Otsuka Holdings Co., Ltd. (4578) Earnings Call Transcript & Summary

Thank you, and thanks for joining. I'm very happy today to present our top line 24-month eGFR results from our study of sibeprenlimab in IgA nephropathy. Next slide, please. As you're aware, IgA nephropathy is a progressive immune-mediated kidney disease. It is the most common glomerulonephritis with a significant disease burden, both in physical, mental as well as emotional health, which worsens with disease severities. Despite current supportive treatments, there still is substantial unmet need with patients continuing to progress, including to kidney failure, dialysis and sometimes transplant as well. The KDIGO guidelines of 2025 set a goal for IgA nephropathy with a goal of reducing the rate of loss of kidney function to less than 1 milliliter per minute per year. And that becomes important as we begin to look at the data. Next slide, please. I want to speak a little bit about sibeprenlimab, its effect and how it likely works in the 4-hit hypothesis or the pathophysiological cascade that results in IgAN. APRIL is a cytokine that works on plasma cell proliferation as well as antibody class switching. With sibeprenlimab, which selectively blocks APRIL, we're able to prevent initiation of the cascade that I'm going to describe right now. The first hit is the production of pathologic galactose-deficient IgA1. What happens then is autoimmune effects with the resultant autoantibodies are developed against this galactose-deficient IgA1. These result in the formation of immune complexes, and that immune complex is deposited into the mesangium of the kidney. This leads to inflammatory response and ultimately to reduction in renal function over time. The goal of APRIL is to reduce that Hit 1, the galactose-deficient IgA1 and therefore, block the initiation of this pathophysiologic cascade and hopefully lead to improved outcomes in patients. Next slide, please. So the Phase III study that Otsuka undertook was the VISIONARY study. The trial design is relatively simple. It's a 1:1 randomization comparing sibeprenlimab 400 milligrams subcutaneously administered every 4 weeks compared to an approximate equal number of placebo patients given placebo subcutaneously every 4 weeks as well. The primary efficacy endpoint, which we reported previously, the 9-month uPCR, occurred at 9 months. What we're going to be talking about today are the final result and the key functional results of eGFR at 104 weeks of treatment. The key inclusion criteria for patients in this study were biopsy-confirmed IgA nephropathy, age greater than or equal to 18 years uPCR of greater than 0.75 or urine protein of greater than 1, eGFR of greater than 30 and stable or maximally tolerated dose of ACE and/or ARB with or without SGLT2 inhibitors. And that stability had to be there for approximately 3 months of treatment. We did look at certain stratification factors, which I'll describe in the results as well. This is comparing baseline uPCR of less than 2 versus greater than 2, eGFR of 30 to 44 versus greater than 45 and SGLT2 inhibitor use, yes or no. We also had an exploratory cohort in the study of patients with a fairly low eGFR, which is not available yet, but we hope to report on shortly. Next slide, please. So as I said, the primary endpoint of the study has previously been reported and additionally published in The New England Journal of Medicine. This was the ratio of uPCR at 9 months versus a baseline based on 24-hour urine collection, where we saw a substantial positive effect with sibeprenlimab treatment. Today, we're going to review key secondary endpoint, the annualized slope of eGFR estimated over 24 months from week 4, that was the first treatment week, and mean change of eGFR estimated from baseline at 24 months. I'll also describe some subgroup analyses of the annualized eGFR slope, a sensitivity analysis looking at the slope from baseline rather than from week 4 to endpoint. And of course, we'll review safety findings from the complete data set. Next slide, please. So let's get into the results here. Next slide. So here, we have the baseline demographics for the patients in the study, 510 total patients, making this the largest IgAN study to date. The key takeaway from here is that the demographics between sibeprenlimab and placebo were well balanced in terms of age, sex, race and geographic region. Next slide, please. Similarly, baseline clinical characteristics of these subjects were balanced between the treatment groups. For example, we see the time from the first biopsy to the randomization of approximately 1.3 to 1.5 years, baseline uPCR of approximately 1.6 to 1.5 and baseline eGFR of 65 and 63.4. So very similar patient characteristics. Similarly, the background treatment of these patients was the same as well with approximately 43% to 47% on SGLT2 inhibitors in particular. Next slide, please. Here is the result of the key secondary endpoint, the annualized eGFR slope estimated over 24 months. We are very pleased to see that the sibeprenlimab group, shown in blue in this slide, we actually saw an increase of 0.3 in the eGFR relative to a decrease of minus 4.2 in the placebo