Denali Therapeutics’ Brain-Penetrant ERT Cuts CSF Heparan Sulfate 91%, Eyes April 2026 PDUFA
Denali’s Phase 1/2 trial of tividenofusp alfa showed a 91% reduction in cerebrospinal fluid heparan sulfate at Week 24, sustained through Week 153, and an 88% urine HS decrease with normalization in most participants. The FDA granted Priority Review of the BLA, scheduling a PDUFA decision for April 5, 2026.
1. NEJM Publishes Pivotal Phase 1/2 Data
Denali Therapeutics announced that The New England Journal of Medicine published results from its open-label Phase 1/2 trial of tividenofusp alfa (DNL310) for Hunter syndrome (MPS II). The peer-reviewed article, featured in the January 1, 2026 issue, details data from 47 pediatric participants (median age: 5 years) treated over as long as 153 weeks. This marks the first publication of a brain-penetrant enzyme replacement therapy engineered to cross the blood-brain barrier, underscoring Denali’s TransportVehicle™ platform’s potential to address both central nervous system and peripheral manifestations of MPS II.
2. Robust Biomarker Reductions and Clinical Improvements
Key secondary endpoints demonstrated a 91% mean reduction in cerebrospinal fluid heparan sulfate at Week 24 (95% CI: 90%–92%; N=44), sustained through Week 153 at 92% (95% CI: 90%–93%; N=16). Urine levels of the same substrate fell by 88% at Week 24 (95% CI: 85%–90%; N=40) and remained 91% below baseline at Week 153 (95% CI: 87%–94%; N=10). Exploratory analysis showed a 76% reduction in serum neurofilament light chain by Week 153 (95% CI: 68%–82%; N=13). Clinically, participants experienced normalization of liver volume after 24 weeks, measurable gains in adaptive behavior and cognition, and hearing threshold improvements across multiple frequencies.
3. Safety Profile and Adverse Events
Tividenofusp alfa’s primary safety and tolerability objectives were met, with infusion-related reactions identified as the most common treatment-related adverse events. Incidence of these reactions decreased with continued dosing, and no new safety signals emerged over the extended treatment period. These findings align with earlier reports, reinforcing the therapy’s tolerability in both enzyme replacement therapy–naïve and previously treated children across the MPS II severity spectrum.
4. FDA Priority Review and Commercial Outlook
Denali’s Biologics License Application for tividenofusp alfa is under U.S. FDA Priority Review, with a Prescription Drug User Fee Act (PDUFA) decision expected by April 5, 2026. The company has secured Rare Pediatric Disease, Breakthrough Therapy, Fast Track and Orphan Drug designations in the U.S., and Priority Medicines status in the EU. Should approval be granted, tividenofusp alfa would represent the first FDA-approved enzyme replacement therapy designed to treat neurological and somatic symptoms of Hunter syndrome, potentially transforming the standard of care for patients living with this life-limiting lysosomal storage disease.