We're going to get started. Thank you very much to everyone here in the room for finding us despite locked doors and escalators and challenging room locations. We really appreciate it. Obviously, a very, very exciting ASN meeting overall, and I think particularly for Vertex Pharmaceuticals. V ery, very happy that you all can be with us tonight for our kidney program updates at the American Society of Nephrology Kidney Week 2026. I do just want to go through the agenda briefly. Reshma will kick us off with some remarks about our R&D strategy and our programs, give a quick portfolio overview. Then I have the pleasure of introducing to many of you, I think for the first time, Dr. Akinlolu Ojo from the University of Kansas, who will discuss the recent AMPLIFIED data and our AMKD program with inaxaplin.
Then we'll hand it over to Dr. Richard Lafayette, whom you all know well, and he will discuss the data released this morning in the New England Journal of Medicine about povetacicept in IgAN. Then we'll have time for your questions. We'll try and keep it really punchy. We do have a hard stop right at 7:00 P.M. Again, thank you for joining us. Please note that we will be making forward-looking statements, and we ask you to consult all of our SEC filings to discuss the risk factors. With that, Reshma?
Thank you so much. Susie, I appreciate it. It is very surprising for me to see so many of you at an ASN. It is a real pleasure to see all of you here for the Vertex event. Believe it or not, when I was an actual practicing nephrologist and would come to ASN as a doctor, there were no real analyst meetings. There were no investors here. There were hardly any people here. T he field has come a long way. Interestingly enough, while Vertex started as a CF company, we are quite the renal company now. This slide talks to you about, on the left side, our strategy, which has not changed. It's a disease-first strategy. We are not about platforms. We are not about franchises.
It simply turns out to be the case that when you think about unmet need, causal human biology, the ability to have validated targets, usually genetic, but pharmacologic is just fine, biomarkers that translate and efficient regulatory and development pathways in a way where we can do our work with a low SG&A spend. It turns out that there are few renal diseases that meet every mark. What you see there are the four renal diseases that are in mid and late-stage development for us. APOL1-mediated kidney disease, Dr. Ojo will talk about that. IgAN, Dr. Lafayette will talk about that one. Membranous is another povetacicept indication. You'll remember when we did the Alpine acquisition, we talked about povetacicept as a pipeline and a product. While we're not going to touch on it today, watch this space for ADPKD. We are excited about a molecule.
It's a small molecule that properly folds a misfolded protein. If that sounds like something you've heard from Vertex before, you have. That's how our CF medicines work. There are some reasons for us to be optimistic there. When you think about these diseases, they are actually rare diseases, many of them in the U.S. or in Europe, but they are big rare diseases. We're talking about 100,000 - 300,000. When you think about IgAN, it's well over 1 million because it's a particularly prevalent disease in Asia. You'll remember for Asia, we have partnerships with Zai Lab. They will be marketing for us in China and other regions. We have another partnership with Ono, who will be bringing this medicine to Japan and other regions. It's an interesting area of rare, but big, rare diseases. The other interesting point to note is the $13 billion.
Let's just round and think about CF as a $10 billion franchise. Many people ask me what I think could be another CF-like franchise, and there are a few, but renal is amongst them. I think when you put these diseases together, the four that I've mentioned, and remember, the ADPKD disease that I'm mentioning to you is only 10% of the overall ADPKD. ADPKD is about 350,000 people worldwide. Our first approach will be appropriate for about 35,000. Just in those four diseases, I see it being about a $10 billion franchise. This is renal in a box, and if you wanted to have a quick reference guide, this is the one to look for. There are some B-cell-driven diseases. That's where povetacicept plays for IgAN and membranous.
Not on the side because it's not in renal, but we also have a trial for povetacicept in myasthenia gravis because that is another one of these very B-cell-mediated diseases. APOL1-mediated kidney disease in the middle. The phase III program is AMPLITUDE, but you would never know that because people are so interested in AMPLIFIED, so Dr. Ojo is going to cover both for you today. The ADPKD program is in phase II proof of concept. I want to just do one slide before I turn over the stage to the stars of the show, Dr. Ojo and Dr. Lafayette. These are all of the results, the latest available from the various APRIL/BAFFs. They're not meant to be there for comparison because these were not head-to-head studies. It's meant as a compilation of information, so everything is in one place at one time.
