Ultragenyx' Apazunersen Fails Primary End Point in Phase 3 Angelman Trial

Ultragenyx Pharmaceutical announced that the phase 3 Aspire study of apazunersen (GTX-102), an investigational antisense oligonucleotide therapy for Angelman syndrome, did not meet its primary end point of change from baseline in Bayley-4 cognitive raw score. The study also did not achieve its key secondary end point, net response on the multi-domain responder index (MDRI), and the company said no differences emerged between the apazunersen and sham-control groups on either measure.¹

Aspire was a randomized, double-blind, sham-controlled trial that enrolled approximately 129 participants aged 4 to 17 years with Angelman syndrome and a genetically confirmed full maternal UBE3A gene deletion; enrollment ran from December 2024 through July 2025.^2,3 Participants were randomly assigned 1:1 to receive intrathecal apazunersen, administered via lumbar puncture as 3 monthly 8-mg loading doses followed by quarterly maintenance dosing escalating to a maximum of 14 mg, or a sham comparator, over 48 weeks.

The MDRI, a key secondary end point that carried a 10% alpha allocation, combined cognition, receptive communication, behavior, gross motor function, and sleep into a single response measure; Ultragenyx reported no separation between arms on that composite or on its individual components. The company said apazunersen's safety profile in Aspire remained consistent with earlier phase 1/2 findings.¹

"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," Emil Kakkis, MD, PhD, CEO and president of Ultragenyx, said in a statement. The company said it would evaluate the future of the apazunersen program, including the ongoing phase 2 Aurora study.¹

The negative phase 3 result stands in contrast to earlier open-label data that supported the program's advancement. In a phase 1/2, open-label, dose-escalating study of 74 patients aged 4 to 17 years with a full maternal UBE3A deletion, participants treated with apazunersen showed developmental gains across multiple symptom domains that were sustained over treatment periods of up to 3 years.⁶ Those findings, presented at the Foundation for Angelman Syndrome Therapeutics conference in November 2024, supported the FDA's decision in June 2025 to grant apazunersen breakthrough therapy designation.⁵

Unlike Aspire, however, the phase 1/2 study was open-label and uncontrolled, and Ultragenyx had described it as a key basis for expecting the randomized, sham-controlled Aspire trial to be well powered to detect a treatment effect.

Apazunersen is designed to inhibit expression of the UBE3A antisense transcript, preventing silencing of the paternally inherited UBE3A allele and restoring expression of the UBE3A protein, which is fully suppressed on the paternal allele in neurons and deleted on the maternal allele in Angelman syndrome.

Separately from Aspire, apazunersen is also being studied in the phase 2, open-label, basket Aurora study (NCT07157254), which was designed to assess safety and confirm efficacy across a broader range of ages and Angelman syndrome genotypes than Aspire enrolled, including patients as young as 1 year and as old as 65 years, as well as those with nondeletion genotypes.⁷ Ultragenyx did not specify in its Aspire announcement whether Aurora enrollment or dosing would continue as planned while the company reassesses the program.

REFERENCES
1. Ultragenyx announces phase 3 Aspire results in Angelman syndrome. News release. Published September 2, 2026. Accessed September 3, 2026. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-phase-3-aspire-results-angelman-syndrome
2. Ultragenyx announces first patient dosed in pivotal phase 3 Aspire study evaluating GTX-102 in Angelman syndrome. News release. Published December 19, 2024. Accessed September 3, 2026. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-first-patient-dosed-pivotal-phase-3-aspire
3. Ultragenyx completes enrollment of phase 3 Aspire study evaluating GTX-102 for the treatment of Angelman syndrome. News release. Published July 31, 2025. Accessed September 3, 2026. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-completes-enrollment-phase-3-aspire-study-evaluating
4. A study to assess the efficacy and safety of GTX-102 (apazunersen) in pediatric participants with Angelman syndrome (Aspire). ClinicalTrials.gov identifier: NCT06617429. Accessed September 3, 2026. https://clinicaltrials.gov/study/NCT06617429
5. Ultragenyx receives breakthrough therapy designation for GTX-102 in Angelman syndrome. News release. Published June 27, 2025. Accessed September 3, 2026. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-receives-breakthrough-therapy-designation-gtx-102
6. Ultragenyx announces positive interim phase 1/2 data in patients with Angelman syndrome after treatment with GTX-102. News release. Published April 14, 2024. Accessed September 3, 2026. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-positive-interim-phase-12-data-patients
7. Ultragenyx announces first patient dosed in Aurora study evaluating GTX-102 in additional Angelman syndrome genotypes and age groups. News release. Published October 30, 2025. Accessed September 3, 2026. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-first-patient-dosed-aurora-study-evaluating