Global Healthcare Conference. My name's Jeff Meacham. I'm the Senior Biopharma Analyst. We're thrilled today to have Vertex Pharmaceuticals, and on stage with me we have Charlie Wagner, Chief Operations and Financial Officer. We have David Altshuler, who is EVP and CSO, and maybe six months from retirement, maybe. Okay. Both legends. Guys, thanks for joining. One legend. I'm aspiring. You shouldn't say that about yourself, Charles. Let's talk first about therapeutics, maybe commercial, and then move over to clinical, so maybe, Charlie, just give us a bit of a status update with the launch in acute pain. You know, are you guys comfortable with the, you know, number of centers, states, you know, institutions looking to next year? Is there more progress to be gained, and we can get into some of the specifics. Yeah, sure thing. Yeah, it's honestly, it's been a terrific year for this launch. It's a significant launch for us, and we feel really great about the progress that we've made so far. Coming into the year, we had three primary goals. One was ensuring broad access with payers, ensuring hospital and healthcare system access, and then also having kind of a terrific first-year seamless experience for physicians and patients. And I think we've made great progress on all of that. We talked in the most recent earnings call about our progress with payers. We've got over 170 million covered lives now in the U.S. in just 9 months or 10 months since the launch, making great progress there. On our way towards our goal of, you know, call it 300 million covered lives or so. So great progress. We have formulary placement in a number of large hospitals and hospital systems, and that honestly has probably gone a little bit better and faster than expected. In terms of the progress during the year, I think the ramp in the prescriptions has been quite remarkable. We communicated on the call that we now have over 300,000 prescriptions written for generics, which means something like 250,000 of Americans have had access to the medicine. And the feedback from physicians and payers has been terrific. We see that the medicine is being used in a wide variety of specialties, from you know orthopedics and plastic surgery to anesthesiology and pain specialists and dentists, and universally the feedback has been excellent. So really happy with the progress with payers, with hospitals, and the patient and physician experience. We do have work to do heading into next year, and, you know, we can talk about that in a bit. Maybe I'll let David comment on some of the other aspects, but feeling really good about the momentum, and specifically in that prescription number, we mentioned we had about 10,000 in the first quarter, 70,000 in the second quarter, and 190,000 in the third quarter, so really nice volume building heading into 2026. Just to follow up, when you look at the, maybe the policy backdrop, is there anything with respect to, you know, a tipping point on Medicare, Medicaid access looking to next year, on the No Pain Act? Is that gonna be impactful, do you think, in, in fiscal 2026? Yeah, listen, we have work to do. And you mentioned a few things there, so maybe I'll go back to the point I was gonna make. On the commercial side, we've got two of the three large PBMs. We have one left to go, and we're making progress there. We're in active conversations. We've made great progress on the Medicaid side of things, have work to do on the Medicare side of things. And those discussions are ongoing right now heading into 2026 as well. And then your last point around policy, you know, the No Pain Act. The No Pain Act is for outpatient procedures in the Medicaid environment. So in terms of actual contribution to the business, it's relatively modest. It's like less than 5% of the patient population. But we had always said that we felt that that would be a meaningful marker of government support for a program, for kind of parity, if you will, for non-opioids. So we were disappointed not to be included on the first draft of the list. We think it's an oversight. We think it's a technicality, and we're gonna continue to work to make sure that suzetrigine gets the right placement. Again, not that, it's essential from a launch standpoint, but we do think it's societally important to see that there's endorsement for alternatives to opioids. Yep. Makes sense. David, let's turn to the clinical aspects of it. So, maybe just give us some historical context for, you know, why looking at chronic pain has been more difficult, you know, not just for you guys, but to show clinical differentiation over and on top of standard of care. I know there are trial designs, there are trial executions and assumptions you have to make. But, you know, you guys did have, you know, differentiation, on LSR and DPN previously, but you has to rise to the level of, you know, of significance. And so that's, you know, that's part of it, right? Yeah. I mean, it's, it's a great question. I think that the, the first thing I would say is our focus right now is on diabetic peripheral neuropathy. And the reason for that is because, first