Otsuka Sibeprenlimab Phase 3 Data Show a Statistically Significant and Clinically Meaningful Proteinuria Reduction for the Treatment of Immunoglobulin A Nephropathy (IgAN)

ANNOUNCEMENT FOR EUROPEAN MEDICAL & PHARMACEUTICAL TRADE MEDIA AND EUROPEAN FINANCIAL MEDIA ONLY

Otsuka Sibeprenlimab Phase 3 Data Show a Statistically Significant and Clinically Meaningful Proteinuria Reduction for the Treatment of

Immunoglobulin A Nephropathy (IgAN)

• In the Phase 3 VISIONARY study, sibeprenlimab achieved a statistically significant and clinically meaningful 51.2% (P<0.0001) reduction in proteinuria from baseline at nine months of treatment when compared to placebo
• Immunoglobulin A nephropathy (IgAN) is a progressive, immune-mediated, chronic kidney disease that can lead to end-stage kidney disease (ESKD) over the lifetime of many patients under current optimised standard care^1,2,3,4
• Sibeprenlimab has been granted orphan designation by the European Commission for the treatment of primary IgA nephropathy⁵

Windsor, United Kingdom – June 6, 2025 – Otsuka Pharmaceutical, Co. Ltd. and Otsuka Pharmaceutical Europe Ltd. (Otsuka) today presented results from a pre-specified interim analysis of the Phase 3 VISIONARY study (NCT05248646) evaluating sibeprenlimab, for the treatment of immunoglobulin A nephropathy (IgAN) in adults. Patients treated with sibeprenlimab achieved a 51.2% (P<0.0001) reduction in proteinuria from baseline (as measured by 24-hour uPCR [urine protein-to-creatinine ratio]) at nine months of treatment when compared to placebo. The study, the largest Phase 3 IgAN trial conducted to date, also showed that 76.3% of patients treated with sibeprenlimab experienced Treatment Emergent Adverse Events (TEAEs) versus 84.5% in the placebo group. Patients who experienced a serious TEAE were 3.9% treated with sibeprenlimab compared to 5.4% treated with placebo. The data were presented during a late-breaking clinical trials session at the European Renal Association (ERA) Congress in Vienna, Austria.

Proteinuria reduction is a recognised surrogate marker correlating with delaying progression to kidney failure and has been used as an endpoint in IgAN clinical trials to support accelerated regulatory approvals.⁶ Sibeprenlimab is an investigational monoclonal antibody that selectively inhibits the activity of APRIL (A PRoliferation-Inducing Ligand).⁷ APRIL plays a key role in the 4-hit process, understood to be implicated in the pathogenesis and progression of IgAN, by promoting the production of pathogenic Gd-IgA1 (Galactose-deficient IgA1) and immune complex formation.^3,8,9,10 If licensed, sibeprenlimab will be provided as a single-dose prefilled syringe for subcutaneous injection every four weeks intended for self-administration or administration by a caregiver at home.

Sibeprenlimab has been granted orphan designation by the European Commission for the treatment of primary IgA nephropathy⁵ and also received Priority Review designation from the U.S. Food and Drug Administration (FDA) last month¹¹ following its Biologics License Application (BLA) in March.¹²

“IgAN is a progressive, autoimmune, chronic kidney disease that can lead to end-stage kidney disease over the lifetime of many patients,” said Andy Hodge, CEO, Otsuka Pharmaceutical Europe Ltd. “While current supportive care helps manage symptoms, there remains a significant unmet need for treatments that target the underlying cause of the disease. We are excited by these interim results and remain committed to developing therapies for patients living with this serious and complex condition.”

The VISIONARY 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 2026.¹³ Further prespecified and exploratory analyses of the data will be conducted to determine the potential of sibeprenlimab for the treatment of IgAN.¹³

About the VISIONARY Study

The VISIONARY study is the largest IgAN trial to date, and is a multicentre, randomised, double-blind, placebo-controlled trial consisting of approximately 510 adult patients with IgAN 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.¹³ The primary efficacy objective is to evaluate the change in 24-hour uPCR at 9 months compared with baseline.¹³ The secondary objective is to evaluate the annualised slope of eGFR estimated over ~24 months.¹³

