Otsuka Pharmaceutical Co., Ltd.
New England Journal of Medicine Publishes Complete Results of Positive Phase 2 Trial
of Sibeprenlimab in Treatment of Immunoglobulin A Nephropathy (IgAN)
- The sibeprenlimab Phase 2 clinical trial results will also be presented this week at the American Society of Nephrology (ASN) Kidney Week.1
- Findings demonstrated that 12 months of sibeprenlimab treatment resulted in significant reductions in proteinuria (protein in urine), a marker of kidney damage compared to placebo in patients with IgAN.1
- IgAN, also known as Berger's disease, is the most common cause of kidney failure in young adults2 and is associated with a 10-year reduction in life expectancy.3
Otsuka Pharmaceutical Co., Ltd. (Otsuka) and its U.S. subsidiaries, Otsuka Pharmaceutical Development & Commercialization, Inc. and Visterra Inc., today announced that the full results of a Phase 2 trial of sibeprenlimab (VIS649) for treatment of immunoglobulin A nephropathy (IgAN; Berger's disease) have been published in the New England Journal of Medicine.1 The topline findings will also be presented in a late-breaking poster session at the American Society of Nephrology (ASN) Kidney Week meeting in Philadelphia, PA.
Sibeprenlimab is an investigational humanized monoclonal antibody that blocks the action of the cytokine A Proliferation Inducing Ligand (APRIL), an immune cell growth factor believed to play a key role in the development and progression of IgAN.1,4,5
The Phase 2 trial randomized 155 adult participants with biopsy-confirmed IgAN to monthly intravenous injections of sibeprenlimab 2, 4, or 8 mg/kg, or placebo for 12 months. The primary outcome measure was the change from baseline in 24-hour urine protein-to-creatinine ratio (uPCR) at month 12. Secondary outcomes included safety and change in estimated glomerular filtration rate (eGFR), a measure of kidney function.1
The study results demonstrated that 12 months of sibeprenlimab treatment in patients with IgAN resulted in significant reductions in proteinuria compared to placebo. At 12 months, geometric mean ratio reduction in 24-hour uPCR from baseline was 47.2%, 58.8%, 62.0%, and 20.0% with sibeprenlimab 2, 4, and 8 mg/kg, and placebo, respectively.1
Beneficial changes in eGFR were also observed in the sibeprenlimab groups compared to placebo. The annual eGFR change was −2.7, +0.2, −1.5, and −7.4 ml/1.73 m2 with sibeprenlimab 2, 4, and 8 mg/kg, and placebo, respectively. This reflects a stabilization of eGFR with sibeprenlimab compared to the eGFR decline observed with placebo.1
The incidence of treatment-emergent adverse events (TEAEs) for patients on sibeprenlimab and placebo was similar. The safety profile of sibeprenlimab showed no evidence of undesirable toxicity or clinically meaningful immunosuppression during this trial and follow-up through month 16.1
"IgAN is the most common form of primary glomerulonephritis and is associated with a significant reduction in life expectancy," said Brian J. G. Pereira, M.D., CEO of Visterra, Inc., and the senior author of the New England Journal of Medicine paper. "Current therapies have modest efficacy, at best, in reducing the rate of chronic kidney disease progression and new disease-specific targeted treatment options would be hugely beneficial."
"We are excited by these results, which bring us one step closer to addressing the critical unmet treatment needs of patients with this complex, life-threatening condition," said John Kraus, M.D., Ph.D., executive vice president and chief medical officer, Otsuka Pharmaceutical Development & Commercialization, Inc. "We look forward to continuing to evaluate the potential of sibeprenlimab in the ongoing Phase 3 trial program."
About Immunoglobulin A Nephropathy
Immunoglobulin A nephropathy (IgAN; Berger's disease) is the most common form of primary glomerulonephritis worldwide and is the most common cause of kidney failure in young adults.1,2 The disease is associated with a reduction in life expectancy of 10 years,3 with at least 30% of affected patients progressing to kidney failure within 20 to 30 years, despite optimized standard of care therapy.6,7
Current standard of care management is based on renin-angiotensin aldosterone system (RAAS) blockers and adequate blood pressure control, but the risk of kidney failure remains high.8
Sibeprenlimab (VIS649) is an investigational humanized immunoglobulin G (IgG2) monoclonal antibody that binds to and blocks the biological actions of the cytokine A PRoliferation Inducing Ligand (APRIL), a key factor in the production of galactose-deficient IgA1 (Gd-IgA1), which has been demonstrated to play a key role in the pathogenesis of IgAN.1,4,5
About the Phase 2 Sibeprenlimab Trial
The multicenter, randomized, double-blind, placebo-controlled, multiple-dose, parallel-group study was conducted in adults with biopsy-confirmed IgAN at high risk of disease progression, despite having received standard-of-care treatment. Participants were randomized 1:1:1:1 to intravenous sibeprenlimab 2, 4, or 8 mg/kg or placebo monthly for 12 months.9
The study was designed to test the safety and efficacy of different doses of sibeprenlimab. The main objectives were to evaluate the safety and tolerability of sibeprenlimab and to evaluate the dose response to different doses of sibeprenlimab on proteinuria and eGFR.9
The study was comprised of three main periods, Screening, Treatment (12 months) and Follow-Up (4 months). The findings from this study form the basis for the subsequent clinical development of sibeprenlimab.9
Visterra is a clinical-stage biotechnology company and a wholly owned subsidiary of Otsuka America Pharmaceutical, Inc. committed to developing innovative antibody-based therapies for the treatment of patients with kidney diseases and other hard-to-treat autoimmune 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 IgA nephropathy and other kidney diseases, immunologically-driven diseases and infectious diseases. Prior to its acquisition by Otsuka, Visterra was funded by investments by Polaris Partners, Flagship Pioneering, the Bill and Melinda Gates Foundation, MRL Ventures Fund, Vertex Ventures HC, Serum Institute of India Private Ltd., Temasek Holdings, Omega Funds, Cycad Group, Lux Capital, Alleghany Financial Group Ventures, CTI Life Sciences Fund and Alexandria Equities. For more information, visit www.visterrainc.com.
- *1Mathur M, Barrat J, Chacko B, et al. A Phase 2 Trial of Sibeprenlimab in Immunoglobulin A Nephropathy Patients. NEJM. 2023
- *2Floege J, Amann K. Primary glomerulonephritides. Lancet. 2016;387(10032):2036-2048.
- *3Hastings MC, Bursac Z, Julian BA, et al. Life Expectancy for Patients From the Southeastern United States With IgA Nephropathy. Kidney Int Rep. 2017;3(1):99-104.
- *4Mathur 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.
- *5Chang S, Li XK. The Role of Immune Modulation in Pathogenesis of IgA Nephropathy. Front Med (Lausanne). 2020;7:92.
- *6Lai KN, Tang SC, Schena FP, et al. IgA nephropathy. Nat Rev Dis Primers. 2016;2:16001.
- *7Gleeson PJ, O'Shaughnessy MM, Barratt J. IgA nephropathy in adults - Treatment Standard [published online ahead of print, 2023 Jul 7]
- *8ClinicalTrials.gov. National Library of Medicine (U.S.). Safety and Efficacy Study of VIS649 for IgA Nephropathy Identifier:
- NCT04287985. https://classic.clinicaltrials.gov/ct2/show/NCT04287985.