The FDA has placed a clinical hold on Denali Therapeutics’ investigational Pompe disease treatment DNL952 following observations of hypersensitivity reactions in mouse studies. The action requires the company to revise several parts of its proposed Phase I study before it may begin.
The hold was disclosed in a filing to the Securities and Exchange Commission (SEC). According to the document, the agency’s decision stemmed from immune reactions identified in mouse models. While the FDA is not requesting additional non-clinical studies, it has instructed Denali to adjust the planned protocol by lowering the starting dose and updating inclusion criteria. The agency is also requiring revised stopping rules and additional safety monitoring measures.
The hypersensitivity findings were noted during the FDA’s 30-day review of Denali’s investigational new drug application for DNL952. The therapy is designed to restore acid alpha-glucosidase (GAA) in individuals with Pompe disease.
Without sufficient GAA, patients are unable to metabolize glycogen, leading to its accumulation in tissues. The condition causes progressive muscle weakness and breathing difficulties, and the infant-onset form can be fatal within a few years if untreated.
Denali stated that hypersensitivity reactions are common in mouse models of Pompe disease and have also been seen in patients receiving enzyme replacement therapy. The company said in the SEC filing that it does not anticipate significant delays to its early-stage plans and intends to submit a clinical trial application in Europe in the first half of next year.
A company spokesperson said, “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.” The spokesperson also noted that Denali expects only minimal scheduling impact once the FDA completes its review.
DNL952 is an experimental enzyme replacement therapy that uses Denali’s Enzyme Transport Vehicle platform, which supports delivery into muscle tissue and across the blood-brain barrier. Denali submitted the investigational new drug application for the therapy in October.
The clinical hold follows other setbacks for the company during the year. Earlier, Denali announced that its small-molecule candidate DNL343 did not significantly slow disease progression in the Phase II/III HEALEY ALS study. Subsequent biomarker analysis also did not show a treatment effect, and the company chose not to move the therapy into the extension phase.
Additional regulatory delays have affected Denali’s Hunter syndrome candidate, tividenofusp alfa. The FDA extended its review by three months after receiving updated pharmacological information categorized as a major amendment. Denali stated that the extension was unrelated to efficacy, safety, or biomarker issues, and an approval decision is now scheduled for April 5, 2026.
As the company prepares for the potential approval of its first marketed therapy, it announced an agreement with Royalty Pharma. Under the arrangement, Denali would receive $200 million if tividenofusp alfa is approved, and Royalty Pharma would receive 9.25% of worldwide sales until specified conditions are met. CEO Ryan Watts said the deal is intended to support the company’s development programs ahead of a possible launch.
Regulatory actions such as an FDA clinical hold are not uncommon in early-stage drug development, particularly for rare disease therapies involving biologics and enzyme replacement approaches. These measures are typically precautionary and are intended to ensure patient safety before first-in-human dosing begins. In many cases, clinical holds are resolved once protocol adjustments are reviewed and accepted by the agency.
For patients and advocacy groups within the Pompe disease community, continued progress in therapy development remains critical. Current treatment options can be limited by immune responses and variable effectiveness, which is why next-generation approaches like DNL952 continue to attract attention. The FDA’s oversight plays a central role in balancing innovation with safety as new treatments move toward clinical evaluation.
