GSK-2982772

Genentech, Inc., a wholly owned subsidiary of Hoffmann-La Roche, has terminated a Phase II study evaluating the selective RIPK1 inhibitor GDC-8264 for the prevention of acute kidney injury in patients undergoing cardiac surgery. According to the ClinicalTrials.gov registry update, Genentech indicated the study was “unlikely to demonstrate a statistically significant clinical benefit” as the basis for the early stop. The trial, which had enrolled 67 participants across sites in the United States, Europe, Australia, New Zealand, South Korea, and Canada, was designed to test whether perioperative RIPK1 inhibition could reduce kidney complications following cardiopulmonary bypass procedures. The termination raises fresh questions about the future of clinical development for GDC-8264 — also known as flizasertib or RO7288817 — although Roche has not publicly confirmed whether the program has been fully discontinued. The Phase II study was a randomized, double-blind, placebo-controlled trial conducted in two sequential parts. Genentech designed the study to enroll adults aged 40 and older who were scheduled for non-emergent cardiac surgery requiring cardiopulmonary bypass — including isolated coronary artery bypass grafting, surgical aortic or mitral valve replacement or repair, and combined procedures. Eligible participants had to carry at least one or two predefined risk factors for acute kidney injury, depending on the type of surgery. The trial’s primary endpoint was the percentage of participants who developed major adverse kidney events within 90 days of surgery, a composite measure known as MAKE90. The scientific hypothesis underpinning the trial was that RIPK1-mediated necroptosis — a pro-inflammatory form of regulated cell death — plays a central role in renal ischemia-reperfusion injury during cardiac surgery. Preclinical studies, including work by Linkermann et al. (Kidney International, 2012), had demonstrated that RIPK1 inhibition reduced tubular cell necroptosis and preserved renal function in murine models of kidney injury. GDC-8264 had shown potent on-target pharmacodynamic activity in a Phase I healthy volunteer study, where it rapidly and completely inhibited release of CCL4, a downstream chemokine marker of RIPK1 pathway activation. The gap between preclinical promise and clinical outcome is not unusual in this therapeutic area. Cardiac surgery-associated acute kidney injury affects up to 30% of surgical patients and is linked to increased mortality, prolonged hospitalization, and progression to chronic kidney disease. Yet no pharmacological intervention has been approved to prevent it. The pathophysiology involves multiple overlapping mechanisms — hemodynamic instability, inflammation, oxidative stress, nephrotoxin exposure — making it difficult to achieve clinically meaningful benefit by targeting a single pathway. The GDC-8264 setback extends a broader pattern of clinical disappointments for the RIPK1 inhibitor class. Beyond Genentech, other sponsors to encounter difficulties include GlaxoSmithKline with GSK2982772, the first RIPK1 inhibitor to enter clinical research in 2014, which was eventually returned to the research stage and is no longer listed in the company’s active pipeline. Sanofi scrapped its last remaining Denali Therapeutics-partnered RIPK1 inhibitor in January 2026. Eli Lilly pulled out of central nervous system (CNS)-focused development of RIPK1 inhibitors partnered with Rigel Pharmaceuticals in November 2025, but continues to develop ocadusertib (LY3871801/R552) for rheumatoid arthritis (Phase II stage) under that partnership. Your email address will not be published. Required fields are marked * Comment * Name * Email * Website