FDA Delays Review Deadline for Hunter Syndrome Agent Tividenofusp Alfa

Denali Therapeutics announced that the FDA has extended its review period for the company’s biologics license application (BLA) for tividenofusp alfa, an investigational therapy for Hunter syndrome, a rare lysosomal storage disorder. The revised PDUFA date for the therapy, which aims to become the first approved treatment for Hunter syndrome, is now set for April 5, 2026.¹

The agency’s decision to extend the review period comes after Denali submitted additional pharmacology data in response to a routine information request as part of the FDA’s standard evaluation process. Importantly, the agency did not request any new efficacy, safety, or biomarker data as part of this amendment.

Denali noted that the supplemental pharmacology information does not alter the original benefit–risk assessment or the overall clinical pharmacology conclusions supporting tividenofusp alfa’s application. The BLA submission, accepted back in July, was through the accelerated approval pathway, and primarily based on data from a phase 1/2, open-label, single-arm study of 47 patients.

"We appreciate the FDA’s continued collaboration throughout the review process,” Ryan Watts, PhD, chief executive officer at Denali, said in a statement. "We continue to prepare for the potential approval and commercial launch of tividenofusp alfa. We feel the urgency to deliver for the MPS community, and we are committed to working together with regulators, physicians, and advocates to bring this important therapy to individuals and families living with Hunter syndrome."¹

Tividenofusp alfa is a fusion protein consisting of iduronate-2-sulfatase (IDS)–the deficient lysosomal enzyme in Hunter syndrome–linked to a transport vehicle antibody fragment that targets the transferrin receptor on the blood-brain barrier. Hunter syndrome results from a deficiency in IDS, leading to GAG accumulation throughout the body and brain, causing progressive neurocognitive decline, organ dysfunction, and shortened lifespan.

Data from the phase 1/2 trial, announced earlier this year, showed that at 24 weeks, treatment with tividenofusp alfa led to normal or near-normal reductions in both central nervous system and peripheral disease biomarkers, including cerebrospinal fluid and urine heparan sulfate and neurofilament light chain (NfL), a marker of neuroaxonal injury. Clinically, patients showed normalized liver volumes, improved hearing thresholds across all tested frequencies, and gains in adaptive behavior and cognitive skills for most participants.²

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The therapy was generally safe and well tolerated, with most treatment-related adverse events (TEAEs) mild or moderate in severity. The most common TEAEs included infusion-related reactions, anemia, vomiting, pyrexia, respiratory infections, and rash. Serious TEAEs occurred in three participants (6.4%), all of which were manageable, resolving or stabilizing with continued treatment; one participant discontinued due to a moderate infusion reaction and unrelated events.

Topline data from the trial, presented at the recently concluded Child Neurology Society (CNS) Annual Meeting, showed that the agent was well tolerated and led to improvements in a number of disease-specific biomarkers and outcome measures. Overall, geometric mean fold change from baseline (CSF-FCFB) in CSF heparan sulfate and uHS were –91.4% and –87.9%, respectively, at week 24, with normalization achieved in a majority and reductions maintained for both biomarkers.³

GM-FCFB in serum NfL, a marker of neuronal damage, showed changes of –21.2% at week 49 and –70.5% at week 104. In addition, at week 49, mean change from baseline on Bayley Scales of Infant and Toddler Development (BSID-III) cognitive raw score and Vineland-3 adaptive behavior were +5.9 and +33.8, respectively, with improvements maintained at the latest follow-up. Notably, all participants reached and maintained normal liver volume from week 24.

Currently, tividenofusp alfa is being evaluated in a phase 2/3, 96-week trial, dubbed COMPASS (NCT05371613). The trial includes 2 cohorts of patients (ages ≥2 to <6; ≥6 to 26 years), using change in CSF FS as the primary outcome. Other secondary outcomes of the trial include changes in Vineland-3 scale, BSID-III, NfL, and 6-Minute Walk Test, among others.⁴

REFERENCES
1. Denali Therapeutics Announces FDA Review Extension of BLA for Tividenofusp Alfa for the Treatment of MPS II (Hunter Syndrome). News release. Denali Therapeutics. October 13, 2025. Accessed October 13, 2025. https://www.globenewswire.com/news-release/2025/10/13/3165786/0/en/Denali-Therapeutics-Announces-FDA-Review-Extension-of-BLA-for-Tividenofusp-Alfa-for-the-Treatment-of-MPS-II-Hunter-Syndrome.html
2. Denali Therapeutics Announces Primary Analysis and Long-Term Follow-Up of Phase 1/2 Study in Hunter Syndrome (MPS II) with Tividenofusp Alfa. News release. Denali Therapeutics. February 6, 2025. Accessed July 7, 2025. https://www.globenewswire.com/news-release/2025/02/06/3022238/0/en/Denali-Therapeutics-Announces-Primary-Analysis-and-Long-Term-Follow-Up-of-Phase-1-2-Study-in-Hunter-Syndrome-MPS-II-with-Tividenofusp-Alfa.html
3. Rajan D, Burton B, Muenzer J, et al. Topline primary analysis of the safety and efficacy of weekly intravenous tividenofusp alfa in mucopolysaccharidosis type II (MPS II): a phase ½ trial. Presented at: 2025 CNS Annual Meeting; October 8-11; Charlotte, NC. ABSTRACT 278
4. A Study to Determine the Efficacy and Safety of Tividenofusp Alfa (DNL310) vs Idursulfase in Pediatric and Young Adult Participants With Neuronopathic (nMPS II) or Non-Neuronopathic Mucopolysaccharidosis Type II (nnMPS II) (COMPASS). Clinicaltrials.gov. Updated August 5, 2025. Accessed October 13, 2025.