Angelman Syndrome Gene Therapy Well Tolerated

The DSMB has recommended that enrollment expand and doses be escalated from 3.3 to 5 mg in 1 cohort of the KIK-AS study.

The gene therapy GTX-102 has been well-tolerated in the first 4 patients with Angelman syndrome (AS) dosed in the phase 1/2 open-label, multiple-dose, dose-escalating KIK-AS study (NCT04259281) in Canada and the UK.1 

Investigators observed promising signs of preliminary efficacy in 3 patients. No serious treatment-related adverse events (AEs) or any AEs related to lower extremity weakness were observed and the data safety monitoring board (DSMB) has recommended that dose-escalation continue as planned incohort 4, which includes children aged 4 to 8 years. In the US, a clinical hold was lifted from the study in October 2021 after patients receiving high doses of GTX-102 experienced lower extremity weakness.

“We are encouraged by the safety, the initial impressions from the investigators and the improvements observed in the clinical global impression scale from early assessments. The changes in multiple functional domains are encouraging and similar to the reported early changes in the original patients from the initial part of the study at these doses,” Scott Stromatt, MD, chief medical officer, GeneTx, said in a statement.1 “It is still early in the study and we look forward to the full assessments at the completion of the Day 128 study visit.”

The KIK-AS study is evaluating GTX-102, an intrathecally-administered antisense oligonucleotidedesigned to inhibit UBE3A-AS expression. In preclinical studies, the gene therapy candidate demonstrated efficacy in reducing UBE3A-AS levels and reactivating the paternal UBE3A allele in animal models of AS. Reactivation of this paternal allele has been associated with improvements in AS neurological symptoms.

READ MORE: FAST Grant Enables Creation of Angelman Syndrome Hotline

In Canada and the UK, the KIK-AS study is enrolling 12 patients with AS and a genetically confirmed diagnosis of full maternal UBE3A gene deletion split into cohorts 4 and 5 by age. Primary outcomes are assessing safety by AEs and secondary outcomes are assessing pharmacokinetics of GTX-102. Exploratory outcomes are assessing preliminary efficacy via overall Clinical Global Impression – Improvement (CGI-I) scale as well as communication, sleep, behavior, gross motor skills, fine motor skills, and seizure subdomains.

In the US, protocols have been amended following the clinical hold and all patients are being treated with 2 mg doses of GTX-102. The trial was put on hold after Ultragenyx announced initial efficacy results but also cases of a serious AE of lower extremity weakness in October 2020. All 5 patients treated with a single administration of the highest dose of GTX-102 experienced this AE as well as 1 patient treated with a single administration of the second-highest dose. In 2 patients, the weakness progressed to an inability to walk or bear weight. The AE has completely resolved in all patients.

“The dosing protocol across the three regions is designed to provide a broad picture on dose response to inform loading and maintenance regimens as we move to the next phase of development,”Stromatt said in a previous statement.2 “We are working with urgency to begin treating study participants in all three regions over the next several months recognizing that there is no approved therapy available for the Angelman community.”

Since the DSMB’s recommendation in Canada and the UK, both patients in cohort 4 have escalated doses from 3.3 mg to 5 mg and an additional patient has been dosed. The DSMB has not yet met for cohort 5, which includes patients aged 8 to 18 years initially receiving 5 mg doses. Full cohort 4 and 5 data is expected in mid-2022.

Patients in the 2 cohorts initially receive 2 doses and are assessed at day 58 before dose-escalating. Individual dose titration up to 14 mgmay also occur if found to be safe and more improvement may be achieved on CGI-I. After titration, patients will receive maintenance doses every 3 months and safety and efficacy will continue to be observed.

GTX-102 is being developed in a partnership between GeneTx and Ultragenyx, as the companies previously announced in 2019. The FDA has granted orphan drug, rare pediatric disease, and fast track designations to the investigational gene therapy.

1. GeneTxAnd Ultragenyx provide preliminary update on phase 1/2 clinical study of GTX-102 In Canada and U.K. Patients with Angelman Syndrome. News release. January 5, 2022.
2. GeneTx and Ultragenyx announce positive interim phase 1/2 data on investigational GTX-102 demonstrating improvement in patients with Angelman syndrome. News release. Ultragenyx. October 26, 2020.
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