of all, it's a very concrete, well-defined path, both in terms of clinical and then, you know, patient use. And, obviously, we have the positive data that you, you know, in, in Phase two. And so we have our first Phase three study, is enrolling well. We started the second study just recently, and we're on track to, enroll complete enrollment in both in 2026. And it's worth noting there's 2 million people, with DPN in, and it's in the U.S. And also, there's not a, a well-established high-quality treatment. If you look at the treatments, there's a lot of rolling turnover 'cause people aren't satisfied with the combination of efficacy, but also of tolerability. And so we see that as a great opportunity. You asked about more broadly chronic pain. You know, there are multiple different kinds of chronic pain. And I think that's one thing that the field is gonna have to evolve in terms of understanding, as you know, exactly which path to get to all of them. But we do believe in the long run that that's an important area and we'll continue to move towards it. Yeah. And we had Marty Makary yesterday, and he was talking about novel, you know, indications, drugs that are like disruptive, innovative, et cetera. Is there an appreciation, you think, at FDA for some of the subtleties between the different chronic pain kind of verticals, if you will? Yeah. I mean, I would say all of our interactions with FDA have been a sign of great interest on their part. We've worked well with them. This question you raised of the different types of neuropathic pain, which obviously there's DPN, there's LSR, there's others, and also other types of chronic pain is an area of evolution. We believe that the selective sodium channel inhibitors, NaV1.8, suzetrigine, and NaV1.7, we continue to work on do have broad applicability across all of this area. But obviously, since this is a new mechanism of action, we have to continue to work with the community, with the regulators to get to that endpoint. From a Vertex perspective, you guys have NaV1.7, but when you look at other mechanisms, NaV1.8 and others, I think Lilly is working on a few more. Are you comfortable with the range of mechanisms at Vertex, or is there a need to maybe add other modalities across the clinical? Yeah. We're very comfortable with where we are. I would say in terms of one, NaV1.8, you know, we have the first selective NaV1.8 inhibitor, obviously the first approval. And as with all things, we continue to work serial innovation on that. But NaV1.7 is really the only other target that has both the genetic validation in humans, both gain and loss of function that show the modulation, but also its biological effect and its role in pain signaling. And, you know, many people have worked on it for a long time and not been able to find a highly selective and effective molecule. And it turned out to be a bit harder than NaV1.8, which is why suzetrigine is now approved, and we haven't. We're still working on NaV1.7. But I do believe we've cracked the underlying challenge, which is to find a highly selective and effective molecule. And so we're in preclinical development, and I do believe we'll be successful, you know, moving forward such molecules and that will have long-term implications for both the effectiveness and the breadth of our pain program. Okay. Then the final question, when you look at DPN, maybe talk about the types of chronic pain. So DPN to me seems closer to an acute setting where the intensity of the pain versus an LSR or chronic back pain. From the different types of chronic pain, you'd have, you know, long-term administration. They're not all created equal, and so they present different challenges in terms of clinical development. Certainly. I think, you know, the one reason why DPN is our current focus is because it is very well-defined. There's a great track record of even with medicines that didn't have the best efficacy and tolerability profile, being able to make it through the trials and get to patients, which is why we feel that the path is most clear there. And, you know, as I said, the first trial is ongoing. The second one will complete enrollment of both next year. And we think that that's the most direct path. Obviously, it's even more pioneering in some other areas, and that'll be for the future. But right now, with the 2 million people with DPN, we feel very confident that's a, you know, a near-term focus. Yep. Okay. That's helpful. Well, let's switch gears to maybe from a commercial perspective. When you look at the requirements for monitoring, when you guys first launched in the first quarter of this year, you know, how has that requirement informed kind of your the pace of new starts and development? Was that a surprise to you? And do you see that going forward as being less of a barrier with respect to switches from TRIKAFTA? Yeah. So with the label, the requirement is for six months of monthly testing, liver monitoring essentially, which, you know, is a consideration for patients. I think the important context, a lyftrek is up to a great start. I think, again, you saw in the most recent