Date: 2018-11-01

Type of information: Development agreement

Compound: RIPK1 inhibitor molecules including DNL747 and DNL758

Company: Denali Therapeutics (USA - CA) Sanofi (France)

Therapeutic area: Neurodegenerative diseases - Inflammatory diseases - Autoimmune diseases

Type agreement: development - licensing - commercialisation

Action mechanism:

  • RIPK1 inhibitorDNL747 is a brain-penetrant small molecule inhibitor of RIPK1.
  • DNL758 is a small molecule inhibitor of RIPK1 that does not penetrate the brain.

Disease: Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and systemic inflammatory diseases as rheumatoid arthritis and psoriasis.


  • • On November 1, 2018, Denali Therapeutics announced that it will collaborate with Sanofi on the development of multiple RIPK1 inhibitor molecules with the potential to treat a range of neurological and systemic inflammatory diseases. The two lead molecules DNL747 and DNL758 target a critical signaling protein known as the receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in the TNF receptor pathway, which regulates inflammation and cell death in tissues throughout the body. The companies plan to study DNL747 in Alzheimer’s disease, amyotrophic lateral sclerosis and multiple sclerosis, and DNL758 in systemic inflammatory diseases such as rheumatoid arthritis and psoriasis.
  • DNL747 is currently being evaluated in early clinical stage trials, known as Phase 1. Phase 1b studies in Alzheimer’s disease and ALS patients are expected to commence in the near-term. Denali will lead Phase 2 clinical trials in Alzheimer’s disease while Sanofi will lead Phase 2 clinical trials in MS and ALS, as well as future Phase 3 trials in all neurological indications.
  • DNL758 is a small molecule inhibitor of RIPK1 that does not penetrate the brain. Sanofi will lead clinical development activities for all systemic inflammatory diseases. The clinical trials are expected to begin in 2019.
  • The collaboration also includes additional pre-clinical RIPK1 inhibitor molecules.

Financial terms:

  • Under the terms of the agreement, Sanofi will make an upfront cash payment to Denali of $125 million, with future development and commercial milestone payments that could exceed $1 billion. Sanofi and Denali 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 1b and 2 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. Phase 3 trials for 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.

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