A phase I, randomized, ascending‐dose study to assess safety, pharmacokinetics, and activity of GDC‐8264, a RIP1 inhibitor, in healthy volunteers

Receptor‐interacting protein 1 (RIP1) is a key regulator of multiple signaling pathways that mediate inflammatory responses and cell death. RIP1 kinase activity mediates apoptosis and necroptosis induced by tumor necrosis factor (TNF)‐α, Toll‐like receptors, and ischemic tissue damage. RIP1 has been implicated in several human pathologies and consequently, RIP1 inhibition may represent a therapeutic approach for diseases dependent on RIP1‐mediated inflammation and cell death. GDC‐8264 is a potent, selective, and reversible small molecule inhibitor of RIP1 kinase activity. This phase I, randomized, placebo‐controlled, double‐blinded trial examined safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single‐ (5–225 mg) and multiple‐ (50 and 100 mg once daily, up to 14 days) ascending oral doses of GDC‐8264 in healthy volunteers, and also tested the effect of food on the PKs of GDC‐8264. All adverse events in GDC‐8264‐treated subjects in both stages were mild. GDC‐8264 exhibited dose‐proportional increases in systemic exposure; the mean terminal half‐life ranged from 10–13 h, with limited accumulation on multiple dosing (accumulation ratio [AR] ~ 1.4); GDC‐8264 had minimal renal excretion at all doses. A high‐fat meal had no significant effect on the PKs of GDC‐8264. In an ex vivo stimulation assay of whole blood, GDC‐8264 rapidly and completely inhibited release of CCL4, a downstream marker of RIP1 pathway activation, indicating a potent pharmacological effect. Based on PK‐PD modeling, the GDC‐8264 half‐maximal inhibitory concentration for the inhibition of CCL4 release was estimated to be 0.58 ng/mL. The favorable safety, PKs, and PDs of GDC‐8264 support its further development for treatment of RIP1‐driven diseases.