Bernstein’s 42nd Annual Strategic Decisions Conference (SDC)

Welcome and thank you for joining us. My name is Will Pickering. I cover U.S. Biotech at Bernstein. I'm privileged to be sharing the stage with Dr. Reshma Keoramani, CEO of Vertex. The company looks very different today from just a few years ago, building on the base in CF with launches in pain, sickle cell, and soon to be in IGAN. And we'll dig into all of those topics and more over the next 50 minutes. I would encourage everyone in the audience to use the Pigeonhole app to submit your own questions so that we can make this as relevant for you as possible. And with that, this being the Strategic Decisions Conference, Reshma, I'd like to start with a broad framing question. What would you say are the top strategic priorities for Vertex, and how does that align with how you're spending your own time?

Okay, great. Well, good morning, Will. Thank you for the invitation. Good morning to all of you. it's really nice to be here. Maybe four or five things to highlight in terms of strategic priorities. In terms of our products, as Will alluded to, just compared to three years ago, we now are in three distinct franchises, whereas we were in just one through the early 2020s. So for us, it's about extending our leadership in cystic fibrosis. The second is to build the next two franchises into blockbuster products. The one after cystic fibrosis is in hematology for sickle cell disease and beta thalassemia with something called Caschevi. It's a CRISPR-Cas9-based medicine that's a one-and-done, potentially curative therapy. The one after that is in pain, first in acute pain with something called Gernavix. It's a non-opioid, peripherally-acting, non-addictive medicine. After we get through those three, the next big thing on our minds is our renal franchise. That franchise looks to have four potential medicines, starting with something called Povatacicept in a disease called IgA nephropathy. It's a rare disease, but it's a common rare disease with about 150,000 people in the Western world. Beyond launching these medicines, setting up that fourth vertical, which I'm sure we'll get back to, I think that's the vertical that is substantial enough to rival cystic fibrosis in terms of its overall potential. We're also focused, my time and the executive committee's time, on building out our company for all of this innovation and this wave of products that are making their way through late stage development and into the clinic. That means a focus on a tech-enabled workforce. How do we responsibly incorporate AI? And I would say, well, compared to two years ago when I thought there was far more hype than reality, today I think there's a lot more reality in companies including at Vertex. And we're also gearing up and building out for things like type 1 diabetes, which is an entirely different approach using a cell-based therapy to potentially cure that disease. That takes a lot of effort, not only in the commercial buildup, but also in manufacturing. And then to just round all that up, compared to cystic fibrosis, which is not only a genetic disease, it's also a disease with a founder effect. What that means is it's really only prevalent in northern and western European people and people of that descent. So that's where our business was. that's very different than something like sickle cell disease or type 1 diabetes or pain. And so we're also building out geographically. And the best example would be the flag that we planted in the Middle East in Riyadh in 2023 to bring Kaschevi to the Middle East.

On the policy front, at the industry level, when you were here last year, it was just a few months since Liberation Day. There are a lot of unknowns about tariffs, Simafin, FDA, you name it. Fast forward to today, are there any sources of policy risk or uncertainty you'd call out as being especially relevant to Vertex?

Vertex is in a somewhat different position than many other companies simply by virtue of our size and what we do. and maybe the thumbnail is that we're reasonably insulated from what has been going on with regard to MFN and some of the work with the larger companies. We did not receive a letter from the administration, and therefore we haven't been inside the room in terms of the deal-making that has been reported. We have a small but mighty team in D.C. We're very aware of the conversations. We monitor them very closely, but we have not been involved in it directly because we simply haven't received a letter to be involved. Cystic fibrosis is a rare disease. There are certain rare disease carve-outs, and that's part of it. the medicine Kaschevi is a Part A medicine, so it's neither B nor D, so that has a certain distance from what's going on. At the moment, we simply do not have any Part B as in boy medicine, so what is being called GLOBE doesn't apply because it applies to Part B. um gernavix is only a medicine that we sell in the u.s so it doesn't have uh mfn because it's only for the u.s and there are of course some considerations for tariffs um the 282 uh reviews just occurred we are making our way through it what i would say is we have a very diverse supply chain. A large portion of our manufacturing happens right here in the U.S. And as you may have heard on our Q1 earnings, we shared that we expect no impact from tariffs

in 26. And on the FDA, how is your interaction with the FDA? Good question. Good question.

