Sage sees a future in tremor treatment after a 'probe' study

Sage CEO Jeff Jonas

Sage Therapeutics ($SAGE) is pressing forward in the field of tremor treatment after its lead drug notched a positive--though not statistically significant--effect on the debilitating condition in Phase II, results the company believes will help light the way for a bigger trial.

In a 25-patient study, the intravenous SAGE-547 improved the severity of shaking compared with placebo for sufferers of essential tremor, the company said. Sage is saving full results for a later medical meeting but noted that patients taking SAGE-547 charted clinically relevant results, with one-third achieving at least a 30% improvement in tremor amplitude, while only 16% on placebo reached the same threshold.

The drug didn't reach statistical significance on its secondary efficacy goals, but Sage says that was never the point: The trial, which the company calls a "signal-finding study," was designed to determine whether SAGE-547's mechanism--modulating the brain's GABAA receptors--could move the needle in essential tremor. The drug, which must be pumped into patients, could never serve as a treatment for a chronic disease like essential tremor, CEO Jeff Jonas said. Instead, the idea behind the study was to determine whether one of Sage's oral GABAA modulators had a future in the disease, he said.

"What we're doing in this study--which is really a probe study--is asking one question: Would you continue to develop a more active drug with this mechanism for this disease?" Jonas said.

And the answer, for Sage, is yes. The company points to post-hoc analysis in which the 17 patients who stayed on for an open-label extension study experienced a dose-dependent effect on tremor amplitude. That, combined with the placebo-controlled results, is enough of a signal to establish a relationship between GABAA modulation and a beneficial effect on essential tremor, the company believes, and the plan now is to take a next-generation molecule into a Phase II study on its own.

And Sage has a candidate in mind: SAGE-217, an oral GABAA treatment, is slated to enter Phase I this year, and if it proves itself safe and tolerable, the company plans to push it into a Phase II essential tremor study in 2016.

The overarching strategy, Jonas said, is to use SAGE-547, already in Phase III for a rare seizure disorder, as a sort of battering ram for GABAA modulators further down the pipeline. By testing SAGE-547 in broader indications, the company can get an idea of whether its mechanism can make a difference in a given disease, using the results to determine which of--or whether--its other candidates can pick up the baton.

"If there were no signal," Jonas said, "we would just abandon the indication altogether."

Sage employed the same principle in a small, open-label study disclosed earlier this summer, in which SAGE-547 demonstrated a marked effect on four women with postpartum depression. Satisfied with the signal, the company is now plotting a larger, placebo-controlled trial in that condition.

Meanwhile, SAGE-547 is in the midst of a Phase III trial in super-refractory status epilepticus (SRSE), a severe seizure disorder that can be fatal. The FDA awarded Sage its fast-track designation in SRSE, promising a speedy review if the drug can achieve its goals in late-stage development.

Essential tremor affects about 10 million people in the U.S., according to Sage, causing involuntary shaking that often forces patients to abandon their careers. Existing treatments are only moderately effective, the company said, and roughly one-third of patients quit taking them due to either unpleasant side effects or middling efficacy.

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