Vera Therapeutics, Inc. (VERA) Earnings Call Transcript & Summary

Good morning, and welcome to the Vera Therapeutics KOL event. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Vera website following the conclusion of the event. I'd now like to turn the call over to your host, Marshall Fordyce, Founder and Chief Executive Officer of Vera Therapeutics. Please go ahead, Marshall.

Thank you, [ Tara ]. Good morning, and welcome. I'm Marshall Fordyce, I'm the Founder and CEO of Vera Therapeutics. We previously shared top line week 24 results from our multinational, randomized, placebo-controlled Phase IIb ORIGIN trial, which focused on the FDA's gold standard analysis intention to treat. Today, we're pleased to share further analyses from the ORIGIN trial that we believe will help put atacicept's Phase IIb results in context across the evolving treatment landscape for IgA Nephropathy and highlight atacicept's potency and competitive position as we plan for our Phase III pivotal trial this year. Before we get started, I want to remind you we'll be making forward-looking statements under the safe harbor act. And as such, we present this disclaimer regarding at-risk statements. I'll begin by providing a brief overview of our program for atacicept and IgAN, then provide detail on the predefined analysis sets in our Phase IIb study, a summary of our Phase IIb results and then highlight upcoming milestones for the program. Then I'll ask Dr. Jonathan Barratt, who leads the Renal Research Group at the University of Leicester, and is an internationally recognized expert in IgA nephropathy to present the results in detail and put them into context of the evolving landscape for IgAN. I'll then provide further detail on our plans for Phase III, which we expect to initiate in the first half of this year, subject to discussions with FDA, and then we'll open the line for questions. As many of you know, Vera's lead molecule in IgA nephropathy is atacicept, a biologic fusion protein that is self-administered as an injection subcutaneously once per week. Atacicept targets the source of IgA nephropathy by inhibiting two circulating cytokines, BLyS or BAFF, and APRIL, which are both important for the survival and maturation of the B-cell lineage and the cells that produce autoantibodies in certain autoimmune diseases. We designed the ORIGIN study to demonstrate whether atacicept's known effect on the upstream causes of IgAN translate into improved kidney function as measured by reduction in proteinuria. We're running a multinational, double-blind, placebo-controlled randomized Phase IIb trial to provide the best evidence to demonstrate a clear treatment effect of atacicept in IgAN patients. This study design enables us to assess whether any factors, other than the treatment itself can influence the primary endpoint, so-called confounders, and make sure that they're well distributed between the treatment and control arms. This study is blinded through 36 weeks and has a primary endpoint analysis of intention to treat, which is the gold standard held by FDA and we anticipate will be required for Phase III. We also had a prespecified per protocol analysis of proteinuria to leverage Phase II learnings for Phase III success and that will be the focus of today's discussion. In early January, we disclosed the top line results from our primary endpoint, intention to treat. This is a conservative assessment that includes all patients who are randomized regardless of whether they followed protocol or not. In the case of our study, that included 116 patients. As previously reported, these results were positive, statistically significant and close to twofold better than the one approved drug Tarpeyo at the week 24 time point. Benchmarking our Phase II primary endpoint against an approved drug gives us confidence that atacicept can hit the primary endpoint of intention to treat in Phase III and substantially improves our probability of success in Phase III since our Phase III study is very similar to our Phase II study. In order to better understand the full effect of atacicept on proteinuria, we prespecified a per-protocol analysis. This is defined as all patients who completed treatment according to protocol. The criteria were prespecified and independent nephrologists from a third-party CRO conducted a blinded review of subjects to identify major protocol violations. They identified 14 patients across all treatment arms. These patients had changes in their background regimen that are likely to have influenced their proteinuria results. Of the 14, 6 had a change in RAAS inhibition during the study; 3 initiated SGLT2 inhibitors too close to baseline; 3 did not reach the week 24 time point; one initiated a steroid during the study and one had compliance less than 80%. The per protocol analysis was not available at the time of our top line disclosure, and this analysis set really provides a more accurate assessment of treatment efficacy because it minimizes potential confounders for proteinuria. The ORIGIN study met its primary endpoint at week 24 by the gold standard ITT analysis with statistical significance, proteinuria reduction by per protocol analysis at the 150-milligram dose demonstrated a 41% reduction from baseline at 24 weeks with a calculated placebo delta of 34%. And at 36 weeks, we see continued reduction in proteinuria, 47% reduction from baseline with a calculated placebo adjusted delta of 48% through the 36-week time point. As previously reported, patients on atacicept had stable renal function as measured by eGFR over 24 weeks. The 150-milligram dose showed Gd-IgA1 reduction of 60% at 24 weeks. And the safety profile for atacicept was similar to placebo. We've selected the 150-milligram dose to advance into Phase III and expect to initiate that trial in the first half of this year, subject to discussions with FDA. And as we look ahead, next quarter, we plan to present an update of the full week 36 results. We're currently preparing for Phase III and plan to announce initiation of that trial before midyear. The Phase IIb ORIGIN study provides a rich dataset, including up to 2 years follow-up, which we plan to continue to analyze and present in conferences throughout 2023 and 2024. Our expected Phase III primary endpoint readout is anticipated to be in the first half of 2025, enabling a BLA submission later that year and an anticipated commercial launch in 2026. With that, I'll ask Dr. Barratt to present the results in detail. Jon?

