hospital, it 's 50% in retail with a fairly broad prescriber base I like the way people who are using it consistently, particularly in the postoperative, for example, post total knee surgery or shoulder or hip, how those who have used it and were early adopters are converting practices over to this. I think that's really important to see because this is acute pain. It's not a medicine where it builds on itself with the same patients. Hopefully, a patient who has acute pain has their pain episode, takes their medicine, and then they are fine. What we then have to do here is make sure that practices convert and people reach for JOURNAVX instead of reaching for an opioid. I like some of the early anecdotal reports around practices making that decision. I think it's really, really important to understand the need to have great reimbursement. If you're doing that, you have to think about, is my patient a Medicare patient or a private pay patient? Is it a patient that does have their insurance reimbursed or not? That adds friction to the process. I'm really happy now to being at the place where the three large PBMs are covering. The last one just started the coverage as of January of this year. Two of the four large Medicare payers, we have signed our contracts with them, and I'm confident we'll get to the other two. As these contractual arrangements come into place and people have access, that gives us the ability to sunset the PSP or patient support programs. That normalizes gross to net [audio distortion] 3x-ing the prescriptions, more than 3x-ing the revenue as we sunset these patient support programs. As we look beyond that, it'll get more and more to be the case as we look at 2027 and beyond, where practices are making their decision to use JOURNAVX, keep opioids not as the first thing they reach for. As patients get more access, and I think word of mouth ends up being important, social and digital ends up being more important. We are looking for even greater momentum. Great. On your broader programs here, in DM1, a muscular disorder- Yeah. -Vertex is developing an internal small molecule program, you also have been licensed an oligo- Yeah. -plus circular peptide approach from Entrada with phase I, II data in the H2. Discuss your view on these assets and what you're looking for in the upcoming data. Yeah. You're exactly right. In DM1 muscular, it's a kind of muscular dystrophy that is even more common than Duchenne muscular dystrophy. It's actually the most common muscular dystrophy out there. We have two approaches. The small molecule approach, which is our internal approach, is still in pre-clinical development, so it's on the bench. I like the progress we're making, and I think a small molecule approach has the obvious benefit of ease of use. The lead program is an asset we in-licensed from Entrada. Here's our scientific bet. It's an oligo linked to a circular peptide, and our scientific bet is that the circular peptide will be important in localizing the oligo to where it needs to be, which is not only in the cell, but in the nucleus, where it can do its work. There are other programs that use other approaches to targeting the oligo to its appropriate location, ours is the circular peptide approach that we think has the greatest likelihood of success. We're in phase II development. I believe that we will have results in the H2 of this year. What we're looking for is splicing as well as early signals of muscle strength. It's a bit difficult to relax and contract, it's hard to let go. There's some particular measurements we do on that. We're going to be looking for early reads on that as well as muscle splicing. Great. As a last question here. Yeah. You do have more pipeline assets behind this. Is there anything else that you want to highlight with regard to either a pipeline asset that you think is super interesting or just your strategy or outlook for the company as we look ahead? Okay. Let's pick two things. I'll pick one in phase III, then I'll pick something that's on the bench to whet your appetite. In phase III, I really like the type 1 diabetes program. It's an allogeneic, so read off the shelf, cell therapy, that is in phase III development. I like this program a lot because the data that we shared last year in the New England shows that 10 of 12 patients treated with this cell therapy were free of insulin with excellent glucose control. That is remarkable. It's never happened with an allogeneic cell therapy. That one is a program that you have to take immunosuppressants with, we're working on follow-on programs with either gentler immunosuppressants or no immunosuppressants through hypoimmune cell editing. I'll pick one on the bench. I'll pick the NaV1.7 program. That one's very interesting because it makes so much sense scientifically, it's so elegant to imagine that we can combine a NaV1.7 with something like JOURNAVX, a NaV1.8 inhibitor, prevent the initiation of the action potential, that's NaV1.7, propagation of the action potential. That's still on the bench, I like the progress that we're making, I look forward to bringing those two as a combination to the pain area. Great. With that, thank you so much, Reshma. Yeah. You bet. Thank you, Salveen.