Okay. Great. Good evening, everyone. My name is Susie Lisa, and as the Okay. Great. Good evening, everyone. My name is Susie Lisa, and as the Okay. Great. Good evening, everyone. My name is Susie Lisa, and as the Okay. 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 2024-2025, and for a broad update on the Vertex Kidney programs. I'll run through the agenda briefly. Our CEO, Dr. Reshma Kewalramani, will open with an overview of our three kidney programs in pivotal development and one currently in a proof of concept study. Following Reshma's remarks, Vertex is extremely pleased and grateful to have three 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 Pove IgA N, which recently completed full enrollment in record time, and the outlook for guidelines in treating patients with serious kidney diseases like IgA N. First, we have the pleasure of hearing from Dr. James A. 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 IgA N 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 Glomerular Disease Center, will provide his perspectives on the RAINIER phase III study for Pove IgAN. We are very pleased to have Dr. Brad Rovin 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. Rovin will discuss the role of guidelines in shaping the standard of care for patients with glomerular disease. We will 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 backgrounders 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. 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. Thank you to Doctors Tumlin, Lafayette, and to Dr. Rovin 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 four renal diseases in either mid or late-stage development, and that is fantastic. I want to emphasize that each of these renal 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 T. 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. Finally, it has to do with having efficient development and regulatory pathways. We couldn't be more pleased that all of those criteria fit these four 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. 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 APOL1-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'll 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 II development. One important thing to mention is that these diseases are sometimes rare. Membranous 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. You add on to that another 300,000 or so in the Western world. These are diseases that are important. There is high unmet need, and many of these diseases are global. The one to call out in particular is ADPKD. You will see that it is 300,000 patients. I will come back to this. Our first approach tackles 10% of that full 300,000. That is about 10%. 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 Squiggles 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. 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 IgA N and which is the cause of disease in membranous. The APRIL-BAFF pathway is particularly important because the APRIL-BAFF-mediated pathway to plasma cells disproportionately affects the autoantibodies and leaves alone your normal antibody production. We can certainly talk more about that. The point I would like to share with you around Povatacicept, in particular, wonderful news for patients with IgA N is that there are many potential drugs coming out. I want to emphasize what I think makes Pove 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 forehead hypothesis. The action here that leads to the disease is the deposition of these immune complexes in the kidney. We need to make sure that the drug gets to the right place. The second is that it is a dual APRIL-BAFF inhibitor. I believe because B-cell maturation requires both APRIL and BAFF, that you do not 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. 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. For Pove, what you should expect is at-home administration via an autoinjector every four weeks, sub-Q 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 four diseases in renal medicine, the two that involve Pove. I expect that there will be more coming in terms of diseases that Pove can potentially treat. The one 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 am going to get ready to turn it over to the esteemed physicians to talk about these, but here is the one-pager that you need to know in all of the Vertex programs. The RUBY-3 trial continues. It has our IgA N patients in it for long-term follow-up, as well as our membranous patients. 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 is done too, but 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. I expect that we will complete the filing in the first half of next year, expecting that the results will be supportive. I am 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 membranous and B-cell-driven diseases, and I get it. There is a lot of enthusiasm for Pove, and I get that as well. 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 simmer for 48 weeks. I also want to let you know that the amplified study, which is a study of AMKD, so people with two alleles who also have another underlying disease, think diabetes, or have lower degrees of proteinuria, that is going to finish enrollment this year. A real look into the future, this is the ADPKD program. The highlight here is, just like in CF, where the underlying cause of disease is a misfolded protein. 