The thing I want to focus on is povetacicept in the middle, and you'll hear a lot about it. We are excited about the fact that the PDUFA date is right around the corner, November 30th. All of the things that you would expect to be going on between the company and FDA are going on, and we are really excited about bringing povetacicept as our first renal medicine. The other thing I want to point out is sort of towards the top of the slide and towards the bottom of the slide. Pre-clinically, povetacicept was specifically engineered to have some characteristics. We wanted those characteristics so that we could get broad tissue penetration, really good binding affinity, as well as potency, and they manifest themselves in the bottom of the slide. This is the ability to have a once-monthly dose with a small volume in an auto-injector.
These are not separate, that sort of, kind of happened to come together by good luck. This is how we engineered this medicine to behave. With that, I am going to turn it over to Dr. Ojo. It is a real pleasure to introduce him. He is an MD PhD scientist. He has worked in multiple disease areas, but you will hear from him why he has a passion for AMKD. We know Dr. Ojo because he sits on the steering committee. The good news on AMPLITUDE, the phase III study, it is fully enrolled. It did take a long time, as we predicted, but it is fully enrolled. The other piece of good news is we are fully on track to be able to share the interim analysis results early next year. Dr. Ojo?
Thank you very much, Reshma. Good evening to all of you. I am a practicing nephrologist, and I also do research, and the focus of my clinical work, as well as my research programs, has been on kidney disease in Black populations for the last three decades. What is represented to you on this slide is the summary of the result of the AMPLIFIED study. The AMPLIFIED study is a study of individuals who have AMKD, but were not studied in the AMPLITUDE trial for a number of very cogent reasons. There are three points to note on these summary results. One is that the two cohorts there, that is Cohort 1, individuals who have very modest amount of excess urinary protein excretion, low level of proteinuria, as well as Cohort 2, individuals who have moderate amount of proteinuria, but also have evidence of diabetic kidney disease or diabetic nephropathy.
Those two cohorts represent the largest fraction of individuals with chronic kidney disease in the United States and in the rest of the world. In the United States alone, these two cohorts represent individuals that numbers in several hundred thousand. The second thing to note is that the participants in the AMPLIFIED study are already on the most contemporary and the most comprehensive background treatment for both chronic kidney disease and diabetic nephropathy were relevant, that is in Cohort 2. T hese are individuals who, before entering the trial, are getting the best treatment for their conditions that we have. The third point to note on this result is the reduction in urinary protein excretion in both cohorts. In both cohorts, the reduction in urinary protein excretion is substantial and clinically meaningful.
You will note that in Cohort 2, the reduction in urinary protein excretion is between 17% and 25%, and the confidence interval crosses one. That does not detract from the significance of these findings. Because if you go back and look at registration trials for RAS inhibition therapy, the RENAAL study that led to the approval of losartan, for example, at three months after randomization, the reduction in urinary protein excretion was 25%, exactly what you see in the Cohort 2 here. At the end of four years of follow-up, reduction in proteinuria continues, and that translated into a 44% reduction in renal outcome and a 30% reduction in cardiovascular outcome.
The numbers that you see here, even though the study population, the study sample is small, is demonstrative of significant clinical benefit on the long run when this study is followed for a longer period of time or if a larger study is conducted in this population. The AMPLITUDE study is a phase III study of inaxaplin in individuals with AMKD. This clinical trial is monumental for a number of reasons, including the fact that it is the first phase III study of a treatment, a disease-modifying treatment in a population that had not had any disease-modifying therapy ever since we have known about the excess burden of kidney disease in people of African ancestry.
