Vertex Pharmaceuticals Incorporated (VRTX) Earnings Call Transcript & Summary

Great. Good evening, everyone. My name is Susie Lisa, and as the Senior Vice President of Investor Relations at Vertex Pharmaceuticals. I'm really thrilled that you could all be here with us tonight in Houston and for those of you on the line as well joining us for the American Society of Nephrology Kidney Week 2025 and for a broad update on the Vertex Kidney program. I'll run through the agenda briefly. Our CEO, Dr. Reshma Kewalramani will open with an overview of our 3 kidney programs in pivotal development and 1 currently in a proof-of-concept study. Following Reshma's remarks, Vertex is extremely pleased and grateful to have 3 physician thought leaders here for you tonight to share their views on the Ruby-3, IgAN and pMN data presented earlier this evening, the RAINIER Phase III study of IgAN, of [indiscernible] IGAN, which recently completed full enrollment in record time and the outlook for guidelines in treating patients with serious kidney diseases like IgAN. First, we have the pleasure of hearing from Dr. James Tumlin, Professor of Medicine and Nephrology at Emory University School of Medicine, Director of Research at Georgia Nephrology and President of NephroNet. Dr. Tumlin will provide a recap of his late breaker presentation of the RUBy-3 data in IgAN and pMN. Next, and to his left, Dr. Richard Lafayette, Professor of Medicine and Nephrology at Stanford University Medical Center and Director of the Stanford glomelular Disease Center will provide his perspectives on the RAINIER Phase III study for Pove and IgAN. And then we're very pleased to have Dr. Brad Roven from the Ohio State University Wexner Medical Center, where he is the Director of the Division of Nephrology, Vice Chair of Research and Professor of Internal Medicine. Dr. Roven will discuss the role of guidelines and shaping the standard of care for patients with glomerual disease. We'll then have plenty of time for your questions for Reshma or any of our physician thought leaders. We recommend that you access the webcast slides as you listen to this call. And please note, too, that there are disease area backgrounder as an appendix to the slide deck. This call is being recorded, and a replay will be available on our website. We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission. And with that, I have the pleasure of turning the call over to our CEO and President, Dr. Reshma Kewalramani.

Susie, thank you so much. Let me add my warm welcome to all of you. It's been a long day, and I appreciate that you're here late in the evening, and thank you to doctors Tumlin, Lafayette and to Dr. Roven for being here. I'll start with this slide. Many of you in the room and listening to the audio today are very familiar with the Vertex strategy. It is about our sandbox approach, which is centered on diseases. We are, as you know, not a therapeutic area company. We are also not a platform company. Yet here we find ourselves tonight at the 2025 ASN with 4 renal diseases in either mid- or late-stage development, and that is fantastic. I want to emphasize that each of these real diseases, IgA nephropathy, membranous nephropathy, AMKD and ADPKD are here, not because I happen to be a nephrologist. They're all here because they fit our research and development strategy to a tea, and that strategy has to do with unmet need. It has to do with knowing the causal human biology. It has to do with having targets that are validated usually genetic, but pharmacologic is just fine. It has to do with having biomarkers that translate and finally, it has to do with having efficient development and regulatory pathways. And we couldn't be more pleased that all of those criteria fit these 4 diseases. You've heard me talk about the status of these particular diseases and where we are with the Vertex potential medicines, I'll call out a couple of points. The first, I am so proud to let you know that the RAINIER, the Phase III study of Pove in IgA nephropathy enrolled in less than 15 months, the fastest of any contemporary IgAN study. I think it speaks volumes to the investigators and to the steering committee, of which Dr. Lafayette is a member. It speaks volumes to the Vertex clinical development team. And boy, does it say something about the sites and the patients who are waiting for medicines to treat their disease. The second thing I'll call out is that the membranous trial is up and running, and that Phase II/III pivotal trial is underway. On APRIL1-mediated kidney disease, we are now at the point where the interim analysis cohort is enrolled. That is a study that we need to wait for 48 weeks before we can turn over the card and I expect that, that will happen at some point next year, given that we enrolled the IA cohort earlier this year. The last thing I will mention is the ADPKD study that is also up and running. It's in Phase I development. One important thing to mention is that these diseases are sometimes rare, membranes is maybe 150,000 or so in the Western world. But at other times, not that uncommon, IGAN, for example, is more than 700,000 in Asia alone. And then you add on to that another 300,000 or so in the Western world. These are diseases that are important, there's high unmet need and many of these diseases are global. The one to call out, in particular, is ADPKD, you'll see that it's 300,000 patients. I'll come back to this. Our first approach tackles 10% of that full 300,000. So that's about 10%. And just hold that in your mind and just think about KALYDECO is to CF, as what I think VX-407 is going to be to ADPKD, the first of serial innovation, and we will get to everyone over time. The schedules slide. You've seen this in a variety of presentations. It has to do with the underlying cause of disease for these B-cell mediated renal diseases like IgA nephropathy as well as membranous. And we can talk a little bit more about this with the experts here. But I want to call out the fact that there are multiple pathways to get to plasma cells. These plasma cells are the cells that are responsible for autoantibody production, which is the cause of disease in IgAN and which is the cause of disease in membrane. And the April Bath pathway is particularly important because the APRIL BAFF mediated pathway to plasma cells disproportionately affects the autoantibodies and leaves alone your normal antibody production, and we can certainly talk more about that. The point I would like to share with you around polvetasecept, in particular, wonderful news for patients with IgAN is that there are many potential drugs coming out. I want to emphasize what I think makes Poly different. First, it was specifically engineered to have high affinity for APRIL and BAFF. It has high potency and it was engineered to have high tissue distribution. You heard about the 4 hypothesis, the action here that leads to the disease is the deposition of these immune complexes in the kidney. So we need to make sure that the drug gets to the right place. The second is that it's a dual APRIL BAFF inhibitor and I believe because B-cell maturation requires both APRIL and BAFF that you don't want to be in a situation where you have unopposed APRIL or unopposed BAFF, and this tackles both. Lastly, this is a disease for which our patients are going to need to take medicine chronically, i.e., for the rest of their lives. So if you look at the markets in which biologics have been active, it is extremely important. It's not an afterthought. It's not a nice to have. It's not some characteristic or attribute of the drug. It's really important that the medicine is in a format at a duration in an injectable where the patient can take it. And for Pove, what you should expect is at home administration via an auto-injector, every 4 weeks, subcu with a volume less than 0.5 mL. To just leave you with a little bit of what's to come. We're here today talking about the 4 diseases in renal medicine, the 2 that involve Kobi. I expect that there will be more coming in terms of diseases that Polvecan potentially treat. And the 1 that I think is next in line is myasthenia gravis, more on that in the coming months as we complete our discussions with the regulatory agencies. All right. I'm going to get ready to turn it over to the esteemed physicians to talk about these, but here's the 1 pager that you need to know in all of the VERTEX programs. The RUBY-3 trial continues. It has our IgAN patients in it for long-term follow-up as well as our membranous patients, and it is the data from these trials that give us the opportunity to think about Pove as a best-in-class medicine. RAINIER, that trial is done enrollment, not done enrollment for the accelerated cohort for the potential accelerated approval that's done, too. the full enrollment is complete. I expect that we will file our first module before the end of this year by way of the rolling submission that was granted by the FDA in addition to the granting of breakthrough status. And I expect that we will complete the filing in the first half of next year, expecting that the results will be supportive. I'm not going to spend a lot of time on Pove's RCT, just to let you know that the RCT is in pivotal development. It is up and running. and we can come back and talk about the specifics of the study design. I do not want to forget about AMKD. There is so much excitement about IgAN and membrane and B cell-driven diseases, and I get it. And there's a lot of enthusiasm for Pove and I get that as well. But I want you to also remember AMKD. This is an incredibly important disease with no treatments available. The IA cohort is done. I expect that we'll have results next year. The data have to similar for 48 weeks. I also want to let you know that the amplified study, which is a study of AMKD, so people with 2 alleles who also have another underlying disease, think diabetes or have lower degrees of proteinuria. That is going to finish enrollment this year. And a real look into the future, this is the ADPKD program. And the highlight here is just like in CF, where the underlying cause of disease is a misfolded protein. And I think I mentioned this earlier today, but it remains true that the only medicines that we know of, small molecules, that properly refold a misfolded protein to lead to therapeutic benefit are the CFTR modulators. We've taken a page out of that book to work on ADPKD. And it is an example of, hopefully, another class of protein folding medicines, medicines that can properly fold a misfolded protein that we hope to get to pivotal development after we get through this Phase II proof-of-concept study. That one is VX407. With that, I'm going to turn it over first to Dr. Tumlin. Those of you who are able to attend this session he just gave an oral presentation on these data. You have the benefit of Dr. Tumlin going through the same data just for you this evening. Dr. Tumlin, I turn it over to you.

