Tividenofusp alfa

Denali’s approach is to hijack a system used to transport iron into the brain, a tack also being taken by multiple competitors. The FDA has approved Denali Therapeutics’ enzyme replacement therapy for a genetic lysosomal storage disease after a string of high-profile rejections for rare disease candidates.In approving Denali’s tividenofusp alfa, now known as Avlayah, the FDA has greenlit the first treatment for Hunter syndrome that can address the condition’s pernicious cognitive symptoms. “Avlayah is the first product approved to address neurologic complications of Hunter syndrome,” Tracy Beth Høeg, M.D., Ph.D., acting director of the FDA’s Center for Drug Evaluation and Research (CDER), said in a March 25 release. “This accelerated approval was based on a surrogate endpoint: reduction of cerebrospinal fluid heparan sulfate, which the review team determined was reasonably likely to predict Avlayah’s clinical benefit.”Denali’s success follows the rejection of another Hunter syndrome candidate, a gene therapy from Regenxbio. When turning down Regenxbio’s RGX-121 in February, the FDA cited issues with the clinical trial’s ability to properly define the patient population, the use of a natural history control arm and the use of a single form of heparan sulfate as a surrogate endpoint. At the time, analysts predicted that Denali had a better chance than Regenxbio because tivi was reviewed by CDER rather than the Center for Biologics Evaluation and Research (CBER). CBER’s outgoing leader, Vinay Prasad, M.D., has sparked controversy for dismissing surrogate endpoints and demanding placebo-controlled trials, even in rare diseases with small patient populations.Additionally, Denali measured more forms of heparan sulfate than just the one assessed by Regenxbio, and included longer-term data in its submission to the FDA, Jefferies analysts noted in early March.But Regenxbio’s rejection did still raise concerns about whether the FDA would accept heparan sulfate as a surrogate biomarker, even as the expert community considered it acceptable for accelerated approval. Avlayah’s approval may help end that debate, analysts from Leerink Partners said in a March 25 note.“The fact that we are seeing this FDA accept [heparan sulfate] as a surrogate endpoint is highly encouraging,” the analysts wrote, noting that Avlayah’s label specifically cites levels of heparan sulfate in cerebrospinal fluid as the basis for accelerated approval.The FDA’s recent rejections of rare disease candidates, including candidates from Disc Medicine and Capricor Therapeutics, among others, have drawn widespread condemnation. Biotech CEOs, physicians and patient advocates alike have all criticized the agency’s actions, and Wisconsin Sen. Ron Johnson, a Republican, has pledged to investigate the FDA’s “bureaucratic idiocy.” Earlier this month, activists from the National MPS Society and other patient advocacy organizations staged a mock funeral outside the FDA to protest the regulator. Hunter syndrome is a type of mucopolysaccharidosis (MPS). Now, the organization is celebrating.“This approval affirms that 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,” Terri Klein, president and CEO of the National MPS Society, said in Denali’s March 25 release.Denali itself faced a delay from the FDA in securing tivi’s approval, with the decision deadline pushed back from Jan. 5 to April 5. Now, the company is set to commercialize its first-ever approved medicine, Denali CEO Ryan Watts, Ph.D., told Fierce last week. “We're ready to launch immediately,” he said.Avlayah should be available in the U.S. two weeks from today at a list price of $5,200 per 150 milligram single-use vial, a Denali spokesperson told Fierce on March 25. Like other enzyme replacement therapies, the exact costs for each patient will vary based on body weight.“Denali is providing a comprehensive suite of access and affordability programs, including co-pay assistance, to help ensure eligible patients can receive Avlayah,” the spokesperson added. “The Denali Copay Program is designed to help eligible commercially insured patients reduce their out-of-pocket costs for this medicine.”Hunter syndrome, or MPS II, is characterized by a deficiency of the enzyme iduronate-2-sulfatase (IDS). IDS is needed to break down large sugars, and without it, the sugars build up to toxic levels. Existing enzyme replacement therapies for Hunter syndrome are unable to penetrate into the brain, leaving them unable to prevent cognitive decline.“About 70% of patients have the severe neurological form” of the disease, with a lifespan of about 15 years, Watts told Fierce last week in advance of the approval announcement. “It's been 20 years since the Hunter syndrome community has seen any new options.”The key data that secured approval came from an open-label phase 1/2 trial that enrolled 47 patients. Avlayah normalized levels of heparan sulfate, the key biomarker, Watts said, and also reduced levels of a marker of neuronal injury.“In addition to that, patients either maintain or gain skills in terms of behavior, cognition and hearing,” Watts added. “We're confident in the data. We're confident in what we're seeing.”Hunter syndrome’s neurological symptoms “have been one of the most challenging and persistent medical needs for the community” for many years, Joseph Muenzer, M.D., Ph.D., a pediatrician and MPS expert at the University of North Carolina who led Avlayah’s pivotal trial, said in Denali's release. “Avlayah will substantially change how we treat patients and has the potential to become a new standard of care.”Avlayah’s approval also came with a rare pediatric disease priority review voucher, Denali said in the release, a program that has just recently been reauthorized by Congress.The approval serves as further proof that Denali’s signature technology, a shuttle meant to deliver medicines across the blood-brain barrier, is the real deal, Watts explained.“Getting large molecules across the blood-brain barrier has been a long-standing challenge in biotech, and something I've worked on now for multiple decades,” Watts said. “We believe we've solved it.”Denali has five clinical programs using its technology, including programs for Alzheimer’s disease, Parkinson’s disease and another MPS known as Sanfilippo syndrome type A. Denali’s approach is to hijack a system that transports iron into the brain, a tactic also being taken by multiple competitors. Korsana Biosciences emerged from stealth just last month with a similar plan to use transferrin receptors to slip Alzheimer’s drugs into the brain, while Roche and AbbVie are also invested in the area.But Watts thinks Denali’s transport vehicle stands out from the competition, as it can shuttle multiple different kinds of therapeutics across the blood-brain barrier. This includes enzymes, as with Avlayah, but also oligonucleotides and antibodies, he said.“The goal is to not just be first, but to be the best,” Watts said.Editor's note: This story was updated at 4:00 p.m. ET with additional information on Avlayah's pricing and availability.

