Greetings. Welcome to Vera phase IIb Week 24 Results Update call. This time, all participants are in listen-only mode. A question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero from your telephone keypad. 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. As such, we present this disclaimer regarding at-risk statements. Today, I'll begin by providing the background to the ORIGIN phase IIb trial that targets the source of disease for IgA nephropathy patients. 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 in this team 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 improve 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 two 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. 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 effect on the upstream causes of IgAN translate into improved kidney function, as measured by reduction in proteinuria and the stability of estimated glomerular 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 arms. That's how the ORIGIN study was designed, and today we're very proud to report positive results after 24 weeks or six 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 vs placebo. 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 dataset available, about a third 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've selected the 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. 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 commonly affects young adults. The ORIGIN trial, as you've mentioned, was a phase IIb study.
It assessed 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'd 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 mils per minute.
Blood pressure had to be controlled. 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. 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. 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 a 24-hour urine collection at week 24. A secondary endpoint, again, change in uPCR in a 24-hour collection at week 36, with eGFR measured over the full 96-week period. Of course, eGFR has been looked at at various time points during the study as well.
The key biomarker, the key driver for immune complex formation in IgA nephropathy, was also looked at in terms of the levels of Gd-IgA1 at various time points during the study. Safety was obviously collected, and I'll talk about that in a later slides. If we can go to the next slide, please. The ORIGIN study was truly a multinational trial and included patients from North America and from the Asian Pacific region and really looked at the concept of reducing proteinuria in these patients and seeing whether we could generate a data that showed a reduction in Gd-IgA1, a reduction in proteinuria with the long-term aspiration of reducing the rate of decline of eGFR.
the study was designed, it was powered to look at a reduction in proteinuria at the 24-week mark within the region of 30% reduction in proteinuria. 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 nine 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, and that data is now published, we saw an 18% reduction in proteinuria at six months of treatment with a 34% reduction at nine months.
This data was strong enough to allow an accelerated approval for Tarpeyo in the United States and a conditional 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 Vera Therapeutics. We can see that these, the magnitude of reduction at nine months, remember this is at nine months, is around the 30%-35% mark that is achievable with the drugs. Two different drugs working in very different ways, a gut-directed steroid and a drug affecting glomerular filtration and glomerular blood flow in terms of endothelin receptor antagonist. I think just remember, this is nine-month data, and of course, what we're presenting today is 6-month data.
We may well be seeing even greater reductions in proteinuria at nine 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. 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 matches really what we would hope to achieve in a phase III study as well. 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. 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. The common reasons for screen failure are, as with all studies in IgA nephropathy, a failure to meet the proteinuria and GFR criteria. That's common across studies. You can see here, 82 patients received atacicept, 34 placebo. There was 1 discontinuation in 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, 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. 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 proteinuria response with atacicept. You can see here these are typical of a high-risk IgA nephropathy population. You can see the age is around 40 years.
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, give or take, in terms of around 63 mils per minute in the overall atacicept group and 66 mils per minute in the placebo group. Already these patients are showing signs of kidney impairment. 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. 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.
You can see here that almost one in five of the patients was already on an SGLT2 inhibitor. Remember, they had to be on an SGLT2 inhibitor at the stable dose prior to being eligible for the study. What we're seeing here is the impact of targeting BAFF and APRIL signaling on top of a RAS inhibitor on top of an SGLT2 inhibitor. 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.
Here we see the key results, the key week 24 proteinuria results. What you can see here is that the proteinuria evaluated on a protein-to-creatinine ratio on a 24-hour urine collection. You can see here a significant difference in those patients treated with 150 mg of atacicept, with a 33% reduction in proteinuria compared to a 7% reduction in those on placebo. Then you can see equally, you can see significant reductions in the 75 and 150 mg combined groups and in the all of those patients treated with atacicept. A very robust response here showing that treatment with atacicept significantly reduces proteinuria. Again, I want to reemphasize, this is at an early time point.
This is at a week 24, which does not mean that this is a maximal proteinuria reduction we're likely to see with this drug. 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. For me, what I take from this data is narrow confidence intervals around the atacicept treated group, and that the proteinuria is continuing to fall.
