The trial included 47 pediatric patients with Hunter syndrome (mucopolysaccharidosis type II, or MPS II), aged 0.3 to 13 years, across multiple international centers, officials from Denali Therapeutics said. Of these, 44 patients had CSF measurements at week 24, with 93% (41 of 44) achieving HS levels below the upper limit of normal, the study showed.

Avlayah demonstrated a mean reduction of 91% in cerebrospinal fluid (CSF) heparan sulfate (HS) levels from baseline by week 24, according to data published January 1, 2026, in The New England Journal of Medicine.

The open-label Phase 1/2 trial enrolled both enzyme replacement therapy (ERT)-naïve and previously treated participants, with 15 patients having no prior ERT and 32 patients previously treated with idursulfase, according to trial records. The primary objective was to evaluate the safety and tolerability of Avlayah (tividenofusp alfa-eknm), while secondary objectives assessed central nervous system and peripheral effects through biomarkers such as CSF and urine HS, adaptive behavior measures, and liver volume changes, the publication noted.

The rapid normalization of CSF HS was observed as early as week 7 in most patients who switched from idursulfase, Denali officials said. Additionally, urine and serum HS levels declined, suggesting improved peripheral activity of the drug. The efficient crossing of the blood-brain barrier at low doses was inferred from the swift reduction in CSF HS, according to the researchers.

On March 25, 2026, the U.S. Food and Drug Administration granted accelerated approval for Avlayah to treat neurologic manifestations in pediatric patients weighing at least 5 kilograms before the onset of advanced neurologic impairment. The approval was based on the surrogate endpoint of CSF HS reduction, which the FDA deemed reasonably likely to predict clinical benefit, Denali Therapeutics confirmed in a GlobeNewswire release. The indication specifies treatment for neurologic symptoms in Hunter syndrome patients prior to advanced disease stages.

Continued approval of Avlayah depends on confirmatory results from the ongoing Phase 2/3 COMPASS trial, which compares Avlayah to idursulfase and includes young adult patients globally, according to company statements. The COMPASS trial also focuses on cognitive and behavioral outcomes and aims to support regulatory submissions worldwide.

The safety profile from the Phase 1/2 trial indicated that infusion-related reactions were the most common adverse events reported. A modest increase in mean serum and CSF neurofilament light chain (Nf-L) levels was observed over six months in one cohort, although high variability in Nf-L levels before and after treatment was noted, suggesting that the utility of Nf-L as a biomarker requires further investigation, Denali researchers said. No specific boxed warnings were identified beyond the general safety evaluation conducted during the trial.

The patient population enrolled in the study ranged from three months to 13 years old and included both presymptomatic and symptomatic individuals, as well as those who were ERT-naïve or previously treated. All patients had baseline CSF HS levels above the upper limit of normal, with no exceptions reported in the trial data. The multi-cohort, single-arm design spanned international sites, reinforcing the global scope of the research.

Natural history data presented in the study showed that serum Nf-L levels increased over 4.5 to 6 months prior to enrollment in one cohort, underscoring the progressive nature of neurologic disease in Hunter syndrome. During treatment with Avlayah, a modest rise in Nf-L was observed, but the clinical significance remains to be determined, according to Denali.

The reduction of CSF HS, a key glycosaminoglycan biomarker, to near-normal levels in the majority of treated patients was highlighted as a critical finding supporting the drug’s potential neurologic benefit. Peripheral biomarker improvements in urine and serum HS further corroborated the drug’s systemic activity.

Denali Therapeutics announced the FDA approval and Phase 1/2 data through multiple channels, including a March 25, 2026, GlobeNewswire statement and investor releases. Global Genes reported interim data on CSF HS normalization across trial cohorts, providing additional context on the drug’s efficacy.

The ongoing Phase 2/3 COMPASS trial remains the pivotal study for confirming the clinical benefits of Avlayah, with enrollment extending to young adult patients and a focus on cognitive and behavioral endpoints. The trial’s results will be critical for supporting broader regulatory submissions and potentially expanding the drug’s approved indications internationally.