Obviously, there's a lot going on, and it's uncommon to have so much discussion about the FDA. The U.S. FDA is genuinely the bright shining light on the hill in terms of policy, evolution, innovation, and there has just been a lot of disruption, and we see that with the news that's coming out with a lot of personnel changes. What I'll say for the Vertex portfolio, and we do have filings in front of the agency. We have a BLA in front of them right now. We have several INDs. We have ongoing interactions on programs in flight. We have not seen any interruption in our ability to secure meetings, to get feedback. for the filings to process within the PDUFA timelines. So we haven't seen impact on our business, but clearly there's a lot going on there.

Moving to CF, how has the Lyftrek launch performed versus your expectations, and what have been the biggest learnings or surprises?

Yeah, yeah. So for those who haven't been following the CF story very closely, Liftrek is our fifth medicine in the CF franchise. And the biggest move was when we had Trikafta approved in October of 2019. And I say that because we went from about 50, 60% of patients being eligible up to Trikafta to 90% being eligible with Trikafta. So that was the big move to get to all of our patients. If you think about CF patients as a full 100% pie, about 5,000 cannot benefit from these CFTR modulator medicines, these pills. And the reason for that is that they don't make any CFTR protein. So you need a different approach. We can get back to that. For the vast, vast majority, 95% of people who could benefit from these medicines with With Aliftrek, we're now at 95% of the patients who can benefit. So Aliftrek is a once-daily medicine. Trikafta was two times a day. Aliftrek has more mutations than even Trikafta. And Aliftrek gets you to even lower sweat chloride levels, which is the marker of what we call the pharmacodynamic marker of this disease. So the launch has gone really well in the U.S. The launch has gone even better outside the U.S. And the reason for that difference is there are a lot more patients outside the U.S. with these ultra-rare mutations. It's just part of the genetics of the disease. And it's also the that the labels are different in terms of monitoring in the US versus outside the US. There's a little bit more monitoring in the first year in the US. That more monitoring is not in the labels outside the US, so the transitions can happen a lot faster, because you don't have to do this additional monitoring. But I'm really happy with how the Lifttrek launch is going. almost all new patients in the U.S. who start on medicine, same thing in the ex-U.S. regions where we have approval and reimbursement, all the new patients are starting on a Lyftrek. And so the bottom line on that, I would say a Lyftrek is the emerging standard of care for CF. And so as we start to think about the next generation of medicines in our portfolio and what do we want to bring out next now we're trying to beat a lift trek we used to try to beat trikafta

thinking about the growth algorithm for cf going forward even as the market has matured the company has still been able to grow revenues substantially faster than population growth you know what are the drivers of that and which are most relevant looking forward yeah um there are three or four

drivers. The most important is patients with CF are living longer. This is a chronic medicine. Patients start at the lowest age group where we have an approval. So for our oldest medicine, Kalydeco, which was approved circa 2012, 2013, we're down now to one month olds. So they start at that age, and they continue lifelong. So the biggest driver is patients are simply living longer. A second driver is this march down in age group. When we start doing our clinical trials and get approvals, we start with the adults, and then we go to five to 11-year-olds, for example, then two to five-year-olds, and so on and so forth. And as we bring these medicines out for the lower age more people come on medicine. The next one is growth through geographic expansion. The vast majority of patients, because of this founder effect that I mentioned, are in Northern and Western Europe and the Americas. That's where we get regulatory approval first and reimbursement first. And then we make our way to the other countries. Think Turkey, think Brazil, and there's growth in those areas. And lastly, as we discussed, when we went from Symdico to Trikafta, we went from 60% eligible patients to 90%. With Oliftrek, we're up to 95%, so these ultra-rare mutations, and those patients now can also be treated with these medicines. You add them all up, and that's where we get the growth. I think it was about 7% growth in CF in 2025. In Q1-26, we reported 6% growth in CF.

Turning to competition, stock has been under a little bit of pressure heading into the competitor readout that's coming up this summer. Obviously, no one knows what the data is going to look like, but maybe speak to your confidence in the durability over the long term of the Vertex CF business, including in scenarios is where the competitor meets the bar that they've set.

