eclitasertib (SAR443122) / Denali Therap, Sanofi, Harvard University - LARVOL DELTA

Anti-inflammatory effect of RIPK1 inhibitor eclitasertib in inflamed human gut tissue (ECCO-IBD 2026) - "Transcriptomic analyses confirmed trends for reduced inflammatory gene expression in biopsies from UC patients exposed to eclitasertib, with greater modulation by tofacitinib as control. The difficulty of reaching statistically relevant thresholds for observed effects might be based on limited sample size, high inter-donor variation but also by intra-donor variation of the biopsies linked to the experimental model. The findings support further investigation of eclitasertib in populations with IBD."

Crohn's disease • Inflammatory Bowel Disease • Ulcerative Colitis • CCL11 • CDK7 • GZMB • IFNG • IL13 • IL1B • IL6 • RIPK1 • TNFA

Inhibition of RIPK1 prevents keratinocyte cell death and reduces skin inflammation in type 1 mediated chronic inflammatory skin diseases. (PubMed, J Allergy Clin Immunol) - "Inhibition of RIPK1 targets two major pathogenic events in LP and CLE: epidermal cell death and type 1 mediated skin inflammation."

Journal • Cutaneous Lupus Erythematosus • Dermatitis • Dermatology • Dermatopathology • Immunology • Inflammation • Inflammatory Arthritis • Lichen Planus • Lupus • Systemic Inflammatory Response Syndrome • CASP8 • CCL20 • IL1B • MLKL • RIPK1 • TNFA

Small-molecule modulators of the necroptotic pathway: A medicinal chemistry perspective. (PubMed, Eur J Med Chem) - "Notably, Several RIPK1 inhibitors (e.g., DNL-788, DNL-758, R-552) have advanced to Phase II clinical trials for indications like multiple sclerosis, ulcerative colitis, and rheumatoid arthritis. Despite these advancements, the field continues to face challenges, particularly the need for chemical scaffold design and therapeutic strategies to address two longstanding challenges: off-target effects and enhancing blood-brain barrier (BBB) penetration. This review systematically summarizes the development history of regulators targeting this pathway, covering emerging multitarget inhibitors, bifunctional molecules, and AI-driven drug design progress, laying an important foundation for related drug discovery research."

Journal • Review • Cardiovascular • CNS Disorders • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammatory Arthritis • Inflammatory Bowel Disease • Multiple Sclerosis • Oncology • Rheumatoid Arthritis • Rheumatology • Ulcerative Colitis • RIPK1

Sanofi keeps mum on future of disappointing Denali pact after scrapping final RIPK1 inhibitor (FierceBiotech) - "The Paris-based drugmaker revealed in its full-year 2025 earnings results (PDF) this morning that it has deprioritized eclitasertib, a receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitor Sanofi had been assessing in a phase 2 study for ulcerative colitis (UC)."

Discontinued • Ulcerative Colitis

RESOLUTE: Dose-finding Study of SAR443122 in Adult Participants With Ulcerative Colitis (clinicaltrials.gov) - P2 | N=187 | Active, not recruiting | Sponsor: Sanofi | Recruiting ➔ Active, not recruiting

Enrollment closed • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

SAR443122/DNL758 (eclitasertib; small molecule RIPK1 inhibitor) for ulcerative colitis (GlobeNewswire) - "The Phase 2 study of eclitasertib in participants with moderate to severe ulcerative colitis is expected to have results in the first half of 2026. The program is being developed by Sanofi."

P2 data • Ulcerative Colitis

A Phase 1b Trial to Evaluate Safety and Effect of SAR443122 on Immune System in Severe COVID-19 (clinicaltrials.gov) - P1 | N=68 | Completed | Sponsor: Sanofi | Phase classification: P1b ➔ P1

Phase classification • Infectious Disease • Novel Coronavirus Disease

Inhibition of RIPK1 prevents keratinocyte cell death and reduces skin inflammation in type 1 mediated chronic inflammatory skin diseases (ESDR 2025) - "To evaluate therapeutic potential, we investigated Eclitasertib, a novel small-molecule kinase inhibitor of RIPK1...Ex vivo treatment of LP skin biopsies downregulated IFNg, TNF, CCL3, CXCL8–11 and pathways associated to inflammation. Thus, RIPK1 inhibition targets two major pathogenic events in LP and CLE: epidermal cell death and type 1-driven inflammation."

Cutaneous Lupus Erythematosus • Dermatitis • Dermatology • Dermatopathology • Inflammation • Inflammatory Arthritis • Lichen Planus • Lupus • Systemic Inflammatory Response Syndrome • CCL20 • CCL3 • CXCL8 • IFNG • IL1B • RIPK1 • TNFA

Eclitasertib: Data from P2 RESOLUTE trial (NCT05588843) for moderate to severe ulcerative colitis in H1 2026 (Sanofi) - Q2 2025 Results

P2 data • Inflammatory Bowel Disease • Ulcerative Colitis

A Randomized Phase I Trial Evaluating Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Eclitasertib, a RIPK1 Inhibitor, in Healthy Participants. (PubMed, Adv Ther) - "Single and repeated doses of eclitasertib were well tolerated in healthy participants and potently inhibited RIPK1 activation."

