Vera Therapeutics, Inc. announced positive 72-week data from the open label extension period of its Phase 2b ORIGIN clinical trial of atacicept in participants with IgA nephropathy (IgAN). In aggregate, the 72-week data with atacicept are consistent with a profile of true disease modification in IgAN. After completing the 36-week randomized, double-blind, placebo-controlled period of the Phase 2b ORIGIN trial, all participants were eligible to receive atacicept 150 mg in the OLE.

Of the 116 randomized participants, 106 completed 72 weeks.Participants treated with atacicept for 72 weeks demonstrated a 62% reduction in Gd-IgA1, a reduction in the percentage of participants with hematuria to 19%, and a 48% reduction in UPCR in the per-protocol (PP) analysis. Importantly, participants had consistent and stable eGFR with 0 mL/min/1.73m2 change from baseline at 72 weeks. Of note, it has been shown that eGFR declines by approximately 1 mL/min/1.73m2 per year in the general population (Baba M, et al.

PLOS ONE 2015). Participants who switched from placebo to atacicept demonstrated similar outcomes across each of the key indicators of IgAN as compared to participants originally randomized to atacicept during the first 36 weeks of the trial, including a 59% reduction in Gd-IgA1, a reduction in the percentage of participants with hematuria to 41%, and a 47% reduction in UPCR in the PP analysis. In addition, eGFR stabilization was observed in participants who switched from placebo to atacicept with a -3.2 mL/min/1.73m2 change from baseline at 72 weeks compared to -4.9 mL/min/1.73m2 at 36 weeks.

Safety data in the OLE were consistent with the randomized period and indicated that atacicept was generally well-tolerated. These data build upon the prior experience of atacicept in randomized, double-blind, placebo-controlled clinical trials in over 1,500 participants to date across different indications ? in which atacicept was generally well-tolerated.

The Phase 2b ORIGIN clinical trial (NCT04716231) is a global, multicenter, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of atacicept in 116 patients with IgAN who continue to have persistent proteinuria and remain at high risk of disease progression despite being on a stable prescribed regimen of a renin-angiotensin-aldosterone system inhibitor (RAASi) for at least 12 weeks that is the maximum labeled or tolerated dose. The Phase 2b ORIGIN clinical trial evaluated three dose strengths of atacicept versus placebo, administered weekly by prefilled syringe. Patients were randomized 2:2:1:2 to atacicept 150 mg, atacicept 75 mg, atacicept 25 mg, or matching placebo.

Upon completion of the 36-week blinded treatment period, all patients were offered open-label atacicept 150 mg for an additional 60 weeks. The primary endpoint was the change in proteinuria as evaluated by urine protein to creatinine ratio (UPCR) at week 24 and the key secondary endpoint was the change in proteinuria as evaluated by UPCR at week 36. Additional exploratory endpoints include change in proteinuria as evaluated by UPCR at weeks 12, 48, and 96; change in estimated glomerular filtration rate (eGFR); change in serum immunoglobulin levels, and serum galactose-deficient IgA1 (Gd-IgA1) levels; safety and tolerability; and serum pharmacokinetics.

The trial met its primary and key secondary endpoints, with statistically significant and clinically meaningful proteinuria reductions and stabilization of eGFR versus placebo through week 36. The safety profile was comparable between atacicept and placebo. The ORIGIN 3 clinical trial is a global, multicenter, randomized, double-blind, placebo-controlled Phase 3 trial evaluating the safety and efficacy of atacicept 150 mg in patients with IgAN who continue to have persistent proteinuria and remain at high risk of disease progression despite being on a stable prescribed regimen of renin-angiotensin system inhibitors (RASi) (ACEi or ARB) for at least 12 weeks that is the maximum labeled or tolerated dose.

The objectives of the trial are to determine the effect of atacicept on proteinuria and preservation of renal kidney function compared to placebo. The Phase 3 trial is composed of up to a 4-week screening period, a 104-week double-blind treatment period, a 52-week open-label extension and 26 weeks of follow-up. Participants will be randomized 1:1 to atacicept 150 mg once weekly subcutaneous injections (N=188) or placebo once weekly subcutaneous injections (N=188) for 104 weeks, followed by a 52-week open-label extension.

The primary endpoint is the change from baseline in proteinuria as evaluated by urine protein to creatinine ratio (UPCR) at week 36. The key secondary endpoint is annualized rate of change in estimated glomerular filtration rate (eGFR) up to week 104. Additional secondary endpoints are the change in Gd-IgA1, change in eGFR up to week 52, and time from randomization to first occurrence of composite kidney failure endpoint event.