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

Good day everyone. Welcome to the Vera Therapeutics October 22 Investor Webcast. [Operator Instructions] This call is being recorded. If you have any objections, please disconnect at this time. I would now like to turn the call over to Marshall Fordyce. Please go ahead.

Thank you, and welcome to Vera's investor webcast today. I'm Dr. Marshall Fordyce, Founder and CEO of Vera. And on behalf of the entire Vera team and all of our partners, I'm thrilled to share with you the final efficacy results of the ORIGIN Phase III trial of atacicept for the treatment of adults with IgA nephropathy. I'm speaking to you from Denver, Colorado, where the annual meeting of the American Society of Nephrology, or ASN, is hosting Kidney Week. ASN is the largest association of nephrologists in the world. Our data were presented this morning by Dr. Jonathan Barratt, the Mayer Professor of Medicine at the University of Leicester and the Head of the Renal Research Group. This morning's open pluntary session with thousands in attendance and standing room only were accompanied by pivotal trial results as published today in the New England Journal of Medicine. I'm deeply honored to have worked with Dr. Jonathan Barratt through the entirety of this research program culminating in today's final efficacy results. Today, we'll have Dr. Jonathan Barratt walk you through the presentation that was shared this morning. and then we'll close and open up for Q&A from any investors and analysts on the call. Thank you so much. Dr. Barratt?