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 VX-407. With that, I'm going to turn it over first to Dr. Tumlin. Those of you who were able to attend his 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. Thanks, Reshma. Yeah, you bet. Good evening, everybody. I'm Jim Tumlin. I'm from Emory, and I'm Director of NephroNet. As Reshma said, it's just a real pleasure to be here tonight. I'm going to be talking about the Povatacicept data in IgA and PLA2 receptor-positive membranous, which is the RUBY-3 trial. This is our disclosures. Most of us have to do consulting work for a lot of folks, including Vertex. Reshma'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 of dendritic cell origin, typically are expressed in Peyer's patches throughout the gut epithelium, typically the terminal ileum. At this location, normally the galactose-deficient IgA1 molecules are produced and then normally secreted into the gut lumen. Look, am I going backwards? Oh, sorry about that. There we go. Right. APRIL and BAFF, as I said before, are dendritic cell origins that modify B-cell development. There's a tremendous amount of overlap between these two 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. 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. That pathway, the development of plasma cell-derived galactose-deficient IgA1, 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 Peyer's patches secrete normally the galactose-deficient IgA1 through the colonic epithelium into the gut lumen, where they work with TLR9 receptors to help contain the trillions of bacteria that we hold in our gut. Some breakdown of that transmission process, either the failure to secrete or the possibility of a back leak of this galactose-deficient IgA1, allows it to re-enter into the circulation. Now, it's important to remember, your immune system has never seen that galactose-deficient IgA1. When it arrives, it functions as a neoantigen. Then your immune system does what it does well. It generates an IgG molecule against the galactose-deficient 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 mesangial cells, stimulating a storm of cytokine release, endothelin, and ultimately the phenotype that we recognize as IgA nephropathy. Now, Reshma's already gone over this, but it just bears repeating. Povatacicept is a very cleverly designed and engineered molecule based off the base wild-type TACI solubilized receptor. In the wild-type, the binding of the protein for BAFF is marginal and has very little APRIL binding. By manipulating the molecular structure, they were able to logarithmically increase both the BAFF and the APRIL binding, allowing two things to happen. It is increased functionality as a sink for these two important cytokines, and it has better tissue penetration. Now, the RUBY-3 trial. Let me just digress for a second. I was helped with ALPINE in the part of the design of this trial. This is one of the first that I had 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 a specific pharmacologic agent in a very short amount of time. That was the rationale by looking at IgA nephropathy and PLA2 receptor-positive membranous. Now, both of these diseases had to have biopsy-proven diseases, obviously. For the IgA, you had to have at least 500 mg of protein per gram. For the membranous, you had to have 1,000 mg. Pretty typical stuff. EGFR above 30, standard maximum RAS ACE-ARB blockade for three months. To be in the membranous wing, you had to have a proven circulating titer of PLA2 receptor antibody titers. Patients then received either 80 mg or 240 mg. At that time, it was unknown what the optimal dose was. This included a dose-finding arrangement. The original study was to go for 24 weeks. It was then extended by 28 weeks and then ultimately extended out to 52 weeks and now has data up to two years. The endpoints include a safety signal, looking for change in UPR, change in GFR, change in the Gd-IgA1 levels and the PLA2 receptor antibody titers, and how many people achieved a rheumatologic remission. We'll come back to that. Here's the demographics. Kind of a standard study for IgA. Patients were in their mid-40s. There was a male-female ratio of around one-third, so predominantly were female. The Asian and Caucasian ratio was roughly 50-50. Time to diagnosis was roughly 2.1 years. ACE-ARB was almost uniform, 86% in the 80 mg dose, 100% in the 240 mg. Protein in the study was around 1.3 g in the 80 mg and 1.2 g in the 240 mg. If you'll look, there are the galactose-deficient IgA1 levels. So 9,068 nanograms per mL versus 7,251 substantial levels of Gd-IgA1. About half the patients had either moderate to severe hematuria at the time of enrollment. As I like to say, here's the money slide. This is what happened with urinary protein changes over time. You can see that in as little as 12 weeks, there was approximately a 35% reduction, 40% reduction in proteinuria, and continued 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 that there was a dose-dependent outcome based on the level of proteinuria. What we always tell our fellows, if you