Lilly signs $960m deal with Rigel to develop RIPK1 inhibitors

Eli Lilly has entered a strategic collaboration with Rigel to co-develop receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitors for immunological and neurodegenerative diseases.

The deal includes an exclusive licence agreement for Rigel’s RIPK1 inhibitor R552, which is ready to enter phase 2 testing, with an anticipated study launch in 2021.

Lilly will co-develop and commercialise R552 across all indications, including autoimmune and inflammatory diseases.

In addition, Lilly will also lead all clinical development of brain-penetrating RIPK1 inhibitors in central nervous system (CNS) diseases. Rigel already has ongoing pre-clinical activities with its lead CNS penetrant RIPK1 inhibitor candidates.

RIPK1 is a signalling protein that is implicated in a number of inflammatory cellular processes, including necroptosis (a type of regulated cell death) and cytokine production.

In the process of necroptosis, cell rupture leads to the dispersion of cell contents, which in turn can trigger an immune response and increase inflammation.

The ethos behind RIPK1 inhibitor development is to offer a new kind of approach towards treating a range of autoimmune, inflammatory and neurodegenerative diseases.

In pre-clinical studies of R552, the RIPK1 inhibitor demonstrated prevention of both joint and skin inflammation in a RIPK1-mediated murine (mice) model of inflammation and tissue damage.

"At Lilly, our immunology strategy is focused on the pursuit of novel targets that have the potential to develop into best-in-class medicines for patients with autoimmune conditions," said Ajay Nirula, vice president of immunology at Lilly.

"RIPK1 inhibitors are a promising approach, and R552 is an exciting addition to our immunology pipeline. We look forward to working with Rigel to advance its clinical development,” he added.

Lilly will pay Rigel $125m upfront as part of the agreement, and will also pay out up to $835m in potential development, regulatory and commercial milestone payments.

Also working within the RIPK1 inhibitor space is Sanofi and Denali Therapeutics. In 2018, Sanofi paid Denali $125m upfront for access to two of the company’s RIPK1 inhibitors.

Last year, the companies reported some less than favourable results for one of those molecules: DNL747.

In a phase 1b study of the RIPK1 inhibitor in Alzheimer’s disease and ALS, DNL747 was found to be safe and well tolerated in humans at the dose being evaluated.

However, in parallel toxicity studies in monkeys, the drug showed dose- and duration-dependent adverse results at higher levels.

Sanofi and Denali believed these findings would impact the ability to further increase the dose of DNL747 and activate higher levels of target inhibition in humans, so halted development of the drug.

However, the two companies are continuing to develop DNL788, which is a similar molecule for the same indications.