Thank you, Marshall. So let me take you through the presentation. So atacicept is a fusion protein that combines the extracellular domain of the take receptor with an Fc domain of IgG. And the drug is designed to block the signaling of 2 critical cytokines BAFF and APRIL that drive B-cell and plasma cell proliferation survival and IgA class switch recombination. And the rationale for using ataciceptin IgA nephropathy is to address the fundamental driver of disease pathogenesis, which is disregulated B-cell and plasma cell function, that results in an excess of pathogenic IgA within the systemic circulation. And this pathogenic IgA drives immune complex formation, and these immune complexes deposit within the glomerulimmizangien where they trigger inflammation, scarring and ultimately, loss of kidney function. And the rationale for using a TACI receptor in IgA nephropathy is to reduce and prevent formation of circulating immune complexes by suppressing pathogenic IgA synthesis, thereby protecting the glomeruli against immune complex deposition and subsequent injury. We know from KDIGO that the target for treatment success in IgA nephropathy is to return the rate of loss of kidney function to what we see in healthy individuals. And that is a loss of GFR of less than 1 ml per minute per year for the rest of the patient's life because we know if we do not achieve this, there remains a substantial lifetime risk of kidney failure in these young individuals. And we know the supportive care treatment is simply not sufficient to achieve this. When we look at the data for the ever-increasing number of CKD drugs that we have seen being approved over the last few years. We know that when we look at composite kidney endpoints, that they can achieve our best a relative reduction in risk of between 16% to 55%, which means that if you have IgA nephropathy, the lifetime risk of kidney failure is barely impacted in their lifetime in terms of risk. So the ORIGIN 3 trial was a global, randomized, placebo-controlled trial of atacicept, which was administered by the patient in their own home. It was a weekly injection of 1 ml and given by subcutaneous injection, as I say, by the patient in their own home. It compared placebo against 150 milligrams of atacicept. It recruited adult patients at risk of progression of their kidney disease and in particular, high risk of progression because of persistent proteinuria despite optimized stable supportive care. When we designed the study initially, the plan was to look at the week 36 change in proteinuria. And indeed, that's what we did. Those data were presented last year and have been published. And the initial plan was to look at the week 104 effect on GFR. But when we saw the results of our Phase IIb study, which showed profound GFR protection, returning the rate of loss of kidney function to what we see in the healthy individual. We as a group felt uncomfortable exposing placebo-treated patients to standard of care only for 2 years because we had seen in multiple clinical trials that supportive care treatment alone was associated with significant loss of kidney function. And what we wanted to do was to protect the patients that are being committed to being involved in our study. And so we explored other alternatives and in agreement with the FDA, we changed our GFR endpoint from a week 104 endpoint to a week 52 endpoint. And as you can see on your screen, the secondary endpoints, which were tested in a prespecified fixed sequence where eGFR change from baseline at week 52 for all patients in the trial annualized eGFR slope through to week 104, using all available data and then changes in proteinuria IgA1 in hematuria at week 52. A long time to sustain 30% reduction in GFR decline through to week 104, on time to the first composite kidney disease progression endpoint. And of course, we were evaluating safety. And this is the first trial that has adopted this approach, but it's a very patient-centric approach in terms of protecting patients with IgA nephropathy from continued loss of kidney function. And of course, this is going to presage every other IgA nephropathy clinical trial to come because the FDA are now looking at 52 week added points for approval going forward. But this is a paradigm shift in how we approach clinical trials in IgA nephropathy. Here's the patient disposition, and I'm really just want you to notice the 3x greater discontinuation of treatment in the placebo arm. Predominantly, and most exclusively due to the fact that patients were losing kidney function the patients or the clinicians were clearly concerned about this and the adverse event similarly reflected loss of kidney function. And of course, when we think about this, if we were to have let the trial continue that number would unlikely have it increased and jeopardize the integrity of the study because we would have had so many non-protocolized events within the clinical trial. And this, of course, is another advantage of a week 52 endpoint is that we maintain trial integrity at a much greater degree than running the trial for longer, particularly in countries where there a suit of available therapies. If we look at the baseline demographics, you can see here these were predominantly a young population, a good mix of races. They already had established kidney damage with a GFR of around 65 mls per minute. They have substantial residual proteinuria, 2.2 grams per day despite good blood pressure control and despite almost universal use of running a detention system inhibitors and 60% to 65% also on an SGLT2 inhibitor. So an incredibly high-risk patient population and possibly one of the highest risk population studied to date in a randomized controlled trial in IgA nephropathy. If we look at the headline data, what you can see here is that treatment with atacicept in this high-risk IgA nephropathy population led to a return to the rate of loss of kidney function that we see in healthy individuals compared to the dramatic loss of kidney function we see on supportive care only. And when we look at the placebo-adjusted difference, we see a placebo-adjusted difference of 5.6 ml per minute at week 52, we see a placebo-adjusted difference of 11.1 ml per minute at week 104 and an annualized eGFR difference of 5 ml per minute per year. And importantly, if you look at the slope for atacicept, you can see that on atacicept, patients are losing less than 1 ml per minute per year, which is the KDIGO target, and is what we would expect to see in a healthy individual. And I just want you to take time to look at the placebo group because this really, I think, justifies our approach. Patients were losing 10% of their kidney function per year. And actually, what we are actively doing now is converting those patients who commit -- who were randomized to placebo on to active therapy to preserve their kidney function because you can see that those patients who would being involved in the study out to 2 years, lost 12 ml of GFR. And remember, they only started with between 60 to 65 ml with an average age of 40 years of life. So this is really, I think, justifies the approach we have taken in protecting patients within our trial and very clearly has allowed us to show substantial benefit with the atacicept at both week 52 and week 104. In terms of our prespecified sensitivity analysis, you can see that the GFR effect was obtained across all prespecified subgroups, both the eGFR change at week 52 and the annualized eGFR slope at week 104. All patients in all subgroups benefited equally from atacicept. If we now look at the composite kidney endpoint. And you can see here a 76% reduction through week 104 in the composite endpoint. I think this is astounding when we think that most end points in these trials occur in the second year of a clinical trial because, of course, they're related to GFR decline and those GFR decline events are much more likely to occur, the longer you were in a clinical study. We were seeing a 76% risk reduction having looked at the data at week 52, with very few patients progressing through to the end of the study. And yet we were still able to see such a significant risk reduction, bearing in mind the risk reductions that have been observed and I mentioned earlier with the general support of CKD care. And importantly, no patient treated with atacicept develop dialysis dependent kidney failure needed a kidney transplant or died during the study. In terms of proteinuria reduction, Gd-IgA1 reduction and hematuria resolution, you can see those data on your screens. And you can see that at week 52 and week 104, we had highly significant placebo-adjusted reductions in proteinuria of 51% at week 52 and 60% at week 104. We had highly significant and relevant reductions in the pathogenetic 4 of IgA at week 52 and week 104, of 67% and 65%, and we saw resolution of hematuria in 97% of atacicept treated patients at week 104. In terms of safety, most adverse events that we noted in the study were mild or moderate in severity and resolved without treatment interruption or discontinuation. Injection site reactions were mild or moderate. The rate of serious adverse events was actually lower in the atacicept group compared to the placebo. And there were no clinically relevant cases of hypogammaglobulinemia, no opportunistic infections and no deaths occurred in the atacicept group. And importantly, because of the nature of this particular drug and drugs of this class, we saw no clinically meaningful effect of antidrug antibodies on PK/PD safety or efficacy. These data have been published today with a simultaneous publication in the New England Journal. And if you want to access the publication, please scan the QR code. So in conclusion, ORIGIN 3 demonstrates that by targeting BAFF and APRIL with atacicept, you gain comprehensive disease modification in IgA nephropathy and most significantly atacicept treatment in a high-risk population of IgA nephropathy patients results in a return to the physiological rate of eGFR loss we see in the general healthy population compared to that substantial loss I showed you that occurred with patients on supportive care only. ORIGIN 3 met all prespecified endpoints, including placebo-adjusted eGFR and composite disease progression benefits atacicept was well tolerated with a favorable safety profile and generally comparable to placebo. Study participants are now transitioning to the open-label atacicept for the remainder of the trial and submission to the U.S. FDA to potential full approval will be happening in 2027, and additional regional regulatory submissions are to follow. So with that, I'm going to hand over to Marshall, I just want to take the opportunity again to thank everyone who contributed to the study, but I'll pass back to Marshall now.

