• Phase 3 VISIONARY study met its primary endpoint at prespecified interim analysis; sibeprenlimab demonstrated a statistically significant and clinically meaningful reduction in 24-hour uPCR after nine months of treatment; the favorable safety profile of sibeprenlimab was consistent with previously reported data.
• Immunoglobulin A nephropathy is a progressive, autoimmune, chronic kidney disease that can lead to end-stage kidney disease (ESKD) over the lifetime of most patients under current optimized standard care.
• Otsuka plans to review interim results with the FDA to enable a potential regulatory submission for accelerated approval; study continues with final results expected in early 2026.

Otsuka Pharmaceutical Development & Commercialization, Inc. and Otsuka Pharmaceutical, Co. Ltd. (Otsuka), today announce positive topline interim data from the ongoing Phase 3 clinical trial of sibeprenlimab for the treatment of immunoglobulin A nephropathy (IgA nephropathy) in adults.

Sibeprenlimab is an investigational, anti-APRIL monoclonal antibody (A PRoliferation-Inducing Ligand) that blocks a key initiating step in the immune pathogenic cascade of IgA nephropathy by limiting Gd-IgA1 production and immune complex formation. IgA nephropathy is a progressive, autoimmune, chronic kidney disease that can lead to end-stage kidney disease (ESKD) over the lifetime of most patients.^1,2,3,4 Otsuka was previously granted Breakthrough Therapy designation for sibeprenlimab following favorable results of the Phase 2 ENVISION clinical trial.³

The pre-specified interim analysis review, conducted by an independent data monitoring committee, found that the Phase 3 VISIONARY study (NCT05248646) 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.⁵ The study, a multicenter, randomized, double-blind, placebo-controlled trial consisting of approximately 530 adult patients (largest of its kind) with IgA nephropathy who were receiving standard-of-care therapy (defined as maximally tolerated ACE inhibitor or ARB +/- SGLT2 inhibitor), was designed to evaluate the efficacy and safety of sibeprenlimab 400 mg administered subcutaneously every four weeks, compared to placebo. The primary efficacy endpoint was to evaluate the change in 24-hour uPCR at 9 months compared with baseline.⁵

“The positive interim data from this trial suggest that by targeting APRIL, we could provide a new therapeutic strategy for people living with this progressive kidney disease,” said John Kraus, M.D., Ph.D., executive vice president and chief medical officer, Otsuka Pharmaceutical Development & Commercialization, Inc. “We look forward to the completion of this study and reviewing the full results at a future timepoint. We are deeply appreciative to the patients with IgA nephropathy who participated in this trial, their caregivers, and investigators, all of whom continue to contribute greatly to this research.”

Brian Pereira, M.D., CEO of Visterra, Inc., an Otsuka U.S. affiliate, which designed and engineered sibeprenlimab, said, “We are encouraged by sibeprenlimab’s continuing progress and its potential to provide a needed and possibly disease-modifying treatment option to IgA nephropathy patients.”

The ongoing Phase 3 study continues in a blinded manner to evaluate the change in kidney function over 24 months as measured by estimated glomerular filtration rate (eGFR) and is expected to be completed in early 2026. Further prespecified and exploratory analyses of the data will be conducted to determine the full potential of sibeprenlimab for the treatment of IgA nephropathy. Otsuka plans to review interim analysis results with the FDA to enable a potential regulatory submission for accelerated approval.

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 blocks the action of APRIL (A PRoliferation-Inducing Ligand), that plays a key role in IgA nephropathy’s four-hit pathogenic cascade. APRIL is an important sustaining factor in IgA nephropathy progression by promoting the production of pathogenic Gd-IgA1 and immune complex formation.​ By binding and neutralizing APRIL, sibeprenlimab may help reduce the amount of immunoglobulin A (IgA) and Gd-IgA1. Lower levels of Gd-IgA1 may then result in reduced auto-antibody production, which in turn may result in fewer immune complexes, decreased immune complex deposits 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.^1,2,3,5 By blocking APRIL, sibeprenlimab may help address one of the IgA nephropathy-specific drivers for nephron loss.

About Immunoglobulin A Nephropathy and APRIL

IgA nephropathy, also known as Berger’s disease, 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. ^{4, 6, 7}

It is characterized by the accumulation of IgA in the kidneys – a type of antibody that plays a critical role in the immune system. IgA nephropathy can lead to progressive kidney dysfunction and, eventually, ESKD, imposing a significant burden on patients.⁶ Despite supportive care, including therapies that focus on treating the symptoms of IgA nephropathy, continued research in the disease remains crucial to uncovering opportunities for advancement in our understanding and treatment of patients.⁶

APRIL (A PRoliferation-Inducing Ligand), a cytokine in the tumor necrosis factor (TNF) family, is integral to the development 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.⁸

About Otsuka

Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: Otsuka–people creating new products for better health worldwide. Otsuka researches, develops, manufactures, and markets innovative products, with a focus on pharmaceutical products to meet unmet medical needs and nutraceutical products for the maintenance of everyday health.

In pharmaceuticals, Otsuka is a leader in the challenging areas of mental, renal, and cardiovascular health and has additional research programs in oncology and on several under-addressed diseases including tuberculosis, a significant global public health issue. These commitments illustrate how Otsuka is a “big venture” company at heart, applying a youthful spirit of creativity in everything it does.

Otsuka established a presence in the U.S. in 1973 and today its U.S. affiliates include Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) and Otsuka America Pharmaceutical, Inc. (OAPI). These two companies’ 2,250 employees in the U.S. develop and commercialize medicines in the areas of mental health and nephrology, using cutting-edge technology to address unmet healthcare needs.

OPDC and OAPI are indirect subsidiaries of Otsuka Pharmaceutical Co., Ltd., which is a subsidiary of Otsuka Holdings Co., Ltd. headquartered in Tokyo, Japan. The Otsuka group of companies employed 34,400 people worldwide and had consolidated sales of approximately USD 14.2 billion in 2023.

All Otsuka stories start by taking the road less traveled. Learn more about Otsuka in the U.S. at www.otsuka-us.com and connect with us on LinkedIn and Twitter at @OtsukaUS. Otsuka Pharmaceutical Co., Ltd.’s global website is accessible at https://www.otsuka.co.jp/en/.

About Visterra

Visterra is a biologics research and early-stage clinical development biotechnology company committed to developing innovative antibody-based therapies for the treatment of patients with immune-mediated kidney diseases and other hard-to-treat diseases. Its proprietary Hierotope® platform enables the design and engineering of precision biologics-based product candidates that specifically bind to, and modulate, key disease targets that are not adequately addressed by traditional therapeutic approaches. The platform also includes Fc engineering capabilities for half-life extension, bispecific antibodies and antibody-drug conjugates (ADCs). Visterra’s pipeline includes programs targeting kidney diseases, immunologically-driven diseases and infectious diseases. Visterra is an indirect subsidiary of Otsuka Pharmaceutical Co., Ltd. For more information, visit www.visterrainc.com.

References

1. 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

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

3. 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.

4. 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/.

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

6. 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.

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

8. Yeo SC et al. Is immunoglobulin A nephropathy different in different ethnic populations? April 2019. https://onlinelibrary.wiley.com/doi/full/10.1111/nep.13592.

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