Ultragenyx eyes pivotal study after mid-stage win in Angelman syndrome


Published: Apr 16, 2024

By Tristan Manalac


Ultragenyx Pharmaceutical on Monday provided a Phase I/II update for its investigational antisense oligonucleotide GTX-102, demonstrating substantial symptomatic improvement in patients with the rare genetic disorder Angelman syndrome.

The California biotech did not provide specific data in its announcement but said that patients in its dose-escalation cohorts saw “rapid and clinically significant improvement” in cognition after 170 days, compared with natural history data. These patients also demonstrated strong behavioral, sleep, hyperactivity, gross motor and receptive communication improvements after GTX-102 treatment, the company announced.

Ultragenyx CMO Eric Crombez in a statement that these interim data show “that treatment with GTX-102 resulted in rapid, multi-domain improvements that continued throughout maintenance dosing,” which in turn could have a “meaningful impact on patients and their families.” Some children have been able to start eating on their own and communicate with their families, Crombez noted.

“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,” Crombez added.

Despite these positive findings, Ultragenyx’s shares fell 7% on Monday, according to Seeking Alpha.

Much of the investors’ apprehension could be due to GTX-102’s safety profile. In the Phase I/II study, Ultragenyx documented three cases of lower extremity weakness, which were deemed serious adverse events and related to the study treatment. All instances were quickly resolved and the patients remain on GTX-102 treatment with no new safety signals.

The FDA has also been notified of these safety events but has so far raised no issues or asked for other actions, according to Ultragenyx.

Angelman syndrome is a rare and neurogenetic disorder caused by a loss-of-function mutation in the maternal allele of the UBE3A gene, which under normal circumstances produces an enzyme that tags other proteins for destruction. Symptoms include cognitive, motor and balance impairment, as well as debilitating seizures. Patients also typically develop anxiety and difficulties sleeping.

GTX-102, an intrathecal investigational antisense oligonucleotide, works by targeting and blocking the expression of the UBE3A-AS gene, which otherwise produces a protein that silences the paternal copy of UBE3A. Nonclinical studies have shown that this mechanism of action reactivates UBE3A expression in neurons, leading to neurological improvements.

Ultragenyx is facing competition in the Angelman syndrome space from Ionis, which is developing its own antisense treatment ION582. Like GTX-102, Ionis’ candidate un-silences the paternal copy of the UBE3A gene to reactivate the production of the protein in neurons. ION582 won the FDA’s Orphan Drug and Rare Pediatric Disease designations in June 2022.

Source: BioSpace