Dr. Barratt, thank you so much for your collaboration with Vera Therapeutics and the design and conduct and now final efficacy analysis of this landmark study with Landmark efficacy results. I'll give a little bit of an overview of what's next within Vera Therapeutics with these data. And then Dr. Barratt, perhaps we could ask you to make a few comments on the meaning of this -- these data for the landscape, the evolving landscape of treatment options for patients with IgAN, and then we'll open up the line to questions with analysts. So first, this marks a very important moment as TRUTAKNA was improved on the basis of accelerated approval on July 7 of this year, and we have now been in commercial mode, launching in the United States. That launch is going well, and we'll be providing an update to investors in November regarding the close of the third quarter and our first earnings call in November. So we look forward to that update. Meanwhile, operationally, on the regulatory side, the Vera team has now started to put together a supplemental BLA, which will be submitted this quarter. And we would anticipate that would be reviewed by FDA leading to what we anticipate being a full approval and updated label in the middle of 2027. Those are the next key data points for the clinical regulatory progress. Also importantly, this week at ASN, the Vera team has released additional data on atacicept or TRUTAKNA now in adolescents with IgA nephropathy as well as the first data will be presented of in an adjacent autoantibody-driven kidney disease, membranous nephropathy, which should be presented on Saturday afternoon. So we look forward to showing those results. as well. With that, Dr. Barratt look for you to put these data into some context for the evolving treatment landscape, and then we'll open up for questions. Dr. Barratt?

Yes. Thank you. I mean, I think the results are absolutely outstanding. I think you saw the impact of being managed on supportive care only and the loss of kidney function. And -- it had always been an aspiration to return the rate of loss of kidney function to the physiological norm. And in fact, we put that in as an aspirational target, never expecting to achieve it in certainly in the next few years into the KDIGO guideline because that data tells us if you can achieve that, you will prevent kidney failure the lifetime of many patients with IgA nephropathy. And the data shows quite clearly that atacicept is capable in an extremely high-risk population of returning the rate of loss of kidney function to what we see in healthy individuals. And importantly, it does it in a way that is safe for patients and that patients tolerate. And indeed, I have been meeting with people in the United States. Looking at the auto-injector that is being used. It is incredibly patient friendly. Patients have no issue taking the drug in the real world. And I think this is just a fantastic addition to what we use to treat our IgA nopropathy, and it would be the first thing I would think of in a patient, I think about in terms of treating to prevent lifetime risk of kidney failure. Data are truly outstanding.

