Ultragenyx's Apazunersen Fails Phase 3 Aspire Trial in Angelman Syndrome

Ultragenyx (RARE) said Wednesday afternoon that its Angelman syndrome therapy apazunersen failed the Phase 3 Aspire study, missing the trial’s primary endpoint and a key secondary endpoint. Shares closed at $26.53 on Wednesday, then fell about 46% in after-hours trading to roughly $14.

Apazunersen, formerly known as GTX-102, is an antisense oligonucleotide delivered intrathecally that is designed to reactivate the silenced paternal UBE3A allele. In Aspire it showed no significant benefit on the primary endpoint of change from baseline in the Bayley-4 cognitive raw score. It also missed the key secondary endpoint of net response in the Multidomain Responder Index (MDRI), which tracks improvement across five clinical domains. Ultragenyx said there were no differences between the treated and sham-control groups that could support efficacy, on either net response or the individual endpoints inside the MDRI. Safety in Aspire was consistent with the Phase 1/2 program.

The study enrolled nearly 130 patients with Angelman syndrome, a rare neurogenetic disorder that causes cognitive impairment, motor difficulties, and seizures. There are no approved therapies for the condition. The readout was the company’s central value driver, according to William Blair, which told investors the failure leaves Ultragenyx with no meaningful value inflection point over the next 12 months.

“We are disappointed by the Aspire result,” CEO Emil Kakkis said in a statement. “Even more, we are disappointed for the global patient community who has invested so much in early-stage research, working to bring a first-ever treatment to their children.”

Ultragenyx said it will evaluate the apazunersen program and “assess its planned operations to define and implement significant expense reductions” while it focuses on its commercial business. That business includes the August approval of Genglycos for glycogen storage disease type Ia and a September 19 PDUFA date for UX111 in Sanfilippo syndrome type A. A second apazunersen study, the Phase 2 Aurora basket trial, keeps enrolling with topline data expected in 2030, though William Blair said the Aspire failure could have negative implications for that program. The Angelman field still has other runners, including Oak Hill Bio’s rugonersen.

The stakes going in were high: apazunersen carried FDA Breakthrough Therapy, Orphan Drug, Rare Pediatric Disease, and Fast Track designations. The failure removes Ultragenyx’s nearest large revenue opportunity in a disease affecting roughly 60,000 people in commercially accessible geographies.

What to watch next: the September 19 UX111 decision, which analysts now frame as an incremental catalyst at best, and any details on the expense-reduction plan.

Source: Ultragenyx Phase 3 Aspire announcement; BioSpace coverage