Denali Moving Forward with Sanofi-Partnered ALS Candidate


Based in South San Francisco, Denali Therapeutics reported positive Phase I data and regulatory progress for two therapeutics the company is developing for amyotrophic lateral sclerosis (ALS). They reported the results at the virtual 2021 Annual Northeast ALS (NEALS) Meeting held on October 6–7.

The first was for its DNL343, which is from a Phase I trial in healthy volunteers. The drug is an elF2B activator. The data showed the drug was generally well tolerated for up to 14 days, with “robust distribution in the central nervous system.” They also evaluated safety, pharmacokinetics, pharmacodynamics and biomarkers related to the cellular integrated stress response (ISR). ISR is a biological pathway associated with ILS and other disorders.

The company also presented preclinical data in a mouse model of vanishing white matter (VWM) disease. elF2B activity is decreased in the VMW disease model, which leads to chronic activation of the ISR. After the mice were treated with DNL343, their body weight and motor function normalized, and ISR gene expression and stress response protein levels were decreased in peripheral tissues and the brain.

Carole Ho, M.D., Denali’s chief medical officer, stated, “Effective treatment options are a critical unmet medical need for people living with ALS. DNL343 and SAR443820 are designed to modulate distinct biological pathways implicated in ALS, including the integrated stress response and inflammation, respectively. We are pleased that the data generated preclinically and in Phase I studies support clinical investigation of both molecules as potential treatments for individuals with ALS.”

The second program is for SAR443820. Denali has partnered with Paris-based Sanofi to develop SAR443820. Sanofi presented plans for a Phase II trial of the drug, which is a RIPK1 inhibitor. In the Phase I trial, the drug demonstrated robust target engagement and the drug doses were generally well tolerated. The Phase II HIMALAYA trial is a multi-center, randomized, double-blind, placebo-controlled study, which an open-label long-term extension study will follow. The study is expected to launch in the first quarter of 2022.

The drug has been granted Fast Track designation by the U.S. Food and Drug Administration (FDA) for ALS. RIPK1 is an important signaling mediator of necroptotic cell death, cytokine release, and inflammatory pathways.

Sanofi and Denali entered their partnership in October 2017 for SAR443820/DNL788, which has potential for ALS, multiple sclerosis (M.S.) and Alzheimer’s disease. Sanofi is heading the Phase I and II development for ALS and M.S. and leads co-development with Denali in Phase III for ALS, Alzheimer’s and M.S.

“We’re very encouraged by the initial results of the Phase I study of SAR443820 for the treatment of ALS,” said Nazem Atassi, M.D., Sanofi’s Global Head of Early Neurodevelopment. “ALS is a devastating disease for patients and their families, with no available cure or effective treatment for slowing its progression. We look forward to launching the Phase II HIMALAYA trial in adults with ALS in early 2022 and to achieving our ultimate goal of helping people living with ALS.”

Late in September, Denali announced the appointment of Dr. Katie Peng to the newly created position of chief commercial officer. She was most recently senior vice president, head of the OMNI Business Unit at Genentech, where she oversaw the neurology, ophthalmology, immunology, respiratory, and rare diseases portfolio.

“I am thrilled to join Denali’s leadership team and build the commercial organization,” Peng said. “Neurodegenerative diseases are one of the biggest unmet medical needs of our time and, like in oncology two decades ago, we are at a time of exceptional progress fueled by new genetic insights and biomarker-informed development. Denali is at the vanguard of this revolution, with a broad pipeline of product candidates with significant promise, and I am excited to contribute to building out critical functions with Denali to help bring life-saving medicines to people with neurodegenerative diseases.”

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