earnings call, we've reported revenues of nearly $500 million in the first nine months of the launch. So very happy with that all together. I think there are a few benefits to Alyftrek. One, it's the best medicine we've produced. It has terrific results on ppFEV1, FEV1, strong results on sweat chloride, once-a-day dosing, great safety profile. So we're thrilled. That said, it follows TRIKAFTA, which also was a fantastic medicine. And there are a number of patients who are super well-controlled and happy on TRIKAFTA. So, I think the significance, there were a number of naive patients who didn't have access to a medicine previously 'cause of a rare mutation or other situations. Uptake in that population has been very quick because they've been eager for a medicine. You've got some patients who had discontinued a CF medicine previously. We're doing our best to track those patients down. They're not always easy to find, but we've seen a nice uptake there as well in discontinued patients. And then you have patients who will switch from TRIKAFTA or one of our older medicines. Switching has been ongoing and steady. We still believe that over time, the majority of patients will switch from TRIKAFTA or one of our older medicines to Alyftrek. But the pace of that is gradual and consistent and rising throughout the year. So, I think it's important to note that the majority of prescriptions written for Alyftrek are for patients who are switching, and so that's significant as well. The label is different in Europe. It doesn't have the liver monitoring requirement, and there are more of those naive patients in Europe. So we expect uptake there will be quicker, but overall, terrific medicine. And I think we're very happy with where we are for the year. In the community, do you see among pulmonologists and sort of CF specialists is there a greater appreciation for sweat chloride as a marker of disease progress? In other words, I think FEV1, when you first launched TRIKAFTA, was, you know, by far and away, that was the, but this has the same FEV1 benefits, but then you add sweat chloride. Is there, you know, in the community, more of a focus on that versus say a year or two ago? Yeah. I mean, I would say, first of all, that doctors and patients in CF have understood for a long time that sweat chloride is a readout of the underlying biology, which is CFTR function. And so it makes a lot of sense, and it's been our goal, from the start to bring as many people as possible to carrier levels of CFTR function because people who have one copy of the CF mutation, parents or siblings or what have you, don't have any disease. So I think underlying there is an understanding of that, now having of the importance of sweat chloride. Now, having said that, you know, our goal for a long time has been to get as many people as possible to carrier levels of sweat chloride, once a day, early in life, obviously maximal benefit in terms of FEV1 with a great safety and tolerability profile. I do think that we're very close to being there. You know, I think one of the things that is sort of worth stepping back and noting is that, you know, the vast majority of people obviously are approved not just for F508del, but also rare mutations now, that we, I think, you know, maximally benefited what you can do with FEV1. I think whatever's left that hasn't responded is actually probably scarring in people who have the disease, which is one reason why treating early in life is so key because you can avoid tissue damage. You know, the majority of people in all of our disease, in all the groups are already below the diagnostic threshold. In some settings, you know, we're getting close to a very substantial majority, even in some cases, already at carrier levels. For example, we recently announced results from the one- to two-year-old study with TRIKAFTA where 70% or so of those kids were already at carrier levels. And so I think that one of the key messages that I think the community understands is we'd like to get to normal CFTR function 'cause that will be the long-term benefit. But right now, there are a lot of them are, you know, reasonably happy with where they are. And I think that's fine because, you know, I think in the long run, they're gonna wanna switch to Alyftrek because it's once a day, because they'll get even better chloride. But I think one of the reasons it's not quite as much rush is their satisfaction with where they already are with TRIKAFTA, which is for the patients a great set of opportunities to have. Yeah. I guess the follow-up on that, the patients that, for example, were treated with TRIKAFTA from newborn on, do you see a growing body of patients that are still pancreatic sufficient, which is a big deal, right, in terms of their disease progress and the economics of that are much more meaningful than a patient who, say, a teenager who takes it? Yeah. I mean, it's a little early to say. It's one of the things I, someone, someone asked me, like, you know, when you think about the future, what are you excited about? One is just to see what happens in the next decade of these young kids