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Great. Good morning, everybody. I'm Terrence Flynn, Morgan Stanley's U.S. Biopharma Analyst. Pleased to be kicking off our 24th Annual Healthcare Conference here in New York City. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com backslash research disclosers. If you have any questions, please reach out to your Morgan Stanley sales representative. I am very pleased to be kicking off the conference this morning with Vertex Pharmaceuticals. Joining me is Reshma Kewal Ramani, who is the company's CEO and president. Thank you so much, Reshma. It's great to see you this morning, bright and early. Good morning, Terrence. So maybe I'll turn it over to you to just give us an update on the company'S diversification journey. I know that's been a big focus of yours as the CEO here. There's been a lot of movement on the Company's pipeline and also the Krenetics acquisition recently. And so maybe just give US a mark to market on kind of where you stand on that journey. You bet. Well, good morning, all, and for you brave souls who've made it here at 7 a.m., it's very nice to see you. We have been on a journey, it's more than 10 years now, to diversify our company and continue to grow. I do want to make sure that we talk about CF for one minute. CF has been and remains important to us, and we see more growth in CF as we now launch a lift trek around the world and get down to lower age groups. We also have our last 5% of patients for which we don't yet have a therapy. And so that foundational pillar of CF continues to go strong. Outside of CF, over the last three years, we've been bringing Caschevy to more people around the globe. And you know Caschevey has a very significant patient journey. And now we're at a point where we can see patients who are initiating, who have first cell collections and have infusions. And so we can see the line of sight into the growth, and it looks very good. And I continue to believe Cashevy is going to grow into a multibillion-dollar asset. Over the last year or so, we've been launching Gernavix in acute pain. This is the first non-opioid in more than two decades, and I really like what I see in the growth there. And then we were talking about the fourth pillar, which was going to be renal medicine, and it is, but I think it's actually going to just switch places with rare endocrine and kinetics, which is our fourth pillar now with Palfonify, which is an approved medicine in the U.S. It's approved in Europe, launched in the U. S. This is a medicine for acromegaly. And then, of course, there is the renal pillar, the PDUFA date for our first renal medicine. POVI in IGAN is November 30th, and I'm sure we'll get into a little bit more there. And there's much more beyond that. In total, there's something like six programs in phase three, more than that in phase two. And I like what's coming out of the bench into the clinic as well. So lots going on inside and outside of CF. Great. Well, no, that's a perfect framing. So I guess, you know, the area I want to dig into first is just your kidney franchise. Obviously, that's been a big focus of investors. You mentioned the POVI-PEDUFA date coming up here. Maybe just level set us on differentiation. I think that's a question we get a lot from investors is there's two competitors that have launched into the market already. So as you come from a third to market position, how do you think about differentiation of POVI? Yeah. So when you think About IgA nephropathy, just to level set, you're looking at something like 300,000 patients between the US and Europe, let's say 150,000 inside the US, and then add another million or so in Asia, where we're going with Zai in China and associated countries, and with Ono in Japan and a few other countries. So it's one of these rare diseases that is a common rare disease. In terms of coming to market, it turns out that this is an interesting area where there are three medicines that are all launching, let's call it within a year or so of each other in the category of April or April bath. In my mind, as I think about IgE nephropathy, and I happen to be a nephrologist, this is a disease that is very well understood in terms of its etiology. It is a B-cell mediated disease. It isn't a disease, but it is a disease that results from autoantibody production. And when you think about it that way, it makes most sense to have a medicine that works on both April and BAF because those are the two cytokines that are most responsible for B-cell development, maturation, and it wouldn't make sense to me to work on only April or only BAF unless you saw some concern in the safety profile. We now have the profile. We put out a fairly extensive press release. The safety profile looks really good. And the efficacy, and this is numerical, and it's cross-trial comparisons. You've got to take this with a grain of salt. But when I look at the numerical response, POVI has the best numerical response in terms of pertinuria, hematuria, GDIGA1 levels, and that's important. But maybe the most important thing, which could be surprising to you, is the fact that it's also