VANCOUVER—The investigational agent SAGE-547 demonstrated a 77% response rate in patients with super-refractory status epilepticus (SRSE), according to the results of an open-label phase I/II study presented at the 68th Annual Meeting of the American Academy of Neurology.

SAGE-547, an IV-administered allosteric modulator of synaptic and extra-synaptic GABA_{^_{_Α}} receptors, also had a favorable safety profile among the 22 evaluable patients, said Eric S. Rosenthal, MD, Associate Director of the Neurosciences Intensive Care Unit at Massachusetts General Hospital in Boston.

The agent is being investigated as adjunctive therapy for SRSE, “a life-threatening neurologic emergency” for which no agents are currently approved. Among those with SRSE, “50% to 70% die or remain severely disabled,” Dr. Rosenthal said. “Patients progress through status epilepticus through refractory status to super-refractory status and have increasing difficulty in being treated as they progress without treatment response.”

The study enrolled patients with an EEG-confirmed diagnosis of SRSE. “Patients had to have failed a first-, second-, and third-line anesthetic agent,” he said. “We excluded patients with anoxic encephalopathy, such as that due to cardiac arrest.”

Study outcome measures were safety and tolerability of SAGE-547, a proprietary solution of allopregnanolone in Captisol; successful wean off continuous third-line IV anesthetic drugs by 96 hours; and successful taper of SAGE-547 by 120 hours.

After a one-day screening, patients were administered a one-hour IV loading infusion of SAGE-547 followed by maintenance infusion. After 48 hours, the third-line agents were weaned and SAGE-547 treatment continued through 96 hours; the dose was then tapered and discontinued over 24 hours. Subjects had routine continuous EEG monitoring from baseline screening until 48 hours after completion of SAGE-547 treatment. Follow-up examinations occurred at days 8, 15, 22, and 29.

“During the study, an amendment allowed for a higher dose to explore dose responsiveness; some patients were treated with 86 μg/kg/hour and others were treated with 156 μg/kg/hour. The standard dose, 86 [μg/kg/hour], is intended to mimic endogenous doses analogous to what might be experienced in the third trimester of pregnancy,” Dr. Rosenthal said.

Among the 25 patients enrolled, “the predominance was male; the mean age was 48, and all of them, by virtue of failing an anesthetic, were intubated,” he said. Patients had been in status epilepticus for a mean of nine days (range, three to 20 days), and on an average of three antiepileptic drugs. Most had experienced at least two wean attempts of a third-line agent.

Etiologies included intracerebral hemorrhage, trauma, tumor, and stroke.

“There were a fraction of patients with decompensated seizure disorders at baseline,” Dr. Rosenthal said. “For some, a final diagnosis was not found, and others had structural brain injury, neurologic infections, or neuroinflammatory disease, like NMDA-receptor encephalitis.”

Of the 17 of 22 evaluable patients (77%) who responded, the rate “appears robust in relation to underlying demographics, as well as the number of agents,” Dr. Rosenthal said. This included age, gender, ethnicity, comorbid medical condition, and underlying AEDs or third-line agents.

“During the actual treatment, if patients were treated with three third-line agents and anesthetics, their response was a little bit lower, but remember, our end point requires them to be weaned off all of these, so if a patient during the study is on three, it takes quite an effort to get off all of them,” he said.

No “statistical signal” in terms of response was observed between the patients treated with the high versus standard doses. An EEG biomarker was found that significantly correlated with plasma concentration of SAGE-547, as calculated in a quantitative EEG suppression ratio.

The majority of the adverse events were “typical as related to the high severity of illness in the baseline population,” Dr. Rosenthal said. The most common adverse events were fever, hypotension, diarrhea, peripheral edema, anemia, and increase in blood urea nitrogen (BUN). Investigators attributed one case each of fever and BUN increase to SAGE-547 treatment.

At least one serious adverse event, including respiratory failure, pulmonary embolism, sepsis, and renal failure, was observed in 64% of patients. The safety review committee found none to be related to SAGE-547, nor were the six deaths, which all were due to underlying medical conditions.

Post hoc analysis found that 16 of 22 patients (73%) were weaned off anesthetic agents and SAGE-547 within five days of initiation of SAGE-547 infusion without the need to reinstate anesthetic agents in the following 24 hours; for 18 of 22 patients (82%), this period was six days.

Based on these results, the randomized phase III study, the STATUS Trial (SAGE-547 Treatment as Adjunctive Therapy Utilized in Status Epilepticus), which is currently enrolling patients and for which Dr. Rosenthal is co-lead principal investigator along with Mark Wainwright, MD, PhD, of Northwestern University, has allowed an extra day for weaning.

The FDA has granted SAGE-547 Fast Track and Orphan Drug designations. The study was sponsored by Sage Therapeutics, Cambridge, Massachusetts.

—Debra Hughes

Trial Supports Further Investigation of SAGE-547 in Super-Refractory Status Epilepticus