Ultragenyx's Angelman syndrome hopeful shows early promise

2024-04-15

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Ultragenyx Pharmaceutical reported encouraging early data for its experimental Angelman syndrome treatment GTX-102, reinforcing the decision to buy out its development partner GeneTx Biotherapeutics for $75 million in 2022. However, despite the early success, investors may have been spooked by reports of serious adverse effects occurring in some patients, pushing Ultragenyx shares down by about 9% on Monday.

The results, to be presented this week at the American Academy of Neurology (AAN) annual meeting, are from a Phase I/II study evaluating GTX-102 in 74 paediatric patients with a genetically confirmed diagnosis of full maternal UBE3A gene deletion.

The antisense oligonucleotide, given by intrathecal injection, works by inhibiting expression of UBE3A-AS which in turn reactivates expression of the paternal UBE3A allele in central nervous system neurons. In preclinical models, this reactivation has been associated with improvements in some of the neurological symptoms that characterise Angelman syndrome, which include developmental delays, speech and motor disabilities, as well as sleep disturbances.

The latest readout is drawn from 39 patients, including two expansion cohorts involving 24 subjects with data out to 170 days, and long-term data from dose-escalation cohorts comprising 15 patients with more than two years of data.

Sustained long-term benefit

According to Ultragenyx, results from the two expansion cohorts showed that GTX-102 led to "rapid and clinically meaningful improvement" across several domains, which included cognition, receptive communication, behaviour, gross motor function and sleep. The company also conducted a multi-domain responder index (MDRI) assessment that covers cognition, receptive communication, behaviour and sleep; GTX-102 resulted in a total net response of +2.0 on that scale.

The dose-escalation cohorts showed long-term increasing and sustained clinical benefit "far exceeding" natural history data at day 758. Ultragenyx said there was a continuing long-term improvement with cognition, exceeding the threshold of clinical significance "by many-fold in many patients." Behaviour, sleep and gross motor function also showed sustained clinically meaningful benefits.

Lower extremity weakness

While the company reported no unexpected serious adverse events, it did say three patients experienced mild-to-moderate lower extremity weakness considered to be related to GTX-102. "All resolved rapidly without sequelae and remain in the study without ongoing safety concerns," it added.

"Our next step is an end-of-Phase II meeting with the FDA and interactions with other health authorities to enable timely initiation of a Phase III pivotal study," stated chief medical officer Eric Crombez.

Previous attempts by other developers to produce an effective therapy for Angelman syndrome have fallen flat. Ovid Therapeutics' lead candidate OV101 missed its primary endpoint in a Phase III study in 2020, and Roche last year scrapped its rugonersen (RO7248824) programme after it underperformed in early testing. Meanwhile, Biogen and Ionis Pharmaceuticals are partnered on BIIB121, an investigational antisense oligonucleotide treatment similar to GTX-102 that's currently in Phase I testing.

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