A Randomized Phase I Trial Evaluating Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Eclitasertib, a RIPK1 Inhibitor, in Healthy Participants.

Abstract

Introduction: Receptor-interacting protein kinase 1 (RIPK1) is a master regulator of inflammation and necroptotic cell death and is implicated in the pathogenesis of several inflammatory and neurodegenerative diseases. This first-in-human study assessed the safety, pharmacokinetic (PK) and pharmacodynamic (PD) properties of eclitasertib, a selective, peripherally-restricted, oral inhibitor of RIPK1.

Methods: This 2-part Phase I trial enrolled healthy participants aged 18-55 years. Part 1 consisted of 2 sub-parts. Part 1a was a double-blind, randomized, single ascending dose (SAD) study with 6 cohorts of 8 participants each randomized 3:1 to single oral dose of eclitasertib (10 mg, 30 mg, 100 mg, 200 mg, 400 mg, or 800 mg) or placebo. Part 1b was an open-label, randomized, three-sequence, cross-over design study to evaluate the relative bioavailability of the prototype formulation versus the drug substance and the effect of food in an independent cohort of 10 participants. Part 2 was a double-blind, randomized, multiple ascending dose study (MAD) with 4 cohorts of 10 participants each randomized 4:1 to receive eclitasertib (50 mg, 100 mg, 200 mg, or 600 mg once daily) or placebo orally for 14 days. Incidence of adverse events (AEs; primary outcome), PK (secondary outcome), and PD properties (exploratory outcome; assessed by reduction in levels of S166 phosphorylated RIPK1) were evaluated.

Results: Single and multiple oral doses of eclitasertib were well tolerated, with no study drug-related severe or serious AEs reported. Medical device-site reactions (includes AEs classified as device-site reaction, vessel puncture-site hematoma/pain, catheter-site pain/hematoma and catheter-site-related reactions) and headache were the most commonly reported AEs in both parts. Overall, the median T_max ranged from 3 to 4 h. C_max and AUC increased sub-dose proportionally. Administration of eclitasertib 100 mg following a high-fat meal did not significantly impact its bioavailability. At doses of 100 mg and above, > 90% inhibition of RIPK1 phosphorylation in human peripheral blood mononuclear cells was observed with eclitasertib at 12 h post-dose in both SAD and MAD studies.

Conclusions: Single and repeated doses of eclitasertib were well tolerated in healthy participants and potently inhibited RIPK1 activation.

Trial registration: EudraCT 2019-001350-25.