Welcome to the Cantor Fitzgerald Global Healthcare Conference. I'm Pete Stavropoulos, and I have Eric Schmidt here with us. We are biotech analysts that cover Vera Therapeutics. Pleased to introduce Marshall Fordyce, CEO, and Robert Brenner, CMO. Welcome.
Thanks so much, Pete.
You know, atacicept is the lead candidate, phase II for IgA nephropathy, and it's designed to address the disease from an immunological standpoint. Just, you know, can you walk us through the therapeutic hypothesis for atacicept, you know, from a mechanistic standpoint, and the drug should be a disease-modifying?
Absolutely. Pete, thanks for the opportunity, and, you know, this is an incredibly exciting time for patients with autoimmune disease. We began with an idea that we can do better for patients with autoimmune disease and move on from an era of steroids and immunosuppressant therapies by being more specific with the known biology of B cells and plasma cells. There are two cytokines, BAFF and APRIL, that drive B-cell survival and maturation, and there is a natural receptor for those cytokines called TACI. And, the molecule that intercepts them both that we're developing now in phase III for IgA nephropathy is called atacicept. It fuses the natural TACI receptor to an Fc domain. So this is a very common drug format that started with Enbrel decades ago, and that's called the fusion protein.
And the hypothesis we had is that atacicept could be a new era for immunomodulatory therapy. We were very strategic in choosing the first disease indication to pursue. It is called IgA nephropathy. It's a severe autoimmune disease of the kidney that affects young people. What we like about this is, number one, it's a really big unmet need. I go to the patient conference every summer, and I meet these patients, and when you're 35 years old, you do not wanna look at a future of dialysis or transplant by the age of 50 . That type of future puts your mortality on par with cancer. So that's a really important thing to understand. This is a serious unmet need. What we also like about it strategically is that there is an efficient clinical regulatory pathway to get there.
That pathway is now a worn path by two approved drugs, Tarpeyo and Filspari, that are now on the market. They're non-disease modifying therapies. They... One is a reformulated steroid, one works downstream to protect kidney function as a endothelin receptor antagonist. They don't target the B cells. Our hypothesis is that if you can target the B cells and dial down that thermostat of overstimulation by inhibiting BAFF and APRIL, everything downstream should get better. Because what I learned in medical school is that when you get IgA nephropathy, all it is, is the B cells forming these clusters of antibodies that bombard the kidney and cause inflammation, fibrosis, and progressive kidney function decline. That's what this disease is. So if you target the source, everything else should get better.
The exciting thing we showed this past January is that that hypothesis is so far supported by a rigorous, global, randomized controlled trial that we ran called ORIGIN 2. It's our phase II-B trial. We read out the results this past year, and the most recent data was shared in January, 72-week results, so that's a year and a half, the longest data set ever shown in this disease for a B- cell modulator. And what we showed is that a two-thirds reduction in the immune complex, which is what we achieve with the atacicept, leads to resolution of inflammation as measured by blood in the urine, or hematuria, of over 80% of patients, improved kidney function, because you can measure that by looking at protein in the urine.
We shouldn't have protein in the urine, and we have a meaningful reduction in protein in the urine over time. That seems to be getting better with time. And then we have GFR, which is what we all get checked when we see our GP doctor. They measure a serum creatinine, they calculate an estimated glomerular filtration rate or eGFR, and all of us lose about 1 ml per minute per year, and if you lose 1 ml per minute per year, you don't go on dialysis in your lifetime. But if you lose more than 2 ml per minute per year, your lifetime risk of dialysis is 50%- 100%, okay? So if we can get a GFR that's close to normal, which is losing 1 ml per minute per year, then you're obviating the need for dialysis in a lifetime.
That is the goal, and that's the data that we shared at ASN at 72 weeks. We showed GFR that's similar to normal function over a year and a half. We do have additional data to complete the two-year timeframe of our phase II trial. We plan to share that data in the fourth quarter this year. But it's a really exciting time 'cause this data set that Vera has generated in IgA nephropathy is just the first indication of other indications where we think atacicept will bring value to patients and change standard of care. We just announced on Monday that we'll be having an R&D Day in a few weeks' time, and that will be a further description of what comes next for Vera after IgA nephropathy. First, we're gonna win in IgAN.
