Sanofi will partner with Denali Therapeutics to develop its receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitor candidates as treatments for neurological and systemic inflammatory diseases, Denali said today, through a collaboration that could generate more than $1.125 billion for the South San Francisco, CA, biotech.

Denali’s RIPK1 inhibitor pipeline consists of candidates designed to target RIPK1, a signaling protein in the TNF receptor pathway that regulates inflammation and cell death in tissues throughout the body.

The RIPK1 inhibitor pipeline includes an unspecified number of preclinical molecules as well as two lead candidates:

  • DNL747, a Phase I brain-penetrant small molecule inhibitor of RIPK1 that Sanofi and Denali plan to study in Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS).
  • DNL758, a small molecule inhibitor of RIPK1 that does not penetrate the brain. The companies plan to study DNL758 in systemic inflammatory diseases such as rheumatoid arthritis and psoriasis.

DNL747 heads the “CNS products” portion of the pipeline, and DNL758 the “Peripheral products” portion.

DNL747 is under study in a Phase I trial that dosed its first healthy volunteers in the Netherlands, Denali said on March 19.

The company added today that it expects Phase Ib trials of DNL747 to begin “in the near-term” in patients with Alzheimer’s and ALS. Denali has agreed to lead Phase II trials in Alzheimer’s, while Sanofi will lead Phase II clinical trials in MS and ALS, as well as future Phase III trials in all neurological indications.

Sanofi has agreed to fully fund Phase Ib and Phase II clinical development costs for DNL747 for MS, ALS, and other neurological indications—except Alzheimer’s, which will be funded by Denali. Sanofi will also fund 70% of Phase III trials for all neurological indications, with Denali paying the remaining 30%.

DNL758 clinical trials are expected to launch next year, Denali said, with Sanofi agreeing to fully fund the clinical development costs for the candidate in systemic inflammatory diseases.

‘Promising Target’

“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,” Denali CEO Ryan Watts, Ph.D., said in a statement. “We are very excited to partner with Sanofi and expand our RIPK1 program into new indications.”

Denali gained access to the RIPK1 pipeline in June 2015 when it acquired Incro Pharmaceuticals for $1.5 million, consisting of $0.9 million in assumed liabilities and $0.6 million in shares of its common stock. A year later, Denali issued an additional $5.3 million in shares of common stock in connection with the acquisition after undisclosed milestones were achieved, according to the company’s Form 10-K annual report for 2017.

Incro initially pursued development of RIPK1 inhibitor treatments through a license and collaboration agreement with Harvard University, though Denali said it discovered both DNL747 and DNL758.

Sanofi agreed to pay Denali $125 million upfront, and potentially $1.095 billion in payments tied to achieving development and commercial milestones—consisting of $600 million in clinical and regulatory milestone payments for CNS Products, and $495 million in clinical, regulatory and commercial milestone payments for Peripheral Products, according to a regulatory filing.

Sanofi and Denali also agreed to equally share commercial profits and losses from DNL747 in the U.S. and China, while Sanofi will pay Denali royalties on DNL747 sales outside those countries, and royalties on worldwide sales of DNL758.

“We look forward to working with Denali on the RIPK1 program as we explore the potential of this mechanism in neurologic and inflammatory diseases,” added Rita Balice-Gordon, Ph.D., Global Head of Rare and Neurologic Diseases Research at Sanofi.

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