Ultragenyx Pharmaceutical RARE stock is down 46% in premarket trading today after the company reported that the late-stage study evaluating its investigational antisense oligonucleotide candidate, apazunersen (GTX-102), for Angelman syndrome (AS) failed to achieve the key goals.

The phase III Aspire study enrolled 129 patients aged four to 17 years with a genetically confirmed diagnosis of AS involving a full maternal UBE3A gene deletion. Patients were randomized equally to receive either apazunersen through an intrathecal injection via lumbar puncture or a sham procedure. Treatment consisted of three monthly 8 mg loading doses followed by a maintenance regimen increasing to a maximum quarterly dose of 14 mg of the candidate. The study assessed outcomes over 48 weeks.

Detailed Results From RARE's Phase III AS Study

Ultragenyx's phase III Aspire study failed to demonstrate a meaningful treatment benefit of apazunersen on its primary endpoint, which measured the change from baseline in the Bayley-4 cognitive raw score. RARE also reported that the study missed its key secondary endpoint of net response on the Multidomain Responder Index (MDRI). The MDRI incorporates five areas considered relevant to AS – cognition, receptive communication, behavior, gross motor function and sleep.

Year to date, RARE stock has gained 15.3% compared with the industry's 9.7% growth.

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Per Ultragenyx, the randomized treatment and control groups were comparable at baseline and consistent with the population previously evaluated in phase II. However, no differences between the groups supported efficacy on Bayley-4 cognition or the MDRI. RARE further reported that there were no meaningful differences in either net response or mean changes across the five individual MDRI domains. At the same time, the safety profile of apazunersen observed in the Aspire study remained consistent with that seen in earlier phase I/II development.

AS is a rare neurogenetic disorder associated with loss of function of the maternally inherited UBE3A gene. The disorder can cause severe cognitive and motor impairment, balance problems, seizures, limited speech, anxiety and sleep disturbances, while individuals generally require lifelong care. Per RARE, AS is estimated to affect approximately 60,000 people in commercially accessible geographies. There are no currently approved therapies for this indication.

Following the setback, Ultragenyx will evaluate the apazunersen program and decide its future disposition. The company also plans to assess its operations and implement significant expense reductions while maintaining support for its commercial business. RARE currently markets Crysvita for X-linked hypophosphatemia and tumor-induced osteomalacia, Dojolvi for long-chain fatty-acid oxidation disorders, Evkeeza for homozygous familial hypercholesterolemia (under partnership with Regeneron), Mepsevii for mucopolysaccharidosis type VII and the newly approved Genglycos (DTX401) for glycogen storage disease type Ia.