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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 dont have enough of an enzyme that helps break down the harmful sugar molecules. Denalis 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 Huntingtons 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 FDAs 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 dont yet have advanced neurological impairment. Pricing will be based on a patients weight, going up to about $811,000 a year for someone who weighs 30 kilograms, a meaningful premium over Takedas 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. '

iStock, Shutter2U Avlayah is the first Hunter syndrome therapy approved to address the condition’s neurologic complications, according to Tracy Beth Høeg, acting director of the Center for Drug Evaluation and Research. The FDA has granted accelerated approval to Denali Therapeutics’ enzyme replacement therapy for Hunter syndrome, handing a much-needed win to the rare disease market. The drug will carry the brand name Avlayah. Wednesday’s approval for Avlayah delivers several firsts for the industry. The therapy is the first new medicine for Hunter syndrome in nearly 20 years, Denali said in its press announcement on Wednesday , adding that Avlayah is the first FDA-approved biotherapeutic that uses the transferrin receptor to cross the blood-brain barrier. Avlayah is also “the first product approved to address neurologic complications of Hunter Syndrome,” according to Tracy Beth Høeg, acting director of the Center for Drug Evaluation and Research. Full approval of Avlayah will hinge on the findings of a confirmatory trial designed to verify its clinical benefits. Denali closed Wednesday’s trading session at $22.47 apiece, up 13% from its previous closing price. The approval is also a “welcome positive” for the broader rare disease space, Stifel analysts said in a Wednesday note. Indeed, the past few months have brought a string of bad news for rare disease drugmakers, driven by inconsistencies and perceived inflexibilities at the highest levels of the FDA. One recent example is that of uniQure, which in November 2025 announced that the regulator changed its tune regarding the development of the company’s Huntington’s disease gene therapy. The agency at that time told uniQure it “no longer agrees” that data from the company’s Phase 1/2 program would be enough for a filing, despite allegedly previously signing off on the study design. The about-face triggered months of back -and- forth , playing out in the public sphere. FDA Rare Disease Leaders Call for Regulatory Consistency After Chaotic Year As the FDA unveils a parade of initiatives aimed at accelerating drug development for rare diseases, experts appeal for a consistent approval process that will support and further catalyze momentum. December 8, 2025 · 8 min read · Heather McKenzie Read more Around 500 patients in the U.S. have Hunter syndrome, a rare, genetic disease that predominantly affects boys and manifests as cognitive delays, behavioral issues and hearing loss. The disease is caused by mutations to the IDS gene resulting in a faulty enzyme that, in turn, leads to accumulation of toxic byproducts across multiple organs and tissues, including the brain. Avlayah works by supplying patients with enough IDS enzyme. Importantly, the drug makes use of Denali’s proprietary TransportVehicle platform, which relies on the transferrin receptor to cross the blood-brain barrier into the central nervous system. This sets it apart from Takeda’s Elaprase , another enzyme replacement therapy for Hunter syndrome, initially approved in 2006. Phase 1/2 data for Avlayah, which served as the basis for Wednesday’s approval, showed that the drug led to a 91% reduction in levels of heparan sulfate in the cerebrospinal fluid, a key disease marker that is “reasonably likely to predict clinical benefit,” according to Denali’s news release. At 24 weeks, 93% of patients treated with Avlayah had heparan sulfate levels comparable to people without Hunter syndrome. For many analysts, Avlayah’s approval derisks Denali’s technology. The FDA’s greenlight “provides a key validation for the company’s differentiated TransportVehicle chemistry for CNS delivery,” which could have promising readthrough to the rest of its pipeline, analysts at William Blair told investors on Wednesday. The firm forecasts peak U.S. Avlayah sales of over $250 million in the late 2030s, with worldwide revenue approaching $1 billion. Stifel agreed with this assessment, calling the nod a “key milestone” for Denali. On Feb. 10, the FDA rejected REGENXBIO’s gene therapy for Hunter syndrome—a decision that put Denali in a good spot —citing concerns over the company’s use of natural history controls to gauge the efficacy of its products, a design feature that REGENXBIO said the FDA had previously agreed to. The FDA also pointed to problems with REGENXBIO’s eligibility criteria for patient enrollment and the validity of the biomarker it used. REGENXBIO, which had thought it had addressed the FDA’s concerns prior to receiving the complete response letter last month, has stated its plans to request a Type A meeting with the FDA to discuss the rejection and a possible resubmission. Rare diseases Denali’s Hunter Syndrome Candidate in the Spotlight After REGENXBIO Rejection The Hunter syndrome space suffered a setback in February when the FDA turned down REGENXBIO’s investigational gene therapy, raising urgent questions about whether competitor Denali Therapeutics can clear the agency’s bar next month. March 16, 2026 · 6 min read · Ben Hargreaves Read more