STAT+: FDA approves Denali Therapeutics drug for Hunter syndrome

The Food and Drug Administration on Wednesday approved a new therapy from Denali Therapeutics for Hunter syndrome, clearing a drug that can do something no existing treatment for the disease has ever managed: reach the brain.

Avlayah (tividenofusp alfa-eknm) is an enzyme replacement therapy designed to treat the neurologic manifestations of Hunter syndrome, a rare genetic condition that primarily affects boys and progressively robs them of speech, cognition, and motor function, typically by their teenage years. The FDA granted accelerated approval based on a biomarker — a 91 percent reduction in cerebrospinal fluid heparan sulfate levels after 24 weeks of treatment — rather than direct evidence of clinical benefit. The approval arrives almost exactly one month after the agency rejected a competing gene therapy from Regenxbio for the same condition, spooking advocates who feared the regulatory door had swung shut on the entire field.

It had not. But the distinction between Denali's success and Regenxbio's failure reveals something important about what the FDA now requires before accepting a biomarker as a proxy for a clinical outcome in rare disease.

Hunter syndrome — mucopolysaccharidosis type II, or MPS II — is caused by a deficiency in the iduronate-2-sulfatase enzyme. Without it, a class of complex sugars called glycosaminoglycans accumulates in cells throughout the body, including the brain. The existing standard of care, Elaprase (idursulfase), has been available since 2005 but cannot cross the blood-brain barrier. It manages systemic symptoms; it leaves the neurodegeneration untouched.

Denali's approach takes the missing enzyme and fuses it to the company's Transferrin Receptor-enabled TransportVehicle platform — a molecular disguise that borrows the brain's own receptor system to smuggle the drug past the blood-brain barrier. Avlayah is the first FDA-approved medicine built on this architecture. The concept has been theorized for decades; Denali spent years engineering the chemistry to make it reliable enough to survive clinical testing.

The Phase 1/2 results, published in the January 1, 2026 issue of The New England Journal of Medicine, showed that 41 of 44 treated patients had cerebrospinal fluid heparan sulfate levels within the normal range by week 24. The trial enrolled patients between the ages of four months and 13 years, split between those who had previously received Elaprase and those who were treatment-naïve. Ryan Watts, Denali's chief executive, focused on what the approval meant for the platform's future.

The confirmatory Phase 2/3 COMPASS trial is already underway. Accelerated approval means the FDA believes the biomarker is reasonably likely to predict clinical benefit — not that it has confirmed it. If COMPASS fails to demonstrate actual neurological or functional improvement, the agency can withdraw the approval.

That contingency is the part that matters most. "Time matters profoundly for families affected by these devastating disorders," said Terri Klein, president of the National MPS Society, in Denali's announcement. Her organization supported the approval as a breakthrough after nearly two decades without new therapeutic options. But the confirmatory trial is the real test, and the families who helped make this day possible know it.

Denali also received a Rare Pediatric Disease Priority Review Voucher — a transferable regulatory prize that can be used to accelerate FDA review of another drug, or sold to another company. Vouchers for rare pediatric diseases have sold for nine figures in recent years. The company did not disclose plans for the voucher.

Denali's stock rose about 9 percent in premarket trading following the announcement, according to data from Seeking Alpha.

The backdrop is the FDA's rejection of Regenxbio's gene therapy RGX-121 in February. That decision, which the agency explained in a rare published complete response letter, cited inadequate external controls in the trial design and, critically, an insufficient surrogate endpoint. Regenxbio used cerebrospinal fluid levels of the D2S6 protein fragment; Denali used total cerebrospinal fluid heparan sulfate. The agency found the narrower marker insufficient evidence that clinical benefit would follow. William Blair analysts had estimated a 70 to 80 percent probability of Avlayah's approval, noting that Denali had "more selectively defined its study population" and used a broader biomarker surrogate than Regenxbio.

Scott Loiler, chief scientific officer of the National MPS Society, told BioSpace that the Regenxbio rejection had left advocates worried. The Regenxbio decision, he said, raised questions about whether rare disease drug development could attract sufficient investor interest when the regulatory bar was this high for a patient population this small.

For now, Avlayah clears a bar that matters enormously to roughly 500 families in the United States and 2,000 worldwide. Whether the biology it targets responds in a way that shows up in a child's development — in language regained, in steps recovered — will be answered over years of follow-up. The biomarker is a strong signal. The COMPASS trial is the proof.

Avlayah is administered once weekly by infusion. Denali said it expects the drug to be available in the United States shortly after approval.