Investor Update Transcript - VRTX 2026-10-24

Susie Lisa, Head of Investor Relations

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. So very, 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 Anaxapaline. And 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 povitacicept in iGAN. And 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 p.m. And 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. And with that, Reshma.

Reshma Kewalramani, CEO

Thank you so much, Susie. I appreciate it. It is very surprising for me to see so many of you at an ASN. And 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. So the field has come a long way. And interestingly enough, while Vertex started as a CF company, we are quite the renal company now. and 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 but 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 a few renal diseases that meet every mark. And 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. Membranus is another POVI indication. You'll remember when we did the Alpine acquisition, We talked about POVIA as a pipeline and a product. And while we're not going to touch on it today, watch the space for ADPKD. We're excited about a molecule. It's a small molecule that properly folds a misfolded protein. And if that sounds like something you've heard from Vertex before, you have. That's how our CF medicines work. So there's 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. So we're talking about 100,000 to 300,000, and when you think about IGAN, it's well over a million because it's a particularly prevalent disease in Asia. You'll remember for Asia, we have partnerships with Zai. They will be marketing for us in China and other regions, and we have another partnership with Ono, who will be bringing this medicine to Japan and other regions. So 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 ADP-KD disease that I'm mentioning to you is only 10% of the overall ADP-KD. So ADP-KD is about 350,000 people worldwide. Our first approach will be appropriate for about 35,000. But 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 POV plays for IGAN and membranous. Not on the side because it's not in renal, but we also have a trial for POV in myasthenia gravis because that is another one of these very B-cell mediated diseases. APOL1 mediated kidney disease in the middle. The phase three 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. And the ADPKD program is in phase two 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, 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 POVY in the middle, and you'll hear a lot about it. But 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 POVY 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, POVY 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 happen to come together by good luck. This is how we engineered this medicine to behave. With that, I'm going to turn it over to Dr. Ojo. It's a real pleasure to introduce him. He's an MD-PhD scientist. He has worked in multiple disease areas, but you will hear from him why he has a passion for AMKD. And we know Dr. Ojo because he sits on the steering committee. The good news on Amplitude, the Phase 3 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.

Akinlolu Ojo, Analyst — Nephrologist, University of Kansas

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 here, that is cohort one, individuals who have very modest amount of excess urinary protein excretion, low level of proteinuria, as well as cohort two, 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 studies are already on the most contemporary and the most comprehensive background treatment for both chronic kidney disease and diabetic nephropathy where relevant, that is in cohort two. So these 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 two, The reduction in urinary protein excretion is between 17% and 25%, and the confidence interval crosses 1%. 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 renal study that led to the approval of Losartin, 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. So 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. Now the amplitude study. The amplitude study is a phase 3 study of inner supling in individuals with AMKD. This clinical trial is monumental for a number of reasons, including the fact that it is the first phase three 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 2b study of intersapline along with 456 study individuals who were newly enrolled into phase 3 for a total of 522. and as Reshma pointed out, the interim analysis is forthcoming beginning of next year. Now what does amplitude, 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. But that's a separate story, and I can share that with you. So what this represents for me is that what we are looking at in Amplified is a study that is showing potential for beneficial clinical outcomes based on urinary protein excretion reduction in a population whose need, whose therapeutic need has never been met before. Ingrishma showed the number of individuals who could benefit who have AMKD in the $250,000 range. I disagree with that estimate. My own estimate would 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 2-APOL1 is 13% in blacks. Individuals who have chronic kidney disease who are black, the prevalence of APOL1-2-RISC-ALEL is about 20%. And if you carry that forward and you see maybe only 70% of those patients have their kidney disease due to MDKD, you will end up on a number between $600,000 and $700,000. And 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 2B study, when the study ended at 12 weeks, those individuals continued to have a monotonic reduction in proteinuria. So the proteinuria did not stop. It was still going down. And if you were to carry Amplify forward, that is probably what you will see. In fact, confident that that is what you will see in this type of situation. The fact that the reduction in proteinuria in cohort two was not as large as cohort one, because those individuals have two diseases. They have diabetic nephropathy, then they have AMKD. And in a supplement doesn't treat diabetic nephropathy, the body does treat EMDKD. The result of Amplified are compelling and whether you call individuals with EMKD, FSGS and hypertensive nephrosclerosis, I think we shouldn't 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. And there's no, I am very confident that as the results of amplitude comes 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. And that is true because we know that Amplify demonstrate that even in population that is It's not as homogenous as the amplitude study, which is what amplified this. It is not an homogenous population, and that is the majority of patients with chronic kidney disease. They are not an 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.

