Denali and Sanofi pause studies with DNL747 in Alzheimer’s and ALS (edited)

(Edit includes Denali’s reply to our email about financial aspect of the agreement)

Denali Therapeutics and Sanofi have paused clinical studies with small molecule RIPK1 inhibitor DNL747 in Alzheimer’s disease and ALS, due to emerging evidence that higher levels of target inhibition may be required for maximizing efficacy, and certain challenges.

“Together with our partner Sanofi, we have decided to pause clinical studies with DNL747 and focus our efforts on accelerating development of DNL788, which we believe has superior drug properties and a more rapid path toward proof-of-concept clinical studies in patients in multiple neurological indications,” said Ryan Watts, Ph.D., CEO.

“Due to emerging evidence that higher levels of target inhibition may be required for maximizing efficacy, and challenges to achieving higher doses imposed by molecule-specific toxicity findings with DNL747, we are pausing additional studies with this molecule,” said Carole Ho, M.D., Chief Medical Officer. “However, I am encouraged by the emerging pathway biomarker data in Alzheimer’s disease and ALS patients, and our experience and learnings with DNL747 should allow us to progress quickly with clinical studies for DNL788. Importantly, DNL788 appears to have a superior preclinical therapeutic window compared to DNL747, facilitating development in multiple indications, including Alzheimer’s disease, ALS and multiple sclerosis.”

To remind, Sanofi was to make an upfront cash payment to Denali of $125 million, with then future development and commercial milestone payments that could exceed $1 billion. Sanofi and Denali were planning to share commercial profits and losses from DNL747 in the U.S. and China equally, while Denali was supposed to receive a royalty from Sanofi for other territories for DNL747 and worldwide for DNL758.

In an email replying to Pharmaceutical Daily’s question about the financial aspect of the agreement with Sanofi, Denali said it does not comment on forward looking financial outlook. “That said, we can confirm that the partnership financial arrangement (which the question was referring to) is still intact (i.e. 747 is exchanged with 788)”

RIPK1, receptor-interacting serine/threonine-protein kinase 1, is a critical signaling protein in the TNF receptor pathway, which regulates inflammation and cell death in tissues throughout the body.

Data from 31 patients in two 29-day Phase 1b studies in Alzheimer’s disease and ALS, and additional data from six ALS patients in an open label extension study, showed that DNL747 was safe and well tolerated at the dose tested with no significant treatment related adverse events. Target engagement of approximately 80% median inhibition of pRIPK1 in blood at trough drug concentration was achieved.

In parallel to the clinical studies, chronic toxicity studies with DNL747 in cynomolgus monkeys showed dose- and duration-dependent adverse preclinical findings at exposures higher than those tested in the clinic. These findings, which are considered off-target and molecule-specific, impact the ability to increase the dose of DNL747 and achieve higher levels of target inhibition without time consuming additional clinical safety studies in patients to evaluate the long-term safety and tolerability.

Denali partner Sanofi is responsible for development of DNL758 and is currently planning further clinical studies in multiple indications based on successful Phase 1 data.