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

Greetings. Welcome to Vera's Phase IIb week 24 Results Update Call. [Operator Instructions] I will now turn the conference over to Dr. Marshall Fordyce, Founder and CEO of Vera Therapeutics. Dr. Fordyce, you may now begin.

Good morning, and welcome. I'm Dr. Marshall Fordyce, Founder and CEO of Vera Therapeutics where we're working to develop innovative, new therapies to improve standard of care for patients with immunologic disease. Today, I'm really pleased to share the top line results from our ongoing multinational, randomized, placebo-controlled Phase IIb trial called ORIGIN. Before we get started, I want to remind you that this teleconference contains forward-looking statements under the Safe Harbor Act. And as such, we present this disclaimer regarding at-risk statements. Today, I'll begin by providing the background for the ORIGIN Phase IIb trial that targets the source of disease for IgA nephropathy patients, and I will summarize today's results and outline next steps for clinical development for atacicept in IgA nephropathy. Next, 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 today's results. I'll then summarize key takeaways from the data, put it into context in the evolving treatment landscape, and outline our plans for Phase III and then open the line for questions. This is an exciting moment for patients with IgAN, and we're grateful to all our partners and stakeholders and this team's effort to develop to deliver these important results. There's emerging evidence in current clinical trials that targeting B cells, the source of pathogenic autoantibodies in IgAN, could be disease-modifying and substantially improved kidney function over time for these young patients. Vera's lead molecule in IgAN is atacicept, a biologic fusion protein that is self-administered as an injection once per week. Atacicept targets the source of IgAN by inhibiting 2 circulating cytokines, BLyS, also known as BAFF and APRIL, which are both important for the survival and maturation of the B-cell lineage. We have previously shown in an earlier randomized placebo-controlled trial that atacicept substantially reduces the causative molecule of IgA nephropathy called galactose-deficient IgA1 or Gd-IgA1. We have also shown that atacicept reduces IgG autoantibodies to Gd-IgA1 and that atacicept reduces immune complexes that form and cause the downstream kidney injury that occurs in these young patients. We designed the ORIGIN study to demonstrate whether atacicept's known effects on the upstream causes of IgAN translate into improved kidney function as measured by reduction in proteinuria and the stability of estimated glomerulal filtration rate or eGFR. The best evidence to demonstrate a clear treatment effect in a novel medication, is to run a multinational, double-blind, placebo-controlled randomized trial so that any factors that might influence the primary endpoint, in this case, proteinuria called confounders are well distributed between treatment arms and control arm. That's how the ORIGIN study was designed. And today, we're very proud to report positive results after 24 weeks or 6 months of treatment. In summary, this clinical trial was positive, meeting the primary endpoint of a statistically significant reduction in proteinuria between the combined arms of 150 milligrams and 75 milligrams versus placebo. Moreover, statistical significance was also achieved for the 150-milligram dose alone, showing a 33% reduction from baseline at 24 weeks. We observed a trend towards further reductions in proteinuria at week 36 with only a partial data set available, about 1/3 of subjects through that time point, which shows that patients on atacicept also had stable renal function as measured by eGFR over 24 weeks. The 150-milligram dose showed a Gd-IgA1 reduction of 60% at 24 weeks and the safety profile of atacicept was similar to placebo. We have selected a 150-milligram dose to advance into a Phase III trial and plan to initiate that trial in the first half of this year. The ORIGIN study continues currently in blinded phase, and we plan to report nine-month data or 36-week data in the second quarter of this year, after which patients will be offered open-label extension for an additional 60 weeks. With that, I will ask Dr. Jonathan Barratt to present the results in detail. Thank you, Dr. Barratt for joining us this morning.