Thank you, Reshma. Well, good evening, everybody. I'm Jim Tumlin. I'm from memory, and I'm a Director of NephroNet. And as Reshma said, it's a real pleasure to be here tonight. And I will be talking about the povetasacepb data in IgA and PLA tub receptor-positive membranes which is the RUBY-3 trial. Okay. Now this is our disclosures. Most of us have do consulting work for a lot of folks, including Vertex. And Rashmi's kind of gone over this, but again, let me just kind of reemphasize -- the understanding of the APRIL and BAFF pathway has been seminal in B-cell modulation., Both of these cytokines, which are a dendritic cell origin typically are expressed empires patches throughout the gut epithelium, typically, the terminal ilium. And at this location, normally the Galician Ig1 molecules are produced and then normally secreted into the gut lumen. Look, am I going backwards. So -- sorry about that. that my math we go. There we go, right. So APRIL and BAFF as I said before, are dendritic cell urgent that modify B-cell development. There's a tremendous amount of overlap between these 2 drugs. They both are involved in class switch. But for simplicity's sake, the BAFF pathway is primarily related to immature B cells up to mature B cells. And then after that, APRIL begins to mature cells toward full on plasma cells which reside in our bone marrow to remind you and do nothing but make the antibody which they're designed to make. Now that pathway, the development of plasma cell-derived galificient Ig1 is the center of the known universe for IgA nephropathy. What happens is -- and you've probably heard this several times, it always bears repeating. As I said a moment ago, these [indiscernible] piers patches secrete normally the Galipisent Ig1 through the colonic empathy into the gut lumen where they work with toll 9 receptors to help contain the trains of bacteria that we hold in our gut. Some breakdown of that transmission process either the favor is secrete or the possibility of a back leak of this scoutificient IgA1 allows it to reenter into the circulation. Now it's important to remember, your immune system has never seen that Galician. So when it arrives, it functions as a neoantigen. And then your immune system does what it does well. It generates an IgG molecule against the galificient IgA1 and creates a circulating immune complex. That's in part where the complement activation comes from is from these IgG antibodies. These circulating complexes deposit within the mesangium of the kidney binding to the mozangio cells, stimulating a storm of cytokine release, endothelium and ultimately the phenotype that we recognize as IgA nephropathy. Now Rashmi has already gone over this, but it just bears repeating. post that is a very cleverly designed and engineered molecule based off the base wild-type attache solubilized receptor. In the wild type, the binding of the protein for BAFF is marginal and has very little April binding. By manipulating the monocular structure, they were able to rhythmically increase both the BAFF and the APRIL binding, allowing it 2 things to happen. It is increased functionality as a sync for these 2 important cytokines, and it has better tissue penetration. Now the RUBY-3 trial. So let me just digress for a second. I was helped with Alpine and the part of the design of this trial. And this is 1 of the first that I'd come across a basket trial where you were able to look at a multiple set of different similar but not necessarily the same immune complex diseases and gather a lot of clinical utility for your specific pharmacologic agent in a very short amount of time. And that was the rationale by using -- looking at IgA nephropathy and PLA 2 receptor positive membranes. Now both of these diseases had to have biopsy-proven diseases, obviously. For the IgA, you had to have at least 500 milligrams of protein per gram. For the membrane, you had to have 1,000 milligrams pretty typical stuff, eGFR above 30, Standard maximum RAS ACAR blockade for 3 months. And then to be in the membranes wing, you had to have a proven circulating tighter PLA receptor antibody titers. The patient has then received either 80 milligrams or 240 milligrams. At that time, it was unknown what the optimal doses, whether this included dose-finding arrangement. The original study was to go for 24 weeks. It was then extended by 28 weeks and then ultimately extended it out to 52 weeks and now has data up to 2 years. The endpoints include a safety signal, looking for change in UPR, change in GFR, change in the GDI G1 levels and the PLA 2 receptor antibody titers and how many people achieved immunoologic remission, and we'll come back to that. Here's the demographics kind of a standard study for IGA. Patients were in their mid-40s. There's a male female ratio of around 1/3, so predominantly were female. The agent and colocation ratio was roughly 50-50. Time to diagnosis is roughly 2.1 years. ACE ARB was almost uniform, 86% of the 8-milligram dose, 100% in the 240. Protein in the study was around 1.3 grams in the 80 and 1.2 grams in the 240. And if you look, there are the gold deficient IgA 1 level. So 9,068 nanograms per ml versus 7,251 substantial levels of GDI G1. About half the patients had either moderate to severe hematuria at the time of enrollment. So as I like to say, here's the money slide. So this is what happened with urinary protein changes over time. You can see that in as little as 12 weeks, that was approximately a 35% reduction a 40% reduction in proteinuria and continue to decline over the ensuing 48 weeks to a total of a 64% reduction in UPCR. To remind the audience, what led to this herculean change in the number of molecules and pharmacologic agents in IgA, it was the observation there was a dose-dependent outcome based on the level of proteinuria, So what we always tell our fellows, if you do anything to get that proteinuria down, you benefited the patient, a 64% drop is substantial. It's also bearing -- should be beared and reminded to the audience that a full 2/3 of these people achieved the target level of 500 milligrams of protein or less. So it's not just a 64 drop from 5,000 to 2,000, it was the target level of proteinuria that affects the outcome long term. And this is something that Rich and Brad and I talked a lot about that is just a remarkable phenomenon of this class of drugs. If you can look, this is the change in GFR over 48 weeks. There was an actual increase in GFR of plus 3.3 ml per meter squared of GFR, which is unheard of tripling. If you then look at [indiscernible] about what happens with the GDI G1 levels, again, within 12 weeks, you see roughly a 57% drop in GD1, further falling down to a nadir level of 77% and -- and that value is precisely the same for the 240 dose. There was no difference in GDIJ1 reduction between the 80 and the 240. If you then ask, what was the outcome with the hematuria. So there's a lot of controversy about hematuria. A lot of people have different opinions about this. But you can see at the hematuria of 12 weeks, about half the patients had resolution of their hematuria. And at that time of that resolution, about 15% of the patients had achieved a complete remission, which is defined as less than 500 milligrams for 24 hours. By week 24, effectively 90% of the hematuria had resolved, and there was a corresponding increase in complete response rates of 32%, 44% and ultimately in 48 weeks a full 53% of the patients had achieved a complete response. If you then look at the -- moving on to the PLA 2 positive memories patient, here is the demographics, a little bit older population than unexpected, predominantly male and also not unexpected. equal distribution between ethnic cohorts time from diagnosis is about 1.3 years. The protein was also expected to be higher. It was 3.8 grams and a full 60% of those people had nephrotic range proteinuria. CARB was 100% in this small cohort of 10 patients. and SGLT2 has seen about 1/3. And once again, this is the effect of the povatasecept on proteinuria. So you see a substantial drop to approximately 35% by week 12 and then further declines at week 48 down to an 82% drop in proteinuria. Once again, whatever you do that you drop or you're benefiting the patient. A similar outcome is seen -- and these are remarkable. You just don't see this. Here's a change in GFR in the member's patients over the 48 weeks. It was a negative 0.3%, milligrams per -- I'm sorry, per minute. Now lastly, if you look at the anti-PLA2 titers, again, you see a significant drop by week 12, you're going down to a further drop of 83%. And then if you ask yourself what percentage of patients achieved an immunologic remission, which they define as less than 14 international units of PLA 2 titers, 44% achieved that by week 12. And by week 48, effectively, all of the patients, all 10, had achieved an immunologic remission. How about complete or partial response rates? So again, this is at 12 weeks, 24, 36 and 48. And you can see that at week 12, approximately 11% had complete response, 33 were partial by week 48, that number had increased to 40% complete response rate, less than 500 milligrams for 24 hours with a full 100% achieving a level of partial response. So if you then look at the -- how well the drug was tolerated. Most of the AEs were mild in severity. There were really no SAEs that were directly attributed to pace no safety concerns with laboratory parameters and no meaningful clinical trends. Now there was 1 patient in the 80 group that had a drop in their -- I'm sorry, into their IgGs less than 300 and it's a little bit difference on that into the case the audience is curious that there was -- if you had a single episode, the drug was held and then it was stopped and then put back on and the recovery rate from that was very rapid, actually. Okay. So in summary conclusions. Povetas asset 80 milligrams given once a month subcutaneously had remarkable effects. -- proteinuria declined by 64% on a week. GFR was stable throughout week 48. GDAGA1 levels dropped by 57% with the week 12 and 77% by week 48. Hematuria was resolved within 24 weeks and 90% of the patients with medium and large levels of hematuria. Clinical remission was achieved by 53%, a similar outcome was seen in membranous with declines in proteinuria, PLA 2 antibodies and a stabilization of GFR. The drug was generally well tolerated. As Reshma indicated, the RAINIER style is going on and coming to conclusion sometime next year. And we're just about ready to get started up with the Olympus Phase III trial in membranous. So thanks a lot. Love to hear some questions from you.

