Research leading up to the ongoing phase 3 trial of SAGE-547, a potential drug for super-refractory status epilepticus, was presented at AAN 2016.
SAGE-547, an allosteric modulator of both synaptic and extra-synaptic GABAA receptors, is currently in Phase 3 clinical development as an adjunctive therapy for the treatment of super-refractory status epilepticus (SRSE). “One thing that’s really exciting is this is the first phase 3 double-blind, randomized trial of a novel agent for status epilepticus, ever. There have been some comparative studies for phenobarbital, pentobarbital, midazolam – never blinded, never randomized…This is really a new opportunity to think about how to develop treatments for this very serious disease,” said Andrew Cole, MD. To date, no drugs have been developed specifically to treat SRSE.
By the time a patient reaches super-refractory status, the estimated mortality is between 20-40%.
The open-label trial “was as much about helping us understand how to operate and work in the intensive care unit with these very severe patients as it was about understanding the safety and activity of our drug,” explained Steve Kanes, MD, PhD. These patients are in a chemically induced coma, have between 20-25 comorbid medical conditions while in the hospital, and are on 12-15 additional medications.
Patients with SRSE who were on a continuous IV infusion of more than one third-line agent (propofol/midazolam/pentobarbital/ketamine) for seizure or burst suppression were eligible for the phase 2 trial,1 if breakthrough seizures occurred during a wean attempt from or during maintenance of the third-line agent. Patients with anoxic brain injury or a very short life expectancy were excluded.
Nine of the 25 patients were female and the average patient age was 48 years (range 10-76 years). The patients had various probable causes of SRSE, commonly infection, intracranial bleeds, worsening seizures, primary and secondary brain tumors, and toxic ingestion. Patients had up to eight attempted weans from third-line agents before being enrolled in the study and experienced an average of nine days of status epilepticus before enrollment.
Seventeen of 22 evaluable patients (77%) were successfully weaned off third-line agent(s) and SAGE-547. Half of the patients reported a final Glasgow Coma score of ≥13. Six patients (24%) died from the underlying cause of SRSE or associated comorbid conditions.
Patients’ ethnicity, age, gender, number of underlying medical conditions “at least in this sample didn’t really seem to have any bearing on whether a patient responded,” said Dr. Kanes.
In a second study,2 the cohort from the phase 2 trial was analyzed in order to design a targeted burst-suppression regimen for the first phase 3 randomized, placebo-controlled clinical trial for SRSE (the STATUS trial). This phase 3 trial is currently ongoing.
Researchers looked at quantitative EEG suppression ratio (qSR) at baseline on anesthetic infusions, qSR associated with the loading and maintenance doses of SAGE-547, and weaning success from anesthetic infusions and SAGE-547 plasma concentrations. This information was used to develop a targeted burst-suppression regimen for the STATUS trial to mitigate against burst-suppression variability across sites.
Baseline qSR was highly variable (range, 0-70% suppression). A statistically significant increase in qSR was associated with SAGE-547 loading dose. This increase was positively correlated with SAGE-547 plasma concentrations over the first 9 hours of infusion. Although the small sample size limited definitive association of baseline or maximum qSR with successful weaning from different anesthetic infusions, analysis is ongoing.
1. Colquhoun H, et al. Phase 2 Data Suggest Heterogeneity of Presentation and Comorbidity Burden Do Not Impact Activity of SAGE-547 in Patients with Super-Refractory Status Epilepticus. Poster presentation P4.210, Apr 19, 2016. AAN Annual Meeting, Vancouver, British Columbia.
2. Rosenthal ES, et al. Quantitative Burst Suppression as a Biomarker in the Phase 2 Trial of SAGE-547: Lessons Learned for the First International Phase 3, Randomized, Controlled Trial for Super-Refractory Status Epilepticus (The STATUS Trial). Poster presentation P4.197, Apr 19, 2016. AAN Annual Meeting, Vancouver, British Columbia.