Vice President GenFleet Therapeutics Inc, Shanghai, China (People's Republic)
Background: GFH312 is a highly selective inhibitor of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) being developed to potentially target autoinflammatory and autoimmune disease. This first-in-human (FIH) study evaluated safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of GFH312 in healthy subjects.
Methods: This is a randomized (3:1), double-blinded, placebo-controlled study, including seven single ascending dose (SAD) and three multiple ascending dose (MAD) cohorts: 5 mg, 15 mg, 45 mg, 100 mg (fasting and fed), 200 mg, 360 mg, 500 mg single dose; 60 mg, 120 mg, 200 mg once daily for 14 days.
Results: 76 subjects completed the study and GFH312 was well-tolerated. Most adverse events were mild, with headache and procedural pain reported most frequently. No deaths, no grade 3 or above AEs or serious TEAEs were reported. Three subjects reported grade 2 AEs in MAD, including vertigo positional, back pain and blood creatinine increase. with the latter considered related to GFH312 and recovered to normal at the end of treatment visit, also other subjects of the same group showed lesser degrees of reversible creatinine elevation. GFH312 was rapidly absorbed, reaching peak plasma concentration 2-8 h post-dose and was eliminated with a half-life of 6.3-23.3 h after a single oral dose. Accumulation following multiple dosing and food effect on absorption were limited. Cerebrospinal fluid (CSF) mean concentrations were 26.6-58.2 ng/mL at 4 h after a single dose. A rapid inhibition of RIPK1 phosphorylation in PBMCs was observed post-dosing in all dose groups.
Conclusion: GFH312 was safe and well tolerated in healthy subjects with favorable PK and sustained target RIPK1 inhibition. The results support further evaluation of GFH312 in clinical studies.
