Assessing Antisense Oligonucleotide Apazunersen in Pediatric Angelman Syndrome: The Aspire Study

Welcome to NeurologyLive^®'s Clinical Trial in Focus. Every month, an ongoing clinical trial in the landscape of neurology is featured, highlighting the design of the study, the targeted patient population, the enrollment criteria, the primary and secondary end points, and its potential implications for clinical care. This month’s spotlight is the global phase 3 Aspire study (NCT06617429) assessing apazunersen (Ultragenyx Pharmaceutical), an investigational antisense oligonucleotide therapy, in pediatric patients with Angelman syndrome (AS).¹

The Aspire study is a randomized, double-blind, sham-controlled trial investigating the efficacy and safety of apazunersen, also known as GTX-102, in participants aged 4 to 17 years with AS and a genetically confirmed full maternal UBE3A gene deletion. The agent is designed to inhibit expression of the UBE3A antisense transcript, thereby preventing silencing of the paternally inherited UBE3A allele and restoring expression of the deficient protein.²

"Apazunersen was specifically engineered to target a crucial and highly conserved region of the UBE3A-antisense transcript. This region, discovered by Scott Dindot, PhD, is believed to be the structural start site and important for its regulation," Kim Goodspeed, MD, MS, senior medical director of global clinical development at Ultragenyx, told NeurologyLive. "Precise targeting of this site resulted in robust and efficient repression of the UBE3A-antisense transcript and reactivation of the paternal copy of UBE3A throughout the [central nervous system] of cynomolgus macaques."

Design of the Trial

Enrollment for the Aspire study began in December 2024 and concluded in July 2025, with approximately 129 participants.³ Participants in the trial will be randomly assigned 1:1 to receive intrathecal apazunersen via lumbar puncture or a sham comparator for 48 weeks. Those assigned to apazunersen would receive 3 monthly 8-mg loading doses, followed by a maintenance period with quarterly dosing escalating to a maximum of 14 mg. Participants in the sham group are eligible to cross over to active treatment after completing their assessments at 48 weeks.

In the study, the primary end point is improvement in cognition as measured by the Bayley Scales of Infant Development (Bayley-4) cognitive raw score, with the multi-domain responder index (MDRI), encompassing cognition, receptive communication, behavior, gross motor function, and sleep, as a key secondary end point with a 10% alpha allocation. Ultragenyx noted that study completion is anticipated in the second half of 2026 and intends to report topline data promptly to support regulatory submission.

"Cognition impacts many different aspects of a child’s abilities. It is the building block for the acquisition and development of many new skills, including both expressive and receptive communication," Goodspeed told NeurologyLive. "The Bayley-4 measures cognition by assessing how children learn, problem solve, and perform on different tasks. This is similar to how we measure an IQ in older children. Changes in cognition as measured by the Bayley-4 may look like the acquisition of new skills, improved ability to follow directions, or ability to express their wants and needs."

Inclusion Criteria

Eligible participants were required to provide written informed consent through a parent or legal guardian and have a genetically confirmed diagnosis of AS, specifically a full maternal UBE3A deletion in the 15q11.2-q13 region. Participants had to be ambulatory, either independently or with assistance, and have platelet counts, prothrombin time/international normalized ratio, and partial thromboplastin time within 1.5 times the normal range. Additional criteria included the ability to comply with study procedures and visits, including lumbar puncture, MRI, and anesthesia without intubation. Girls of childbearing potential were required to use highly effective contraception or abstain from sexual activity from the time of consent through at least 6 months after the final dose of apazunersen, and boy participants were required to agree to abstinence or use acceptable contraception during the study and for at least 3 months following the final dose.

Exclusion Criteria

Participants were excluded if they had recent changes in medications, supplements, or dietary interventions for AS in 1 month of screening, with the exception of weight-based dose adjustments. Exclusion criteria also encompassed conditions that could increase the risk of an unsuccessful lumbar puncture or bleeding, including the use of anticoagulant or antiplatelet therapies. Additional exclusions included known hypersensitivity to apazunersen or its excipients, medical conditions or laboratory abnormalities that could compromise safety or interfere with study assessments, pregnancy or breastfeeding, prior exposure to investigational treatments, including gene therapy or antisense oligonucleotides, or concurrent enrollment in another interventional trial.