As you know, people of African ancestry, they carry a fourfold excess risk of kidney failure compared to any other racial ethnic group, and for the last 50 years, we have not found a treatment that will address their core problem. We have had a variety of ameliorative therapies that are non-specific and not targeted to the underlying mechanism of disease. That is why AMPLITUDE is different. As Reshma said, this study is now fully enrolled. It included 66 patients who were carried over from phase II-B study of inaxaplin, along with 456 study individuals who are newly enrolled into phase III for a total of 522. As Reshma pointed out, the interim analysis is forthcoming beginning of next year.
What does AMPLIFIED study means for someone like myself who is a clinician who see these patients and somebody who is interested and has worked in this area for a very long time? In fact, the reason why I went into nephrology was to be able to study kidney disease in Blacks. T hat's a separate story, and I can share that with you. What this represents for me is that what we're looking at in AMPLIFIED is a study that is showing a potential for beneficial clinical outcomes based on urinary protein excretion reduction in a population whose therapeutic need has never been met before. I think Reshma showed the number of individuals who could benefit, who have AMKD in the $250,000 range. I disagree with that estimate. My own estimate will put that number between 600,000 and 700,000 people in the United States alone.
If you recall, 7 million Black patients in the U.S. have chronic kidney disease. The prevalence of two APOL1 is 13% in Blacks. Individuals who have chronic kidney disease who are Black, the prevalence of APOL1 two risk allele is about 20%. If you carry that forward and you say maybe only 70% of those patients have their kidney disease due to AMKD, you will end up on a number between 600,000 and 700,000. That is a conservative estimate in my judgment and in my experience. As I pointed out, AMPLIFIED represents a significant, meaningful reduction in proteinuria. You can leave the statistics aside, and it is important to note that in the phase II-B study, when the study ended at 12 weeks, those individuals continued to have a monotonic reduction in proteinuria. The proteinuria did not stop. It was still going down.
If you are to carry AMPLIFIED forward, that is probably what you will see. In fact, confident that is what you will see in this type of situation. The fact that the reduction in proteinuria in Cohort 2 was not as large as Cohort 1, it is because those individuals have two diseases. They have diabetic nephropathy, and they have AMKD. Inaxaplin does not treat diabetic nephropathy, but it does treat AMKD. The results of AMPLIFIED are compelling, and whether you call individuals with AMKD, FSGS, and hypertensive nephrosclerosis, I think we should not get hung up on that. I think we should focus on the underlying driver of disease, which is the presence of two allelic variants that are pathogenic in causing this particular disease condition.
I am very confident that as the results of AMPLITUDE come along early next year, what we are going to see is a continuous evidence of improvement in clinical outcome based on what we know today. That is true because we know that AMPLIFIED demonstrates that even in population that is not as homogenous as the AMPLITUDE study, which is what AMPLIFIED is. It is not a homogenous population, and that is the majority of patients with chronic kidney disease. They are not a homogenous group. There is a demonstrable benefit, as shown by reduction in proteinuria, which is a strong marker of improvement in renal outcome. At this point, I will turn it over to Dr. Lafayette.
Thank you, Dr. Ojo. I am going to ask you guys to hold your questions, and we will get through IgAN, and then we are all available to you. Dr. Lafayette.
Pleasure. It is wonderful to see you again. I think Dean Ojo’s presentation gives us that full sense of promise where a small proof of concept, but through blood, sweat, and tears phase II program is showing amazing promise. This is where we were last year when we talked about the phase II results of povetacicept, and then this year, we are able to sort of fulfill that with the phase III interim analysis. I am going to go ahead and go through the presentation that we are going to give tomorrow. Again, I promise it should be under eight minutes. Otherwise, I will get pulled off the stage tomorrow. We will see how this is going to go. Someone please feel free-
I got you.
To timing.
I am ready.
Thank you. As you know, RAINIER is our ongoing global phase III randomized, double-blind, placebo-controlled trial, which is evaluating povetacicept in adults with biopsy-proven IgA nephropathy, who in the screening period have proven to be at high risk by having substantial proteinuria, a urine protein-creatinine ratio greater than 0.75 grams per gram, eGFR greater than 30 mils per minute. They are very well treated patients who are on maximum-dose RAS inhibitors and allowed to have standard of care with SGLT2 inhibitors, MRAs, and even endothelin blockers if it was available and stable at baseline. They get randomized 2 : 1 to povetacicept every four weeks in a small injection versus placebo, and every four weeks in a small injection. As you well know, the interim analysis was planned.