We think that IgA nephropathy is a very large unmet need, a very large potential market. We will be on track to get to commercialization in 2026, and you will hear more about how we plan to ensure that we have a very significant presence in that market in 2026 and well beyond.
... Okay, you know, you did mention that you had 36- week data. I believe you presented it at ERA, June 2023. You know, then you had 72- week data that you presented earlier this year. Just, you know, the difference, I know. So then you flipped, you know, from placebo control to open label. So with that caveat, you know, what was, what did you observe, you know, in terms of proteinuria, in terms of reduction of of IgA and the the pathogenic forms, you know, as you went from 36 to 72?
Yeah. So the design of our phase II trial was a multinational, randomized, double-blind, placebo-controlled trial. Just that I finished saying that, I think everyone's brain turned off. What that means is that that's the gold standard approach to getting to the truth in clinical science. It's the most important medical innovation of our generation, or not of our generation, of the modern medical world, is the randomized control trial. That's how you get to the truth. Because confounding, meaning the influences on your endpoint that could push it up or down, that don't have to do with the drug itself, are evenly distributed between the two arms.
So our RCT is super important to get to the truth, and we ran this RCT within that blinded fashion for nine months or 36 weeks to ensure that we knew that we had a significant reduction in proteinuria versus placebo, and that's what we accomplished. It was statistically significant at 24 weeks and 36 weeks, and it was a clinically meaningful result of, of over 30% delta from placebo. So that was a, a key de-risking moment for us in phase II in planning for phase III. So the first thing to understand about our phase II is that we ran a very phase III-like phase II study. That's what we do in drug development. That's what biopharma does on a large scale, is you have to de-risk your phase III trial.
It's a big investment to go into phase III and expand the sites and do a larger study, get closer to commercialization, spend more on CMC. That's why we do what we do, and we accomplished that in phase 2. The innovation here is that then everyone switched to TACI 150, our phase III dose, and we followed them over a two-year period. So the open-label extension says, "Okay, 150 wins. That's the best dose. How does that look over time?" and we were so excited to see that the GFR was stable, not just at 36 weeks, but well beyond, at a year and a half, and we'll see at two years if it continues to track on this normal trajectory.
Now, in phase III, we'll be blinded for a full two-year period, and so that will have a control arm through two years. But that design is unique in the field among all B-cell modulators being developed for IgA nephropathy. Atacicept is the only one to have this two-year data in phase II, so that distinguishes us as we get to commercial launch in 2026, and I think it's really important, a data point we don't talk about a lot, Pete, is: How many patients in open label extension are still taking atacicept?
And that injection-
That's a significant number. It's over 90% of patients at a year and a half are still self-injecting 1 ml once a week. So what is this drug product? We've been studying this as a prefilled syringe. Patients get a box, they take it home, and once a week on a Saturday, they wake up and they clean their skin, and they do a 1 ml quick injection through a small gauge needle, a 27-gauge needle. It's a one, you know, small volume. What is that profile? It's the same as Ozempic. Rob had dinner last night with someone on Ozempic. Like, people take this kind of format all the time, and so we think that's a very winning profile.
When you look across the space, we're the only program to study self-administration at home. That, again, de-risks not just the phase III and it's the outcome, but that tells us patients are willing to take this. We know that already from phase II, and that's a very meaningful insight into how we think this drug's gonna launch in 2026 and beyond.
Now, you know, going back to the clinical data, you know, Robert, I think the first time that I met you out in San Francisco on January, you know, you brought up hematuria.
Yeah.
You know, and you know, I think investors overlook that, and they focus only on proteinuria. And so just, you know, just give us a sense of, you know, the importance of hematuria and what resolving it actually means, you know, and translates from a pathobiological perspective.