Thank you, Dr. Barratt. With that, I'll turn it over to the operator and open up the line for questions.

[Operator Instructions] Our first question comes from Anupam Rama with JPMorgan.

Can you hear me?

Yes.

Cool. Thank you. And congrats on the prolinary session, the data and the publication as well this morning. So one for the company, and then one for Dr. Barratt. So can you speak to how you think about the composite data presented earlier today for take and semiperlumab that we saw this morning at the pulmonary, and how we should put population differences, time point differences and composite endpoint definition depresses into context? And then for Dr. Barratt, I'd love to hear your perspective on that topic as well.

Thanks for the question on Anupam. I'd actually like to ask Dr. Barratt to answer that question really in both context. He's been an important collaborator. And as he highlighted, this is likely one of the patient populations that we were really concerned about throughout the program on those on standard of care. And you can see in the GFR decline in patients on placebo what we faced when we asked patient volunteers to join the trial. And it was really the company in collaboration with Dr. Barratt and the a retain the steering committee for ORIGIN 3 to end the trial before all 428 patients made it to 2 years and the randomization phase and give everyone an opportunity to benefit from TRUTAKNA. Now that was the thinking, as Dr. Barratt has highlighted. But Dr. Barratt, maybe you can highlight some of the differences across study trough comparisons.

Yes. So I think whatever I'm looking at data, first of all, I want to understand how sick the patient population ones that was included in the trial. So I look at the baseline proteinuria, I look at the baseline GFR, I look at the distribution of patients because we know patients from Asia progressed faster. And I look at the background therapy and the use of background therapy. And you can see when you look at the data for ORIGIN 3, that this is probably the highest risk population recruited to a Phase III clinical trial to date. Then -- and that's backed up by the fact that you look at the deterioration in the placebo arm, which is losing close to 6 ml per minute per year. And that is when I look at that and then I compare against other Phase III trials, you can see that actually there were potentially lower-risk populations included in other trials. So that then helps me interpret the protection that is achieved by particular therapy in terms of that delta in GFR slope that we see. Now of course, in terms of the composite kidney endpoint, that is very much a function of how long you follow patients out. If you follow patients for longer, you are going to have more events, that's the whole fundamental of a trial that's endpoint driven. It takes time to accumulate those endpoints. We made the strategic decision to protect the patients in our trial, who were taking placebo because we knew that they were going to be losing substantial proportion of their kidney function. Therefore, we made the decision to look at the data at week 52, accepting that we would have less follow-up on the entire cohort. And the consequence of that will be less event. And that, I think, is the major driver for when -- for looking at the frequency and the relative risk reduction of these events, when we look at the analysis. And I think what's astounding is that even though we had relatively shorter follow-up in our patients compared to a completed 2-year trial. You see it still saw such a highly significant reduction in the risk of endpoint events. So I think -- those are the drivers for why there appears to be a disparity, but you're not comparing apples with apples here. And I think we need to be absolutely clear in terms of how we interpret these data in the context of other clinical trials. I think it's fair to say this population is sicker than many of the other Phase III trials, and it's astounding that we saw even with such a shorter follow-up compared to others, this protection against composite in the composite kidney endpoint.

Our next question comes from Ritu Baral with TD Cowen.