At 36 weeks, we are expected to see a robust proteinuria reduction and wanted to look at other biomarkers, including the impact on galactose-deficient IgA1, an important marker of disease response, looking at hematuria, and of course, looking at safety and tolerability. This is the population that we have in this interim analysis. It reflects very well with the overall study population and has been consistent with the studies you have been seeing presented here and over the last five years. This global population is representative of high-risk patients who are going to have progressive kidney failure over the short term. These are 40-year-old, slightly predominantly men, predominantly Asians, but globally represented, who have substantial proteinuria despite their excellent baseline therapy at around 1.5 grams per gram as a mean value. Their eGFR is depressed from normal, running around 60 - 70 mils per minute.
There is modest prior treatments with immunosuppression, but it is well-balanced between the groups. Here you can see that hematuria was defined only on dipstick by moderate or large amount, not including small. We have half the patients who have substantial hematuria at baseline. Again, by protocol, all patients had to be on maximally tolerated RAS inhibition, and they are. There is a sizable number, two-thirds, who are on stable SGLT2 inhibitors at baseline, and significant numbers of patients on MRAs, and even a few on endothelin blockers. Again, very well-balanced at baseline. Again, here is the money shot is the drug works beautifully and as predicted from the phase II program, right there in the exact same region where at this endpoint at week 36, we see a very robust 52% reduction in proteinuria. Again, no doubt, statistically significant and highly clinically meaningful with no change.
On the right-hand side, you can see that time course, that there is rapid separation between placebo and the povetacicept group, such that there is already clinically meaningful reduction in the early weeks. Difference here is this is urine protein-to-creatinine ratio, which is actually more noisy and can fluctuate, but yet you are seeing this very clear progressive reduction in proteinuria out to about five months, which is stable to the 36-week period. Again, in subgroup analysis, we really cannot define a subgroup that does not respond beautifully to this intervention. With that, again, 50% reduction in proteinuria seen regardless of age, race, of baseline protein, baseline kidney function, hematuria, or use of SGLT2 inhibitors. Again, so far, looks like every patient group does wonderfully, and this is driven by very consistent rapid control of galactose-deficient IgA1, the putative antibody, and antigen that contributes to IgA nephropathy.
You can see this very robust reduction by nearly 80% at the end of this interim analysis period. Associated with that is a very early progressive accrual of patients whose cardinal feature of IgA nephropathy is also resolving over time. By 20 weeks, again, you see more than 80% of patients having resolution of their hematuria associated with their therapy. Even more so, we have our KDIGO guidelines telling us our target must include not only excellent reduction in proteinuria, but getting to a target of less than 0.5 grams per day. Here, our KDIGO aligned goal of the 24-hour urine UPCR, less than 0.5 grams per gram, occurred in nearly half of the patients. This is group, again, with high-grade proteinuria at baseline, and even better, coming to a completely normal proteinuria in a much larger fraction.
Nearly one in six patients normalized their proteinuria on this study within this interim analysis at just 36 weeks. Again, safety, just like in phase II and with this class, is just beautiful. Please remember it's a 2:1 randomization, so look at the percentages, not the numbers. You can see that overall adverse events are percentage-wise lower. Otherwise, if you look all up and down at any AE infections-related events, other than injection site reactions, which are mild, did not cause patients to leave the study. Overall, low in number, only one in seven patients, having meaningful injection site reactions that led to them complaining and it being listed as an AE. Of course, no deaths. During these times, as in phase II, this is tolerated just the same as placebo.