who are treated. It's a little early just to say because of the exactly what that'll turn out to be. But obviously the hope, and I think there's reason to be reasonably confident about this is that when you treat kids at a very young age, you know, KALYDECO is approved down to age one month. And that when you treat kids that early on, that hopefully the systemic benefits go beyond just the acute benefits. And so I can't give you the exact answer because it's a little too early to say in terms of the number of kids treated, but I'm very eager to see how that plays out over time. And the hope would be, and I think it's reason to believe this hope that, when you treat kids that early with, you know, levels below the diagnostic threshold and in many cases carrier levels, they're gonna hopefully have as normal a life as possible. David, where are we with respect to the nonsense mutations, the premature stop codon patients? I know you have a collaboration with Moderna. Maybe just give us a bit of a context for that. It's been more of a technical challenge to address that population. You know, I think it'd be helpful to talk about why that is. And then, you know, in addition to mRNA, what other kind of technologies or methodologies could you use to address that part of the population? It's a great question. You know, the gene for cystic fibrosis was cloned in 1989. And in the first decade of the 1990s, everyone thought gene therapy would be the solution. And in fact, the way our CF program started was after that decade not having succeeded, there was a frustration, and it led to, let's try a small molecule approach, a frustration in the community that led ultimately to our program. And one reason why even today, now, 35 years after the cloning of the gene, it hasn't succeeded for the 5,000 or so people who don't respond potentially to our medicines is mostly, I think, because of delivery to the lung. If you said, what's the challenge? I think there's so many technologies now, whether it's gene therapy, gene editing, RNA, mRNA, what have you, that if you can get them into the right cells in a safe and tolerable way, it should benefit the patients. But I think the delivery is the hard part. And in the case of our collaboration with Moderna, we spent many years, the mRNA part was a little bit more straightforward. They're very expert in it and that moved forward. But we worked really hard to discover the best LNP we could, both in terms of delivery, but also preclinical safety. And we're now in the, as you know, study where we're treating a multiple ascending dose. It's a one-arm study because nobody improves in the absence of treatment. We'll be following, in addition to safety, tolerability, FEV1 because there's no sweat chloride measurement 'cause it doesn't get into the bloodstream. Certainly, we look very forward to seeing those results. But if you're going back to your question of what's the hard part, it's actually not, in my opinion, whether you're doing mRNA or gene editing or gene therapy, it's actually, can you get to the right cells? Then the last point I'll make is some people say, well, couldn't you do gene editing and like do one time, let's say, inhalation and never have to treat again? And that's very unlikely, at least based on current knowledge, 'cause to do that, you'd have to get into the stem cells, like not the lining of the lung, but the stem cells to treat once forever. And that's not something anyone has ever shown the ability to do. So having to dose repeatedly, inhale, get to the right cells, that's the challenge. But again, we're excited to see the results of 522. It's the best program, certainly in terms of all the data we have to date that I've seen. But until you, as always is the case, until you have clinical data, you can't say what the outcome is. Yep. Yeah. Then the last question, I guess, Charlie, a few from a commercial perspective. You mentioned earlier, you know, the monitoring requirements, the lack of them, I guess, in Europe. When you look sort of not just Europe, but broadly OUS, is there a potential for Alyftrek to have maybe a broader reach than you got with TRIKAFTA just given the totality of the profile, given the once a day, given the sweat chloride benefit in addition to FEV1? In other words, is this a more marketable drug kind of globally versus what Vertex had with TRIKAFTA? I mean, listen, we're, you know, our goal obviously is to reach CF patients wherever they are. We've talked recently about some of the countries where we've expanded access and reach, so places like Turkey and Mexico and Brazil. You know, listen, TRIKAFTA and Alyftrek are both fantastic medicines. Again, Alyftrek is the best available CFTR modulator there is. And so, you know, so it's, I suppose, in countries where they don't have access to medicines at all, it's reasonable to assume we would start with a conversation about Alyftrek, but, you know, I think we were making great progress with TRIKAFTA as well, so I don't think there's anything significant there about unlocking new geographies. There are patients with high unmet need who are waiting