Ultragenyx Pharmaceutical Inc. a program update on GTX-102 for the treatment of Angelman syndrome (AS), including encouraging interim data from the open-label, dose-escalating Phase 1/2 study in pediatric patients who have a genetically confirmed diagnosis of full maternal UBE3A gene deletion. Interim results on 9 patients from the U.K./Canada arm and 2 patients from the U.S. arm of the Phase 1/2 study demonstrate a meaningful improvement in clinical disease and an acceptable safety profile. These interim data supported a protocol amendment to the Phase 1/2 study that was approved by the U.K. and Canadian health authorities in May 2022 to initiate additional, new cohorts of patients at higher monthly loading doses.

The study has begun to enroll under the amended protocol and has dosed the first patient in these new cohorts. The protocol approved in the U.K. and Canada permitted enrollment of up to 12 patients; the companies completed enrollment at 6 patients in the younger Cohort 4 and capped enrollment at 4 patients in the older Cohort 5 based on early encouraging safety and efficacy data in order to amend the protocol and begin dosing newly enrolled patients at higher levels. As of the data cut off, 9 of these 10 patients dosed had reached study Day 128 or further.

Six patients in younger Cohort 4 initiated dosing at 3.3 mg and 4 patients in older Cohort 5 initiated dosing at 5 mg. Patients were titrated on an individual basis. Four patients of the younger Cohort 4 reached the first pre-maintenance dose (PMD) visit at Day 170 and received 7.5 mg doses, and one of these patients reached the second PMD dose at 10 mg.

Data were available on 3 patients through the first PMD visit by the data cutoff. Three of the older Cohort 5 patients reached the first PMD dose and received 10 mg doses, and one of these patients had data available by the data cutoff. The protocol approved in the U.S. permitted enrollment of up to 8 patients enrolled into two groups, an active and an age-matched comparator group.

Four patients ages 4 to =8 years old have received 4 monthly 2 mg doses of GTX-102 and 2 patients had Day 128 data available at the time of analysis. There have been 14 patients to receive treatment thus far, 10 under the U.K. and Canada protocol, and 4 under the U.S. protocol. Of these, 7 patients have received cumulative doses over 20 mg, and 13 patients have over 147 days of exposure to treatment.

There have been no treatment-related serious adverse events of any type nor adverse events related to lower extremity weakness observed in these patients. The most common adverse events in the U.K./Canada Cohorts (Cohorts 4 and 5) were vomiting (5/10), COVID (4/10), upper respiratory infection (3/10) and transient back pain (2/10). In the U.S. Cohort, 2 of 4 patients had no adverse events, a third had transient difficulty in sleeping and the fourth patient had emesis, upper respiratory infection, and asymptomatic EBV hepatitis that resolved and the patient resumed dosing.

Cerebrospinal fluid (CSF) protein levels have remained stable throughout the course of the study consistent with absence of inflammation. There was one case of CSF protein elevation in the U.K./Canada protocol that was due to an asymptomatic reactivation of Varicella Zoster Virus. The protein normalized and the patient resumed dosing without any issues.

One subject in the U.S. protocol had a single modestly elevated CSF protein that resolved on the subsequent assessment. The “AS Change Scale” (Clinical Global Impression of Change, or CGI-C-AS) and the “AS Severity Scale” (Clinical Global Impression of Severity, or CGI-S-AS) are clinician assessments used to assess patients across five domains (sleep, behavior, communication, gross motor, and fine motor skills) and overall change. The AS Change Scale is a relative scale of improvement, and the AS Severity Scale is an objective scale with criteria for each change in domain severity.

AS Change Scale evaluations at Day 128 show 7 out of 9 patients improved from Baseline in at least 3 of 5 domains and in the overall score. These data are supported by the AS Severity Scale evaluations taken at Baseline and Day 128 where 6 patients exhibited a decrease in severity in at least 2 of 5 domains and in the overall score. Furthermore, one patient from Cohort 4 showed a 2 or 3-point improvement in the AS Severity Scale across all 5 domains at the PMD assessment at Day 170.

This suggests continued improvement from Day 128 prior to receiving the fifth dose. These promising improvements in the AS Change and Severity Scale scores were also supported by the other clinical measurements including the Bayley Scales of Infant and Toddler Development (Bayley-4), which is administered by a trained psychologist; the Vineland-3 adaptive behavior scale, which is administered by a clinician; and the Observed Reported Communication Ability (ORCA), a caregiver-reported questionnaire. AS Change Scale evaluations taken at Baseline and Day 128 in 2 patients show both had relative improvement from baseline in at least 3 of 5 domains and overall.

These data were supported by AS Severity Scale evaluations taken at Baseline and Day 128 where both patients exhibited a decrease in severity in at least 2 of 5 domains and overall. Under the new study amendment approved in the U.K. and Canada, additional dose-selection cohorts will sequentially enroll new patients at incrementally higher starting doses ranging from 7.5 to 14 mg based on age. A younger Cohort 6 will begin dosing at 7.5 mg and an older Cohort 7 at 10 mg.

Once clinically sufficient efficacy is observed, two expanded cohorts will enroll 20 patients in each age range using the optimal dosing algorithm determined from the dose-selection cohorts. These patients would provide the longer-term efficacy and safety information for the program. Ultragenyx will seek to initiate the amended protocol in the U.S. pending discussions with the FDA.

In the Maintenance phase, patients from all cohorts will receive treatment with GTX-102 once every 3 months after the patient's last monthly dose of GTX-102, with incremental dose escalations possible to a maximum dose of 14 mg based on achieving an adequate clinical response.