Denali’s Avlayah Reduces CSF Heparan Sulfate by 91% in Phase 1/2 Trial for MPS II

Denali Therapeutics announced on January 1, 2026, that its drug Avlayah (tividenofusp alfa-eknm) reduced cerebrospinal fluid heparan sulfate (HS) levels by 91% in a Phase 1/2 international trial involving 47 pediatric patients with Hunter syndrome (MPS II). According to the study published in The New England Journal of Medicine, the reduction in CSF HS, a biomarker for neurological disease, supported the U.S. FDA’s accelerated approval of Avlayah in March 2026.

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.