For those of you less familiar, there is a company that is supposed to report results from a late phase one, so let's call it a 1B study in patients, with a medicine from their portfolio added to our medicine, Trikafta. So that's what we're talking about here. I think the important, to the direct question about my confidence in the durability of our franchise, the overwhelming majority of patients who are eligible for medicine, and when I say overwhelming majority, I mean 90% plus patients who are eligible for our medicines are on medicine. They start their medicine in the case of Kalydeco at one month of age, and in the case of Trikafta at two years of age, and they continue this for life. People take their picture, and they send it to us, and they post it on social media with their Trikafta box or their Lyftrek box. There's an emotional attachment to their medicine because it's the first thing that has made them feel not like a patient anymore. And so when I see that kind of the data are spectacular with the medicine, it's the one area that I've worked in where the data actually gets better in the real world as we collect registry data and such than what you even saw in the clinical trial. I expect that our franchise will be durable for a long time to come because of safety, efficacy in the clinical trials, added to safety and efficacy in the real world, added to going all the way down to the youngest age group. It's very difficult to imagine that a child who starts on medicine that's helping them at age two does not continue with that medicine later on. Last thing I'll say is if you think about Kalydeco, which was our first medicine, The first approval was, let's say, 2012, 2013. It was in 2024 that we got down to one month old. So that's a 12-year journey. And we work exceptionally fast. So that's a long time for one to be in an area and to keep that drug development effort up. We can talk very specifically about details, But I think the top line is, I have very high confidence in the Vertex portfolio. At the end of the day, if somebody wants to add a medicine to Trikafta, I find that interesting, Trikafta is still a Vertex medicine.

Serial innovation has been a big part of the Vertex R&D strategy. As it becomes increasingly difficult to demonstrate incremental benefit on FEV1 relative to your approved products. What's your interest in collecting either longer-term outcomes data or extra-pulmonary disease manifestations, just other ways of measuring the incremental value of your new products?

Well, this is an incredibly important question because we're coming upon a time for CF that one might liken to the journey that, for example, multiple myeloma went through or a disease like HIV. we're at the point where the measurements we used to use, we have reached an asymptote. And so the question is an excellent one. Well, what next? I think it's actually a really, really difficult question to answer. When we look at carriers, carriers are those people who have one CF allele. They are the parents of kids with CF, for example. They have no disease that you can identify. They're fairly normal. you can think about their sweat chloride levels and the variability around that. When we look at the Eliftrek sweat chloride levels and the variability around that, they're virtually superimposable. So we're at that. Our goal for the last 25 years was get our patients to carry your levels of sweat chloride, and we seem to be approaching that asymptote. So we are looking at these very long-term outcomes, like you mentioned, what happens to exocrine and endocrine pancreas function, what happens to liver function, what happens to longevity, what happens to hospitalization, lung transplant, things that take years. And we do that work in registries because we're very fortunate. CF has almost 100% capture in the U.S. registry and there's an equivalent registry outside the U.S. I don't know that it's humanly possible to do an RCT. We've done some detailed evaluations. It would be thousands of patients in a rare disease and very, very long periods of time. And I don't even know if that's really required because of the registry being as robust as it is. I'll tell you one anecdote. In the country of Switzerland, there are virtually no lung transplants. I think there was one done in 2024 compared to many being done for cystic fibrosis for this reason. So I think that the registry collection of these kind of long-term data are going to be very telling, which is why I go back to the durability of the franchise. It takes five years, 10 years, 15 years to look at longevity, pulmonary transplants, hospitalizations and such, and we are fortunate to have that data.

Excellent. Moving to Povey, I wanted to ask about the upcoming launch. So this is your fourth franchise, but it's also the first one in which you're competing directly with other branded therapies. How are you approaching the launch differently?

Yeah. So POVI is the asset that we acquired through the Alpine acquisition in 2024. It is what is called a dual APRIL-BAF inhibitor. It's a way of modulating B cells, and it is B cells that are the bad actors for this disease, IgA nephropathy. There are other medicines that are trying to do the same thing. And what I would say is clinically, scientifically, medically, the difference for POVI is that it's highly potent, has very high binding affinity, has really excellent tissue distribution, and therefore has qualities that lead to the kind of profile you've seen. We've put out a press release. It hasn't been presented at a conference. It will be. But the press release was, frankly, a novella. It's very detailed, and you can get most of what you want to see. The efficacy is it looks best in class. The safety, it looks very favorable. And very importantly, and I want to emphasize this, this is not an add-on or a nice-to-have or look at that, how sweet. It's very, very important. This is another chronic biological therapy. It's an injectable. You have to take it over the course of your lifetime. Our medicine is once monthly, low volume, 0.46 mils, auto-injector at home. And that suite of clinical efficacy, favorable safety profile, and these characteristics, It's not the trikafta, which is our medicine in CF, but it is the trifecta of what we are looking for in this disease. So I'm thrilled with the results. We are planning our launch as we speak. We've hired our field force. We've deployed the first wave. We are looking to bring our high science cell approach that we have in CF2 nephrology. we're looking to cover 80 plus percent of the nephrologists who serve the patients who have this disease. We're looking to bring the best in class patient services programs like we did in CF. And the other advantage we have is we're already well underway with additional renal diseases that could be tackled by this medicine. So physicians as nephrologists, as we learn how to use these medicines, and as you know, we've had a dry spell in nephrology for 20 years. So this is a very new period for us with medicines that can actually tackle the underlying cause of disease. This is a medicine that we can use in multiple renal diseases, which I see as a great advantage. I happen to be a nephrologist by background and training, and so I can say that this is one of the most exciting periods that we've been through, not just for Vertex,

