1st Angelman Patient in UK Dosed in Trial of Gene Therapy GTX-102

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A first patient in the U.K. has been dosed in the resumption of a Phase 1/2 clinical trial evaluating the safety of the gene therapy GTX-102 in children and adolescents with Angelman syndrome.

The open-label study (NCT04259281), known as KIK-AS, is being run at Oxford University and is also underway in the U.S. and Canada. Its three sites are recruiting a total of up to 20 patients lacking the maternal UBE3A gene. Site and contact information can be found here.

“We are really excited to have dosed the first study participant with a promising potential treatment,” Dora Markati, MD, a researcher with Oxford’s department of pediatrics and a trial investigator, said in a press release. “We are only at the start of a new era in therapeutics!”

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KIK-AS was put on a clinical hold in late 2020 after five patients in the U.S. experienced muscle weakness in their legs and feet as a serious — but reversible — side effect of GTX-102 given at its highest trial dose.

The companies developing the therapy — GeneTx Biotherapeutics and Ultragenyx Pharmaceutical — were then cleared to resume the clinical trial in the U.K., Canada, and the U.S. after limiting GTX-102’s dose range and switching to intrathecal (into the spinal canal) administration via a lumbar puncture.

A first patient was dosed in Canada in October 2021, with dosing scheduled for three other enrolled children.

“The road before having a treatment for every child with Angelman syndrome in the UK and in the world is still very long, but this is an important first step,” said Laurent Servais, MD, PhD, who is coordinating the clinical trial in the U.K. Servais is a professor at the MDUK Oxford Neuromuscular Centre and head of STRONG, the two research groups leading the clinical trial in Oxford.

The trial’s primary goal is to see if GTX-102 is safe and well tolerated in children and adolescents, ages 4 to 17, with Angelman syndrome due to a complete deletion of the maternal copy of the UBE3A gene, which is known to cause the disease.

GTX-102 is an antisense oligonucleotide — a short piece of DNA or RNA — that can bind to a molecule called the UBE3A antisense transcript, or UBE3A-AS, that normally silences the paternal copy of UBE3A. This is expected to reactivate the paternal copy of UBE3A in the brain, which may compensate for the missing maternal copy.

In the U.K. and Canada, enrolled patients will be split into two groups based on age: one of children ages 4 to 7 and the other with children and adolescents ages 8 to 17. Younger children will receive 3.3 mg of GTX-102 given as three to four monthly doses. Older patients will be given 5 mg of GTX-102, also as three to four monthly doses. All may then move to a maintenance phase during which they will receive GTX-102 every three months up to a maximum of 14 mg.

In the U.S., eight treatment-naïve patients, ages 4 to 7, will be assigned to either an active treatment or age-matched control group. The active group will receive four monthly doses of GTX-102 at 2 mg. After assessments, control patients are expected to be treated with a dosing regimen similar to the initial group. All who complete this trial phase will be eligible move to its maintenance phase and receive 2 mg of GTX-102 every three months.

Safety and tolerability will be assessed in terms of reported side effects, with evidence of therapy effectiveness explored through changes in patients’ communication and motor skills, behavior, and sleep. KIK-AS is due to conclude in January 2023.

The STRONG research group, in collaboration with Usha Kini, MD, is also running a first natural history study for Angelman syndrome in the U.K. The study (NCT05100810), supported by FAST UK, will contribute to the validation of biomarkers and other clinical measures that could aid in evaluating patient response to a given therapy.