for medicine, and we wanna bring the best one that we can. The other wrinkle, just to keep in mind, you know, in Europe and other places where we already do have access, in many cases, Alyftrek is a new reimbursement discussion. They've already. We've already got a reimbursement agreement in place for TRIKAFTA. There are a couple of smaller markets where we have a portfolio agreement where you can bundle Alyftrek in right away. But otherwise, with, with those exceptions, it's a new reimbursement discussion. And so that naturally just takes some time anyways. Maybe, maybe just one other thing to add to that, Charlie, is the rare mutations that Alyftrek treats and TRIKAFTA does as well, but Alyftrek has even more, are a bigger factor in some parts of the world than others, and you know, Delta F508 is a founder mutation from Northern Europe, and so even in Southern Europe, let alone other countries, the ability which Alyftrek has the best profile of treating rare mutations expands the potential, and we're seeing that, I think, more in Europe. Yeah. Good point. You know, than in the U.S. as well, so those are other advantages of medicines that can treat the largest number of rare mutations, not just Delta F508. Good point. That makes sense. Well, let's switch gears to talk about POVI. So, this has been increasingly part of our conversations with investors. So they've sort of moved from pain to, to POVI and the mechanism of, of BAFF/APRIL. Maybe just give us a bit of a, a background of that, of what initially was interesting to you with respect to the Alpine deal. And then when you look at the mechanisms and, and of autoimmune through BAFF/APRIL and IgAN, these are definitely exciting science, new unmet needs, you know, for Vertex. So give us maybe the, the, the background to it. I wanna talk a little bit about how this ended up in the sandbox. Absolutely. Yeah. Yeah. So, you know, we use this term the sandbox, which is for a disease-focused company. What are those diseases that have all the criteria from great unmet need, number of patients, mechanism of action, et cetera? And, a couple of years ago, we decided just to see if we were missing any opportunities to basically review all of medicine. We actually looked at every ICD-9 code, outside of cancer and infectious disease. And, when we looked at that, I'll give a shout out to Aaron Reames, who's our head of external innovation, who did a fantastic job. One thing that emerged was these B-cell mediated disorders, IgAN, but also membranous nephropathy and also some others where we saw one, there was a great unmet need and a large number of patients and a lot of diagnosis, but also where this APRIL/ BAFF inhibition was emerging as an exciting and potentially transformative approach. Then, of course, we looked at all the different potential assets that were available. There were multiple. And we felt that, and we still feel that, POVItacicept really had the best overall profile for at least a couple of reasons, a few reasons, I should say. One is it's engineered to have the best affinity and potency and preclinical evidence of tissue distribution. So that should give you the greatest efficacy. The early data clinically, you know, overall was and remains very encouraging. And then also with biologics, it's obviously very important to have, you know, the easiest, the most convenient way for patients if they have to have injections. You know, as we head forward, we see we're gonna have the lowest volume once a month auto injector. So the combination of all those things and multiple diseases seemed to us a very compelling opportunity to have a potentially best-in-class approach to this broad opportunity. And we're glad not only have we been able to make the progress. You know, the Alpine acquisition amazingly was like 15 months. It was, let's see. 18 months ago. 18 months ago. Yeah. Which is not that long. And sort of the integration, but also the rapid enrollment of the RAINIER trial, the initiation based on preclinical data of membranous nephropathy. We also have, you know, a couple of other diseases we've talked about following. It's really very rapid progress. And, we're super excited to, as you know, we're looking for our interim analysis data soon, and we're already working on rolling submission. And so obviously we have to see the interim analysis data, but assuming it holds up, it's, I think it's a truly exciting opportunity for 2026 and beyond. Yeah. And just in the, for the IgAN data, I know there's a number of assets out there, you know, similar mechanisms, but what do you see as maybe the potential for differentiation with POVI in, in IgAN versus, Vertex others? Yeah. Listen, I think that a couple of things to keep in mind. One, you know, there is a lot of innovation going on right now in renal medicine, but that's because there was no innovation ongoing for a really long time, so the unmet need among patients with IgA nephropathy and other renal diseases is enormous, and so from a commercial and from a business standpoint, obviously there's a huge opportunity there. With POVI in particular, I think, you