GTX-102 Leads to Significant Improvements in Trial, But Also Causes Muscle Weakness

Use of GTX-102, GeneTx Biotherapeutics and Ultragenyx’s investigational therapy for Angelman syndrome, led to substantial improvements in disease symptoms among children and adolescents across several treatment areas — including behavior, communication, sleep, and gross and fine motor function — according to data from the first five participants treated in the ongoing Phase 1/2 KIK-AS trial.

“These initial GTX-102 findings raise the possibility of improving some of the significant symptoms of Angelman syndrome,” Emil D. Kakkis, MD, PhD, CEO and president of Ultragenyx, said in a press release, noting the participants in the study were ages 5 to 15.

However, interim data from the trial (NCT04259281) also showed that when given at the highest doses, GTX-102 caused the children and adolescents to develop serious, but reversible, muscle weakness in their legs and feet.

Based on these findings, the companies suspended dosing and also halted patient enrollment into the trial. After reviewing all of the study data, GeneTx Biotherapeutics and Ultragenyx decided to amend the trial’s protocol to decrease the therapy’s dose range, as well as change the way GTX-102 is administered.

The therapy’s dose will be lowered to the safe range where clinical benefits were first observed, and then increased at a slower pace, based on each patient’s response and age. GTX-102’s mode of administration also will be altered to reduce the participants’ local contact time with the medication as it is given — done as an intrathecal injection, or an injection directly into the spinal canal.

The two companies will present both protocol alterations, which are expected to lower the risk of treatment-related side effects, to the U.S. Food and Drug Administration for approval before resuming patient enrollment and dosing in KIK-AS.

“So far we are seeing rapid improvements in multiple areas, including some kids doing things they’ve never done before, and I don’t believe this rate of progress in development skills has been seen before in Angelman syndrome,” said Elizabeth M. Berry-Kravis, MD, PhD, trial investigator and professor of pediatrics, neurological sciences and biochemistry at Rush University Medical Center, in Chicago.

“It is especially amazing that families are asking me repeatedly when they can start treatment again despite the side effects that their child experienced. That speaks to the value of what they were seeing in their child,” Berry-Kravis added.

GTX-102 is an antisense oligonucleotide that is designed to target and inactivate the UBE3A antisense transcript. That molecule normally shuts down the activity of the paternal copy of the UBE3A gene in the brain during a natural process known as genomic imprinting. Of note, antisense oligonucleotides, or ASOs, are small molecules that can bind to RNA molecules and destroy them or change the way they are processed.

By inactivating the UBE3A antisense transcript, GTX-102 is expected to promote the reactivation of the paternal copy of UBE3A in the brain, which in turn may compensate for the lack of a functional maternal copy of the gene that is known to cause Angelman.

KIK-AS was designed to assess the safety, tolerability, and preliminary efficacy of multiple doses of GTX-102 in up to 20 children and adolescents, ages 4–17, with Angelman.

During the trial, once it resumes, the participants will be assigned to one of five dosing groups. Each child will receive four monthly doses of GTX-102, administered by intrathecal injections, following an individual dose escalation scheme.

After completing the six-month study, the children and adolescents will have the option to enroll in an open-label extension study to continue treatment with GTX-102.

Interim findings now announced by the companies included data from the first five patients treated in KIK-AS, who all were in the first three dosing groups.

All five patients showed improvements in the Clinical Global Impression of Improvement Scale for Angelman Syndrome (CGI-I-AS). That seven-point scale assesses changes in a patient’s condition across five key domains that include communication, fine and gross motor skills, behavior, and sleep.

At day 128, after approximately four months, three patients saw their overall CGI-I-AS scores increase by two points, corresponding to a “much improved” condition. Meanwhile, two participants saw their scores increase by three points, reflecting a “very much improved” health state. In individual domains, all five patients had “much improved” or “very much improved” scores on at least two measures.

With some participants, the improvements were already apparent within the first few weeks following their first dose.

These improvements in overall CGI-I-AS scores and individual key domains also were supported by data from caregiver-reported outcomes, which suggested that children and adolescents receiving GTX-102 became more communicative, self-sufficient, social, and able to engage in physical activities over the course of the study.

However, four participants developed serious, but reversible, muscle weakness in their lower extremities — their legs and feet — after receiving the highest dose of GTX-102. That dose was approximately 10 times higher than the initial low dose given to those in the first dosing group. The remaining patient also experienced the same weakness after receiving the second-highest dose tested, which was approximately six times higher than the initial dose of the first dosing group.

In two children, the muscle weakness progressed to the point where they were no longer able to walk or bear their own weight.

Nevertheless, this side effect was deemed to be mild or moderate in all cases.

The muscle weakness fully resolved in four patients within 19 to 70 days following GTX-102 interruption and treatment with intravenous immunoglobulin (IVIg) and corticosteroids. In the fifth patient, muscle weakness improved after three to four weeks, and is now nearly resolved.

These episodes of muscle weakness also were accompanied by an increase in the levels of proteins found in the cerebrospinal fluid (CSF), the liquid that circulates in the brain and spinal cord. That effect has been reported previously in other studies of intrathecally administered ASOs. MRI scans performed afterward also found signs of local inflammation in the nerves located in the patients’ lower back where the intrathecal injections had been administered.

No other serious adverse events were reported. Other adverse events reported in KIK-AS included headache, fatigue, and temporary ataxia, or a lack of muscle control or coordination of voluntary movements. Temporary ataxia happened in all five patients beginning two to six hours following treatment administration and lasted one to three days. None of the patients withdrew from the study prematurely.

Additional data from the first five patients dosed in KIK-AS will be presented at the Foundation for Angelman Syndrome Therapeutics (FAST) Global Summit in December. Additional safety and efficacy data from the trial are expected to be announced in 2021.