Vera Therapeutics, Inc. Class A Common Stock Study update

Please go ahead. Thank you, and welcome to Vera's investor webcast today.

I am Dr. Marshall Fordyce, founder and CEO of Vera, and on behalf of the entire Vera team and all of our partners, I am 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 am 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 plenary session, with thousands in attendance in standing room only, were accompanied by pivotal trial results as published today in "The New England Journal of Medicine." I am 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 will have Dr. Jonathan Barratt walk you through the presentation that was shared this morning, and then we will close and open up for Q&A from any investors and analysts on the call. Thank you so much. Dr. Barratt?

Thank you, Marshall. Let me take you through the presentation. Atacicept is a fusion protein that combines the extracellular domain of the TACI receptor with an Fc domain of IgG. The drug is designed to block the signaling of two critical cytokines, BAFF and APRIL, that drive B-cell and plasma cell proliferation, survival, and IgA class switch recombination. The rationale for using atacicept in IgA nephropathy is to address the fundamental driver of disease pathogenesis, which is dysregulated B-cell and plasma cell function that results in an excess of pathogenic IgA within the systemic circulation. This pathogenic IgA drives immune complex formation, and these immune complexes deposit within the glomerulus and mesangium where they trigger inflammation, scarring, and ultimately loss of kidney function.

The rationale for using atacicept 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. That is a loss of GFR of less than 1 mil 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. We know that 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, at best, a relative reduction in risk of between 16%-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. The ORIGIN3 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 mil, 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. 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.

What we wanted to do was to protect the patients that had committed to being involved in our study. 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. As you can see on your screen, the secondary endpoints, which were tested in a pre-specified fixed sequence, were 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 Gd-IgA1 and hematuria at week 52, a long time to sustained 30% reduction in GFR decline through to week 104, and time to the first composite kidney disease progression endpoint. Of course, we were evaluating safety.

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. Of course, this is going to presage every other IgA nephropathy clinical trial to come because the FDA are now looking at 52-week endpoints for approval going forward. But this is a paradigm shift in how we approach clinical trials in IgA nephropathy. Here's the patient disposition, I really just want you to notice the 3 times greater discontinuation of treatment in the placebo arm. Predominantly, and almost exclusively due to the fact that patients were losing kidney function, the patients or the clinicians were clearly concerned about this, and the adverse events similarly reflected loss of kidney function.

Of course, when we think about this, if we were to have let the trial continue, that number would unlikely have increased and jeopardized the integrity of the study because we would have had so many non-protocolized events within the clinical trial. 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 are a surfeit 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 mils per minute.

They had substantial residual proteinuria, 2.2 grams per day, despite good blood pressure control and despite almost universal use of renin-angiotensin system inhibitors, and 60%-65% also on an SGLT2 inhibitor. So an incredibly high-risk patient population, and possibly one of the highest risk populations 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. When we look at the placebo-adjusted difference, we see a placebo-adjusted difference of 5.6 mils per minute at week 52.

We see a placebo-adjusted difference of 11.1 mils per minute at week 104, and an annualized eGFR difference of 5 mils per minute per year. Importantly, if you look at the slope for atacicept, you can see that on atacicept, patients are losing less than 1 mil per minute per year, which is the KDIGO target and is what we would expect to see in a healthy individual. 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. Actually, what we are actively doing now is converting those patients who were randomized to placebo onto active therapy to preserve their kidney function, because you can see that those patients who had been involved in the study out to 2 years lost 12 mils of GFR.

Remember, they only started with between 60 to 65 mils, with an average age of 40 years of life. 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 atacicept at both week 52 and at week 104. In terms of our pre-specified sensitivity analyses, you can see that the GFR effect was obtained across all pre-specified 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, you can see here a 76% reduction through week 104 in the composite endpoint.