Rationale:
GABAergic cortical interneurons from the medial ganglionic eminence (MGE) are promising therapeutic targets in developing novel therapeutics for drug-resistant epilepsy. We developed a cortical MGE-type GABAergic interneuron cell therapy candidate, NRTX-1001, derived from human pluripotent stem cells for single-dose administration into seizure foci. NRTX-1001 is under investigation in two open-label, multicenter Phase I/II trials for drug-resistant unilateral and bilateral mesial temporal lobe epilepsy (MTLE), with a randomized, sham-controlled Phase III trial (EPIC: EPIlepsy Cell Therapy) planned for 2H 2025.
Methods:
The Phase I/II trial (NCT05135091) investigates a single-administration of intra-hippocampal NRTX-1001 in 28 adults with unilateral MTLE: 18 with hippocampal sclerosis (Cohorts 1-low dose & 2-high dose), and 10 without sclerosis (Cohort 3). Immunosuppression to promote allograft persistence is initiated preoperatively and ends after year one. Quarterly visits monitor AEs, seizure frequency, EEG, brain imaging, and neuropsychological metrics. The primary endpoint is one-year safety; the secondary is seizure frequency at months 7-12 post-administration.
Results:
As of 24 March 2025, data for the first ten subjects in Cohorts 1 and 2 (5 low dose, 5 high dose) who have been followed for 9-24 months post-treatment demonstrate that NRTX-1001 has been well-tolerated. Five SAEs to date were deemed unrelated to NRTX-1001. No severe or serious AEs were attributed to surgery. All other AEs were non-serious and attributed to temporary immunosuppression and resolved in the five subjects who discontinued it. In months 7-12, Cohort 1 low dose (n=5) median monthly seizure reduction was 92% for all disabling seizures, and 80% of subjects achieved >75% reduction. In months 13+, median monthly disabling seizure reduction reached 97%. All 4 subjects with marked seizure reduction in year one maintained seizure control in year two after discontinuing immunosuppression. In the high dose cohort, the latest 6-month epoch (months 4-9) showed 72% median monthly disabling seizure reduction, with 80% of subjects achieving >50% reduction. All subjects showed stable or improved neurocognition on word retrieval and verbal and visuospatial memory tests. Quality of life improved in 6 of 10 subjects, including all 5 in Cohort 1 with 18-24 months of follow up. Updated data from 18 subjects (Cohorts 1 & 2) will be presented, detailing seizure frequency, AEs, and neuropsychological outcomes. First-ever data from Cohort 3 and bilateral MTLE trials will also be presented.
Conclusions:
The data from two ongoing Phase I/II studies of NRTX-1001 GABAergic interneuron cell therapy have been encouraging. One-time NRTX-1001 administration offers potential for durable seizure control in drug-resistant MTLE without brain tissue removal or ablation. Phase III EPIC, a randomized, sham-controlled, double-blind study evaluating NRTX-1001 in adults with drug-resistant MTLE is expected to begin enrollment in 2H 2025.
Funding:
CIRM: CLIN2-13355; CLIN2-17135