Denali therapy candidate fails to slow ALS progression in trial

Safety, efficacy data from HIMALAYA study expected at upcoming conference

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Denali Therapeutics’ SAR443820 (DNL788) treatment candidate — now in late-stage clinical testing for amyotrophic lateral sclerosis (ALS), per the company’s website — has failed to significantly slow disease progression in adults in a Phase 2 trial.

The experimental therapy “did not meet the primary endpoint of change” in outcomes measures relative to a placebo in trial, Denali reported in a Securities and Exchange Commission (SEC) filing. That means that the HIMALAYA study, which had been testing SAR443820 versus the placebo in more than 300 ALS patients, has failed to meet its primary goal.

Detailed study results were not disclosed in the filing, but co-developer Sanofi, which is running the trial, plans to present additional safety and efficacy data at an upcoming scientific conference, Denali noted.

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Slowing ALS progression was main goal of HIMALAYA trial

SAR443820 is an oral inhibitor of RIPK1, an enzyme that plays an important role in inflammation and cell death within the central nervous system (CNS), which is comprised of the brain and spinal cord. Both inflammation and cell death are key features of many neurodegenerative diseases, including ALS and multiple sclerosis (MS), for which SAR443820 also was being developed.

RIPK1 levels are found to be increased in the spinal cord of ALS patients.

The molecule is designed to be brain-penetrant, meaning it can cross the selective blood-brain barrier that normally prevents substances circulating in the bloodstream from entering the CNS. This barrier can pose a significant challenge to developing treatments for brain disorders.

By blocking RIPK1, SAR443820 is intended to ease neuroinflammation and cell death, thereby slowing the progression of neurodegeneration. It was awarded fast track designation from the U.S. Food and Drug Administration in 2021 for the treatment of ALS. That designation aims to speed a therapy’s clinical development.

The global Phase 2 HIMALAYA trial (NCT05237284) enrolled 305 adults with ALS, ages 18-80, whose symptoms had emerged within the prior two years. The participants were randomly assigned to receive SAR443820 or a placebo, taken as oral tablets twice daily for 24 weeks, or about six months.

After that, all participants could enter an open-label treatment period and receive SAR443820 for about 1.5 more years (80 weeks). In an open-label study, both participants and researchers know the exact treatment patients are given.

During the trial, participants could remain on stable regimens of other ALS therapies, such as Radicava (edaravone), Relyvrio (sodium phenylbutyrate and taurursodiol), or riluzole (sold as Rilutek, Tiglutik, and Exservan). Patient dosing began in May 2022.

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Developers still testing SAR443820 as MS therapy

The trial’s main goal was to evaluate whether SAR443820 could slow disease progression, as assessed by changes in scores on the revised ALS Functional Rating Scale (ALSFRS-R), a commonly used measure in ALS, after 24 weeks.

While the SEC filing reported that this primary goal was not met, no information was provided regarding any secondary endpoints. Specifically, the trial was testing SAR443820 for secondary outcomes that included survival, respiratory function, muscle strength, and safety.

Sanofi acquired certain clinical development rights to SAR443820 in a 2018 collaboration agreement with Denali, which also covered a number of other molecules originally developed by Denali.

One of them was a RIPK1 inhibitor called DNL747, which was being developed for ALS and Alzheimer’s disease. The companies paused its development in 2020, and decided to shift their focus to SAR443820.

It is unclear how these findings will impact the companies’ plans for SAR443820 in ALS, but the compound is still being developed as a possible treatment for MS, Denali noted in the SEC filing. In MS, the therapy also is in Phase 2 clinical testing.

“Sanofi intends to present the detailed efficacy and safety results of the ALS Phase 2 HIMALAYA study at a future scientific forum,” Denali stated in the SEC filing.