Despite being the second most prevalent mental disorder with a third of the general population reporting insomnia complaints and 10 percent meeting the strict definition of insomnia disorder, the treatment options for the disease are lacking. Considering that many treatments lead to tolerance and dependence and the potential for morning sedation, drugs using new mechanisms of action are sorely needed.

Enter Sage Therapeutics Inc., which presented data last month from a phase I/II trial testing SAGE-217, a GABA-A positive allosteric modulator, in healthy participants using a model of insomnia in which participants went to bed five hours earlier than their habitual bedtime.

The drug improved sleep efficiency to a median of 85 percent and 88 percent at the 30-mg and 45-mg doses tested, respectively, compared with a median of 73 percent for placebo.

"With other therapies such as Lunesta and Ambien demonstrating a smaller degree of improvement in a primary insomnia setting, we will be most focused on seeing if the magnitude of benefit with SAGE-217 persists in future studies," Raymond James analyst Laura Chico wrote in a note to clients.

SAGE-217 also met a pair of secondary endpoints: wake after sleep onset and total sleep time. Subjects were only awake during the night for a median of 55 minutes and 42.5 minutes on the 30-mg and 45-mg doses, respectively, compared to 113 minutes after taking placebo. Total sleep time was 406.25 minutes and 420.25 minutes for the two doses, compared to 350 minutes for placebo.

The one outlier on the secondary endpoints was latency to persistent sleep, which is defined as the duration from lights-off to first epoch of 20 consecutive non-wake epochs, which is determined by polysomnography. Neither of the doses showed a statically significant improvement in latency to persistent sleep compared to placebo.

The lack of signal on the latency to persistent sleep endpoint could have to do with the protocol for the phase-induced trial in which patients took the medication 30 minutes – plus or minus 15 minutes – before they went to bed. "Management believes this may have to do with the pharmacokinetics of the drug (whereby peak serum concentrations – Cmax – are not reached until one hour post administration)," J.P. Morgan analyst Cory Kasimov explained in a note to clients.

Sage's management is still deciding on a path forward for SAGE-217, be it in primary insomnia or to treat sleep problems as a result of another disease, such as Parkinson's disease.

"For our part, we're encouraged by the magnitude of effect, and while insomnia remains a call option in our estimates, we do think the data has broader potential implications to further establish SAGE-217's differentiated profile," Chico concluded.

The "call option" has to do with the fact that the Cambridge, Mass.-based company is also developing SAGE-217 as a treatment for major depressive disorder and other affective disorders and has another drug, brexanolone, that's scheduled to be submitted to the FDA for postpartum depression in the first half of 2018.

In December, Sage presented phase II data showing that SAGE-217 produced a statistically significant mean reduction in the Hamilton Rating Scale for Depression 17-Item total score from baseline to day 15 of 17.6 points, compared to 10.7 points for placebo. (See BioWorld, Dec. 8, 2017.)

A phase II trial for SAGE-217 in postpartum depression is underway with data expected in the fourth quarter of 2018, while trials testing the drug in bipolar depression and Parkinson's disease are scheduled to start this year.

On the back of the insomnia and depression data, Sage announced pricing of a secondary offering last week, raising approximately $575 million by selling about 3.5 million shares at $164 per share with the potential for an additional $86 million or so if the underwriters invoke their option to purchase additional shares.

Searching for new targets

While Sage has shown that GABA-A appears to be a solid target for insomnia, Danielle Posthuma and colleagues at Vrije University in Amsterdam reported results of a massive genetic study searching for genes associated with insomnia.

The pre-reviewed data, published on bioRxiv, came from an analysis of 1.3 million genetic samples collected from the U.K. Biobank and the consumer DNA testing company 23andme Inc., of Mountain View, Calif. It is believed to be the first genetic analysis to break the 1-million-patient mark, the sheer number of available samples goes to show how pervasive insomnia really is.

The screen identified 202 loci linked to insomnia. Those loci implicated 956 genes through positional, expression quantitative trait loci and chromatin interaction mapping.

The most promising of the genes were involved in locomotory behavior and genes expressed in the claustrum, which has been implicated in the coding of incoming stimuli, and medium spiny neurons, where up and down states that are characteristic of slow wave sleep have been described.

Interestingly, there were weak genetic correlations with other sleep-related traits, although there were strong genetic correlations with traits previously identified as being associated with psychiatric and metabolic disorders.

While the data generated could be helpful to drug companies, the researchers clearly understand there's a long ways to go translate the findings into treatments. "These findings are starting points for the development of new therapeutic targets for insomnia and may also provide valuable insights for other, genetically related disorders," the paper concludes.