Phase II Success Paves Way for Angelman Syndrome Pivotal Trial for Ultragenyx

Ultragenyx Pharmaceutical has reported promising results from a Phase I/II clinical trial of its experimental drug GTX-102, which is being developed to treat patients suffering from the rare genetic disorder known as Angelman syndrome. Although the company did not disclose specific details, it indicated that the participants in the trial exhibited significant improvements in cognitive abilities after 170 days of treatment, as compared to the natural progression of the disease. In addition to cognitive enhancements, the patients also showed marked improvements in behavior, sleep patterns, hyperactivity, motor skills, and communication abilities.

Eric Crombez, the Chief Medical Officer at Ultragenyx, highlighted that the interim results suggest that GTX-102 has the potential to bring about rapid and extensive improvements across various domains, which could have a profound effect on the quality of life for both the patients and their families. Crombez mentioned that some children have even started to eat independently and communicate with their families after receiving the treatment.

The next phase for GTX-102 involves a meeting with the FDA to discuss the trial's end and to plan for the initiation of a Phase III pivotal study. Despite the positive interim data, Ultragenyx's stock prices experienced a 7% drop, possibly due to concerns over the drug's safety profile. During the Phase I/II study, three serious adverse events involving lower extremity weakness were reported, which were related to the treatment. However, these issues were promptly resolved, and the patients continued to receive GTX-102 without any new safety concerns.

The FDA has been informed of these safety events, and Ultragenyx has stated that no further issues have been raised by the regulatory body. Angelman syndrome is a neurogenetic disorder characterized by cognitive, motor, and balance impairments, along with severe seizures and sleep disturbances. The condition arises from a mutation in the maternal allele of the UBE3A gene, which normally produces an enzyme that marks proteins for degradation.

GTX-102 functions by targeting the UBE3A-AS gene, inhibiting its expression and thereby preventing the silencing of the paternal UBE3A gene. This mechanism is believed to reactivate the expression of UBE3A in neurons, leading to neurological improvements. Ultragenyx is not alone in its pursuit to treat Angelman syndrome; it faces competition from Ionis, which is developing a similar antisense treatment called ION582. Both GTX-102 and ION582 aim to reactivate the production of the UBE3A protein in neurons, with ION582 having received FDA designations for being an orphan drug and for treating a rare pediatric disease in June 2022.