Otsuka Reports Positive Phase 3 Interim Results for Sibeprenlimab in Adult IgA Nephropathy Treatment

On October 22, 2024, Otsuka Pharmaceutical Development & Commercialization, Inc. and Otsuka Pharmaceutical Co., Ltd. announced positive interim results from their Phase 3 clinical trial of sibeprenlimab for treating immunoglobulin A nephropathy (IgA nephropathy) in adults. This investigational drug is an anti-APRIL monoclonal antibody designed to disrupt a critical step in the immune pathogenic cascade of IgA nephropathy by reducing Gd-IgA1 production and immune complex formation. IgA nephropathy is a chronic autoimmune kidney disease that can progress to end-stage kidney disease (ESKD) over time.

Following favorable outcomes from the Phase 2 ENVISION clinical trial, sibeprenlimab was granted Breakthrough Therapy designation. An independent data monitoring committee's pre-specified interim analysis of the Phase 3 VISIONARY study (NCT05248646) confirmed that sibeprenlimab significantly reduced the 24-hour urine protein-to-creatinine ratio (uPCR) compared to placebo after nine months of treatment.

The VISIONARY study is a multicenter, randomized, double-blind, placebo-controlled trial including approximately 530 adult patients with IgA nephropathy who are receiving standard-of-care therapy. The trial aims to assess the efficacy and safety of sibeprenlimab, administered subcutaneously every four weeks in 400 mg doses. The primary efficacy endpoint is evaluating the change in 24-hour uPCR at nine months from baseline.

John Kraus, M.D., Ph.D., executive vice president and chief medical officer of Otsuka Pharmaceutical Development & Commercialization, Inc., expressed optimism about the interim results, suggesting that targeting APRIL may offer a new therapeutic strategy for this progressive kidney disease. Kraus also expressed gratitude towards the patients, their caregivers, and the investigators involved in the trial.

Brian Pereira, M.D., CEO of Visterra, Inc., an Otsuka U.S. affiliate responsible for designing and engineering sibeprenlimab, was encouraged by the drug's progress and its potential as a disease-modifying treatment for IgA nephropathy patients.

The ongoing Phase 3 study will continue in a blinded manner to evaluate kidney function changes over 24 months, as measured by estimated glomerular filtration rate (eGFR), with completion expected in early 2026. Further analyses will be conducted to assess the full potential of sibeprenlimab. Otsuka plans to discuss the interim results with the FDA to explore the possibility of accelerated approval.

Sibeprenlimab, formerly known as VIS649, was developed by Visterra, Inc. It functions by blocking APRIL, a cytokine that promotes the survival and class switching of B cells to produce IgA, particularly the pathogenic galactose-deficient IgA1 (Gd-IgA1) that forms immune complexes in the kidneys. By neutralizing APRIL, sibeprenlimab potentially reduces Gd-IgA1 levels, leading to fewer immune complexes, decreased kidney deposits, reduced proteinuria, and less kidney inflammation. This mechanism may slow kidney damage and progression toward ESKD by addressing one of the specific drivers of nephron loss in IgA nephropathy.

IgA nephropathy, also known as Berger’s disease, typically affects adults aged 20-40 years and often leads to ESKD over patients' lifetimes. It is characterized by the accumulation of IgA in the kidneys, causing progressive kidney dysfunction. Continued research is essential to advance the understanding and treatment of this disease.

APRIL is crucial in IgA nephropathy's development and progression, promoting the production of pathogenic Gd-IgA1 and subsequent immune complex formation in the kidneys. Otsuka Pharmaceutical Co., Ltd. is dedicated to creating innovative products to address unmet medical needs, particularly in mental, renal, and cardiovascular health. Its U.S. affiliates, Otsuka Pharmaceutical Development & Commercialization, Inc. and Otsuka America Pharmaceutical, Inc., employ 2,250 people focused on mental health and nephrology.

Visterra, a subsidiary of Otsuka, specializes in developing antibody-based therapies for immune-mediated kidney diseases and other difficult-to-treat conditions using its proprietary Hierotope® platform. This platform enables the design of precision biologics-based product candidates targeting disease mechanisms inadequately addressed by traditional therapies.