Angelman trial, page-45

Ultragenyx Announces Successful End-of-Phase 2 Meeting with FDA for GTX-102 Angelman Syndrome Program:

July 17, 2024
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Alignment with FDA on Phase 3 study primary endpoint of Bayley-4 cognition and key secondary endpoint of Multi-Domain Responder Index (MDRI)
Phase 3 study on track to initiate by the end of this year​

NOVATO, Calif., July 17, 2024 (GLOBE NEWSWIRE) -- Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE) today announced the successful completion of an end-of-Phase 2 (EoP2) meeting with the U.S. Food and Drug Administration (FDA), supporting its Phase 3 study plans for GTX-102, an antisense oligonucleotide for Angelman syndrome.
“FDA alignment on our Phase 3 study design for GTX-102 allows for rapid initiation of a global double-blind sham-controlled pivotal study by the end of this year,” said Eric Crombez, M.D., chief medical officer at Ultragenyx. “In addition to this pivotal study in patients with a full UBE3A gene deletion, we are working to initiate a study to evaluate GTX-102 in patients with other mutations. This will allow for the potential treatment of more children and adults impacted by this devastating disease.”
Phase 3 design and next steps
The EoP2 meeting focused on discussion of the Company’s interim Phase 1/2 data and resulted in alignment with the FDA on the Phase 3 study design and endpoints. The pivotal Phase 3, will be a global, randomized, double-blind, sham-controlled trial and will include a 48-week primary efficacy analysis period enrolling approximately 120 patients with Angelman syndrome with a genetically confirmed diagnosis of full maternal UBE3A gene deletion. The primary endpoint will be improvement in cognition assessed by Bayley-4 cognitive raw score. Control patients completing the study will be eligible to roll over onto treatment after the double-blind period is over.
Previously disclosed results from the Phase 1/2 study showed that UBE3A gene deletion patients treated with GTX-102 experienced rapid, progressive and clinically significant improvement in cognition, as assessed by Bayley-4, that was far greater than the minimal change observed in Natural History data¹ in deletion patients. UBE3A gene deletion patients are at the severe end of the clinical spectrum, with lower Bayley scores at baseline, and demonstrate a much slower rate of skill attainment compared to, for example, UBE3A missense mutation patients, who demonstrate higher Bayley cognition improvement in Natural History data.² In the Phase 1/2 study, GTX-102 treated patients also demonstrated meaningful improvements in other domains of communication, motor function, sleep problems, and behavior.
The Phase 3 study will include the key secondary endpoint of the Multi-domain Responder Index (MDRI) across all five domains of cognition, receptive communication, behavior, gross motor function, and sleep. Individual secondary endpoints were also discussed and aligned on with the FDA for the domains of communication, behavior, motor function and sleep. Additional feedback on the conduct and analysis of these endpoints may be received from the FDA’s Division of Clinical Outcomes Assessment


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