Thanks very much, Marshall. So if we can go to the next slide, please. So just a quick reminder on the design of ORIGIN. So ORIGIN is a multinational, randomized, placebo-controlled trial powered to detect to 28% difference between the pooled 75- and 150-milligram doses of atacicept and placebo. The randomized phase lasts for 36 weeks. And today, I'm going to discuss the 24- and 36-week data. ORIGIN recruited adults with biopsy-proven IgA nephropathy at high risk of disease progression; meaning that despite being on maximal tolerated ACE inhibitor or ARB, they still have at least 0.75 grams of protein in their urine, with the lower level of eGFR allowed for entry being 30 mls per minute. The primary endpoint was proteinuria at 24 weeks. And the secondary endpoints include proteinuria reduction at 36 weeks and eGFR up to 96 weeks, Gd-IgA1 reductions in safety. Could you go on to the next slide, please. So it's well reported that a 30% reduction in proteinuria is known to be clinically meaningful in our IgA nephropathy. This is based on natural history studies of IgA nephropathy patients, in which a 30% reduction in proteinuria at 9 months is associated with a significantly slower rate of loss of kidney function and a potential delay of end-stage kidney disease by over 10 years. As you all know, the first and only drug approved in IgA nephropathy showed an approximately 18% reduction in proteinuria at 6 months and a 31% reduction at 9 months, and was granted accelerated approval for patients with IgA nephropathy and proteinuria greater than 1.5 grams per day. If we go to the next slide. The ORIGIN study is a multinational trial that includes patients in the U.S., countries in Europe and the Asia Pacific region. And as you can see from the graph on the slide here, enrollment was not overrepresented by any single country in this study. If we go to the next slide. So the 210 patients screened, 116 patients were enrolled. Previously, I presented the intention to treat population, which is all 116 subjects that were randomized. Today, I'm going to present the per protocol population. And as you've heard already, this was a prespecified population in which prior to unblinding, blinded third-party physicians determined whether protocol violations had occurred. And those subjects where there had been a protocol violation were excluded as previously described by Marshall, giving a total population of 102 patients for the per protocol analysis. Because the majority of subjects who violated the protocol were due to changes in background regimen, assessing proteinuria reduction by the per protocol analysis is a more accurate way to compare ORIGIN results to other programs. Just to note again, there was a low discontinuation rate in this study, 2% of the atacicept arm, and 3% in the placebo arm. If we go to the next slide. As I previously presented, the study enrolled patients who were at high risk of IgA nephropathy progression, and were on current optimized support of care, allowing us to make a clear assessment of the treatment effect of atacicept compared to placebo on top of what is regarding currently as standard of care therapy in a diverse global population. Average age was 39, 59% were male, 44% of Asian ancestry and the average eGFR was 63 mls per minute, with an average UPCR of 1.6 grams per gram. Patients were an optimized dose inhibitor or ARB, but in addition, if a subject was also on a stable dose of an SGLT2 inhibitor, without change for at least 8 weeks, they were allowed to enroll in ORIGIN. And as you can see, 14% of subjects on SGLT2 inhibitors were enrolled in ORIGIN. If we go to the next slide. So here, you can see the change in proteinuria as evaluated by the UPCR, the urine protein to creatinine ratio for 24-hour collection. And you can see a significant and dose-dependent reduction in proteinuria in those patients treated with atacicept compared to placebo. For the 150-milligram dose at week 24, there was a 41% reduction compared to a 10% reduction of placebo with a calculated delta of 34% and a p-value of 0.025. At week 36, with 38% of subject data available, a 47% reduction was seen compared to an increase of 3% on placebo with a calculated delta of 48%. We go to the next slide. So when we look at a responder analysis, and this is a responder analysis of those patients who had an over 50% reduction in proteinuria at week 24, what you can see here is that 33% of those patients on atacicept 150 milligrams experienced a 50% reduction in proteinuria. If we go to the next slide. This is a slightly different responder analysis. But here, you can see, of those patients who had a baseline proteinuria of over 1 gram per gram, 43% of those patients on atacicept 150 milligrams achieved a proteinuria of less than 1 gram per gram at week 24. If we go to the next slide. So this is -- as our data presented previously, which is the primary endpoint, which was an intention to treat analysis, looking at the change in proteinuria as evaluated by the UPCR at week 24 of the pooled 75- and 150-milligram dose groups. And as you've heard already, that achieved statistical significance and showed a 31% mean reduction compared to baseline with a p-value of 0.037 compared to placebo. The magnitude of proteinuria reduction by this analysis was clearly affected by major protocol violations as you can see if you compare this data to the per protocol analysis. And in this graph here, you now see the 150-milligram and 75-milligram dose effects over time. And you can see there's a clear dose dependence and is statistically significant reduction in proteinuria at week 24 for the atacicept 150-milligram arm, with evidence of further proteinuria lowering for 150 milligrams at week 36. If we go to the next slide. So now putting the atacicept Phase II data in the context of the emerging treatment landscape, you can see that the magnitude of proteinuria reduction seen in ORIGIN have the best-in-class potential, especially given the rigor of the trial design and analysis. And you can see here the Vera data with the intention to treat and per protocol analysis data presented. And here, you can see that we compare the atacicept results to the other multinational randomized placebo-controlled trials with data at week 24 and 32. But given the differences in study design across these studies and the analyses that are thus, far being performed, we believe the best comparison is atacicept and TARPEYO. And although they have not been compared directly in a head-to-head study, the intention to treat and full analysis set analyses are similar. And what you can see here is that atacicept shows approximately a twofold greater reduction in proteinuria at the week 24 time point. The Novartis study of Iptacopan and the Anylam study of Cemdisiran, you can see the data presented on your screen. You can note that there were significantly fewer patients. And at present, the analysis that was being performed on specified -- that we do not have p-values. Notably, the atacicept Phase II study is the only one of those studies that has allowed patients on SGLT2 inhibitors to be enrolled in the study. If we go to the next slide. So if we now look at the comparisons across the multinational randomized specific controlled trials, looking at week 36 now. We can see that atacicept's 48% delta is the highest reported in the field, again, suggesting best-in-class potential. And if we look at the data for sibeprenlimab, which was reported at ASN late last year, which is a [indiscernible] -- approach, you can say that they reported a 43% delta in this Phase II study of an intravenous infusion. Both of these -- both of the results you see at the moment are not specified because the data has not been presented in terms of the analysis that's been performed. If we go to the next slide. What you can see here is the eGFR data. And looking at the eGFR data, both for the intention to treat population and the per protocol analysis, you can see that there is stability of eGFR for patients on atacicept. That's what we might expect because at this early time point we wouldn't expect to see a significant decline in eGFR for patients on placebo. If we go to the next slide. As I've shown previously, the safety results indicate that atacicept was well tolerated with adverse events similar to placebo. 2% of serious -- there was 2% of serious adverse events overall and not on the 150-milligram arm. There was a 1% discontinuation rate. Infections was similar between atacicept and placebo arms, and there were no cases of hypokalemic popular anemia. So placing into context the efficacy data and the safety data I've just described, I believe these data are very exciting and show a significant impact on renal function as measured by proteinuria and strongly support advancing atacicept into Phase III. So I'm now going to turn back to Marshall to continue the presentation.