Here you have the result that povetacicept treatment leads to rapid, sustained, clinically meaningful reductions across multiple outcome measures. We have the beautiful triad of reducing proteinuria, our most direct predictor of eGFR benefit, as well as hematuria, galactose-deficient IgA1. It's a very remarkable reduction of proteinuria, 52% reduction at just 36 weeks. We're going to hope that this is progressive, but that's already something that's going to predict amazing outcomes when we get to the end of the study and look at eGFR. Again, the benefit's consistent across all of our subgroups. Again, importantly, including the North American subgroup, and that there's high numbers of patients who are getting even to clinically meaningful targets of proteinuria reduction.
Again, a very fabulous, sustained, safe reduction in galactose-deficient IgA1, hematuria resolution in the vast majority of treated patients, and a safety marker that looks identical to placebo thus far. Again, remember povetacicept was dosed as Q4 week sub-Q dosing in a prefilled syringe. It will be available in open label extension already in an auto-injector, so at a very low volume, so also in a very convenient package. The take home is this is transformational efficacy, something we hadn't seen in previous classes, that has disease-modifying characteristics to it for sure, and a beautiful safety patient-centered viewpoint. Thanks for looking at that.
Again, hopefully, you've already dived into the New England Journal of Medicine, because I know that's your homework and due diligence that you need to do. You can come back for the presentation tomorrow, but other than the Q&A, it won't be meaningfully different. Thanks for your attention.
Dr. Lafayette, thank you. I will invite you to join on stage.
Yes, thank you.
We will make sure that. We have some mics in the back.
Yep. I have one here.
Susie, are we ready to take questions?
I will start just briefly with one we got online, but also wanted to mention, we also have Duncan McKechnie here, who is our Chief Commercial Officer, if you have commercial questions as well. Reshma, just a quick one from Terrence Flynn at Morgan Stanley. Can you comment on confidence for povetacicept in FDA approval in IgAN, and that the label will not have any different monitoring requirements relative to atacicept or Vera?
I am confident.
Great.
Hi. Ananda Ghosh from H.C. Wainwright. Question for Dr. Ojo. Given the PARASOL recommendation a couple of weeks back on the eGFR duty, how important is stat sig for the one-year endpoint? The next question is maybe for the company. How many patients are we expecting to be reported at the 12-month endpoint for the eGFR?
Yep. The first question is about 12-month endpoint?
Yeah. How important do you think is a stat sig at one-year eGFR endpoint, given that the PARASOL body alluded to that the one-year eGFR is generally noisy, which also most of the KOLs also agree. Would you like to see a stat sig at the one-year endpoint for AMPLITUDE? Or if there is a directionality, you will be happy, and if there is a considerable proteinuria reduction along with it?
The one-year endpoint is not noisy for a disease condition that has a more rapid rate of progression. Individuals with AMKD typically have a rate of loss of eGFR of between 5 and 8 mils per minute per year. If you follow those people for one year, there is no noise in the benefit that you see if there is a true benefit. That is one. Secondly, if you look at all the previous studies that have looked at proteinuria earlier than 12 months, the 12-month result always correlates in terms of eGFR reduction with the degree of reduction in proteinuria. I have a high degree of confidence in the 12-month eGFR endpoint in this type of population.
In a population with chronic kidney disease that is indolent and progresses at a rate of maybe 2 or 3 mils per minute per year, yes, you have a lot of variability, and lab error alone can give you a variation that may approach that number, but not at 5, 6, 8, or 10 mils per minute rate of loss of eGFR.
I guess one for the physicians on povetacicept. Can you talk about how you see the B-cell modulators being used longer-term in the real world as it relates to drug holidays? Then maybe for Duncan, how long should we expect it to take to establish reimbursement?
Okay. Why don't we go to Dr. Lafayette first, then we'll come back to Duncan.
Yeah, I think data is very incomplete for off-drug activity. We've had very limited release for atacicept, where it did show a signal that eGFR could decline relatively rapidly off the drug, and then others have only shown stability. We know that the immune situation tends to return to baseline within about four to six weeks after discontinuation of multiple B-cell modifiers. I think we have to have some balance. We are planning right now, of course, to look at long-term extensions, see continuous dosing for up to five years. I think that there's a lot of backroom discussions about if patients want to get pregnant, if patients just are doing very well and want to come off the medication and see what happens. That's almost certainly going to be reasonable to try.