know, David touched on it, but I just reiterate, there are really three points. One, POVI is specifically engineered for optimal potency, affinity, and tissue distribution. All that engineering and all the preclinical work pointed to significant potential that we're seeing play out in the clinic with significant reductions in proteinuria, hematuria, GD-IGA1. And then lastly, the point that David made, you know, when you've got a chronic medicine or chronic disease that leads to end-stage renal disease, you need to be really consistent and good about taking your medicine on schedule. And therefore, things like dosing and convenience come in. And to David's point, at less than half a milliliter, it's a very small dose. We'll be launching with auto injector and monthly dosing. That's a great overall profile. And so for us, when you look at those three things, we think POVI has the potential to be best in class. It's very differentiated, and we'll be going into a large market with a lot of unmet needs. So we feel really good about the opportunity for POVI. And not just IgAN, you have PMN, you have other. Yeah. Can you talk a little bit about maybe the mechanism that where else could you go? Sure. With respect to BAFF/APRIL? Yeah. No, definitely. I mean, even though our discussion here is initial focus is on IgAN and PMN, this is really about B-cell mediated diseases. And I do think it's an extremely interesting and promising area over the last five years to see how B-cell mediated diseases can be significantly benefit from these approaches, that reduce the B-cell activity. One of the things that is exciting about BAFF/APRIL is it seems that evidence is that there's your autoimmune B-cells that are causing the disease, but then there's also your memory B-cells and others that protect you, let's say, from infections. And BAFF/APRIL seems to do a very nice job of separating those two. It seems to have a great much greater impact on the autoimmune portion than it does, and it leaves the sort of immunity to other things intact. Now, when we say where else could this be a focus, there are two areas we've called out at least to date, although there may be others in the future. One is warm autoimmune hemolytic anemia, which reminds us to go back to medical school, warm and cold, et cetera. But warm autoimmune hemolytic anemia, where that's part of the Ruby Four study. And one of the things actually we liked about Alpine was they'd done these basket studies where you could learn quickly about it. So we're waiting to see more data on that, but we do believe that if that data is supportive, there's an opportunity there that would be valuable. And then the other is PMN, remember, God, I'm like getting too old. That's right. The PMN? No, not PMN. GMG. GMG. Yeah. GMG. Thank you. I'll just keep shouting out. I know. I know. You can see why they anyway. And that's a case where, again, it's a disease with some therapies that have made a difference, but there's still a need right now for cyclical therapy and having a constant therapy that would be able to help people would be very valuable. And there is, in addition to sort of the theoretical benefit, there's also some data, early clinical data from another asset that shows potential transformative advantage. So we are talking to the agency about how we might pursue that as well. Yeah. Sjögren's is one that's also been thrown out as, you know. Yes. It's, again, we haven't talked about it, but certainly an interesting area to look at. Yeah. And so within the renal space, you guys have obviously APOL1 as well. Maybe talk about that, as another asset in the portfolio. I know, you know, Reshma being the nephrologist. Yeah. Right. Likes to talk about the whole kidney portfolio. Yeah. She always likes to say, "It's not because I'm a nephrologist," but nonetheless, she was a great nephrologist. And so in addition to IgA nephropathy and PMN, there's also, as you said, APOL1-mediated kidney disease. And that is another significant opportunity. I think the estimate's about 150,000 people who could potentially fit the criteria we're working on. We're in Phase 3. We've completed enrollment of the interim analysis cohort. And that one has a 48-week follow-up, which means that 2026, later in the year, we should have that data as well. And if you remember, it's a genetically validated target. We are many years ahead of anybody else. And if you look at the VOC data we had, it was in people with focal segmental glomerulosclerosis with very significant proteinuria for a significant period of time. We had a 47.6% reduction in proteinuria in 13 weeks. And that's quite remarkable if you look at other proteinuria conditions. And so we're in Phase 3. I'm super excited to see what those results look like because, you know, we don't know for certain, but, you know, the benefit could stay stable at 13 weeks. That could be the maximal effect. Obviously, there's always the theoretical, so they could not be as much as you want, but there's other reasons to think it could continue to fall in the long period of time. And so that, I think, is a potentially really