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Awesome. Last session of the day. Thank you very much for all for joining us today. My name is Mohit Bansal. I'm one of the biotech and pharma analysts here at Wells Fargo. And I have the Vertex IR team with us. Susie Lisa had IR and Manisha Pai. She's part of the IR team as well. So thank you very much both of us, both of you to join us. Thanks for having us, Mohit. I don't have ED investor relations. Sorry, I did not have the title. Thank Thank you. So exciting times at Vertex. There's a lot more to talk about, not just CF at this point. So talk a little bit about what you are, where investors are asking most of the questions and where you're spending most time in terms of talking about the Vertex story at this point. Sure. So I think it is an exciting time and we have sort of a catalyst rich period coming up. So I'd say most of the conversations relate around that. I will say, you know, recent news last month, we had been getting a lot of CF questions heading into competitor data that I think, you know, ended up being not as much of a concern as many had thought. And so CF questions have gone back more towards commercial aspects, the lift-track switch, which continues to go very well, and then our next-gen 3.0 family of therapies that are in the pipeline. But the majority of questions, I think, focus on upcoming catalysts, and that's primarily within our new disease area pillar of renal therapies, namely disease-modifying therapies that addressing unmet need in the renal area where, you know, historically they've had basically repurposed cardiovascular medicine. So really, we're calling it a renal renaissance and a very exciting time. The most near-term catalyst would be on our Anaxaplan therapy, which is for APOL1-mediated kidney disease, and that's where you said that you should expect, you know, in the next couple of months, our phase two proof-of-concept study for a patient population expansion study called Amplified, which is looking at patients with two APOL-1 alleles and then two cohorts, one that has more modest level of proteinuria, and the other cohort has the two APL-1 alleles and type 2 diabetes. So you'll get that proof of concept data sometime in the coming months. The next catalyst that's super exciting will be our November 30th PDUFA date for povitacicept in IGAN. So this will be the first commercial launch in the renal area. We're very excited for that. We are launch ready. Our sales force is hired. We have very high degrees of nephrology experience in that sales force given the depth of the pipeline. the clinical differentiation of POVI, the safety profile, and the patient administration benefits. So we're very excited for that. And then the next, you get a couple other data sets before the end of the year, likely one in myotonic dystrophy type 1, which is certainly timely right now. We can go into more detail there. In our CF therapies, VX828 is the first of the NextGen 3.0. You could see data before the end OF the year. And we'll complete enrollment in our two phase three diabetic peripheral neuropathy studies, and that's in the chronic pain space. We'll complete enrollment for the end of the year. Those are 12-week studies that would put us on pace for data sometime in the first half of 2027, likely. And then, very importantly, is you'll get the phase three interim analysis in the 1st quarter of 2026, and then we'll get the phase on enaxiplin in the sort of primary or pivotal study there of primary AMKD, which is patients with two APL1 alleles and heavy proteinuric burden. And so we're very excited for that. It's been a long time coming and likely would be our second launch commercially in the renal space. Awesome. And sorry, I would just add too, Crenetics just closed last week. Right. And so more to come there in terms of updating guidance, but continue to be encouraged by the Palsanify launch in the U.S. and hoping to be able to accelerate launches outside the U。S. and then look forward to Melnat in CAH and completing enrollment in that phase three study. I think those are most of the key catalysts, but it is a lot going on between now and the first half of next year. Clearly a lot is going on, basically, and we barely mentioned CF here. Awesome. So let's just talk, why don't we start with the time, like in the chronological order, the catalyst here, right? So enoxaplant, NAMKD, but let's just talk about the phase two portion of the trial. So there is a population expansion study for diabetic patients, and you have characterized this being a little bit more risky than the broader patient population. So talk about that. And then also I want to touch upon the moderate proteinuria patients, because so far with this molecule we have only seen data in FSGS patients. So how much does the moderate proteinuria patient data set de-risk the eventual trial, at least for the proteinuria endpoint? Sure. So maybe to start with that group and then go back to diabetes, I think that the data that you have seen was the phase 2, the portion of the phase 23 for the pivotal, right? And yes, that was an FSGS population. But what we think, and we have long held this belief, is that what is crucial is not the FSGS diagnosis, but the confirmation that you have two APOL1 variants, right? You need the genetic test. And FSGS is just a histological confirmation. It's a scarring pattern, but you don't see patients referred for biopsy to confirm that unless they have a very heavy proteinuric burden. So in the phase three study, it's