Wednesday, June 22, 2016

SAGE-547 for super-refractory status epilepticus

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 GABAΑ 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.”…

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.

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