Ultragenyx Reports Successful End-of-Phase 2 FDA Meeting for GTX-102 in Angelman Syndrome

Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE) has announced the successful completion of an end-of-Phase 2 (EoP2) meeting with the U.S. Food and Drug Administration (FDA), which supports its Phase 3 study plans for GTX-102, an antisense oligonucleotide aimed at treating Angelman syndrome. The Phase 3 study is set to begin by the end of this year. Eric Crombez, M.D., the chief medical officer at Ultragenyx, highlighted that FDA's alignment on the Phase 3 study design allows for a swift initiation of a global, double-blind, sham-controlled pivotal trial. This trial will not only focus on patients with a full UBE3A gene deletion but also plans to include patients with other mutations to potentially treat a broader range of individuals affected by Angelman syndrome.

During the EoP2 meeting, discussions centered on the company’s interim Phase 1/2 data, resulting in alignment with the FDA on the Phase 3 study design and its endpoints. The pivotal Phase 3 trial will be global, randomized, double-blind, and sham-controlled. It will feature a 48-week primary efficacy analysis period and aims to enroll around 120 patients with a genetically confirmed diagnosis of a full maternal UBE3A gene deletion. The primary endpoint will focus on cognitive improvement measured by the Bayley-4 cognitive raw score. Patients in the control group who complete the study will be eligible to transition to treatment after the double-blind period concludes.

Previous Phase 1/2 study results indicated significant cognitive improvements in UBE3A gene deletion patients treated with GTX-102, as measured by the Bayley-4 cognitive scores. These improvements were notably greater than those observed in Natural History data for deletion patients. Such patients typically exhibit severe symptoms and slower skill acquisition compared to UBE3A missense mutation patients, who show higher cognitive improvements in Natural History data. Additionally, GTX-102-treated patients demonstrated meaningful enhancements in communication, motor function, sleep, and behavior.

The upcoming Phase 3 study will also include the Multi-Domain Responder Index (MDRI) as a key secondary endpoint, covering cognition, receptive communication, behavior, gross motor function, and sleep. Other individual secondary endpoints in these domains were also discussed and agreed upon with the FDA. Feedback on these endpoints' conduct and analysis may be received from the FDA’s Division of Clinical Outcomes Assessment.

Ultragenyx also engaged with the European Medicines Agency (EMA) in a PRIME meeting, securing acceptance of the overall Phase 3 study design, dosing, and evaluations. A meeting with Japan’s Pharmaceuticals and Medical Devices Agency is anticipated in the coming weeks to discuss the Phase 3 study design further.

In addition to the randomized, controlled Phase 3 study, Ultragenyx plans to initiate an open-label clinical study to assess the safety and efficacy of GTX-102 in patients with different Angelman syndrome genotypes and various age groups. This additional study aims to broaden the range of Angelman patient types that can be treated.

GTX-102, an investigational antisense oligonucleotide administered via intrathecal injection, targets and inhibits UBE3A-AS expression. Nonclinical studies have demonstrated that GTX-102 reduces UBE3A-AS levels and reactivates paternal UBE3A allele expression in CNS neurons. Reactivating paternal UBE3A expression in animal models of Angelman syndrome has shown improvements in neurological symptoms. GTX-102 has received Orphan Drug Designation, Rare Pediatric Disease Designation, and Fast Track Designation from the FDA, as well as Orphan Designation and PRIME designation from the EMA.

Angelman syndrome is a rare neurogenetic disorder caused by the loss of function of the maternally inherited UBE3A gene allele. It is characterized by cognitive and motor impairments, balance issues, and seizures. While individuals with Angelman syndrome have a normal lifespan, they require lifelong care and cannot live independently. There are no approved therapies for Angelman syndrome currently, but the potential for symptomatic improvement at any age has been suggested by studies in adult animal models.

Ultragenyx is a biopharmaceutical company focused on developing novel treatments for serious rare and ultra-rare genetic diseases. The company has built a diverse portfolio of approved therapies and product candidates targeting diseases with high unmet medical needs and clear biological targets. Ultragenyx's strategy emphasizes efficient drug development to deliver safe and effective therapies to patients urgently.