Dr. Barratt, as you look across the data presented today at ASN and from previous conferences. But since we have the first sort of comprehensive data sets from an April versus April Bath agent and accumulating evidence. Is there any signal across the data sets that suggest differential biology in the sort of single target versus dual agents. Where could we look at biomarkers -- the only biomarkers we have to measure at the moment pro -- proteinuria hematuria and GFR, and they're probably not going to tell us the full story of how these drugs are impacting on biology. I think what's really pleasing for me is when we look at the 2 trials now, 2 international trials looking at combined BAFF and APRIL inhibition that were presented this morning, 2 trials targeting both BAFF and APRIL into different populations run by 2 different study teams that validated almost to the decimal point, the treatment effect of combining BAFF and APRIL inhibition. Both in terms of treatment efficacy but also safety. And that I think is incredibly powerful that we now have 2 studies in entirely different populations showing that this isn't a fluke event. This is a true finding from 2 completely separate clinical trials. So I think that is incredibly powerful. I think where we are potentially going to see differences when we look mechanistically, outside of the very blunt tools we use in terms of hematuria proteinuria GFR. And I think the other thing is we have -- this is still a relatively short time scale in terms of following patients. remembering that we are likely to need to treat patients for 30, 40 years. And I think the data on BAFF inhibition certainly in lupus nephritis is that the role of BAFF and blocking BAFF. It becomes much more important. The longer the patient is on treatment to provide continued immunological control. So we are at the early stages of understanding these drugs. And I think we're going to need longer-term data and we are going to need to look from a biochemical perspective at biomarkers that we haven't had the opportunity to look at yet. But I come back to the fact what I think is most striking is the fact we have had 2 completely independent studies targeting BAFF and APRIL that have delivered the same incredible efficacy with a safety and tolerability profile that is incredibly reassuring.

Our next question comes from Pete Stavropoulos with Cantor.

Rob and Sean, congrats on the presentation and also another publication. A question for Dr. Barratt. We had a look at TRUTAKNA's impact on subgroups for our proteinuria last year at ASN. And today, you provided that on subgroups for the final analysis. What are the key takeaways from those analyses. And what do they tell you about TRUTAKNA? And just sort of a follow-up on Anupam's question, I may have missed it, maybe you said something. But was there any differences in what the composite endpoints measured for TRUTAKNA versus vymj. So will the sensitivity analyses looking at subgroup showed a highly consistent treatment effect of atacicept across all prespecified subgroups. And I'm just looking at the other screen here. The prespecified subgroups were age above and below 40, male versus female, region of recruitment, Americas, Europe, Asia Australia versus Asia, white versus nonwhite above or below 1.5 grams per gram of proteinuria, a GFR above or below 45 and above or below 60 and whether the papas an SGLT2 or not. And irrespective of those subgroups, the treatment effect was identical. So nothing to suggest there are a group of patients who are going to do less well on atacicept. In terms of the definition of the composite kidney endpoint for the ORIGIN 3 trial. It comprised a greater than or equal to 30% decline in GFR, sustained for greater than 30 days, an eGFR less than 15, sustained for greater than 30 days chronic dialysis for greater than 30 days, kidney transplant or death. And you'll have to excuse me because I'm not -- I don't -- I can't remember, even though I'm a member of the visionary trial. I cannot -- I don't want to be misquoted for the composite kidney endpoint for that trial, but it will be in the New England Journal publication.

Our next question comes from Paul Choi with Goldman Sachs.

And congratulations on the data presentation at the plenary and the New England Journal article. I want to ask maybe Dr. Barratt first. I guess, now that we've seen the detailed data here as well as longer-term follow-up for drugs in this class, APRIL and APRIL RAFF inhibitors. How are you and your colleagues as well as the medical societies thinking about shortening sort of the watchful waiting period after using background therapies such as ASRs and SGLT2s and sort of potentially shortening the time to getting on one of these new IgAN therapies. That's my first question. And then, second, for the company for Marshall and team, can you maybe update us on how you're thinking about uptake of TRUTAKNA might inflect once you get the full data here on the label here next year and just sort of how that is something that doctors or insurers are waiting for at this point?

So I think we are promoting no wait and see. The KDIGO guideline is explicitly clear, we want simultaneous therapy targeting the disease modification and the CKD aspects of disease. And so everything that has been talked about is if you have a patient at risk of progression, which is more than 0.5 gram of proteinuria per day, but you need to simultaneously target the disease with a drug like TRUTAKNA and you -- or ideally like TRUTAKNA, you might say, and target the CKD aspects of disease. So no waiting and no period of measuring response is immediate therapy with both disease modification and CKD treatment.

