Rare Daily Staff

GeneTx Biotherapeutics and Ultragenyx Pharmaceutical reported that the U.S. Food and Drug Administration has accepted GeneTx’s Investigational New Drug application for GTX-102, an experimental antisense oligonucleotide being evaluated for the treatment of Angelman syndrome.

Enrollment in the phase 1/2 study is expected to begin in the first half of 2020.

“The FDA’s clearance of the IND to evaluate GTX-102 in patients with Angelman syndrome represents a significant milestone for the Angelman community,” said Paula Evans, CEO at GeneTx, which was launched by the patient advocacy organization FAST to develop medicines for Angelman patients. “Assessing an investigational therapy that aims to address the underlying cause of this devastating disorder has the potential to meaningfully alter the clinical course of patients’ lives.”

Angelman syndrome is a rare, neurogenetic disorder caused by loss-of-function of the maternally inherited allele of the UBE3A gene. The maternal-specific inheritance pattern of Angelman syndrome is due to genomic imprinting of UBE3A in neurons of the central nervous system, a naturally occurring phenomenon in which the maternal UBE3A allele is expressed and the paternal UBE3A is not. Silencing of the paternal UBE3A allele is regulated by the UBE3A antisense transcript (UBE3A-AS), the intended target of GTX-102. In almost all cases of Angelman syndrome, the maternal UBE3A allele is either missing or mutated, resulting in limited to no protein expression. This condition is typically not inherited but instead occurs spontaneously.

Individuals with Angelman syndrome have developmental delay, balance issues, motor impairment, and debilitating seizures. Some individuals with Angelman syndrome are unable to walk and most do not speak. Anxiety and disturbed sleep can be serious challenges in individuals with Angelman syndrome. While individuals with Angelman syndrome have a normal lifespan, they require continuous care and are unable to live independently.

Angelman syndrome is not a degenerative disorder, but the loss of the UBE3A protein expression in neurons results in abnormal communications between neurons. The condition is often misdiagnosed as autism or cerebral palsy.

GTX-102 is an experimental antisense oligonucleotide designed to target and inhibit expression of UBE3A-AS. Studies show that GTX-102 reduces the levels of UBE3A-AS and reactivates expression of the paternal UBE3A allele in neurons of the CNS, and that reactivation of paternal UBE3A expression in animal models of Angelman syndrome improves some of the neurological symptoms associated with the condition.

“Based on preclinical data, we believe that GTX-102 offers tremendous promise and may one day provide patients with a potentially transformative therapeutic option,” said Camille Bedrosian, chief medical officer of Ultragenyx.

GeneTx’s phase 1/2 study, named KIK-AS (Knockdown of UBE3A-antisense in Kids with AS), is expected to enroll 20 patients at multiple trial sites, beginning in the first half of 2020. The goal of this multiple dose, dose escalating, open-label study is to examine the safety, tolerability, and pharmacokinetics of GTX-102 in pediatric patients with Angelman syndrome. On February 15, 2020 GeneTx will open a website with more information on the KIK-AS study and provide a toll free number for parents and caregivers to obtain information on enrolling into the clinical study.

The FDA has granted GTX-102 Orphan Drug and Rare Pediatric Disease designations. In August 2019, GeneTx and Ultragenyx partnered to develop GTX-102, with Ultragenyx receiving an exclusive option to acquire GeneTx.

Photo: Paula Evans, CEO of GeneTx

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