Of course, we have to remember that we would be planning to use this drug on a continuous basis over a two-year period, in all likelihood in a phase III study. I would imagine, and would hope that that proteinuria would continue to fall over the full time period of that study. 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 on 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. Of course, the full 36-week data will be presented when it is available. If we go to the next slide.
What we also need to present is obviously the GFR data. This is short-term data. Quite honestly, I was not expecting to see any difference. Indeed, the curves overlap because we're talking about a chronic disease that slowly causes kidney failure, and we're talking about a very short period of time here over 24 weeks. We will need to wait for that 36 week and possibly even the 96 week data to see what's happening with the GFR. This is what one would have expected in IgA nephropathy at such an early time point. If we go to the next slide.
Equally, re-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, that abnormal form of IgA that precipitates the formation of immune complexes and IgA deposition in the kidneys. We can see here in 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. 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.
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. We can see those here for IgG, IgA, and IgM. You can see the % reductions. You can see reductions of 60% roughly of IgA, 34% reductions in IgG at the higher dose of atacicept, and 70% reductions in IgM. 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 their normal immunoglobulins, not that abnormal Gd-IgA1, but their normal immunoglobulins that potentially could increase the risk for infections, which is the thing that clearly everyone wants to be confident about.
Of course, we've got a large data set with atacicept already in multiple autoimmune diseases which suggest that it is a safe and effective treatment. What happens with absolute levels of immunoglobulins and levels where we know there is an increased risk of infection? 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 less liter or 300 milligrams per deciliter, which is a defining mark for hypogammaglobulinemia.
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 424, which is incredibly reassuring in terms of thinking about these young patients and normal immunoglobulin levels. If we go now to the next slide, what we can see here is the treatment emergent adverse events, which of course is always something 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. What about treatment emergent adverse events?
What you can see here are 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 one 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 reaction and a single positive hepatitis B DNA test that was normal without treatment 3 weeks later and had normal liver function throughout. Serious treatment emerging adverse events were observed in 2% of patients in all atacicept arms 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 builds 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. Clearly one of the particular areas that we're interested in are infectious risks and infections. Here you can see, looking specifically at infections observed during the trial, all were either mild or moderate, none were severe, and the rates on atacicept were comparable to those on placebo. You can't think about an infection without thinking about COVID in today's environment. 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, was followed by full recovery. At least half of these patients had their atacicept continued during their infection. Those that had it discontinued, they were restarted afterwards. 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 groups, 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 for me personally is, has me worried about the impact of COVID. If we go to the next slide, please. In terms of a safety summary, and a summary of the efficacy.
What I think we can say is that atacicept is well-tolerated in large IgA nephropathy patients. There have been no reported deaths. There's 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, there were no serious adverse events in the 150 milligram group. 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 a trajectory of proteinuria response that looks like proteinuria is going to fall even further with more prolonged treatment with atacicept.
With that, I'm going to hand back to Marshall, and 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. 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. Beyond that, net 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 six months, which is an early time point relative to the benchmark set of the approved drug, Tarpeyo, and what we believe with submitted data for sparsentan can coming.
This is incredibly encouraging from an 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. I think Dr.
Barratt already highlighted one of the key features, which is that this trial, in 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 six and nine months. 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. Atacicept's 33% reduction vs 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. Those specific results and safety compared to placebo have also not been reported. You're seeing an early look at APRIL BLyS in 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 six months to nine 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 dataset 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 vs 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 immune suppressant medications. How does this safety profile look in a, in a relatively healthier population? The clinical safety reviewed by Dr.