R ight now, I think we have to go with the biology and say that we're planning to see these drugs as very long-term commitments, and that attempts to really figure out drug-free periods of time or moving to other more conservative therapies are going to have to be very carefully monitored and figured out over the near term. W e will see longer and longer extension, and I do hope we will learn more about off-drug exposure.
Duncan, do you want to make a comment on what you're thinking about for access and reimbursement?
Yeah, sure. T hat was loud. A quick bit of framing. Firstly, about 70% of the IgAN patients are commercial patients. O ur focus really is the commercial business, the three PBMs there. We have been working with them, and engaging with them since July 2025. W e've been talking to them about IgAN and povetacicept for a significant period of time. We have a high sense of urgency in order to secure coverage. I would say that probably first half 2027 is when you could expect to hear some very specific announcements about coverage. In the meantime, it's likely that there will be many patients covered on a case-by-case basis, and like the other organizations in this space, we are putting in place a bridge program so patients can have access to povetacicept ahead of formal coverage.
Thank you so much. Other questions?
Andy Chen, Wolfe Research. Maybe a question for the two doctors. Now that we have complement inhibitors approved and we don't have a lot of data on complement inhibitors, and we have far more on in BAFF/ APRIL, but absent more data, how are you going to use complement inhibitors versus BAFF/ APRIL?
Richard, do you want to take that one?
Yeah. I think complement is really an important feature of IgA nephropathy and a lot of complement-mediated kidney diseases, which ultimately may include APOL1 diseases as well. I really think that there's lots of ways to control complement. Again, the only mature program is iptacopan, where we've seen GFR data that's stunning and wonderful, but only half as good as what we've seen across B-cell modulators. Given that, it may be that the best way to control complement activation is to control immune complexes first. You get rapid control, as you see, of hematuria, of proteinuria, of those immune complexes. If we want to have a complement-reducing therapy, it may be a B-cell modulator as our top choice.
Again, I think we have to offer patients options, and complement agents can be offered in multiple different ways: as pills or as intermittent infusion so far for the approved drugs. It can be an option. Again, if we want the highest efficacy, and still want to control complement, we can achieve that with B-cell modulators.
Dr. Ojo, anything to add?
No, nothing to add on that.
Hi. I am for software director at Goldman Sachs. Two questions for us. Maybe one for the Vertex team. Just if there is anything you can share about the powering for the interim, for inaxaplin in early next year. For the KOLs, just speak to the importance of the small volume auto-injector and how that could impact uptake, and if you think patients who are on an agent given via PFS would want to switch over.
Sounds good. On inaxaplin and the AMPLITUDE phase III interim analysis for early next year, we haven't shared the powering or the number. Maybe what I could say, I won't give you the number or the powering, but maybe a roundabout way to say it is you could expect a couple of hundred people in the interim analysis set. You heard today the overall number is a little north of 500. Maybe that's one way you can think about it. Dr. Lafayette and Dr. Ojo, do you have any comments to make about the biologic and its format and what that means?
A comment?
Go ahead.
A t least in terms of povetacicept, we have discussed this together quite a bit and been public about it, that the sense when you talk to patients, and again, this is something I often defer back to you who asked the question is, what do you think? Would you like a large volume injection frequently under your skin, or would you like a small volume injection under your skin, and would you like to have to pull the plunger, put the needle in yourself, or would you like a device that just does it for you without you even really having to look? I say it in that way because I always think you are going to answer, yeah, less frequent, smaller, without doing a lot of work is going to be preferable.
I know you got access to Vertex's patient survey, which supports other instruments that we have seen that really suggest that most patients feel the same. If offered a choice between frequent versus infrequent, they will like it infrequently, and small volume auto-injector will be quite preferred.