Reshma Kewalramani, CEO

Thank you, Dr. Ojo. I'm going to ask you guys to hold your questions, and we'll get through IGAN, and then we're all available to you. Dr. Lafayette.

Akinlolu Ojo, Analyst — Nephrologist, University of Kansas

Pleasure.

Richard Lafayette, Analyst — Physician

It's 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 povytacacept, and then this year we're able to sort of fulfill that with the Phase III interim analysis. So I'm going to go ahead and go through the presentation that we're going to give tomorrow. And again, I promise it should be under eight minutes, otherwise I'll get pulled off the stage tomorrow. So we'll see how this is going to go. Someone please feel free to time me. I got you. I'm ready. So as you know, RANIR is our ongoing global phase 3 randomized double-blind placebo-controlled trial, which is evaluating POV in adults with biopsy-proven IgA nephropathy, who in this screening period have proven to be at high risk by having substantial proteinuria, urine protein-cracking ratio greater than 0.75 grams per gram, EGFR greater than 30 mLs per minute. They're very well-treated patients who are on maximum-dose RAS inhibitors and allowed to have standard care with SGLT2 inhibitors, MRAs, and even endothelium blockers if it was available and stable at baseline. And they get randomized two-to-one to povotacacept every four weeks in a small injection versus placebo every four weeks in a small injection. And then, as you well know, the interim analysis was planned. At 36 weeks, we're 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. So 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've 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. So 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 GFR is depressed from normal, running around 60 to 70 mLs per minute. And there's modest prior treatments with immunosuppression, but it's well balanced between the groups. Here you can see that hematuria was defined only on dipstick by moderate or large amount, not including small. So we have half the patients who have substantial hematuria at baseline. And again, by protocol, all patients had to be on maximally tolerated RAS inhibition, and they are. But there's a sizable number, two-thirds, who are on stable SGLT2 inhibitors at baseline, and significant numbers of patients on MRA and even a few on endothelin blockers. But again, very well balanced at baseline. And again, here's 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's rapid separation between placebo and the Povitacacept group, such that there's already clinically meaningful reduction in the early weeks. The difference here is this is urine protein-to-creatinine ratio, which is actually more noisy and can fluctuate, but yet you're 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 can't not 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. So again, so far, it looks like every patient group does wonderfully. And this is driven by very, very consistent, rapid control of galactose-deficient IJ1, the putative antibody, and antigen that contributes to IJ nephropathy. And you can see this very robust reduction by nearly 80% at the end of this interim analysis period. And associated with that is a very early progressive accrual of patients whose cardinal feature of IJ nephropathy is also resolving over time. and 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 KDGO 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. And here our KDGO-aligned goal of the 24-hour urine UPCR, less than 0.5 grams per gram, occurred in nearly half of the patients. This is a group, again, with high-grade proteinuria at baseline, and even better, coming to 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. And again, safety, just like in phase two, and with this class, is just beautiful. Please remember, it's a two-to-one randomization, so look at the percentages, not the numbers. But you can see that overall adverse events are percentage-wise lower. But otherwise, if you look all up and down at any AE infections-related events that 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. And so during these times, as in phase two, this is tolerated just the same as placebo. So here you have the result that povotacacet 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 GFR benefit, as well as hematuria, galactose-deficient IJ1. 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 GFR. Again, the benefits 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 glaxos-deficient IgA1, hematuria resolution in the vast majority of treated patients, and a safety marker that looks identical to placebo thus far. Again, remember, Povetacacept was dosed as Q4-week sub-Q dosing in a pre-filled 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. And so 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. So thanks for looking at that. And, 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. And you can come back for the presentation tomorrow, but other than the Q&A, it won't be meaningfully different. So thanks for your attention.

