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A status update on SRSE efforts
CAMBRIDGE, Mass.—At the recent 68th American Academy of Neurology Annual Meeting in Vancouver, biopharmaceutical company Sage Therapeutics Inc. presented data from five abstracts covering results for SAGE-547 and its efficacy in super-refractory status epilepticus (SRSE). SAGE-547 is an allosteric modulator of synaptic and extra-synaptic GABAA receptors, an intravenous agent in Phase 3 clinical development as an adjunctive therapy for the treatment of SRSE.
Status epilepticus (SE) is an acute medical emergency of persistent, unremitting seizure lasting greater than five minutes. SE patients are first treated with benzodiazepines, and if they don’t respond, they are treated with other, second-line anti-seizure drugs. If the seizure persists, the patient is diagnosed with refractory SE (RSE) and placed into a medically induced coma via anesthetic agents and antiepileptic drugs. After 24 hours, physicians try to wean the patient from the anesthetic agents, but if the seizure has not resolved, the medically induced coma must be maintained. At this point, the patient is diagnosed as having SRSE.
According to Dr. Steve Kanes, chief medical officer of Sage, “We estimate that the annual incidence of SRSE in the United States is approximately 25,000 patients per year.”
“SRSE is a devastating, life-threatening condition that is widely misunderstood, likely underdiagnosed, lacks widely adopted clinical treatment standards, and has an incidence rate and cost of care that have been historically difficult to ascertain. The research underway at Sage, some of which is being presented this year at AAN, helps to provide a more disciplined understanding of the disease as well as highlighting the importance of further development of SAGE-547 for SRSE,” Kanes said in a press release.
Two of the presented abstracts focused on the efficacy of SAGE-547 in SRSE in an open-label Phase 1/2 study. The study demonstrated that the 77-percent key efficacy endpoint response rate—being weaned off anesthetic agents while SAGE-547 was administered at the maintenance dose—was unrelated to age, gender, ethnicity, co-morbid medical condition, underlying medical condition or previous antiepileptic or third-line agent treatment. Post-hoc analysis involving the duration of the weaning period demonstrated that 73 percent of evaluable subjects were successfully weaned off both anesthetic agents and SAGE-547 within five days of starting the infusion without the need to reinstate anesthetic agents in the following 24-hour period. Eighteen of 22 (82 percent) evaluable subjects were weaned off both anesthetic agents and SAGE-547 within six days of starting infusion without the need to reinstate anesthetic agents in the following 24-hour period, the key efficacy endpoint of the Phase 3 clinical trial. Sixty-four percent of patients had at least one serious adverse event, though the Safety Review Committee determined that none were drug-related.
The study also found an exploratory pharmacodynamic biomarker that was significantly correlated with the plasma concentration of SAGE-547, in spite of high baseline variability and the presence of background medications. Sage is now enrolling a global Phase 3 randomized, double-blind, placebo-controlled clinical trial in SRSE, known as STATUS, and expects top-line results in the second half of this year.
“If successful, we believe the results from this Phase 3 clinical trial, together with other clinical data obtained from the SAGE-547 development program and results of completed and ongoing nonclinical studies, could form the basis of an NDA submission for SAGE-547 in the U.S.,” Kanes tells DDNews. “The FDA granted us orphan drug designation for SAGE-547 in the treatment of SE including SRSE, and Fast Track designation for our investigational new drug application for SAGE-547 as a treatment for SRSE.”
One of the abstracts, titled “Incidence and Cost of Super-Refractory Status Epilepticus,” estimated SRSE’s burden of illness in the United States, finding that mean length of stay (LoS) was 16.5 days, with significant use of the ICU. Patient LoS in the analysis ranged from just two days to more than 800.
Another abstract covered a proof-of-concept study of SAGE-547 evaluating the GABA mechanism as a potential treatment for essential tremor. In this study, a significant reduction of tremor was seen, with no serious adverse events. Sage plans to develop SAGE-217, its next-generation GABAA modulator, for essential tremor in a Phase 2 trial later this year, pending successful completion of current Phase 1 trials.
“SAGE-547 acts as a synaptic and extrasynaptic modulator of the GABAA receptor,” explains Kanes. “GABA is the major inhibitory neurotransmitter in the CNS, and mediates downstream neurologic and bodily function via activation of GABAA receptors. We believe that allosteric modulation of the GABAA receptor has the potential to be well-suited for the treatment of seizures and certain other CNS disorders because it allows for the fine-tuning of neuronal signals rather than complete activation or complete inhibition.”