SHERIDAN, WYOMING - December 8, 2025 - Denali Therapeutics is facing another regulatory setback after the U.S. Food and Drug Administration (FDA) placed a clinical hold on DNL952, its enzyme replacement candidate for Pompe disease, citing preclinical hypersensitivity signals and demanding protocol changes before the company can start Phase I studies.
FDA Flags Hypersensitivity Risk Before First Human Dosing
The clinical hold, disclosed in an SEC filing, stems from "hypersensitivity reactions" observed in mouse models. While the agency has not required additional non-clinical studies, it is insisting on a more conservative first-in-human plan. Denali has been asked to lower the proposed starting dose for DNL952 and implement "revised inclusion criteria, adjusted stopping rules and unspecified safety monitoring commitments" before the program can proceed.
For sponsors working on novel, brain-penetrant biologics, the move underlines regulators' increasing focus on early safety signals-especially in rare diseases where patient populations are small and risk tolerance is low. Denali has submitted its response and currently "anticipates minimal delays" to Phase I, with early-stage studies now expected to begin in the first half of 2026, pending FDA feedback.
DNL952: Enzyme Transport Vehicle Approach to Pompe Disease
DNL952 is an experimental enzyme replacement therapy (ERT) built on Denali's proprietary Enzyme Transport Vehicle (ETV) technology. The platform is designed to deliver therapeutic enzymes efficiently into skeletal muscle and across the blood-brain barrier, aiming to restore activity of acid alpha-glucosidase (GAA) in tissues where glycogen accumulation drives disease.
In Pompe disease, GAA deficiency leads to progressive glycogen buildup in multiple organs, causing muscle weakness, respiratory compromise and, in severe forms, life-threatening cardiopulmonary complications. Existing ERTs have improved outcomes but leave significant residual burden, particularly in skeletal muscle and the central nervous system. If DNL952's ETV-enabled delivery can be proven safe and effective in humans, it could offer a differentiated profile in a market where long-term functional gains remain an unmet need.
A Difficult Year for Denali's Neurology Pipeline
The Pompe hold caps a challenging period for Denali. In January, the company reported that its small-molecule asset DNL343 failed to significantly slow disease progression versus placebo in the Phase II/III HEALEY ALS study. A subsequent biomarker analysis also showed no meaningful effect on neurofilament light, prompting Denali to halt extension-phase testing and leave the drug's future "uncertain."
In October, the company disclosed an FDA decision to extend the review of tividenofusp alfa, its investigational Hunter syndrome therapy, after Denali submitted updated pharmacology data that regulators deemed a "major amendment." Denali stressed that the delay was not related to "efficacy, safety or biomarkers," but the target action date has been pushed to April 5, 2026. The DNL952 hold adds another layer of execution risk to a portfolio built around blood-brain barrier transport platforms in high-stakes rare diseases.
Regulatory and Strategic Implications for Rare Disease Developers
From a B2B perspective, the FDA's stance on DNL952 offers several readthroughs for other rare disease and neurology developers:
- Preclinical immunogenicity and hypersensitivity in animal models are drawing closer scrutiny when sponsors propose aggressive starting doses or rapid dose escalation in first-in-human studies.
- Complex biologics with novel transport mechanisms, such as ETV-enabled ERTs, may encounter more conservative regulatory expectations, even when mechanistic rationale is strong.
- Program-level risk management becomes critical in platform companies: setbacks in ALS, Hunter syndrome and now Pompe heighten pressure on Denali to demonstrate that its BBB transport technologies can translate into clear clinical benefit without disproportionate safety trade-offs.
For investors and partners, the company's ability to resolve the hold quickly, align with FDA on revised parameters and still initiate Phase I in the first half of 2026 will be a key indicator of execution resilience and regulatory rapport.
What to Watch Next
Stakeholders will now focus on three near-term milestones: lifting of the DNL952 hold and initiation of human trials in Pompe, the April 2026 FDA decision on tividenofusp alfa in Hunter syndrome, and any updates on Denali's broader ETV platform strategy. How the company sequences these events-and communicates risk-benefit assessments to clinicians and patient advocates-will shape its positioning in the competitive rare neurology and lysosomal storage disorder markets.
For detailed updates on Denali's rare disease pipeline, regulatory interactions and ETV programs, visit the Denali Therapeutics corporate website.