Updated Clinical Data for Povetacicept in IgA Nephropathy Support Advancement to Phase 3 Trial

Jonathan Barratt, MD

Credit: IgA Nephropathy Foundation

Alpine Immune Sciences has announced updated clinical data for povetacicept in IgA nephropathy (IgAN) from the phase 1b/2a RUBY-3 study, which will be presented as a late-breaking poster at the World Congress of Nephrology meeting taking place from April 13-16, 2024, in Buenos Aires, Argentina.¹

According to the April 10 release, povetacicept was well tolerated and associated with urine protein to creatinine ratio (UPCR) reductions of > 60% at 36 weeks, linked to remission, resolution of hematuria, and stable renal function as measured through estimated glomerular filtration rate (eGFR). Additionally, Alpine Immune Sciences noted a successful end of phase 2 meeting with the US Food and Drug Administration to support advancement to a registrational, placebo-controlled phase 3 study of povetacicept in IgAN targeted for the second half of 2024.¹

“I think fundamentally, what we'd like to do is to switch off the production of that pathogenic Gd-IgA1,” Jonathan Barratt, MD, Mayer Professor of Renal Medicine at the University of Leicester, explained in an interview with HCPLive, describing agents in development looking at other ways to stop IgA production beyond budesonide (Tarpeyo)’s targeting of the mucosal immune system. Specifically, he mentioned the targeting of B cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) signaling that stops the production of Gd-IgA1, as seen with povetacicept.²

Povetacicept is a potent dual antagonist of the BAFF and APRIL cytokines, both of which play key roles in the pathogenesis of multiple autoimmune diseases via their roles in the activation, differentiation, and/or survival of B cells, T cells, and innate immune cells. In preclinical studies, povetacicept has exhibited greater potency versus other BAFF and/or APRIL inhibitors alone and B cell depletion and has demonstrated initial activity in patients with IgAN. Along with IgAN, it is currently in development for multiple other autoimmune kidney diseases, systemic lupus erythematosus, and autoimmune cytopenias.¹

RUBY-3 is a multiple ascending dose, multi-cohort, open-label, phase 1b/2a study of povetacicept in patients ≥ 18 years of age with biopsy-confirmed autoimmune glomerulonephritis, including IgAN, primary membranous nephropathy, lupus nephritis, and renal ANCA-associated vasculitis. Additional inclusion criteria for the trial required patients to be on maximally tolerated ACEi/ARB therapy, have well-controlled blood pressure, and be receiving disease-specific immunosuppressive therapy where applicable.^1,3

In the study, povetacicept was administered subcutaneously once every 4 weeks for up to 104 weeks. Key endpoints include proteinuria, eGFR, renal response, and disease-related autoantibodies.¹

According to the release, as of March 1, 2024, a total of 41 patients with IgAN had received povetacicept 80 mg or 240 mg. Treatment with povetacicept 80 mg subcutaneously Q4W has been associated with a clinically meaningful improvement in proteinuria, with a 64.1% reduction from baseline in UPCR at 36 weeks, associated with stable renal function as assessed by eGFR.¹

Additionally, 67% of participants achieved remission, defined as UPCR < 0.5 g/g, ≥50% reduction in UPCR from baseline, and stable renal function (≤ 25% reduction in eGFR from baseline). Resolution of hematuria, defined as negative or trace/small hematuria in patients with non-negative/trace hematuria at baseline, was achieved in all patients with data available at 36 or more weeks.¹

Additionally, treatment with povetacicept 240 mg subcutaneously Q4W has been associated with similar improvements in proteinuria, stable renal function, and remission, based on initial data through 12 and 24 weeks. Treatment with both doses was associated with significant reductions in the key disease-related biomarker galactose deficient IgA1 (Gd-IgA1), with the 80 mg dose achieving a 68.9% reduction at 40 weeks and the 240 mg dose achieving a 78.6% reduction at 20 weeks. Both doses achieved reductions in IgA/C3 and Gd-IgA1/C3 ratios and have been well tolerated in IgAN, with no instances of IgG < 3 g/L and no severe infections.¹

“These data strongly support the inhibition of APRIL/BAFF pathways by povetacicept and its efficacy in the treatment of IgAN as well as the need for further clinical development. If approved, povetacicept could be used a front-line disease modifying treatment in IgAN,” James Tumlin, MD, professor of medicine at Emory University School of Medicine, founder and CEO of NephroNet Clinical Trials Consortium, said in a press release.¹

According to the release, Alpine Immune Sciences plans to advance to a registrational trial in IgAN later this year with RAINIER, a randomized, double-blind, placebo-controlled, phase 3 study to evaluate the safety and efficacy of povetacicept in patients with IgAN at risk of progression to kidney failure. Additionally, the company detailed plans to explore povetacicept’s potential in other autoimmune diseases in the ongoing RUBY-3 and RUBY-4 studies, and through the initiation of the phase 2 DENALI study in systemic lupus erythematosus.¹

References:

1. ^{Alpine Immune Sciences. Alpine Immune Sciences Shares Updated Clinical Data from Povetacicept in IgA Nephropathy. News Details. April 10, 2024. Accessed April 11, 2024. https://ir.alpineimmunesciences.com/news/news-details/2024/Alpine-Immune-Sciences-Shares-Updated-Clinical-Data-from-Povetacicept-in-IgA-Nephropathy/default.aspx}
2. ^{Brooks, A. FDA Awards Full Approval to Budesonide (Tarpeyo) in Treatment of IgA Nephropathy. HCPLive. December 20, 2023. Accessed April 11, 2024. https://www.hcplive.com/view/fda-awards-full-approval-to-budesonide-tarpeyo-in-treatment-of-iga-nephropathy}
3. ^{Campbell, P. Early RUBY-3 Data Shows Promise for Povetacicept in Glomerulonephritis. HCPLive. November 4, 2023. Accessed April 11, 2024. https://www.hcplive.com/view/early-ruby-3-data-shows-promise-for-povetacicept-in-glomerulonephritis}