Lilly Terminates CNS Portion of $960M RIPK1 Inhibitor Collaboration with Rigel

Eli Lilly has decided to withdraw from the central nervous system (CNS) component of its $960 million collaboration with Rigel Pharmaceuticals, focusing on receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitors. The announcement, made in Rigel's third-quarter earnings release, marks a significant shift in the partnership originally established in 2021.

Collaboration Restructuring

The original agreement, which included $125 million upfront and up to $835 million in milestone payments, saw Lilly taking the lead in clinical development and potential commercialization of brain-penetrating RIPK1 inhibitors for CNS diseases. Rigel had been conducting preclinical activities on lead CNS-penetrant RIPK1 inhibitor candidates prior to the collaboration.

Despite the termination of the CNS portion, the core of the partnership remains intact. The primary focus of the collaboration, the phase 2-ready RIPK1 inhibitor ocadusertib, continues to progress in development.

Ongoing Development of Ocadusertib

Lilly has advanced ocadusertib into a phase 2 trial for adults with moderately to severely active rheumatoid arthritis. This progress keeps the substantial milestone payment structure in play for Rigel, maintaining the potential for significant financial returns from the collaboration.

RIPK1 Inhibitors: Mechanism and Industry Interest

RIPK1 activation plays a crucial role in programmed cell death, with excessive activation potentially leading to inflammation. In normal cellular processes, RIPK1 is cleaved by caspase-8 to maintain balance. However, in certain autoinflammatory diseases, mutations prevent this cleavage, resulting in uncontrolled cell death and inflammation.

The pharmaceutical industry continues to show interest in RIPK1 inhibitors. Recently, Novartis secured an option on a blood-brain-barrier-crossing platform from Sironax, which includes RIPK1 inhibitors targeting neurodegenerative and immune/inflammatory diseases. Conversely, Sanofi discontinued a RIPK1 inhibitor from its collaboration with Denali Therapeutics following unsuccessful phase 2 results in multiple sclerosis.