Thank you, Dr. Barratt. We're now preparing to initiate our Phase III program. We have alignment with FDA regarding our Phase III design and can leverage our Phase II global operations for a rapid start for Phase III. Dose selection is complete and has conducted in Phase II. We will test the self-administered subcutaneous formulation in Phase III as we did in Phase II. We're positioned well because Phase II informs Phase III, both operationally as well as from a data standpoint. We're in a strong position to not require much change within protocol and operations. Entry criteria and study conduct will be very similar in Phase III. And we have the additional ability using subgroup analyses and other insights from our global Phase II program to make slight modifications to maximize efficacy in Phase III and ensure strong results. The Phase III study design will be another global randomized, placebo-controlled trial of atacicept, this time single dose 150 milligrams as a self-administered 1 milliliter subcutaneous dose once weekly compared to placebo. The primary endpoint will be proteinuria reduction at week 36 with a confirmatory secondary endpoint of estimated eGFR at 104 weeks or 2 years. Entry criteria for Phase III are very similar to Phase II. Turning next to our development timeline. We project primary endpoint readout for the Phase III study in the first half of 2025 and we anticipate submitting our BLA later that year. With that, I'd like to open up the lines for questions. And Dr. Barratt, Dr. Lin and myself will be available to respond. Tara, happy to open the lines up now.

