The Phase III Aspire study of apazunersen (GTX-102) in Angelman syndrome failed to meet its primary endpoint, leaving the condition without an approved disease-modifying therapy. Ultragenyx Pharmaceutical (Nasdaq: RARE) reported that the study showed no difference between treated and control groups on the Bayley-4 cognitive raw score, the primary measure, nor on the Multidomain Responder Index (MDRI), a composite key secondary endpoint spanning five functional domains.
As per the press release, the baseline characteristics of randomized patients were comparable and consistent with those enrolled in earlier studies, offering no obvious confound to explain the divergence from Phase I/II signals. The safety profile was consistent with prior experience.
Apazunersen is an antisense oligonucleotide (ASO) delivered intrathecally, designed to suppress the UBE3A antisense transcript (UBE3A-AS) that silences the paternal copy of the UBE3A gene in neurons. In Angelman syndrome, the maternally inherited UBE3A allele is absent or non-functional; reactivating the paternal copy is the central therapeutic rationale. The drug held FDA Breakthrough Therapy Designation, Orphan Drug Designation, Rare Pediatric Disease Designation, and Fast Track Designation, as well as PRIME designation from the EMA — a regulatory profile that reflected the strength of the Phase I/II package.