The FDA granted accelerated approval to Denali Therapeutics’ rare disease drug Avlayah, bucking a recent trend of rejections in the space that has put the agency under political pressure. Avlayah, whose generic name is tividenofusp alfa, will be able to treat patients with Hunter syndrome, a rare genetic disorder that manifests in childhood, who weigh at least 5 kg “prior to advanced neurologic impairment,” according to a Denali press release . It comes with a boxed warning for hypersensitivity (including anaphylaxis) that’s consistent with Avlayah’s drug class, Denali said. The company also received a rare pediatric disease priority review voucher. On a conference call with investors Wednesday afternoon, Denali executives said the price for a single-use vial of Avlayah is $5,200. Most patients require two to three vials per week, though the dosage depends on a patient’s weight. The annual cost for a child weighing 10 kg is about $270,000, rising to about $811,000 for a patient who weighs 30 kg, chief commercial officer Katie Peng said on the call. Denali’s stock price $DNLI was up about 5% in midday Wednesday trading. The drug’s approval comes after the FDA, led by Commissioner Marty Makary, has raised the bar for rare disease drugs, walking back earlier promises of regulatory flexibility that spanned multiple presidential administrations. Though regulators have approved some rare disease treatments in President Donald Trump’s second term, many others — particularly cell and gene therapies — are seeing roadblocks placed where companies previously believed there would be none. “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,” Makary said in a press release Wednesday. “We will continue to do everything we can to accelerate treatments for rare diseases.” In an interview, Denali CEO Ryan Watts said the company’s conversations with the FDA and its drug review teams were “consistent” and “constructive.” That has differed from how other companies have described their recent experiences with the FDA. Watts declined to comment on other drugs or speculate on the FDA’s thinking. Notably, Avlayah won accelerated approval using a novel biomarker called heparan sulfate, a complex carbohydrate that builds up in toxic levels in a handful of deadly neurological diseases. For its studies, Denali proved that Avlayah’s ability to lower heparan sulfate levels in patients’ cerebrospinal fluid is “reasonably likely” to predict a clinical benefit. Avlayah’s fate ended up different from two other treatments where researchers were attempting to use heparan sulfate as a surrogate biomarker. Ultragenyx and Regenxbio , developing gene therapies for Sanfilippo syndrome type A and Hunter syndrome, respectively, each saw their treatments rejected within the last 12 months. As a group, the companies were attempting to seize on the FDA’s apparent rare disease shift to allow for more accelerated approvals. But it’s not yet clear why Avlayah proved a stronger case to use heparan sulfate. An FDA spokesperson didn’t immediately respond to a request for comment. The drug’s approval is contingent on a successful confirmatory study in which Denali is currently 95% enrolled, the FDA said in its release. Watts said the data are expected to read out in the first half of 2028. Avlayah’s label also mentions its use to treat the “neurologic manifestations” of Hunter syndrome, which executives say opens the door to treating pre-symptomatic patients. Analysts on Wednesday’s call seemed skeptical, asking executives if the confirmatory trial could remove that language from the label. Chief medical officer Peter Chin said such language reflects the nature of the accelerated approval. Watts also emphasized he’s not worried about the label. “We think the wording is great,” Watts said in the interview. “The vast majority of patients develop neurological manifestations, whether it’s hearing deficits, behavior or cognition. It’s just a timing of when that happens.” Avlayah is Denali’s first approved product and a validation of sorts for its pioneering work in neuroscience . Though Denali arrived with a splash — its $217 million Series A in 2015 was, at the time, the largest first-round raise in biotech history — development of Avlayah was not straightforward. In 2021, Denali disappointed Wall Street with its first snapshot of biomarker data in Hunter syndrome. The company also faced other setbacks in Alzheimer’s and Parkinson’s. But the company turned its fortunes with more positive data readouts in 2023 and 2024 , enabling it to seek accelerated approval. Executives are hopeful that it can use heparan sulfate as the basis for other drug applications in similar diseases, particularly its own Sanfilippo syndrome type A program. “On the question of Sanfilippo, I think what this precedent sets is that [heparan sulfate in the cerebrospinal fluid] is an approvable surrogate marker,” Chin said. Now, Denali will have to succeed on the commercial front. Peng said the company plans to launch Avlayah on April 9. Watts noted the company will not be guiding to specific sales figures until it completes the reimbursement process.