Ultragenyx Reports Positive Interim Phase 1/2 Data in Patients with Angelman Syndrome

Rare Daily Staff

Ultragenyx Pharmaceutical reported positive new data from the phase 1/2 study of GTX-102 for the treatment of patients with the rare neurogenetic disorder Angelman syndrome.

Patients in expansion cohorts A & B treated with a set dose and regimen of GTX-102 showed rapid and clinically meaningful improvement across multiple domains consistent with or exceeding dose-escalation cohorts 4-7 data at Day 170. Treatment of the dose-escalation cohorts 4-7 showed long-term increasing and sustained clinical benefit far exceeding natural history data at Day 758.

These data will be presented at the 76th Annual American Academy of Neurology Meeting in Denver on April 16.

Angelman syndrome is caused by loss-of-function of the maternally inherited allele of the UBE3A gene. 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 generally not inherited but instead occurs spontaneously. It is estimated to affect approximately 60,000 people in commercially accessible geographies.

Individuals with Angelman syndrome have a lifelong neurodevelopmental disorder including cognitive impairment, motor impairment, balance issues, and debilitating seizures. People with Angelman syndrome have a normal lifespan, but 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.

GTX-102 is an investigational antisense oligonucleotide delivered via intrathecal administration and designed to target and inhibit expression of UBE3A-AS, which is involved in silencing the paternal UBE3A allele. Nonclinical studies have shown that GTX-102 reduces 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, Rare Pediatric Disease, and Fast Track designation from the U.S. Food and Drug Administration, and Orphan Designation and PRIME designation from the European Medicines Agency.

The Phase 1/2, open-label, multiple-dose, dose-escalating study is evaluating the safety and tolerability of GTX-102 administered by intrathecal (IT) injection to pediatric patients with Angelman syndrome with a genetically confirmed diagnosis of full maternal UBE3A gene deletion. The study is also assessing clinical response as measured by a panel of efficacy assessments for the functional domains impacted in Angelman syndrome. The study has enrolled and treated 74 patients in both dose-escalation and expansion cohorts. Patients in Cohorts 4-7 (dose-escalation) are receiving long-term maintenance dosing. Data from the expansion cohorts will be used to verify the GTX-102 dose and treatment regimen for the pivotal Phase 3 study.

New expansion cohorts A & B data include Day 170 results on 24 patients, and long-term dose-escalation cohorts 4–7 data include up to Day 758 results on 15 patients.

Cognition among new expansion cohorts A and B showed rapid and clinically significant improvement compared with natural history data. Day 170 data were consistent with the treatment benefit observed in the dose-escalation cohorts at a similar timepoint. Behavior showed rapid improvement exceeding the treatment benefit observed in the dose-escalation cohorts at Day 170. Hyperactivity and noncompliance showed rapid and clinically significant improvement at Day 170 compared with natural history data, providing further insight into one of the most commonly reported behavioral issues. Sleep showed rapid and clinically meaningful improvement exceeding treatment benefit observed in the Dose-escalation Cohorts at Day 170.

Receptive communication assessed by Bayley-4 showed rapid improvement compared with Natural History data. Day 170 data were consistent with the treatment benefit observed in the Dose-escalation Cohorts at a similar timepoint.

Gross Motor function assessed by ASA showed rapid improvement exceeding the treatment benefit observed in the Dose-escalation Cohorts at Day 170. Gross motor assessments as measured by Bayley-4 were not performed at Day 170 in the Expansion Cohorts to reduce patient testing burden and are not included in this analysis at this timepoint.

Multi-domain Responder Index (MDRI) analysis across the four domains of cognition, receptive communication, behavior and sleep resulted in a total net response of +2.0. The majority of patients had already achieved a total net response of +2 to +4 domains, demonstrating improvement exceeding the minimally important difference threshold in several domains even at this early Day 170 timepoint.

Cognition continuing long-term improvement compared with Natural History data and exceeded the threshold of clinical significance by many-fold in many patients in the dose-escalation cohort up to Day 758. All other markers showed sustained and clinically meaningful improvement compared with natural history data.

There were no unexpected serious adverse events. Three patients had serious adverse events (mild to moderate) of lower extremity weakness assessed as related to study treatment. All resolved rapidly without sequelae and remain in the study without ongoing safety concerns.

“The totality of these interim data demonstrates that treatment with GTX-102 resulted in rapid, multi-domain improvements that continued during maintenance dosing. These broad developmental gains are having a meaningful impact on patients and their families,” said Eric Crombez, chief medical officer at Ultragenyx. “For example, we’re hearing about children who are now able to routinely communicate their needs to family members, which greatly improves their ability to interact with their caregivers. We have also heard from families about their children who are accumulating additional developmental gains such as running, swimming and independent eating.”

He said the company will have an end of phase 2 meeting with the FDA and interactions with other health authorities to enable timely initiation of a phase 3 pivotal study.

Photo: Eric Crombez, chief medical officer at Ultragenyx