Barratt, I think is reassuring in the evolving dataset. That's incredibly important as we carry forward an immune modulator into phase III and towards 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. 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. As of 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 de-risked 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 at 150 milligrams in 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. The one 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 vs baseline are comparable to what we see today in our reporting on atacicept vs placebo. We believe the dual inhibition of APRIL and BLyS may confer important potency advantages, which is evidenced in the current dosing profile. Atacicept is the only B-cell agent at less than 200 mg 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 mg 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 mg to placebo with a primary endpoint of proteinuria at nine months and a secondary endpoint of eGFR at two 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 nine 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 de-risking 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 six months, as reviewed by Dr. Barratt. That proteinuria curves appear to be continuing to separate, suggesting that maturing nine-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. IgAN is not a disease of six months. It's a disease of 30-year-old patients on average who are facing dialysis and transplant within a decade or two. 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 vs placebo, with the objective of lending comfort to regulators for approval and physicians for adoption. Finally, ease of administration with a single 1 ml self-administered subcu injection vs larger volumes from other approaches. With that, I'd like to open up the lines for questions and with Dr. Barratt and Celia Lin and myself available to respond. Thanks very much for your attention. I look forward to your questions.
Thank you. We'll now be conducting a question and answer session. If you'd like to ask a question today, please press star one from your telephone keypad and a confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment please while we pull for questions. Once again, that is star one to ask a question. Thank you. Thank you. Our first question is from the line of Anupam Rama with JP Morgan. Please proceed with your question.
Hey, guys. Thanks so much for taking the question. 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, you know, 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. 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? Based on your experience, at what time 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.
The efficacy results you see from us, we believe are directly relevant to the phase III study population we anticipate as well as the approvable population. Dr. Barratt, would you take the second part of Anupam's question?
Yeah. 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 maximal 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. 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.
For me, the graph that interests me the most, and I, 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. I want to achieve that in a way that patients are able to manage in terms of the treatment they give themselves. We know atacicept is well tolerated in terms of its ability to be administered, but also in terms of its safety.
For me, in terms of the magnitude of proteinuria, by its very nature, I'm not imagining that we're gonna see a maximal effect very early on because of the way that it works, and that I'm gonna be really interested in seeing how things develop at 36 weeks and over the longer period. 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. That will really, you will see that at a two-year GFR endpoint, which is what studies are looking at here. I hope I answered your question.
Thanks so much for taking the question, guys.
Our next question comes from the line of Liisa Bayko with Evercore ISI. Please proceed with your questions.
Hi there. Thanks for taking my question. I guess first one, I have been getting some questions on measuring proteinuria and kind of spot vs 24-hour and the difficulty in getting 24-hour samples. Can you maybe speak to that?
Yeah. I'm happy to go on that, Marshall, if you like.
Yeah, please do.
In the Kidney Health Initiative 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. That's where the patient collects the urine for 24 hours, you take an aliquot of that, and then you do a protein to creatinine ratio. That 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. To be quite honest, I would not recommend using a spot urine for any kind of study 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 two years ago now.
You were able to collect samples relatively easily throughout the study? I just feel.
The practicalities of that. 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. 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. We essentially, they just dial a number and someone comes and collects it for them. It really, in terms of deliverability, is not an issue in the context of a clinical study. We've run patient focus groups, not...
In my general work across this area, we've run a number of patient focus groups. I speak to patients, and it's absolutely fine. That's the same in North America, it's the same in Asia. you know, we've got multiple ways of making this more amenable to patients, and it's really not seen as a problem. A lot of actual GN clinics do this for their normal standard of care patients as well, not just in the context of clinical trials.
I want to ask, you know, about the connection between reduction of Gd-IgA1 and proteinuria, because amongst some of these compounds, we see, you know, upwards of 60%, you know, reduction in Gd-IgA1, but then we see, you know, 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?
That is a great question, 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. We are just starting to understand that relationship. We can see that a drug that doesn't reduce Gd-IgA1, like rituximab, doesn't impact on proteinuria. We've got an RCT that shows you can deplete B cells with rituximab, with a CD20 approach. It had no effect on Gd-IgA1, it had no effect on proteinuria. We are seeing consistently across this class of drug an impact on Gd-IgA1 and an impact on proteinuria, but we don't understand the pro...
I wish I could draw you a graph that showed if it go proteinuria, if Gd-IgA1 goes down at three months by this amount, it's gonna mean proteinuria goes down by this much at six months. We simply do not have enough data yet to be able to answer that question. It will come with studies like the ORIGIN study and the phase III study that Vera are planning. We will start to be able to understand that much more closely. 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. Consistently, drugs that modify Gd-IgA1 reduce proteinuria and improve kidney function outcomes, which is what's really exciting.
