Denali Therapeutics Announces Positive Clinical Results and Regulatory Advances for Developmental Programs in Amyotrophic Lateral Sclerosis (ALS)
Category: Small Molecules
Posted on Thursday 07 October 2021 11:15
- The eIF2B DNL343 activator achieved safety and biomarker objectives in a phase 1 study in healthy volunteers; a phase 1b study started in people with ALS in the third trimester of 2021
- US Food and Drug Administration (FDA) Fast Track designation for SAR443820 / DNL788, an inhibitor of RIPK1, for the treatment of ALS; Sanofi to launch phase 2 study in people with ALS in the first quarter of 2022
SOUTH SAN FRANCISCO, CA, USA I October 06, 2021 IDenali Therapeutics Inc. (NASDAQ: DNLI), a biopharmaceutical company developing a broad portfolio of product candidates designed to cross the blood-brain barrier (BBB) for neurodegenerative diseases, today announced positive clinical results for Phase 1 and Regulatory advancements for two investigational small molecule therapeutics in development for the treatment of amyotrophic lateral sclerosis (ALS) at the 2021 Northeast ALS Annual Meeting (NEALS) to be held virtually October 6-7.
“Effective treatment options are a critical unmet medical need for people living with ALS,” said Carole Ho, MD, medical director of Denali. “DNL343 and SAR443820 are designed to modulate distinct biological pathways involved in ALS, including the integrated stress response and inflammation, respectively. We are delighted that the data generated in the preclinical and in the Phase 1 studies support the clinical study of both molecules as potential treatments for people with ALS.
“We are very encouraged by the initial results of the Phase 1 study of SAR443820 for the treatment of ALS,” said Nazem Atassi, MD, Global Head of Early Neurodevelopment at Sanofi. “ALS is a devastating disease for patients and their families, with no cure available or effective treatment to slow its progression. We look forward to launching the Phase 2 HIMALAYA trial in adults with ALS in early 2022 and reaching our ultimate goal of helping people living with ALS.
Highlights of clinical and preclinical data of eIF2B DNL343 activator presented to NEALS
Denali reported positive results from a phase 1 study in healthy volunteers (n = 95) in which the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple escalating doses of DNL343 were evaluated. Results demonstrated that DNL343 was generally well tolerated up to 14 days of administration, with robust distribution in the central nervous system (CNS) and predictable dose-related increases in DNL343 exposure with a pharmacokinetic profile. supporting a single daily dose. Biomarker evaluations have also been performed in relation to the integrated cellular stress response (ISR). ISR is a biological pathway implicated in ALS and other diseases. After healthy volunteers were treated with DNL343, samples of their blood cells were put under stress ex vivo, and significant changes in ISR biomarkers were observed, confirming pathway engagement.
Denali also presented preclinical data in a mouse model of endangered white matter disease (VWM), a genetic and progressive disorder that causes severe neurological symptoms after exposure to certain stressors. EIF2B activity is reduced in the VMW disease model leading to chronic activation of ISR, making it a relevant model to demonstrate target engagement and modulation of ISR by DNL343. After treatment with DNL343, body weight and motor function were normalized in these mice. In addition, the expression of the ISR gene and the levels of stress response proteins were reduced both in peripheral tissues and in the brain. A similar PK / PD relationship was observed in mice and humans, supporting dose selection of DNL343 in the ongoing Phase 1b study in participants with ALS.
The Phase 1b study (NCT05006352) is a 28-day, multicentre, randomized, placebo-controlled, double-blind study followed by an 18-month open-label extension designed to assess safety, pharmacokinetics and PD of DNL343 in approximately 30 participants with ALS. Dosage in this study began in the third quarter of 2021.
Highlights from RIPK1 Inhibitor SAR443820 Clinical Trial Design Presentation to NEALS and Fast Track Designation
Denali’s partner Sanofi presented plans for a Phase 2 study of the RIPK1 inhibitor SAR443820 in participants with ALS based on positive results from a Phase 1 study in healthy volunteers. In this study, robust target engagement was demonstrated at generally well tolerated doses. The phase 2 study, named HIMALAYA, is a multicenter, randomized, double-blind, placebo-controlled study followed by a long-term open-label extension to evaluate the efficacy and safety of SAR443820 in adult participants with ALS. This phase 2 study is expected to begin in the first quarter of 2022.
The US FDA has granted Fast Track designation to SAR443820 for the treatment of ALS. Fast Track is an FDA process designed to facilitate the development and expedite the review of drugs to treat serious conditions and meet an unmet medical need. The Fast Track designation may allow early and frequent communication with the FDA regarding the development of SAR443820 for the treatment of ALS. This designation also allows for continuous review of the marketing application.
About the eIF2B DNL343 Activator
Modulating eIF2B activity with DNL343 is a novel and targeted experimental approach with first-order potential for the treatment of ALS. eIF2B is an intracellular protein complex that regulates protein synthesis and is necessary for neuronal health and function. When neurons are under stress, as occurs in ALS, eIF2B activity is suppressed. This leads to impaired protein synthesis and results in the formation of “stress granules”, which are considered to be a precursor to the aggregation of TDP-43, a pathology characteristic of ALS. DNL343 is designed to activate eIF2B and thereby restore protein synthesis, disperse TDP-43 aggregates and improve neuronal survival. DNL343 is an investigational drug and has not been approved by any regulatory authority for commercial use.
About RIPK1 SAR443820 / DNL788 Inhibitor
SAR443820 / DNL788 is a novel CNS-penetrating small molecule inhibitor of RIPK1, a critical signaling mediator of necroptotic cell death, cytokine release, and inflammatory pathways. Denali and Sanofi entered into a broad collaboration in October 2018 for the global development and commercialization of RIPK1 inhibitors. This includes CNS penetrating molecules such as SAR443820 / DNL788, which was evaluated in a Phase 1 study in healthy volunteers, with potential development for neurological indications such as ALS, multiple sclerosis (MS) and MS. Alzheimer’s disease (AD). Sanofi is leading the Phase 1 and Phase 2 development of SAR443820 / DNL788 for ALS and MS and leading the co-development of SAR443820 / DNL788 with Denali in Phase 3 clinical trials for ALS, AD and MS. SAR443820 / DNL788 is an investigational drug which has not been approved by any regulatory authority for commercial use.
About Denali Therapeutics
Denali Therapeutics is a biopharmaceutical company developing a broad portfolio of product candidates designed to cross the blood brain barrier (BBB) for neurodegenerative diseases. Denali pursues new treatments by rigorously evaluating genetically validated targets, designing delivery through BBB, and guiding development with biomarkers that demonstrate target and pathway engagement. Denali is based in southern San Francisco. For more information, please visit www.denalitherapeutics.com.
THE SOURCE: Therapeutic Denali