Abstracts

Rationale: Super-refractory status epilepticus (SRSE) is a life threatening medical emergency that affects25,000 Americans annually. SRSE is characterized by unremitting seizures that are resistant tofirst, second and third line anticonvulsant therapies leading to cycles of anesthesia asalternative medication regimens are attempted. In a preclinical model of status epilepticus,allopregnanolone stops aberrant ictal activity. However, one of the limitations imposed byanesthetic therapy is that electrographic seizures are reduced, precluding the use of spike andwave ictal activity to monitor the physiological effect of a newly introduced compound. Here wedescribe the preclinical development of an EEG based biomarker for CNS target engagementthat we subsequently adapted for use in a Phase I/II clinical trial of SAGE-547 (a proprietaryformulation of allopregnanolone) for the adjunctive treatment of SRSE (ClinicalTrials.govIdentifier: NCT02052739).Methods: The rat lithium-pilocarpine EEG model was used to investigate pharmaco-resistant statusepilepticus (SE). Allopregnanolone (0.3-15 mg/kg, IV) was administered alone and incombination with the anesthetic pentobarbital (10 mg/kg) 60 minutes after SE onset. The EEGsuppression probability (SP), defined as the instantaneous probability of the total powerdropping below baseline, was determined over a seven hour period. Clinically, EEG recordingswere obtained from SRSE patients prior to SAGE-547 administration, during the loading phase(286.6 µg/kg over 1 hour) and for a 7 hour period of maintenance (86 µg/kg/hr). The raw EEGsignal was assessed for changes in suppression ratio (SR), defined as the instantaneousprobability of the total power dropping below 3 µV.Results: Pre-clinically, allopregnanolone administered alone significantly increased SP at plasmaconcentrations above 18,000 nM. Similarly, loading and maintenance of SAGE-547 in thePhase I/II trial led to a clear increase in SR in anesthetized patients (p<0.01; paired t-test).Interestingly, compared to the preclinical studies, much lower plasma concentrations (50-900nM) of allopregnanolone were required to significantly increase SR in patients. To explore thepossibility that the heightened potency of allopregnanolone was related to the co-administrationof an anesthetic, additional rodent studies were performed. When administered in combinationwith a sub-active dose of pentobarbital (10 mg/kg), the concentration of allopregnanolonerequired to significantly increase SP decreased 16 fold.Conclusions: These studies establish the utility of SP as a preclinical biomarker and the related endpoint, SR,as a clinical biomarker for electrographic CNS suppression, even in the setting of generalanesthesia. Moreover, these studies demonstrate for the first time that SAGE-547 infusionmodulates a detectable physiological endpoint in patients.