• Denali and Sanofi pause DNL747(a) clinical activities based on the totality of DNL747 data and a superior profile of backup compound DNL788(b)
  • Denali and Sanofi intend to accelerate DNL788 for development in neurological indications, with plans to initiate clinical testing by early 2021
  • Safety endpoints were met in Phase 1b patient studies with DNL747 in ALS and Alzheimer’s disease, however further dose escalation to achieve higher levels of target inhibition may be limited by preclinical chronic safety data
  • Sanofi successfully completed the Phase 1 healthy volunteer study with peripherally-restricted RIPK1 inhibitor DNL758(c), and further clinical studies in multiple indications are being planned

SOUTH SAN FRANCISCO, CA, USA I June 09, 2020 I Denali Therapeutics Inc. (NASDAQ: DNLI), a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (“BBB”) for neurodegenerative diseases, today announced the results from its Phase 1b studies with small molecule RIPK1 inhibitor DNL747 in Alzheimer’s disease and ALS, and provided a broad RIPK1 program update including DNL788 and DNL758.

“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. “We’d like to thank all patients who took part in these studies. Your participation is critical in the ultimate success of developing medicines for these terrible diseases.”

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.

“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.”

Data from the completed Phase 1 study with peripherally-restricted RIPK1 inhibitor DNL758 in healthy volunteer subjects display an encouraging profile, as the molecule appears safe and tolerable at doses tested. 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.

(a) SAR443060, (b) SAR443820, (c) SAR443122

About Denali

Denali Therapeutics is a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the BBB for neurodegenerative diseases. Denali Therapeutics pursues new treatments by rigorously assessing genetically validated targets, engineering delivery across the BBB and guiding development through biomarkers that demonstrate target and pathway engagement. Denali Therapeutics is based in South San Francisco.  For additional information, please visit http://www.denalitherapeutics.com/.   

SOURCE: Denali Therapeutics