Hunter syndrome patients can manage the disorder with a drug that addresses disease symptoms throughout the body except the brain — a key limitation for treating this rare neurological disorder. The blood-brain barrier serves an important protective role, but it also keeps many drugs out.
The FDA has approved a Denali Therapeutics biologic drug that crosses the blood-brain barrier to treat Hunter syndrome. The regulatory decision gives Denali its first commercial product. It also blazes a new regulatory path for Denali and others to follow for brain-penetrating drugs in development for a range of neurological conditions.
The FDA approval announced Wednesday covers the treatment of neurologic manifestations of Hunter syndrome in pediatric patients weighing at least 5 kg (about 11 pounds) before their disease advances to neurologic impairment. The intravenously infused drug, known in development as tividenofusp alfa, will be marketed under the brand name Avlayah. South San Francisco-based Denali expects to launch the product in two weeks.
Hunter syndrome is a rare enzyme deficiency, also called a lysosomal storage disorder. In this inherited disease, patients lack iduronate-2-sulfatase (IDS), an enzyme key to the function of lysosomes, a component of cells that breaks down material. Consequently, glycosaminoglycans (GAGs), a type of sugar, builds up in tissues. The disease manifests as organ dysfunction, joint stiffness, hearing loss, neurocognitive symptoms and impaired development. In severe cases, the disorder can become fatal in a patient’s teens.
Like other inherited enzyme deficiencies, enzyme replacement therapy is a standard treatment for Hunter syndrome. Takeda Pharmaceutical’s Elaprase, an engineered version of IDS approved by the FDA in 2006, is currently the standard of care. But this therapy does not penetrate the brain, leaving the cognitive complications of the disease unaddressed.
Avlayah is comprised of an engineered version of IDS that’s fused to what Denali calls a TransportVehicle, or TV, which leverages the binding capability of an antibody without using a full-length antibody. A TV employs only the domain of an antibody that binds to a target. In Avlayah, the domain is engineered to bind to the transferrin receptor. This receptor is highly expressed on the cells of the blood-brain barrier, where they transport iron across the membrane. By binding to these receptors, Denali’s drug can hitch a ride to deliver IDS into the central nervous system. Speaking during a conference call Wednesday, CEO Ryan Watts said this approach addresses both systemic and neurologic aspects of Hunter syndrome.
Denali is not alone in using the transferrin receptor for brain drug delivery. Companies developing Alzheimer’s disease drugs that work this way include AbbVie and Korsana Therapeutics. Alzheimer’s is also represented in Denali’s pipeline. With Avlayah, Denali can now claim to have the first FDA-approved transferrin receptor-enabled medicine engineered to cross the blood-brain barrier.
Denali’s FDA submission was based on the results of an open-label Phase 1/2 study that enrolled 47 pediatric Hunter syndrome patients. Results showed a 91% reduction in cerebrospinal fluid levels of heparan sulfate, a component of GAGs, at 24 weeks. At this time point, 93% of participants (41 of 44 patients) had heparan sulfate levels within the range of people who don’t have Hunter syndrome. Results were presented last year during the WORLDSymposium conference and published early this year in the New England Journal of Medicine.
Reducing heparan sulfate levels is a surrogate endpoint, a biological measure that’s likely to predict clinical benefit. The FDA decision based on this surrogate goal is an accelerated approval. An ongoing Phase 2/3 study for Avlayah could provide the confirmatory data to support full FDA approval. In addition to pediatric patients, this study is enrolling young adults up to age 25. The trial is comparing Avlayah to Elaprase.
Avlayah, which is dosed according to patient weight, is administered as a weekly infusion that takes about four hours. The most common adverse effect reported in clinical testing was infusion-related reactions. The drug’s label carries a black box warning for hypersensitivity reactions, including anaphylaxis.
Denali set a wholesale price of $5,200 per 150 mg vial of the drug, which translates to $270,000 a year for maintenance dosing for a 10 kg patient (about 22 pounds) and $811,000 for a 30 kg (about 60 pounds) patient. Chief Commercial Officer Katie Peng said most pediatric patients will require two to three vials per week, depending on weight. Hunter syndrome is already part of newborn screening, which will enable Denali to reach patients earlier in their disease. While the label specifies treatment of patients who have neurologic manifestations, Denali’s review of medical literature and claims data found that about 90% of Hunter’s syndrome patients have neurologic manifestations. That means Denali will be able to reach most Hunter syndrome patients. Worldwide, the company estimates about 2,000 Hunter’s syndrome patients are in commercially addressable markets.
Watts noted that Denali is entering a well-established enzyme replacement therapy market that has precedent for adoption and reimbursement. The company can build on this existing infrastructure as it continues development of other TV-delivered therapies for other enzyme deficiencies such as Sanfilippo, Pompe disease, and Gaucher disease.
“So when we talk about Avlayah, we see it not just as a product, but as the foundation of a durable, multi-program franchise in lysosomal storage disorders,” Watts said.
In a research note, William Blair analyst Myles Minter said the Avlayah approval validates Denali’s TV platform and de-risks other programs that use the technology. He added that the Sanfilippo program, DNL126, will benefit from a streamlined regulatory approach.
The FDA approval of Avlayah came with a rare pediatric disease priority review voucher. While those awarded such vouchers may use them to speed up the regulatory review of another rare disease drug, many companies opt to sell them to big pharma companies. Chief Operating and Financial Officer Alex Schuth said Denali plans to sell its voucher.
Photo: Jolygon, Getty Images
