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

Abstract

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.

Safety, pharmacokinetics, and target engagement of a brain penetrant RIPK1 inhibitor, SAR443820 (DNL788), in healthy adult participants

“…Overall, SAR443820 was well‐tolerated in this study, without raising any safety concerns in the dose escalation and safety profile was consistent with that of other brain penetrant RIPK1 inhibitors. 9 , 26 Mild abnormalities in laboratory values were observed related to SAR443820, however, the safety data do not suggest a dose‐dependent trend. Two cases of asymptomatic ALT increase (≥2‐fold ULN but limited <3‐fold ULN) were reported in this study, but none were considered as clinically relevant.…”

“…Two cases of asymptomatic ALT increase (≥2‐fold ULN but limited <3‐fold ULN) were reported in this study, but none were considered as clinically relevant. Similar to SAR443820, other RIPK1 inhibitors, such as SAR443060, 9 GSK2982772, 20 and GFH312, 26 were found to be well‐tolerated with no reports of ALT abnormalities in healthy participants. Taken together, it may be assumed that the liver function abnormalities may not be a mechanism‐based consideration.…”

Virtual screening of flavonoids as potential RIPK1 inhibitors for neurodegeneration therapy

“…Recent preclinical and clinical studies have unquestionably recognized the roles of RIPK1 in neurogenerative disorders ( Li & Yuan, 2023 ; Scarpellini et al, 2023 ; Xu, Zhang & Zhuang, 2023 ). In a phase I clinical trial, a small molecule GFH312 showed significant RIPK1 inhibition with a tolerability profile comparable to that of the placebo ( Lickliter et al, 2023 ). Despite demonstrating promise in targeting RIPK1 for the treatment of Alzheimer’s disease, SAR443060, another orally bioavailable CNS penetrant investigational agent, was abandoned due to long-term toxicities ( Vissers et al, 2022 ).…”