Reshma Kewalramani, CEO

Dr. LaFrey, thank you. I'll invite you to join on stage.

Richard Lafayette, Analyst — Physician

Yes, thank you.

Reshma Kewalramani, CEO

And we will make sure that we have some mics in the back. And, Suzy, are we ready to take questions?

Susie Lisa, Head of Investor Relations

And I will start just briefly with one we got online, But I also wanted to mention, we also have Duncan McKechnie here, who is our Chief Commercial Officer, if you have commercial questions as well. Rasha, just a quick one from Terrence Flynn at Morgan Stanley. Can you comment on confidence for POVI in FDA approval in IGAN, and that the label will not have any different monitoring requirements relative to Atsuka or Vira? I am confident.

Ananda Ghosh, Analyst — AC WinRite

This is, hi, Ananda Ghosh from WinRite. Question for Dr. Rojo. So, you know, given the Parasol recommendation a couple of weeks back on the EGFR, do you think how important is StatSeq for the one-year endpoint? And then the next question is maybe for the company. Like, how many patients are we expecting to be reported at the 12-month endpoint for the EGFR?

Akinlolu Ojo, Analyst — Nephrologist, University of Kansas

Yeah. So your first question is about 12-month endpoint.

Ananda Ghosh, Analyst — AC WinRite

Yeah, like how important do you think is a STAT-SIG at one-year EGFR endpoint, given that the parasol body, you know, kind of alluded to that, you know, the one-year EGFR is generally noisy, which also most of the cables also agree. So 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 protein area reduction along with it?

Akinlolu Ojo, Analyst — Nephrologist, University of Kansas

The one-year endpoint is not noisy for a disease condition that has a more rapid rate of progression. So individuals with AMKD typically have a rate of loss of EGFR of between 5 and 8 mLs per minute per year. And 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. And secondly, there are, 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. So I have a high degree of confidence in a 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 mls 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 mls per minute rate of loss of EJFAR.

Speaker 3

I guess one for the physicians on POV. 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? And then maybe for Duncan, how long should we expect it to take to establish reimbursement?

Reshma Kewalramani, CEO

Okay. Why don't we go to Dr. Lafayette first, then we'll come back to Duncan.

Richard Lafayette, Analyst — Physician

I think data is very, very incomplete for off-drug activity. We've had very limited release for a tachycept, where it did show a signal that GFR 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. So 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. But I think that there's a lot of backroom discussions about if patients want to get pregnant, if patients just are doing very, very well and want to come off the medication and see what happens. That's almost certainly going to be reasonable to try. but right 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 but we will see longer and longer extension and I do hope we will learn more about off-drug exposure.

Reshma Kewalramani, CEO

Duncan, do you want to make a comment on what you're thinking about for access and reimbursement?

Duncan McKechnie, Other

Yeah, sure. Wow, that was loud. Yes, so a quick bit of framing. Firstly, about 70% of the IGAM patients are commercial patients, so our focus really is the commercial business, the three PBMs there. We have been working with them and engaging with them since July 2025. So we've been talking to them about IGAN and Povetachycept 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 Povetacacept ahead of formal coverage.

Reshma Kewalramani, CEO

Thank you so much. Other questions?

Andy Chen, Analyst — Wolf Research, LLC

Andy Chen, Wolf 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 BAPFAPRIL but absent more data how are you going to use complement inhibitors versus BAPFAPRIL?

Reshma Kewalramani, CEO

Richard, do you want to take that one?

