FDA Approves Tividenofusp alfa-eknm, Targeting Neurologic Manifestations of Hunter Syndrome

The FDA has granted accelerated approval to tividenofusp alfa-eknm (Avlayah; Denali Therapeutics) for the treatment of neurologic manifestations of Hunter syndrome (mucopolysaccharidosis type II, or MPS II) in presymptomatic or symptomatic pediatric patients weighing at least 5 kg when initiated prior to advanced neurologic impairment.^1,2

The approval, granted to Denali Therapeutics and announced jointly by Denali and the FDA, represents the first time any therapy has been specifically authorized to address the neurological complications of a disease affecting an estimated 500 people in the United States, almost exclusively males.^1-3

Phase 1/2 Clinical Data Supporting Approval

The accelerated approval was based on a phase 1/2 multicenter, open-label trial conducted on 47 pediatric patients with MPS II aged 3 months to 13 years. At week 24, the 44 patients with available measurements showed an approximate 91% (95% CI, 89%–92%) average decrease in cerebrospinal fluid heparan sulfate (CSF HS) from baseline—a surrogate end point the FDA determined was reasonably likely to predict clinical benefit.^1,2

At baseline, no patients had CSF HS levels below the upper limit of normal; by week 24, 93% of tividenofusp-treated patients with CSF measurements had achieved levels below that threshold. Beyond biomarker reductions, the trial also demonstrated stabilization or improvement in adaptive behavior, cognition, and hearing, as well as normalization of liver volume at 24 weeks, clinical signals that are particularly meaningful for families and caregivers.^1,2,4

Safety Profile and Monitoring Requirements

Tividenofusp’s labeling carries a boxed warning for allergic reactions, including anaphylaxis, and the FDA recommends that patients initiate therapy in a health care setting that is equipped for appropriate medical monitoring. The most common adverse events (AEs) include upper respiratory tract infection, ear infection, fever, anemia, cough, vomiting, diarrhea, and rash.¹

Of particular importance for pharmacists involved in medication therapy management: hemoglobin should be monitored at baseline, at 3 months after therapy initiation, and periodically thereafter due to the risk of anemia. Kidney function and urine protein levels also require ongoing monitoring given the risk of membranous nephropathy. The most common treatment-related AEs in the phase 1/2 trial were infusion-related reactions, which decreased with continued use.^1,2,4

How Tividenofusp Works

Tividenofusp is composed of the iduronate-2-sulfatase (I2S) fused to Denali's proprietary TransportVehicle platform, which leverages receptor-mediated transcytosis via the transferrin receptor to actively ferry the enzyme across the blood-brain barrier. Administered as a once-weekly intravenous infusion, the drug delivers I2S to lysosomes in both the central nervous system (CNS) and peripheral tissues—targeting the full spectrum of Hunter syndrome manifestations rather than somatic disease alone. For pharmacists, this mechanism is clinically meaningful: it signals that the product's safety and monitoring requirements extend beyond those of conventional enzyme replacement therapies (ERTs) to include CNS-related considerations.^1,4

A Disease Without a Neurological Answer—Until Now

Hunter syndrome is a rare X-linked recessive lysosomal storage disorder that is caused by a deficiency of the enzyme I2S, leading to progressive accumulation of glycosaminoglycans across nearly all cell types, tissues, and organs. Clinical manifestations span skeletal deformities, cardiomyopathy, airway obstruction, and, in most patients, neurological decline, with severe cases typically fatal in the second decade of life.³

The existing standard of care, idursulfase (Elaprase; Takeda Pharmaceuticals), is an intravenous ERT that addresses somatic symptoms but cannot cross the blood-brain barrier, leaving the progressive cognitive and behavioral deterioration that defines the most severe form of the disease unaddressed as a critical care gap. Pharmacists who have previously counseled families managing Hunter syndrome on idursulfase infusions should be aware that the approval of tividenofusp represents a fundamentally different therapeutic approach.^1,5

What Pharmacists Need to Know

Tividenofusp received breakthrough, fast track, priority review, and orphan drug designations. As an accelerated approval, continued marketing authorization may be contingent on results from the ongoing phase 2/3 COMPASS confirmatory trial (NCT05371613), which is more than 95% enrolled and randomly assigns participants 2:1 to receive either tividenofusp or idursulfase for up to 96 weeks. Pharmacists managing patients with rare diseases or supporting specialty pharmacy services should monitor this trial for full approval data and stay current on Denali's patient support infrastructure as the drug moves into commercial availability.¹

“In the meantime, families with young children with Hunter syndrome will have access to a product that may favorably alter the course of the disease at the crucial time in life when there is the greatest potential for benefit,” Tracy Beth Hoeg, MD, PhD, acting director of the Center for Drug Evaluation and Research at the FDA, said in the news release.¹

REFERENCES

1. FDA approves drug to treat neurologic manifestations of Hunter syndrome. News release. FDA. Released March 25, 2026. Accessed March 25, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-treat-neurologic-manifestations-hunter-syndrome

2. Denali Therapeutics announces U.S. FDA approval of AVLAYAH (tividenofusp alfa-eknm) for treatment of Hunter syndrome (MPS II). News Release. Denali Therapeutics. Released March 25, 2026. Accessed March 25, 2026. https://investors.denalitherapeutics.com/news-releases/news-release-details/denali-therapeutics-announces-us-fda-approval-avlayahtm

3. Wraith JE, Scarpa M, Beck M, et al. Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr. 2008;167(3):267-277. doi:10.1007/s00431-007-0635-4

4. Denali Therapeutics Inc. The New England Journal of Medicine publishes Phase 1/2 study of Denali Therapeutics' tividenofusp alfa (DNL310) for Hunter syndrome (MPS II). News release. December 30, 2025. Accessed March 25, 2026. https://www.globenewswire.com/news-release/2025/12/30/3211341/0/en/The-New-England-Journal-of-Medicine-Publishes-Phase-1-2-Study-of-Denali-Therapeutics-Tividenofusp-Alfa-DNL310-for-Hunter-Syndrome-MPS-II.html

5. Leal AF, Benincore-Flórez E, Rintz E, et al. Mucopolysaccharidoses: from understanding to treatment, a century of discoveries. Biology (Basel). 2023;12(4):563. doi:10.3390/biology12040563