do anything to get that proteinuria down, you benefit the patient. A 64% drop is substantial. It also should be beared and reminded to the audience that a full two-thirds of these people achieved the target level of 500 mg of protein or less. It is not just a 64% drop from 5,000 to 2,000. It was the target level of proteinuria that affects the outcome long-term. This is something that Rich and Brad and I talk 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, truthfully. If you then look and ask about what happens with the Gd-IgA1 levels, again, within 12 weeks, you see roughly a 57% drop in Gd-IgA1, further falling down to a nadir level of 77%. That value is precisely the same for the 240 dose. There was no difference in Gd-IgA1 reduction between the 80 and the 240. If you then ask, what was the outcome with the hematuria? There is a lot of controversy about hematuria. A lot of people have different opinions about this. You can see at the hematuria at 12 weeks, about half the patients had resolution of their hematuria. At that time of that resolution, about 15% of the patients had achieved a complete remission, which is defined as less than 500 mg 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 48 weeks, a full 53% of the patients had achieved a complete response. If you then look at the moving on to the PLA2R positive membranous patient, here is the demographics, a little bit older population, not 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. ACE-ARB was 100% in this small cohort of 10 patients, and SGLT2 was seen about in a third. Once again, this is the effect of the Povatacicept on proteinuria. 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 proteinuria, 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 membranous patients over the 48 weeks. It was a - 0.3 mL per minute. Now, lastly, if you look at the anti-PLA2R titers, again, you see a significant drop by week 12. You're going down to a further drop of 83%. If you ask yourself what percentage of patients achieved an immunologic remission, which they define as less than 14 international units of PLA2R 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? 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 mg for 24 hours, with a full 100% achieving a level of partial response. If you then look at how well the drug was tolerated, most of the AEs were mild in severity. There were really no SAEs that were directly attributed to Povatacicept. No safety concerns with laboratory parameters and no meaningful clinical trends. Now, there was one patient in the 80 group that had a drop in their, I'm sorry, into their IgGs of less than 300. And there's a little bit of difference on that. It's in the case the audience is curious, that 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, Povatacicept at 80 mg given once a month subcutaneously had remarkable effects. Proteinuria declined by 64% within week 48. GFR was stable throughout week 48. Gd-IgA1 levels dropped by 57% within week 12 and 77% by week 48. Hematuria was resolved within 24 weeks in 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, PLA2R antibodies, and a stabilization of GFR. The drug was generally well tolerated. As Reshma indicated, the RAINIER trial 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. Thanks a lot. Love to hear some questions from you. We will next go to Rich, please, if you can. Sure. Dr. Lafayette, why don't you come up and then we'll do questions together, Jim. Absolutely. All right. Sounds great. Again, good evening. Rich Lafayette from Stanford. Great to see most of you again. 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. Yeah, there you go. Again, it's great to be with you. I just have this long-standing interest in glomerular disease and autoimmune disease and thinking about moving forward to actually treating and stalling 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? 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 an 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. Better yet, in this study, the kidney function is indeed completely stable. 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. 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. As mentioned, the RAINIER is the pivotal trial for Povatacicept, 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. If the GFR changes anything approaching the perfect stability of the RUBY-3, then that's going to be a well-overpowered study. It is super cool. This phase three 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. As you heard, there is an increasing number of patients who will be on SGLT2 inhibitors as well. They can have a urine protein-to-creatinine ratio also to predict that greater than 1 gram per day or greater than 0.75 grams per gram. As you know, the primary endpoint is the nine-month proteinuria, which looks like it is predicted to do very well, and the confirmatory criteria will be the two-year change in GFR slope. We will look at other biomarkers. We will look at what happens in galactose-deficient IgA1. We'll look at the hematuria response. We'll look at the change in GFR every way we can measure it by two years. 