Idursulfase

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. '

The US FDA has granted accelerated approval to Avlayah (tividenofusp alfa-eknm), an enzyme replacement therapy developed by Denali Therapeutics for the treatment of neurologic manifestations of Hunter syndrome (mucopolysaccharidosis type II, or MPS II). The decision marks the first FDA-approved biologic designed to cross the blood-brain barrier and the first new treatment option for MPS II in nearly 20 years. It is also Denali’s first approved product, validating the company’s proprietary TransportVehicle platform, which engineers therapeutic proteins to traverse the blood-brain barrier via transferrin receptor-mediated transcytosis. The FDA also awarded Denali a Rare Pediatric Disease Priority Review Voucher in connection with the approval. Indication specifics Avlayah is indicated for the treatment of neurologic symptoms in pediatric patients weighing at least 5 kg with Hunter syndrome, provided treatment is initiated prior to advanced neurologic impairment. The drug carries Breakthrough Therapy, Fast Track, and Orphan Drug designations. Because the approval was granted under the accelerated pathway, it was based on a surrogate endpoint — reduction of cerebrospinal fluid heparan sulfate (CSF HS) — considered reasonably likely to predict clinical benefit. Continued approval may depend on verification of clinical benefit in a confirmatory trial. AVLAYAH is not recommended for use in combination with other enzyme replacement therapies. The label includes a boxed warning for hypersensitivity reactions, including anaphylaxis. The approval rests on data from a Phase I/II international, multi-center, open-label trial enrolling 47 pediatric patients aged 0.3 to 13 years, including both enzyme replacement therapy-naïve and previously treated individuals. By week 24, Avlayah demonstrated a 91% reduction in CSF HS from baseline (95% CI: 89%, 92%), and 93% of treated patients (41 of 44) achieved CSF HS levels within the range observed in individuals without Hunter syndrome. The most common adverse reaction was infusion-related reactions. Results were published in The New England Journal of Medicine in January 2026. Denali is conducting the ongoing Phase II/III COMPASS study, a randomized trial comparing Avlayah to idursulfase, to generate confirmatory evidence and support global regulatory submissions. Disease context Hunter syndrome affects approximately 500 individuals in the United States and 2,000 worldwide. It is caused by deficiency of the iduronate 2-sulfatase enzyme, leading to accumulation of glycosaminoglycans in tissues including the brain. The neurologic manifestations — cognitive decline, behavioral changes, loss of speech and mobility — affect nearly all patients and have represented the central unmet need in MPS II for decades. Since 2006, the only FDA-approved therapy has been idursulfase (Elaprase), marketed by Takeda, which addresses somatic symptoms but does not cross the blood-brain barrier. Avlayah, composed of the IDS enzyme fused to Denali’s TransportVehicle platform, is engineered to bind the transferrin receptor on brain endothelial cells, enabling delivery to both peripheral tissues and the central nervous system. It joins a small but growing field of blood-brain barrier-crossing biologics; pabinafusp alfa (Izcargo), developed by JCR Pharmaceuticals using a different transferrin receptor-targeting approach, was approved in Japan in 2021 but has not received FDA or EMA approval. Gene therapy candidates, including RGX-121 from REGENXBIO, remain in clinical development. For Denali, the approval provides a commercial foundation and a proof of concept for the TransportVehicle platform, which the company said has five additional programs in clinical development across neurodegenerative diseases and lysosomal storage disorders. Leave a Reply Cancel reply Your email address will not be published. Required fields are marked * Comment * Name * Email * Website