transformative medicine as well. We'll have to see the data. Also when you imagine, you know, as we look forward, not many years, but in the near future, the possibility of being able to launch IgA nephropathy, membranous nephropathy, and APOL1-mediated kidney disease means we could go quite rapidly from not being, in this renal space to having multiple potential medicines. I think that, as nephrology expands, hopefully we can be a leader in nephrology. Yeah. Let me follow up on that. If you think about the, what are the commercial sort of consequences of that? I know, you know, these are specialty markets. So that's as Vertex as it gets. But, historically, when you have, you know, indications that haven't really seen a lot of innovation and have a lot of patients, you have to, you know, have some bumps in the road, reimbursement and access wise. So is there anything that, you know, you guys could help do today that could help smoothen out, you know, kind of set the stage, I guess, for the commercial launch here looking a few years? You wanna talk maybe regulatory and I'll talk commercial? Sure. I think there's a couple of things. From a regulatory point of view, I think what Charlie's mentioning is one, the enthusiasm in the renal space for these new medicines. One of the things, actually just before I get to regulatory, there was the ASN, just a few weeks ago, and everyone said how it was like a transformative time where it used to be you'd go to that because there really hadn't been many dramatic advances actually since dialysis. The meeting was buzzing because of all the exciting advances, and so I think one thing is when going into a new area like this, it matters that the doctors and the patients are excited and interested, and they are, and then from a regulatory point of view, there's this movement towards understanding for certain conditions the effect of proteinuria as a predictive marker. And so obviously that's in IgAN, the ability to potentially get approval with interim analysis, I should say, and accelerated approval with proteinuria. And I think that's another way in which the field is moving forward. And while one has to and will develop the long-term outcomes of hard outcomes, I think that's another advantage to this area because there's a biomarker that can be measured by doctors that regulators, you know, agree has value. And I think should make it a little more direct than something where there's nothing to measure that the doctors and regulators believe in. Yeah. And from a commercial standpoint, you know, we've always said that our strategy is disease first. So we have not typically worried about synergies downstream, though in the case of renal medicine, we have significant synergies between POVI and AMKD and ADPKD as well. I think you saw that, to David's point, at ASN. We had the largest share of voice at ASN. We had a terrific meeting there. There's an incredible awareness of Vertex and our emerging portfolio in renal medicine. So internally, as we're thinking about building the field force and marketing and other efforts around renal, we're able to do it with the thought that we've got POVI plus AMKD plus ADPKD. We've got a broad portfolio. It gives us a lot of reason to be in front of healthcare providers. It gives us a lot of reason to think about synergies from a commercial and a marketing standpoint. So, I think it's a, you know, it's a wonderful opportunity for us. Yes. That makes sense. Still lots of cover. So Casgevy, let's talk about that from maybe a commercial context, Charlie, you know, how are you thinking about, you know, next year with respect to the access and reimbursement? And then maybe for David, you know, what, you know, I know you talked about you're still finding better conditioning regimens. Maybe help us with the timelines on making that, you know, maybe a more, you know, easier kind of administration. Yeah. Commercially, I think Casgevy's in a great place. You know, I think we did a good job at the launch signaling that 2024 was gonna be a foundational year. We know that the patient journey from the time that they meet with their physician to considering all of the aspects of the treatment and have cell collection, go through manufacturing, get reinfused, it's a long journey. It's measured in many months. So we knew that, and we knew therefore that patient dosing and revenue would take a while to start to materialize. I think we're seeing great progress in 2025. We mentioned on the call that we expect revenue for the year to be north of $100 million for Casgevy, which shows a nice steady ramp over the course of the year. And if you look at some of the metrics we've provided in terms of patient initiations and patients undergoing for cell collection, you can, for lack of a better word, see that the patient funnel is building significantly, which gives us clear line of sight to a number of patients who we would expect to be infused in 2026, so it is, given the length of the patient journey; it's taken a while for the ramp to develop, but very happy with the progress we made in 2025. And I think, you know, it's