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

Abstract Background 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. Methods 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 SpO2/FiO2 ratio, and biomarkers of severe COVID-19 were explored. Results 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 SpO2/FiO2 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. Conclusions Eclitasertib was well tolerated with consistent trends toward more rapid resolution of inflammatory biomarkers and clinical improvement in severe COVID-19 patients than placebo. ClinicalTrials.gov identifier NCT04469621, first posted on clinicaltrials.gov on July 14, 2020

Additional file 1 of 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

Supplementary materia

Lyon, entre Empire et Royaume (843-1601): textes et documents

Directeurs d'ouvrage: Charansonnet (Alexis), Gaulin (Jean-Louis), Mounier (Pascale), Rau (Susanne).Directeur d'ouvrage adjoint: Chartrain (Frédéric).Affiliation : Blostin, Marine (Éducation nationale)Chopin, Hervé (Université Lyon 2, Doctorant ; Archéologie et archéométrie, UMR 5138)Clot, David (Université Lyon 2)Collet, Étienne (Cité scolaire « L’Astrée », Boën-sur-Lignon ; CIHAM, UMR 5648)Dauphant, Léonard (Université de Lorraine)Galland, Bruno (Archives départementales du Rhône)Ganivet, Pierre (Université d’Auvergne ; CMH, EA 4232)Hélary, Xavier (Université Lyon 3 ; CIHAM, UMR 4658)Le Roux, Nicolas (Université Lyon 2 ; LARHRA, UMR 5190)Lévy, Tania (Docteur en histoire de l’art, Université Paris-Sorbonne)Nadiras, Sébastien (Archives nationales de France)Paquant, Marthe (CNRS ; IHPC-GRAC, UMR 5037)Reveyron, Nicolas (Université Lyon 2, IUF ; Archéologie et archéométrie, UMR 5138)Rubellin, Michel (Université Lyon 2 ; CIHAM, UMR 5648)Théry-Astruc, Julien (Université Lyon 2 ; CIHAM, UMR 5648)Zeller, Olivier (Université Lyon 2 ; Environnement, ville, société, UMR 5600)Mercier, Karyn (CNRS ; CIHAM, UMR 5648)International audienceCette anthologie propose une reconstitution inédite de l’histoire de la ville de Lyon de 843 à 1601. Les textes et images, assortis d’une présentation, mettent en exergue la situation frontalière de la ville, ses changements d’appartenance politique et les conséquences de son annexion par la France en 1312

Plasma lysosphingolipids in GRN-related diseases: Monitoring lysosomal dysfunction to track disease progression

International audienceGRN mutations are among the main genetic causes of frontotemporal dementia (FTD). Considering the progranulin involvement in lysosomal homeostasis, we aimed to evaluate if plasma lysosphingolipids (lysoSPL) are increased in GRN mutation carriers, and whether they might represent relevant fluid-based biomarkers in GRN-related diseases. We analyzed four lysoSPL levels in plasmas of 131 GRN carriers and 142 non-carriers, including healthy controls and patients with frontotemporal dementias (FTD) carrying a C9orf72 expansion or without any mutation. GRN carriers consisted of 102 heterozygous FTD patients (FTD-GRN), three homozygous patients with neuronal ceroid lipofuscinosis-11 (CLN-11) and 26 presymptomatic carriers (PS-GRN), the latter with longitudinal assessments. Glucosylsphingosin d18:1 (LGL1), lysosphingomyelins d18:1 and isoform 509 (LSM18:1, LSM509) and lysoglobotriaosylceramide (LGB3) were measured by electrospray ionization-tandem mass spectrometry coupled to ultraperformance liquid chromatography. Levels of LGL1, LSM18:1 and LSM509 were increased in GRN carriers compared to non-carriers (p < 0.0001). No lysoSPL increases were detected in FTD patients without GRN mutations. LGL1 and LSM18:1 progressively increased with age at sampling, and LGL1 with disease duration, in FTD-GRN. Among PS-GRN carriers, LSM18:1 and LGL1 significantly increased over 3.4-year follow-up. LGL1 levels were associated with increasing neurofilaments in presymptomatic carriers. This study evidences an age-dependent increase of β-glucocerebrosidase and acid sphingomyelinase substrates in GRN patients, with progressive changes as early as the presymptomatic phase. Among FTD patients, plasma lysoSPL appear to be uniquely elevated in GRN carriers, and thus might serve as suitable non-invasive disease-tracking biomarkers of progression, specific to the pathophysiological process. Finally, this study might add lysoSPL to the portfolio of fluid-based biomarkers, and pave the way to disease-modifying approaches based on lysosomal function rescue in GRN diseases