likely you will see a high percentage of FSGS patients, but if you had FSGS, you were welcome. If you didn't, you Were welcome, as long as you had two ApoL1 alleles and a high proteinuric burden. So I think in the modest proteinuria group here, we think the important thing is inhibition of Apo L1. Right. And we have 98% plus inhibition Of that, and that's why we have confidence. We still need to see the data, but in this proof of concept, in that more moderate proteinuria group, it's not FSGS that we're treating. It's the APOL1 inhibition, and hence our view or optimism for the data. The one difference, obviously, will be you have less dynamic range because you're starting at a lower point. There's less reduction if you could on an absolute basis because you aren't starting at 0.7 or 0.8, right? You're starting in something like 0.3 or lower. Now, to your diabetes question, I think there, too, we're excited for that data. But the question here is we know we're inhibiting ApoL1. What we don't know is how much of their kidney function is impaired by their type 2 diabetes as opposed to the Apo1, and we're not treating the type 2 diabetes, right? So that's what we look forward to learning. I think that we are quite pleased with how rigorous we were. It was a real challenge to enroll the interim analysis in the more homogeneous population of the phase 3 study, amplitude, and now we're looking forward to having, you know, decent 20-plus patient-sized cohorts in each of those two arms for the amplified data in the coming months. Got it. So you are more, like, you think the probability is higher for a good data set in the moderate-patriotic patient followed by the diabetes patient? I think you could say there's a clearer through line, if you will, and just more of a question mark on the type 2 diabetes impact upon kidney function. Yes. Got It. And these trials are, These cohorts are a gating factor for you to expand the program into those indications. That's right. We talk about in the amplitude study, the pivotal study with interim analysis next year, that we view that as about 150,000 patients in the U.S. and Europe, and that if you expand the separate cohorts here from amplified, it's likely adding about 100,000 additional patients to the target population. Got it. So one question we get. So moving to the Amplitude phase three trial. So these are so similar that I have to say phase two and phase three. So I think the agreement with the FDA was that at one year mark based on protein reduction and where do you stand on EGFR, it could be a potential file label data set at that point. So the question we get a lot is that Is one year time point enough to see good enough improvement on AGFR or like the ranges of outcome could be like you continue the trial or not? That's right. So it is a 40 week, 48 week end point for the interim analysis of the amplitude phase three study. And the endpoints there, the accelerated approval endpoint, to be clear, is the change in EGFR from baseline. And then in addition, right, it is the reduction in proteinuria. And I would say that our confidence in this study stems from two things. One is that in the phase two portion of this phase two, three study, we saw at just 13 weeks a 47.6% reduction in proteinuria, and that's pretty dramatic, and it continues to decline from there, and so that sort of proteinuria reduction, I think it's reasonable to assume would be associated with stabilization of EGFR, right, and you have to look at how it's doing versus placebo on top of current standard of care. The second thing is that we know that AMKD patients, the rate of decline of their EGFR is about 50% faster than typical CKD patients, and so they're losing about six or seven per year versus something more like losing four or so, three or four, for or typical CKD patients. So that's why we think that at 48 weeks, we are hopeful that we can show this, demonstrate this type of result in addition to strong reduction in UPCR. Got it. And then how should we think about the disclosure there? So FDA wants to see EGFR data, not in this indication, but I mean, typically in IGAN, they do want to see GFR data but you do not necessarily want to disclose it. So like, should we expect data on both endpoints or just proteinuria when you? I think that for the Amplitude Anaxipline study and the interim analysis, that's the end point. So we will disclose that 48-week EGFR, and if it's successful, right, then we will continue to enroll the study. Sorry, we hope, we're on target to complete enrollment by the end of this year, right? But we would continue to follow patients for the full two-year endpoint. Okay. IGAN, and I would say that the field may be changing in AMKD, but it's not there yet, and it is still clearly this EGFR endpoint. In IGAN in contrast, as you know, the agency has moved to UPCR as an endpoint, and I think there is still debate ongoing about disclosures of one- or two-year EGF-R. The U.S. FDA clearly will accept one-year EGFR data. Other global regulators will not, right? There isn't a path to accelerated approval in Europe. And there are more patients in Asia with IGAM than there are in U.s. and Europe combined. So that's some of the work that we're going back to consider in terms of disclosures and timing on POVI and IGAM. Got it. So for POVI, FDA is allowing one- year EGFFR at this point. Got it? So that's probably the reason some of your competitors are looking at the early data and then just trying to. I think some who are more focused solely on the domestic