Thank you, Marshall. And it's a real pleasure to be here to present these exciting data. As you mentioned, I'm a Professor of Nephrology at the University of Leicester in the U.K. and day-to-day look after patients with IgA nephropathy. So very much understand the challenges we face in managing this really important disease that are commonly affects young adults. And so the ORIGIN trial, as you've mentioned, was a Phase IIb study. It assessed 4 doses of -- 3 doses of atacicept and placebo, 25 milligrams, 75 milligrams and 150 milligrams of atacicept, with the objective of looking at a 24-month -- 24-week endpoint in proteinuria and followed by a 36-week endpoint with an open-label extension, as you can see in the diagram with 150 milligrams of atacicept out to 96 weeks. This study recruited patients who remained at high risk of progressive kidney failure despite optimized supportive care. These were adult patients over the age of 18, who had been on a stable and optimized dose of RAS inhibitor for a minimum of 12 weeks with persistent proteinuria that you can see here and with a GFR of at least 30 ml per minute. Blood pressure had to be controlled. And importantly, as you'll see when we discuss the patient characteristics, we are starting to see the introduction of other supportive care measures such as SGLT2 inhibitors. And I think that's really important to future-proof these results in the context of what's likely to change in the coming years in terms of supportive care, and we're already thankfully being able to include patients on SGLT2 inhibitors in this study. The efficacy endpoints were a 20 -- change in UPCR measured on the 24-hour urine collection at week 24 and the secondary endpoint, again, change in UPCR on a 24-hour collection at week 36 with eGFR measured over the full 96-week period. But of course, eGFR has been looked at various time points during the study as well. And the key biomarker, the key driver for immune complex formation in IgA nephropathy was also looked at team in terms of the levels of Gd-IgA1 at various time points during the study and safety was obviously collected, and I'll talk about that in a later slide. If we can go to the next slide, please. So the ORIGIN study was truly a multinational trial and included patients from North America and from the Asia Pacific region and really looked at the concept of reducing proteinuria in these patients and seeing whether we could generate data that showed a reduction in Gd-IgA1, a reduction in proteinuria with a long-term aspiration of reducing the rate of decline of eGFR. And when the study was designed, it was powered to look at a reduction in protenuria at the 24-week mark in the region of 30% reduction in proteinuria. And so why do we want to think about a 30% reduction in proteinuria? Well, we know that this is clinically meaningful. Particularly a 30% reduction at 9 months or a later time point, in fact, has been shown to improve the outcome in patients with IgA nephropathy. And potentially delay the time to kidney failure and the need for dialysis or transplant by over a decade. If we compare what we've seen with the only drug currently approved for the treatment of IgA nephropathy, Tarpeyo, that data is now published. We saw an 18% reduction in proteinuria at 6 months of treatment with a 34% reduction at 9 months. And this data was strong enough to allow accelerated approval for Tarpeyo in the United States. And under precision approval in the European Union. We know that there's data already submitted to the FDA for sparsentan. And that showed a difference in proteinuria reduction of 35% between placebo and treated arms in the press release from Travere. So we can see that these -- the magnitude of reduction at 9 months, remember, this is at 9 months, is around the 30% to 35% mark. That is achievable with the drugs, 2 different drugs working in very different ways. I've got directed steroids and a drug affecting glomerular filtration and glomerular blood flow in terms of endothelial receptor antagonist. And I think just remember, this is 9-month data. And of course, what we're presenting today is 6-month data. And we may well be seeing even greater reductions in proteinuria at 9 months once we have the full data set. If we can go to the next slide. I've already mentioned that this is a multinational study. I think it's really important to understand the mix of patients. And there was a very nice even spread of patients across the study, both from North America, from Europe and from Asia. You can see no single country dominated recruitment and no area of the world dominated recruitment. This was evenly spread and that is really what we would hope to achieve in a Phase III study as well. But this shows how translatable the results of this Phase II study are to the wider global population and the wider global Phase III population that will be included in the Phase III atacicept study. If we go to the next slide. So if we look now at the disposition of the recruited patients. What you will be able to see here is of the 232 patients screened, we had 116 eventually randomized and treated. And the common reasons for screen failure are as with all studies in IgA nephropathy are failure to meet the proteinuria GFR criteria. And that's common across studies. You can see here, 82 patients received atacicept, 34 placebo. There was 1 discontinuation of the placebo arm. And this was because