in general in our field. On the payer front, how aggressive do you expect them to be in trying to of extract concessions for favorable access, particularly within the April and or April Baff class?

Two comments on that. One is the consequence of having something like IgA nephropathy or any of these aggressively declining renal function diseases is death, dialysis, or transplantation. It's very obvious what's going to happen. And in that regard, those consequences are very well understood by payers. The expense of transplantation or dialysis is known and very high. And I think for that reason, payers are very educated on this field and are willing to pay for medicines that bring value. So that's a good foundation. And you can see that with the most recent launches that have happened in this area. With regard to rebates, discounts, and all of that, That's part of how the U.S. system works, and it's important, therefore, to have a really high-class payer access team, and we have that.

PMN is your second indication for Pervi, and I believe you recently completed the Phase 2 enrollment. Could you frame the opportunity here and compare and contrast it with IGAN?

So IgA nephropathy and PMN, primary membranous nephropathy, are both what we call glomerular diseases. These are rare, but common rare diseases. If we say there's about 350,000 or so people with IgA nephropathy in the Western world, and another million-plus in Asia. There's about 100, 130,000 people with membranous nephropathy in the Western world and then add a few hundred thousand more in Asia. This membranous disease is another B-cell-mediated disease. In this one, your B-cells are making antibodies to something called PLA2R. In IGAN, the B cells are making these antibodies against something called GDIGA1. So they're similar in that they're these glomerular diseases. They're well understood. The way you know you have one of these diseases is you have a decrease in kidney function. You're spilling protein or blood in your urine. Your doctor does a biopsy, and we know the diagnosis. So those are commonalities. In membranous, we're trying to curb the amount of PLA2R in your body, and we're trying to get your proteinuria down, and we're trying to get your hematuria down, and we want to stabilize your renal function so you don't move on to death dialysis and transplantation. Very similar goals to IgA nephropathy. There, we're trying to get your GDIGA1 down, proteinuria down, hematuria down, so that you don't go on to these bad outcomes. That one, exactly as Will said, we have our data in Membranus, and it's very good-looking data, and something called the Ruby 3 study. It was a basket study that our Alpine colleagues started. So we know that the data look really nice. The Phase 2 portion of the Phase 2, 3 study is done in terms of enrollment. The Phase 3 portion of the study is up and running. And this one is a traditional approval. Remember, the IgA nephropathy is an accelerated approval. This one is a traditional approval. We need to treat patients for 104 weeks. And remission is the endpoint for membranous. Same drug, though, POV. The thing that we're doing in the phase 2 portion is dose-ranging POV. The dose for IGAN is 80 milligrams, and we're testing 80 and 240 for the membranous study.

Moving to AMKD, you're seeing investors begin to- Another kidney disease. Yes, yes. You're seeing investors begin to dig into that a little bit more. What are the aspects of the drug and the trial design that give you confidence for that phase three trial that you've got? And maybe you could touch on the implications from the AMAZE data that came out.