the most patient-friendly dosing. This is a biologic. A patient will be taking this for the rest of their life, and their ability to take a small volume, POVI, is 0.46 mils. In an auto-injector once monthly is a very favorable presentation, and I think that's actually going to be one of the greatest differentiators. I also think our ability to support patients through their journey is going to Be important. We've learned a ton doing the same in cystic fibrosis. I think that's going to be important. And the last thing I'll call out is we have built the largest sales force, and that is to serve patients where they are. There's certainly centers of excellence and large clinics, but there's also a smaller number of patients in the community setting, and we want to be able to serve all patients. Great. Maybe just one follow-up there is that, you know, GFR or kidney function is the other endpoint that you guys are studying. The trial is going on for two years to look at that. So as you think about positioning the kidney function data, you know, how do you think About the importance of that in either a label or at some point down the road, given, you Know, one of your competitors will already have some of that data. Yeah. So this one has been a rapidly evolving field. 10 years ago, 15 years ago. The FDA wasn't yet comfortable with pertinuria as an accelerated endpoint in the community. The renal community has been working with the FDA, with academic centers, with industry to get proteinuria to be it. We are now at a point where proteinuria is routinely accepted in IGAN as an accelerated approval endpoint. And your point, Terrence, is around, all right, where are we with GFR? On GFR, the agency has been hinting, and in the spring renal meetings, they all but said they're going to get comfortable with one-year GFR as the endpoint, as opposed to two years GFR, which is where it was at prior to those meetings with the FDA. Where we are is that we want to launch POVI around the globe. That is our ambition. That's what we are going to do. For that to happen, we have to meet the global regulators where they are, and global regulators, so think MHRA for the UK, the EMA for EU, and the Asian regulators, not to mention Australia, are not yet at the point where pertinence is acceptable. They are at the part where two-year GFR is okay, and so we're methodically making our way around to understand where they are with one-year GFR, but we won't cut our data set early because our ambition and our goal is to have POVI go around the globe. It is true that the FDA has become increasingly comfortable, and they've all but said one-year GFR would be acceptable to them. Great. So it seems like you're unlikely going to get that one-years GFR on because you want to preserve the integrity of the data set for the global. That's exactly right. That's actually right. If you cut the data early, as you remember, the FDA had instructed all three companies in the April-April BAF space to not share the GFR because it was ongoing. And so once you cut the GFR and share it, that would be the concern for, if the U.S. is okay with it, that would been the concern of the global regulators. Okay. Maybe there's one on the commercial side. You mentioned you're going to have one of the largest renal sales forces out there. What have been some of your early conversations with payers? Obviously, we've seen, you know, a couple quarters from Otsuka now in terms of the uptake of their Igand drug, but how are your preliminary conversations with kind of payers going and anything to update us on there? there? Yeah. On the payer side, they are familiar with the disease. They are familiar with pertinuria, the accelerated approval, the correlation to GFR and such. And they're very familiar withthe outcomes of patients with IgA nephropathy. Unfortunately, that is progression to dialysis, transplantation, or death. And the value of slowing that progression is well understood to them. So we've been in conversations, the ones that we are allowed to have legally and appropriately, since about last summer. We've targeted and discussed POVI with more than 70% of payers, and the conversations have been productive and positive. I expect that we will be able to secure reimbursement. I suspect that it will be the kind of reimbursement that would be appropriate and commensurate with what you've already seen in the field. But this one seems like the payers are familiar and they are understanding of the value of medicines that prevent death, dialysis, or transplantation. Okay, great. I think the other thing as we think through differentiation is breadth of program or breadth of indication set on a label. I think back at some of the historical examples here where that is oftentimes pretty important as you think about formulary positioning. So maybe just give us an update on kind of where we stand with the POVI program in terms of breadth of opportunity and the next set of data that we should focus on here. Yeah. I think the Alpine team did a really nice job in studying POVI in multiple potential indications by way of these Phase II basket studies that they