FDA clears Denali's 'game-changer' Hunter syndrome drug

Denali Therapeutics' Avlayah is the first drug for neurological complications associated with the rare lysosomal storage disorder Hunter syndrome to be approved in the US.

Enzyme replacement therapy Avlayah (tividenofusp alfa) works in the same way as the only other drug in the class for Hunter syndrome – Takeda's Elaprase (idursulfase) – but is viewed as a step forward because it can cross the blood-brain barrier.

Hunter syndrome, also known as mucopolysaccharidosis type II (MPS II), is a rare, X-linked recessive genetic disease caused by a deficiency in the enzyme iduronate-2-sulfatase that causes toxic levels of glycosaminoglycans (GAGs) to build up in the body and can lead to developmental delays, in some cases resulting in severe cognitive and physical problems within the first two years of age. It affects around 500 people in the US, almost exclusively males.

The FDA has given an accelerated approval for Avlayah on the strength of a phase 1/2 trial in 47 patients, which showed that the drug was able to reduce levels of a GAG biomarker for MPS II, heparan sulphate, by 91% in the cerebrospinal fluid after 24 weeks. Denali's drug uses a transferrin-based drug delivery technology that allows it to penetrate the central nervous system and, like Elaprase, is administered by intravenous infusion once weekly.

The approved indication for Avlayah covers use in presymptomatic or symptomatic children, weighing at least 5 kg, who have not yet progressed to advanced neurological impairment.

Denali is running a confirmatory phase 2/3 trial, called COMPASS, to convert the accelerated clearance to a full approval and also to support regulatory filings in other countries.

Avlayah is the South San Francisco company's first approved product, and the company said it plans to launch the drug in the next couple of weeks, with a wholesale price of $5,200 per vial, which would translate to an annual cost of $270,000 to $811,000, depending on patient weight. It hopes to convert around three-quarters of the US population to its drug.

FDA Commissioner Marty Makary said that the approval is an example of the agency exercising regulatory flexibility, whilst still adhering to its obligation to approve drugs based on "substantial evidence" of effectiveness.

News of the new treatment option has been celebrated by the National MPS Society, whose chief medical officer, Terri Klein, said: "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."

There have been concerns that the FDA was tightening up its stance on rare disease therapies, including the use of surrogate endpoints, in light of recent decisions such as its rejection of Disc Medicine's bitopertin for erythropoietic protoporphyria (EPP). However, the publication of new guidance on rare diseases has gone some way to address those fears.

"When strong science and advocacy come together, meaningful change, continued progress and hope are possible for individuals living with MPS and other rare diseases who are waiting for treatments," said Klein.

The approval also gives Denali a valuable rare paediatric disease priority review voucher (PRV), which can be sold on to another company and typically change hands for $100 million to $200 million.