clear you'll see a significant increase in 2026. We'll comment on that when we give our guidance in February. Okay. And, you know, before I talk about some of these other approaches, which I will, I do think what Charlie was saying in terms of the what is actually an innovative foundation for how to launch such a medicine, how to work with ATCs, I think is actually the more important near-term factor than what I'm gonna describe, only because that that's been a lot of foundation building, and I think it's gonna play out over time. But there are certainly multiple things we're investing significantly into, in the long run, be able to expand more dramatically. The most near-term is improved conditioning. So Busulfan obviously has its own challenges. And so we've been working for some time on finding novel assets that are developing, finding, or in the end, it's turned out we have to develop them internally that have an affinity for hematopoietic stem cells. So they more specifically than Busulfan reduce those and also some way of actually, again, without damaging anything else, reducing them. We're working on that. We're in late preclinical development with the first such opportunity, but as always, we do serial innovation. So we have others behind that. The second thing we're looking at, like others, is in vivo delivery. And that, again, is very easy to think about, but it has more challenge 'cause to get the hematopoietic stem cells and not be editing elsewhere is gonna be a challenge, but we're working on that. And some of the things we're doing for improved conditioning, identifying novel assets to have the affinity for the right cells could also be of value in delivering a gene editing in vivo to that. And then the third thing, which doesn't get as much attention, but I think has great long-term potential, is a small molecule that could reduce BCL11A and induce and increase fetal hemoglobin. One way of thinking about this is, you know, the genetic studies suggested that BCL11A would be a good target. Casgevy proves that if you can modulate BCL11A, you can have the outcome we're seeing, which is quite, quite remarkable. And so we've been working for years on a small molecule approach to do that. And again, while it's still in the research Phase, I think given our background in terms of doing CF and doing genetics and doing some Inaxaplin and some of these others, I have the confidence that we have the best chance of finding such a molecule. And if we did, of course, that would have even broader benefit. Right. And Joe, I didn't mean to skip over. Part of your question was about access and reimbursement. You know, the two largest markets for Casgevy are the U.S. and the Middle East, essentially. We have great access and reimbursement across both regions. We also have great access and reimbursement in Europe as well, particularly in larger markets like the U.K., Italy, Germany. So access and reimbursement isn't a rate limiter on Casgevy at this point. Okay. And then in just the last minute here, when you think about, you know, uses of capital, you guys are highly profitable, generating a lot of cash. You've done the Alpine deal. You haven't done a lot of larger transactions. So Charlie, how are you thinking about, you know, sort of this, the strategy from here? Is there a need, an urgency to do something, or do you have enough therapeutic areas, right, that you're diversified enough, but I wasn't sure if there's an interest or need to maybe add a new vertical? Yeah. I mean, listen, we've been very consistent in describing and I think executing our capital allocation strategy. You know, first and foremost, we try to preserve flexibility to invest in the business internally and externally. I am particularly proud of the Alpine transaction. You know, David talked about it. It closed 18 months ago, under our ownership. The program has accelerated, and obviously we're in a great place in terms of being in the clinic right now. And that was a kind of a, you know, perfectly sized deal at the perfect stage of development, one where we could still add value and feel really good about the value that we paid. So we'll continue to prioritize investment in innovation and in BD. You know, we're open to all sorts of types and sizes of transactions. It took us a while to find Alpine, but when we found it, we moved really quickly and decisively. So if we have the opportunity to either add on to one of our existing verticals or perhaps another disease that's already in our sandbox, we would, you know, we'd be interested in doing something like that. But we have incredibly high standards for science and medicine, and something's gotta cross that threshold. Secondarily, we are active with our share buyback program as well. That's the other component of our capital allocation. We've bought back something like $2 billion worth of shares this year, taking advantage of some of the stock price dislocation that we saw in the second quarter in particular, and so feel really good that we've been buying back at high volumes at these prices. Awesome. Guys, thank you very much. Thank you.