Yeah. Thanks, Pete. I would begin by saying, you know, in Vera's view, and we've, I think, been pretty consistent with our narrative, back to January, and we will continue to communicate this way moving forward, there were four findings that in aggregate allow us to demonstrate that we have disease modification with this mechanism in IgA nephropathy. That begins with reduction in a component of the immune complex, the autoantigen or galactose-deficient IgA1, and in the 72-week data, we had a 65% reduction of the Gd-IgA1 in patients who received the atacicept. But importantly, there's another measure which, although it's used routinely in clinical practice, and nephrologists recognize it's a hallmark of disease, and that's hematuria or blood in the urine, it hasn't really been used to help contextualize patients' response to therapy before.
The team at Vera, prior to my arrival, gets all the credit because when they designed the ORIGIN program, they included the use of conventional urine dipstick to quantify, in a semi-qualitative way, what the hematuria burden was in patients, and we could look at that over time dynamically and measure response to therapy. In this disease, hematuria is a readout of the burden of inflammation at the level of the glomerulus, which has been bombarded with the circulating immune complexes. So resolution of blood in the urine or hematuria is a good way of identifying that the inflammatory burden within the kidney is resolving. In the 72-week period from the ORIGIN 2b study that we shared in January, showed that 75%-80% of patients who had blood in their urine at baseline had resolution of that over time while on atacicept.
I think it's really important, in addition to thinking about the GFR slope, in addition to thinking about proteinuria, which is the approvable endpoint for accelerated approval, and in addition to thinking about reduction in the immune complex burden, hematuria is one more component that tells a fulsome story. Why it's important is there are many mechanisms of action of drugs that can reduce proteinuria. Not all of them have a big impact on GFR, and far fewer of them have any impact on hematuria and that inflammation. It also allows us to look at drugs that are anti-inflammatory and say, "What is the pace of resolution?" The data that we've demonstrated with atacicept is the rate of improvement in the presence of hematuria is very quick, and that compares favorably to other drugs that are so-called anti-inflammatory at the level of the kidney.
Can we go back to mechanism for a moment? Marshall, you mentioned the dual mechanism, APRIL-BAFF for TACI. Others in the field are just looking at APRIL. How would you expect that, either molecularly or clinically, to manifest itself in terms of potential differences?
Yeah, so, first, the biologic mechanism of inhibiting both BAFF and APRIL, to us, makes the most sense. That's what we know about B-cell biology, and using the native TACI receptor, is truly the same approach as, say, Enbrel. Inhibiting one of those, you know, it has been tested preclinically, so there's never been a head-to-head trial of APRIL only versus BAFF/APRIL dual inhibition, so we don't have that, the benefit of that, visibility, but preclinically, you need both to get the same effect, and it may make some biologic sense that if you inhibit only one aspect of a parallel biologic pathway, you may have upregulation of the other, for example, so I think it's an open question around long-term efficacy.
And I think we need to see what that looks like in clinical data over time to really assess you know the role of BAFF plus APRIL versus APRIL alone. So far, what do we know? We know IV infusion of APRIL only from sibeprenlimab is an interesting approach, but I think it remains to be seen what that clinical data look like over time.
All right, you did initiate the phase III ORIGIN is ongoing. We expect that out of the first half of 2025. You completed enrollment recently. Congratulations on that. And so, I guess, you know, one of my questions is, you know, as the treatment landscape has been evolving, all right, you have new mechanisms of actions that are being implemented. So in the phase II-B portion, you did have a portion of patients on SGLT2 inhibitors. And so, like, you know, how are you thinking about that in the phase III? You know, what's the minimum or maximum amount of patients you want on SGLT2 inhibitors? And also, you have the approval of Filspari. Are any of those patients on Filspari, or you're not allowing?
Yeah, I mean, we can't give insight into the baseline characteristics yet until we've got the full data set. We did. I think we're the only program to run an RCT that had SGLT2 inhibitors in the phase II trial, and that was about 15% of patients. We would expect that number to grow, but it doesn't concern us in terms of showing a therapeutic effect. These are patients who are on a variety of background regimens, ACE or ARB or SGLT2, and despite having that renoprotective effect on the kidney, trying to control blood pressure in the kidney, essentially, they're still producing a gram of protein in the urine per day.
