Otsuka Pharmaceutical, Co. Ltd. (Otsuka) and Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) today announce the filing of a Biologics License Application (BLA) with the U.S. Food and Drug Administration (FDA) for sibeprenlimab, an investigational monoclonal antibody that selectively inhibits the activity of APRIL (A PRoliferation-Inducing Ligand) in adults with immunoglobulin A nephropathy (IgAN). APRIL plays a key role in the 4-hit process of IgAN pathogenesis and is an important initiating and sustaining factor in IgAN progression by promoting the production of pathogenic Gd-IgA1 and immune complex formation. Sibeprenlimab is a single-dose prefilled syringe for subcutaneous injection every four weeks intended for self-administration or administration by caregiver, providing patients the option of convenience at home.

IgAN is a progressive, autoimmune, chronic kidney disease that is associated with a high risk for progression to end-stage kidney disease (ESKD) over the lifetime of many patients.¹ In 2024, the FDA granted a Breakthrough Therapy designation for sibeprenlimab following favorable results of the Phase 2 ENVISION clinical trial.² This designation accelerates the development and regulatory review of potential new medicines intended to treat a serious condition and address a significant unmet medical need. If approved, sibeprenlimab would be administered via injection every four weeks, which would allow patients the convenience and option of self-administration in the home setting.³

The BLA submission, Otsuka's first, is supported by results from the Phase 2 ENVISION clinical trial (NCT04287985) and the Phase 3 VISIONARY clinical trial (NCT05248646), which met its primary endpoint by demonstrating that sibeprenlimab produced a statistically significant and clinically meaningful reduction in 24-hour uPCR (urine protein-to-creatine ratio) compared to placebo after nine months of treatment.⁴ In the trial, the safety profile of sibeprenlimab was favorable and consistent with previously reported data.

"This BLA filing marks an important milestone in Otsuka's commitment to address unmet needs in kidney diseases," said John Kraus, M.D., Ph.D., executive vice president and chief medical officer, Otsuka Pharmaceutical Development & Commercialization, Inc. "Sibeprenlimab's unique mechanism of action inhibits the activity of APRIL and addresses an IgA-specific driver of kidney loss in IgA nephropathy. APRIL is a cytokine that plays a key role in the pathogenesis of IgA nephropathy and we are optimistic about its potential to be an important treatment option for this progressive kidney disease. On behalf of Otsuka, we are grateful to every patient, caregiver and healthcare professional who has contributed so much to advancing this important research."

The VISIONARY study is a multicenter, randomized, double-blind, placebo-controlled trial consisting of approximately 530 adult patients (largest trial to date) with IgA nephropathy who were receiving standard-of-care therapy (defined as maximally tolerated ACE inhibitor or ARB +/- SGLT2 inhibitor), designed to evaluate the efficacy and safety of sibeprenlimab 400 mg administered subcutaneously every four weeks, compared to placebo. The primary efficacy endpoint is to evaluate the change in 24-hour uPCR at 9 months compared with baseline.⁴ The secondary endpoint is to evaluate the annualized slope of eGFR estimated over ~24 months.⁴

"This BLA for sibeprenlimab represents a significant achievement in our journey to bring innovative treatments to patients with IgA nephropathy," commented Brian Pereira, M.D., CEO of Visterra, Inc., the U.S. affiliate of Otsuka that designed and engineered sibeprenlimab. "We look forward to the FDA's review and are grateful for the opportunity to help develop a treatment that could alter the course of this challenging kidney disease and improve patient outcomes."

About Sibeprenlimab
Sibeprenlimab (formerly VIS649) was designed and engineered by Visterra, Inc., a wholly owned subsidiary of Otsuka. Pre-clinical and early-stage trials of sibeprenlimab were also conducted by Visterra.

Sibeprenlimab is an investigational monoclonal antibody that selectively binds to and inhibits the activity of APRIL and plays a key role in the 4-hit process. By binding and inhibiting APRIL, sibeprenlimab may help reduce the amount of immunoglobulin A (IgA) and Gd-IgA1 levels. Lower levels of Gd-IgA1 provide less substrate for immune complex formation, and may also result in reduced auto-antibody production. Decreased immune complex creation should result in diminished deposition in the kidney, and reduced proteinuria and kidney inflammation. By reducing the production of Gd-IgA1, sibeprenlimab may help slow kidney damage and progression toward ESKD.^2,4,5,6 By inhibiting APRIL, sibeprenlimab may help address one of the IgA nephropathy-specific drivers for nephron loss.

About Immunoglobulin A Nephropathy and APRIL
IgA nephropathy is a progressive, autoimmune, chronic kidney disease that typically manifests in adults aged 20-40 years and leads to ESKD over the lifetime of most patients.^1,7,8

IgA nephropathy is characterized by the accumulation of Gd-IgA1 complexes in the kidneys. IgA nephropathy can lead to progressive loss of kidney function and, eventually, ESKD, imposing a significant burden on patients.⁷ Despite supportive care, there is an unmet need for treatments that address the root cause of the condition. Continued research in the disease remains crucial to uncovering opportunities for advancement in our understanding and treatment of patients.⁹

APRIL, a cytokine in the tumor necrosis factor (TNF) family, is integral to the pathogenesis and progression of IgA nephropathy. It 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.⁹

References

1. Pitcher, D. Braddon, et. al Long-term outcomes in IGA nephropathy. Clinical journal of the American Society of Nephrology : CJASN. https://pubmed.ncbi.nlm.nih.gov/37055195/.

2. Mathur M, Barratt J, Suzuki Y, et al. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VIS649 (Sibeprenlimab), an APRIL-Neutralizing IgG2 Monoclonal Antibody, in Healthy Volunteers. Kidney Int Rep. 2022;7(5):993-1003.

3. Otsuka Pharmaceutical Development & Commercialization, Inc., Sibeprenlimab Prefilled Syringe for the Treatment of IgA Nephropathy. Human Factors Formative 1 Study Report for Commercial Development Phase.

4. Otsuka Pharmaceutical Development & Commercialization, Inc.Visionary Study: Phase 3 Trial of Sibeprenlimab in Immunoglobulin A Nephropathy (IgAN). Clinicaltrials.gov.

5. Mathur M, Barratt J, Chacko B, et al. A Phase 2 Trial of Sibeprenlimab in Immunoglobulin A Nephropathy Patients. NEJM. 2023 https://www.nejm.org/doi/full/10.1056/NEJMoa2305635

6. Chang S, Li XK. The Role of Immune Modulation in Pathogenesis of IgA Nephropathy (nih.gov)

7. Cheung, Chee Kay & Boyd, JKF & Feehally, J.. (2012). Evaluation and management of IgA nephropathy. Clinical Medicine. 12. s27-s30. 10.7861/clinmedicine.12-6-s27.

8. Lai K. Iga nephropathy. Nature reviews. Disease primers. 2016. https://pubmed.ncbi.nlm.nih.gov/27189177/.

9. Cheung CK, Barratt J, Liew A, Zhang H, Tesar V, Lafayette R. The role of BAFF and April in IGA nephropathy: Pathogenic mechanisms and targeted therapies. Frontiers in nephrology. February 1, 2024.