Ultragenyx to seek accelerated approval for rare disease gene therapy

The biotech said Wednesday it will seek accelerated approval for its Sanfilippo syndrome type A gene therapy after the FDA appeared receptive to using a carbohydrate called heparan sulfate as a marker that’s reasonably likely to predict clinical benefit. Should the AAV9 gene therapy called UX111 be approved, it would be the first treatment approved using the biomarker.

“This is a pivotal moment in drug development for both rare disease and beyond, and specifically in neurology,” Heather Lau, Ultragenyx’s executive director of global clinical development, told Endpoints News. “It takes time to see the full effects on cognition, language and other aspects of brain function, so it’s critical to identify an early marker that you have therapeutic or target engagement.”

Ultragenyx plans to submit the application in late 2024 or early 2025, according to a press release. The company also announced plans Wednesday afternoon to raise $350 million in a public offering.

Accelerated approvals have proliferated in recent years as immuno-oncology drugmakers like Merck have aimed to break Keytruda into as many cancer indications as possible. Trials are typically designed using tumor shrinkage as a surrogate biomarker, with clinicians and the FDA reasoning that smaller tumors lead to improved survival outcomes.

Historically, the regulatory pathway has also been used for cholesterol drugs like statins. In those cases, lower amounts of LDL cholesterol were deemed reasonably likely to predict a benefit for patients.

Using accelerated approval in rare diseases has not taken off as quickly. Unlike tumors or LDL cholesterol, there isn’t a biomarker that could apply to every single rare disease, and smaller patient populations make running confirmatory studies more challenging.

Sarepta Therapeutics, in particular, has faced criticism for drawing out the time between receiving accelerated approval for its Duchenne muscular dystrophy drugs and launching the confirmatory studies designed to measure whether the benefit seen in the open-label trials can be replicated. The gene therapy Elevidys that received accelerated approval has also faced pushback for conversion to full approval after it failed a confirmatory trial.

But the FDA’s recent decisions signal a willingness to engage with other biomarkers more seriously. Last year, regulators approved a Biogen drug called Qalsody for a genetic form of ALS, marking the first accelerated approval for a biomarker called neurofilament that is implicated in a wide range of neurodegenerative diseases.

Ultragenyx’s Lau said she views heparan sulfate as different from other biomarkers because of its strong relationship to patients’ underlying disease.

“Part of the burden on us and the community was to educate the FDA that, indeed, heparan sulfate is intimately related to the biochemical defect,” Lau said. “We have a single enzyme defect leading to a deficiency of an enzyme and accumulation of that specific metabolite.”

She cautioned that, like with any accelerated approval, the clinical benefit of Ultragenyx’s therapy as defined by the FDA may not be guaranteed. Confirmation of the benefit might also take several years, given that researchers are looking at infants and young children.

“That’s the nature of accelerated approval,” Lau said. She declined to comment on timing for a potential UX111 confirmatory study.

An accelerated approval of UX111 will likely have implications for other companies developing drugs in neurodegenerative diseases. Denali Therapeutics and Regenxbio are working on therapies for Hunter syndrome and have floated heparan sulfate as a potential surrogate biomarker.

Regenxbio said in February it will seek accelerated approval based on biomarker data. Denali hasn’t publicly commented on a timeline for when it will file with the FDA, but told investors in its quarterly update that the FDA is open to discussing accelerated approval.

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