Great. Thank you, Marshall. So at this time, we'll be conducting a Q&A session with our speakers. [Operator Instructions] So our first question comes from Priyanka Grover from JPMorgan.

This is Priyanka on for Anupam Rama. I had a couple of questions. What medical meeting are you targeting? And on Slide 24, you talk about the subgroup analyses that we performed to guide Phase III. Will these subgroup analyses be presented at an initial full medical conference presentation? And the other question I had is what is your level of confidence that the 36-week data are replicated in the full analysis in 2Q? And what gives you this confidence?

Yes. Good questions. So just first -- to the first question, we will target the major renal meetings, both European Renal Association as well as Kidney Week, and we'll provide specifics as those dates get closer. Number two, about subgroup analyses. These are important insights from Phase II in forming Phase III. I can share that at a high level. We're confident in atacicept's efficacy according to proteinuria and all subgroups. It's not yet decided whether we'll share that data in detail in a public forum. These are important insights that set us up for Phase III operations, protocol and conduct. And then finally, we are confident in the week 36 data. This is a portion of the data, 38% of all subjects who are representative of the average that we see at week 24. And of course, we'll provide an update when the full dataset is in.

So our next question comes from Liisa Bayko from Evercore.

Marshall, can you go through some of the reasons for protocol violations and in particular, the change of RAAS inhibitor medications. Like why would that affect proteinuria in a negative way? It seems like when we did our back of the envelope, it was about a 10% change for those five patients that were taken out of the analysis. And why we're changing that medication, for example, and some of the others are a little obvious, but that seemed to be a big one, and I was curious. And then my next question is just around what you can do with Phase III to try to kind of reduce as much as possible these protocol violations?

Yes. Good question. I think it's well known that changes in RAAS inhibition, ACE inhibitors, angiotensin receptor blockers can have an effect of tens of percents on proteinuria. So one can imagine, regardless of treatment arm, both an increase in dose or a decrease in dose having that effect in individuals. And it's important to protocolize background regimens, not only in IgAN clinical studies, but in other studies. Changes in background regimen can threaten the primary endpoint. This was an approach that we took in Phase II to recommend stability of these treatments. And I can say that it's several changes we can make going from Phase II to Phase III can optimize the intention-to-treat number going into Phase III. So these are protocol violations that were identified. These happen at this rate. Similarly, with the study of this size, with about 30 subjects per arm, you can imagine 3 to 5 subjects having a significant impact on the primary endpoint. So this is all within our expectations of what we'd expect to see.

So our next question comes from Ritu Baral from Cowen.

Dr. Barratt, a question for you. How do you expect these immunomodulatory drugs to -- well, how would you expect their clinical benefit to behave as you think about different baseline characteristics? I think as we look at some of these trials that are on Slide 19, there were different baseline UPCRs. Would you expect, I guess, a greater benefit or less of a benefit as you sort of go down that grams of protein? And then a corollary, Marshall, for you. I believe, since you are changing the UPCR from the Phase III -- down in the Phase III versus the Phase II, what do you expect baseline to end up?

Should I go first...

Yes. Go ahead, Dr. Barratt.

So I think this approach of targeting the production of pathogenic IgA is going to be fundamental to any treatment going forward in this disease. We know that the background therapy with RAAS inhibitors, with SGLT2 inhibitors is protective to proteinuria kidney disease, but it does nothing to the underlying pathology of this disease in terms of stopping IgA deposits in the kidneys. That's the rationale for this approach. And so, my view is that this approach is going to be important in all patients with IgA nephropathy, whether you have high levels of proteinuria or you have lower levels of proteinuria. And in my view, and we will have a publication coming out shortly, looking at over 4,000 patients with IgA nephropathy in U.K. rare disease registry, we are going to start to make arguments that actually we need to lower the threshold at which we treat patients because we've got to prevent them from developing kidney failure in their lifetime. And so for me, an approach that targets the fundamentals of this disease in terms of turning off the production of pathogenic IgA is going to be critical in all patients with IgA nephropathy, not only those with IgA nephropathy and their native kidneys, but also those with IgA nephropathy and the risk of developing recurrent disease in a kidney transplant. So I think the baseline characteristics help you re-stratify. But in actual fact, they for me, are not relevant to which patient with IgA nephropathy justifies an approach like this because any patient who's had a kidney biopsy, who has IgA nephropathy requires a drug that is going to turn off production of pathogenic IgA. I'll hand over to Marshall.