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. That's the study design. What's wonderful about it, of these 600 patients who are in the trial, they were offered a two-to-one randomization. We went globally to know the centers who could recruit IgA 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. Again, super excited, and the phase two data really predicts great things here. 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. Thank you. Yeah, I know. I'm going to fall off the stage. That'd be bad. I'll help you. Yeah. Yeah, I'm a klutz. It's okay. Hi, everyone. It's a pleasure to be here. My name is Brad Rovin. I'm the Division Director of Nephrology at The Ohio State University. Just to be clear, I have a huge interest, as Jim and Rich, in immune-mediated glomerular diseases, and I also write guidelines. I guess I'm going to freestyle this a little bit. This is sort of the money slide, if you will, as Jim puts it, of the new KDIGO guidelines, but let's just talk about where we've evolved from. For my entire career as a nephrologist until about three or four 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. For those of us, I think in referral centers, which three of us are, that was not what we're seeing. Most of the time, patients came to us, and yes, they were seen in the community for a while, but they had impaired GFR. Lots of times, they came in with severely impaired GFR, and there was nothing left to do. It did not seem to be that much of a benign disease. The RADAR trial came along, which is really a registry from the United Kingdom, 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. Lots of other studies came out, including ones in the United States, Germany, and Sweden, confirming these data. One of the new things that the KDIGO guidelines are—and do you all know what KDIGO means? Kidney Disease Improving Global Outcomes. These are our kidney guidelines. Every society has their own guidelines. Anyway, the bottom line is that we now realize that this is not a benign disease, and we need to be much more vigilant. 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. Of course, we use proteinuria, as Rich and Jim said, as 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. The first thing we did in the KDIGO guideline was substantially lower the goal of where we wanted proteinuria to be. Instead of less than a gram per day, we wanted the proteinuria to be as low as it can go. Sort of for sure, less than 500 mg, but even better if we can do it. That is 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? You have heard the four-hit hypothesis. It is a reasonable start. It is probably not the right answer. There is 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. 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 do not take a really long time to where we see end-stage kidney disease?" That is where we got the accelerated approval format based on proteinuria with a follow-up of glomerular filtration rate or kidney function. 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. Now, for the first time, we have drugs that intervene immunologically besides glucocorticoids. I am not here to bad-mouth glucocorticoids, but why not? But I treat a lot of young folks with lupus and lupus nephritis, and no one likes steroids. That is not true. One of my patients loves it. She keeps asking me for steroids. Anyway, most people do not like it because of all the acute side effects, and they do not even know what they are getting into with the chronic damage that it causes. We wanted something that would be reasonable and something that would be attacking a precise part of the immune system. 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. When we redesigned the KDIGO guidelines, we realized that we now have several drugs that were coming down the pike, and we only did the guidelines up to what was approved, okay? We know we're behind, and we're going to fix it, and we know that some of the BAFF-APRILs are going to get approved shortly, and this will hopefully go up for PDUFA date very soon or file for it. We will revise these as much real-time as possible. The goal of the guidelines of IgAN treatment has become to 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 did not even get rid of galactose-deficient IgA at that point. Clearly, the companies that were going for bafinapril, which of course is hitting the B- cell, were taking a risk because there was already a precedent that this might not work. Instead of not working, it was, as you see, spectacular. That is the only word I can use to describe it. Just for full disclosure, I do not do consulting with Vertex, okay? I was not part of this trial. I saw the data today when Jim presented it, and I was next to my junior faculty member, and I said, "What the hell is this? This is unbelievable." I think that should be your reaction because, as Jim has emphasized and as Rich has emphasized, we do not see many therapies which prevent the decline in GFR, okay? That's unprecedented. These declines in proteinuria are also unprecedented. 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 are B-cell-mediated. 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. The guidelines are broken up into two 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. We realized with the armamentarium of new drugs, we had the ability to treat both the chronic kidney disease and now the immunologic disease in parallel. 