Hypersensitivity reactions in a mouse model prompted the agency to suspend Denali’s planned Phase I development for DNL952 for Pompe disease.
The FDA has placed a clinical hold on Denali Therapeutics’ Pompe disease therapy DNL952, requesting specific amendments to the protocol before the biotech initiates a Phase I study for the asset.
The pause, revealed in an SEC document on Thursday, was triggered by “hypersensitivity reactions” detected in mouse models. While the FDA did not ask Denali to conduct additional non-clinical studies, it is asking the biotech to lower the starting dose of the drug in its proposed Phase I study.
Denali will also implement other protocol changes, including revised inclusion criteria, adjusted stopping rules and unspecified safety monitoring commitments.
The company has responded to the FDA’s hold and “anticipates minimal delays” in the Phase I development of DNL952, according to the regulatory filing. In a statement to Fierce Biotech, a company spokesperson said that Denali expects to start early-stage studies of the drug “in the first half of 2026, pending the agency’s feedback.”
DNL952 is an experimental enzyme replacement therapy packaged using Denali’s proprietary Enzyme TransportVehicle technology, allowing its delivery into muscles and across the blood-brain barrier. The aim is to restore levels of the GAA enzyme, which in Pompe disease is deficient, rendering the body unable to metabolize glycogen, leading to its buildup in various organs.
Patients with Pompe disease, a rare and debilitating disorder, suffer from breathing problems and muscle weakness. In severe cases, the condition can be life-threatening.
Denali filed an investigational new drug application for DNL952 in October. That application has now been put on hold by the FDA, continuing what has been a difficult year for Denali. In January, the biotech reported that its small-molecule drug candidate DNL343 failed to significantly slow disease progression versus placebo in the Phase II/III HEALY ALS study of amyotrophic lateral sclerosis.
DNL343 was unable to redeem itself in a biomarker analysis, with follow-on data from HEALEY ALS showing no significant treatment effect on neurofilament light, a key indicator of nerve damage. As a result, Denali decided to not push through with testing DNL343 in the study’s extension phase and at the time said it would “assess potential future development opportunities” for the drug. Its future remains uncertain.
Then, in October, Denali announced that the FDA pushed back its target action date for tividenofusp alfa, the biotech’s investigational treatment for the rare Hunter syndrome. The delay was triggered by updated pharmacological information that Denali submitted, which the regulator deemed a major amendment to the application. Denali insisted that the review extension was “not related to efficacy, safety or biomarkers.” A decision is now expected on Apr. 5, 2026.