We'll next go to Rich, please.

So again, good evening, Rich Lafayette from Stanford. Great to see most of you again. So you heard this fabulous data coming along. You forgot your thank you to all of your colleagues and friends, Jim, it's very, very, very mean of you. So again, it's great to be with you just have this long-standing interest in glomerular disease, an autoimmune disease and thinking about moving forward to actually treating and installing the progression of kidney disease and never having to worry about the intricacies, the morbidity and mortality of end-stage kidney disease transplant is fascinating, but wouldn't it be great if we never had to really think about replacing kidneys because they continued to work. So the kind of data that Jim just showed you is completely pivotal in this field. to not only achieve all of your dreams. You have immune complex disease, you can show in the blood that those causes of the immune complexes are being well controlled. You can look in the urine and see that signs of kidney inflammation are improved by resolution of hematuria. You can see a dramatic reduction of proteinuria which is our best predictor that the kidney function is going to stay stable and better yet in this study, the kidney function is indeed completely stable. So everything you would want to achieve is there. Plus it's a well-tolerated once-a-month shot of a small volume that's tolerable with an infection profile that looks like the background population and no laboratory risks. So given that, you, of course, want to move forward with a way to show that, that data is absolutely reproducible, and that's what RAINIER is all about. And as mentioned, RAINIER is a pivotal trial for povetaclecept, the registrational trial, which is well powered to demonstrate both a clinically and statistically significant reduction in proteinuria and the same clinical and statistically significant stabilization of GFR. And if the GFR changes anything approaching the perfect stability of the RUBY-3, then that's going to be a well overpowered study. So it's super cool. This Phase III study takes patients with biopsy-proven IgA nephropathy at high risk of progression, more than 1 gram of protein a day despite optimized background therapy of at least RAS inhibitors. And as you heard, this increasing number of patients who will be on SGLT2 inhibitors as well. Again, there -- they can have a urine creatinine ratio also to predict that greater than 1 gram per day of greater than 0.75 grams per gram. And as you know, the primary endpoint is the 9-month proteinuria, which looks like it's predicted to do very well and the confirmatory criteria will be the 2-year change in GFR slow. And then we will look at other biomarkers. We'll look at what happens in glycosuficient IgA 1. We'll look at the hematuria response. We'll look at the change in GFR every way we can measure it by 2 years. And then we'll look at hard outcomes as well, looking at 30% reduction in GFR and the proportion of patients who come to dialysis, transplant or non-accidental death. So that's the study design. What's wonderful about it of the 600 patients who are in the trial, they were offered a 2:1 randomization. We went globally to know the centers who could recruit icy nephropathy. We have a well-balanced population as a plan by having our centers global and hopefully, we will be able to share data early like next year. So again, super excited, and the Phase II data really predicts great things here. So I will turn it over to Brad to talk more about how that fits with our guidelines of what we're trying to achieve and our clinical knowledge of what we're trying to achieve in this disease.

