Good afternoon, everyone. Thanks for joining us for the Vera Fireside Chat at the TD Cowen I&I Summit. With us from Vera, we have CEO Marshall Fordyce, CFO Sean Grant, and Chief Medical Officer Rob Brenner. Guys, thank you for joining us, and congratulations on your, again, presentation at ASN, that first ASN plenary, and as well as the concurrent NEJM publication. I guess maybe we could start there, if that's all right. Lots of new biomarker detail with the ASN presentation and in the guts of the publication. Maybe could you highlight for us the most important features of the biomarker data that was revealed in there?
Yeah, Ritu, thanks so much. It's great to be here and have a chance to share the excitement that we felt in Houston at ASN at the largest gathering of nephrologists in the world. As you pointed out, we had a plenary presentation last Thursday and a concomitant publication in the New England Journal. Great to have our data from Phase III peer-reviewed, and then we announced our BLA filing the next day. We are on track to bring this new potential medicine to patients really next year. To your question, Rob, maybe you could describe what the most salient features were that we showed that was new at ASN last week.
Yeah, thanks, Marshall, and thanks, Ritu. I'll start just with the cadence of how the data was shared. We began by reviewing the results of the long-term Phase IIb program, where we showed that over two years we had an impact on a quartet of findings that we believe defines true disease modification in IgA nephropathy. It begins with reduction in the autoantigen, and in the Phase II program, there was a 2/3 reduction over two years. Resolution of blood in the urine, which is a good marker for the amount of inflammation within the filtering component of the kidney. We saw that 75% of patients had resolution of hematuria while they were on study. We showed that patients had a reduction in the amount of proteinuria, or protein in their urine, which is the key surrogate measure that's used by FDA for the granting of accelerated approval.
We had showed that that was north of 50% in the Phase II experience. Most importantly, we showed that over those two years, a population of patients who had a biopsy-proven kidney disease had an annual rate of loss of GFR of minus 0.6 mL per minute, which is the same as what we see in the healthy population. From there, we talked about the Phase III program. The design was nearly identical. Populations were nearly identical with one exception. In Phase II, we had 15% of patients on SGLT2 inhibitors. In the Phase III, it was a little bit north of 50%. In a 36-week readout for the first 201 participants, we shared the following results. One, that we had a 46% reduction in proteinuria in patients who were treated with atacicept. We had a 7% reduction in patients treated with placebo.
Using a mixed effects model, the placebo-adjusted reduction in proteinuria was 42%, well north of the 30% threshold that FDA is looking for to trigger an accelerated application. Second, we showed a breakdown of all the subgroups that were pre-identified for patients who were in this interim analysis set. Regardless of age, their sex, the time of when they were biopsied, their baseline GFR, their baseline proteinuria, presence or absence of SGLT2 inhibitors, their race, there was no impact of any of those parameters on attenuating the benefit of atacicept versus placebo for reducing proteinuria. I know there's been some chatter in the community about another subgroup analysis from a competitor that also looked at regional differences where those were observed. From the data that we presented from the podium, we did not see that there were any deviations in the efficacy across subgroups. We also showed.
Go ahead, Rob.
Yeah. We also showed for the first time that patients who were treated with atacicept versus placebo in the Phase III had very similar changes in the autoantigen, the Gd-IgA1, as we saw in the Phase II, so about a 2/3 reduction. We saw a similar amount of resolution of hematuria in that 75%-80% range. Across Phase II and Phase III, similar results for the autoantigen, Gd-IgA1, similar results for resolution of hematuria, similar results for reduction in proteinuria. We're not disclosing the eGFR from the ongoing Phase III per FDA guidance, but we've got two years of eGFR data from the Phase II that looks to be the same as the healthy population. Finally, we shared a more comprehensive view of the safety data, and we think the results are favorable and comparable to placebo. We haven't seen evidence of opportunistic infections.
This doesn't appear to be an immunosuppressive prescription for patients. There were some mild injection site reactions more common in the atacicept group, but they were self-limited and didn't lead to discontinuations. Overall, I think Dr. Lafayette concluded the presentation talking about what the promise is for patients in the future. In our webcast later that day, along with Dr. Lafayette, Dr. Barrett also echoed the same really motivational view of what the future prescription will look like for patients who are suffering from this disease.
Rob, you touched on geography, and I think there have been two topics of conversation around geographic response. One, from early studies, from certain studies, they tended to be sort of East Asian heavy, whether we were talking Telitacicept early studies or some of the Sibeprenlimab enrollment. Is there thoughts around differential activity in the East Asian population? The other point of investor conversation at the conference itself was around the Sibeprenlimab North American study and its sub-30% UPCR reduction. As you mentioned, the 30% is what FDA looks for. It seems very materially different than their 50%-something top line. Any thoughts on differential response by either East Asian population or what could drive variability in a North American population? Have you guys ever had conversations with FDA about minimum North American population or minimum effectiveness specific to the North American population?