this patient had initiated a prohibited treatment for a concomitant disease. We had 1 discontinuation in the atacicept arm due to an elective surgery unrelated to the underlying kidney disease, and we had 1 discontinuation due to an adverse event, and I'll talk a little bit more about that later in the presentation. If we can move to the next slide. So if we now look at the baseline characteristics for this population. I think this is really important to focus on because this tells you the types of patients that we're seeing this proteinuric response with atacicept. And you can see here, these are typical of a high-risk IgA nephropathy population. You can see the age is around 40 years. A small -- a slight majority of males as you might predict in IgA nephropathy. And you've got a good mix of races here with roughly 50-50 in terms of White, Caucasian and Asian across the different groups. eGFR is very similar, the give or take in terms of around 63 mls per minute in the overall Atacicept group and 66 mls per minute in the placebo group. So already, these patients are showing signs of kidney impairment and the UPCR, again this is in grams per gram. You can see which is averaging around 1.6 grams per gram, which equates approximately to 2 grams per 24-hour urine proteinuria. And what's really pleasing for me to see is that we're seeing the effect of this drug on top of not only RAS inhibitor but also SGLT2 inhibitors and you can see here that almost 1 in 5 of the patients were already on an SGLT2. Remember they have to go on SGLT2 at the stable dose prior to being eligible for the study. And so what we're seeing here is the impact of targeting BAFF and APRIL signal on top of a RAS inhibitor on top of an SGLT2 inhibitor. And this is really important to understand the additive value from both an efficacy point of view, but also from a safety perspective, in terms of not that we would predict there would be any safety issues here, but it's always reassuring to see that this drug is working well in combination with what is going to be standard supportive care as we go forward in IgA nephropathy. If we move to the next slide. So here, we see the key results, the key week 24 proteinuria results. And what you can see here is that the protein are evaluated on a protein to creatinine ratio on a 24-hour urine collection. And you can see here a significant difference in those patients treated with 150 milligrams of atacicept with a 33% reduction in proteinuria compared to a 7% reduction in those on placebo. And then you can see equally, you can see significant reductions in the 75 and 150 milligram combined groups and in all of those patients treated with atacicept. So a very robust response here showing that treatment with atacicept significantly reduces protein. And again, I want to reemphasize this is at an early time point. This is a week 24, which does not mean that this is a maximal proteinuria reduction we're likely to see with this drug, and we'll come on to that, but this is what we see at week 24. If we go to the next slide. For me, actually, the most exciting result is not only the fact that we are seeing this magnitude of proteinuria reduction at this early time point, but also that we are seeing a trajectory of proteinuria reduction that is continuing to fall. Now we have to caveat that at week 36, we don't have the complete data set. So we just need to be really clear about that. But for me, what I take from this data is narrow confidence intervals around the atacicept treated group. And that proteinuria is continuing to fall. And of course, you have to remember that we would be planning to use this drug on a continuous basis over a 2-year period in all likelihood in the Phase III study. And we will in a -- and I would imagine and would hope that, that proteinuria would continue to fall over the full time period of that study. And of course, the greater the reduction in proteinuria and not only the reduction, but also the ability to sustain that reduction, relates very closely to the protection of kidney function that we're going to see over the longer term period. You can see a fall and you can see that fall continuing and being sustained out to 36 weeks on the data that we have at the moment. But of course, the full 36-week data will be presented when it is available. And so if we go to the next slide. What -- we also need to present is obviously the GFR data, but this is short-term data. And quite honestly, I was not expecting to see any difference. And indeed, the curves overlap because we're talking about a chronic disease that's slowly causes kidney failure, and we're talking about a very short period of time here over 24 weeks. So we will need to wait for that 36-week and possibly even the 96-week data to see what's happening with the GFR. But this is what 1 would have expected in IgA nephropathy at such an early time point. If we go to the next slide, I think what's equally exciting as with the proteinuria data is the biomarker Gd-IgA1, which, as we saw in the smaller Phase II study that I presented over a year or so ago. We see robust reductions in Gd-IgA1, but abnormal form of IgA that precipitates the formation of immune complexes and IgA deposition in the kidneys. And you can see here a very nice reduction over the 24-week period. Again, looking at the trajectory, it may well be that we're going to see even further reductions at week 36. We need to