Pauline Anderson

April 23, 2015

WASHINGTON, DC — A novel agent designed to treat super-refractory status epilepticus (SRSE) is proving successful in 71% of patients, a new phase 1/2 clinical trial showed. Results also uncovered no drug-related adverse events.

"We are very excited about these results," Stephen J. Kanes, MD, PhD, chief medical officer, Sage Therapeutics, told Medscape Medical News.

"The results we are seeing so far in early phase development are very encouraging and we intend to put it to a phase 3 test starting in the middle of the year."

The study was presented here during the featured Emerging Science session at the American Academy of Neurology (AAN) 67th Annual Meeting.

Dr Stephen J. Kanes

Persistent State

A solution of allopregnanolone, SAGE-547 is an intravenous allosteric modulator of both synaptic and extrasynaptic γ-aminobutyric acid type A (GABAA)receptors. It's believed that allopregnanolone is effective as an anticonvulsant when prolonged seizure activity has become resistant to benzodiazepine treatment.

Status epilepticus, a persistent state of continuous seizures, is often associated with an underlying medical condition, such as a brain tumor, stroke, infection, or epilepsy itself. About 150,000 people develop status epilepticus in the United States every year.

Patients are said to be have SRSE if first-, second-, and third-line therapies have failed and they remain in status for over 24 hours, according to Dr Kanes. About 60% of these patients die or are very severely disabled, he said. An estimated 25,000 people are diagnosed with SRSE every year in the United States.

There is currently no approved treatment for SRSE.

The new open-label trial included 20 patients, aged 2 to 65 years, with SRSE (mean age, 51 years) at 18 sites in the United States. The study design involved a 4-day treatment period followed by a 1-day taper and then a 3-week follow-up.

"We're interested in seeing whether or not in the 24 hours after the drug is given and then stopped, whether patients stay out of status, so it's really an intervention trial," commented Dr Kanes.

The study found that 12 of the 17 evaluable patients (71%) were successfully weaned off their anesthetic agents after 2 days while SAGE-547 was being administered, and then were successfully tapered off SAGE-547 after 4 days.

In addition, on the Glasgow Coma Scale (GCS), responding patients showed rapid early improvement, with GCS scores of almost 8 for responders vs 3 for nonresponders at day 5. The effect for responders tended to be sustained to day 29.

About 65% of patients reported serious adverse events, he noted. However, none were considered drug-related.

None of the five deaths that occurred during the study were linked to the drug. "All were related to underlying conditions," said Dr Kanes. "Some deaths were in patients who were successful in the study and some in patients who were not successful."

In nine other evaluable patients for whom the drug was used on an emergency basis, the success rate for the drug was 78%. Here, too, no serious drug-related adverse events occurred.

This past year, Sage Therapeutics has achieved "several very important regulatory milestones," Dr Kanes noted. These include having its SRSE drug being granted Orphan Drug status and Fast Track designation.

The company is gearing up for a phase 3 trial of this agent. The trial will randomly assign 126 patients at up to 150 centers in Europe and the United States to receive SAGE-547 or placebo.

Sage Therapeutics is also investigating the same drug for treatment of postpartum depression, which affects an estimated 20% of women following childbirth and is associated with low levels of allopregnanolone, and essential tremor, which affects over 10 million Americans and is linked to GABAA receptor dysfunction.

Asked to comment, Amy Brooks-Kayal, MD, president, American Epilepsy Society, and chief and Ponzio Family Chair in Pediatric Neurology, Children's Hospital Colorado, Aurora, said there's "an urgent need to develop new therapies" for treating SRSE, which is a "life-threatening condition" for which current therapeutic options have been exhausted.

"The data from the phase 1/2 studies suggest that SAGE-547 (allopregnanolone) has a favorable safety profile and give preliminary indication of potential for efficacy," said Dr Brooks-Kayal. "These findings are very encouraging and support moving this compound into phase 3 trials to more fully determine efficacy."

Robert Fisher, MD, professor, neurology, Stanford University, California, and a past president of the American Epilepsy Society, pointed out that the new drug has a different mechanisms from that of conventional antiseizure drugs, and that while he called the results "highly promising," he added that controlled trials are required.

The study was funded by Sage Therapeutics. Dr Kanes is an employee of Sage.

American Academy of Neurology (AAN) 67th Annual Meeting. Emerging Science 004. Presented April 22, 2015.

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