Abstracts

Rationale: Intracerebroventricular delivery (ICV) of sodium valproate (VPA) has been shown to be safe and efficacious in previous work describing preliminary experience (Lancet EClinicalMedicine 22 (2020) 100326). Patients implanted in the initial study have been maintained continuously for periods of over 4 years. We report sustained benefit with long-term use of ICV sodium valproate in this patient cohort.

Methods: A first generation fully implanted ICV delivery system (IVDS) comprised of a pump, connected via a subcutaneous tunnelled catheter to an intraventricular catheter was used to continuously deliver sodium valproate into the lateral ventricle. A blinded dose ranging study was undertaken. Five subjects with medically refractory focal seizures of mesial temporal origin were implanted with the system after 30-day seizure baseline period. Sodium valproate doses were evaluated during a blinded phase of 15-60mg/day with one week at each dose with a blinded placebo week dropped in randomly, assessing safety and pharmacokinetic features of the agent delivered in this manner. Following the blinded period subjects were entered into an open-label long-term follow up study evaluating safety and efficacy of the drug and delivery system. Doses of 80-200 mg/day were used. The system requires refilling at approximately 4-week intervals at these doses.

Results: The implantation procedure was well tolerated and there were no significant surgical complications. Sodium valproate administered in this manner was well tolerated and not associated with dose-limiting side effects at ICV doses of up to 200 mg/day. Pharmacokinetic analysis indicated that up to 20x concentration in CSF was achieved compared to usual therapeutic oral doses, and with a 6x decrease in serum concentration. Seizure reductions were previously reported at 3-months and 12-months (60%, 81%). Importantly, these results have now been maintained at 82% at month 24 (range 27%-100%); no ‘wearing off’ effect observed. Responder rate was 80% at all time points. Therapy has been successfully delivered for over 183 cumulative subject months on-study (mean = 37, range = 36-38 months) with a total of 263 refills (mean = 53, range = 48-56 refills) as of 01 June 2021. Quality of life metrics also showed clinically meaningful improvement.

Conclusions: ICV administration of sodium valproate is safe and effective long-term using an implanted drug delivery system. Clinically significant reduction of seizures was observed in all patients, and the benefits have been maintained over periods of years. No dose limiting side effects of sodium valproate developed, despite the high concentrations reached. Other ASDs, and potentially other therapies designed to address other manifestations relating to specific aetiologies could be delivered by this method, which opens new treatment options in refractory epilepsy. An international multicenter randomised phase 2b study of ICV sodium valproate utilizing a next generation delivery system is now underway.

Funding: Please list any funding that was received in support of this abstract.: Industry sponsored (Cerebral Therapeutics, Inc.) and funded research.