wait and see that. But again, consistent with that early data from that early Phase II study, we see robust reductions in Gd-IgA1. If we go to the next slide. Again, we saw -- as we saw in the Phase II earlier study, we see robust reductions in the other immunoglobulins consistent with its mode of action. And we can see those here for IgG, IgA and IgM. And again, you can see the percentage reductions. You can see reductions of 60% roughly of IgA, 34% reductions in IgG at the highest dose of atacicept and 70% reductions in IgM. But I think what's really important, and I think, again, this speaks to the safety. And what we want to know is how many of these patients are going to have reductions in the normal immunoglobulins, not that abnormal Gd-IgA1, but the normally immunoglobulins that potentially could increase the risk for infections, which is the thing that clearly everyone wants to be confident about. And of course, we've got a large data set with atacicept already in multiple autoimmune diseases which suggests that it is a safe and effective treatment. But what happens with absolute levels of immunoglobulins and levels where we know there is an increased risk of infection. So if we go to the next slide, I think this is a really important slide to show you that with the atacicept, each of the doses and in particular, the 150-milligram dose that is going to be taken forward into the Phase III. What you see is that there is no single patient. And in fact, the group as a whole did not fall below that level of 3 grams per liter or 300 milligrams per deciliter, which is a defining mark for hyperemia. So yes, we saw percentage reductions that you saw, but in absolute terms, no patient had a sustained reduction in IgG below the lower limit of normal. No patient had a study drug discontinuation or interruption through to week 24, which is incredibly reassuring in terms of thinking about these young patients and normal immunoglobulin levels. So if we go now to the next slide, what we can see here is the treatment emerging adverse events, which, of course, is always the thing that we very much want to know about. We can see that atacicept is effective at reducing proteinuria, reducing that key biomarker of IgA nephropathy, but what about treatment emergent adverse events. And what you can see here at the top level data, and you can see very comparable data across the different arms of the atacicept treatment alongside placebo. The majority of study drug-related TEAEs were injection site reactions and just 1 contributed to drug discontinuation. And that was that patient I mentioned in the earlier disposition slide. That patient discontinued after 3 injections due to injection site reactions and a single positive hepatitis B DNA test. That was normal without treatment 3 weeks later and had normal liver function throughout. Serious treatment emergent adverse events were observed in 2% of patients in all atacicept arm and in 9% of patients in the placebo arm. I think these results, to me, clearly demonstrate the safety profile for atacicept in IgA nephropathy patients that is comparable to placebo. And built upon the prior integrated analysis of atacicept in randomized double-blind placebo-controlled clinical trials in over 1,500 patients to date. If we can go to the next slide. So clearly, 1 of the particular areas that we're interested in are infectious risks and infections. And here, you can see looking specifically at infections observed during the trial, all were either mild or moderate, none with severe and the rates on atacicept were comparable to those on placebo. And you can't think about infection without thinking about COVID in today's environment. And what you can see here is that about 25% of patients got COVID during the trial, but none were judged as severe. One did lead to hospitalization, but was followed by full recovery. And at least half of these patients had the atacicept continue during their infection. Those that had it discontinued, they were restarted afterwards. So COVID is not seen as a significant issue here in terms of worsening COVID or in fact, from the data that we have making COVID more likely. You can see the data across the placebo and atacicept, which again is incredibly reassuring. When we go into the future, not knowing what the COVID situation is going to be, this drug clearly does not have a signal that gets -- that for me personally has me worried about the impact of COVID. So if we go to the next slide, please. So in terms of safety summary and a summary of the efficacy completely. What I think we can say is that atacicept is well tolerated in IgA nephropathy patients. There have been no reported deaths, has a low rate of 2% of serious adverse events overall and 1 discontinuation due to an adverse event. The infections were balanced between atacicept and placebo and were no serious adverse events in the 150-milligram group and no patient discontinued atacicept due to low serum immunoglobulin levels. With that, we have a drug that is capable of resulting in significant reductions in proteinuria at 24 weeks, significant and sustained reductions in this abnormal form of Gd-IgA1 and the trajectory of proteinuria response that looks like proteinuria is going to fall even further with more prolonged treatment with atacicept. So with that, I'm going to hand back to Marshall. I'm very happy to take any questions at the end of the call.

