Dosing Begins in Canada for Phase 1/2 Trial of GTX-102 in Children

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by Patricia Inacio PhD |

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The first patient has been dosed in Canada as part of a Phase 1/2 clinical trial of the investigational therapy GTX-102 in children and adolescents with Angelman syndrome.

The open-label KIK-AS trial (NCT04259281), which is also underway in the U.S. and U.K., has enrolled three other patients who are scheduled to begin dosing, according to a press release from GeneTx Biotherapeutics and Ultragenyx Pharmaceutical, the therapy co-developers.

The trial aims to enroll up to 20 pediatric patients (ages 4 to 17) with Angelman due to a complete deletion of the maternal UBE3A gene.

Enrollment is open for the clinical sites in Canada and the U.K., but not for the site in the U.S. More information is available here. Data from the first participants are expected before the year’s end, with the trial’s completion scheduled for January 2023.

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“We have been actively working with our principal investigators across all three regions over the past several months to efficiently execute this Phase 1/2 trial and can now move forward rapidly with study enrollment,” said Scott Stromatt, MD, chief medical officer of GeneTx, in the release.

The trial recently received the green light to resume enrollment in Canada after it was placed on hold because five patients in the U.S. had experienced serious, but reversible, muscle weakness in their legs and feet after being treated with the highest doses of GTX-102. Regulatory officials in the U.K. also approved its start there in June, after adjustments were made to the trial’s protocol in dosing and treatment administration.

The study’s primary goal is to assess the safety and tolerance of multiple doses of GTX-102. Secondary goals include the therapy’s pharmacokinetics (how a medicine moves through the body) and its concentrations in blood and cerebrospinal fluid (the fluid surrounding the brain and spinal cord), as well as exploratory efficacy measures.

Among these are disease severity using the Clinical Global Impressions-Severity adapted to Angelman syndrome (CGI-S-AS). The CGI-S-AS assesses six domains: behavior, gross and fine motor function, expressive and receptive communication, and sleep. Its scores range from one to seven, in which higher scores mean worse outcomes. Additional measures will include communication, sleep, behavior, motor skills, and seizures, evaluated after four months of treatment.

“This is an in-depth study to evaluate both safety and measures of efficacy across multiple domains in Angelman Syndrome that will inform us on the optimal endpoints to evaluate in the registrational program,” Stromatt said.

Under an amendment to the trial’s original protocol — which includes lowering the initial dosing range and changing its administration route for intrathecal (spinal canal) injection — 12 patients will enroll in one of two groups, depending on their age: patients 4 to 7 will enroll in group 4, while older patients, 8 to 17, will join group 5.

Two patients in group 4 (younger group) will initially receive 3.3 milligrams (mg) of GTX-102, and two in group 5 (older group) will receive 5 mg. After two doses, they will be evaluated by a data safety monitoring board (DSMB), which will then recommend whether to continue enrolling another eight patients.

After the two doses and clinical evaluation, patients will be given two higher doses.

Patients will then transition into a maintenance phase, during which GTX-102 will be given every three months, and they will  continue being monitored. Each participant may receive up to 14 mg of GTX-102, if safety is maintained and if they have not reached a “much improved” score in at least two domains of the CGI-S-AS.

“The dosing schedule across the three arms of this study, in the U.K., Canada, and the U.S., is designed to achieve a cumulative dose range similar to the original study where we saw impact across domains beginning at the lowest dose of 3.3 mg and meaningful improvements at 13-20 mg of cumulative dosing in younger patients,” said Emil D. Kakkis, MD, PhD, CEO and president of Ultragenyx, in the release.

“Based on the prior data, we believe this study should contribute meaningfully to our understanding of dose response and safety in this program,” he added.

GTX-102, called an antisense oligonucleotide, targets the molecule underlying Angelman syndrome (UBE3A antisense transcript, or UBE3A-AS), preventing it from working. Antisense oligonucleotides are small molecules that bind the messenger RNA molecule — the molecule generated from DNA that serves as a template for protein production — and degrade it or change how it is processed.

By inactivating the UBE3A-AS, GTX-102 is believed to induce the reactivation of the paternal copy of UBE3A in the brain as a way to compensate for the lack of a working maternal copy of the gene.