FDA Grants Accelerated Approval to Tividenofusp Alfa for Neurologic Hunter Syndrome

The FDA has granted accelerated approval to tividenofusp alfa-eknm (Denali Therapeutics) for the treatment of neurologic manifestations of Hunter syndrome, also known as mucopolysaccharidosis type II (MPS II), in pediatric patients. Marketed as Avlayah, it becomes the first therapy specifically engineered to cross the blood-brain barrier in this rare lysosomal storage disorder.¹

“The approval of AVLAYAH is a new era for the Hunter syndrome community as we deliver the first FDA-approved therapy designed to cross the brain’s protective barrier for individuals and families living with this debilitating disease,” Ryan Watts, PhD, co-founder and chief executive officer at Denali, said in a statement.¹ “This approval reflects the determination and partnership of the MPS community, as well as the FDA’s collaborative engagement to incorporate biomarker evidence to help accelerate the development of urgently needed treatments.”

Data Supporting Approval

The FDA’s accelerated approval of tividenofusp alfa was supported by data from an ongoing phase 1/2, open-label study of 47 patients with Hunter syndrome, with findings that have matured over time. Previously reported data demonstrated substantial reductions in both central nervous system and peripheral disease biomarkers.

At 24 weeks, treatment led to geometric mean reductions of –91.4% in cerebrospinal fluid (CSF) heparan sulfate and –87.9% in urinary heparan sulfate, with normalization achieved in most patients. These biomarker changes were accompanied by reductions in serum neurofilament light (NfL) chain, including –21.2% at week 49 and –70.5% at week 104, suggesting a potential effect on neuroaxonal injury.^2,3

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In addition to biomarker improvements, early clinical signals were observed across multiple domains. Patients demonstrated gains in adaptive behavior, as measured by the Vineland Adaptive Behavior Scales (Vineland-3: +33.8), and in cognitive function, assessed by the Bayley Scales of Infant and Toddler Development (BSID-III: +5.9). These were accompanied by the normalization of liver volume and improvements in hearing thresholds, pointing to both systemic and neurologic impacts.

Building on these earlier findings, the dataset submitted to the FDA further confirmed central nervous system (CNS) target engagement. At 24 weeks, cerebrospinal fluid (CSF) heparan sulfate levels were reduced by approximately 91% (95% CI, 89%–92%), with 93% of treated patients achieving normalization.

These results formed the basis of the accelerated approval, as CSF heparan sulfate is considered a surrogate end point reasonably likely to predict clinical benefit. Across analyses, tividenofusp alfa has demonstrated a generally consistent safety profile, with most treatment-emergent adverse events mild to moderate and infusion-related reactions among the most commonly reported events.

“The FDA approval of AVLAYAH represents a breakthrough advance as the first therapeutic innovation for the Hunter syndrome community in nearly 20 years,” Joseph Muenzer, MD, PhD, Director of the Muenzer MPS Research and Treatment Center and the Bryson Distinguished Professor in Pediatric Genetics at the University of North Carolina at Chapel Hill, said in a statement.¹

“The neurologic manifestations of Hunter syndrome, which affect nearly all patients, have been one of the most challenging and persistent medical needs for the community and a central focus of many years of scientific research,” Muenzer added in a statement.¹ “As the first FDA-approved, brain-penetrant medicine for Hunter syndrome, AVLAYAH will substantially change how we treat patients and has the potential to become a new standard of care.”

Addressing a Longstanding Gap in Care

Hunter syndrome is caused by deficiency of iduronate-2-sulfatase (IDS), leading to accumulation of glycosaminoglycans across tissues, including the brain. Although enzyme replacement therapies have been available for years, they do not cross the blood-brain barrier, limiting their ability to address neurologic decline, which is a major driver of disability and disease burden.

A Novel Delivery Platform to Reach the Brain

Tividenofusp alfa is a fusion protein combining IDS with a transferrin receptor–targeting transport vehicle designed to enable delivery across the blood-brain barrier via receptor-mediated transcytosis. According to Denali, this approach represents the first FDA-approved therapeutic strategy using this mechanism, enabling enzyme delivery to both peripheral tissues and the CNS, an advance that may have broader implications across neurologic and lysosomal storage diseases.

Watts added, “This milestone validates our TransportVehicle platform and its potential to overcome the long-standing challenge of delivering biologic medicines across the blood-brain barrier, with the aim to transform the treatment of a wide range of neurodegenerative diseases, lysosomal storage disorders and other serious diseases that impact millions worldwide."¹

Ongoing Confirmatory Study

As part of the accelerated approval pathway, continued approval of tividenofusp alfa will depend on confirmatory evidence from the ongoing phase 2/3 COMPASS trial (NCT05371613). This 96-week, global study is evaluating the therapy in both younger pediatric patients and older individuals with Hunter syndrome, aiming to better define its impact across a broader disease spectrum.

The primary end point focuses on change in CSF heparan sulfate, a biomarker closely tied to disease activity in the central nervous system. Secondary and exploratory outcomes include measures of adaptive behavior, cognitive development using the Bayley Scales of Infant and Toddler Development (BSID-III), and functional assessments such as the 6-minute walk test.

Investigators are also tracking NfL chain levels to better understand the therapy’s effect on neuroaxonal injury over time. Together, these data are expected to provide a more complete picture of whether the biomarker reductions observed in earlier studies translate into sustained and clinically meaningful neurologic benefit.⁴

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REFERENCES
1. Denali Therapeutics Announces U.S. FDA Approval of AVLAYAH™ (tividenofusp alfa-eknm) for Treatment of Hunter Syndrome (MPS II). News release. Denali Therapeutics. March 25, 2026. Accessed March 25, 2026. https://investors.denalitherapeutics.com/news-releases/news-release-details/denali-therapeutics-announces-us-fda-approval-avlayahtm
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 March 25, 2026. 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, 2025; 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.