The FDA has placed a hold on Denali Therapeutics’ plans to launch a phase 1 rare disease trial, citing concerns about immune reactions to the investigational treatment recorded in preclinical mouse studies.
The regulator has requested that Denali adjust its trial protocol “to include a lower starting dose, revised inclusion criteria, certain safety monitoring commitments and stopping rules,” the Bay Area biotech said in a Dec. 4 filing with the Securities and Exchange Commission (SEC).
The FDA identified the concerns during its 30-day review of Denali's Investigational New Drug (IND) application for an enzyme replacement therapy dubbed DNL952. The agency is not asking the biotech to conduct any additional preclinical research.
“We have submitted our response to the FDA and plan to start the phase 1 study in the first half of 2026, pending the agency’s feedback,” a Denali spokesperson told Fierce Biotech.
Denali doesn't expect the hold to significantly delay its phase 1 plans, according to the SEC filing, and the biotech still intends to submit a clinical trial application in Europe in the first half of next year.
The issue stems from overactive immune responses, called hypersensitivity reactions, in mice given DNL952, a therapy meant to restore acid alpha-glucosidase (GAA) in Pompe disease. Patients without this enzyme cannot break down a complex sugar called glycogen, which builds up in cells and causes progressive muscle weakness, among other symptoms. Without treatment, the infant-onset form of the disease is fatal within a few years.
Hypersensitivity is a broad term that encompasses mild allergies to lifelong autoimmune disorders like Type 1 diabetes. It is common in mouse models of Pompe, Denali said in the release, and has also been observed in patients with the disease treated with enzyme replacement.
Other developers working on Pompe treatments have previously faced FDA clinical holds. In 2022, the agency paused Astellas’ phase 1/2 study of gene replacement therapy AT845 after a trial participant developed nerve damage.
That hold was lifted in January 2023, and Astellas anticipates the trial wrapping up in 2030, according to ClinicalTrials.gov.
In October—the same month Denali announced its IND submission for DNL952—the company also learned that the FDA had delayed an approval decision for the biotech’s lead Hunter syndrome asset tividenofusp alfa (tivi) by three months to April 2026.
Denali has been gearing up for a potential approval of tivi, which would be the company’s first market launch. Today, the biotech announced a deal with Royalty Pharma that will see Denali receive $200 million should tivi gain approval. In return, Royalty would get 9.25% royalty payments on worldwide sales of the drug until certain conditions are met.
The Royalty deal is meant to bolster Denali’s development programs as the California company readies for tivi’s potential debut, CEO Ryan Watts, Ph.D., said in a release announcing the deal.