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. That's one side of the diagram. You can think about the drugs that are doing that. I'll just name them, and I don't consider them competitor drugs, so I don't feel bad about naming them, but the Atrasentan 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. We say to start simultaneously the initiation of a modulating therapy, a disease-modifying therapy. What are the current disease-modifying therapies that are approved for IgA nephropathy? Nothing. I mean, 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 currently our only disease-modifying therapy. I do not want to compare drugs or anything, but this will fit into the disease-modifying therapy window very nicely. When we get questions, we can talk about where we think this is going to fit in the hierarchy of the paradigm. I am sure you guys are curious as to our thoughts on this. 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-mediated. Throw them on an ACE 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. 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. That's why this algorithm was started. You can see now maybe how this is going to be modified with new drugs as they become approved. The KDIGO guidelines only talk about drugs that have been approved and for which we have evidence. 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. 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 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. 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. Is this sufficient? Can I stop here? Oh, he wants me to stop. Okay. Thank you. Thank you Thank you for stopping. Thank you. To all three of you, thank you. Dr. Lafayette and Dr. Tumlin, we have about 30 minutes for your questions now. We'll start in the room. We have a few online. Anybody? Can we get a mic right here, please? Hi, Carter Gould, Cantor Fitzgerald. Thank you for hosting this, Vertex. This was very helpful. Nice weekend. Maybe for the doctors, maybe just following on the last line of conversation around some of the inertia in the community, how important is showing stable eGFR, even an improvement in eGFR, in really disrupting that inertia in the community and sort of waking up the field? Let me take a quick stab at that. Great question. Most of us, all three of us here, trained on what is broadly called the Brenner hypothesis. Barry Brenner, famous division director at the Beth Israel Brigham, sorry. He had this postulate that if your GFR fell below 65, you were done, and that there were compensatory mechanisms within the kidney that led to an inexorable decline toward dialysis irrespective of what you did. That dogma persisted for 40 years and is just patently untrue. To your point, the question you're asking is, and I think this is worth pointing out, there's been almost a philosophical change among nephrologists in the last five 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 five years ago, if you can flatten that curve, a person can do pretty well at 25 mL of clearance. 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. They say, "I'm sorry, ma'am. There's nothing that can be done for you," and prepare her for dialysis. This opens the door to flat GFRs and a completely different paradigm. Yeah. 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. That is why the guidelines are so strong. Those are the parts of getting the goal that is going to be the first lesson. I do think we can get that out there relatively quickly. I want to add just one 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 budesonide, 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 that, three times what was seen even in the membranous group and even less so among this. That is why Brad took the time to say, "We just don't see this." It truly is. The rest of the three of us have been trying to figure out why this has been going on. We don't know. I have some thoughts, but I'll share with you later. It's fascinating from a biologic standpoint as well. 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 pike faster than we've ever seen in nephrology. These are drugs that are basically foreign to most nephrologists. It's just not in IgA. The same thing is happening in lupus and to a lesser extent in some of the other diseases. We, as a community, have developed—we're all part of a society called the International Society of Glomerular Diseases. It's fairly newly formed. 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. We will have special expertise in these kinds of diseases. We do not want to impinge or take patients away from the nephrologist out in the real world. 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 one 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. We are 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. With that, we have lots of qualifying criteria to get these things up, running, and certified. 