The U.S. Food and Drug Administration (FDA) has placed a clinical hold on Denali Therapeutics’ investigational Pompe disease therapy, DNL952. The decision comes after “hypersensitivity reactions” were observed in mouse models during preclinical testing, according to an SEC filing made public Thursday.
As part of the hold, the FDA is requiring Denali to make several changes to its planned Phase I study protocol. These include lowering the starting dose of DNL952, revising inclusion criteria for trial participants, adjusting stopping rules, and implementing additional safety monitoring measures. However, the agency did not request further non-clinical studies at this time.
Denali stated in its regulatory filing that it has responded to the FDA’s concerns and expects only minor delays in moving forward with the Phase I trial. A company spokesperson told Fierce Biotech that early-stage studies are now anticipated to begin “in the first half of 2026, pending the agency’s feedback.”
DNL952 is designed as an enzyme replacement therapy using Denali’s proprietary Enzyme TransportVehicle technology. This approach aims to deliver therapeutic enzymes into muscles and across the blood-brain barrier, targeting restoration of GAA enzyme levels that are deficient in Pompe disease patients. The condition is characterized by glycogen buildup in organs due to insufficient GAA enzyme activity, leading to muscle weakness and respiratory problems that can be life-threatening.
Denali submitted an investigational new drug application for DNL952 in October, but this application is now on hold following the FDA’s intervention. The setback adds to a challenging year for Denali. Earlier in January, its small-molecule candidate DNL343 failed to show significant benefit over placebo in slowing progression of amyotrophic lateral sclerosis (ALS) during a Phase II/III study. Biomarker analyses also failed to demonstrate a treatment effect on neurofilament light levels—a marker of nerve damage—leading Denali to halt further development of DNL343 within that trial extension.
In October, another delay arose when the FDA extended its review timeline for tividenofusp alfa—Denali’s experimental treatment for Hunter syndrome—after receiving updated pharmacological data from the company. Denali clarified that this review extension was unrelated to issues of efficacy or safety and expects a regulatory decision by April 5, 2026.
