Denali and Sanofi to press forward with RIPK1 drug in Alzheimer’s and other brain diseases

Brain
Inhibiting the enzyme RIPK1 may tamp down inflammation in the brain, preventing the death of neurons and halting tissue damage. (VSRao / Pixabay)

Just two weeks after Sanofi laid out $125 million to take a stake in two RIPK1 inhibitors being developed by Denali, the two companies are advancing one of those drugs into clinical trials in three of the toughest-to-treat neurological disorders.

Denali announced on Monday that the drug, called DNL747, will be tested in Alzheimer’s disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). The decision came after a phase 1 study in healthy volunteers showed the drug to be safe, the company said.

RIPK1 (enzyme receptor-interacting serine/threonine-protein kinase 1) is an enzyme that regulates immune cells known as macrophages. Denali’s researchers have been investigating the potential of inhibiting RIPK1 as a way to stop the production of inflammatory molecules. They believe DNL747 can halt the death of neurons and stop tissue damage in the brain.

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But safety has been a concern with RIPK1 inhibition: Denali had to scrap a brain-penetrating RIPK1 inhibitor back in 2016 after 16 patients in a clinical trial developed liver abnormalities. So the results from the DNL747 phase 1 trial will likely generate some interest in the neurology research world.

Denali says it will provide more details about the phase 1 data at its R&D day in New York City on Dec. 10.

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“We are excited that we are able to achieve near complete inhibition of RIPK1 activity at doses that are well tolerated in healthy subjects,” said Carole Ho, M.D., chief medical officer of Denali, in the statement. She added that Denali and Sanofi aim to start trials in Alzheimer’s, ALS and MS “shortly.”

Sanofi is not the only Big Pharma excited about the potential of RIPK1 inhibition. GlaxoSmithKline said last week that its RIPK1 inhibitor, GSK095, prolonged survival in mouse models of pancreatic ductal adenocarcinoma when given alongside a PD1 checkpoint inhibitor. The company is now launching a clinical trial of GSK095 in combination with Merck’s Keytruda.

Denali and Sanofi are also working on a second RIPK1 candidate, DNL758, which will be examined for treating inflammatory diseases such as rheumatoid arthritis and psoriasis. They predict that drug will enter clinical trials in 2019.