Thank you so much, Dr. Barratt. We're very pleased to announce this positive data from a multinational randomized placebo-controlled trial, which is the strongest evidence supporting efficacy as well as safety. And I appreciate Dr. Barratt's summary of these results, which met the primary endpoint as designed with statistical significance on the combined doses of 150 milligrams and 75 milligrams. And then beyond that, met statistical significance for the 150-milligram dose alone with a 33% reduction in proteinuria from baseline, which, as Dr. Barratt reviewed, is a clinically meaningful reduction at 6 months, which is an early time point relative to the benchmark set by the approved drug, Tarpeyo and what we believe with submitted data for sparsentan coming. So this is incredibly encouraging from an efficacy perspective. We chose to look at week 24, an early time point, so that we could move rapidly with positive data from Phase II into Phase III, and that's precisely what we're doing. With atacicept 150 milligrams selected, we're initiating our Phase III trial in the first half of this year. I want to take a minute and put these data into the broader context of the evolving treatment landscape. And I think Dr. Barratt already highlighted 1 of the key features, which is that this trial and its robust design by multinational and well-distributed sites and patients, we demonstrated on top of ACE inhibitor or ARB, as well as on top of any SGLT2 use, which also is becoming common in some regions, we've demonstrated a clinically meaningful treatment effect. We believe that atacicept has a developing profile that supports a best-in-disease potential as a novel therapeutic for patients with IgAN. Today's results are the first results from a multinational, randomized placebo-controlled trial for a dual BLyS APRIL inhibitor in IgAN patients, and they compare favorably to other available results particularly when you're attentive to the difference between 6 and 9 months. And that's what's shown on this slide. Proteinuria reduction at the early 24-week time point has not generally been reported in multinational studies, but atacicept's 33% reduction versus baseline compares favorably to the available data from the reformulated corticosteroid budesonide or Tarpeyo, which showed approximately an 18% reduction from baseline at 24 weeks. The only other B cell modulating therapeutic in development, which promises to be disease-modifying through the mechanism that I've described, is the intravenous sibeprenlimab, which has not reported results at week 24. Dose-specific results and safety compared to placebo have also not been reported. So you're seeing an early look at APRIL BLyS and a robust study that compares favorably to available multinational, randomized, placebo-controlled trials and compares favorably with a good trend moving from week 24 to week 48 or 6 months to 9 months. It's important to add to today's safety profile that a key component to the overall safety profile of atacicept, we've previously seen in atacicept's data set that in over 1,500 patients in autoimmune disease and more systemic autoimmune disease such as systemic lupus or rheumatoid arthritis in which patients have -- are systemically ill from their disease as well as concomitant medications such as steroids and other immune modulators that we've seen balance in safety between atacicept at all doses up to 150 milligrams versus placebo. The question that we were asking going into ORIGIN is in a much relatively healthier population, IgAN patients are not systemically ill. They're not on concomitant steroids or other immunosuppressant medications. How did this safety profile look in a relatively healthier population? And so the clinical safety reviewed by Dr. Barratt, I think, is reassuring in the evolving data set, and that's incredibly important as we carry forward an immune modulator into Phase III and towards and to its patients. This slide reviews that the -- targeting the APRIL BLyS mechanism is well established from a safety perspective starting with BLyS only. This is the marketed product, belimumab or Benlysta over 7,000 patients in randomized controlled trials have defined and characterized the safety profile of that agent, and it's been on the commercial market for over a decade. In addition to that data, atacicept's dual inhibition of BLyS APRIL adds to a well-characterized safety database as we move from Phase II to Phase III. To our knowledge, there are no randomized controlled trial data describing the safety of targeting APRIL alone, and we await that data so that we can start to compare the results. But as at present, we do not have comparative safety data with that immune modulatory mechanism. Among the B cell modulator treatments in develop for IgAN, we believe that atacicept is the most well characterized and therefore, the most derisked going into Phase III. Atacicept is the only B-cell modulator advancing into Phase III this year, where the Phase III dose administration was studied in a multinational randomized controlled trial in Phase II. It is also the lowest dose, self-administered as 150 milligrams and a 1 ml injection subcutaneous once per week. Importantly, our Phase II trial was conducted in patients with elevated proteinuria as reviewed by Dr. Barratt. The average proteinuria at baseline was 1.6 grams per gram, which is the population at highest risk for disease progression and the 1 approved drug in IgAN patients, Tarpeyo is approved only for patients with 1.5 grams or greater. The magnitude of proteinuria effect between B cell modulating programs are difficult to compare at this stage. For sibeprenlimab, week 24 results were not reported. And the trial was done with an intravenous formulation. For BION-1301, because proteinuria is known to be susceptible to changes due to blood pressure, medication changes and intercurrent illness among other confounding factors, we believe a well-powered multinational, randomized, double-blind, placebo-controlled trial must be run to assess how the effect sizes might compare. Gd-IgA1 reductions reported by the BION-1301 program versus baseline are comparable to what we see today and our reporting on atacicept versus placebo. We believe the dual inhibition of APRIL and BLyS making for important potency advantages which is evidenced in the current dosing profile. Atacicept is the only B-cell agent at less than 200 milligrams and is delivered as a single ml, making subcutaneous injection simple for patients to use. On the basis of these positive results, we've selected the 150-milligram dose for a Phase III trial. The design of the Phase III trial will be another multinational, randomized, double-blind, placebo-controlled trial comparing atacicept 150 milligrams to placebo with a primary endpoint of proteinuria at 9 months and the secondary endpoint of eGFR at 2 years. Last quarter, we achieved preliminary alignment with FDA regarding our Phase III design and approach, enabling a projected study start in the first half of 2023. Over the next 18 months, we look forward to reporting multiple catalysts for Vera's pipeline, including 36-week results or 9 months results from the ORIGIN study in the second quarter of this year, and initiating the IgAN Phase III trial in the first half of this year. The ORIGIN data is a key derisking event for the atacicept program. We accomplished what we set out to do, which was a positive study and very importantly, properly designed a randomized placebo-controlled trial. We hit the primary endpoint and all biomarker data was supported and dose-dependent effects, including a stable eGFR trend, a clean safety profile and a clearly active drug in a robust study design. We're strongly encouraged by the early proteinuria data at 6 months as reviewed by Dr. Barratt, and that proteinuria curves appear to be continuing to separate, suggesting that maturing 9-month data could be even more compelling. We continue to think that hitting both BLyS and APRIL is essential for robust efficacy in the long run, which is why we will be focused on longer-term renal function data and eGFR stabilization as the true benchmark for efficacy ultimately for patients. Again, it's not a disease of 6 months, it's a disease of 30-year-old patients on average who are facing dialysis and transplant within a decade or 2. We think the long game for an effective and successful IgAN therapy also rely on few other important factors beyond efficacy, including speed of execution. We have regulatory alignment from FDA to start that Phase III soon and have all global sites from the Phase IIb study to leverage, which means faster activation for trial recruitment. A well-characterized safety database that is well balanced versus placebo with the objective of lending comfort to regulators for approval and physicians for adoption. And finally, ease of administration with a single 1 ml self-administered subcu injection versus larger volumes from other approaches. With that, I'd like to open up the lines for questions and with Dr. Barratt and Dr. Lin, myself available to respond. Thank you very much for your attention. I look forward to your questions.

