Sanofi, which is leading development of the Denali Therapeutics-partnered molecule, disclosed little about the clinical trial results in ALS. But this Phase 2 failure follows the 2020 clinical trial pause of a different partnered molecule that addresses the same target.

By FRANK VINLUAN
Amyotrophic lateral sclerosis develops through multiple pathways, so drug research in this neuromuscular disorder has pursued multiple targets. One of those targets faces some doubts after an ALS drug candidate from partners Sanofi and Denali Therapeutics failed to meet the goal of a mid-stage clinical trial.
Denali disclosed the Phase 2 clinical trial failure in a Friday regulatory filing. The South San Francisco-based biotech said Sanofi informed it that the brain-penetrating drug, known at Denali as DNL788 and renamed SAR443820 by the pharmaceutical giant, did not meet the main endpoint of showing a change in the ALS Functional Rating Scale-Revised, a scoring assessment for evaluating symptoms in ALS patients. No other information was disclosed. Sanofi plans to present detailed efficacy and safety results at a future scientific meeting, according to the filing.

The Denali drug is a small molecule designed to block RIPK1, a signaling protein that regulates inflammation and cell death in tissues throughout the body. In 2018, Sanofi and Denali struck up a multi-drug research alliance in neurological and inflammatory diseases. The partnership kicked off with the pharmaceutical giant paying its new partner $125 million up front. The pact put Denali in line for $1 billion in milestone payments.

The partnership’s ALS research initially focused on DNL747, a Denali molecule that reached Phase 1b testing in Alzheimer’s and ALS. Preliminary clinical trial results in 2020 showed this molecule hit its target and was safe and well tolerated. Parallel to this clinical trial, a toxicity study was conducted in monkeys. Results from this research indicated challenges for increasing the dose to achieve higher levels of target inhibition—which the companies concluded may be necessary for maximizing efficacy. Sanofi and Denali decided to pause research with this molecule, shifting focus to others in the partnership, including DNL788/SAR443820.

In 2021, the companies reported Phase 1 results showing that DNL788/SAR443820 was safe at all doses tested in healthy volunteers. Furthermore, the results showed the molecule engaged its target. The collaboration agreement called for Sanofi to lead Phase 2 development in ALS and multiple sclerosis. The ALS study enrolled 305 participants randomly assigned to receive the study drug or a placebo twice daily for 24 weeks.

In a note sent to investors, Leerink Partners analyst Marc Goodman wrote that the trial’s failure in ALS was disappointing, given that the study was well powered and the drug had shown strong engagement with its target in Phase 1 testing. The Phase 2 failure suggests that inhibiting RIPK1 may not be the right approach to treat ALS, he said.

However, Goodman added that more could be learned from the trial’s 52-week open-label extension study to further assess the drug’s safety and efficacy. Every participant who elects to continue in this extension study will receive the experimental drug. The main goal of the extension study is a combination assessment of function and survival. Meanwhile, the Phase 2 study in MS has completed its enrollment of 174 patients. Sanofi is continuing this study, Denali said in the regulatory filing.

If blocking RIPK1 proves to be ineffective in treating ALS, the implications could extend beyond Sanofi and Denali. In 2021, Eli Lilly paid Rigel Pharmaceuticals $125 million up front to begin a partnership on that biotech’s RIPK1-blocking small molecules. The lead program in this partnership has reached Phase 2 testing in rheumatoid arthritis. A molecule with the capability of penetrating the central nervous system is still in preclinical development. In its financial reports, Rigel said this molecule could address neurodegenerative diseases such as Alzheimer’s disease and ALS.

More ALS clinical trial news is coming soon. Amylyx Pharmaceuticals won FDA approval for Relyvrio, a drug that addresses two pathways key to neuron survival. The 2022 regulatory decision was based on results from a placebo-controlled Phase 2 test. A longer and larger Phase 3 clinical trial is ongoing. The company expects topline data will become available in the second quarter of this year.

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