conducted. For us, after POVI and IGAN, that's the November 30th PDUFA date, I expect the next phase three readout to be in membranous nephropathy. I think that has an advantage to our first discussion point around differentiation. I think nephrologists are going to find it helpful and easier for their clinical practice to pick a single B-cell modulating drug across the various glomerular diseases that they're dealing with. And so having POVI in IGAN and POVI and membranous, I think, will be valuable. I do think membranus will be next, and I think the one after that is going to be in myasthenia gravis. The myasthena program is in Phase II. The membranious nephropathy program is In Phase III. And to close out on membranouse, the DSMB has met, and they have picked 80 milligrams, which is the same dose that we had studied in Phase 2 in the Ruby 3 trial in the event you want to look at those data as the Phase 3 dose. Great. And then as we think about read-through, I guess, from IGAN to these two other indications, either one of those that you'd put a higher probability than the other, or are they both about the same given B-cell biology? How do you think about reading through from IGAn to those two? Yeah, I think it's reasonable to look at the Phase 2 Ruby 3 trial for membranous to get a sense of where that's going. It's the same dose. It's 80 milligrams, so you know the safety because we just announced the results from the interim analysis accelerated approval cohort for IGAN. And there are lots of similarities between IGAN and membranous. As GDIGA1 is to IGAN, PLA2R is to membranus, and you can see what that reduction was. So I think that's a very, it's a reasonably easy analogy to make. I am very excited about the MySenior opportunity because there is a wild-type tachy that already completed a study, a phase two study in a China-only population, so you got to think about that. But when you look at the timeline, and if you plot, for example, time on the x-axis and the ADL, the activities of daily living on the y-axis, the wild-type tachy in that China- only cohort had really nice results. Of course, POVI is an engineered tachY. It has better binding affinity. It's higher potency, better tissue distribution. So I am very excited about this. This is a patient population that has a disease that is one of the most B-cell-mediated diseases, if I can call it that way. And while there are medicines that are available that have been real game changers, unfortunately they have to be cycled on and cycled off, but the disease doesn't cycle. And POVI would be a medicine that could be taken consistently over the period of the patient's life, and I think that could bring a real benefit. Okay, great. Maybe we'll move over to anaxiplin, which is another one of your pipeline assets. This is for ApoL1-mediated kidney disease. Right. And so first, maybe just, again, give us a little bit of background on the disease and the need there, and then as we think about the upcoming data from Amplified, I'd like to dig into that a littlebit, because I think that's expected in the fall here. And this is from a phase two study. Absolutely. So staying with the renal franchise, this is about enaxiplin in a disease called AMKD, APOL1-mediated kidney disease. The disease itself is fairly new. It was just described in about 2010 or so. And basically it's a disease that occurs only in people of recent sub-Saharan African descent. It is a very rapidly progressive disease, and fundamentally what you see is if you have two ApoL1 alleles versus if you don't, your risk of progression is something like 5x, 6x. It's extremely high compared to those who do not have ApoR1. There are about 150,000, let's say 100 to 150, 000 people with AMKD in the United States. It's largely a disease in the Western world that is in the U.S. And these patients have no medicines that have been specifically approved for their condition. We have a program that is going to read out. It's called Amplitude early next year. It's in Phase 3 development. We have an agreement with the FDA for potential extension. and the accelerated approval is based on one-year GFR. The FDA is not yet comfortable in AMKD, unlike in IGAN, for proteinuria to be the accelerated-approval endpoint. That study finished its enrollment in the IA cohort last year. We are on track to finish the full cohort enrollment in QH of this year, and we're fully on track for the Phase III interim analysis readout early next. that's amplitude. But as Taryn said, there is another study, Amplified, and we do have to talk to the teams about not naming them so similarly. Amplify is a 2B study. That one we'll read out this year and in the fall is about right. We are on track for that readout this fall. That one I would think of as an expanded population, as an indication expansion from amplitude. So Amplify has two cohorts in that phase two study. Cohort one is modest proteinuria, so up to 0.3 to 0,7 grams of proteinuria whereas Amplitude is more than 0.7 grams. And cohort two in Amplified is patients who have AMKD, so they have two APOL1 alleles, but they have a second disease and that second kidney disease