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Sage Preps For Final Test As Epilepsy Drug Holds Up in Small Study

Xconomy Boston — 

The patient numbers keep growing for Sage Therapeutics, but, at least for now, the story is the same—its experimental epilepsy drug remains promising. Now comes the hard part: testing it in a big, randomized, placebo-controlled trial.

Cambridge, MA-based Sage (NASDAQ: SAGE) is announcing the full results from a Phase I/II trial of its lead drug, SAGE-547, in patients with a rare, life-threatening form of epilepsy called super refractory status epilepticus (SRSE). There are no FDA approved therapies for SRSE; patients have continuous seizures despite anti-epileptic drugs, have to be placed into a medically induced coma to stop them, and can’t be safely woken up by other treatments. The goal for SAGE-547 is clear-cut: it’s supposed to help these people wake up, and get at least a chance to resume their lives.

Sage went public last year off of early data from this trial (at the time, four patients), and the numbers have held up as more patients have been treated. As of today, Sage says that SAGE-547 has been able to wean 17 out of 22 patients (77 percent) who could be evaluated in its trial off of anesthetics, and stay off those drugs without suffering another seizure within a day of completing treatment. That’s important, because getting these patients to wake up, and stay seizure-free for at least a day will be the primary goal of Sage’s Phase 3 trial—the last study required before filing for regulatory approval.

CEO Jeff Jonas says that four of the responders later relapsed during a 30-day follow-up, but that those cases were because of their underlying medical disorder. People develop SRSE for a variety of reasons—from stroke to cancer to drug overdoses—and SAGE-547’s goal is to rescue patients from that crisis, rather than resolve the medical problems that triggered seizures in the first place.

“They would’ve met the regulatory endpoint [in the Phase 3 trial],” he says. “We can’t be held accountable for—nor can the drug be expected to cure—a stroke.”

The coming Phase 3 study will be a much stiffer test for Sage. The trial it’s reporting on today is an early study, designed to see if the drug is safe. (Sage reports that that’s the case so far, with no serious drug-related side effects.) The Phase I/II trial is also a single-arm, open label study, meaning the drug isn’t being tested against a comparator, and patients aren’t randomized.

Nonetheless, Sage believes it’s on the right track. Jonas told Xconomy previously that the company would’ve been happy with a 50 percent response rate. And today, while he says response rates for SRSE patients to current therapies are variable and tough to measure—“that’s one of the reasons we’re going to do a placebo-controlled study,” he says—the company believes they’re around 35 percent.

“We’re very pleased with what we’ve seen,” he says. “The caveat is that this was an open-label [study].”

That’s about to change, because Sage will soon begin enrolling patients in its Phase 3 study; an expected 126-patient, randomized, controlled trial that’ll test SAGE-547 against, basically, any type of anti-epileptic drug a doctor can throw at SRSE. According to chief medical officer Stephen Kanes, patients will each get randomly assigned an IV dose of SAGE-547, or a placebo—along with anti-epileptics and whatever the doctor’s standard of care is for the patient’s underlying condition—for six days while being weaned off of the anesthetics. After that’s done, investigators will see if patients are seizure-free for 24 hours.

“The way we’ve designed the study is that doctors could basically take their best shot with or without SAGE-547,” Jonas says.

Sage will test patients in the drug group at a lower dose of SAGE-547, and then put all non-responders from the drug and control groups on a higher dose of SAGE-547 afterwards. Data are expected anywhere from one to two years after the trial starts.

Status epilepticus affects about 150,000 people each year in the U.S. Roughly 25,000 of those patients are “super refractory,” meaning that they don’t respond to treatment with benzodiazepines (now-generic drugs that have been around for decades) or other anti-seizure drugs, and they can’t be taken out of induced comas without suffering seizures.

SAGE-547 is a formulation of allopregnanolone, an allosteric receptor modulator designed to create equilibrium among the neurotransmitters in the brain and calm the overexcitement of brain signals that are thought to lead to disorders such as status epilepticus. The drug is supposed to do so for SRSE patients by dialing down the inhibitory transmitter known as GABA.