Thank you, Jon.
That's great.
I might add to that, Liisa, just so that you're aware, you know, we saw a 60% reduction in this well-powered and 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. We haven't seen that quantified for the Otsuka program of sibeprenlimab yet, although they qualitatively said that it was observed to be reduced, but it wasn't quantified.
Okay. Thank you. Just final question for Dr. Barratt.
You know, are you expecting, you know, as you look at the other studies, are you expecting, you know, 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, you know, the data that's been reported and baseline values, the 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, protein. I think the data that I've presented here today for Vera is very reliable. I think the, you know, 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 confounders are in terms of what might be an explanation for different magnitudes of proteinuria with different agents targeting different pathways. That's a very long conversation, I'm afraid, in terms of thinking about all the potential confounders that could impact on a 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.
Clearly, the FDA and the EMA agree with that, and that was the work that came out of that KHI work group. 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, you know, what are the potential differences between the studies that might explain different responses? 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. That's, that takes a long time to discuss that in terms of teasing out the study design, the patient populations. 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. 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. I'm getting even more excited about the fact that proteinuria is continuing to fall and therefore What are we gonna 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, you know, what's happening. If these drugs...
Just because you have one drug that's reducing proteinuria by a certain percentage and atacicept's reducing it, doesn't mean to say that you aren't gonna get equal benefit by adding the two together because they're working in different ways. 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 has a 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 SGLT2 inhibitors and RAS inhibitors, which I think, you know, moves us on very nicely to the phase III planning.
Yeah. 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. It only had 15 patients total. If you look at the publication from that study, you'll see that atacicept at 25 milligrams with an N at start of 6, over time, they achieved over a 50% reduction. A 57% reduction was seen by week 72 in that study. 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.
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. 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 de-risk 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 a 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.
Thank you. The next question is from the line of Ritu Baral with Cowen. Please share your questions.
Good morning, everyone. Thanks for taking the question. Dr. Barratt, I wanted to ask about your opinion on differential safety of atacicept vs some of the other programs. You know, 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? I've got a follow-up.
Yeah. I think Marshall presented the slide looking at the total experience of atacicept use across different autoimmune diseases in randomized controlled trials. 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. In most of those other studies, the atacicept was used with steroids, with calcineurin inhibitors, with other immunosuppressants. The safety database for atacicept is particularly strong in my view, in terms of volume and length of follow-up. I think it's important to think about the IgA nephropathy population here. The major concern for any drug that targets B cells is what is it going to do to normal immunoglobulin production?
Are we going to render people hypogammaglobulinemic with all the risks that go with that? We know our experience with rituximab, a completely different approach, CD20, can lead to hypogammaglobulinemia, that is a potential concern. What's really reassuring about this data set is that even though there were reductions in immunoglobulins, no patient was persistently rendered hypogammaglobulinemic in terms of IgG levels, which is really reassuring. We need to see that volume of data from any drug in this class in IgA nephropathy patients. As Marshall showed, there is less information available about the other drugs. Clearly, that's going to be accumulated over time. 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 I've just shown you.
We've got the safety data from other autoimmune diseases. We also have the fact that actually in this study, the 150 milligrams subcutaneous dose was tolerated by patients, was easily administered and is a suitable way of administering this treatment. We have that data. We have data on its mode of administration in other diseases such as lupus nephritis and lupus. We know from the data we have today that a subcutaneous formulation of 150 milligrams of atacicept is acceptable for patients. We have all of that safety data. If we put that in the context of the other therapies, that data just doesn't exist at the moment just because they're less further advanced in their drug development programs than with atacicept. We have that reassurance.
As Marshall used the term de-risk, we know that this formulation can be delivered to patients effectively and safely. Where we are today is that we have that database to support the further development of atacicept. That for me as a clinician, 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.
Marshall, just a quick follow-up for you. Do you plan on meeting with FDA again before starting the phase III in a formal end of phase II meeting, and will you have the 36-week data in hand to show them before pushing the button on phase III?
We're driving directly to phase III based on our existing interactions with FDA, and we're comfortable initiating the trial with our current communication.
Got it. Thanks.
Yep.
