Denali makes ALS play, hustling Sanofi-partnered drug into phase 2 and sharing early data on internal program

Denali Therapeutics has set out its play for the amyotrophic lateral sclerosis (ALS) market, revealing early-phase data on one asset and plans to move a Sanofi-partnered program into phase 2 early in 2022.

The new data come from a phase 1 trial that gave eIF2B activator DNL343 to 95 healthy volunteers. Denali emerged from the study with evidence DNL343 is generally well tolerated, gets to the central nervous system and has a pharmacokinetic profile that supports once-daily dosing. The study also saw changes in integrated stress response biomarkers, suggesting DNL343 engages with its target and acts on a pathway implicated in ALS.

Denali saw enough positive signs in the early data to start a phase 1b study, which recently set out to enroll 30 ALS patients and randomize them to receive one of two doses of DNL343 or placebo. While the trial is primarily looking at the adverse event profile of DNL343, it will also start the process of answering outstanding questions about how patients respond to the molecule.   

“Primary pushback from investors is: hard to know what we have until there is more clinical data, biology around ALS is extremely challenging, preclinical models are not well predictive,” analysts at Jefferies wrote in a note to investors. The analysts expect Denali to eventually land a big partnership to fund the program. 

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Denali has already partnered its other clinical-phase ALS prospect, DNL788. Sanofi paid $125 million for rights to the RIPK1 inhibitor and one of its siblings in 2018. The other candidate, DNL747, ran into toxicity problems last year, adding to concerns raised by Denali’s earlier RIPK1 inhibitor DNL104 and leading the partners to focus on DNL788.

DNL788, also known as SAR443820, came through a phase 1 study in healthy volunteers without setting off any alarms, leading the partners to outline plans to enroll 261 ALS patients in a midphase clinical trial. The study is set to start early next year and assess changes in clinical outcomes, such as an ALS functional rating scale, and biomarkers. 

Denali’s internal and Sanofi-partnered ALS programs tackle the disease from different angles and, as it stands, are targeting slightly different patient populations. The RIPK1 study is enrolling patients two years after diagnosis, compared to three years in the eIF2B clinical trial.