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 which plays a key role in the 4-hit process.⁷By selectively binding and inhibiting APRIL, sibeprenlimab may help reduce the amount of immunoglobulin A (IgA) and Gd-IgA1 levels.⁹Lower levels of Gd-IgA1 should provide less substrate for immune complex formation.⁸Decreased immune complex formation should result in diminished deposition in the kidney, and reduced proteinuria and kidney inflammation.^8,14 By reducing the production of Gd-IgA1, sibeprenlimab may help slow kidney damage and progression toward ESKD.^3,7,9,10 By inhibiting APRIL, sibeprenlimab may help address one of the IgAN-specific drivers for nephron loss.⁹

About IgAN and APRIL

IgAN is a progressive, immune-mediated, chronic kidney disease that typically manifests in adults aged 20-40 years¹³ and leads to ESKD over the lifetime of many patients.^1,2,3,4

IgAN is characterised by the accumulation of Gd-IgA1 complexes in the kidneys. IgAN can lead to progressive loss of kidney function and, eventually, ESKD, imposing a significant burden on patients.¹⁵ Despite supportive care, there is an unmet need for treatments that address the root causes of the condition.^1,2,6,8 Continued research in the disease remains crucial to uncovering opportunities for advancement in our understanding and treatment of patients.³

APRIL, a cytokine in the tumor necrosis factor (TNF) family, is integral to the pathogenesis and progression of IgAN. It promotes the survival and class switching of B cells to produce IgA, including the pathogenic galactose-deficient IgA1 (Gd-IgA1) that forms immune complexes in the kidneys.³

About Otsuka

Otsuka Pharmaceutical Co., Ltd. is a total healthcare company that focuses on each individual’s potential to enhance their well-being. Our medical-related business provides treatments and diagnostics for both physical and mental health. Our nutraceutical business supports daily health maintenance and improvement. Otsuka’s products and services are based on scientific evidence, under the guidance of our corporate philosophy: Otsuka-people creating new products for better health worldwide.

Otsuka Europe employs around 500 people and focuses on psychiatric and neurologic disorders, nephrology and immunology, haemato-oncology, and digital therapeutics. Otsuka Pharmaceutical Europe Ltd. is a part of Otsuka Pharmaceutical Company, Ltd., a subsidiary of Otsuka Holdings Co., Ltd. headquartered in Tokyo, Japan.

For further information on Otsuka, please visit www.otsuka-europe.com.

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.

Contacts for Media
Otsuka in the EU
Alison Ross
Otsuka Pharmaceutical Europe Ltd. ARoss@Otsuka-Europe.com
+44 776 833 7128

Otsuka in the U.S.
Robert Murphy
Corporate Communications
Otsuka America Pharmaceutical, Inc.
robert.murphy@otsuka-us.com

References
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2 Rajasekaran A, et al. Am J Med Sci. 2021;361(2): 176–194.
3 Cheung CK, et al. Front nephrol. 2024;3:1346769.
4 Cheung CK, et al. Nat Rev Nephrol. 2025;Jan;21(1):9-23.
5 European Medicines Agency. Orphan designation for treatment of primary IgA nephropathy. Available at: https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-21-2444. Accessed June 2025.
6 Thompson A, et al. Clin J Am Soc Nephrol. 2019;14(3):469-481.
7 Mathur M, et al. N Engl J Med. 2024;390:20-31.
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10 Chang S, et al. Front. Med. 2020;7:92.
11 Otsuka Announces FDA Acceptance and Priority Review of Biologics License Application for Sibeprenlimab in the Treatment of Immunoglobulin A Nephropathy (IgAN). https://www.otsuka-us.com/news/otsuka-announces-fda- acceptance-and-priority-review-biologics-license-application bla#:~:text=Sibeprenlimab%20demonstrated%20a%20statistically%20significant,the%20Phase%203%20VISIONA RY%20trial.&text=The%20BLA%20has%20been%20granted,date%20of%20November%2028%2C%202025.
Accessed June 2025.
12 Otsuka Files Biologics License Application (BLA) for Sibeprenlimab in the Treatment of Immunoglobulin A Nephropathy. Available at: https://www.otsuka-us.com/news/sibeprenlimab-receives-us-fda-breakthrough-therapy- designation-treatment-immunoglobulin. Accessed June 2025.
13 Rizk D, et al. 2025; Patient Baseline Characteristics in the Ongoing Phase 3 VISIONARY Trial (Poster). World Congress of Nephrology 2025, India, Feb 6–9, 2025.
14 Kant, Sam, et al. Am J Kidney Dis. 2022;79(4):582-600.
15 Cheung CK, et al. Clinical Medicine. 2012;12(6):s27–s31.

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