Phase 1 study of ABI-009 (nab-rapamycin) for surgically refractory epilepsy (RaSuRE).

Objective: Seizures that are refractory to medical and surgical therapy increase the risk of morbidity and mortality in children with epilepsy. Novel therapeutic trials for this population remain sparse and suboptimal. This Phase 1 study evaluates the (1) safety, tolerability, and (2) preliminary efficacy of ABI-009 (nab-rapamycin) in children with medically and surgically refractory epilepsy.

Methods: Children with medically intractable epilepsy and a history of resective surgery who experienced >8 seizures during the 30-day baseline were included. Participants maintained their existing antiseizure medication regimens throughout the study. ABI-009 was administered over 3 weeks using a 3 + 3 dose-escalation design, with dosing cohorts of 5, 10, and 20 mg/m. Treatment was then discontinued, and participants were observed for a 90-day follow-up period. Data were collected on seizure frequency, seizure type, adverse events, medical and laboratory assessments, the Quality of Life in Childhood Epilepsy (QOLCE), and the Nisonger Child Behavior Rating Form (NCBRF).

Results: Twelve participants received ABI-009 and completed all study visits. Seizure etiologies included tuberous sclerosis complex, focal cortical dysplasia, and hemimegalencephaly, although Mammalian target of rapamycin involvement was not required for inclusion. No doses were missed, and dose escalation progressed through all levels. The maximum tolerated dose was 20 mg/m. All 12 participants experienced at least one treatment-emergent adverse event (TEAE), with the majority being mild (80%). No participants withdrew from the study voluntarily or by necessity secondary to TEAEs, and there were no serious adverse events. The median change in the weekly seizure rate was a 37.6% reduction from baseline to treatment completion. The treatment response rate (≥25% seizure reduction) was 66.7%, and two participants achieved seizure freedom by follow-up.

Significance: ABI-009 was deemed safe and tolerable in a pediatric cohort with medically and surgically refractory epilepsy, establishing a maximum tolerated dose of 20 mg/m and showing early signs of efficacy.