Yeah, I'll start with the latter part of your question first. We've not had deep conversations with the agency about regional differences. We've had multiple conversations with the agency after they've been privy to both our Phase II and our Phase III results. As we announced last week, we've now submitted our BLA to FDA. They'll have an opportunity to go through that in all the detail they want. To this point, that has not been an area of vibrant conversation between the sponsor and the agency. From our data set, patients who are of Asian descent or non-Asian descent behave very similarly in terms of their reduction in proteinuria.
While I appreciate that the data from some of the other competitors have had some disparate initial results between North America or South America and the rest of the world, I do note that Europeans have behaved similarly to patients from the Far East. It is a little bit difficult for me at this point to say with any conviction that I have clarity of what explains the result that the other sponsors have received. I really think it is up to them to provide the context for what they think is going on. I think once we have a product label, we will have a better sense of what the agency thinks.
At this point, I think what my colleagues, Vera and I, want to do is highlight the strength and the breadth of data that we've collected across efficacy and safety running two randomized controlled experiments, all of which use the same dose, 150 mg in a 1 mL small volume prefilled syringe, self-administered at home by patients across the totality of the program. Our confidence that we're poised to launch with an autoinjector for patients to administer at home on a weekly basis. We think that when we look at the efficacy, the safety, and the experience that patients have, we're poised to assume a leadership position once we get to the commercial stage. I'll leave it at that.
Got it. Going back to your hematuria reduction, that appears to be more rapid than other Phase III data sets from B-cell modulators. First of all, how should we think about hematuria in relationship to eGFR, in relationship to overall IgAN disease? Of course, we're always looking for a reason that APRIL BAFF will look different than APRIL only. Does this contribute to that?
Yeah, I would say that the Vera team has supreme confidence that if we know that we've got a disorder of B-cell origin that drives kidney pathology, and the B-cell is the source of both the autoantigen and the autoantibody, which come together to form pathogenic immune complex, which bombard the kidney and drive local inflammation followed by fibrosis and nephron loss, that it makes all the sense in the world if we're able to come up with a reagent that can reduce the two main cytokines that fuel B-cell activity, that that would be a lucid approach to intervene and to try and drive true disease modification. I know that there are other sponsors that have monoclonal antibodies against APRIL alone. In a world where that's all we could do, I would be super enthusiastic about that.
There is a reason I joined Vera nearly two years ago. It is because I believe that having a comprehensive intervention against the two cytokines that are the acting agents that drive activity of this cell type is poised to be the long-term solution for this and other diseases of autoimmunity. That is why I am here, and I bet my career on being here with the rest of the team. In terms of hematuria, this is an old-school test to take a urine dipstick point-of-care device and interrogate a urine sample from a patient in the office. It is also a remarkable window into thinking about the burden of active inflammation in a patient at a given point of time in a disease like IgA nephropathy, which is characterized by hematuria.
I am thrilled that the smart folks at Vera, who designed the program before my arrival, had the foresight to include sequential measures of hematuria using a urine dipstick. We started doing that as early as four weeks in the clinical program. By that time, we saw that we already had an impact on hematuria. I think we're seeing a very early example of the anti-inflammatory benefit locally of turning off the production of pathogenic immune complex.
How does that relate to what is the potential impact of that inflammation on eGFR or potentially, I mean, independent of eGFR? Are there other things like, I don't know, transplant risk?
It's both independent and related. It's independent in that it's a separate measure. At the end of the day, what we care about most is stabilizing GFR and reducing the lifetime risk where dialysis or transplant would be required. That's the objective of nephrologists globally when they're treating patients. There is a little bit of a relationship. Patients who have active glomerular inflammation have a physiologic reason to have reduced GFR acutely. We know this from a myriad of preclinical studies. There is a benefit to acutely evaporating that local inflammation. The real objective is the chronic impact on the rate of loss of kidney function. If we can get to that point where patients are only losing the same amount as a healthy 40-year-old, we've gone a long way to change their lifetime risk of needing renal replacement therapy.
How do KOLs, but also maybe community nephrologists, interpret relative efficacy of the two lead drugs that are going to be approved around the same time, atacicept and Sibeprenlimab, very likely? Beyond eGFR, does hematuria matter in which drug they reach for? Any mechanistic rationale or theories in the literature as to how those two mechanisms could separate down the line?
Yeah. First, in terms of how physicians are thinking about it and community physicians versus academic physicians, look, at 9:00 A.M. on the first Thursday of ASN, there were 8,000 people in a room to hear the atacicept Phase III ORIGIN results. I know that there are other programs in late-stage development, but they were not being presented in that forum. There are about 8,000 nephrologists who prescribe therapeutics for kidney disease in the United States. There were about 8,000 people in the auditorium hearing our data. I think we went a long way for comprehensively communicating to our future customers.
The fact that a QR code came up at the end of Dr. Lafayette's presentation where people could download the New England Journal of Medicine immediately and have access to all of the data and the full manuscript, I think was a great value for clinicians who are going to be thinking about stack-ranking drugs in the future. We know that we have competition, and we welcome that. We look forward to not only competing on the clinical side, but commercially. I think we're well poised to reach those audiences with a compelling narrative. It's grounded on, I think, the leading data set in the field, a clinical data set, a safety data set, and a patient experience that I think is unmatched. We definitely view ourselves as being in the lead at this point in time. I do think that docs are looking at both the constellation of measures that support true disease modification.