On that point, I will just make one note. I do not know if it has already happened or coming, but there is a poster presentation of patient preference at this ASN meeting. It already happened. Okay. If you want, I am sure Susie can get you that. I will make another plug. There is another study that just went online like two days ago on a non-peer-reviewed online publication, and what that one evaluates is the volume and viscosity of various ones of these APRILs and BAFFs, and you can peruse through that and look at the viscosity and volume and what that might mean. Susie, back to you.
Question from Brian Abrahams at RBC on inaxaplin. One for you, Reshma, "What is the go-forward plan for inaxaplin in diabetics?" For Dr. Ojo, I think you touched on this, but his question is, "How do you think the more modest proteinuria benefits will translate to meaningful reduction in the kidney function decline in that Cohort 2 population?"
Why don't I go first, and then I'll go to Dr. Ojo. The plan for the diabetic cohort, remember that's the phase II-B cohort, is to go talk to the FDA about what they want to see and what they need to see for inclusion in the label when we go to them with the AMPLITUDE phase III study. I'll have more to say about that next year. As you know, when you are trying to figure out what next, you need to go to the agency at a particular time point in the clinical development program. The best next time point for us to go to them is when we have AMPLITUDE phase III results, and we can ask them all of our questions about what they want to see and how they want to see this included in the label at that time.
More on it next year after AMPLITUDE. The point of the matter is we'll talk about type 2 diabetes once we get to that phase III population. Dr. Ojo, I think the question for you is how do you view the more modest proteinuria in AMPLIFIED and how that translates to GFR versus the AMPLITUDE population?
I'll start by saying that any amount of excess urinary protein excretion is bad for renal function. Proteinuria is a There's a vicious cycle that when you are excreting protein in the urine, it causes reduction in renal function, and further reduction in renal function causes so it's a vicious cycle. If you have a 20%, 25% reduction in proteinuria that is sustained over time, it is not conceivable, and there's no empirical evidence that that does not lead to improvement in rate of loss of renal function. That is why some of these other studies in IgAN you see approval based on proteinuria alone. As I mentioned, in the RENAAL trial, RENAAL is the losartan registration trial for type 2 diabetic nephropathy. At three months in 1,500 patients, the reduction in proteinuria was 25%.
When it got to two years, the reduction in proteinuria was 30%, and at four years, it was 45%. 45% that you are seeing in Cohort 1 here at 12 weeks in the AMPLIFIED. That 25% reduction at three months in the RENAAL study translated when those participants were followed to a 44% reduction in adverse renal outcome in the long run. You have to remember that proteinuria is not just a problem for the kidney alone. In fact, CKD is a small problem for the kidney, is a bigger problem for the heart. Anytime you have proteinuria or CKD, it is a precursor of aggressive cardiovascular disease.
When we are treating people with kidney disease to reduce proteinuria, we're not only aiming to preserve renal function, we're trying to prevent cardiovascular disease because majority of individuals who have chronic kidney disease will never live long to get to dialysis. They will die from cardiovascular disease. That is why you see 100,000 out of 37 million Americans who have CKD gets to dialysis every year. A lot more people than 100,000 with CKD die from their cardiovascular disease that has been, if you will, driven aggressively by the presence of CKD.
Great.
Can I do a follow-up?
Sorry, we'll let someone else do it. I apologize. Then this is our last question. In the back. Sorry?
Hi, one for the company. Maybe Duncan, if you can talk about the payer discussions you have had so far. Should we expect povetacicept to receive a parity access at launch, or is there a meaningful risk of a step therapy through an established APRIL pathway product? Maybe one for the doctors here. Based on looking across all the BAFF/APRIL inhibitors, do you see a clinically meaningful difference today in terms of the data you have seen so far? Or do you need to see more data like eGFR to conclude which drug is better? Thank you.
Maybe we go to Rich first, then we go to you, Duncan.
Sure.
Yeah. I'll reply that, as you said, across this class, it's really remarkable the wonderful proteinuria reduction that we've seen, the rapidity of that, the association with galactose-deficient IgA1 reduction, and improvement in hematuria. Numerically, this looks a tiny bit better. I can say yay, congratulations. I certainly am going to watch for what I'm sure will be meaningful GFR protection. W e're going to look to see how that compares. Again, predictably, it'll probably be near 100% protection of kidney function. Depending on how this high-risk group does progress, we'll see how the separation looks. I t looks really promising. It's a great agent. Comparing it to the others, it's a little premature, but all the signals look wonderful.