[Operator Instructions] And our first question is from the line of Anupam Rama with JPMorgan.

Marshall, you kind of talked about this, but relative to competitive programs, can you put the proteinuria reductions that you're seeing in the patient population in terms of into context in terms of the geographies and race at baseline, which differs across programs? I think there's literature out there that suggests that Asian patients have a more progressive form of the disease relative to non-Asians. And then for Dr. Barratt, what would you say to those who might push back that the proteinuria reductions that you're seeing here in ORIGIN missed the mark on a placebo-adjusted basis at 24 weeks? And then based on your experience, at what type point would you expect to see some sort of clinically meaningful separation on eGFR?

Thanks so much for your question, Anupam, and I'll take the first part and then hand to Dr. Barratt. As Dr. Barratt pointed out, as a well-distributed global study, we had a good balance of race with about 40% Asian and about 50% Caucasian in the racial makeup of the trial. I think that the global status of this study as well as the baseline proteinuria of about 1.6 grams per gram, reflects the high-risk population and the population that currently has an approved drug. There is no precedent for getting a drug approved at lower proteinuria doses. So the efficacy results you see from us, we believe, are directly relevant to the Phase III study population we anticipate as well as the approvalable population. Dr. Barratt, would you take the second part of Anupam's question?

Yes. I mean, I think for me, it's all about trajectory. I think if we look at the 24-week data, I'm very encouraged by the magnitude of proteinuria reduction at 24 weeks, to be quite honest. With a drug that is likely to take some time to reach its maximum effect just because of its nature of action, it's not a drug that is a direct anti-inflammatory drug, like a complement inhibitor, it is not a drug that is directly impacting on the kidney inflammation per se, it is a drug that is targeting the pathway very much at the beginning of the process. And therefore, there will be a lag between targeting B cells, targeting the production of Gd-IgA1, targeting then the downstream in complex formation and inflammation that results as a consequence of that. So for me, the graph that interests me the most, and as I say, I think the 24-week data are great, is what's happening at 36 weeks. That trajectory of continued sustained decline in proteinuria, which is what I want to achieve for my patients. And I want to achieve that in a way that patients are able to manage in terms of the treatment they give themselves. And we know atacicept is well tolerated in terms of its ability to be administered, but also in terms of its safety. So for me, in terms of the magnitude of proteinuria by it's very nature, I'm not imagining that we're going to see a maximum effect very early on, because of the way that it works. And that I'm going to be really interested in seeing how things develop at 36 weeks and over the longer period because if we can sustain the reduction in proteinuria, down at 36 weeks at greater levels and even more further on, it's only going to do more to preserve GFR. And that will really -- you will really see that a 2-year GFR endpoint, which is what studies are looking at here. So I hope I answered your question.

Our next question comes from the line of Liisa Bayko with Evercore ISI.

I guess first one, I have been getting some questions on measuring proteinuria and kind of spot versus 24-hour the difficulty in getting 24-hour samples. Can you maybe speak to that?

Yes, Dr. Barratt. This is Marshall, if you like?

Yes, please do.

So in the KHI working group that we are as part of with the American society of Nephrology and the FDA, we agreed unanimously that the most accurate way of assessing proteinuria is with a UPCR on a 24-hour collection. So that's where the patient collects the urine over 24 hours. You take a pallet of that, and then you do a protein to creatinine ratio. In fact, essentially takes into account the possibility that a patient may not have peed every single drop for the full 24 hours into the container. That is the most reliable way of assessing proteinuria. Spot urines are notoriously inaccurate. And to be quite honest, I would not recommend using a spot urine for any kind of studies such as the ORIGIN study. You can measure it, it's easy to do every clinic visit, and you can look at trends, but actually, the variation is so large that actually it's really difficult to interpret. The gold standard is a 24 hour collection and a UPCR on that 24-hour collection as is included in the KHI white paper that we published about 2 years ago now.

And you were able to collect samples relatively easily throughout the study? I just I feel this...