Yeah, yeah, definitely. So continuing with the alphabet soup of kidney diseases, AMKD is APOL1 mediated kidney disease. As I said, I was a trained nephrologist. I finished all my training in the early 2000s. This disease was not even named when I finished being a nephrologist. So this disease was just described in about 2010 or so. So it's very new. It's a disease that comes about by having two of these APOL1 alleles. It's a disease of people from sub-Saharan Africa only. And it's a disease where you have exceptionally aggressive decline in kidney function. So if you have two APOL1 alleles, you have a decline in renal function, so GFR, and you're spilling protein, those are the people we studied in our phase three program. The phase three program has an interim analysis built in, and we have an agreement with the FDA that if the interim analysis is positive, we have a path to accelerated approval. That interim analysis cohort completed enrollment last year. We expect results from the interim analysis in early 27 the full enrollment for the study will complete this year and we're on track to do that and what you're really looking for here is gfr stabilization that's the end point that we in the agency have agreed to at one year that's a real move for the agency because usually in not certain diseases like IGAN, where they've gotten to a point of comfort for pertinuria to be the accelerated endpoint, you have to do two years. So the study that I'm describing in AMKD is a two-year study. If we meet the accelerated approval endpoint, that we will know next year early. Will mentioned MAZE data. It's another company, and while I don't like talking about other companies, I understand that you'd like our perspective on this. Here's what I'll say. The vertex belief is that when you are studying something like AMKD, but you add some heterogeneity into that, it is unclear what you're going to get out the other end. And so we don't do that. So our amplitude trial, that's the phase three study I just described, is two APOL1 alleles, heavy proteinuria, no other kidney disease. That's who we studied. It is worthy of study to think about people who may have two APOL1 alleles, modest proteinuria, and a low renal function. It's a perfectly good question, and we're asking that question in a separate trial called AMPLIFIED. That's in phase two. It's also a worthy question to ask, what about two APOL1 alleles and a second disease that can impact the kidney? Think diabetes. It's a good question to ask, but these are different than the phase three program because in the modest proteinuria group, you have to have some amount of headroom to show a reduction in protein. There has to be some amount of dynamic range. So we did not want to mix the modest protein group with the heavy protein group. And if you throw in a second disease like diabetes, you don't know, and epidemiology that you can study tells you, it's a bit unknown, how much of the contribution of renal disease is the APOL1 part of it, and how much of the disease is the diabetes part of it. Our drug does not take care of diabetes. Our drug only takes care of the APOL1 part of it. So we've studied those two patients, modest proteinuria, and what happens with a second kidney disease in a separate trial called Amplify. That's in phase two. I expect the results in the second half of this year. If the results are positive, that would mean we have the opportunity to add another 100,000 or so patients to the epi of amplitude. So we believe there's about 150,000 people or so that would be eligible based on amplitude. If this is positive, I would add another 100,000. If it is not positive, it means nothing for amplitude. And the relationship to the other companies that they studied diabetics and non-diabetics in their phase two trial, and they made some divisions of people who have a particular kind of kidney disease, another alphabet term called FSGS. but by the time you do fsgs non-fsgs diabetes non-diabetes there's two people in each cell and it's very very difficult to tell what the answer to the question is and so i think in retrospect you'd say the wisdom of our decision making was sound to do this separately um our data from phase two is 46.7 reduction in protein that's a very strong number and so i'm looking forward to the

amplitude results. Thinking a bit more blue sky, do you think this drug perhaps at a lower dose could help prevent AMKD in the first place? I think it's a really interesting question and I

think it's honestly not so much about the drug as it is about the pathophysiology of disease for AMKD. The best that we understand AMKD, and we understand a lot of it, it's a genetic disease, It takes two alleles. If you have one allele, it does not look like it has a risk associated with progression of kidney disease. If you have one allele, it prevents, it is protective against a particular kind of disease in Africa. So it's kind of like if you think back to the malaria story. So it has all of these relationships. What the protein does is it punches pores, holes in the glomerular basement membrane, which leaks potassium, which then leads to damage, and that leaks protein. But it does look like you need a second hit. That second hit is, it might be an infection, it might be an inflammatory reaction, it might be something that we can't figure out, but it does look like you need a second hit. And so the prevention question is interesting because how will we know if we actually prevented the disease or you just didn't get a second hit on the disease? I also think preventative medicines are more difficult from a payer access perspective because it is hard to know whether you were or were not going to get the disease and did you prevent it. So I think the best way to do drug development in this area is look at patients with two APOL1 alleles with proteinuria and reduced renal function and treat them and treat them early so that they never go on to this horrible outcome of death dialysis or transplantation.