So hi, everyone. It's a pleasure to be here. My name is Brad Rovin. I'm the Division Director of Nephrology at Ohio State Universe the Ohio State University. Just to be clear. I have a huge interest as Jim and Rich in immune glomerular diseases. And I also write guidelines. And so I guess I'm going to freestyle this a little bit. These are the -- this is sort of the money slide, if you will, as Jim puts it of the new KDAGO guidelines. But let's just talk about where we've evolved from. So for my entire career as a nephrologist until about 3 or 4 years ago, we sort of were under the assumption that IgA nephropathy is a benign disease, don't worry about it, give them an ACE inhibitor, see them every few years and the patients are going to do well. And that -- for those of us, I think, in referral centers, which 3 of us are, that was not what we're seeing. Most of the time patients came to us, and yes, that were seen in the community for a while. but they had impaired GFR. And lots of times, they came in with severely impaired GFR, and there was nothing left to do. And so it didn't seem to be that much of a benign disease. Then the RADAR trial came along, which is really a registry from the U.K. and showed that patients that had reductions in proteinuria down below a gram still had a substantial risk to progress to end-stage kidney disease. Then lots of other studies came out, including ones in the United States, Germany and Sweden. sort of confirming these data. So one of the new things that the KDIGO guidelines are -- and do you all know what KDIGO means, kidney disease improving global outcomes. So these are our kidney guidelines. Every society has their own guidelines. But anyway, the bottom line is that we now realize that this is not a benign disease, and we need to be much more vigilant, and so we started working on when we should start to take care of patients with IgA nephropathy and really be serious about it and also what the endpoint or goal of IgA nephropathy treatment is. And of course, we use proteinuria as Rich and Jim said, is a surrogate marker of clinical outcome, but we're not treating a disease for proteinuria alone. What we want is that we hope that we treat the disease and the proteinuria will resolve, and that's our biomarker. It's not a very good biomarker as it turns out. and we know this from many other glomerular diseases, but it's what we have to work with now. So the first thing we did in the KDIGO guideline was substantially lower the goal of where we wanted proteinuria to be. So instead of less than a gram per day, we wanted the proteinuria to be as low as it could go. So sort of, for sure, less than 500 milligrams, but even better if we can do it. And so that's one of the goals of therapy. The second goal of therapy always has been, but never was available to us, how can we intervene in the pathologic process that causes IgA nephropathy. So you've heard the 4-hit hypothesis. It's a reasonable start. It's probably not the right answer. There's probably more involvement, but we certainly know that lots of parts of the immune system are involved, not the least of which are antibodies and antibodies against aberrant antibodies and immune complex deposition which initiates glomerular injury, that invokes other parts of the -- other injury mechanisms that promote kidney decline in patients with IgA nephropathy. And the real watershed point for us, I think, was a public-private partnership mediated really through the kidney health initiative from the ASN, where the FDA and a bunch of us got together and said, how can we do trials in this disease that don't take a really long time to where we see end-stage kidney disease. And that's where we got the accelerated approval format based on proteinuria with a follow-up of glomerual filtration rate or kidney function. And historically, that is one of the most important sort of events in the history of now what we see as IgAN drug development. That really promoted a lot of smart people at pharma, working with folks like us to develop drugs to intervene. So now for the first time, we have drugs that intervene immunologically besides glucocorticoids. And I'm not here to bad mouth glucocorticoids, but why not? But I treat a lot of young folks with lupus, lupus nephritis and no one like steroids. Well, it's not true. One of patients loves that she keeps asking me for steroids. But anyway, most people don't like it because of all the acute side effects and they don't even know what they're getting into with the chronic damage that it causes. So we wanted something that would be reasonable and something that would be attacking a precise part of the immune system. And now we have these drugs. And I think the BAFF APRIL inhibitors or blockers are really emblematic of where we wanted to go with this. So when we redesigned the KDIGO guidelines, we realize that we now have several drugs that were coming down the pike, and we only did the guidelines up to what was approved, okay? And we know we're behind. and we're going to fix it. And we know that some of the BAFF APRIL are going to get approved shortly, and this will hopefully go up for PDUFA date very pretty soon or file for it. and we will revise these as much real-time as possible. But the goal of the guidelines of IgAN treatment has become, tackle the immunologic disease and try to intervene in the pathways of injury that are causing the initial part of IgA nephropathy, get rid of the antibodies and the autoantibodies that are involved. Rich and Jim and I did a study a long time ago. We thought about this a long time ago. We did anti-CD20, let's get rid of all the antibodies, and we were sure that was going to work in IgA. Not only did it not work, we didn't even get rid of galactose-deficient IgA at that point. So clearly, the companies that were going for BAFF and APRIL of course, is hitting the B cell, we're taking a risk because there is always already a precedent that this might not work. And instead of not working, it