Richard Lafayette, Analyst — Physician

Yeah, so I think complement is really an important feature of IJ nephropathy and a lot of complement mediated kidney diseases which ultimately may include APL1 diseases as well. But I really think that there's lots of ways to control complement. And again, the only mature program is the Tachypan, 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. So 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. And so if we want to have a complement reducing therapy, it may be a B-cell modulator as our top choice. Now, 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. So it can be an option. But again, if we want the highest efficacy and still want to control complement, we can achieve that with B-cell modulums.

Akinlolu Ojo, Analyst — Nephrologist, University of Kansas

No, nothing to hide on it.

Speaker 10

Just if there's anything you can share about the powering for the interim for a NAXPLAIN in early next year, and then for the KOLs, just kind of speak to the importance of the small volume auto-injector and how that could impact uptake.

Reshma Kewalramani, CEO

And if you think patients who are on an agent, given via pfs would want to switch over sounds good uh on inaccipline and the amplitude phase three interim analysis for early next year we haven't shared the powering or number but maybe what i could say um 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 and you heard today the overall number is a little north of 500. So maybe that's one way you can think about it. Dr. Lafayette and Dr. Ogier, do you have any comments to make about the biologic and its format and what that means?

Richard Lafayette, Analyst — Physician

So at least in terms of POVI, we've 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 of 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? And so I say it in that way because I always think you're going to answer, yeah, less frequent, smaller, without doing a lot of work is going to be preferable. And I know you've got access to Vertex's patient survey, which supports other instruments that we've seen that really suggest that most patients feel the same. If offered a choice between frequent versus infrequent, they'll like it infrequently, and small volume auto-injector will be quite preferred.

Reshma Kewalramani, CEO

On that point, I'll just make one note. I don't know if it's 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'm sure Susie can get you that. And I'll make another plug. There's 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 BAFs, and you can peruse through that and look at the viscosity and volume and what that might mean. Susie, back to you.

Susie Lisa, Head of Investor Relations

Question from Brian Abrams at RBC on anaxiplin. One for you, Reshma. What is the go-forward plan for anaxiplin in diabetics? And for Dr. Ojo, I think you touched on this, But his question is, how do you think the more modest protein or your benefits will translate to meaningful reduction in the kidney function decline in that cohort two population?

Akinlolu Ojo, Analyst — Nephrologist, University of Kansas

Okay.

Reshma Kewalramani, CEO

Why don't I go first, and then I'll go to Dr. Ojo. So the plan for the diabetic cohort, remember that's the phase 2B 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. So 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. And 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. So more on it next year after amplitude. And the point of the matter is we'll talk about type 2 diabetes once we get to that phase 3 population. Dr. Ojo, I think the question for you is how do you view the more modest proteinuria in Amplify and how that translates to GFR versus the amplitude population?

Akinlolu Ojo, Analyst — Nephrologist, University of Kansas

So I'll start by saying that any amount of excess urinary protein excretion is bad for renal function. And proteinuria is 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. and if you have a 20-25% reduction in proteinuria that is sustained over time it is not conceivable and there is no empirical evidence that that does not lead to improvement in rate of loss of renal function and that is why some of these other studies in IGAN you see approval based on proteinuria alone And as I mentioned, in the RENAL trial, RENAL is the Lossartine 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 one here at 12 weeks in the amplified. That 25% reduction at three months in the renal study translated when those participants were followed to a 44% reduction in adverse renal outcome. 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. It's a bigger problem for the heart. Anytime you have proteinuria or CKD, it is a precursor of aggressive cardiovascular disease. So 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 get 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.

Susie Lisa, Head of Investor Relations

Sorry, we'll let someone else do it. I apologize. And then this is our last question. In the back, sorry.

Brian Abrahams, Analyst — RBC

One for the company. Maybe, Duncan, if you can talk about the peer discussions you have had so far. Should we expect Povie to receive like a parity access at launch, or is there a meaningful risk of a kind of a step therapy through an established kind of April pathway product? And maybe one for the doctors here. Based on looking across all the BAP April inhibitors, and 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 kind of conclude which drug is better?

