SARASOTA, FL and NOVATO, CA, USA I September 27, 2021 I GeneTx Biotherapeutics LLC and Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), companies partnered in the development of GTX-102, an investigational treatment for Angelman syndrome, today announced that the U.S. Food and Drug Administration (FDA) has removed the clinical hold and GeneTx may begin dosing naïve patients in the Phase 1/2 study of GTX-102 in pediatric patients with Angelman syndrome. GeneTx previously received clearance, under a separate amendment, to begin the Phase 1/2 study in the United Kingdom and Canada.

“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,” said Scott Stromatt, M.D., Chief Medical Officer of GeneTx. “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.”

Phase 1/2 study design in the United States
The Phase 1/2 open-label, multiple-dose study evaluates the safety, tolerability, and plasma and cerebrospinal fluid concentrations of GTX-102 in pediatric patients with Angelman syndrome with a genetically confirmed diagnosis of full maternal UBE3A gene deletion.

Naïve Patient Dose-loading Phase
Under the amended U.S. protocol, eight patients (4 to < 8 years of age) who were not previously treated with GTX-102 will be enrolled into two groups, an active group and an age-matched comparator group. The active group will receive four monthly 2 mg doses of GTX-102, while the comparator group will have limited assessments at baseline and Day 128. Patients in the comparator group will then be eligible to receive GTX-102 under the same dosing strategy as the active group.

Maintenance Phase
All U.S. patients who have completed the dose-loading phase will then move to a maintenance phase during which they will receive 2 mg of GTX-102 every three months and continue to be monitored for response and safety.

Phase 1/2 study design in U.K. and Canada

Under the protocol approved in the U.K. and Canada, approximately 12 patients will be enrolled into two cohorts split by age: patients ages 4 to < 8 years will be enrolled into Cohort 4, and patients ages 8 to < 18 years will be enrolled into Cohort 5. Two in the younger cohort and two in the older cohort will be enrolled first and assessed after two doses by a data safety monitoring board. If recommended, then an additional four patients can be enrolled in each of the two cohorts.

The starting doses in Cohorts 4 and 5 will be 3.3 and 5 mg, respectively. Patients will receive three to four monthly doses, titrated individually through smaller steps than the first three cohorts in the original study with dose increases based on response and enhanced safety monitoring. Patients will then move to a maintenance phase during which they will receive GTX-102 every three months and continue to be monitored for response and safety. In this phase, individual dose titration may continue if safety is sustained, and the clinical response is not much improved in at least 2 domains up to a maximum dose of 14 mg.

About Angelman Syndrome

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. It is estimated to affect 1 in 12,000 to 1 in 20,000 people globally.

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. Angelman syndrome is often misdiagnosed as autism or cerebral palsy. There are no currently approved therapies for Angelman syndrome; however, several symptoms of this disorder can be reversed in adult animal models of Angelman syndrome suggesting that improvement of symptoms can potentially be achieved at any age.

About GTX-102

GTX-102 is an investigational antisense oligonucleotide delivered via intrathecal administration and designed to target and inhibit expression of UBE3A-AS. Nonclinical studies show that GTX-102 reduces the levels of UBE3A-AS and reactivates expression of the paternal UBE3A allele in neurons of the CNS. Reactivation of paternal UBE3A expression in animal models of Angelman syndrome has been associated with improvements in some of the neurological symptoms associated with the condition. GTX-102 has been granted Orphan Drug Designation, Rare Pediatric Disease Designation, and Fast Track Designation from the U.S. Food and Drug Administration (FDA). In August 2019, GeneTx and Ultragenyx announced a partnership to develop GTX-102, with Ultragenyx receiving an exclusive option to acquire GeneTx.

About GeneTx Biotherapeutics

GeneTx Biotherapeutics LLC is a startup biotechnology company singularly focused on developing and commercializing a safe and effective antisense therapeutic for the treatment of Angelman syndrome. GeneTx was launched by FAST, a patient advocacy organization and the largest non-governmental funder of Angelman syndrome research. GeneTx licensed the rights to antisense technology intellectual property from the Texas A&M University System in December 2017.

About Ultragenyx Pharmaceutical Inc.

Ultragenyx is a biopharmaceutical company committed to bringing novel therapies to patients for the treatment of serious rare and ultra-rare genetic diseases. The company has built a diverse portfolio of approved medicines and treatment candidates aimed at addressing diseases with high unmet medical need and clear biology, for which there are typically no approved therapies treating the underlying disease.

The company is led by a management team experienced in the development and commercialization of rare disease therapeutics. Ultragenyx’s strategy is predicated upon time- and cost-efficient drug development, with the goal of delivering safe and effective therapies to patients with the utmost urgency.

For more information on Ultragenyx, please visit the company’s website at:

SOURCE: Ultragenyx Pharmaceutical