Thank you, Dr. Barratt. I think the comment from -- or the question from Ritu is how are we changing baseline proteinuria going from Phase II to Phase III? It's a slight modification. In Phase II, we used 0.75 as the cutoff. And as we go into Phase III, we'll use 1 gram per gram as the entry criteria. Of course, even with the 0.75, we ended up enrolling an average proteinuria of 1.6 grams per gram over time. And now we have data on efficacy in both patient population above and below that threshold. So we're confident in the efficacy that we see here being replicable in Phase III.

Marshall, would you expect the baseline to spend be pretty much equivalent between Phase III and Phase II?

I would. I think these are minor modifications.

Our next question comes from Rami Katkhuda from LifeSci Capital.

I guess I may be extrapolating a bit, but it looks as if proteinuria reductions with the 75 mg dose have started to plateau at week 36, while the 150 mg dose continues to decrease over time. Was that a consideration when deciding on the dose for the Phase III trial? And do you expect proteinuria to kind of continue to decrease beyond the week 36 time point? And secondly, did the protocol violations occur at a few specific clinical sites? Or were they distributed across geographies?

Great. Both good questions, Rami. So the second one first. No, we did not identify a specific site that had these. These were distributed across the global sites involved in the trial. We agree, I think, looking at the dose response, we're pleased to see that 150 milligrams outperformed 75 milligrams, and agree that 150 milligrams has deepening proteinuria reductions going from baseline to week 12 to week 24 and now week 36. I think we don't yet know what the kinetics are of proteinuria reduction, what the dual inhibition of BLyS-APRIL. As we have on these doses. But agree that there seems to be a plateauing effect at 75 milligrams but a deepening effect at 150 milligrams. So expectations beyond that. I think sometimes B cell modification has a longer-term benefit that one can see. That's certainly been seen for the belimumab or Benlysta programs and other diseases. So I think targeting the source of the disease and having a disease-modifying effect over time, as we've shown previously in 2022, atacicept actually reduces Gd-IgA1, reduces autoantibodies and reduces immune complex. We've shown that in the prior randomized trial in Phase IIa. Now we're showing that, that translates into proteinuria benefit, and we'll see how that continues to translate beyond week 36. Thankfully, ORIGIN will be run for 2 years. So we'll be able to have ongoing data trying to answer that question.

Our next question comes from Maury Raycroft from Jefferies.

I was wondering for the per protocol analysis, can you clarify what cohorts the 14 patients were in? And is there anything additional you can say related to setting expectations for the full 36-week data, potentially comment on eGFR expectation specifically?

Yes. Good question, Maury. I think that we've shown what the reasons are, the five reasons that we've listed for major protocol violations, which I think are reasonably tied to an effect on proteinuria. They're distributed across all three treatment arms. We provided both the per protocol and ITT analyses in the slide deck that delineates which patients as well are in each analysis at. So I think that's all in good shape. We have -- we've got a sense that as we move to week 36, these are representative of the full patient population. We don't expect that number to change substantially.

Got it. And anything you can say for eGFR expectations? And when you get the full 36-week data, will you have to get final clarity from FDA on the protocol? Is that basically the next step for getting that final FDA feedback?

Yes. Sorry, I missed your question on the GFR. So yes, our expectation is that GFR is really going to be stable through 36 weeks, and we would not expect -- it's an early time point to start to expect significant decline in placebo. So, so far, at week 24, the data looks stable on both atacicept and placebo, and then we do expect that to continue into week 36. I have -- just to interrupt here, Tara, I've got a question online I'd like to address. One question was what do we mean by prespecified? And when was the analysis added. So this analysis was a part of the statistical analysis plan that was clearly -- those need to be in place with criteria and predefinition prior to unblinding. So this was prespecified prior to the unblinding of the study in -- unblinding of this analysis in December. Happy to take the next question, Tara.

Great. Thank you, Marshall, and thank you, Maury, for the question. So our next question comes from Laura Chico from Wedbush.

I apologize. I think I missed this earlier, but with respect to the protocol violations, why are these not uncovered, I guess, in the initial QC of the data? I think you mentioned this is a blinded third-party CRO. So just trying to understand why these weren't originally raised earlier? And then one question on the expectations around the presentation of the full dataset. Will you be including the 25 mg cohort in that? And then final question, I think serious adverse events were actually higher in the placebo group relative to the treatment group. So just wondering if you could characterize those at all?

Sure. I'll try to grab each of those. So actually, Laura, can you repeat the first question?

Sure. Too many at once. Just with respect to the protocol violations, I think I missed this earlier, but why wasn't this originally raised in the initial QC?