Journal • P1 data • PK/PD data • CNS Disorders • Inflammation • Pain • RIPK1

RESOLUTE: Dose-finding Study of SAR443122 in Adult Participants With Ulcerative Colitis (clinicaltrials.gov) - P2 | N=182 | Recruiting | Sponsor: Sanofi | Trial completion date: Sep 2026 ➔ Dec 2026 | Trial primary completion date: Nov 2025 ➔ Feb 2026

Trial completion date • Trial primary completion date • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

Eclitasertib: Data from P2 RESOLUTE trial (NCT05588843) for moderate to severe ulcerative colitis in 2026 (Sanofi) - Q4 & FY2024 Results

P2 data • Inflammatory Bowel Disease • Ulcerative Colitis

Harnessing dual-mode RIPK1 ligands for cross-species anti-necroptosis inhibitor compounds. (PubMed, Bioorg Med Chem Lett) - "Using Eclitasertib as a starting point, and applying our previous, published knowledge regarding cyclic malonamides, we successfully identified a library of active compounds. The active enantiomer of the most balanced and promising compound was subjected to pharmacokinetics and in vivo hypothermia study in mice."

Journal • Inflammation • CDK7 • RIPK1

Eclitasertib: Data from P2 RESOLUTE trial (NCT05588843) for moderate to severe ulcerative colitis in 2025 (Sanofi) - Q1 2024 Results

P2 data • Inflammatory Bowel Disease • Ulcerative Colitis

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. (PubMed, Respir Res) - P1b | "Eclitasertib was well tolerated with consistent trends toward more rapid resolution of inflammatory biomarkers and clinical improvement in severe COVID-19 patients than placebo."

Clinical • Immunomodulating • Journal • P1 data • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases • CDK7 • CRP • RIPK1

Denali Therapeutics Reports Fourth Quarter and Full Year 2023 Financial Results and Business Highlights (GlobeNewswire) - "Sanofi is conducting the Phase 2 trial of SAR443122/DNL758 in UC....There was no collaboration revenue for the quarter ended December 31, 2023, compared to $10.3 million for the quarter ended December 31, 2022. Collaboration revenue was $330.5 million for the year ended December 31, 2023, compared to $108.5 million for the year ended December 31, 2022. The decrease in collaboration revenue of $10.3 million for the quarter ended December 31, 2023, compared to the comparative period in the prior quarter was primarily due to a decrease of revenue earned under the Sanofi Collaboration of $10.0 million for a milestone triggered in December 2022 upon first patient dosed in a Phase 2 study of SAR443122/DNL758 in individuals with UC."

Commercial • Trial status • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

Denali Therapeutics Announces Key Anticipated 2024 Milestones and Priorities to Further Advance Its Therapeutics Portfolio for Neurodegeneration and Lysosomal Storage Diseases (GlobeNewswire) - "Eclitasertib (SAR443122/DNL758) (Peripheral RIPK1 Inhibitor): Ulcerative colitis (UC)...2024 expected progress and milestones: Continue Phase 2 UC study."

Trial status • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

Dose-finding Study of SAR443122 in Adult Participants With Ulcerative Colitis (clinicaltrials.gov) - P2 | N=182 | Recruiting | Sponsor: Sanofi | Trial completion date: Apr 2026 ➔ Sep 2026 | Trial primary completion date: Jun 2025 ➔ Nov 2025

Trial completion date • Trial primary completion date • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

CLEan: Proof of Concept Study of SAR443122 in Patients With Cutaneous Lupus Erythematosus (clinicaltrials.gov) - P2 | N=78 | Completed | Sponsor: Sanofi | Active, not recruiting ➔ Completed

Trial completion • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus

CLEan: Proof of Concept Study of SAR443122 in Patients With Cutaneous Lupus Erythematosus (clinicaltrials.gov) - P2 | N=78 | Active, not recruiting | Sponsor: Sanofi | Recruiting ➔ Active, not recruiting | Trial completion date: Apr 2024 ➔ Jun 2023 | Trial primary completion date: Sep 2023 ➔ May 2023

Enrollment closed • Trial completion date • Trial primary completion date • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus

CLEan: Proof of Concept Study of SAR443122 in Patients With Cutaneous Lupus Erythematosus (clinicaltrials.gov) - P2 | N=88 | Recruiting | Sponsor: Sanofi | Trial completion date: Jul 2023 ➔ Apr 2024 | Trial primary completion date: Jun 2023 ➔ Sep 2023

Trial completion date • Trial primary completion date • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus

Denali Therapeutics Announces Key Anticipated 2023 Milestones for Its Therapeutic Portfolio for Neurodegeneration and Lysosomal Storage Diseases (GlobeNewswire) - "SAR443122/DNL758 (peripherally-restricted RIPK1 inhibitor): CLE and UC...2023 expected progress and milestones:...Continued recruitment of participants with ulcerative colitis in the Phase 2 study."

Enrollment status • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

Dose-finding Study of SAR443122 in Adult Participants With Ulcerative Colitis (clinicaltrials.gov) - P2 | N=182 | Recruiting | Sponsor: Sanofi

New P2 trial • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

CLEan: Proof of Concept Study of SAR443122 in Patients With Cutaneous Lupus Erythematosus (clinicaltrials.gov) - P2 | N=88 | Recruiting | Sponsor: Sanofi | Trial completion date: Mar 2023 ➔ Jul 2023 | Trial primary completion date: Feb 2023 ➔ Jun 2023

Trial completion date • Trial primary completion date • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus

Denali Therapeutics Reports Fourth Quarter and Full Year 2021 Financial Results and Business Highlights (GlobeNewswire) - "SAR443122/DNL758 (peripherally-restricted RIPK1 inhibitor): CLE, UC...Announced that Sanofi plans to initiate a Phase 2 trial of SAR443122 in ulcerative colitis (UC)."

New P2 trial • Inflammatory Bowel Disease • Ulcerative Colitis