The Use of GTX 102, an ASO as a Potential Therapeutic for Angelman Syndrome

Quick Overview

Dr. Scott Stromatt, Chief Medical Officer at Genetics, presented preliminary data from a Phase 1 trial of GTX-102, an investigational drug for Angelman Syndrome. GTX-102 is an antisense oligonucleotide (ASO) that targets RNA expression to activate a paternal gene that is typically silenced in individuals with Angelman Syndrome. The Phase 1 trial involves four monthly doses of GTX-102 given intrathecally by lumbar puncture. The primary objective is to determine the safety of GTX-102, while secondary objectives include determining pharmacokinetics and exploring functional domains of Angelman Syndrome. The trial has treated five patients to date, with doses ranging from 3.3 milligrams to 105.3 milligrams. Plasma pharmacokinetics showed dose-proportional levels of GTX-102 in the blood. Dr. Berry-Kravis will present the clinical data.


In this talk, Dr. Scott Stromatt, Chief Medical Officer at Genetics, and Dr. Berry-Kravis, a professor of pediatrics and co-director of the Angelman Syndrome Clinic at Rush University, present preliminary data from the Phase 1 trial of GTX-102 as a potential therapeutic for Angelman Syndrome. They emphasize that GTX-102 is an investigational drug and has not been approved by the FDA or any regulatory authority. The data presented are interim and do not provide definitive conclusions on efficacy or safety.

Understanding GTX-102 and Angelman Syndrome

GTX-102 is an antisense oligonucleotide (ASO), a single-stranded synthetic molecule composed of DNA and RNA. ASOs target RNA and alter RNA expression, thereby affecting protein production. In Angelman Syndrome, there is a missing or dysfunctional UBE3A maternal gene. GTX-102 activates the paternal copy of the gene, which is typically silenced. The goal of treatment with GTX-102 is to turn on the paternal gene and produce UBE3A protein.

Phase 1 Clinical Trial

The Phase 1 clinical trial of GTX-102 is a first-in-human study involving four monthly doses. It is a dose escalation study without a placebo control, and GTX-102 is administered intrathecally by lumbar puncture. The primary objective of the trial is to determine the safety of GTX-102, while the secondary objective is to determine the drug’s pharmacokinetics.

Study Design and Inclusion/Exclusion Criteria

The study includes a screening period of up to four weeks, four monthly doses of GTX-102, and a six-week follow-up period. The key inclusion criteria for participants are a full maternal UBE3A gene deletion, age between four and 17, stable seizure control, normal kidney and liver tests, and the ability to tolerate anesthesia. The key exclusion criteria include recent changes in medication or diet for Angelman Syndrome symptoms, inability to ambulate independently or with assistance, and bleeding or platelet disorders requiring intubation.

Exploratory Endpoints and Functional Domains

The study examines multiple functional domains of Angelman Syndrome, including communication, sleep, behavior, gross motor skills, fine motor skills, and seizures. Exploratory endpoints measure these domains to determine the impact of GTX-102 on clinical change. The combination of multiple tests will be required to understand the drug’s effects fully.

Dose Escalation and Safety Monitoring

The dose escalation starts with cohort one receiving 3.3 milligrams of GTX-102. After the second dose, a waiting period of two weeks allows the independent external data safety monitoring board to review the safety data. This board consists of an expert pediatric neurologist, a pediatric anesthesiologist, and a statistician. If the safety data is cleared, cohort one patients continue treatment, and cohort two starts treatment. This process continues for subsequent cohorts.

Preliminary Data and Patient Demographics

To date, five patients have been treated with GTX-102. The patients were treated at Rush University prior to the COVID-19 pandemic. The doses tested ranged from 3.3 milligrams to 36 milligrams. The patients’ ages ranged from five to 15 years old. The cumulative doses administered ranged from 20 milligrams to 105.3 milligrams.

Pharmacokinetics and Clinical Data

The plasma pharmacokinetics of GTX-102 showed dose-proportional levels in the blood. The drug was not detectable 28 days after administration, prior to the next dose, in either the blood or the cerebral spinal fluid. Further clinical data will be presented by Dr. Berry-Kravis.

In conclusion, the Phase 1 trial of GTX-102 as a potential therapeutic for Angelman Syndrome is ongoing. The preliminary data presented here provide insights into the safety and pharmacokinetics of the drug. Further research is needed to determine the efficacy and long-term effects of GTX-102.

Talk details

  • Title: The Use of GTX 102, an ASO as a Potential Therapeutic for Angelman Syndrome (Dr Scott Stromatt)
  • Author(s): Scott Stromatt
  • Author(s)’ affiliation: GeneTx Biotherapeutics
  • Publication date: 2021-01-02
  • Collection: 2020 FAST Science Summit