So I just wanted to -- yes. So the practicalities of that. So actually, the way we do it and the way we facilitate this is we give the patient the container, they take it home, they do the collection, and we book a taxi to pick it up to drop it off at the hospital. So we've got loads of really neat tricks that allow us to make this as easy for the patient as possible. So they're not having to go backwards and forwards to the clinic. They can do it on a day that suits themselves. And we essentially -- they just dial a number and someone comes and collects it for them. So it really -- in terms of deliverability is not an issue in the context of a clinical study. And we've ran patient-focused groups, not my general work across this area. We've run a number of patient focus groups, I speak to patients, and it's absolutely fine. And that's the same in North America. It's the same in Asia. We've got multiple ways of making this more amenable to patients. And it's really not seen as a problem. And a lot of actual GN clinics do this for their normal standard of care patients as well, not just in the context of a clinical trial.

And then I would like to ask about the connection between reduction of Gd-IgA1 and proteinuria, because among some of these compounds, we see upwards of 60% reduction in Gd-IgA1, but then we see different outputs in terms of proteinuria. Is this just a function of small studies? Or are these things truly connected? Are there differences in baseline like how are you thinking about how predictive changes in Gd-IgA1 are in terms of proteinuria?

It's a great question. And we are just at the very beginning of understanding that relationship. We have never had a drug before that has been capable of reducing Gd-IgA1. So we are just starting to understand that relationship. We can see that the drug that doesn't reduce Gd-IgA1 like rituximab does not impact on proteinuria. So we've got an RCT that shows you can deplete these cells with rituximab with a CD20 approach, it had no effect on Gd-IgA1 and no effect on proteinuria. So we are seeing consistently across this class of drug and impact on Gd-IgA1 and an impact on proteinuria, but we don't understand the -- I wish I could draw you a graph that showed if it goes approaching -- if Gd-IgA1 goes down, 3 months by this amount, it's going to mean proteinuria goes down by this much of 6 months. We simply do not have enough data yet to be able to answer that question. But it will come with studies like the ORIGIN study and the Phase III study that they are planning. We will start to be able to understand that much more closely. But undoubtedly, Gd-IgA1 is the principal driver for immune complex formation, and we are only just starting to have drugs that are capable of modifying that and consistently drugs that modify Gd-IgA1 reduce proteinuria and improved given option outcomes, which is what's really exciting.

Thank you, Jon, and I might add to that Liisa, just so that you're aware, we saw a 60% reduction in this well-powered well broadly designed study. The only other program we're aware of that's quantified its Gd-IgA1 reduction is the BION-1301 program, which had an open-label K series that's reporting about a 60%, 65% reduction. And we haven't seen that quantify for the Otsuka program sibeprenlimab yet, although they qualitatively said that it was observed to be reduced, but it wasn't quantified.

Okay. And then just final question for Dr. Barratt. Are you expecting -- as you look at the other studies, are you expecting -- do you think that the proteinuria data we have so far is reliable or would you be surprised if those numbers change? I mean there are quite substantial differences as we look across the competitive landscape in terms of the data that's been reported and baseline value size of study, et cetera. Do you think the proteinuria data are reliable? Or do you expect these numbers may change over time? Like how are you thinking about that?

Sorry, just to clarify, pro -- so I think the data that I presented here today for Vera is very reliable. I think that, that is what we would hope to see with a drug that is protecting kidney function. I think the magnitude, if you were going head-to-head across the different studies, you've got to think carefully about what the compounders are in terms of what might be an explanation for different magnitudes of proteinuria with different agents targeting different pathways. And so that's a very long in terms of thinking about all the potential confounders that could impact on the drug's ability to reduce proteinuria. I think proteinuria in IgA nephropathy, in my view, is a highly robust biomarker of future kidney function protection. And clearly, the FDA and the EMA agree with that, and that was the work that came out of that KHI Work Group. So I think the data itself that we presented today is robust. I think if you wanted to compare head-to-head across studies, you need to be thinking what are the potential differences between the studies that might explain different responses. And there are lots of reasons why there may be differences across the absolute magnitude that you're seeing across studies that may or may not be related to the drug. And that takes a long time to discuss that in terms of teasing out the study design, the patient population. Is there a placebo group? What's the racial mix, background therapy, all of those kind of things can influence this. I think as Marshall has said, this has been a study that has been designed that is forward thinking. And here I'm drawing in the fact that SGLT2 inhibitor use was included and allowed, which I think is very forward thinking. It's used the best way of assessing proteinuria. It's looked at an early time point. And clearly, everyone wants the data as quickly as possible. But for me, that's incredibly reassuring, but I'm getting even more excited about the fact that proteinuria is continuing to fall. And therefore, what's going to be -- what are we going to see at 36 weeks, which is when you look at that table that Marshall put up, that's when everyone else has been looking at proteinuria. And that's where we can start thinking about what's happening and if these drugs -- and just because you have 1 drug that's reducing proteinuria by a certain percentage and atacicept reducing it, doesn't mean to say that you aren't going to get equal benefit by adding the 2 together because they're working in different ways. So I think that's the other thing to think about. It's not a head-to-head winner takes all here. We've got a really exciting set of data here with a drug that is well tolerated and also has very good safety profile. We need to move on and think about that in the context of what other things we might do. And we've got that now in the context of opportunities , which I think moves us on very nicely to the Phase III planning.

