Ultragenyx Pharmaceutical is deliberating the fate of its Angelman syndrome candidate, apazunersen, after the drug failed to show benefit in a Phase III trial.
During the late-stage, single-arm ASPIRE trial (NCT06415344), the antisense oligonucleotide (ASO) therapy did not trigger a significant change from baseline in cognition – missing the trial’s primary endpoint. Patients given apazunersen also didn’t accrue any significant general benefits from the drug as per the Multidomain Responder Index (MDRI), resulting in the medicine also missing its secondary endpoint in this study.
Go deeper with GlobalData
Discover B2B Marketing That Performs
Combine business intelligence and editorial excellence to reach engaged professionals across 36 leading media platforms.
Apazunersen demonstrated a similar safety profile in the ASPIRE trial to that of the Phase I/II study.
Following this Phase III miss, Ultragenyx plans to evaluate the course of the apazunersen development programme, which currently only spans Angelman syndrome. According to Jefferies analysts, the failure of the drug in all five sub-domains of the MDRI “indicates a clear signal failure and not a design failure”.
Meanwhile, William Blair analysts note that the ASPIRE results could potentially have negative readthrough to the ongoing AURORA study (NCT07157254), which is evaluating the drug in patients with deletion or non-deletion type Angelman syndrome. “We believe that even if the Aurora study meets its primary endpoint, commercialisation will be challenging given the limited size of the addressable population,” the analysts added.
Angelman syndrome is a rare genetic disease caused by the loss of function of a gene called UBE3A, which is associated with gene regulation and brain development. Patients with this condition often experience cognitive and movement impairment, as well as balance issues and seizures. Ultragenyx claims that around 60,000 people have Angelman syndrome in commercially accessible geographies, and there are currently no approved disease-modifying therapies (DMTs) indicated for the condition.
Moving forward, Ultragenyx’s CEO, Emil Kakkis, notes that the company will maintain focus on its “growing commercial business”, which now includes nearly approved glycogen storage disease therapy, Genglycos (pariglasgene brecaparvovec-opnr).
The deliberations by Ultragenyx come as the ASO treatment approach grows in notoriety, with drugs like Biogen and Ionis Pharmaceuticals’ spinal muscular atrophy (SMA) therapy, Spinraza (nusinersen) making waves within its indication. Alongside their role in rare diseases, ASO-based therapies are also being explored in neurodegenerative conditions like Alzheimer’s disease, as well as metabolic indications such as lipid disorders.
However, manufacturing issues continue to plague the modality, which is commonly associated with high production costs and issues around scaling.