"Because apazunersen is given by lumbar puncture and injection directly into the spinal fluid, Ultragenyx decided against administering an invasive placebo that won’t benefit participants. Instead, we are using the sham-control design so that we can robustly test the safety and efficacy of apazunersen in comparison to a control group that do not receive active treatment in a less invasive study design," Goodspeed said.

Phase 2 Aurora Study

In addition to the phase 3 Aspire study, apazunersen is being evaluated in the phase 2, open-label, basket Aurora study (NCT07157254) to assess safety and confirm efficacy across a broader range of ages and AS genotypes.⁴ Data from Aurora are expected to expand the treated population to include younger and older patients, as well as individuals with nondeletion genotypes not enrolled in Aspire. Although Aspire is fully enrolled and focuses on patients aged 4 to 17 years with a genetically confirmed full maternal UBE3A deletion, the Aurora study plans to enroll approximately 60 participants aged 1 to less than 65 years across all genotypes and will include additional countries or regions not represented in Aspire.

Aurora will include 4 study cohorts defined by age and genotype. Cohort A will enroll participants aged at least 1 to less than 4 years with deletion-type AS, with the Bayley-4 cognitive raw score as the primary end point. Cohort B will include participants aged at least 4 to less than 18 years with uniparental paternal disomy or imprinting center defects, and cohort C will include participants aged at least 18 to less than 65 years with any AS genotype; the primary end point for both cohorts B and C will be the MDRI response. Cohort D will enroll participants aged at least 4 to less than 18 years with UBE3A gene mutations, also using the MDRI response as the primary end point.

The company noted that study cohorts A, B, and C will be single-arm, whereas participants in cohort D will be randomly assigned 2:1 to receive apazunersen or no treatment. All cohorts include a 48-week primary efficacy period, with participants in the no-treatment group crossing over to receive their first loading dose of apazunersen at 24 weeks. Following completion of the Aurora study, participants in all cohorts may continue therapy in a long-term extension study.

Phase 1/2 Study

In June 2025, the FDA granted breakthrough therapy designation for apazunersen as a treatment for patients with AS. The agency’s decision was supported by positive data from Ultragenyx’s phase 1/2 open-label, multiple-dose, dose-escalating study (NCT04259281) in 74 patients aged between 4 and 17 years with a full maternal UBE3A gene deletion.⁵ In the study, findings indicated that participants treated with apazunersen demonstrated consistent developmental gains, with improvements across multiple symptom domains observed and sustained over treatment periods of up to 3 years.⁶

"The phase 1/2 data presented at FAST in November 2024 reinforce that the Aspire phase 3 primary end point of cognition, as measured by Bayley-4, appears very well powered to show statistically significant separation between the GTX-102 and sham arms. GTX-102 has consistently demonstrated an acceptable safety profile," Goodspeed added. "In addition to changes in cognition, we have observed improvements in other key symptoms that matter to families, including better balance and sleep, and a reduction in challenging behaviors."

"Each individual experience is unique, but as an example, some participants in the phase 1/2 study are now able to help in the kitchen, have learned to swim, and are able to go out in public with their families. In a disorder like AS that is typically characterized by severe neurodevelopmental disability, frequent falls, and disruptive behavior, families can feel isolated, but we hear consistently that the improvements seen in response to apazunersen are making everyday family experiences possible again," Goodspeed said.

REFERENCES
1. Bruns R, Liaqat K, Nasir A, et al. Undiagnosed rare disease clinic identifies a novel UBE3A variant in two sisters with Angelman syndrome: the end of a diagnostic odyssey. Congenit Anom (Kyoto). 2024;64(3):155-160. doi:10.1111/cga.12566
2. Ultragenyx announces first patient dosed in pivotal phase 3 Aspire study evaluating GTX-102 in Angelman syndrome. News release. Ultragenyx. December 19, 2024. Accessed December 19, 2025. 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. Ultragenyx. July 31, 2025. Accessed December 19, 2025. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-completes-enrollment-phase-3-aspire-study-evaluating
4. Ultragenyx announces first patient dosed in Aurora study evaluating GTX-102 in additional Angelman syndrome genotypes and age groups. News release. Ultragenyx. October 30, 2025. Accessed December 19, 2025. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-first-patient-dosed-aurora-study-evaluating
5. Ultragenyx receives breakthrough therapy designation for GTX-102 in Angelman syndrome. News release. Ultragenyx. June 27, 2025. Accessed December 19, 2025. 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. Ultragenyx. April 14, 2024. Accessed December 19, 2025. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-positive-interim-phase-12-data-patients