is type 2 diabetes. The reason I consider them expansion cohorts is obviously when you have lower pertinuria, this modest pertinuric cohort, the dynamic range is smaller. And when you Have2 kidney disease, it's not clear what kidney disease is causing your pertinura. Is it 50-50 type 2 diabetics and AMKD? Is it disproportionately AMKB, disproportionately type 2 diabete? And, of course, our medicine, an axoplin, only takes care of the AMKD portion. And so that's why that's an indication expansion, a potential indication expansion. Those results could expand the 150,000 people in the U.S. to maybe add another 100,000 or so. So that's what the amplified study looks like. Great. Maybe we'll just focus on the modest proteinuria cohort. What would you view as kind of a good result there, and what are the implications then for the amplitude study as we think about that phase three, if we see the data from cohort one? Recognizing cohort two is type 2 diabetic, so again, a bit more of a wild card, but in cohort one, how do you think about what the bar is for success there? Yeah. I hesitate to offer a bar. I think what I said when we were doing the phase two for amplitude is double-digit pertinuria improvements would be beneficial. Some took that to mean 10.1%. Others took it to mean 99.9% improvement. I would say anything in the 20%, 30% range would be positive. Again, remember, in modest pertinaria, your dynamic range is just smaller. But I think if you have double-digit improvement in that line, I think that would be a positive. If I'm remembering correctly, the lowest level of pertinuria that later turned out to have value when the sponsor did the time to ESRD dialysis or death trial was something like 14%, 15%. So I think numbers like that tell you that those are values of pertinary improvement where when you go on to do the hard outcomes trials, you show benefit. Great. And just remind us what would be needed for an indication expansion here. Would you need a separate Phase 3 program for both of these, or could you somehow use this Phase 2 data in support, assuming amplitude was positive and supported the primary approval? Like how does the regulatory path work, I guess, for these indications? It's really an excellent question, Terrence. And the real answer is I don't know as we sit here today. We haven't had our end of phase two meeting with the FDA because we're not at the point of having the phase two data. What I would say is the way to think about this is secure the results from the amplified study. If positive, have discussions with regulators around what the next steps are. And I strongly suspect that what you say is about right, that they'd want to see what amplitude says, because amplitude would be the study that has the pertinuria improvement and the GFR endpoint. And then what additional work the agency might want to See in the lower pertinaria group or the diabetic cohort group would come after that. But I wouldn't expect this to be the kind of situation, and you know Vertex moves very fast, where after we have the amplified data, we'd be moving on to more clinical trials. It's the kind of situation where we need to have conversations with the regulators. Okay, great. Before we move to one commercial question I had, it's just on the Amplitude Phase 3 trial you mentioned, one-year GFR, I know in IGAN there was a lot of debate about kind of slope of decline, and fortunately with the data we've seen so far from some of the drugs is stability of GFR. In this disease, you mentioned, you know, very rapid progression, unfortunately. So how do we think about what kind of delta or what we'd want to see on a GFR endpoint from amplitude? Yeah. So you'll remember that the AMKD patient population, even in comparison to how we used to think about IGAN, although I think our own views are evolving, IGAN it turns out is not a slowly smoldering disease. as you can see from the results that have been revealed, one-year GFR declines quite rapidly. AMKD is known to be a rapidly declining renal condition, which is why the agency was comfortable with one- year GFR and why we were able to power the study to that end. I won't share with you what our power calculations are, but based on the rapidity of decline in AMKB, we have confidence that we've powered the study correctly in that we'll be able to show a difference at the one-year point. Okay, great. It's actually interesting that you can show that difference now with IGAN at the One-Year Point. Yeah, for sure. All right, so we'll stay tuned for that data next year. The commercial opportunity, kind of similar question to POVI. Walk us through kind of how you're thinking about the build-out here, the roll-out, less competition here, so you guys are in a first-to-market position. But I know there's some work on the diagnosis front that you and the team have been doing. Yeah. So this one is exceptionally high on metanyl. There is no targeted therapy in this area. And as we already discussed, the progression of kidney disease is unfortunately very fast. So here, the thing to think about is diagnosis. AMKD as a disease was just described in 2010, and