Our next question's from the line of Rami Katkhuda with LifeSci Capital. Please proceed with your questions.
Hey, guys. Thanks for taking my questions as well. To Dr. Barratt's earlier point, this is the first study with a B-cell modulating therapy that allows background SGLT2 inhibitor use. I guess, are those patients considered more refractory, and are there any additional efficacy implications there?
I'll have.
Dr. Barratt. Yeah. Would you provide your perspective on that?
Yeah. I mean, I think, I think with the publication of EMPA-KIDNEY at the ASN, in November with the DAPA-CKD, SGLT2 inhibitors are gonna be used for all patients with proteinuria CKD and IgA nephropathy. I don't think it's gonna earmark out anyone who is more resistant or difficult to treat. I think it is going to become standard of care. Now clearly what that will mean is that if you have 100 patients who were eligible for a clinical trial with 1 gram of proteinuria, some of those will no longer be eligible because their proteinuria will fall. The vast majority will still remain eligible, because SGLT2 inhibitors do not reduce proteinuria by that much.
You will have a group of patients enriched for those that still have proteinuria despite being on an SGLT2 inhibitor, but I think you're not gonna be able to find patients with IgA nephropathy who aren't on an SGLT2 inhibitor in the next two or three years, apart from those that just can't simply tolerate taking the drug. I think we need to accept that that is going to become standard of care across the globe. It will happen at different speeds because the drugs, 'cause of the cost of the drug and how countries access drugs, but it's going to be par for the course.
I think that's what's really great about this study, is it's already accumulated data in a reasonable number of patients about this drug in patients on an SGLT2 inhibitor, which is really good news in terms of thinking about at any potential or looking for any potential interactions. Not that I imagine there would be any, but it's really good to future-proof the study and the data in that way.
Got it. I guess the ORIGIN study had a relatively high baseline proteinuria compared to some of the other studies within the class. I guess, is it known whether there's a correlation there between baseline values and proteinuria reductions?
The sensitivity analyses that I'm aware of that have been done in a variety of studies have not shown that the baseline proteinuria influences the % reduction in proteinuria that you will see with the drug.
Got it. Thank you, guys.
Our next question is from the line of Maury Raycroft with Jefferies. Please proceed with your questions.
Hi, good morning, and thanks for taking my questions. I have one for Dr. Barratt. Though there are caveats with cross-trial comparisons based on the ATSUGA and Chinook APRIL-only data and RemeGen dual mechanism of action data, we get a sense of how APRIL-only inhibition contributes to efficacy. When you look at the total Vera data and the RemeGen data, what evidence or observations indicate how BLyS inhibition is contributing, or do you think BLyS inhibition will contribute more to sustained or longer-term benefit?
Yeah, that's a really great question. I think it's a really interesting thing that you mentioned at the end in terms of will inhibition of BAFF in addition to APRIL impact on the more longer-term efficacy in terms of B-cell survival and B-cell recovery. I think theoretically there are lots of reasons why one might suspect that the BAFF, the impact of inhibiting BAFF is going to have positive effects. I mean, Marshall showed you the data for Benlysta. We know that a BAFF-only approach in lupus, a classical autoimmune disease driven by immune complexes, is efficacious. We just need to be able to have the time and the ability to investigate precisely how this is working in IgA nephropathy. I think it's too early to say.
I think there are a number of Really exciting reasons why combining BAFF and APRIL could give additional efficacy. I think the important thing to take from this data is it doesn't appear to be impacting in any negative way on safety. That's a really important thing to say. You know, look at those immunoglobulin levels. We're not rendering people hypogammaglobulinemic by the combined approach. In terms of safety, I think we really have got some nice reassuring data there. In terms of efficacy, I think there are a number of really interesting hypotheses about how this could be beneficial, looking at taking the work from Benlysta and from lupus nephritis. We need to prove that, and that's going to be about doing the phase III. It's all going to be about looking at the longer-term outcomes in the ORIGIN study.
It's about investigating and doing biomarker analyses to see what added value we are being able to generate by combining BLyS and APRIL inhibition. I don't know, Marshall, whether you wanted to follow up with any comments.