Great. Great question, Paul, and I'll address this and maybe ask Matt Skelton, our Chief Commercial Officer, to make additional comments. We're on the ground here at ASN in Denver. We're speaking to nephrologists. It was the largest collection of nephrologists in that opening plenary session. There is no doubt a shift in how nephrologists are thinking about treating their patients with IgA nephropathy. This is the creation of a new medical category. What you're seeing are the stages of validation of that data. A year ago, we had a surrogate endpoint that's now in the label showing a reduction in proteinuria and a very broad indication statement. So that really enables physicians to prescribe TRUTAKNA to all patients, they believe are at risk of disease progression with the biopsy-proven IgAN diagnosis. On the other hand, important for us to advance that validation to these final efficacy analyses. Now presented and because of the good work of this team in a peer-reviewed publication simultaneously today. That's an immediate tool for the medical community. On the commercial side, of course, the sales force is restricted in their detailing and sales work to stick to the current label. That, of course, will be enabled and unlocked next year with a full approval label and, of course, the key data points that you've seen here, and I would highlight the eGFR annual slope difference of 5.0, which is a phenomenal benefit on the GFR that we've shown in this population and the improvement and avoidance of terrible outcomes like death, dialysis and transplant we hope to be included in that label. Matt, would you like to make any comment on the commercial inflection we might anticipate?

Sure. Sure. Thanks, Marshall. Yes, I would expect a nice inflection point when we can actively promote the comprehensive data set and look forward to that full approval, but I do think, Paul, also having a plenary session today, a New England Journal publication the news of these results is going to be into the community pretty fast. So yes, I hope that answers the question, Paul.

Our next question comes from Farzin Haque with Jefferies.

One question for the management. Do you have a potential responder analysis, specifically like what proportion of the patients are getting below clinically relevant thresholds like less than 1 gram, 0.5, 0.3. And then for Dr. Barratt. I'm trying to resolve something. If patients are achieving on average like 50% reduction in the PCR. This still leaves the average patient with like residual proteinuria roughly calculating like 0.8 grams, depending on the baseline. So how should we think about the clinical significance of that residual proteinuria if the ADF clearly stabilizing. Like do you need to change the definition? Like should we move away from trying to drive patients to much lower absolute PSL levels?

Farzin, thanks for the question. And I think I'll just say that, that analysis is not currently available. And we believe that the more important analyses are the impact on GFR and renal composite endpoints. But Dr. Barratt, maybe you could speak about the relevance of residual proteinuria in the context of standard of care as designed in this trial, ASR plus an SGLT2 inhibitor, which is about 60% of the trial plus TRUTAKNA versus placebo with the results that we're presenting today and the meaningfulness of a residual proteinuria.

Yes. I mean, I think it's a great question, and it's a real hot topic. And I think we are redefining our understanding of the significance of proteinuria with drugs like atacicept. We are seeing that actually you can have residual proteinuria and maintain your GFR or return your GFR loss to physiological rates. And that's not true with drugs of other classes. And it's important also to understand that the proteinuria reduction you achieved with atacicept translates to, as Marshall said, a 5 ml per minute per year protection against declining kidney function, an identical reduction in proteinuria with a predominantly hemodynamically acting drug delivers less than 1 ml per minute per year protection against continued kidney function decline. And this is making us completely rethink and the interpretation of reductions in proteinuria and residual proteinuria, and we need to think about these in the context of the drug that achieved that change. And the implications for proteinuria, if you were on a drug like atacicept are completely different to the implications of a protein reduction in residual proteinuria if you're on a hemodynamically acting drug. So I would say, watch this space because we are doing a lot of work behind the scenes looking at the implications of this disassociation between proteinuria and GFR protection that we're seeing with drugs like atacicept, which fundamentally target the base pathophysiology of IgA nephropathy.

Our next question comes from Ryan Deschner with Raymond James.