was, as you see, spectacular. And that's the only word I can use to describe it. And just for full disclosure, I don't do consulting with Vertex, okay? I was not part of this trial. I saw the data today when Jim presented it. And I said -- I was next to my junior faculty member, and I said, "What the hell is this?" This is like unbelievable. And I think that should be a reaction because as Jim has emphasized and as Rich has emphasized, we don't see many therapies, which prevent the decline in GFR. okay? That's like unprecedented. And these declines in proteinuria are also unprecedented. And I work on a lot of different glomerular diseases, and I certainly would like to start bringing these drugs to other diseases because you left a blank spot as to other B-cell-mediated diseases. turns out a lot of our kidney diseases or B cell mediated. So if you're thinking about current and the future because I hear you're all smart business people, you should be thinking about what else this can be applied to. There's a whole bunch of stuff. I digress the guidelines. So the guidelines are broken up into 2 formats. What we normally see what -- he's my fishing partner, and it's remarkable that not either of us have drowned yet, when we go fishing together. Okay. I have pictures for the audience later. Anyway, the other thing we realized that's very true for places like the United States where we don't really screen for disease is when we see patients with IgA nephropathy, most often, they also have chronic kidney disease by the time we see them. So we realized with the armamentarium of new drugs, we have the ability to treat both the chronic kidney disease and now the immunologic disease in parallel. And so we made this sort of new idea or algorithm, which is simultaneously to start treating the chronic kidney disease and prevent further progression of damage to the kidney by the processes that have already been initiated by IgA nephropathy. So that's one side of the diagram. And you can think about the drugs that are doing that. and I'll just name them, and I don't consider them competitor drugs, so I don't feel bad about naming them, but the Astrasentans and the sparsentan that are controlling the hemodynamics and some of the other mediators that are sort of set into process with the deposition of the immune complexes. At the same time, -- and most importantly is we want to stop the IGA process. And so we say to start simultaneously the initiation of a modulating therapy, a disease-modifying therapy. And what are the current disease-modifying therapies that are approved for IgA nephropathy? Nothing. Well, steroids. I mean, steroids -- systemic steroids are not approved for IgA nephropathy. They have the potential for disease modification. in that they do decrease galactose-deficient IgA. We know that Nefecon is out there, and it is a steroid gut associated and that is right now our -- currently our only disease-modifying therapy. And I don't want to compare drugs or anything, but this will fit into the disease-modifying therapy window very nicely. And then when we get questions, we can talk about where we think this is going to fit in the hierarchy of the paradigm, I'm sure you guys are curious as to our thoughts on this. So we want to start both simultaneously. We want to arrest the disease, and then we want to continue treating the chronic kidney disease that most of these patients have from the beginning. If you go to Asia, for example, Japan screens kids for hematuria and looks for IgA nephropathy early on, if they start treating the patients early, they may not have chronic kidney disease, so they may only need to treat the immunologic disease. Nonetheless, I don't know why any of us think that we have an immune-mediated disease, and we don't need to treat it. You would never say to me, "Oh, it's a lupus patient. " Well, we know it's immune meat, throaACE inhibitor -- and we'll see how they do a few months later because by then, they may be ready for dialysis. Yes, IGA is a more slow-moving disease. So we have a little bit of discretionary time, but I think my motto is time is nephrons. and that's what I use in a lot of my lectures, I would like to start this very early on. So that's why this algorithm was started. And so you can see now maybe how this is going to be modified with new drugs as they become approved. The KDIGO guidelines only talk to go that have been approved and for which we have evidence but you can tell that we might be able to fold in the B-cell inhibitors very nicely on the side of the diagram talking about immunologic disease. And we know that other drugs coming down the pike may actually like the complement inhibitors inhibit after the injury has started some of the damage to the kidney. So this invoked a flurry of unhappy activity and letters to us when we put it out for public review. I think the community needs to be educated. We're doing -- trying to do a very thorough job of educating our community because I think we're a little bit naive in the nephrology world. We haven't had therapies in the past to do this. and we stand to be fairly conservative and traditional. And I would suggest to you that we can actually, with these new drugs, modify for our patients what's happening in a profoundly important way and that's the message we need to get out, and I think we're doing it. So is this sufficient? Should I stop here? Oh, he wants me to stop. Okay.

To all 3 of you. Thank you.

[indiscernible], we have about 30 minutes for your questions now. We'll start in the room. We have a few online. Anybody we get a mic right here, please. .

Carter Gould, Cantor Fitzgerald. Thank you for hosting this Vertex. This was very helpful. Nice weekend. Maybe for the doctors. Maybe just following on like the last line of conversation around some of the inertia in the community. how important is showing stable eGFR even an improvement in eGFR and really disrupting that inertia in the community and sort of waking up the field?

