The RIPK1 inhibitor pipeline continues to expand with over 10 companies developing 12+ therapeutic candidates, despite a significant setback when Sanofi discontinued its Phase 2 multiple sclerosis trial in October 2024. The diverse pipeline spans early discovery through Phase 2 development, targeting inflammatory and neurodegenerative diseases through inhibition of Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1).
Sanofi's Multiple Sclerosis Setback
Sanofi's decision to halt its Phase 2 clinical trial of oditrasertib in patients with relapsing and progressive multiple sclerosis marked a notable disappointment for the RIPK1 inhibitor field. The experimental therapy failed to demonstrate a significant reduction in neurofilament light chain (NfL) levels, a biomarker associated with neurodegeneration, and did not meet any major secondary endpoints. The trial discontinuation was disclosed in a recent SEC filing by Denali Therapeutics, Sanofi's development partner.
Leading Pipeline Candidates
SAR443122 (Sanofi)
SAR443122, also known as DNL758, represents Sanofi's continued commitment to RIPK1 inhibition despite the multiple sclerosis setback. This small molecule inhibitor targets RIPK1 within the tumor necrosis factor (TNF) receptor pathway, which regulates inflammation and cell death throughout the body. Sanofi has successfully completed Phase 1 studies with this peripherally-restricted RIPK1 inhibitor for SARS-CoV-2 viral infection and is currently conducting a Phase 2 clinical trial for cutaneous lupus erythematosus. The company plans to initiate a Phase 2 trial in patients with ulcerative colitis.
GFH312 (GenFleet Therapeutics)
GenFleet Therapeutics has achieved a significant milestone as the first Chinese company to advance a RIPK1 inhibitor into clinical development. GFH312 is a small molecule inhibitor of receptor-interacting serine/threonine protein-1 (RIP1) kinase, functioning as a key regulator of the TNF-α downstream pathway. Preclinical data demonstrated GFH312's effectiveness in suppressing both peripheral and neuronal inflammation, reducing pathological and behavioral deficits, and improving survival in animal models with acute systemic inflammation from multiple tissue injury. The Phase 1 trial is exploring safe dose ranges and tolerability in healthy subjects.
R552 (Rigel Pharmaceuticals)
R552, developed through a collaboration between Rigel Pharmaceuticals and Eli Lilly, targets the enzyme involved in cellular processes including inflammation and cell death. The partnership focuses on co-developing and commercializing this RIPK1 inhibitor for potential treatment of immunological and neurodegenerative diseases. R552 has completed Phase 1 clinical trials, with Phase 2 clinical trial planning underway as part of the collaboration.
Mechanism and Therapeutic Potential
RIPK1 inhibitors represent a novel therapeutic approach by blocking the activity of Receptor-Interacting Serine/Threonine-Protein Kinase 1, an enzyme involved in regulating inflammation, cell death (especially necroptosis), and immune responses. Overactivation of RIPK1 has been linked to several diseases, including autoimmune disorders, neurodegenerative conditions, and inflammatory diseases. By inhibiting RIPK1, these drugs aim to reduce excessive inflammation and tissue damage.
Pipeline Diversity and Development Stages
The RIPK1 inhibitor pipeline encompasses various development stages, from discovery and preclinical research through Phase 2 trials. Key companies actively developing RIPK1 inhibitors include Sanofi, Genfleet Therapeutics, Rigel Pharmaceuticals, GlaxoSmithKline, AbbVie, Voronoi, Boston Pharmaceuticals, Sironax, and Nuevolution.
The therapeutic candidates are being developed across multiple routes of administration, including oral, parenteral, topical, intradermal, intramuscular, intranasal, subcutaneous, and infusion delivery methods. The pipeline primarily consists of small molecule inhibitors, though other molecule types including monoclonal antibodies, peptides, and vaccines are also under investigation.
Strategic Collaborations and Market Dynamics
The RIPK1 inhibitor space features several strategic collaborations, with the Rigel-Eli Lilly partnership representing a significant industry alliance. These collaborations, along with licensing agreements and financing arrangements, are driving advancement in the RIPK1 inhibitor market despite the challenges highlighted by Sanofi's multiple sclerosis trial discontinuation.
The diverse pipeline and multiple therapeutic targets suggest continued industry confidence in RIPK1 inhibition as a viable therapeutic strategy, even as companies navigate the complexities of targeting this pathway across different disease indications.
