The FDA has approved Denali Therapeutics’ enzyme replacement therapy for inherited lysosomal storage diseases, breaking a series of recent rejections of rare disease drugs by the agency.
By approving Denali’s tibidenosp. alfa, now known as Avraya, the FDA has given the green light to the first treatment that can address the harmful cognitive symptoms of Hunter syndrome.
“Abraya is the first product approved to address the neurological complications of Hunter syndrome,” Tracy Beth Hogue, MD, 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 of reduction in cerebrospinal fluid heparan sulfate, which the review team determined was reasonably likely to predict Avraya’s clinical efficacy.”
Denali’s success follows the rejection of another Hunter syndrome candidate, Regenxbio’s gene therapy drug. In rejecting Regenxbio’s RGX-121 in February, the FDA cited issues with the clinical trial’s ability to adequately define the patient population, the use of a natural history control group, and the use of a form of heparan sulfate as a surrogate endpoint.
At the time, analysts predicted 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, Dr. Vinay Prasad, has been controversial for rejecting surrogate endpoints and calling for placebo-controlled trials, even for rare diseases with small numbers of patients.
Additionally, Denali measures more forms of heparan sulfate than just the one evaluated by Regenxbio and included long-term data in its submission to the FDA, Jefferies analysts noted in early March.
However, Regenxbio’s rejection still raised concerns about whether the FDA would accept heparan sulfate as an alternative biomarker, even though the expert community considered it acceptable for accelerated approval. Analysts at Leerink Partners said in a March 25 note that Avraya’s confirmation could end that discussion.
“The fact that we see this FDA acceptance of[heparan sulfate]as an alternative endpoint is very encouraging,” the analysts wrote, noting that Avraya’s label specifically cites heparan sulfate levels in cerebrospinal fluid as the basis for accelerated approval.
The FDA’s recent rejection of rare disease drugs, including candidates from Disc Medicine and Capricor Therapeutics, has drawn widespread criticism. Biotech CEOs, doctors, and patient advocates alike have criticized the FDA’s actions, and Republican Wisconsin Sen. Ron Johnson has vowed to investigate the agency’s “bureaucratic stupidity.”
Earlier this month, activists from the National MPS Association and other patient advocacy groups held a mock funeral outside the FDA to protest regulators. Hunter syndrome is a type of mucopolysaccharidosis (MPS). Now the organization is celebrating.
“This approval confirms that when strong science and advocacy are combined, meaningful change, continued progress, and hope are possible for people living with MPS and other rare diseases awaiting treatment,” Terry Klein, president and CEO of the National MPS Association, said in Denali’s March 25 release.
Denali itself has faced delays from the FDA in getting approval for Tibi, with the decision deadline pushed back from January 5th to April 5th. The company is now on track to commercialize its first-ever approved drug, Denali CEO Dr. Ryan Watts told Fierce last week. “We’re ready to go right away,” he said.
Hunter syndrome (MPS II) is defined by the absence of an enzyme called iduronate-2-sulfatase (IDS). IDS is necessary to break down large sugars, but without them sugars accumulate to toxic levels. Existing enzyme replacement therapies for Hunter syndrome cannot penetrate the brain and therefore cannot prevent cognitive decline.
“About 70% of patients have severe neurological symptoms” and have a life expectancy of about 15 years, Watts told Fierce last week ahead of the approval announcement. “It’s been 20 years since the Hunter Syndrome community saw a new option.”
The key data to secure approval came from an open-label Phase 1/2 study that enrolled 47 patients. Abraya normalized levels of heparan sulfate, an important biomarker, and also lowered levels of markers of nerve damage, Watts said.
“In addition, patients maintain or gain behavioral, cognitive, and auditory skills,” Watts added. “We’re confident in the data. We’re confident in what we’re seeing.”
The neurological symptoms of Hunter syndrome have long been “one of the most challenging and persistent medical needs for our community,” Joseph Munser, M.D., a pediatrician and MPS expert at the University of North Carolina who led Avraya’s pivotal clinical trial, said in a statement from Denali. “Avlayah has the potential to revolutionize the way patients are treated and become a new standard of care.”
Denali said in a release that Avraya’s approval also comes with priority review vouchers for rare pediatric diseases, a program that was just recently reauthorized by Congress.
Watts explained that the approval is further proof that Denali’s signature technology, the shuttle intended to deliver medicines across the blood-brain barrier, is real.
“Getting large molecules to cross the blood-brain barrier is a long-standing challenge in biotechnology, and one I’ve been working on for decades,” Watts said. “We believe we have solved it.”
Denali has five clinical programs using its technology, including programs for Alzheimer’s disease, Parkinson’s disease, and another form of MPS known as Sanfilippo syndrome type A.
Denali’s approach is to hijack the system used to transport iron to the brain, a technique also used by several competitors. Just last month, Corsana Biosciences emerged from stealth with a similar plan to use transferrin receptors to deliver Alzheimer’s drugs to the brain, and Roche and AbbVie are also investing in the field.
But Watts believes Denali’s vehicles stand out from competitors because they can cross the blood-brain barrier and shuttle multiple different types of therapeutics. This includes enzymes, like Avlayah, but also oligonucleotides and antibodies, he said.
“The goal is not just to be first, but to be the best,” Watts said.