group. This results in a treatment difference of 4.5 milliliters per minute per 1.73 meter square per year. This is well within the KDIGO guidelines, which target limiting an annual eGFR decline of less than 1. We're actually a little higher than baseline in this end result, really an unprecedented finding in a 2-year evaluation of eGFR in IgAN. Next slide, please. We also assessed, as a sensitivity analysis, the annualized eGFR slope estimates from baseline. What I had shown previously was from week 4 where treatment had been initiated. Here, we see a very similar finding of plus 4.7 sibeprenlimab superior to placebo. Next slide, please. When looking at the various stratifications that I spoke about earlier, if we look at the forest plot here with -- on the right of the vertical line would be an improvement favoring sibeprenlimab, the left would be favoring placebo. Every point, as you can see, and the confidence intervals favor sibeprenlimab over placebo in this stratification. So we looked at uPCR 24 hours, either less than 2 or greater than 2, and we see treatment effects favoring sibeprenlimab in both instances. We looked at screening eGFR, either 30 to 44 or greater than 45. And again, we see a benefit of sibeprenlimab relative to placebo. Finally, we assessed the presence or absence of SGLT2 inhibitors, which are an emerging treatment in IgAN, and we found that whether a patient was on or not, they still receive benefit with sibeprenlimab compared to placebo. So again, it appears that patients benefited regardless of their baseline uPCR, eGFR or use of SGLT2 inhibitors. Next slide, please. Now this result was quite impressive to us when we saw these top line results just recently. Here is the graphical representation of the change from baseline in eGFR over 24 months. The blue represents sibeprenlimab, the gray represents placebo. And what you can see in the placebo group is a continual decline over the 2 years that you would expect in a progressive renal disease like IgAN. However, in the sibeprenlimab-treated group in blue, we see actually a stabilization of kidney function with actually a mean improvement in eGFR seen after 2 years of treatment. This is, again, an unprecedented result where we're actually finding that compared to baseline, we see stabilization of kidney function in IgAN for sibeprenlimab-treated patients, clearly demonstrating a disease-modifying effect of this compound in this disease, a truly, truly remarkable outcome that we hope will benefit patients. Next slide, please. Of course, we have to balance even stunning efficacy with safety. And when looking at the safety of sibeprenlimab, broadly speaking, the outcomes are very similar to the placebo group. Overall, treatment-emergent adverse events occurred in approximately 90% of patients, which isn't a surprise when you follow patients over 2 years. However, when looking at what investigators consider treatment-related adverse events, we also see a similar distribution between sibeprenlimab and placebo, 35% versus approximately 33%. Now when we're dealing with a compound that is -- has immune modulating effects like sibeprenlimab does through its blockade of APRIL, there can be concerns about the potential for infections or infestations. So when reviewing those as a group, we found that sibeprenlimab actually looked slightly better numerically compared to placebo, an incidence of 1.9% versus 4% in placebo. And again, the other assessments here are similar between the 2 groups. Now if we go to the next slide, we actually break down some of the adverse events that we see here. Again, we're seeing a fairly similar distribution between sibeprenlimab and placebo among these adverse events. We do break down those infections and infestations for your review here. But again, similar proportion of patients were affected, whether they took sibeprenlimab or placebo. So in general, we are seeing in the safety of sibeprenlimab broadly similar to that of placebo in this 2-year study. Next slide, please. So just to conclude, we're obviously very excited about this data. Sibeprenlimab, which is a selective APRIL blocker, demonstrated improvement in eGFR relative to placebo, which resulted in clinically meaningful stabilization of kidney function over 24 months in patients with IgA nephropathy. The eGFR effects in the VISIONARY trial are the largest reported to date for a Phase III trial in IgA nephropathy and indeed meet the eGFR treatment goals proposed by the 2025 KDIGO IgA nephropathy guideline. Additionally, sibeprenlimab showed treatment effects that were consistent across prespecified stratification subgroups, and that indicates a broad therapeutic applicability to patients with IgA nephropathy. Further, at 24 months, safety remained favorable with similar rates of overall adverse events and infections between groups. Further analyses of the VISIONARY 2-year results will be presented at upcoming scientific congresses. As you might imagine, this is a large data set, and we have a number of other items that we're still investigating, and we look forward to presenting those at the appropriate scientific forums. So I appreciate your attention during this presentation.