FDA Grants Accelerated Approval to Denali’s Hunter Syndrome ERT

Rare Daily Staff

The U.S. Food and Drug Administration granted accelerated approval to Denali Therapeutics’ Avlayah, a first-of-its-kind enzyme replacement therapy designed to reach the brain and body in children living with Hunter syndrome, a rare lysosomal storage disorder that can cause severe neurologic decline. Avlayah is the first new FDA-approved treatment option for Hunter syndrome in nearly two decades.

The FDA approved Avlayah to treat neurologic manifestations of Hunter syndrome, also known as mucopolysaccharidosis type II, in presymptomatic or symptomatic pediatric patients who weigh at least 5 kilograms and have not yet developed advanced neurologic impairment. The decision is based on biomarker data, and continued approval will depend on confirmatory results from an ongoing late-stage trial.

Hunter syndrome is caused by mutations in a single gene that lead to a deficiency of an enzyme called iduronate 2-sulfatase, or IDS, which normally helps break down complex sugars known as glycosaminoglycans, or GAGs. Without enough IDS, GAGs build up inside cells throughout the body, including the brain, leading to progressive damage in multiple organs and tissues starting in early childhood. Children with Hunter syndrome can experience developmental delays, cognitive and behavioral changes, hearing loss, joint stiffness, and organ problems, and some may eventually lose the ability to speak and walk.

Avlayah is an intravenous enzyme replacement therapy that combines the missing IDS enzyme with Denali’s proprietary TransportVehicle platform, which is engineered to bind to the transferrin receptor on blood vessels and carry the therapy across the blood-brain barrier. Once inside the body’s cells, the fused protein is taken up into lysosomes, where the IDS enzyme is expected to break down the accumulated GAGs.

In a phase  1/2 clinical trial of 47 children with Hunter syndrome, Avlayah reduced levels of a key disease-related sugar, heparan sulfate, in the cerebrospinal fluid by 91 percent from baseline at 24 weeks, and most participants reached levels seen in people without the disease. The most common side effects were infusion-related reactions, which tended to decrease with continued use, and longer-term studies are underway to show whether the biomarker changes translate into meaningful benefits in thinking, behavior, and everyday function.

Avlayah’s approval comes through the FDA’s accelerated approval pathway, which allows earlier access to medicines for serious conditions based on a surrogate marker that is reasonably likely to predict clinical benefit. Denali’s confirmatory phase  2/3 COMPASS trial, enrolling children and young adults with Hunter syndrome in North America, South America, and Europe, will compare Avlayah with the older enzyme replacement therapy idursulfase to confirm how well the new drug works over time.

In connection with the approval, the FDA granted Denali a Rare Pediatric Disease Priority Review Voucher, which can be used or sold to speed up the review of another experimental therapy. Avlayah also received breakthrough therapy, fast track, and orphan drug designations from the agency, and has Priority Medicines status from the European Medicines Agency, where it is still under review.

“This accelerated approval for MPS II based on a biomarker as a surrogate endpoint is an extraordinary day for the MPS and rare disease community,” said Terri Klein, president and CEO of the National MPS Society, noting that the move underscores how “time matters profoundly” for affected families.