Safety, pharmacokinetics and target engagement of novel RIPK1 inhibitor SAR443060 (DNL747) for neurodegenerative disorders: Randomized, placebo‐controlled, double‐blind phase I/Ib studies in healthy subjects and patients

Abstract

RIPK1 is a master regulator of inflammatory signaling and cell death and increased RIPK1 activity is observed in human diseases, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). RIPK1 inhibition has been shown to protect against cell death in a range of preclinical cellular and animal models of diseases. SAR443060 (previously DNL747) is a selective, orally bioavailable, central nervous system (CNS)-penetrant, small-molecule, reversible inhibitor of RIPK1. In three early-stage clinical trials in healthy subjects and patients with AD or ALS (NCT03757325 and NCT03757351), SAR443060 distributed into the cerebrospinal fluid (CSF) after oral administration and demonstrated robust peripheral target engagement as measured by a reduction in phosphorylation of RIPK1 at serine 166 (pRIPK1) in human peripheral blood mononuclear cells compared to baseline. RIPK1 inhibition was generally safe and well-tolerated in healthy volunteers and patients with AD or ALS. Taken together, the distribution into the CSF after oral administration, the peripheral proof-of-mechanism, and the safety profile of RIPK1 inhibition to date, suggest that therapeutic modulation of RIPK1 in the CNS is possible, conferring potential therapeutic promise for AD and ALS, as well as other neurodegenerative conditions. However, SAR443060 development was discontinued due to long-term nonclinical toxicology findings, although these nonclinical toxicology signals were not observed in the short duration dosing in any of the three early-stage clinical trials. The dose-limiting

New developments and opportunities in drugs being trialed for amyotrophic lateral sclerosis from 2020 to 2022

“…SAR443820 is an inhibitor of receptor-interacting serine/threonine protein kinase 1 (RIPK1), an intracellular protein that is activated by tumor necrosis factor alpha (TNF‐α) through TNF receptor 1 and can induce neuroinflammation by increasing microglial activity and cytokine release and mediate neuronal cell death through apoptosis and necroptosis ( Yuan et al, 2019 ; Vissers et al, 2022 ). The inhibition of RIPK1 was found to block oligodendrocyte death, microglial inflammation and axonal degeneration in both SOD1G93A mice and Optn−/− mice ( Yuan et al, 2019 ).…”

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

“…In vivo studies have shown beneficial effects of RIPK1 inhibitors in myocardial ischemia and reperfusion injury settings 12–14 . A few RIPK1 inhibitors have progressed to human clinical trials for the treatment of inflammatory and central nervous system (CNS) diseases 15–20 …”

“…[12][13][14] A few RIPK1 inhibitors have progressed to human clinical trials for the treatment of inflammatory and central nervous system (CNS) diseases. [15][16][17][18][19][20] Here, we report results from the phase I first-inhuman study of GFH312 (Clini calTr ials.gov Identifier: NCT04676711), a highly selective small molecule targeting RIPK1 with potent in vitro inhibition of human RIPK1 kinase activity, with a 50% inhibitory concentration (IC 50 ) of 40 nM, that has shown potent anti-necroptosis effects in multiple cell line models, and protective effects in neurological and inflammatory disease models (F. Zhou, F. Xie, and Z. Huo, unpublished data).…”

Targeting RIPK1 kinase for modulating inflammation in human diseases

“…Structurally RIPK1 kinase has a hydrophobic pocket associated with its activation segment that is highly amenable for developing small molecule inhibitors which can stabilize its inactive conformation and allows BBB passage ( 19 – 22 ). Human clinical trials of small molecule RIPK1 inhibitors have demonstrated safety of targeting RIPK1 kinase ( 23 – 25 ). These studies demonstrated the feasibility and safety of targeting RIPK1 in humans.…”