No, I think those are the key points, and important to recognize that, BLyS BAFF is a has been shown to be clinically efficacious and is a commercial product. No question in our view that BLyS BAFF is a key, if not the key, survival and maturation factor in B-cell pathway. Whereas APRIL appears to act further down the pathway and important probably in antibody class switching. That's the theoretical overlapping and non-redundant impact of these two circulating cytokines. We think impacting both is important for long-term efficacy, and I think it, as Dr. Barratt has outlined, it's too early to tell exactly its impact. We'll see over time how the data set matures.
Here we're achieving a statistically significant result and a clinically meaningful one, that we think has a high probability of translating from phase II to phase III because we're studying this in a similar population, similar design, and with the same dose and presentation.
Got it. All very helpful. Maybe a quick question for Marshall. You mentioned the IgAN phase III is pretty much set to start. Can you talk more about what the sample size will be and also your expectations on two-year eGFR data?
Yeah. I'm happy to share a bit on our view on eGFR data. As you noticed, our study design has a 36-week or nine-month primary endpoint with proteinuria and a two-year secondary endpoint of eGFR, where we would expect to see on the placebo arm a consistent decline. We're not putting forward a target N publicly yet, but we'll provide more detail in the near future.
Got it. Okay. Thanks for taking my questions.
Our next question comes from the line of Laura Chico with Wedbush Securities. Please proceed with your questions.
Thank you very much for fitting me in here. I guess I wanted to go back to the proteinuria reductions at 24 weeks here. If I'm just doing some back of the envelope math, the 25 mg cohort looks like it might be numerically greater than the other cohorts, but I guess I'm trying to contextualize that relative to the Gd-IgA1 changes you're reporting here. So I guess it's two questions. One, could you kind of walk through the 25 mg cohort data? And then just verifying there is no current Gd-IgA1 through the nine-month time point for the patients that have made it past that point in the study. Thanks.
Sure. Thanks for the question, Laura. I can say that when you look at how we're presenting the combined doses, we did have variable responses at different doses. Very clearly, the only single dose that hit statistical significance was 150 milligrams of atacicept. It was not statistically significant for 25 or 75 milligrams. While point estimates can change at these different time points that we have, and you can see from our graph, we looked at 24-hour urine collection and proteinuria at week 12 and week 24. We're starting to look at week 36 in a small subset. I think the totality of the data as we've reviewed it internally, is clearly pointing to 150 milligrams as the selected dose.
That's really, where we are, from that perspective. Your second question, Laura, was about what?
Any Gd-IgA1 reduction data?
Ah.
the six-month time point at this point?
We've chosen to wait for the full data set for really the totality of week 36 data. We felt at this stage it was important to show a continuing trend beyond week 24 to share that we see a trend towards continued reduction in proteinuria, which is what we're seeing in the phase IIa JANUS trial as well beyond 24 weeks.
Thanks very much, guys.
Thank you. Our final question today comes from the line of Ed Arce with H.C. Wainwright. Please proceed with your questions.
Great. Thanks for squeezing me in. First, a couple of questions for Dr. Barratt. Firstly, Dr. Barratt, you had mentioned that there is a, with this mechanism, a bit of a lag in effect, so the mechanism works a bit slower, and you've mentioned several times that the trajectory out to 36 weeks so far is encouraging. First question is, how much more incremental proteinuria reduction would you expect at 36 weeks? Separately, the 30% reduction in proteinuria in the meta-analysis that was associated with an eGFR slope benefit was mentioned earlier in this call as well. Could you clarify if that reduction is relative to placebo or baseline? I have a couple follow-ups.
Yes, I'll answer the second question first. The second question is yes, it's relative to placebo. This is the delta, proteinuria change. If you know the publication, you'll see there's a continuous relationship between magnitude of proteinuria reduction and the hazard ratio for an event, which in the initial analysis was a doubling of serum creatinine, end-stage kidney disease or death. The more proteinuria reduction you have, the better outcome it is for your kidneys. That's what we'd expect in IgA nephropathy. The 30% value has been chosen because it roughly halves the relative risk of an event or the hazard ratio for an event. That's where the 30% comes from, but it's a continuous relationship between the two. The more proteinuria reduction we have, the better.
