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DNL 104, a Centrally Penetrant RIPK 1 Inhibitor, Inhibits RIP 1 Kinase Phosphorylation in a Randomized Phase I Ascending Dose Study in Healthy Volunteers
Author(s) -
Grievink Hendrika W.,
Heuberger Jules A.A.C.,
Huang Fen,
Chaudhary Rinkal,
Birkhoff Willem A.J.,
Tonn George R.,
Mosesova Sofia,
Erickson Rebecca,
Moerland Matthijs,
Haddick Patrick C.G.,
ScearceLevie Kimberly,
Ho Carole,
Groeneveld Geert Jan
Publication year - 2020
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1615
Subject(s) - pharmacology , amyotrophic lateral sclerosis , medicine , pharmacokinetics , tolerability , adverse effect , disease
Receptor‐interacting serine/threonine‐protein kinase 1 ( RIPK1 ) regulates inflammation, cytokine release, and necroptotic cell death and is implicated in pathogenic cellular pathways in amyotrophic lateral sclerosis ( ALS ), Alzheimer's disease ( AD ), and multiple sclerosis. Inhibition of RIPK 1 activity protects against inflammation and cell death in multiple animal models. DNL 104 is a selective, brain‐penetrant inhibitor of RIPK 1 phosphorylation in clinical development for AD and ALS . DNL 104 was tested in 68 healthy volunteers to investigate safety and tolerability, pharmacokinetic profile in plasma and cerebrospinal fluid, and pharmacodynamic effects of RIPK 1 inhibition in peripheral blood mononuclear cells in a first‐in‐human, placebo‐controlled, double‐blind, randomized single‐ascending dose (SAD) and multiple‐ascending dose (MAD) study. DNL 104 was well‐tolerated in the SAD group and during the dosing period of the MAD group. However, postdose liver toxicity in 37.5% of subjects was observed in the MAD , and assessed to be drug related. We demonstrate that DNL 104 leads to RIP 1 kinase inhibition, and this is not associated with central nervous system ( CNS ) toxicities, supporting future development of CNS penetrant RIPK 1 inhibitors.