First evaluation of SAGE-547 to treat super-refractory status epilepticus in children published in Annals of Neurology
SAGE Therapeutics has announced that SAGE-547, an allosteric modulator of GABAA receptors, was used to treat super-refractory status epilepticus (SRSE) in two pediatric patients. The research, published online in the Annals of Neurology, is the first report of SAGE-547 treatment in children. Following treatment with SAGE-547, resolution of status epilepticus (SE) was demonstrated in both patients after weaning from general anesthetic infusions with no drug-related serious adverse effects. Both patients were treated with SAGE-547 under emergency-use Investigational New Drug Applications.
“Refractory status epilepticus is a medical emergency with high risk for poor outcome. In both of these cases, the patient had been put in a medically induced coma to control seizures, and there were multiple unsuccessful attempts to wean the patient from anesthetic agents prior to treatment,” said Mark Wainwright, M.D., Ph.D, director of the pediatric neurocritical care program at Northwestern University Feinberg School of Medicine and senior author of the study. “There are no truly effective treatments for refractory status epilepticus – it is incredibly exciting to work with a new therapy that may help both pediatric and adult patients affected by this disorder.”
The first patient, who was treated at Ann & Robert H. Lurie Children’s Hospital of Chicago, was an otherwise healthy 11-year-old girl who presented with SE caused by an autoimmune disorder with antithyroid and anti-glutamic acid decarboxylase antibodies. She received an infusion of SAGE-547 over five days, after which pentobarbital sedation was weaned and discontinued. Over the remainder of the hospitalization she had intermittent, controllable seizures. She was transferred for inpatient rehabilitation, regained her ability to walk, and is now back at home, continuing to show cognitive improvement, reading, doing arithmetic and playing the piano.
The second patient, a two-year-old girl, presented with SE associated with a febrile illness. SAGE-547 was infused over four days and tapered off between 96 and 120 hours. SE resolved after SAGE-547 treatment and 12 days following the completion of treatment with SAGE-547 all anti-seizure therapies were discontinued. She was transferred to inpatient rehabilitation and is now able to walk and speak. In both patients, there were no drug-related serious adverse effects detected by any of the laboratory tests used.
“Mortality in refractory status epilepticus can be as high as 35 percent, and previously, pediatric patients have not participated in studies to test the effectiveness of SAGE-547,” said Stephen Kanes, M.D., Ph.D., chief medical officer of SAGE and co-author of the study. “Our ongoing Phase1/2 clinical trial has yielded promising results in adult patients with super-refractory status epilepticus, and we are excited about the possibility of delivering this treatment to children, as well.”
SAGE-547 is an allosteric modulator of both synaptic and extra-synaptic GABAA receptors. GABAA receptors are widely regarded as validated drug targets for a variety of CNS disorders, with decades of research and multiple approved drugs targeting these receptor systems. SAGE-547 is an intravenous agent in Phase 1/2 clinical development as an adjunctive therapy, a therapy combined with current therapeutic approaches, for the treatment of SRSE, as well as in an exploratory Phase 2 clinical trial for the treatment of essential tremor.
About Status Epilepticus (SE)
SE is a life-threatening seizure condition that occurs in approximately 150,000 people each year in the U.S., of which 30,000 SE patients die. We estimate that there are 35,000 patients with SE in the U.S. that are hospitalized in the intensive care unit (ICU) each year. An SE patient is first treated with benzodiazepines, and if no response, is then treated with other, second-line, anti-seizure drugs. If the seizure persists after the second-line therapy, the patient is diagnosed as having refractory SE (RSE), admitted to the ICU and placed into a medically induced coma. Currently, there are no therapies that have been specifically approved for RSE; however, physicians typically use anesthetic agents to induce the coma and stop the seizure immediately. After a period of 24 hours, an attempt is made to wean the patient from the anesthetic agents to evaluate whether or not the seizure condition has resolved. Unfortunately, not all patients respond to weaning attempts, in which case the patient must be maintained in the medically induced coma. At this point, the patient is diagnosed as having SRSE. Currently, there are no therapies specifically approved for SRSE.
 DeLorenzo, Robert J., Pellock, John M., Towne, Alan R., Boggs, Jane G. Epidemiology of Status Epilepticus. J Clin Neuro 1995; 12(4): 316-325.
Pediatric super-refractory status epilepticus treated with allopregnanolone, Mark S. Wainwright MD PhD et al., Annals of Neurology, DOI: 10.1002/ana.24295, published online 31 October 2014.
Source: SAGE Therapeutics