Reshma Kewalramani, CEO

Maybe we go to Rich first and then we go to you, Duncan.

Richard Lafayette, Analyst — Physician

Yeah, so 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-sufficient IGA reduction, and improvement in hematuria. Numerically, this looks a tiny bit better, so I can say, yay, congratulations. But I certainly am going to watch for what I'm sure will be meaningful, GFR protection. But we're going to look to see how that compares. Again, predictably, it'll probably be your 100% protection of kidney function. And depending on how this high-risk group does progress, we'll see how the separation looks. So it looks really promising. It's a great agent. Comparing it to the others, it's a little premature. But all the signals look wonderful.

Reshma Kewalramani, CEO

Duncan, a little bit on what you're expecting on payer.

Duncan McKechnie, Other

Yeah, so maybe I'll just, the first part of that, I think, was what we're hearing from nephrologists, I would say, a little bit like Dr. Lafayette, has said incredibly positive reactions to povitacic symptoms. I would say specifically, this is all about the product that's the easiest to use. So this 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. And in terms of the payers, the answer to the question is, no, we're not expecting step edits through other April Baff or other type products.

Reshma Kewalramani, CEO

I know Susie said one last question, but there are two. We'll just get them done. Let's do it.

Andy Chen, Analyst — Wolf Research, LLC

Thanks.

Manoj, Analyst — Jefferies

This is Manoj from Jeffries. Just one on, so do you expect any meaningful switch when POV gets onto the market? Do you 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 kind of get on to COVID just trying to understand? Yep.

Reshma Kewalramani, CEO

So 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. So, you know, it seems like the more likely sources of patients are patients who are coming into the system and want to try a therapy. But there's nothing that obstructs a person who says, look, the only thing available was a once-weekly medicine, or look, there was only a pre-fill syringe. I want an auto-injector, or my doctor prefers this. There's nothing that obstructs that. But I think if you just look at the number of patients, there's maybe 1,000 on an April, April bath, and there's $149,000 not on anything. So it seems more likely they would come from there. Dr. Lafayette, I don't know if you have anything you'd add.

Richard Lafayette, Analyst — Physician

I'll just agree. It will be technically, I think, easy to switch unless there's some massive price differential or, you know, technical company insurer problem. But I think it will be possible. And our patients are more and more proactive. I'm thinking of a patient of mine who's on SIBI doing extremely well and still every visit saying, like, wow, I wonder if I should go to an auto-injector instead. And, you know, 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 will be switches.

Reshma Kewalramani, CEO

Now, Susie, if you want the last question.

Ananda Ghosh, Analyst — AC WinRite

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? And what does that tell you?

Reshma Kewalramani, CEO

Dr. Ojo, you want to take that one?

Akinlolu Ojo, Analyst — Nephrologist, University of Kansas

So you can, as you know, Parasol is a combination of multiple data sets. and there are, 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 APOL-1 data analysis could do is to supplement the type of information that we will see from the amplitude interim analysis. It is a clinical trial. Amplitude is a clinical trial.

Reshma Kewalramani, CEO

It's a large clinical trial. and you know a lot of factors come into meta-analysis of multiple data sets from various sources the best value of parasol APO1 data is collaborating evidence in my judgment and I just want to clarify before we call it a wrap the parasol group is doing amazing work there's 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 protein orient igan. That has not happened in AMKD. And I want to be abundantly clear that our agreement with the FDA for potential accelerated approval is based on one-year GFR. That's where they are. If parasol can move them, so be it. But our agreement is based on one-year GFR.

Susie Lisa, Head of Investor Relations

Terrific. Thanks, everyone. Really appreciate it. Dr. Odo, So Dr. Lafayette, Dr. Kewal Ramani, thank you for your time, and that's a wrap.

Reshma Kewalramani, CEO

Thank you all very much.

Akinlolu Ojo, Analyst — Nephrologist, University of Kansas

Thank you.