Avlayah is indicated for pediatric patients who are either presymptomatic or symptomatic and weigh at least 5 kilograms before the onset of advanced neurologic impairment, according to FDA documents. The therapy, developed by Denali Therapeutics of South San Francisco, marks the first approved treatment targeting central nervous system involvement in Hunter syndrome, also known as mucopolysaccharidosis type II (MPS II), officials said. The FDA granted Avlayah accelerated approval after reviewing data from a phase 1/2 clinical trial involving 47 pediatric patients aged between 3 months and 13 years.

At 24 weeks, the trial demonstrated a 91 to 93 percent reduction in cerebrospinal fluid heparan sulfate, a surrogate biomarker linked to the disease’s neurologic manifestations, according to published results in the New England Journal of Medicine in January 2026.

Ninety-three percent of patients achieved cerebrospinal fluid heparan sulfate levels within the range observed in individuals without Hunter syndrome, sources confirmed. The FDA determined that this surrogate endpoint is reasonably likely to predict clinical benefit, enabling the accelerated approval pathway.

Denali Therapeutics received multiple designations prior to approval, including breakthrough therapy, fast track, priority review, and orphan drug status, according to FDA announcements. Acting Director of the Center for Drug Evaluation and Research, Dr. Tracy Beth Hoeg, M.D., Ph.D., noted that Avlayah addresses neurologic complications affecting approximately 500 individuals in the United States, predominantly males. FDA Commissioner Marty Makary, M.D., M.P.H., described the approval as a milestone for children and families affected by the disease.

Avlayah is administered as an intravenous infusion once weekly, per FDA prescribing information. The therapy is engineered to cross the blood-brain barrier by utilizing a transferrin receptor-mediated transport mechanism, enabling central nervous system delivery that was previously unattainable with standard enzyme replacement therapies. It targets the underlying deficiency of iduronate 2-sulfatase (IDS) enzyme and the accumulation of glycosaminoglycans responsible for Hunter syndrome’s multisystemic effects, according to Denali’s press release.

Safety information includes a boxed warning for hypersensitivity reactions, including anaphylaxis, necessitating initiation under medical supervision. The most common adverse events reported were upper respiratory tract infections, fever, anemia, and gastrointestinal symptoms. Infusion-related reactions were the most frequent side effects but tended to decrease with continued treatment, sources said. Monitoring for anemia and renal complications is recommended during therapy.

Continued approval of Avlayah is contingent upon verification of clinical benefit in an ongoing phase 2/3 confirmatory trial named COMPASS. This randomized, controlled study enrolls children and young adults across North America, South America, and Europe, comparing Avlayah to standard care with idursulfase. The trial aims to confirm improvements in cognitive and functional outcomes beyond biomarker reductions, according to clinical trial registries and FDA communications.

Denali plans to make Avlayah available in the United States shortly after approval, supported by a patient assistance program, company representatives said. The FDA also awarded Denali a Rare Pediatric Disease Priority Review Voucher in conjunction with the approval.

Hunter syndrome is a rare X-linked lysosomal storage disorder caused by mutations in the IDS gene, leading to progressive accumulation of glycosaminoglycans in various tissues. The disease affects physical and mental development, the skeleton, heart, respiratory system, and brain, with neurologic decline nearly universal in affected boys, according to medical literature and FDA background documents. Approximately 500 patients in the U.S. live with the condition, predominantly males due to its X-linked inheritance pattern.

Avlayah represents the first Hunter syndrome therapy approved to address cognitive and neurologic manifestations in nearly two decades, analysts from William Blair noted in a recent report. They forecast peak U.S. sales exceeding $250 million by the late 2030s, with worldwide sales potentially reaching $1 billion. The approval underscores advances in central nervous system delivery technology, validating Denali’s Transport Vehicle chemistry platform for treating neurologic diseases.