Genentech has elected to stop a phase 2 trial of a RIPK1 inhibitor early and dump the asset after an analysis revealed the candidate was unlikely to meet the study’s primary endpoint.
Flizasertib, also known as GDC-8264, was removed from Genentech’s pipeline in the first quarter of this year, a company spokesperson confirmed to Fierce Biotech, after interim data “indicated that the study was unlikely to demonstrate a significant clinical benefit.”
The Roche subsidiary was testing flizasertib’s ability to treat acute kidney injury after heart surgery, a common complication that can follow procedures like coronary artery bypass, valve replacements and aortic surgeries due to reduced blood flow to the filtering organs.
The terminated study was a randomized, placebo-controlled phase 2 trial that began in January 2025 and enrolled 67 patients, according to the federal clinical trials database. The primary efficacy endpoint, which flizasertib was not set to deliver on, was the percentage of patients who develop persistent complications in the 90 days following a surgery-induced kidney injury.
Genentech announced the discovery of GDC-8264 last fall in a paper (PDF) published in the Journal of Medicinal Chemistry. At the time, the biotech’s scientists described the small molecule as having “excellent target selectivity and druglike attributes for once-daily oral dosing.”
Flizasertib’s descent is another blow for the RIPK1 inhibitor field, which has struggled to produce an approved medicine despite numerous biotechs and Big Pharmas pursuing the target. RIPK stands for receptor-interacting serine/threonine-protein kinase, with RIPK1 part of a family of enzymes that help regulate inflammation and cell death.
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GSK had the first-ever RIPK1 inhibitor okayed for clinical research back in 2014, but later kicked it back to the research stage; that asset, GSK2982772, is no longer listed in GSK’s pipeline. The British pharma also dropped a different candidate in the class for the development of prostate cancer in 2019.
French drugmaker Sanofi bought into the modality in 2018 through a pact with Denali Therapeutics, but has steadily pulled back due to a string of phase 2 failures. Sanofi scrapped its last remaining Denali RIPK1 inhibitor at the end of January.
Eli Lilly, too, has had a rethink of RIPK1. After signing a deal worth as much as $960 million with Rigel Pharmaceuticals back in 2021, Lilly reneged on the central nervous system-focused portion of the partnership. The star of that deal, though, Rigel’s ocadusertib (now coded LY3871801), is still being tested in a phase 2 trial for rheumatoid arthritis.
Meanwhile, there may be potential for an already approved drug to be repurposed as a RIPK1 inhibitor. Last summer, a team of Korean scientists discovered that phensuximide, which was once used to treat epilepsy, can restrain RIPK1’s inflammatory activity.