Duncan, a little bit on what you're expecting on payer.
Yeah. M aybe the first part of that, I think, was what we are hearing from nephrologists. I would say a little bit like Dr. Lafayette has said, incredibly positive reactions to povetacicept. I would say specifically, this is all about the product that is the easiest to use. T his idea that it is a one-monthly auto-injector, roughly two seconds to inject, low volume, low viscosity, that is incredibly important in this market. I n terms of the payers, the answer to the question is no, we are not expecting step edits through other APRIL/BAFF or other type products.
I know Susie said one last question, but there are two. We will just get them done. Let us do it.
Okay, thanks. This is Manoj from Jefferies. Just one on, so do you expect any meaningful switch when povetacicept gets onto the market? Do we expect any meaningful switch from the existing approved drugs? And also, how easy a patient already on a drug to switch from one drug and then get onto povetacicept? Just trying to understand.
Yep. The question is, do we expect switches? I think it can occur. I think it's a matter of mass volume. Let's say there's 150,000 people with IgA nephropathy. Let's say there's 1,000 people on one of the existing drugs. Take 2,000 people. There's 148,000 who are not on anything. It seems the more likely sources of patients are patients who are coming into the system and want to try a therapy. T here's nothing that obstructs a person who says, "Look, the only thing available was a once-weekly medicine," or, "Look, there was only a prefill syringe. I want an auto-injector," or, "My doctor prefers this." There's nothing that obstructs that. I think if you just look at the number of patients, there's maybe 1,000 on APRIL/BAFF, and there's 149,000 not on anything. I t seems more likely they would come from there.
Dr. Lafayette, I don't know if you have anything to add.
Yeah. I'll just agree. It will be technically, I think, easy to switch, unless there's some massive price differential or a technical company insurer problem. I think it'll be possible, and our patients are more and more proactive. I'm thinking of a patient of mine who's on sibeprenlimab, doing extremely well, and still every visit saying, " I wonder if I should go to an auto-injector instead." And we haven't made that jump, but just the fact that that's being thought of and patients know they have options, and if they do think it's more convenient, less painful, there'll be switches.
Now, Susie, if you want the last question. All right?
Okay. Just a follow-up on Brian's question, and anyone can answer. Given the moderate proteinuria patient population for the AMPLIFIED Cohort 1, what was the biggest takeaway from the PARASOL data with respect to eGFR. W hat does that tell you?
Dr. Ojo, you want to take that one?
Yes. As you know, PARASOL is a combination of multiple data sets. Because of the variability among the type of patients in the PARASOL data, I don't think we can draw a conclusion from that data set at this point when we have the opportunity to see the interim result of the AMPLITUDE study, and we have the corroborating result of the AMPLIFIED. I think what the PARASOL APOL1 data analysis could do is to supplement the type of information that we will see from the AMPLITUDE interim analysis. AMPLITUDE is a clinical trial. It's a large clinical trial, and a lot of factors come into meta-analysis of multiple data sets from various sources. The best value of PARASOL APOL1 data is corroborating evidence, in my judgment.
I just want to clarify before we call it a wrap. The PARASOL group is doing amazing work. There is a lot of work going on in the field, and you saw it happen with IgAN, where the work done by the field, by doctors, by FDA, by patients, led to a movement away from GFR to proteinuria in IgAN. That has not happened in AMKD. I want to be abundantly clear that our agreement with the FDA for potential accelerated approval is based on one-year GFR. That is where they are. If PARASOL can move them, so be it, but our agreement is based on one-year GFR.
Terrific. Thanks, everyone. Really appreciate it. Dr. Ojo, Dr. Lafayette, Dr. Kewalramani, thank you for your time.
Thank you.
That is a wrap.
Thank you all very much.
Thank you.