Ultragenyx Pharmaceutical (RARE) stock dropped 45% in aftermarket trading on Wednesday after its experimental drug apazunersen failed to hit its targets in a Phase 3 clinical trial for Angelman syndrome.
Ultragenyx Pharmaceutical Inc., RARE
The trial, called Aspire, tested whether apazunersen could improve cognitive and developmental outcomes in young children with the condition. It missed both the primary endpoint, a change in Bayley-4 cognitive raw score, and the key secondary endpoint, the net response in the Multidomain Responder Index (MDRI).
Ultragenyx said there were no meaningful differences between patients who received the drug and those in the control group. The safety profile was consistent with earlier studies, but that offered little comfort.
CEO Emil Kakkis called the result disappointing, particularly for patients and families who had invested hope in the drug. “We are disappointed for the global patient community who has invested so much in early-stage research,” he said.
Angelman syndrome affects roughly 1 in 15,000 live births and is caused by a loss of function in the UBE3A gene. It causes cognitive impairment, seizures, and severe developmental delays. There are currently no approved disease-modifying treatments.
The failed Aspire result also raises questions about Aurora, a related study testing apazunersen in Angelman syndrome patients with different genetic subtypes.
William Blair analyst Sami Corwin noted that even if Aurora hits its primary endpoint, commercialization would be difficult. The addressable patient population is simply too small to support a viable commercial product, she said.
Apazunersen had held several FDA designations, including Breakthrough Therapy and Orphan Drug status. Those designations reflected early optimism from Phase 1 and 2 data, making the Phase 3 failure all the more unexpected.
Ultragenyx said it will now evaluate the apazunersen program and decide what to do with it. The company also plans to implement expense cuts as it reassesses operations.
Despite the setback, Ultragenyx pointed to its growing commercial pipeline as a source of stability.
Last month, the company received FDA approval for Genglycos, a gene therapy for glycogen storage disease type Ia, also known as Von Gierke disease. It was the first gene therapy approved for that condition.
The company is also awaiting a potential approval for UX111 in Sanfilippo syndrome and is expanding existing products to new markets. Kakkis said the company remains on track toward profitability in 2027.
The Aspire trial enrolled patients comparable in baseline characteristics to those in Phase 2, making the divergent outcomes harder to explain and adding to investor unease.
Ultragenyx said it will continue supporting its commercial business while the pipeline is reassessed in light of the apazunersen outcome
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