Once-promising Angelman treatment fails to meet main goal in trial
No difference seen among children in cognitive scores versus a sham injection
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A global, late-stage clinical trial testing the injection therapy apazunersen (GTX-102) in children with Angelman syndrome has failed to meet its main and secondary goals, according to developer Ultragenyx Pharmaceutical.
Data from the Phase 3 trial, which tested the once-promising therapy candidate in more than 100 youngsters with the genetic condition, showed no improvement in cognitive test scores with apzunersen compared with a sham treatment. Further, other testing showed no differences in measures of behavior or motor function, Ultragenyx stated in a company press release announcing the results of its Aspire study (NCT06617429).
In an earlier trial, positive data suggested the treatment might lead to long-term cognitive gains among children with Angelman.
“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,” said Emil Kakkis, MD, PhD, CEO and president of Ultragenyx. “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.”
A complex neurological disorder, Angelman is caused by defects in the gene UBE3A. All individuals inherit two copies of the gene, one from each biological parent; the copy inherited from the biological father is normally inactive in certain brain cells.
Angelman develops when the copy inherited from the mother is mutated or missing, so these brain cells don’t have an active version of the functional gene. It causes physical and intellectual disabilities.
Apazunersen showed promise in earlier trial in children
Apazunersen is designed to switch on the UBE3A gene copy inherited from the biological father, thereby providing cells with an active, functional version of the gene.
The Aspire trial enrolled 129 children with Angelman, who were randomly assigned to receive apazunersen or a sham comparator for about a year. The study’s primary goal was to see if apazunersen would outperform the sham treatment in improving cognition, as measured by a standardized test called the Bayley-4 Cognitive Raw Score.
According to Ultragenyx, the study missed that main goal, with the results showing no difference in cognitive scores between children given apazunersen or the sham comparator. Study results also showed no difference between apazunersen and the sham treatment in response rates on the Multi-domain Responder Index (MDRI), a composite measure assessing cognitive, behavioral, and motor function.
Aspire specifically enrolled participants with a maternal deletion mutation, meaning the UBE3A copy from the biological mother was entirely absent. In parallel, Ultragenyx has also been running a Phase 2 study called Aurora (NCT07157254) to test the therapy among children with a wider range of mutation types.
Ultragenyx said it will review data from the completed Phase 3 trial to determine whether, and if so, how, to continue development of apazunersen.
Apazunersen has been awarded multiple designations from regulatory authorities, including breakthrough therapy and orphan drug status in the U.S. and PRIME designation in the European Union. All of these are designed to support the development of new treatments.
The company had been optimistic about its therapy candidate based on data from an earlier Phase 2 trial that suggested its use might lead to long-term developmental and cognitive gains in Angelman patients.
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