genetic testing is not commonplace. So when we started the Phase III trial, we started to do genetic testing as part of the trial infrastructure so that patients who were diagnosed with AMKD, if they qualified, could go into the clinical trial. Separately, we also started up testing, genetic testing, in the real world, offering free testing as appropriate with groups like NITERA. So they have genetic testing for genetic kidney disease. If you're a nephrologist and you have a patient that you suspect could have AMKD, you could avail yourself of free testing. Through those programs, which have been going on for quite a few years now, three, four years now. We've already identified a number of patients. And so if and when a drug is approved, we would have a bit of a head start in patient identification. But that's going to be the primary focus of our sales team if and when the drug is improved to make sure that physicians are aware and the education has already started that genetic testing is happening. I will tell you as an aside, as we talk to nephrologists, which we're doing now largely for IGAN, It's interesting enough that AMKD has really captured the hearts and minds of nephrologists because they see it as the first precision medicine opportunity in nephrology. And so we have the advantage of being able to do education on both these dimensions, IGAN and AMKB. Okay, great. Maybe just two follow-ups. The first, I know you're not going to guide on pricing because it's too early, but just obviously maybe talk to us about some of the puts and takes, high level. this disease versus IGAN. It sounds like they're similar prevalence numbers, again, similar rapidity of kidney decline, but anything else that we should think about, potential price points. And the second is leveraging your existing infrastructure. You mentioned you're building out already with one of the largest renal sales force. Can you use that for an exoplan or is there an incremental build that you need to do there? Yeah. So the overlap between the physicians treating enaxiplin or who could use enaxiplin for AMKD and who might use POVI for IGAN is about 70%. So there's a hefty overlap, but it's not 100% overlapping circles. The reason we decided to build the largest team for IgA nephropathy versus the other April or April BAPs is this desire to get to all patients, whether they're in centers of excellence, large practices, or the smaller ones, and then we have to, we also have the advantage of being able to then bring out an axoplin, but we also had programs after that. We talked about membranous, and there's an ADPKD that's autosomal dominant polycystic kidney disease after that one, so we have an expectation to be in renal medicine for a long time across a number of diseases. But first things first, and it is indeed POVI in IGAN that we think we're going to be there first. On pricing for enaxiplin, I think that the right way to think about it is these medicines, if they're approved, whether it's POVI or enaxiplin, they will come with data on GFR and proteinuria that speak to its potential in time to death dialysis and transplantation. That's all the same. So I think the price points that you're seeing now are fair enough. I think when you do the health economics, whether you do it formally or for something like a NICE or an NHS, or you do it in a less formal way for other payers, the health economics are very supportive. So I think it's a reasonable proxy with what you're seeing in the current wave of medicines. Okay, great. You mentioned in the beginning how important the cystic fibrosis franchise has been, but also will be on the forward. You're, again, rolling out the Gen, I forget, 3.0, 4.0 at this point of the Lyft track. It's been so many years now, and obviously it's been great to see all the progress. Maybe just high level, talk about some of the puts and takes as we think about that franchise in 2027. Obviously, you mentioned you're still going to some ofthe lowest age groups now. You have the LyFT track conversion going on. I'm not sure if there's any other geographies left, but anything we should think about for 2027? Yes, maybe three things as you think about the near term, so let's call it the next few years. For the here and now, it is about getting a lift track around the globe. It is regulatorily approved in almost all regions. In some regions, we're working on pricing and access. Where we have regulatory approval and access, it is about, you know, getting people who would prefer to be on a lift Trek. It's the best medicine we think we've made to date. So people who are in Trikafta, they want to be on a once daily medicine or they just want to be on the best medicine that we think we've made. That is the switch that's happening. There are also naive patients. So for example, in certain countries like Italy, there's a lot of these ultra rare mutations for which a Lyft Trek has an approval. And so there are some of these very rare mutations that are coming on to Ali. So think about the ALI launch around the globe. Then think about ALI in the original ALI application. It was six years and above. We're working on two