Denali Therapeutics (NASDAQ:DNLI) said the U.S. Food and Drug Administration has granted accelerated approval to AVLAYAH (tividenofusp alfa-eknm) for the treatment of Hunter syndrome (mucopolysaccharidosis type II, or MPS II), marking what company executives described as the first enzyme replacement therapy engineered to reach both the body and the brain.
On a conference call discussing the approval, Denali’s leadership team said the FDA decision was based on a surrogate biomarker—cerebrospinal fluid (CSF) heparan sulfate (HS)—and represents the first FDA-approved biologic designed to cross the blood-brain barrier using the company’s Transport Vehicle platform. Denali said AVLAYAH’s approval is the first meaningful therapeutic advance for the MPS II community in nearly two decades and could establish a regulatory and scientific framework for other lysosomal storage disorders.
Disease background and unmet need
Chin noted that the current standard of care is intravenous enzyme replacement therapy (ERT), which does not cross the blood-brain barrier. As a result, neurologic manifestations—including cognitive decline, behavioral symptoms, and hearing loss—remain inadequately addressed, while some peripheral disease features may persist or progress despite treatment. Denali positioned AVLAYAH as a “whole body” approach intended to target both peripheral and neurologic manifestations.
Clinical data and FDA label highlights
Denali said the clinical results supporting approval were published in The New England Journal of Medicine from a phase I/II study of tividenofusp alfa in pediatric Hunter syndrome patients. Chin said treatment led to “large and sustained reductions” in biomarkers of disease activity in both the central nervous system and periphery, including normalization of CSF HS to levels seen in unaffected children. He also said neurofilament light (NfL), described as a marker of neuronal injury, was reduced to normal levels, and urine heparan sulfate normalized in previously treated and ERT-naive participants.
In functional and clinical measures, Chin cited continued skill gains in Vineland Adaptive Behavior and improvements in Bayley Scales cognitive raw scores, as well as maintained improvements in hearing threshold measured by pure tone average. He characterized safety findings as consistent with ERTs and manageable for chronic therapy, with infusion-related reactions the most common adverse event and decreasing over time after initial treatment.
Denali highlighted several elements of the U.S. prescribing information, including:
- Accelerated approval basis: CSF heparan sulfate as a surrogate biomarker reasonably likely to predict clinical benefit.
- Indication: Treatment of neurologic manifestations in pre-symptomatic or symptomatic pediatric patients weighing at least 5 kg, initiated prior to advanced neurologic impairment.
- Use limitation: Not recommended for use in combination with other enzyme replacement therapies.
- Dosing: Maintenance dosage of 15 mg/kg once weekly by intravenous infusion over approximately four hours, initiated with a dose-escalation regimen.
Chin also cited pharmacodynamic results described in the label, including a 91% mean reduction in CSF HS from baseline and 93% of patients below the upper limit of normal at week 24. For total urine glycosaminoglycans (GAG), Denali said 68% of patients were below the upper limit of normal at week 24.
Safety labeling includes a boxed warning for hypersensitivity, including anaphylaxis; guidance on infusion-associated reactions; anemia monitoring recommendations; and monitoring guidance following a reported case of membranous nephropathy related to immune complex deposition, according to Chin.
Confirmatory study and broader pipeline read-through
Denali said it is continuing development through the ongoing COMPASS phase II/III confirmatory study in approximately 63 participants. Chin said the trial is a head-to-head randomized controlled study versus standard-of-care ERT across disease phenotypes and a broad age range, designed to evaluate neurologic and somatic clinical outcomes and including adults living with Hunter syndrome.
Executives said the approval could inform other programs, particularly DNL126 for Sanfilippo syndrome. Chin said the precedent suggests CSF HS could be an approvable surrogate marker, while also emphasizing that each disease has unique considerations and that Sanfilippo has no standard of care.
Commercial launch plans, pricing, and access
Chief Commercial Officer Katie Peng said Denali’s launch focus will be shaped by reimbursement mechanics rather than patient or physician enthusiasm, describing an “S-curve” uptake dynamic as coverage policies and workflows mature. AVLAYAH is expected to be available in the United States “two weeks from tomorrow,” she said, with 2026 focused on activation and access and 2027 expected to bring adoption acceleration.
Peng described the U.S. market as concentrated, with most treated patients managed by clinical geneticists in about 100 centers of excellence, enabling a small and focused field team. She said Denali has established relationships with major MPS II centers and has profiled and segmented accounts ahead of launch.
Denali provided prevalence and incidence estimates discussed on the call, stating approximately 30 new U.S. patients are diagnosed each year, with roughly 500 patients living with MPS II in the U.S. and about 2,000 worldwide. Peng said Denali’s opportunity is to capture about 75% of the treated U.S. prevalent population, with the potential to address the entire MPS II population if COMPASS is positive. She also pointed to increasing newborn screening in the U.S. as a factor that could identify patients earlier.
On pricing, Peng said AVLAYAH’s wholesale acquisition price is $5,200 per 150 mg single-use vial, with weekly dosing at 15 mg/kg. She said most pediatric patients will require 2–3 vials per week depending on weight, with an annual maintenance cost of about $270,000 for a 10-kg infant and about $811,000 for a 30-kg child.
Peng said Denali Patient Services will provide support including benefit investigation, prior authorization assistance, treatment coordination, educational resources, and financial assistance where appropriate, with the objective of reducing time from prescription to first infusion.
On the call, Denali also said the FDA granted a Rare Pediatric Disease Priority Review Voucher with the AVLAYAH approval. Chief Financial and Operating Officer Alexander Schuth said the company intends to transfer or sell the voucher to support operating expenses and long-term goals, without providing timing details.
About Denali Therapeutics (NASDAQ:DNLI)
Denali Therapeutics is a clinical‐stage biopharmaceutical company focused on developing therapies for neurodegenerative diseases. The company’s research leverages a proprietary Blood–Brain Barrier Transport Vehicle (TV) platform designed to enable large molecules, including antibodies and enzymes, to penetrate the central nervous system. Denali’s approach includes small molecules, monoclonal antibodies and gene therapy candidates aimed at key drivers of disorders such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.
Among Denali’s lead programs is an orally delivered leucine‐rich repeat kinase 2 (LRRK2) inhibitor for Parkinson’s disease, and an anti‐TREM2 antibody designed to modulate microglial activity in Alzheimer’s patients.
