Immunomodulatory and clinical effects of receptor-interacting protein kinase 1 (RIPK1) inhibitor eclitasertib (SAR443122) in patients with severe COVID-19: a phase 1b, randomized, double-blinded, placebo-controlled study.

Publication date: Feb 28, 2024

Targeting receptor-interacting serine/threonine protein kinase 1 could mitigate the devastating sequelae of the hyperinflammatory state observed in severe cases of COVID-19. This study explored the immunomodulatory and clinical effects of the receptor-interacting serine/threonine protein kinase 1 inhibitor SAR443122 (eclitasertib) in patients with severe COVID-19. In this Phase 1b, double-blinded, placebo-controlled study (NCT04469621) a total of 82 patients were screened, of whom 68 patients were eligible and randomized (2:1) to receive eclitasertib 600 mg (300 mg twice daily) or placebo up to 14 days. Primary outcome was relative change in C-reactive protein from baseline to Day 7. Time to clinical improvement using 7-point ordinal scale, ventilator/respiratory failure-free days, change in SpO/FiO ratio, and biomarkers of severe COVID-19 were explored. Geometric mean ratio (point estimate [90% confidence interval]) of the relative change from baseline in C-reactive protein with eclitasertib vs. placebo on Day 7 was 0. 85 (0. 49-1. 45; p = 0. 30). Median time to 50% decrease in C-reactive protein from baseline was 3 days vs. 5 days (p = 0. 056) with eclitasertib vs. placebo. Median time to ≥ 2-point improvement on 7-point clinical symptoms scale was 8 days vs. 10 days with eclitasertib vs. placebo (p = 0. 38). Mean ventilator/respiratory failure-free days, change in baseline-adjusted SpO/FiO ratio, and clinical biomarkers showed consistent numerical improvements with eclitasertib vs. placebo. The most frequently reported treatment-emergent adverse events were gastrointestinal disorders and condition aggravated/worsened COVID-19 pneumonia. Eclitasertib was well tolerated with consistent trends toward more rapid resolution of inflammatory biomarkers and clinical improvement in severe COVID-19 patients than placebo. NCT04469621, first posted on clinicaltrials. gov on July 14, 2020.

Concepts Keywords
300mg Biomarker
Immunomodulatory COVID-19
July Immunomodulatory
Nct04469621 Inflammation
Pneumonia

Semantics

Type Source Name
disease MESH COVID-19
drug DRUGBANK Serine
drug DRUGBANK L-Threonine
disease MESH sequelae
disease VO time
disease MESH respiratory failure
disease MESH gastrointestinal disorders
disease MESH pneumonia
disease MESH Inflammation

Original Article

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