Further preliminary safety and efficacy data from a Phase 1/2 clinical trial into the investigational therapy GTX-102 in children and adolescents with Angelman syndrome may allow the study to resume patient enrollment and dosing.
GeneTx Biotherapeutics and Ultragenyx , which are co-developing the treatment, shared these data in presentations at the recent Foundation for Angelman Syndrome Therapeutics (FAST) Global Summit. They support previous signs of treatment safety and potential efficacy.
The companies placed the trial on hold last year after five patients treated at the highest doses developed serious, but reversible, muscle weakness in their legs and feet. Plans were announced to amend the study’s protocol, lowering the treatment’s dosing range and changing how it is given by intrathecal (spinal canal) injection.
These protocol changes will be presented to the U.S. Food and Drug Administration (FDA) for approval, and patient enrollment and dosing will start again if they are accepted, GeneTx and Ultragenyx announced in a press release.
“We better understand the serious adverse events reported with GTX-102 at higher doses and we see a way forward to redose patients and to enroll new patients into the clinical trial. We are working with FDA to reach agreement on a modified trial design,” said Scott Stromatt, MD, chief medical officer of GeneTx, who was one of the presenters at FAST.
GTX-102 is an antisense oligonucleotide designed to target the molecule that causes Angelman syndrome (UBE3A antisense transcript, or UBE3A-AS) and to prevent it from working. By inactivating the UBE3A-AS, GTX-102 is expected to promote the reactivation of the paternal copy of UBE3A in the brain, which may compensate for the lack of a working maternal copy of the gene, which is known to cause Angelman syndrome.
The KIK-AS (Knockdown of UBE3A-antisense, NCT04259281) is an open-label trial evaluating the safety, tolerability, and preliminary efficacy of multiple doses of GTX-102 in up to 20 children and adolescents (ages 4 to 17) with Angelman.
Each child is to receive ascending, once monthly doses of GTX-102, administered by intrathecal injections, with dose escalation now to be determined for each child. Once the trial is finished, patients will be invited to participate in an open-label extension study and continue receiving GTX-102.
Previous results had show that treatment led to substantial improvements across several treatment areas — including behavior, communication, sleep, and gross and fine motor function. However, muscle weakness within one month of the highest doses being given — four children after the final, 36 mg injection, and one child at 20 mg — were reported. All have been successfully treated and fully resolved, the companies stated, and no patients have withdrawn from the trial.
Treatment should the trial resume will be given at doses below 20 mg, the release reported.
Data presented at FAST from the first five patients treated with GTX-102 in the first three dosing groups show that plasma levels of GTX-102 were dose proportional, and GTX-102 did not accumulate in the blood or cerebrospinal fluid (the fluid surrounding the brain and spinal cord).
All five patients showed improvements in the Clinical Global Impression of Improvement Scale for Angelman Syndrome (CGI-I-AS), which included changes in five key domains (communication, seizure frequency, fine and gross motor skills, behavior, and sleep).
The communication domain of the CGI-I-AS showed “much improved” or “very much improved scores” in four of five subjects.
In the Bayley Scales of Infant and Toddler Development (Bayley-4) — which assesses the development of infants and toddlers — several patients improved on receptive or expressive communication sub-scales.
In the Observed Reported Communication Ability (ORCA) — which measures different types of expressive, receptive, and pragmatic forms of communication — three patients had clinically relevant increases at day 128, while two patients did not have notable changes.
Seizure frequency, as evaluated by electroencephalogram (EEG) readings at the beginning of the study and day 128, decreased in three of the four evaluated patients, with one patient showing minimal change or a slight increase. Due to the variability in tracing these assessments will be repeated after long-term treatment.
Readings from the ActiMyo, a device worn by patients to record motion signals and measure hourly distance walked, stride length, and stride speed, revealed that one patient who had a decrease in distance walked due to the lower extremity weakness, now gained in meaningful gross and fine motor abilities.
Clinical response appeared to last three to five months after the last dose of GTX-102. While most patients have retained many caregiver-reported clinical changes, some are experiencing a loss of effect.
Preclinical studies in non-human primates also showed lower limb weakness that generally resolved 24 hours after treatment.
In these studies, monthly dosing of GTX-102 was able to reduce the levels of UBE3A-AS in different brain regions relevant to Angelman syndrome.
“GTX-102 demonstrates a paternal UBE3A gene targeting strategy can result in substantial clinical activity and in a more rapid time frame than we expected,” Stromatt said in the release.
“I am excited by the preliminary findings presented at the FAST scientific symposium. A tremendous amount of work was put into understanding the UBE3A-AS transcript and developing GTX-102, so it is great to see how those efforts have translated into initial indications of effect,” added Scott Dindot, PhD, an associate professor at Texas A&M University and executive director of Molecular Genetics at Ultragenyx.
GTX-102 has received fast track, orphan drug and rare pediatric disease designations from the FDA as a potential Angelman treatment.
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