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. Agreed. It's hard for the general nephrologist who spends 80% of their time on dialysis to actually make the conversion and keep up with the literature. We think this is a huge step forward for the care of our patients. We are very excited about that. I am absolutely optimistic, and I'm not an optimistic guy, if you knew me. No, he's not. I am absolutely optimistic that we are going to solve the problem that you said very quickly. Adam? Thank you. I really appreciate it. This is Adam on for Jess, JP Morgan. Just a few from me. What's the best way to think about the placebo response that we might expect in the RAINIER study? If I ask another one, for the RUBY-3, can you speak on the circulating immunoglobulin data as of this latest cut? Was it similar to what we saw before? Thank you. Let's flip that into two questions. Let me ask Dr. Lafayette to tackle RAINIER. And then I'll ask you, Dr. Tumlin, to tackle RUBY-3. Dr. Lafayette? Yeah. I think great pains have been taken for RAINIER to really get a stable population. Again, the criteria and the site selection is one 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. You still, even though I would expect a single-digit proteinuria change in the placebo patients, have to build in your risk analysis for as high as 10% or 15%. This proteinuria response that Pove's been showing is so spectacular that it should do well. You always build in the idea that there's maybe that same placebo part response to the active therapy group as well. I don't think there's any significant likelihood, especially with the way that the study's powered, that a slightly more robust placebo response 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. Right. Dr. Tumlin. Yeah. That's a question we've gotten a lot. The protocol, because when the drug first came out, remember that there was a context that a similar but not the same drug called Atacicept had a signal of infection in a lupus study that was done. Appropriately, everybody was concerned about over-immunosuppression with this new class of drugs as you're feeling your way around it. They did a rather rigorous endpoint so that if your IgG levels drop below 300, you only have a single episode of that. 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. Just to give you an idea, the recovery rate of that IgG was very rapid. This was at the 80 mg dose. At the higher doses, there were more incidents of it, but in a way, that's kind of moot because we're not going to the 240 dose in IgA. Moreover, when you compare that to some of the other previous studies, Atacicept, they had to have two sequential levels of IgG below 300 before they held the drug. It is a matter of rigor and where they were in the development of the drug. Sadia? Hi, Sadia Rahman on behalf of Mohit at Wells Fargo. Thanks for taking the question. I wanted to get your thoughts on the eGFR trending up to + 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? Even if the agents ultimately do look similar in the controlled trials out to two years, how do you expect Pove could differentiate given increased potency maybe further out or on other endpoints? Why do not we split that into two questions? Dr. Tumlin, maybe I could ask you to comment on the plus 3.2, which has caught a lot of attention. Then maybe Dr. Lafayette and Dr. Rovin, maybe you want to comment a little bit on how do you see these drugs shaking out? It is a really great question. I sort of alluded to the fact that the three of us have been trying to, "What? How does this happen?" Right? There are a lot of things to remember. A lot of things are speculation that no one knows the answer to. Let us make sure that is really clear. We do not, I do not know why this GFR stabilized in comparison to budesonide, where you saw a 6 mL per minute year drop over time. What could it be? It's important to remember that one of the functions of the mesangial cell within the glomerulus, these are myoepithelial cells. The body has the ability to increase and decrease the volume of the glomerulus or the glomerular surface area in real time. These are under the control of ANG2, aldosterone, norepinephrine, endothelin. All these vasoconstrictive hormones can vasoconstrict that. This is what I find attractive about this idea. This is a dynamic and rapid process. You see that GFR flattening within three months. That's not likely to be a hematologic event. We've thought about some other ideas. I think that's one answer. The main answer is we don't know, but it's super exciting. He meant hemodynamic effects. What did I say? Hematologic. Hematologic. Hemodynamic. Thank you. Just not to confuse. Dr. Lafayette, any comments on how you see the various agents being differentiated as you think about RAINIER? Yeah. I think we're going to have to watch for complete data sets. I think there's tremendous strength that we have five agents that are B-cell modulators that very effectively reduce galactose-deficient IgA. Each one of them is showing spectacular safety. Each one is showing a nice effect on proteinuria and hematuria. All are looking marvelous at stabilizing GFR. It makes it extraordinarily unlikely that this phase two data is a fluke and that will not get recreated in phase three. That's the first thing. I know you guys are poised and waiting to ask about BAFF plus APRIL versus APRIL alone. I'm not going to worry about the hazards of jumping in there. Again, with this Pove