A phase I randomized, double‐blinded, placebo‐controlled study assessing the safety and pharmacokinetics of RIPK1 inhibitor GFH312 in healthy subjects

Receptor‐interacting protein kinase 1 (RIPK1) mediates necroptosis and inflammation in various pathophysiologies, emerging as a pharmacological target for neurodegenerative and inflammatory indications. This phase I, first‐in‐human, placebo‐controlled study evaluated the safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of GFH312, an RIPK1 inhibitor, in healthy adults. Subjects received GFH312 as a single ascending dose up to 500 mg (part I) or once‐daily repeated doses up to 200 mg for 14 days (part II). PKs were assessed using plasma and cerebrospinal fluid (CSF); PDs were assessed by phospho‐RIPK1 levels. Seventy‐six subjects were enrolled between April 2021 and June 2022: 38 (part I) and 19 (part II) received GFH312; 14 and five received placebo, respectively. At least one treatment‐emergent adverse event (TEAE) occurred in 42.1% (part I) and 63.2% (part II) of subjects receiving GFH312, compared with 42.9% and 40.0% of subjects receiving placebo, respectively. The most common TEAE was headache (21.1%). Two treatment‐related TEAEs were reported in part I and four in part II. No serious TEAEs were reported. Systemic absorption was rapid; exposure (area under the concentration‐time curve from time zero to the last measurable concentration and maximum plasma concentration) increased with dose level. The GFH312 CSF concentration post 100 mg single dose was approximately fourfold higher than the half maximal inhibitory concentration of human monocyte‐derived macrophages necroptosis with expected central nervous system penetration. Subjects receiving GFH312 had decreased phospho‐RIPK1 levels in peripheral blood mononuclear cells postdose. In conclusion, GFH312 was well‐tolerated and demonstrated RIPK1 inhibition in healthy subjects. Ongoing studies will inform the use of GFH312 in potential indications.