Abstracts

Rationale: SAGE-547 is a solution of allopregnanolone in Captisol®. There is evidence indicating a role for allopregnanolone in the treatment of seizures and status epilepticus (SE). In the rat Lithium-Pilocarpine model of SE, acute administration of allopregnanolone eliminates SE, both behaviorally and electrographically, at 60 minutes supporting the hypothesis that SAGE-547 may provide anticonvulsant efficacy at a time when prolonged seizure activity has become resistant to benzodiazepine treatment. The objectives of the initial Phase 1/2 (547-SSE-201) study were to evaluate the safety and tolerability of SAGE-547 in SRSE patients within an open-label design. Secondary objectives were to assess the efficacy and pharmacokinetics (PK) of SAGE-547 Injection modeled for a steady state exposure of 150 nM allopregnanolone, and to assess overall outcomes at 1 month post treatment.Methods: Under an open-label single-arm study design, patients 2 years and older diagnosed with super-refractory status epilepticus (SRSE) underwent 5 days of SAGE-547 treatment. SAGE-547 was administered adjunctive to standard of care as a 1- hour loading dose and a subsequent 4-day continuous infusion, followed by a 1-day taper and a 3-week follow-up period extending to day 29. Blood samples measured pharmacokinetics and drug exposure. Outcome measures were: 1) Successful wean off of continuous intravenous anti-seizure medications (cIV-AED) after hour 48, 2) Successful taper off SAGE-547 after hour 96. Additional measures included Clinical Global Impression of Severity/Improvement, GCS and cEEG.Results: The 547-SSE-201 trial recruited 25 patients who all received open-label therapy with SAGE-547. 77% (19/22) of evaluable patients were successfully weaned off both the anesthetic agent(s) used to suppress status epilepticus as well as the SAGE-547 study drug infusion. Responses were not related to underlying medical condition, type or number of cIV-AED administered, underlying AED treatment, age, gender or ethnicity. Mean exposure was approximately 200 nM [66ng/mL for standard dosing regimen and 345 nM (115 ng/mL) for the higher exposure. Response rate was not related to dose or exposure. 65% of patients experienced at least 1 serious adverse event and 5 patients died during the trial. Neither the SAE’s nor the deaths were attributed to SAGE-547 administration.Conclusions: This phase I/II clinical trial demonstrated preliminary evidence for efficacy of SAGE-547 in SRSE as measured by successful weaning of anesthetic infusions in previously refractory patients. Subsequent evidence for SAGE-547 clinical efficacy will be determined by an upcoming phase III randomized placebo-controlled trial.