Let me take a quick stab at that. So great question. So most of us, all 3 of us here, training what's broadly called the Brinarian hypothesis, it's Barry Brenner famous Division Director at the Beth [indiscernible] Brian. And he had this postulate that if your GFR fell below 65, you were done. And there were compensatory mechanisms in the kidney that led to a nexible decline toward dialysis, irrespective of what you did. And that dogma persisted for 40 years is just patently untrue. And to your point, the question that you're asking is, and I think this is embarrassed pointing out there's been almost a philosophical change among nephrologists in the last 5 years that this idea that if you get a young lady with IgA nephropathy and she has 25 GFR, which would have been considered a death sentence 5 years ago, if you could flatten that curve [indiscernible] can do pretty well with 25 mills of clearance. And so this becomes an objective in itself. A lot of times, unfortunately, physicians have a period of fatalism. They'll get this down to a certain point, I'm sorry, ma'am, there's something that can be done for you and prepare her for dialysis. This opens the door to flat GFRs in a completely different paradigm.

Yes. And I just want to emphasize that, that's really the key thing to your question is getting that word out to not tolerate loss of kidney function, particularly in IgA nephropathy, where we now have tools, multiple tools that in a good number of patients because not everything works for everybody, but that you really -- that's got to be your goal. And that's why the guidelines are so strong. And those are the parts of getting the goal that is going to be the first lesson. And I do think we can get that out there relatively quickly.

I want to add just 1 real quick thing before Brad jumps in. In one of the previous trials, and I'm not sure how much I can actually say, but in one of the previous in the delayed release benessonide, -- to put this into context, the placebo group in that study had an annualized decline of 9 ml per minute per year, which was what is what we're seeing even in the membranous group and even less so among this. So this -- so that's why Brad took the time to say, we just don't see this. And it truly is -- and the rest of the 3 of us have been trying to figure out why this has been going on, we don't know. But I have some thoughts, but I'll share with you later. But it's a very -- it's fascinating from a biologic standpoint as well.

So I want to answer your question in a different way that I think will be relevant to everyone in the room. You are looking at the development of drugs that are coming down the pipe faster than we've ever seen in nephrology. And these are drugs that are basically foreign to most nephrologists, and it's just not in IgA. The same thing is happening in lupus and to a lesser extent in some of the other diseases. And so we, as a community, have developed -- were all part of a society called the International Society of Glomerular diseases. It's fairly newly formed. And one of our first tasks was to start to put together glomerular disease centers of excellence, where people like us are throughout not the country, but the world. and we will have special expertise in these kinds of diseases. And we don't want to impinge or take patients away from the nephrologist out in the real world. But in my own practice, obviously, a university practice, we have dialysis physicians and general nephrologists and GN doctors. We have a whole GN clinic. When 1 of my partners sees a patient that has GN, they refer them to us to take care of. Just like if you have cancer, you go to a cancer hospital. And so we're in the process now of working out and we have a white paper ready to go, the criteria to be a glomerular disease center of excellence. And with that, we have lots of qualifying criteria to get these things up, running and certified. And so to get the word out will be much easier with these concentrated foci of people dedicated to these diseases because the disease field has become so complicated, it's hard for the general nephrologists who spend their time on dialysis to actually make the conversion and keep up with the literature. And we think this is a huge step forward for the care of our patients. So we're very excited about that. So I am absolutely optimistic and I'm not an optimistic guy, if you know me. I am absolutely optimistic that we are going to solve the problem that you said very quickly.

I really appreciate it. This is Adam on for Jess. JPMorgan. Just a few from me. What's the best way to think about the placebo response that we might expect in the RAINIER study? And then if I ask another one for the RUBY 3, Can you speak on the circulating immunoglobulin data as of this latest cut? And was it similar to what we saw before?

Let's flip that into 2 questions. Let me ask Dr. Lafayette to tackle RUBY -- I'm sorry, to tackle RAINIER and then I'll ask you Dr. Tumlin to tackle RUBY 3. Dr. Lafayette.

Yes. So I think great pains have been taken for Renier to really get a stable population -- so again, the criteria and the site selection is 1 that you're going to really choose patients who meet the inclusion criteria again, that opportunity to have them on stable background therapy, particularly to lock in the RAS inhibitors and SGLT2 inhibitors really makes the likelihood of a substantial placebo effect low. Now proteinuria is variable. And so you still -- even though I would expect a single-digit proteinuria change in the placebo patients. you have to build in your risk analysis for as high as 10% or 15%. But this proteinuria response that Pove been showing is so spectacular that it should do well. And then you always build in the idea that there's maybe that same placebo part response to the active therapy group as well. So I don't think there's any significant likelihood, especially with the way that the study is powered, that a slightly more robust placebo response will make -- will cloud anyone's judgment about the efficacy of the drug.

The second question was in RUBY 3 tell you a little bit more about immunoglobulins. -- that let.

Yes. So the -- that's a question we've gotten a lot. And so the protocol because when the drug was first came out, remember that there was a context that are similar but not the same drug called atacatercept had a signal of infection in a lupus study that was done. And so appropriately, everybody was concerned about over immunosuppression with this new class of drugs as you're feeling your way around it. So they did a rather rigorous endpoint so that if your IgG levels drop below 300, you only have a single episode of that, and then that drug was held until there was a restoration of that IgG level. If you fell below 150, you were removed from the study. And so just to give you an idea, the recovery rate of that IgG was very rapid, and this is at the 80-milligram dose. At the higher doses, there were more incidents of it, but in a way, that's kind of moved because we're not going to the 240 dose in IgA. Moreover, when you compare that to some of the other previous study, theta, they had to have sequential levels of IgG below 300 before they held the drug. So it's a matter of rigor and where they were in the development of the drug.

Sadia Rahman on for Mohit, Wells Fargo. So I wanted to get your thoughts on the EGFR trending up to plus 3 ml per minute in this trial. Do you see a mechanistic explanation for an EGFR improvement in IgA nephropathy and maybe greater benefit than what some of the other B-cell agents are showing in their trials. And even if the agents ultimately do look similar in the controlled trials out to 2 years, how do you expect Pove could differentiate given increased potency maybe further out or on other endpoints?