The other thing that's really important, it's not just a number on a particular day that matters. It's being able to keep the proteinuria down and maintain that level of proteinuria reduction. That's what's particularly exciting about the data that we've just seen, is that the proteinuria is going down, and it's continuing to fall with continued treatment. That's what I would expect, because the kidney is no longer being inundated with immune complexes. We know, sorry to go on, if we take a kidney out of a patient with IgA nephropathy and put it into someone who has kidney failure but doesn't have IgA nephropathy, over time, when that kidney is not faced with lots of immune complexes, the kidney will clear whatever IgA is within that kidney, it will remodel, and it will repair itself to some extent.
We know that because there have been examples of kidneys being transplanted, then repeat kidney biopsies, the IgA eventually goes away. The kidney is capable of dealing with a certain amount of IgA deposition. What I think is happening with atacicept is it's turning off that continual deposition of IgA immune complexes. The kidney is then taking time to rebalance, to clear the complexes that have been there, to remodel, to repair. That's going to take time, and we know it takes time. We know it takes months and months. We're going to get some initial reductions because there's no longer re- deposition and inflammation. Over time, I can see that getting greater and greater. Here we're talking six to 12 months. I still think we will be seeing improvements in proteinuria down at 12 months.
I think that's likely to continue with continued therapy. The more proteinuria we get reduced, the greater the impact is going to be on the rate of decline of kidney function. This is not a disease that we're going to see a quick result, and then that's it. Everything's happened, we're gonna need to follow these patients, which is why I think the 36-week data is gonna be really interesting. My guess is we're gonna see a trajectory that still suggests things are gonna continue to get better.
Okay, great. One question, Marshall, for you and the team, related to the actual 24-week data. There's, you know, two groups here of focus. First, the pooled doses 75 and 150, which was the primary endpoint, as well as the 150, which alone, which is what you're taking into phase III. The 150, as you reported, had a reduction of 33%, and the pooled doses had a reduction of 31%. The placebo had a reduction of 7%. I'm just trying to get at the placebo-adjusted reductions. My math, the 150 had a placebo reduction of 26%, and the pooled data had a placebo-adjusted reduction of 24%. If you could confirm that or correct that as necessary. Thanks so much.
Yeah. Ed Arce, I would correct it. It's actually 28%. When you do these comparisons, you can't do a simple arithmetic subtraction, because these, we analyze these data the same way that FDA has guided as well as others, which, the detail is in the footnote on slide 13 in terms of our approach to looking at differences between active and placebo. You know, I think the important thing here is that is to recognize that placebo arms in multinational randomized controlled trials in IgAN patients does change over time. We've seen that in other programs. We had a minus 7% at the week 24 time point. You can see on slide 14 that that may be returning towards baseline as we get to week 36.
That delta is likely to change. When we look at the standard that we're looking to reach to say that we have something that's clinically meaningful, we believe that 30% delta from the baseline is the right way to think about that. I think placebo-adjusted rates are important to achieve statistical significance. We achieve statistical significance in both the primary analysis of combined doses as well as 150 alone because we made conservative estimates around effect size as well as a potential dropout. While that distance was narrowed, narrower than expected because of the 7% reduction in proteinuria in the placebo arm at the week 24 time point, we still achieved statistical significance.
We feel very solid in being able to claim a positive study based on stat sig as well as a clinically meaningful reduction, given that we're in the 30% range for single dose as well as combined doses.
Great. Thanks so much. Appreciate it.
Yeah.
Thank you. We've reached the end of the question and answer session. I'll now turn the call over to Dr. Fordyce for closing remarks.
With that, I want to thank Dr. Barratt for walking through the data and providing his important perspective on these data in detail, as well as these data in the context of what truly is an exciting changing landscape for patients with IgA nephropathy. I would leave you all with the important view that a global randomized control trial that's placebo-controlled provides robust and de-risked profile for us going from phase II into phase III. We're incredibly excited to bring this molecule closer to phase III and BLA filing and ultimately to patients. With that, we'll close the call. Thank you very much for your time and good questions this morning.
This will conclude today's conference. You may disconnect your lines at this time. Thank you for your participation.