study, you're seeing beautiful, better reduction in proteinuria. To be fair, it's not placebo-controlled, and you know that in the audience. You're seeing this uptick in GFR. I would say that my colleague was right. It may well be a hematologic effect. By that I mean, a reduction of inflammation in the kidney may make those glomerular cells and tubular interstitial cells focus better. Dr. Rovin sees that all the time when we treat acute lupus nephritis. We see that when we treat other acute diseases. Even though he's right, we don't know because we haven't done the tests and the biopsy studies later will maybe reveal that. That will be very exciting. I think the BAFF- APRIL part is there is great biological rationale to think, again, BAFF and APRIL both control plasma cell tone and antibody production. BAFF by itself has been a very effective hormone to block in other immune diseases. It is very, very appealing to believe that with the safety that we're seeing, that that will accumulate greater benefit over time. Obviously, the devil's going to be in really being able to show you guys and the doctors and the patients that there is a differentiator. Again, when I've met with the others, the fact that this is a very tiny dose once a month, it gets down to patient preference, patient-reported outcomes. I think that's a really critical differentiator here. That certainly favors the development. I think those are issues. You guys know because many of us had conversations and Vertex knows that there's great power in Salesforce, advertising, patient and community relationships. If there is 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 one company than the other. That, again, is company management. That is an initial list and to head off further questions. Can I talk about mechanism? So you know And there is a question down here. Okay. You had asked something about mechanistic. You know, as Jim said, we have been thinking hard about this. Take a page a little bit out of lupus and lupus nephritis. We have been using Belimumab, which is a BAFF antagonist, for a long time. When we tested it in lupus nephritis, I was involved in that trial. One of the most amazing things I saw was that it preserved GFR. Now here's a B-cell drug, and it's a pure BAFF. There's no APRIL involvement here that's preserving GFR. I did a lot of reading about BAFF and what it can do. It has some effects on fibrosis. You would not expect that to occur very quickly in a setting that would be more long-term. If you go back really far to the initial animal experiments with taking away or creating animals whose B-cells do not make antibody but are still around and put them in a mouse that gets lupus in general, these mice do not 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. Excellent answer. Okay. 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. That's my current, and you understand this is my opinion. I don't have data for this. We are trying, we're struggling in a good way. It's a good struggle to figure out what's going on with this. It's clear. I don't think it's a fluke because all of these drugs are showing the same thing. This is not a phase two trial fluke, in my opinion. You wanted to know positioning? Or Or there's a question here. I think there's a question here, and we haven't heard it just yet. Let's see where we go. Hi, Ananda Ghosh from H.C. Wainright. Two questions on the trial and some regulatory aspects, and then one on commercial. Maybe the first one, how do the baseline characteristics and event rates of RAINIER compare with the RUBY-3? Then a quick follow-up in how do you look at the hard endpoints when you look at the current competitive landscape? How important are the getting it right with respect to the hard endpoints? How closely proteinuria reduction correlates with the improvement in hard endpoints from the historical trials? That is the second question. 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 penetrance. How exactly Vertex is thinking about it, especially given that IgAN is kind of a silent disease also. There is an issue with kind of identifying who are actually getting the disease. Three. Okay. Let's break that up into two questions. I'll come back and talk about how Vertex is thinking about commercializing. Let me break that apart from the first question, which was about twofold. How do you think about proteinuria and the GFR endpoint, and then proteinuria and the hard endpoints? Just so that everyone's 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 quote-unquote hard endpoint of time to dialysis, death, or transplantation can be decades. The FDA and other regulatory agencies around the globe have accepted that the slope of GFR is the acceptable final endpoint. What you're going to see in the RAINIER trial is proteinuria, and then the final endpoint is going to be the GFR slope. Rich, do you want to talk about how you see proteinuria to GFR and then GFR to hard endpoints? Yeah. First, let me just confirm that the design of RAINIER is a very, very similar population as that in RUBY-3. Again, it's not like we're trying to compare apples and oranges. It's apples and apples. Very, very similar populations. There's likely to be an even higher proportion of patients on