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Ultragenyx to Study Angelman Syndrome Treatment in US With FDA Protocol Amendment Approval

NEW YORK – Ultragenyx Pharmaceuticals on Wednesday said the US Food and Drug Administration has approved a protocol change in its Phase I/II trial of GTX-102, an antisense oligonucleotide therapy it is developing for treating Angelman syndrome in pediatric patients who have lost function of the maternal copy of UBE3A gene allele.

Novato, California-based Ultragenyx has been enrolling the Phase I/II trial of GTX-102 outside of the US and working on establishing the dose and treatment regimen for use in Phase III trials. The protocol amendment approved by the FDA allows the company to increase loading and maintenance doses for patients enrolled at US trial sites in line with those given to patients in expansion cohorts at trial sites in Europe, Australia, and Canada.

"Agreement on the protocol amendment enables comparable dose ranges across all geographies and allows us to move forward rapidly to complete the study," Scott Stromatt, senior VP and chief medical officer of neurology clinical development at Ultragenyx, said in a statement, adding that the company is in the process of activating multiple US study sites. "We are eager to expand the study in the US to build on the encouraging data, which demonstrate important clinical activity across multiple functional domains impacted by Angelman syndrome with an acceptable safety profile."

In the Phase I/II dose-escalating trial, Ultragenyx is evaluating the safety and tolerability of GTX-102 and assessing clinical response by measuring the impact the drug has on the functional domains affected in Angelman syndrome. As of early May, 13 patients have received GTX-102 for more than a year and some patients have been on the drug for more than 18 months. The company aims to enroll a total of 40 patients in the trial.

Angelman syndrome is a rare, neurogenetic disorder that affects between 1 in 12,000 and 1 in 20,000 people worldwide and is characterized by developmental delay, debilitating seizures, and mobility issues; patients can't speak or live independently. The syndrome is caused by loss of function of UBE3A. Normally, in nerve cells only the maternally inherited copy of the gene is turned on, but in 70 percent of patients with Angelman syndrome, a segment of chromosome 15 containing UBE3A is deleted.

To participate in Ultragenyx's trial, patients must have a confirmed diagnosis of Angelman syndrome due to a full maternal UBE3A gene deletion. GTX-102 is designed to reduce levels of the UBE3A antisense transcript and reactivate expression of the paternally inherited UBE3A allele in neurons. In animal models of Angelman syndrome, reactivation of paternal UBE3A expression by GTX-102 improved some neurological symptoms seen with the condition, according to Ultragenyx.