At the end of the day, the GFR is going to be the most important thing. The fact that we already have a two-year data set where we show GFR stability has put atacicept in a bucket of one in terms of the B-cell modulating drugs that have been under investigation to date. We'll see what we learn from future data releases from our competitors. As of now, there's one data set that supports a long-term GFR benefit with intervention.
As the eGFR data sets mature, I mean, obviously, the first placebo-controlled one was generated by you guys in your Phase IIb. But as those mature and are released, how can you compare eGFR? We've asked doctors a million times, "How do you compare UPCR?" The answer is this 10%-15% range. But as we look at eGFR, what is the variability of that slope measure that communicates equivalence to the field? And is it possible for a more potent, say, B-cell drug to actually improve eGFR in IgAN?
I think it'd be difficult to propose that over a long period of time that you can actually increase GFR in patients who already have a form of chronic kidney disease. We don't know how to augment someone's endowment of nephrons beyond a point of where they start. In the absence of that, the only thing that would come to mind would be something that could potentially be actually deleterious, which we've seen in the past with Bardoxolone. So I.
The hyperfiltration. Right.
Exactly. I think the best we can do is what we see in healthy people. Healthy people lose about 1 mL per minute per year of GFR after the age 40. If there's a data set that looks roughly similar to minus 1 mL per minute per year, I think we've reached the asymptote of what we can achieve in clinical medicine. That gives us a goalpost to shoot for. The wonderful thing about the Vera story with atacicept is we've demonstrated that we can achieve that in Phase II. That's what has, in large part, generated such excitement within industry, within the prescribing community, with payers, with regulators, and most importantly, with patients and their families about what the future holds.
Got it. Hypogammaglobulinemia, the low IgG that pops up in this drug class. There's been a lack of those findings with the Taci. We've seen this with other drugs in the class, both APRIL BAFF and APRIL. I mean, what could be driving this? What does this mean for real-world use? I guess, one, is this a function of potency, or is it some other aspect of binding? Two, when does it become relevant and worth monitoring for if it pops up?
Yeah. Let me start with the atacicept program. For us, the most important thing is to look at patient safety. As I shared, across the Phase II and Phase III program, we have not really seen an increase in infectious risk, or certainly, we have not seen an increase in opportunistic infections. This does not feel to me to be an immunosuppressive prescription. I am talking about atacicept administered at 150 mg by patients at home once a week. That is that data set. For other forms of B-cell modulation using other drugs at other doses in other intervals, I do not know what the impact is. We can look broadly at immunoglobulin levels and changes over time for a population, but that does not tell you what the data looks like for the outliers.
I realize that there's a Phase I data set for the Vertex program that has a definitive number for the number of cases with hypogammaglobulinemia. It's something that we haven't seen to date with the atacicept program. I don't know how that correlates to the overall mean change in IgG that they've seen in the program that they inherited from Alpine. I don't know how that's impacting their approach to monitoring it in their ongoing Phase III study. I don't know how it's going to be viewed by regulators when they look at their data set. What I am confident in is that when atacicept's delivered as a weekly self-injection of 150 mg, we haven't seen evidence of hypogammaglobulinemia, and we haven't seen evidence of opportunistic infection. I think that's going to be the information that regulators are looking at when they review our BLA.
Got it. Last question. I know we're a couple of minutes over. The Pioneer Basket study, some first data is due this quarter. What data should we expect? What are the most important endpoints in FSGS and membranous nephropathy that are being studied in the study?
Yeah. This Phase II program began in the first half of this year. We're looking at a cohort of patients who have IgA nephropathy but wouldn't meet conventional Phase II and Phase III registrational trial inclusion criteria. As far as I'm aware, we're the only sponsor looking at all comers with IgA nephropathy, even at a pre-approval stage. Given the quality of our long-term Phase II results, we felt it was important to bring forward our investment to study all comers with the disease. Once we're in those sites treating those patients, we can also look at other forms of autoimmune kidney disease. That includes patients with membranous nephropathy who have the autoantibody called anti-PLA2R directed against the glomerular antigen, and also patients with focal segmental glomerulosclerosis, minimal change disease who have antinephrin autoantibodies.
For those new cohorts, we're going to look at reduction in the autoantibody levels as well as proteinuria and other clinical measures. For the IgAN patients, we're going to look at the same parameters that we've been looking at in the ORIGIN 2B and ORIGIN 3 program. In aggregate, there will be a lot of data that we're going to be able to look at as we get further into the program and into 2026. We'll pick our spots for where the best place to share some of that data is, whether it's at an upcoming investor conference or if we want to wait to one of the early academic meetings in the 2026 calendar.
Got it. With that, we are five minutes over time. Really appreciate your patience. Folks, if you have any questions that were not addressed and you'd like answers to, please let me know. I will get them answered for you. Thank you, everyone, for joining us.
Thanks, Ritu.
Thank you.