Why don't we split that into 2 questions? Dr. Tumlin, maybe I could ask you to comment on the plus 3.2%, which has got a lot of attention and then maybe Dr. Lafayette, Dr. Rovin, maybe you want to comment a little bit on how do you see these drugs shaking out?

So it's a really great question. And I sort of alluded to the fact that the 3 of us have been trying to what? How does this happen, right? And so -- there's a lot of things to remember, a lot of things is speculation that no 1 knows the answer to. Let's make sure that's really clear. We do not -- I don't know why this GFR stabilize in comparison to bunesonide, where you saw a 6 ml per minute year drop over time. So what could it be? Well, it's important to remember that 1 of the functions in the mesangial cell within the glomeruli, these are myoepithelial cells. So the body has the ability to increase and decrease the volume of the glomerulus, or the glomerual surface area in real time. And these are under the control of ANG2, aldosterone, norepinephrine in the dealer, all these vasoconstrictive hormones can vasoconstrict that -- this is what I find attractive about this idea. This is a dynamic and rapid process. And you see that GFR flattening within 3 months. That's not likely to be a hematologic event. We thought about some other ideas, not -- so I think that's 1 answer. The main answer is we don't know, but is super exciting.

He meant hemodynamic effect.

What did I say? Hematologic .

Human cell .

Hemodynamic -- just -- Not to confuse.

[indiscernible] any comments on how you see the various agents being differentiated as you think about RAINIEr?

Yes. I think we're going to have to watch for complete data sets. I think there's tremendous strength that we have 5 agents that are B-cell modulators that very effectively reduce gladden and that each one of them are shrunk spectacular safety. Each one is showing a nice effect on protenrian hematuria and all are looking marvelous at stabilizing GFR. So it makes it extraordinarily unlikely that this Phase II data is a fluke and agreed that will not get recreated in Phase III. So that's the first thing. Then I know you guys are poised in waiting to ask about Bats April versus April alone. So I'm not going to worry about the hazards of jumping in there. Again, with this POI study, you're seeing beautiful better reduction in proteinuria, but to be fair, it's not placebo-controlled, and you know that in the audience. you're seeing this uptick in GFR. And I would say that my colleague was right, it may well be a hematologic effect. By that mean a reduction of inflammation in the kidney may make those glomerular cells and tubular [indiscernible] focus better. Dr. Rovin see all the time when we treat acute lupus nephritis. We see that when we treat other acute diseases. So even though this right, we don't know because we haven't done the test and the biopsy studies later will maybe reveal that, but that will be very exciting. So I think the bat April part is there is great biological rationale to think again, BaFinboth control, plasma cell tone and antibody production. BAF by itself has been a very effective attractive hormone to block in other immune diseases. So it's very, very appealing to believe that with the safety that we're seeing that, that will accumulate greater benefit over time. But obviously, the devil is going to be in really being able to show you guys and the doctors and the patients that there is a differentiator. Again, we didn't meet with the others. The fact that this is a very tiny dose once a month. It gets down to patient preference, patient-reported outcomes. And I think that's a really critical differentiator here. and that certainly favors the development. So I think those are issues. And then you guys know because many of us had conversations and Vertex knows that there's great power in sales force, advertising, patient and community relationships. And if there's not in the end, clear differentiation. Those things are what wins the battle at the end of the day, together with insurance regulation and sort of whether somehow the insurance intermediary has a better deal with 1 company than the other, but that again is company management. So that's an initial list and to head off further questions.

Can I talk about mechanism will So...

What's the question down here?

Okay. You had asked something about mechanistic. And as Jim said, we've been thinking hard about this. But -- let's take a page a little bit out of lupus and lupus nephritis. We've been using belimumab, which is a BAFF antagonist for a long time. And then when we tested it in lupus nephritis, I was involved in that trial. And one of the most amazing things I saw was that it preserved GFR. So now here's a B-cell drug, and it's a pure bath. There's no APRIL involvement here. that's preserving GFR. And I did a lot of reading about BAFF what it can do. And so it has some effects on fibrosis. You wouldn't expect that to occur very quickly in a setting that would be more long term. But if you go back really far to the initial animal experiments with taking away or creating animals whose B cells don't make antibody but are still around and put them in a mouse that gets lupus in general, these mice don't develop antibodies, but they still develop kidney injury, which suggests that the B-cell in and of itself even without the antibody production is relevant to the pathogenesis of disease. Okay. So putting down the B cells, if you will, with a BAFF APRIL inhibitor, and I'm leaning on the BAFF side now, may actually be important in maintaining glomerular and/or tubular function. So that's my current -- and you understand this is my opinion. I don't have data for this. But we are trying -- we're struggling in a good way. It's a good struggle to figure out what's going on with this. But it's clear. I don't think it's a fluke because all of these drugs are showing the same thing. So this is not a Phase II trial fluke in my opinion. And you wanted to know positioning or you -- there's a question.

I think there's a question here and we haven't heard just yet. Let's see where we go.

[indiscernible] Two questions on the trial and some regulatory aspects and then 1 on commercial. Maybe the first one, how do the baseline characteristics and event rates of rainier compared with the -- then a quick follow-up. And how do you look at the hard end points when you look at the current competitive landscape? -- how important are the getting it right with respect to the hard end points? And how closely proteinuria reduction correlates with the improvement in hard end points. from the historical trials? That's the second question. And maybe third one is a quick follow-up. A lot of posters on currently approved drugs, not kind of getting to where it should be in terms of penetrants. So how exactly Vertex is thinking about it, especially given that IgAN is kind of a silent disease also. So there is an issue with kind of identifying who are actually getting the disease, so 3.

Okay. Let's break that up into 2 questions. I'll come back and talk about how Vertex is thinking about commercializing. But let me break that apart from -- the first question was about twofold. How do you think about pruteinuria and the GFR endpoint and then proteinuria and the hard endpoints. And just so that everyone is following the plot. In renal medicine, there is an acceptance by the FDA for proteinuria to be a regulatory enabling endpoint for accelerated approval. -- because many kidney diseases, including IgAN, the time to go all the way to the "hard endpoint of time to dialysis, death or transplantation can be decades the FDA and other regulatory agencies around the globe has accepted that the slope of GFR is the acceptable final end point. So what you're going to see in the RAINIER trial is proteinuria and then the final endpoint is going to be the GFR slow. Rich, do you want to talk about your UC proteinuria to GFR and then GFR 2 hard endpoints.

