Patient Trials Planned or Underway for 2 Oral ALS Therapies, Denali Says

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by Vanda Pinto, PhD |

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Early trials in healthy adults supported the safety and tolerability of two potential oral therapies for amyotrophic lateral sclerosis (ALS) — DNL343 to prevent the cellular stress that can promote toxic protein granules, and DNL788 to block a protein linked to brain inflammation — Denali Therapeutics reported.

A Phase 1b trial in ALS patients is underway for DNL343, and a Phase 2 trial of DNL788 in patients is planned for early next year.

Work in animal models and human cells showed that DNL343 helped to prevent the chronic activation of the cellular integrated stress response — a form of cellular stress that contributes to the formation of toxic protein granules in ALS patients. Similarly, DNL788 (also known as SAR443820, and being jointly developed by Denali and Sanofi) showed a potential for robust inhibition of its target protein, RIPK1.

Results from DNL343’s clinical and preclinical studies, as well as details from DNL788’s planned Phase 2 trial, to be called HIMALAYA, were recently shared at the 2021 Annual Northeast Amyotrophic Lateral Sclerosis (NEALS) meeting, held online Oct. 6–7.

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“DNL343 and SAR443820 are designed to modulate distinct biological pathways implicated in ALS, including the integrated stress response and inflammation, respectively,” Carole Ho, chief medical officer at Denali, said in a press release.

“We are pleased that the data generated preclinically and in Phase 1 studies support clinical investigation of both molecules as potential treatments for individuals with ALS,” Ho added.

DNL343 is an orally available, small molecule designed to activate EIF2B, a protein complex required for protein production. In response to stress, cells suppress EIF2B production leading to impaired protein production and the formation of toxic aggregates made up of proteins and other molecules.

These clumps, known as stress granules, are thought to be precursors of TDP-43 aggregation, an ALS hallmark. Activating EIF2B is meant to restore protein synthesis, clear TDP-43 aggregates, and improve the survival of nerve cells.

Denali is testing the safety, pharmacokinetics, and pharmacodynamics of ascending doses of DNL343, given either as a single time treatment or on multiple consecutive days, in healthy volunteers. Pharmacokinetics is the movement of drug into, through, and out of the body, while pharmacodynamics refers to the effects of a drug on the body.

The Phase 1 clinical trial (NCT04268784), which is still recruiting healthy adults at the Centre for Human Drug Research (CHDR) in Leiden, Netherlands, showed that DNL343 was generally well tolerated for up to 14 days of dosing.

The therapy was also well distributed in the central nervous system, and pharmacokinetics data supported a once daily dosing. DNL343 also efficiently lowered markers of integrated stress response, which was confirmed in a mouse model with chronic activation of this stress pathway.

Building on findings in this trial, the company launched a Phase 1b trial (NCT05006352) in September of oral DNL343 in ALS patients. The trial, which is also ongoing at the CHDR, is enrolling up to 30 adults, ages 18 to 80, whose symptoms started within the last three years.

Participants will be randomly assigned to a low or high dose of DNL343, or to a placebo, given daily for 28 days. Those who complete this randomized part may continue or start with treatment for an additional 18 months in the study’s open-label extension.

DNL788 (SAR443820) is a small molecule that works by inhibiting RIPK1. Increased activity of this protein causes inflammation and cell death in the brain. It also contributes to neurodegeneration in conditions such as ALS.

A Phase 1 trial (NCT04982991) is investigating its safety, tolerability, and pharmacokinetics in about 16 healthy East Asian (Chinese and Japanese) adults. The trial, taking place at a site in the U.K., is currently recruiting volunteers. Additional details on eligibility criteria can be found here.

Volunteers are being given one of three ascending oral doses of DNL788 over three treatment periods. Preliminary trial results showed that DNL788 binds to RIPK1 at doses that are generally well tolerated, Sanofi reported.

The company is now planning to initiate the Phase 2 and multicenter HIMALAYA study, in which adults with ALS will be randomized to treatment with DNL788 or to a placebo. Those who complete the main trial will be invited to enter its open-label and long-term extension, where all will be given the active treatment.

“We’re very encouraged by the initial results of the Phase 1 study of SAR443820 [DNL788] 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 available cure or effective treatment for slowing its progression.

“We look forward to launching the Phase 2 HIMALAYA trial in adults with ALS in early 2022 and to achieving our ultimate goal of helping people living with ALS,” Atassi added.

The U.S. Food and Drug Administration (FDA) has placed DNL788 on its fast track, a designation expected to accelerate its development by making Denali and Sanofi eligible for more frequent meetings with the FDA, and to speed a potential review for approval.