Ultragenyx Pharmaceutical, a biopharmaceutical company focused on the development of novel products for rare and ultra-rare diseases, announced topline data from the Phase 2 study of UX007 in glucose transporter type-1 deficiency syndrome (Glut1 DS) patients with seizures. The study did not meet the primary endpoint of reducing the frequency of total number of observable and absence seizures among patients treated from baseline to Week 8 with UX007 compared to placebo. When evaluating each seizure type independently, treatment with UX007 did show a reduction in absence seizures captured on EEG, but not observable seizures captured by diary.
“These data suggest that UX007 has a clinically meaningful effect in Glut1DS patients with absence seizures,” said Emil D. Kakkis, M.D., Ph.D., Chief Executive Officer and President of Ultragenyx. “We look forward to studying UX007 in our Phase 3 study in Glut1 DS patients with movement disorders, and continue to evaluate our plans in the seizure indication.”
Efficacy Results
UX007 did not meet the primary endpoint of the study during the eight-week placebo-controlled treatment period when evaluating observable and absence seizures together. Patients treated with UX007 (n=25) demonstrated a reduction of 13.4% in overall seizure frequency (p=0.41) relative to placebo (n=11).
For the pre-specified secondary analysis of the primary endpoint, patients with absence seizures (n=19) demonstrated a 47.3% reduction (p=0.009) in seizure frequency after eight weeks of treatment with UX007, compared to baseline. While clinically significant, this did not meet the statistical significance threshold of 0.005 using the pre-defined multiplicity adjustment. Patients with observable seizures (n=17) demonstrated a 9.1% reduction (p=0.29) in seizure frequency following treatment.
Among UX007 treated patients with any absence seizures (with or without observable seizures; n=19), 42% were responders (50% or greater reduction in seizure frequency). Of those with absence seizures on EEG at baseline (n=10), 80% were responders. Of the patients who had absence seizures as determined by EEG (without observable seizures; n=8), 88% were responders and no patients were assigned to placebo.
There was no difference in cognitive function as assessed by CANTAB in patients treated with UX007 compared to placebo.
Safety/Tolerability Results
Two of the 36 enrolled patients discontinued treatment during the eight-week placebo-controlled period, and 12 patients have discontinued during the extension period to date. Two patients discontinued due to adverse events, four patients due to tolerability reasons, and eight due to compliance or study burden issues.
There were no deaths, and no treatment-related serious adverse events. During the placebo-controlled period, 18 patients (72%) in the UX007 arm had treatment-related adverse events (AEs) and five patients (45%) in the placebo arm had treatment-related AEs. Most AEs were mild-to-moderate GI events including vomiting, diarrhea, and abdominal pain. Some gastrointestinal events were managed by adjusting dosing or dosing with food.
Phase 2 study design
The randomized, double-blind, placebo controlled Phase 2 study assessed the safety and efficacy of UX007 in patients with Glut1 DS. Thirty-six patients who met a pre-specified seizure count criteria in either observable seizures, such as generalized tonic-clonic or focal seizures, or absence seizures were randomized in a 3:1 ratio to either UX007 or placebo. Dosing was initiated over a 2-week titration period until the patient reached the target dose of 35% of total daily calories from UX007. A daily seizure diary was used to capture observable seizures and an electroencephalography (EEG) was used at baseline and week 8 to capture absence seizures. Following the double-blind period, patients were given the option of rolling into an open-label extension period during which they were treated with UX007. Frequency reduction percentages provided are estimated based on the pre-specified statistical modeling.