Yes. Maybe, Liisa, I'd like to -- what you're asking is a really important point, and I'd like to drive it home. How reliable are proteinuria results? Everyone should be aware that atacicept was studied in a prior randomized controlled trial, a Phase IIa trial that had fewer patients, that only had patients total. And if you look at the publication from that study, you'll see that atacicept at 25 milligrams with an end and start of 6, over time, they achieved over a 50% reduction of 57% reduction was seen by week 72 in that study. Now we looked at that data, and we didn't over-index. We didn't rely on that number because it wasn't an adequately powered study that controlled for confounder. And so it's important to know that atacicept at multiple doses has been able to accomplish greater than a 50% drop in proteinuria over time, but it really must be studied in an adequately powered, global, randomized controlled trial. So if we're looking for evidence that atacicept can get point estimates above the 40% mark, they're there even in the prior study. What's really important is that we're creating a reliable, robust data package in Phase II, so that we can derisk Phase III for ourselves as well as for regulators and have an approvable drug that we can get to patients. That's the most critical message I can send to you today regarding the reliability of proteinuria. This is a global, placebo-controlled randomized trial that was adequately powered to show at least statistically significant difference, which was achieved and at least a 30% change from baseline, which was achieved in combined doses and single dose. I think we can take the next question.

And the next question is from the line of Ritu Baral with Cowen.

Dr. Barratt, I wanted to ask about your opinion on differential safety of atacicept versus some of the other programs. The IgG level falls on Slide 18 seems to have sort of nice tight error bars. Can you just speak to your experience looking at the other programs, how atacicept may fall in relative balance, at least on the safety and tolerability aspect? And then I've got a follow-up.

Yes. So I think Marshall presented the slide looking at the total experience of atacicept use across different autoimmune diseases in randomized controlled trials. So that's a real positive, I think, in terms of having that volume of data. You have to remember that the atacicept is used in IgA nephropathy without concomitant immunosuppression. In fact, other immunosuppression is an exclusion criteria. But in most of those other studies, the atacicept was used with steroids with calci inhibitors with other immunosuppressants. So the safety database for atacicept is particularly strong in mighty in terms of volume and length of follow-up. And I think it's important to think about the IgA nephropathy population here and the major concern for any drug that targets B cells is what is it going to do to immunoglobulin production? Are we going to render people hypogammaglobulinemic with all the risks that go with that. And we know our experience with rituximab, a completely different approach, CD20 can lead to hypogammaglobulinemia, and that is a potential concern. But what's really reassuring about this data set is that even though there were reductions in immunoglobulins, no patient was persistently rendered hypogammaglobulinemic terms of IgG levels, which is really reassuring. And we need to see that volume of data from any drug in this class in IgA nephropathy patients. And as Marshall showed, there is less information available about the other drugs. Clearly, that's going to be accumulated over time, but at this present moment in time, the most data we have regarding safety and in fact, regarding tolerability is with atacicept. We know the safety data we've just shown you. We've got the safety data from other autoimmune diseases. And we also have the fact that actually in this study, the 150-milligram subcutaneous dose was tolerated by patients and was easily administrated and is a suitable way of administering this treatment. So we have that data, and we have data on its mode of administration in other diseases, such as lupus nephritis and lupus. So we know from the data we have today that a subcutaneous formulation of 150 milligrams of atacicept is acceptable for patients, and we have all of that safety data. And then if we put that in the context of the other therapies, that data just doesn't exist at the moment. Just because of the -- because they're less further advanced in the drug development programs than with atacicept. So we have that reassurance. And as Marshall used the term derisked, we know that this formulation can be delivered to patients effectively and safely. And so where we are today is that we have that database to support the further development of atacicept. For me, as a finished that's clearly good news. And it's that we have that data that I can look at when I'm talking to my patients about this treatment.

And then, Marshall, just a quick follow-up for you. Do you plan on meeting with FDA again before starting the Phase III in a formal and Phase II meeting? And will you have the 36-week data in hand to show them before pushing the button on Phase III?