Trial for GTX-102 to Open Enrollment Soon in the UK

The United Kingdom’s Medicines Healthcare Products Regulatory Agency (MHRA) has authorized a Phase 1/2 clinical trial to test the investigational therapy GTX-102 in children and adolescents with Angelman syndrome.

The open-label KIK-AS trial (NCT04259281), which also has been given a green light in Canada, is expected to open enrollment in the U.K. soon. Clinical data from the first patients are expected before the end of the year.

Enrollment for clinical sites in the U.S. is pending an amendment to the trial’s protocol — by GeneTx Biotherapeutics and Ultragenyx Pharmaceutical, the therapy’s co-developers — to address key issues raised by the U.S. Food and Drug Administration (FDA).

“We’ve made significant progress on the regulatory front over the past few weeks with the Phase 1/2 study cleared to begin enrollment in two countries. Based on our recent discussions, we are encouraged about our proposal to begin redosing patients in the U.S. pending FDA agreement,” Scott Stromatt, MD, chief medical officer of GeneTx, said in a press release.

The study was placed on hold in November after five patients in the U.S. experienced serious, but reversible, muscle weakness affecting their legs and feet after receiving the highest dose of GTX-102.

Despite this, marked improvements were seen in the Clinical Global Impression of Improvement Scale for Angelman Syndrome, which evaluates changes in a patient’s condition across domains such as communication, motor skills, behavior, and sleep.

The amendment to the study’s protocol includes lowering the treatment’s initial dosing range and changing its administration route for intrathecal (spinal canal) injection.

“GTX-102 has demonstrated clinical activity in the first five patients dosed in the study, and the modified trial design approved by the MHRA and Health Canada intends to explore the benefit of repeat doses at the lower end of the dosing range previously tested in order to help mitigate the risk for serious adverse events caused by localized inflammation,” Stromatt said.

The trial’s main goal is to assess the safety, tolerability, and preliminary efficacy of multiple doses of GTX-102 in up to 20 people (ages 4 to 17) with Angelman caused by a complete deletion of the maternal UBE3A gene. Additional goals include the assessment of the therapy’s pharmacokinetics (how a medicine moves throughout the body) and its concentrations in blood and cerebrospinal fluid (the fluid surrounding the brain and spinal cord).

Under the new protocol approved in the U.K. and Canada, 12 patients will be enrolled in one of two groups, according to their age: patients 4 to 7 years will enroll in group 4, while older patients (8 to 17) will join group 5.

Patients in group 4 will be given, at first, 3.3 milligrams (mg), and those in group 5 will receive 5 mg of GTX-102, given in three to four monthly doses. This will be followed by an individual dose-escalation scheme, depending on response and enhanced safety monitoring.

Patients then will move into a maintenance phase during which the investigational therapy will be given every three months. In this phase, each participant may receive up to 14 mg of GTX-102.

GTX-102 is an antisense oligonucleotide designed to target and inactivate the molecule that causes Angelman syndrome (UBE3A antisense transcript, or UBE3A-AS). That reactivates the paternal UBE3A gene. Antisense oligonucleotides are small molecules that can bind to RNA (the template molecule for protein production) and degrade it or change how it is processed.