moving to pain maybe you could talk about where you are in the launch today and there's a lot of questions about when we'll start to see you know realized price improve yep yep yep so pain for us

most people divide pain into two categories acute and chronic we are vertex we do everything differently, so we do pain into three categories. Acute, and then we have neuropathic, and then we have everything else. Neuropathic and the everything else are forms of chronic pain, but the reason we divide it that way is because we are most interested and believe that we can commercialize with our specialty sales force approach in acute and neuropathic. I believe that our medicines will work on the other think musculoskeletal pain low back pain i believe our medicine will work in that chronic condition but we won't commercialize in a primary care area so we'll get to that later so i'll put that in a box right now what we're talking about in and will's question pertains to acute pain we've launched this medicine called gernavix it's a nav 1 8 inhibitor. It's a peripherally acting drug that is a non-opioid, does not have addictive potential, and I can say that confidently because there are no receptors to NAV1-8 centrally. This is a peripherally acting drug. We launched it in March of last year. We talked about the fact that we've had over 500,000 scripts by the end of last year, and our guidance, and I feel very confident about it is that we will 3x the number of scripts this year, and we will more than 3x the revenue this year. The use is broad, commensurate with the label, surgical and non-surgical uses. In surgical, the bread and butter uses post-hip surgery, post-knee surgery, orthopedic surgeons, general surgeons doing belly surgery anesthesiologists using this medicine and in the community it's fractures sprains acute flare-up of whatever pain aches you very broad base of prescribers I like the depth that we're seeing and about 50% of the use is in hospital and about 50% of the use is in the community. The important point is that we see this as a franchise that we are going to build and hopefully lead in over the next not only years but decades. Acute, neuropathic, and we will also get to chronic, although as I said we won't commercialize there by ourselves because I do see that as a primary care cell. So as you think about this franchise that we're looking to build and lead over many, many years, if not decades, we want to do a couple of things, which is make sure that the pricing is commensurate to the value that this is bringing, make sure that patients and doctors who want to use this medicine have a seamless experience, and therefore, while we go through the access, which takes time, that patients get the medicine. And so we have a PSP program, a patient support program. We provide free drug if the patient comes to the CVS counter or wherever they go and the drug is not yet covered by their insurance company, we cover the cost. And what that means is that the gross to net isn't yet normalized. We said that we expect the gross to net to normalize by the second half of this year. I expect that that will happen, and I expect that the revenue will not only be commensurate with the script growth, but it will exceed the script growth as we guided to earlier in the year.

Great. One question from the audience. You've invested more in sales and marketing for generatics than originally envisioned. Is pain still a Vertexian category, and is Vertex still the best owner for this drug?

Yeah, I love the word Vertexian. It's how we describe ourselves. Yes, Vertex is the right group to commercialize this medicine. We secured all three major PBMs in terms of reimbursement at value that recognizes this innovation in less than one year. That is not an easy task, and it is indeed Vertex who did that. On the Salesforce size, we are a specialty Salesforce company, right? That doesn't mean we are going to have a Salesforce that is the CF size. CF is 14, 1, 4. That's not specialty. That's very specially CF. we had always planned to bring more sales reps on at the right time. When the reimbursement got to be at a particular point, we thought that would be the right time to pull the trigger for a bigger sales force. And that's what we did. Because obviously early in the launch, it was not a reimbursed medicine. There was a lot of the PSP program in play. So know that we've been thinking about this diligently as we think about everything. The first wave was the first wave by design. The second wave was the second wave by design. And I'm looking forward to doing even more in this area.

Great. One more here on the diabetic pain study. Could you speak to how important it is to beat Lyrica versus just beat placebo?

The regulators have been abundantly clear. We have to beat placebo. That is what they want to see. That is the bar for regulatory approval. We decided to include a gabapentin arm in one of the two studies so that we had a reference group so that we can have some kind of context for the magnitude of the treatment effect. But it's extremely clear what we need to do.

Yeah. You've talked about acute pain alone being a multi-billion dollar opportunity. Could you talk about the role that evidence generation going forward needs to play to unlock that?

