Otsuka Submits BLA for Sibeprenlimab in Treating IgA Nephropathy

Otsuka Pharmaceutical Co. Ltd. and its subsidiary Otsuka Pharmaceutical Development & Commercialization, Inc. have announced the submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for sibeprenlimab. This investigational monoclonal antibody targets APRIL, a proliferation-inducing ligand, and is designed for use in adults with immunoglobulin A nephropathy (IgAN). IgAN is a progressive autoimmune kidney disease that often leads to end-stage kidney disease over a patient's lifetime. The involvement of APRIL in IgAN pathogenesis is significant, as it contributes to the production of harmful Gd-IgA1 and facilitates immune complex formation. Sibeprenlimab is presented as a prefilled syringe for subcutaneous injection, offering patients the convenience of self-administration every four weeks.

The FDA granted sibeprenlimab a Breakthrough Therapy designation in 2024, following promising outcomes from the Phase 2 ENVISION clinical trial. This designation is intended to expedite the development and regulatory evaluation of new medicines that address serious conditions with significant unmet medical needs. If approved, sibeprenlimab would allow patients an accessible treatment option that can be administered at home via monthly injections.

Supporting the BLA submission are data from the Phase 2 ENVISION trial and the Phase 3 VISIONARY trial. The latter confirmed sibeprenlimab's ability to significantly reduce urine protein-to-creatine ratio (uPCR) over 24 hours compared to a placebo after nine months of therapy. The safety profile of sibeprenlimab was consistent with earlier reports, showing favorable outcomes.

John Kraus, M.D., Ph.D., and executive vice president at Otsuka Pharmaceutical Development & Commercialization, Inc., emphasized the significance of this BLA filing. He highlighted sibeprenlimab's unique mechanism, which inhibits APRIL activity and targets a specific driver of kidney damage in IgAN. Kraus expressed optimism about the therapeutic potential of sibeprenlimab to address the progressive nature of IgAN and extended gratitude to all individuals who contributed to the related research.

The VISIONARY study stands as the most extensive trial conducted for IgAN to date, involving around 530 adult participants who were receiving standard-of-care treatments like ACE inhibitors or ARBs, possibly combined with SGLT2 inhibitors. This randomized, double-blind, placebo-controlled trial aimed to evaluate the efficacy and safety of sibeprenlimab, administered every four weeks. The primary efficacy endpoint was the shift in 24-hour uPCR after nine months, while a secondary endpoint analyzed the annualized slope of estimated glomerular filtration rate (eGFR) over approximately 24 months.

Brian Pereira, M.D., CEO of Visterra, Inc., Otsuka's U.S. affiliate responsible for the design and engineering of sibeprenlimab, acknowledged the BLA submission as a pivotal step towards bringing innovative treatments to IgAN sufferers. He expressed anticipation for the FDA's review and the opportunity to develop a treatment that could potentially change the trajectory of this challenging kidney disease, thereby enhancing patient outcomes.

Sibeprenlimab, previously known as VIS649, was developed by Visterra, Inc., a subsidiary of Otsuka. Pre-clinical and early-stage trials were also conducted by Visterra. By specifically binding to and inhibiting APRIL, sibeprenlimab aims to reduce IgA and Gd-IgA1 levels. Lower Gd-IgA1 levels mean fewer substrates for immune complex formation, potentially leading to decreased auto-antibody production. This reduction in immune complexes could result in decreased kidney deposition, inflammation, and proteinuria, ultimately slowing kidney damage and progression towards end-stage kidney disease.

Immunoglobulin A nephropathy is an autoimmune chronic kidney condition that commonly emerges in adults aged 20-40. It is marked by the buildup of Gd-IgA1 complexes in the kidneys, which can progress to a significant loss in kidney function and end-stage kidney disease, posing substantial challenges for patients. Despite existing supportive care, therapeutic options targeting the condition's root cause remain inadequate, underscoring the importance of ongoing research to advance treatment and understanding of IgAN.

APRIL is a cytokine in the tumor necrosis factor family, crucial to IgAN pathogenesis and progression. It supports the survival and class switching of B cells to produce IgA, especially the pathogenic Gd-IgA1 that forms harmful immune complexes within the kidneys.