FDA Approves Denali's Avlayah for Neurologic Hunter Syndrome Under Accelerated Pathway

The FDA has granted accelerated approval to Denali Therapeutics' Avlayah (tividenofusp alfa-eknm), an enzyme replacement therapy for the neurologic manifestations of Hunter syndrome, the company announced on March 25. Denali said it is the first FDA-approved biologic specifically designed to cross the blood-brain barrier.

The approval covers presymptomatic or symptomatic children weighing at least 5 kg who start treatment before advanced neurologic impairment. Continued approval may be contingent on confirming clinical benefit in a confirmatory trial. The drug is given by intravenous infusion once a week.

Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is a rare genetic disorder caused by a lack of the enzyme iduronate 2-sulfatase (IDS). Without it, complex sugars called glycosaminoglycans build up in cells throughout the body, including the brain. Denali said the disease, which mainly affects boys, affects about 500 people in the US and 2,000 worldwide. Avlayah fuses the IDS enzyme to Denali's TransportVehicle platform, which binds the transferrin receptor to carry the enzyme across the blood-brain barrier.

The evidence behind the approval

The accelerated approval is based on a surrogate endpoint: the level of heparan sulfate in cerebrospinal fluid, which the FDA accepted as reasonably likely to predict clinical benefit. The data come from an international, open-label Phase 1/2 trial in 47 patients aged 0.3 to 13 years, 15 of whom had not received enzyme replacement therapy before and 32 of whom had. The trial's primary objective was safety and tolerability.

Avlayah reduced cerebrospinal fluid heparan sulfate by 91% (95% CI, 89% to 92%) from baseline by Week 24, and 93% of patients (41 of 44) had levels within the range seen in people without Hunter syndrome, Denali reported. The most common adverse reaction was infusion-related reactions. The Phase 1/2 results were published in The New England Journal of Medicine on January 1.

The prescribing information includes a boxed warning about the risk of severe allergic reactions, GxP News reported. The outlet said Denali set the price at $5,200 per 150 mg vial, a list price, and that Denali's shares rose 8.4% after the announcement.

Confirmatory trial and voucher

The ongoing Phase 2/3 COMPASS study, which randomizes patients 2:1 to Avlayah or idursulfase, the existing enzyme replacement therapy, is intended to provide the confirmatory evidence. Cohort A has completed enrollment and Cohort B is enrolling, according to Denali. The study includes young adults.

"The neurologic manifestations of Hunter syndrome, which affect nearly all patients, have been one of the most challenging and persistent medical needs for the community," said Joseph Muenzer of the University of North Carolina at Chapel Hill, lead investigator of the Phase 1/2 trial, in Denali's release.

In connection with the approval, the FDA granted Denali a rare pediatric disease priority review voucher, which can be used for priority review of a future application or sold to another company. Denali said Avlayah would be available in the US shortly after approval.