So all of those patients, whatever their background is, by the time they're getting screened, they've been on it for, what, three months, and they're still producing a gram of proteinuria a day, and we're confident that we can show a therapeutic effect on top of that background, given what the baseline characteristics are.
All right, and, study power. What's the cushion for variance?
We were very conservative in this. We showed detail, I think, at ASN about a year ago, so I'd have to remember exactly what that was, but it's well over 90%. You know, first, you need to power the primary endpoint, which is proteinuria at nine months, and you know, we achieved statistical significance with 30 subjects per arm in phase II. This is, we're powering now with 100 subjects per arm, now randomized one to one, so we're well over 90% powered for the primary endpoint, and well-powered for GFR as well.
All right. So, I mean, we have less than ten minutes left. Really important topic. There were recent draft guidelines for KDIGO. Just sort of what were your takeaways from those draft guidelines?
Yeah, Rob-
Yeah.
I'll ask you.
Yeah, so, the international treatment guidelines are put out by an organization called KDIGO, and there have been guidelines for IgA nephropathy. They've just been evolved, and so there's a draft out for public comment today. It's funny, John Barratt, who's one of the leaders of the effort, was recently on a podium the last couple of days and said, "You know, from the time that we drafted these to now, they're already outdated."... and that speaks to the intensity of data generation and corporate activity in the space, which is great for everybody.
I would say that the key takeaways for me is what is really phenomenal for patients, is that the guideline authors are now recommending that a fundamental goal of therapy is to get patients to a point where their GFR slope is about 1 ml per minute loss or less. That's consistent with the GFR loss that we see in the healthy population without biopsy-proven kidney disease. Why is that so important? It's important because for the most part, patients with IgA nephropathy present when they've already lost maybe 40% of their normal kidney function. So that means at any level of progression above and beyond what normal people experience, because they're starting at a much lower baseline, their lifetime risk of requiring dialysis or transplant is significant, maybe even approaching 100%.
Therefore, if what we're really trying to do is avoid the need for renal replacement therapy, and we know that we don't find patients till they've already lost a big amount of their kidney function, we have to try and strive to get to a GFR rate of loss that looks like healthy people, the people who are in this room. How do we get there? There is no data that I'm aware of with steroids. There is no data I'm aware of with complement inhibition. There's no data that I'm aware of aware of with endothelin receptor antagonists, or SGLT2 inhibitors, or ACE inhibitors, or ARBs, that in IgAN gets you to a GFR rate of loss of only minus one ml per minute per year.
However, the data that we showed back in January at 72 weeks shows that the slope of GFR loss on atacicept is similar to the normal population of about -1 ml/min/year. Therefore, while our product's not yet approved and our data isn't influencing the guidelines per se today, the door is open that in the future, we have a solution to the threshold that the guideline authors are saying is what the goal of therapy is. So looking forward, I think it's a great opportunity to align the data package that we're developing with what the guideline authors think is important for patients.
So, you know, when I read the guidelines, I mean, to me, it looks like the framework's there just to drop atacicept and atacicept-like molecules, you know, right into, you know, the treatment paradigm. I mean, it specifically called out the reduction of IgA immune complexes, right? It also called out how you measure that. You know, and it wasn't via immune complexes, because I know it's difficult to do so-
Yes.
But it's actually by the reduction of Gd-IgA1. You know, so that's one aspect to me, you know, really pointing to B-cell modulators and B-cell depleters. The other thing that I also noticed was they said, you know, it's not only about, you know. It's also about stopping the ongoing inflammation, but it suggested language that, you know, stopping the ongoing inflammation should not be in lieu of, you know, basically. So am I reading it correctly, or?
I think the draft guidelines have done a very good job of trying to provide a framework for prescribers to think about the goals of therapy. We wanna reduce inflammation, we wanna do everything we can to slow the progression of kidney disease. We want to not be thinking about the risk of adverse long-term outcomes, only in patients who have high proteinuria. So it's a reframing of what the important aspects are of thinking about how you define patients at risk, and importantly, what the goals of therapy are. And to your point, I do think there's congruity with the way that this is articulated in the guidelines to fit in sync with the kind of data that we've generated in phase II and the data we expect to have at the time of approval.
