Dive Brief:
- Denali Therapeutics on Wednesday won Food and Drug Administration approval for the first biologic designed to cross into the brain to treat neurological symptoms of Hunter syndrome.
- Hunter syndrome is a rare genetic condition in which certain sugar molecules build up and damage to the skeleton as well as multiple organs including the heart and brain. The potentially life-threatening disease almost always strikes boys, and symptoms usually begin between the ages of two and four. The FDA estimates it affects about 500 Americans.
- People suffering from Hunter syndrome don’t have enough of an enzyme that helps break down the harmful sugar molecules. Denali’s Avlayah is a weekly infusion designed to deliver the enzyme to tissues and the central nervous system and reduce levels of those molecules.
Dive Insight:
Analysts hailed the approval as a positive sign at an agency that has given wildly different signals to rare disease drugmakers under the second Trump administration.
FDA Commissioner Martin Makary has repeatedly touted initiatives designed to give the agency more flexibility in speeding potentially transformative medicines to market. But under his leadership, the FDA has blindsided investors with surprise rejections, regulatory reversals and an unusual public spat over the fate of a UniQure gene therapy for Huntington’s disease.
The trend has drawn criticism from newspaper opinion pages and lawmakers, much of it aimed at Vinay Prasad, the controversial head of the office that regulates vaccines and gene therapies. Prasad is now stepping down, but the pressure on Makary remains. Makary installed a team that “treated the patient-focused flexibility built into rare-disease regulation as a flaw rather a necessity,” the Wall Street Journal wrote earlier this month.
In the case of Avlayah, the FDA opted for an accelerated approval based on a Phase 1/2 study that showed the medicine could reduce levels of a molecule known as heparan sulfate in cerebrospinal fluid. To stay on the market, the agency can demand research showing that reduction translates into a real clinical benefit for patients. Denali already has a confirmatory trial under way to do that.
Makary called the approval a milestone and appeared to be addressing critics in the FDA’s statement. “The FDA is capable of doing two things: one, exercising regulatory flexibility; and two, complying with our obligation under the law to approve drugs based on ‘substantial evidence’ of effectiveness,” he said. “We will continue to do everything we can to accelerate treatments for rare diseases.”
The FDA cleared Avlayah for pediatric patients who weigh at least 5 kilograms, or 11 pounds, and don’t yet have advanced neurological impairment. Pricing will be based on a patient’s weight, going up to about $811,000 a year for someone who weighs 30 kilograms, a “meaningful premium” over Takeda’s enzyme replacement therapy Elaprase, which sells for about $500,000, Stifel analyst Paul Matteis wrote in a note to clients.
The FDA had originally planned to give Denali an answer on its application in January but delayed the decision date to review more data submitted by the company. Meanwhile, the agency recently rejected a gene therapy for Hunter syndrome from Regenxbio, raising some concern about whether Denali would ultimately succeed with its plan to seek approval based on the heparan sulfate biomarker.
After all the setbacks for drugmakers who thought they were in step with the FDA, this is a “clear step in the right direction for rare disease sponsors,” Matteis wrote. “This at least draws a line in the sand and shows that this FDA is still willing to be somewhat flexible.”
The approval is the first for Denali, a well-funded company focused on neuroscience that has seen setbacks in other research, including for ALS. As part of the approval, Denali received a priority review voucher that it can sell to another drugmaker; they regularly fetch $150 million or more.
