RARE Daily

GeneTx and Ultragenyx Halt Dosing in Angelman Study

October 27, 2020

Rare Daily Staff

GeneTx and Ultragenyx halted dosing in a phase 1/2 study of their experimental therapy GTX-102 in patients with the neurodevelopmental condition Angelman syndrome following serious adverse events in five patients receiving the highest or second highest dose of the therapy, but said interim results demonstrate improvement in patients.

The companies said preliminary results from patients treated indicate substantial improvements in all patients in at least two disease domains including communication, behavior, sleep, gross motor function, and fine motor function as measured by the Clinical Global Impression of Improvement Scale for Angelman Syndrome (CGI-I-AS) at day 128.

At the highest doses, all five patients experienced a serious adverse event of lower extremity weakness believed to be related to local inflammation due to GTX-102. Following these events, the companies paused enrollment and dosing. These events were assessed as mild or moderate in severity and have generally improved over a period of a few weeks while disease domain improvements have been sustained for three months.

The companies are amending the study protocol to reduce the dose-level range and modify the administration process, which is expected to reduce further drug-related serious adverse events.

Individuals with Angelman syndrome have developmental delay, balance issues, motor impairment, and debilitating seizures. Some individuals with Angelman syndrome are unable to walk and most do not speak. Anxiety and disturbed sleep can also be serious challenges. While individuals with Angelman syndrome have a normal lifespan, they require continuous care and are unable to live independently. Angelman syndrome is not a degenerative disorder, but the loss of the UBE3A protein expression in neurons results in abnormal communications between neurons. The condition is often misdiagnosed as autism or cerebral palsy. There are no currently approved therapies for Angelman syndrome.

GTX-102 is an experimental antisense oligonucleotide designed to target and inhibit expression of UBE3A-AS. Nonclinical studies show that GTX-102 reduces the levels of UBE3A-AS and reactivates expression of the paternal UBE3A allele in neurons of the CNS. Reactivation of paternal UBE3A expression in animal models of Angelman syndrome has been associated with improvements in some of the neurological symptoms associated with the condition. GTX-102 has been granted Orphan Drug designation, Rare Pediatric Disease designation, and Fast Track Designation from the U.S. Food and Drug Administration.

The study design includes five dosing cohorts in which patients were to receive four monthly doses of GTX-102 on an intra-patient dose escalation scheme. Five patients between the ages of 5 and 15 with deletions in the maternal UBE3A gene region were enrolled in the first three cohorts and are included in the interim data analysis.


Initial indications of benefit have been observed in all five treated patients across the key domains of communication, fine and gross motor skills, behavior, and sleep as measured by the CGI-I-AS. In some patients these initial indications of clinical improvement were observed by the investigator early in the study at the two lowest dose levels and began within weeks of the first dose.

At day 128, all patients had a meaningful improvement in their individual global CGI-I-AS score, which evaluated overall improvement across five domains specific to the symptoms of Angelman syndrome. All five patients were assessed as ‘much improved’ or ‘very much improved’ on the 7-point global scale of -3 to +3 with a mean change of +2.4. All patients had at least two symptom domains that were assessed as ‘very much improved’ or ‘much improved’ and at least three domains that were ‘minimally improved’ or better (Score of 3, 2, or 1).

Supporting the CGI-I-AS improvements were changes in other domain-specific measurable endpoints. All patients experienced numerical increases in the sub-scale growth scores of expressive and/or receptive communication of the Bayley Scales of Infant and Toddler Development (Bayley-4) domains, and three patients showed improvements in the Observed Reported Communication Ability (ORCA) measure of expressive, receptive, and pragmatic communication.

“The UBE3A antisense transcript targeted by GTX-102 is a viable target for treatment,” stated Scott Stromatt, chief medical officer of GeneTx. “The results observed to date are encouraging and we look forward to resuming dosing at lower doses to help avoid side effects.”

Photo: Scott Stromatt, chief medical officer of GeneTx

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