Yeah. Good. Thank you.
Okay.
And then going back to, to what you just said, you know, in terms of the level of proteinuria, you know, again, that's sort of been redefined. And, number one, why? And, number two, I guess that that impacts also, you know, where you would fit in some type of,
Yeah, look, if someone has made it to a consultant nephrologist, they've had the decision made that they're gonna go to the biopsy suite and have a biopsy needle put into their kidney, take a piece of tissue out, have it processed and reviewed by a pathologist, and we learn that they have now a biopsy-proven kidney disease. I think it's less important as to what the amount of proteinuria is in their urine, that we say they have an immune complex-mediated kidney disease that has a B-cell origin.
In the future, when we live in a world where we've got B-cell modulators that are able to bind BAFF and APRIL, we have the ability to turn off the faucet of the production of those pathogenic immune complexes that are bombarding the kidney, and that is the best chance we have of altering their course of where they might be at great risk for going on to dialysis or need to transplant, to where we reduce that to background. That's the goal, and to me, it's. I don't wanna discriminate patients who have got higher or moderate or lower levels of proteinuria. They all have an immune complex-mediated kidney disease.
Yeah.
From an investment standpoint, you know, we're almost inundated with new companies in the B-cell modulation field for IgAN therapy. You guys are differentiated, obviously, being two, three, four years ahead of some of the competition, and just how do you, how do you maximize the benefit for small groups?
Yeah, I think first is the quality of the data. So first, efficacy is king, and that's what we believe in drug development. So it has to be the most efficacious drug. That's what people will take. That's how we see areas of medicine. I mean, we should take a step back. These moments don't happen all the time for patients. All of us on the Vera team, on the executive team, have led or contributed to drug development and launches in areas that had incredible innovation. For me, it was in HIV and hepatitis C at Gilead. And, you know, efficacy wins. Efficacy wins. Then there are other innovations, assuming safety continues to be good and tolerability look good, you're looking at additional components like convenience.
And what we've liked about atacicept from the very beginning, it's supported by this greater than 90% retention through a year and a half, is that the product is something that young patients will take over time. So I think, you know, what we plan to do is, first, have the best quality data, second, a great product, third, get to market soon, and as we just announced last week, we're on track to do that in 2026. So time matters. These are not opportunities that, you know, that stay open forever. And then it becomes a, you know, competition to out-innovate oneself. And certainly we take a view that lifecycle management is built into a drug launch in the modern era.
No one gets to be alone long in this disease, and so, we've taken that seriously from the very beginning, and we'll continue to speak to that, as that story unfolds.
All right, I guess, we have one minute left. Just to sort of reiterate, what are your expectations for the two-year data?
Yeah.
you know, what's a win-win, you know, and how confident are you?
Yeah, well, first, a win, it's amazing to be saying it, a win is normal kidney function, right? So, you know, I'm the non-nephrologist on the stage, and Rob has been telling me, "We don't get to see this often, or we have never seen, ever, a drug that returns patients who have a progressive kidney disease that puts people on dialysis and get them to the normal range." So what is the normal range? It's a slope of minus one mL per minute per year. So at 96 weeks, which is roughly two years, the point estimate of minus two is normal.
And if our error bars are, you know, if we're in that range, that is an absolute grand slam and change in standard of care. It gets us consistent with a life without a dialysis or transplant. That's the target, to us, a win. And we're confident that, you know, getting from 72 to 96 weeks, we'll be able to track consistently.
Excellent.
Yeah.
Any other questions, Eric? All right. Appreciate you coming to the Cantor Conference. Always great seeing you. Look forward to the R&D Day. Look forward to ASN. Well, you did say you're presenting there. My assumption is that you're gonna be presenting ASN, and so, thank you for coming.
Thanks, Pete.
Thank you.
Thank you, Eric.
Thank you.