opportunity versus we are thinking about the entire global opportunity. Got it. So stay tuned. Got it, very helpful. So moving to POVI. Ahead of the launch later this year, so I mean you are preparing for a broad launch the law with a large field force here talk a little bit about like you are probably going to be you had the third one to the market but you have the best offering in terms of overall profile of the product talk a little bit is there a low-hanging fruit or Kirigo guidelines updating to like less is better kind of situation so so like like how should we think about the early adopters and and ultimately before you know your profile kind of broadens the scope for you yeah I think that we've been very happy to see the early launches from competitors and the reactions in the marketplace right I again patients are typically otherwise very healthy and on the younger side right there 40 in their 40s typically and sort of have been these ticking time bombs but there are 160,000 patients in the U.S. that are biopsy confirmed in terms of their diagnosis. And even with the strong launches that you've seen, we're still talking very small penetration into those 160,000 or so patients. I think that we are really looking forward to our PDUFA date and launch later this year. Our sales force is in place and ready. I think we're quite pleased to see how many of them have prior nephrology experience, given their optimism around the broader renal pipeline that we have. I think the messaging clearly will be on the trifecta, as you mentioned, of better clinical data, clean safety profile, and then the patient administration characteristics, which we think are clearly differentiating in terms of once weekly low volume 0.46 ml, sorry, once monthly low-volume auto-injector at home, and I think that this will be a market where we will, I think you will see switching, and we'll go after switchers, and will go after de novo patients as well. I think initially, as the field, right, is moving so fast, and you see fairly recent changes to Cadego guidelines, right? In terms of trying to get patients to that threshold of 0.5 in terms of their proteinuria. I think, initially, you probably will see physicians targeting higher proteinuric burden patients, but would expect to see that coming down over time and a goal to get more and more patients to those guidelines. And Cadeagle also, right, recall instead of previously it was treat serially, ACEs, ARBs, SGLT2s, then disease-modifying therapies. Now I think it is more of a move to do things concurrently and recognizing sort of, you know, saving nephron sooner is better. And so looking to get patients on these disease- modifying therapies. And So between share of voice, the clinical profile, clean safety, the patient administration benefits, and then also we think our expertise in CF with patient programs around getting them on drugs, supporting them on drug, helping them with reimbursed access, et cetera, that's important in a chronic therapy as well, and our expertise and CF will serve us well there too, and that's how we're looking to have winning share. Very helpful. And we have seen EGFR data for, like DJI EGFFR for Vizet, then some EGIFR data for Vera as well. So how do you internally think about those EGFI data sets? They look more robust than anything that we have see in IGAN so far. So let's say using Vizat as a benchmark, I mean, do you, so do you have to be in that ballpark? Is there a number where it looks inferior or superior to existing therapies, or how do you think about that? Yeah, I think that there are a couple ways to look at it. On the one hand, stabilization, you could say, is stabilization. Right. But we do think that There's potential that, again, sort of back to time is nephrons, if you will, and you'd rather save more of them sooner. Right. And if you're on a chronic therapy, could, you know, a 42% reduction versus something in the 30% reduction in UPCR, does that compound over 10 years? And we think that it potentially will. We also know that, you know, we had best-in-class results from our interim analysis in terms of reductions in GDIGA1 and resolution of hematuria, as well as in getting the percentage of patients to those Cadego guidelines. So I think all of that is what will help differentiate us. Understanding that those are strong, you know, EGFR itself is a proxy for progression to end-stage renal disease and death dialysis and transplant, right? So I Think understanding these other endpoints like proteinuria, hematuria, and GDI, GA are proxies for EGF-R. There's strong understanding by physicians and even payers there. So, I don't think we'll necessarily, I think we are well a position to advocate our case, if you will. Got it, completely makes sense. Thank you. The other indication which doesn't get talked a lot about is by Sinha Gravis here. I mean, Vore has shown, or Imogen has seen some interesting data in China there. So mechanistically, how BAF and APRIL could differentiate versus what is out there, FCRNs are the front line, and then you have complement inhibitors out there. What is the value proposition for myofascial inhibitor in myasthenia gravis based on your thoughts? Yeah, I think we view myasthena gravis as, if you will, sort of the poster child for a B-cell mediated disease. So being able to inhibit at really two points on the maturation cycle, we think is very compelling. And the data out of China with a wild type, we felt did support that view of myasthenia gravis as being sort of a prime candidate for