The rare neurological disorder Angelman syndrome leads to a range of developmental and movement problems in children, who have no FDA-approved therapeutic options. A closely watched Ultragenyx Pharmaceutical drug just lost its best chance to become the first one.
Ultragenyx’s apazunersen did not meet any of the goals of its Phase 3 test, the company announced after Wednesday’s market close. While specific details about those results remain undisclosed for now, Ultragenyx did say there were no differences in treated patients and the control group that could support efficacy of the experimental therapy. The trial failure raises questions about the approach taken by apazunersen and raises the stakes for other companies in clinical development with Angelman drugs designed to work in a similar way.
The root of Angelman is UBE3A, a gene that provides instructions for making an enzyme key to proper nervous system development and function. While a child inherits two copies of each gene, one from each parent, for some genes only one is a working copy. For UBE3A, the working copy comes from the mother. In Angelman, function of this gene is lost while the gene from the father is silent. Apazunersen is an antisense oligonucleotide designed to inhibit the long non-coding RNA that silences the paternal UBE3A gene. The goal is to activate this gene to enable children to produce the key enzyme that they lack.
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Apazunersen was initially developed by GeneTx Biotherapeutics, where the experimental therapy was named GTX-102. In 2019, Ultragenyx began a collaboration on this program. In 2022, when the therapy had reached Phase 1/2 testing, Ultragenyx acquired GeneTx for $91.2 million up front.
Ultragenyx’s Phase 3 Aspire study enrolled 129 patients age 4 to 17 with a genetically confirmed deletion of maternal UBE3A, the most common type of Angelman. Participants were randomly assigned to receive apazunersen, administered as an injection into the spine, or a sham procedure. Patients started with a loading dose once a month followed by maintenance dosing every three months. The main trial goal was measuring at day 338 the change in score from baseline according to a rating scale used to assess childhood development.
Ultragenyx said the randomized cohorts were comparable at baseline and were consistent with the patients studied in the open-label Phase 2 trial. But in the sham-controlled Phase 3 test, Ultragenyx said apazunersen did not show efficacy according to the main trial goal, nor did it meet a key secondary goal assessing multiple measures of clinical function.
“Based on everything we observed in the robust Phase 1/2 clinical development program and long-term extension study, we are disappointed by the Aspire result,” Ultragenyx President and CEO Emil Kakkis said in a prepared 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.”
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Ultragenyx said it is assessing what to do with the apazunersen program. A corporate restructuring is also coming, with the company forecasting “significant expense reductions.” While Ultragenyx already has commercialized medicines for rare diseases, they’re small revenue generators. For 2025, the biotech reported $673 million in total revenue from four products, a 20% increase compared to the prior year.
Last month, Ultragenyx added a new product to its portfolio with the FDA approval of Genglycos, a gene therapy for an ultra-rare inherited enzyme deficiency called glycogen storage disease type Ia. But this one-time treatment is not expected to become a big source of revenue. Ultragenyx faces a Sept. 19 decision date for UX111 for mucopolysaccharidosis type III (MPS III), also called Sanfilippo syndrome type A. William Blair still expects approval for this gene therapy, but analyst Sami Corwin said in a research note that the bank’s investment thesis for Ultragenyx had centered on the Angelman drug. A separate Phase 3 test is evaluating apazunersen in even rarer Angelman genotypes. Corwin said even if this trial meets its main goal, commercialization will be challenging given the much smaller patient population.
Apazunersen’s failure has implications beyond Ultragenyx. Ionis Pharmaceuticals and Oak Hill Bio each have paternal UBE3A-activating antisense drug candidates. Ionis’s obudanersen is expected to have Phase 3 data next year. Oak Hill’s rugonersen, acquired from Roche, is heading into pivotal testing that will be supported by capital from a SPAC merger on track to close by the end of the year.
In a research note, Leerink Partners analyst Joseph Schwartz said that the gains observed in Phase 2 testing of Ultragenyx’s drug may have reflected natural developmental progression, practice effects (improvement in cognitive assessment as a patient takes the same test multiple times), and expectation bias. He added that activating paternal UBE3A can still work, but Ultragenyx’s trial failure moves potency to the front and center of this debate. Higher and more potent doses of the Ionis and Oak Hill drugs may yet prove successful, but that needs to shown with results from well-controlled studies.
“The open issue now is evidence: until exposure, EEG, and biomarker data for apazunersen are disclosed, underdosing remains our hypothesis, and the burden sits with the more potent candidates to demonstrate that reactivation translates into clinical function,” Schwartz said.
Photo: Sundry Photography, via Getty Images