Lilly exits Rigel alliance, adding to RIPK1 scrap heap

Eli Lilly Terminates RIPK1 Inhibitor Partnership with Rigel

Eli Lilly has terminated its partnership with Rigel Pharmaceuticals for two investigational RIPK1 inhibitors, effective June 15. This decision means Lilly will return all rights to the assets and will no longer be responsible for milestone or other payments to Rigel. The collaboration, initiated in February 2021 with a $125 million upfront payment and potential milestones up to $835 million plus tiered royalties, had previously seen Lilly pull out of a central nervous system program in October 2025. This termination adds to a series of setbacks for the RIPK1 modality across the pharmaceutical industry, impacting the future of Rigel's remaining asset, ocadusertib, currently in a mid-stage trial for rheumatoid arthritis.

• Eli Lilly is ending its collaboration with Rigel Pharmaceuticals for two RIPK1 inhibitors, with the termination taking effect on June 15. As a result, Lilly will relinquish all rights to the licensed compounds and related programs, freeing them from any future milestone or other payment obligations to Rigel. This move follows an SEC filing by Rigel on April 16, confirming the dissolution of the agreement.
• The partnership, established in February 2021, involved Lilly licensing the RIPK1 blockers for an initial $125 million upfront payment, with Rigel eligible for up to $835 million in milestones and tiered royalties. Prior to this full termination, Lilly had already discontinued the central nervous system program for one of the RIPK1 inhibitors in October 2025, leaving ocadusertib as the sole remaining asset in a mid-stage rheumatoid arthritis trial.
• Lilly's withdrawal from the Rigel alliance underscores a broader trend of setbacks for the RIPK1 modality within the pharmaceutical industry. Other major players like Sanofi, in partnership with Denali Therapeutics, halted a Phase 2 multiple sclerosis study for oditrasertib in October 2024 due to lack of efficacy on a key biomarker. Roche also recently terminated a mid-stage study for flizasertib in acute kidney injury, citing unlikelihood of significant clinical benefit.

Rigel Regains Ocadusertib: Assessing Its Broader Pipeline

Ocadusertib is being investigated across multiple chronic inflammatory conditions beyond rheumatoid arthritis, expanding its potential therapeutic applications. The compound is currently being evaluated in inflammatory bowel disease and psoriasis, though specific intervention model details were not available in the literature reviewed.

The Broader Challenges Facing RIPK1 Inhibitors

Ocadusertib, a selective RIPK1 inhibitor, is being investigated for chronic inflammatory diseases beyond rheumatoid arthritis, including inflammatory bowel disease and psoriasis. However, the available literature does not provide specific information about the intervention models for clinical trials in these additional indications.

RIPK1 Inhibitors: Clinical Hurdles Mount After Lilly Partnership Ends

Eli Lilly's decision to terminate its partnership with Rigel Pharmaceuticals for two investigational RIPK1 inhibitors marks a significant inflection point for the entire RIPK1 modality. This move, which returns all rights to Rigel and halts substantial potential milestone payments, underscores the persistent challenges in translating promising preclinical science into clinical success for this target. The termination follows a prior withdrawal from a central nervous system program and adds to a growing list of setbacks for RIPK1 inhibitors across the industry.

Receptor-interacting serine/threonine kinase 1 (RIPK1) has long been identified as a crucial regulator of both inflammation and programmed cell death, or necroptosis, making it an attractive target for a wide array of chronic inflammatory and neurodegenerative conditions, including rheumatoid arthritis (RA), inflammatory bowel disease, psoriasis, and even Alzheimer's disease. Preclinical studies have consistently demonstrated that inhibiting RIPK1 can prevent cell death and reduce inflammation in various disease models. Rigel's ocadusertib, for instance, showed high potency and selectivity in preclinical assays, effectively inhibiting necroptotic responses and demonstrating favorable pharmacokinetics and target engagement in early human trials.

However, the path to clinical validation has been fraught. A pivotal Phase II study of another RIPK1 inhibitor, GSK2982772, in moderate to severe RA patients, concluded that the tested exposure levels did not translate into meaningful clinical improvement. This outcome, combined with Lilly's exit, raises critical questions about the optimal therapeutic window, patient selection, and the overall translatability of RIPK1 inhibition in complex human diseases. For Rigel, this means navigating the mid-stage development of ocadusertib for RA without a major partner, a daunting task given the capital requirements and the now heightened skepticism surrounding the modality. The broader pharmaceutical landscape will likely view this as a cautionary tale, potentially leading to a re-evaluation of investment in novel targets within complex inflammatory pathways. Future success for RIPK1 inhibitors may hinge on identifying specific patient subsets, developing more precise biomarkers, or exploring indications where RIPK1's role is more acutely defined and less redundant with other pathways.