Denali Therapeutics and Sanofi have joined efforts to develop small molecule inhibitors of the RIPK1 enzyme, a new class of potential therapeutic agents for a range of neurological and inflammatory diseases, including amyotrophic lateral sclerosis (ALS).
The collaboration agreement is focused on the clinical development of two new compounds, DNL747 and DNL758, and includes other RIPK1 inhibitor molecules currently in preclinical development. RIPK1 (receptor-interacting serine/threonine-protein kinase 1) is involved in processes that affect both cell survival and programmed cell death.
DNL747, in development for ALS, Alzheimer’s disease, and multiple sclerosis, is a small molecule inhibitor of RIPK1 that can pass the protective blood-brain-barrier to reach the brain. Its safety is currently being evaluated in healthy volunteers in an early Phase 1 clinical trial being conducted in the Netherlands.
When hyperactive, the RIPK1 enzyme can impair the production of nerve cells protective of the myelin layer, an event that can contribute to the development of several neurodegenerative disorders.
Preclinical studies in experimental models of ALS have shown that overactive RIPK1 damages myelin and nerve cells in the spinal cord, an hallmark feature of ALS. This finding suggests that blocking, or inhibiting, RIPK1 may prevent the underlying damage that promotes the disease.
The companies are planning to initiate Phase 1b studies in patients with Alzheimer’s disease and ALS in the near future.
According to the agreement’s terms, Denali will lead Phase 2 clinical trials of DNL747 in Alzheimer’s disease while Sanofi will lead Phase 2 studies in ALS and multiple sclerosis (MS), as well as future Phase 3 trials in all neurological indications.
“RIPK1 is a promising target with the potential to bring disease modifying medicines to patients suffering from neurodegenerative diseases as well as systemic inflammatory diseases. We are very excited to partner with Sanofi and expand our RIPK1 program into new indications,” Ryan Watts, PhD, CEO of Denali, said in a press release.
“With its considerable infrastructure and experience in both clinical development and commercial functions, Sanofi is an ideal partner for Denali to maximize the clinical and commercial success of our RIPK1 program,” he stated.
A second RIPK1 inhibitor candidate, DNL758, is a small molecule inhibitor of RIPK1 that cannot enter the brain. The clinical development of this agent will be led by Sanofi and focus on treating systemic inflammatory diseases, such as rheumatoid arthritis and psoriasis. Clinical trials are expected to open in 2019.
“We look forward to working with Denali on the RIPK1 program as we explore the potential of this mechanism in neurologic and inflammatory diseases,” said Rita Balice-Gordon, PhD, global head of rare and neurologic diseases research at Sanofi.