SGLT2 inhibitors, where studies are showing consistently that these agents, and in RUBY-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. That's the first thing. The second about proteinuria is that, again, it is an accepted likely endpoint. That's why it's there for accelerated approval. One of the very, very important points is that it is a benefit to patients with IgA nephropathy to reduce proteinuria. It is very clear that reductions of greater than about 25%-30% will effectively predict benefits on GFR. Crucially, every drug that gets the same degree of proteinuria is not appearing to get the same benefit on that GFR preservation. That is what is so exciting here, that for, yes, even better proteinuria reduction, but if it were the same, the GFR stability of not slowing progression from, as Jim said, six to eight to having it, which is very nice, but going from six and eight to not progressing at all, it means instead of doubling your time to dialysis and saying, "I was going to go on six years, so thank you. I am going to go on 12," that is great. 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. Different agents, different mechanisms give us different relationships between proteinuria and GFR. 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 is saying. This is not a new concept. In the lecture set that I have, this goes all the way back to Jim Donadio's group at Rochester in 1997, the first author is Rayford. What's remarkable with that paper is the same as Heather Richie's paper from Toronto, which is the same from the RADAR data. Basically, if you're in a nephrotic range, you have about a 50%-60% chance of going on to dialysis within five years. How we missed this all this time is a whole nother discussion. To Rich's point, getting the protein down has a tremendous effect. What Reshma earlier mentioned, this administrative change is what really opened the door. Instead of going on to a slow disease that takes 10-15 years to see the GFR change, using the surrogate protein has become acceptable. On commercialization, maybe three 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 2025. 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. I expect that you can do the math there and the timelines for when this medicine will be approved. Second, this fits our approach for commercializing in specialty markets to a T. There's about 7,000-8,000 nephrologists in the U.S. The accelerated approval and the timelines I just provided is for the U.S., and then it'll be the two-year GFR endpoint for Europe. In the U.S., it's about 7,000-8,000 nephrologists. The vast, vast majority of patients with IgA nephropathy are seen at about 5,000 nephrologists or so. We expect that a Salesforce of about 150 people or so will serve this patient population. Of course, we have additional medicines coming, hopefully for AMKD, for 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. 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. 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 tell you, "Yes, please administer 2 mL in two different injections." They're going to ask for the smallest volume with the smallest needle and an auto injector. And for Povatacicept, you should expect an auto injector at home. It's 0.46 mL of dosing, and it's once monthly SubQ. Those studies to do human factors engineering, etc., those have also been completed and will be filed with the BLA that we were just talking about. Susie, I still see five minutes on the clock, so we can get a couple more questions in. We're good in the room? Any other questions? I wish we had one emailed in. Sure. Perhaps more for you, if you or for the physicians. Comment on how the data today increases your confidence in RAINIER for IgAN, anticipated accelerated approval timing, as well as for the pipeline beyond. Yeah. 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 is obviously high given how quickly it was enrolled. Because we used our voucher and we secured rolling review, the confidence is very high, as in certain, that there will be a six-month review expecting that the results will be supportive. Time going by is extremely helpful in that regard. With the other programs, time going by has a similar profile. For membranous, we are at that point where we are starting the pivotal trial, which means we now have the data. What Dr. Tumlin showed you was a subset of the full data set. You should expect that there will be more presentations at upcoming renal meetings for those data. 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. The fact that we were able to get that study enrolled and increase genotyping rates has been really great. ADPKD, slightly different stage. That one has just started phase two. I hope by this time next year, we'll have enrolled that trial and we'll have data to share. The fact is that we have completed phase one. The PK is very well behaved. The safety looks good, and that is very important for a molecule that's about to enter phase two. I think that's a good place to call it. Dr. Rovin, Dr. Lafayette, Dr. Tumlin, thank you so much. Thank you to the Z strategy teams from Vertex that are here and my colleagues, Miroslava Minkova and Kristin Hodous from IR. Thank you all. Appreciate it. Thank you.