a B-cell inhibitor. And we think with the design, the engineering that's gone on to Taki in terms of its tissue distribution and penetration, et cetera, that we would be hopeful that we could show even better results in myasthena gravis. So we're currently enrolling a phase two study. It's a 12-week study. We haven't given timelines on that, but that's another catalyst to look forward to probably over the next 12 months or so. And sorry, on FCRNs and others, right, I think the key advantage of Baf-April inhibition is that you, other therapies, right? You need to cycle on and cycle off, but the autoantibodies continue to develop, right. So with a BAF April inhibitor, you could have chronic therapy and you wouldn't need to cycle on, cycle off, and you could have sustained benefit. Makes sense. So the phase two study is actually not that big a study, like 30 patients across placebo, and I think there are two treatment arms there. So given the small size here, what exactly are you looking for? Because I think you'll make a go-no-go decision for phase three based on this. So what exactly are you looking for to make that decision here? Yeah, we haven't given a bogey for that. I have to ask. Yeah, you had to ask, but we do think that the 12-week data on those 30 patients or so will be sufficient, given what we hope, I guess we could hint at the magnitude of the treatment effect, right, that we hope to see that that's enough time and enough patients in order to be able to make a decision. Fair to assume you'll be looking at biomarkers as well, more than not just the MGADL and all those things, right? Yes, that's right, yeah. Okay, got it. Very helpful. Moving to the pain franchise, Gernavex, I mean, so initially it was off to a little bit slower launch, and now it seems like you're getting traction in last couple of quarters, and with the family placement at hospitals and all that. Talk a little about what you are seeing in terms of how P&T committees are actually implementing Gernavax, and what are the gating factors at this point for generics uptake here? Yeah, I think we've been pleased with the progress in terms of adoption, whether it's by formulary or treatment protocols or care pathways. And there's all different aspects, whether it is inpatient, outpatient, ambulatory surgery center, et cetera. And you see different levels of adoption at different facilities, ranging from let's have a more measured adoption inclusion on our formulary to we've done the work and we're comfortable here, let's open it up broadly. But I think that it's one of the key drivers to the strong prescription growth that we've seen this year where we remain on track to hit our goal of tripling prescriptions in 2026 versus 2025. But it is one of many factors. So formulary care pathway, treatment protocol adoption, along with improvement in reimbursed access and covered lives, as well as the doubling of the sales force, our marketing initiatives and celebrity spokespeople like Jason Tatum. We're also, I think, very encouraged to see of late more and more physician-sponsored studies being published. For instance, orthopedic surgeons in particular are publishing their single center series of, say, total knee, and you're seeing really compelling results of 90% plus type opioid-free results from some of the most painful surgeries out there. So I think that and then presenting it, we are doing more and more in terms of our patient outreach and micro-targeting of it, directed TV advertisements and radio, et cetera. So I Think it's the combination of this really sort of all-out approach that is leading to the strong growth in scripts and continued improvement in terms it grows to net. I'm happy to talk about that more if you'd like as well. Yeah, let's just talk about that because, like, I mean, there was also a part portion there, part where, you know, hospital versus retail split is also slightly more tilted towards hospital versus what you would want to see in long term. That's why the script length is also shorter. So talk a little bit about that as well, because we are just using the script and multiplying with whatever number is there. But that's probably not true. Sure. So we very purposely are thinking about this for the long term and therefore went after a broad, and it's a very broad label, right, moderate to severe acute pain. So we went after trying to be as broad as possible in terms of types of prescribers as well as settings of care. And so the market itself for acute pain is about one-third in-hospital use and two-thirds at home or retail. Our mix continues to be a bit more 50-50 because we are focused on those in-hospital prescribers who will then take it to their ancillary clinics, et cetera. So trying to build for the long-term and focus there. And I should have mentioned one of the other key drivers of script growth is this breadth of prescrivers, where I think we're north of 36,000 prescribes. And it ranges from ER and trauma docs to orthopods to dentists, obviously, you know, plastics, OBGYN, anesthesiologists, et caetera. So pleased with that. But I think that the average hospital script is something more in kind of the two to five day range versus a retail script is something in the 14 day range. But I Think the real sort of lag, if you will, between the revenue recognition that we initially hoped to see versus what we now expect is is related more towards reimbursed access and some of the delays there and where our patient support program essentially is still being triggered, if you will, at