Sanofi and Denali Therapeutics ink €1.125bn deal in neurology/inflammation

Denali Therapeutics Inc.'s small molecule drug candidates DNL747 and DNL758 target the receptor-interacting serine/threonine-protein kinase 1 (RIPK1) downstream the TNF receptor pathway, which regulates inflammation and cell death in tissues throughout the body. RIPK1 is overexpressed in inflamed microglia and other cells in the brain. Activation of the enzyme also results in cell death via necroptosis, i.e. in monocytes and oligodendrocytes. In preclinical tests, RIPK1 inhibition was sufficient to block the production of pro-inflammatory cytokines and necroptosis.

Sanofi wants to assess the potential of DNL747  in neurological diseases such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease. The company's second RIPK inhibitor, DNL758, will be clinically tested in systemic inflammatory diseases such as rheumatoid arthritis and psoriasis.

Under the agreement Denali Therapeutics receives $125m upfront and future milestones that may exceed $1bn. Sanofi and Denali Therapeutics will share commercial profits and losses from DNL747 in the U.S. and China equally, while Denali will receive a royalty from Sanofi for other territories for DNL747 and worldwide for DNL758.

Phase Ib and II clinical development costs for DNL747 will be fully funded by Sanofi for MS, ALS, and other neurological indications, except in Alzheimer's disease, which will be funded by Denali. IF the drug candidates make it to Phase III trials, all neurological indications will be jointly funded by Sanofi (70%) and Denali (30%). Sanofi will fully fund the clinical development costs for DNL758 in systemic inflammatory diseases.

Safety of DNL747, a small molecule drug that can cross the blood-brain barrier, is currently being evaluated in a Phase I trial. Phase Ib studies in Alzheimer's disease and ALS are expected to commence next year. DNL758 is a small molecule that does not penetrate the brain. Sanofi will lead clinical development activities starting next year for all systemic inflammatory diseases.