to five, and then we're going down the age groups. So that's the next thing that you can anticipate. The last thing is emerging countries. Think Brazil. Think Turkey. There are some countries that we're still getting to in terms of reimbursement, smaller countries, but important nonetheless. And that would be what we are thinking about in the near term with the commercialized medicines in CF. Those medicines, Ali is part of what we call NG 2.0, next gen 2.5. The next one after that is next gen 3.0. There are three medicines in that one, VX, I should call them potential medicines, Vx 828, which is the lead, Vex 581, and Vx 272. And then after that, there's a next-gen 4.0, and you can believe that there will be a 5.0 and beyond. Until we can demonstrate to ourselves that we have reached the peak of the best sweat chloride that we can achieve, we're going to keep going. We've talked about the fact that we believe we've already achieved that asymptote for PPFEV1, the lung measurement, and we're getting awful close to sweat chloride. We have submitted some abstracts to the fall North American CF meeting. And fundamentally, when you diagram out the Gaussian distribution of sweat chloride in carriers or normals, you'll see that it's the center point, the median is about 30 millimole, and then there's a normal distribution around that. And when you look at people treated with a lift track, for example, it closely approximates that Gaussian distribution, telling us that we're getting close. But as long as we haven't proven that to ourselves, we're going to keep going. And that's what NG 3.0 and 4.0 is about. Great. One follow-up, as you mentioned, the global rollout of a lift rack. I know historically every year there's pricing declines in a lot of these geographies. given the profile of a lift track, does that allow you to at least keep price more stable than maybe otherwise you would if you just had Trikafta? Or should we expect kind of the same progression as you typically see, which is pricing declines year over year? A lift track and actually Trikahta before it, in the ex-US regions, you know that you have to go for a rebid every three years, four years, as the contracts call for. What they look at is real world data. And the real world data that they're looking at is the decline of lung function. And Tri and now Allie are one of the few medicines that I've ever worked on that actually look better in the real World than they even did in the clinical trial because you see this flattening of the decline of lung function, everybody's lung function just like kidney function declines. It's about maintaining it the most stable levels that you can. And we have been able to hold price steady in some countries based on that kind of real-life data. But I wouldn't want to leave you with the impression that that's doable in all countries across the globe. There are some countries by just simply the way the country operates, there are expectations of price declines. But where there is an opportunity to present data and decisions are made on that data, we have been able to hold price stable because the data are even better in the real world. Great. Maybe just in the last couple of minutes, anything else on the pipeline that you'd want to highlight for us? I know you guys have also a deep early stage pipeline. You mentioned some of the Gen 3.0 cystic fibrosis assets, but ADPKD, but anything else that should be on our radar in the next six months? All right. I'll call out a few, but don't tell anyone that I called those out and left some of the others behind. Maybe in the phase three pipeline, the thing to call out is the type one diabetes program. There's the Zamyla cell program that's the cell therapy that could be a one-and-done curative therapy, and I am super excited about that one. But I'm even more jazzed about the Type O program that I think I mentioned on the earnings call because that opens up the opportunity to even more patients than the Type A program. The IND is cleared, and I'm excited about dosing patients in that Phase I-II study. Also in Phase III is Atumelnant. that is an asset that came to us by way of the kinetics acquisition. Atrium melanin is a medicine that I see having multi-billion dollar potential and the opportunity to serve 20,000 patients some number between 15 and 20, 000 in the US add another 15,000 ex-US for CAH, congenital adrenal hyperplasia as well as a second disease called Cushing's disease. And atrium melanin is in phase 3 development for CAH, phase 1-2 development for Cushing. And if I pick something from the very earlier stage pipeline, and this is not in the next six months, but I really like the progress that we're making in the NAV1-7 space. As you know I have a lot of enthusiasm for this opportunity of making a combination NAV1718. That one's in late preclinical development, so we have chemical matter, and now it's a matter of going through the standard procedures to bring that potential medicine into the clinic. Great. Well, I think we're up against time, but thank you so much, Reshma. Really great to see you. Very nice to see You, Terrence, and thank you all.