the point of care in retail prescriptions. So it's like a safety net. It kicks in sort of blinded to both the patient and the pharmacist. If there isn't reimbursed access, we don't want that patient to walk away or call their physician and say, I couldn't get my drug, right? We're trying to convert entire practices. So the PSP kicks in if you don't have reimbursed access. And what we're finding is sometimes you may have coverage at the parent plan level, and it takes time to implement at the child plan level, or there may be some minutiae or technical aspects of how the script is written for a 14-day quantity limit or a prior auth that is getting in the way sometimes, and the PSP is being triggered when it technically shouldn't be, and we're working through those issues and why we expect we'll keep the PSPs in place as we work through them and continue to expect to see more revenue recognition. Got it. So that is more of a 27-story, or is it... We talked about a more normalized gross to net in sort of mid-2027, probably something plus-minus 50% range. Got it. Makes sense. Talk about the DPN trial as well a little bit here. I mean, you had robust data in Phase 2. So the drug is active. The question here is placebo responses, because a lot of pain trials have been killed because of the placebo response here. So to that extent, how are you managing that part of the control arm of the trial and site training and all those aspects of things? Yeah, so thanks for remembering the phase two, right? We had greater than a two-point improvement in NPRS, and so we know there's activity here. And I think sort of the good news of having to narrow our focus, if you will, in peripheral neuropathic pain is by going to DPN is there's a lot more clinical trial experience, both in terms of CROs and sites and our own, and as well as with regulators. So a controlled number of sites, significant training in terms OF how to manage placebo effect, and I think a better understanding OF how TO characterize the pain, how TO work with patients, et cetera. So I think we are optimistic and excited to complete enrollment of those two studies by the end of the year, as I mentioned, and then see the data from there. But it is a lot about training and management of placebo effect. And with more experienced sites in this type of pain and a limited number of sites, we hope to be able to address that. Got it. Very helpful. So last one, last set of questions about the chronic steel, right? So the one question we get a lot is that, I mean, you talked about $5 billion peak opportunity there versus, you know, at that point concerns were somewhere around $3 billion for the company there. So in your internal projections, like, where do you see the disconnect between, like what you projected versus what analysts were projecting for Krenatix at that time? Yeah. So I can talk to you about how we get to that approximate $5 billion number in peak sales. And there are multiple ways to get there. So first with Palsonify, which is approved for acromegaly, we see that as a blockbuster opportunity. The launch is off to a great start. And, you know, our goal is to accelerate it, to expand outside of the U.S. And then at Humelnant in congenital adrenal hyperplasia, we See that as the larger opportunity, as a multibillion dollar opportunity. So between those two, you could get to $5 billion. and at you Melvin is also being studied in Cushing's disease which could provide additional upside on top of that so that's how we think about it and five billion doesn't include the early stage assets at all at this point that's right right okay got it that's all upside awesome so and then you will disclose the financial impact once you close now you have closed the deals the next quarter you should expect the updated that's right very helpful so last question for both of you Wells Fargo healthcare conference 2027 I hope you are here I hope I'm here so we are sitting here next year same time by the the dates are same, 8th to 10th September, nice plug. Or our calendars. So what would make you look back at the year and say it was a great year for us? I think that it'll be, we look forward to saying we have a diversified commercial revenue picture with established disease area pillars across five areas. right? CF, hematology, acute pain or pain, broadly speaking, the specialty rare endocrinology with the kinetics acquisition, and then in renal and potentially September 27, you know, getting close to a second launch potentially in reinal at that point in time. And, you Know, hopefully sitting on top of good DPN data in pain, a strong POVID launch at that point in time, continued strength in the CF outlook, continued progress in CasGevi in terms of number of patients and their essentially functional cure and the amazing outcomes there, and then continue to push the earlier pipeline, whether that's in DM1 or in ADPKD or in other areas. But I think it's those five established pillars, three of which are commercialized today. And with the kinetics closing, we've got the fourth, but expanding that and then bringing along, we didn't even mention type 1 diabetes, right? But then also I think hopefully getting close to a second, a successful first launch in renal and getting close zu a second potentially. Anything, Brad? That was pretty comprehensive. I'm not sure I have anything of value to add on top. Thank you very much. On that high note, really appreciate you coming here and all the best. Okay. Thanks, Mohit. Thank you. Thank you, Mohith. Thank you so much.