Yeah. So in acute pain, and often is the case for medicines that are used inside a hospital setting or within a hospital network, hospitals want to do their own studies. Networks want to do their own studies. And pain is very interesting, right? We have a very broad label by design. It is, gernavics is indicated for the treatment of moderate to severe acute pain, whatever the etiology. And we did the data package for what the regulators wanted to see. So we're doing a lot more phase 3B, phase 4 studies and providing a lot more data post the approval because it's such a broad label. So, for example, we published some data in abstract form that has to do with the use in a variety of other surgical types, knees, shoulders, belly procedures, aesthetic procedures. And what we're doing in this is looking to see how it's used in multimodal therapy. Of course, the studies we did for regulatory approval are monotherapy, because we wanted to study the pure effects, safety, and efficacy of a single therapy. But that's not how medicines are used in the real world. Pain medicines are used in multimodal approaches. So these studies that we completed are multimodal use, and we evaluated, for example, what happens to opioid use, and opioid use goes down compared to historical controls. And we intend to do more of this as people tell us they're interested in the use in spinal procedures or they're interested in the use. There's actually an interesting use going on in the community, especially with oral surgeons who do wisdom teeth extractions in young adults. And they're particularly sensitive to not wanting to prescribe opioids. So there's a lot more study going on because there's a lot more interest great and uh when do you see the first nav 1.7 yeah so this is um a really important program a very hard nut to crack nav 1 7 has even this is uh sodium voltage gated channels 1.7 as opposed to 1.8 which is gernavics It has even more genetic validation than NAV-1-8. The NAV-1-7 is the, you'll remember the kindred, the family in Pakistan who are firewalkers. They feel pressure, they're normal in every other way, except they don't feel pain. That's where the big idea came from many years ago, to study 1-7s. Everyone has tried to do this, including ourselves, and we've been at it for more than 20 years. It's just a really hard nut to crack. I'm very happy with the progress that's been made. I will call it in late preclinical development. What you can take away from that is that we have chemical matter. And the real big idea here is I would like to leapfrog where we are, take the NAV1-7s, which I believe would work as a monotherapy, but combine them with NAV1-8s and make that combination the next wave of drug development that we do. For the uninitiated, that's scientifically very elegant to me because NAV1-7s are what's responsible for the initiation of the action potential, and NAV1-8 carries that action potential, so it makes so much sense to me to combine the two. Pre-clinically, what we see is NAP1-7 plus NAP1-8 has a synergistic, not additive, but synergistic effect. So, super exciting. I'll just leave it at late pre-clinical development. Okay, okay.

On capital allocation, are you considering any change to your historical approach, for example, ramping the buyback or a larger appetite for BD?

No. I think our approach to capital allocation has worked really well. We are very interested in using our capital to support innovation, be that internal or external. You know our sandbox. You know our approach that applies equally to anything internal, anything external. Commensurate with our increasing size and our balance sheet, we are doing more stock buybacks, and I think that's a really fruitful way to return value to shareholders, so you should expect more of the same. Okay, okay. In the past, you've described

Vertex as TA agnostic, but now that, you know, you're starting to build more of a critical mass in Reno, is there a case to be made that that should make this more of a deliberate focus

going forward? I know it's going to sound unbelievable, but it is true. The reason we have a renal franchise is not because I'm a nephrologist. It really isn't. And we didn't go about trying to create a renal franchise. Our sandbox of diseases, and you know we're a disease first company, we're not a therapeutic area company. We're not a platform company. We are at our core and part of our strategic underpinning of our r&d strategy is to be a disease area company amkd the whole alphabet soup apol1 mediated kidney disease it's in our sandbox adpkd which we didn't talk about but that's another renal program in phase two development that's a really neat program this is autosomal dominant polycystic kidney disease because it's also a protein folding defect, which is, harkens back to CF, which is also a protein folding defect. That's in our sandbox. IG nephropathy was in our sandbox. Membranus was sandbox adjacent because it's a smaller disease, and we would have gone after IGAN, which is in our sandbox, but membranus just comes along because of all of those similarities it just happens that these all are in reno we are not anti-synergy please don't get me wrong we love the fact that we have four diseases in a given vertical it's fantastic but i also don't want to leave you with the wrong impression our core belief is that we are really good at understanding causal mechanisms of disease disease and then going after those. And we're not afraid if one of the diseases we understand and have deep insights in and we think we can crack that one, if it happens to be CF, which is a pulmonary disease, and if the next one we believe we can go after is in the kidney, we're not afraid of that. Sales and marketing is not the hardest thing in our industry. translating basic science from the lab with higher success rates than has been industry average, that's the big problem in our industry, and that's why we've oriented ourselves around this strategy, which we believe will lead to greater success. It's not going to be 100% success, but we believe it's going to lead to greater success.

We're nearing the end of our time today, and we hope to have you back next year. So in that vein, how do you think that Vertex could look differently as a company a year from now? And what would you highlight as especially notable for investors?

I think the biggest thing to look for is the emerging fourth franchise from the company. And it will happen to be in renal.

All right. Very good. Thank you so much.

Thank you, Will.