Yes. So first, let me just confirm that the design of RAINIER is a very, very similar population as that in RUBY 3. So again, it's not like we're trying to compare apples and oranges, it's apples and apples. So very, very similar populations. -- there's likely to be even higher proportion of patients on SGLT2 inhibitors where studies are showing consistently that these agents and in will be 3, I'm not sure that you examined whether the results are the same in SGLT2 inhibitors or not, but others have shown these drugs are still effective. So that's first thing. The second about proteinuria is that, again, it is an accepted likely endpoint. That's why it's there for accelerated approval. But one of the very, very important points is that it is a benefit to patients with IgA nephropathy to reduce proteinuria, and it's very clear that reductions of greater than about 25% to 30% will effectively predict benefits on GFR. But crucially, every drug that gets the same degree of proteinuria is not appearing to get the same benefit on that GFR preservation. And that's what's so exciting here is that for, yes, even better proteinuria reduction, but if it were the same the GFR stability of not slowing progression from as Jim said, 6 to 8 to having it, which is very nice, but going from 6 and 8 to not progressing at all, it means instead of doubling your time to dialysis and saying, "Well, it's going to go on 6 years. So thank you. I'm going to go on 12. That's great. But when you're 30 years old, and you can tell someone if you maintain your response and this is a drug, you're never in your life going to need dialysis or have advanced chronic kidney disease and its complications, that's why it's spectacular, and we're smiling. So different agents, different mechanisms give us different relationships between proteinuria and GFR. And it's not that it was wrong, that proteinuria is not a good predictor. It's just it's different based on how you get there.

Let me just add a little bit to what Rich was saying. This is not a new concept. In the lecture set that I have, this goes all the way back to Jim Donatio's group at the rechester in 1997, the first all was from Raiford. And what's remarkable with that paper is the same as had the Rice's paper from Toronto, which is the same from the RADAR data. basically, if you're a nephrotic range, you have about a 50% to 60% chance of going on to dialysis within 5 years. And so how we missed this all this time is a whole another discussion. And so to Rich's point, getting the protein down has a tremendous effect and what Reshma earlier mentioned this administrative change is what really opened the door, instead of going on to a slow disease. It takes 10 to 15 years to see the GFR change using the surrogate protein has become acceptable.

On commercialization, maybe 3 points to make. The first, just to set the stage, I do expect that the first module will go in before the end of the year '25, I expect that we'll complete the filing for accelerated approval in the first half of next year. We've decided to use one of our pediatric vouchers and that guarantees a priority review, reducing the review period from 10 months to 6 months. So I expect that you can do the math there and the time lines for when this medicine will be approved. Second, this fits our approach for commercializing in specialty markets to a tea. There's about 7,000, 8, 000 nephrologists in the U.S., the accelerated approval and the time lines I just provided is for U.S. and then it will be the 2-year GFR endpoint for Europe. So in the U.S., it's about 7,000, 8,000 nephrologists and the vast, vast majority of patients with IgA nephropathy are seen at about 5,000 nephrologists or so. We expect that a sales force about 150 people or so will serve this patient population. And of course, we have additional medicines coming hopefully for AMKD or ADPKD, and there is synergy and overlap there. With regard to differentiation, I think we've already covered those points. I do think the safety and efficacy are clearly first and foremost. And the physicians are going to want to assess benefit risk. But again, I would not underestimate the importance of how the medicine is going to be administered in a chronic biologics market. It is critically important to have a format, a dosing interval and a volume of administration that fits for a patient to be able to take this for a long time. And market research, it's not actually rocket science, but market research also confirms once a month is preferred to more frequently than that. Small volume is preferred to more volume. No patient is going to get -- tell you, yes, please administer 2 ml in 2 different injections. They're going to ask for the smallest volume with the smallest needle and an autoinjector. And for beta -- you should expect an auto-injector at home, it's 0.46 ml of dosing and its once-monthly subcu. Those studies to do human factors, engineering, et cetera, those have also been completed and will be filed with the BLA that we were just talking about. Susie, I still see 5 minutes on the clock, so we can get a couple of more questions in Any other questions?

I had 1 e-mailed in perhaps more for you, if you -- or for the physicians comment on the data today increases your confidence an for an anticipated accelerated approval timing as well as for the pipeline beyond?

Yes. One of the really important elements of time just simply passing is that we have more patients enrolled. We have the opportunity to see what the enthusiasm of the sites and the physicians are and it's obviously high given how quickly it was enrolled, and because we use our voucher and we secured rolling review, the confidence is very high, as uncertain that there will be a 6-month review expecting that the results will be supportive. So time going by is extremely helpful in that regard. With the other programs, time going by has a similar profile for membranes we are at that point where we're starting the pivotal trial, which means we now have the data what Dr. Tumlin showed you was a subset of the full data set. So you should expect that there will be more presentations at upcoming renal meetings for those data. And so more time going by just gives you more ability to look at the data, which, of course, increases confidence because the sample size goes up. On AMKD, we have already passed that magical point of interim analysis enrollment. That is a huge milestone. That study was hard to enroll. And we've talked about the fact that, that study would be hard to enroll because unlike in CF, for example, where there is universal newborn screening, that is 100% not the case in AMKD. And so the fact that we were able to get that study enrolled and increase genotyping rates has been really great. ADPKD slightly different stage. That 1 has just started Phase I. So I hope by this time next year, we'll have enrolled that trial when we will have data to share. But the fact is that we have completed Phase I, the PKs very well behaved. The safety looks good, and that is very important for a molecule that is about to enter Phase II.

I think that's a good place to call it. Dr. Rovin, Dr. Lafitte, Dr. Tumlin, thank you so much. Thank you to the strategy teams from Vertex that are here and my colleagues [indiscernible] from IR. Thank you all. Appreciate it.

Thank you.