Nonbenzodiazepine GABA-A Agonists

By | March 23, 2015

As mentioned, non-benzodiazepine gamma aminobutyric acid-A agonists in clinical development are very similar in terms of mechanism of action, safety, and efficacy to the currently marketed non-benzodiazepine hypnotics zolpidem, zopiclone, and zaleplon (which are sometimes referred to as the “Z” drugs). Consequently, none of these clinical-stage compounds is likely to offer major benefits in terms of safety and / or efficacy compared with the three marketed agents. Nevertheless, minor improvements in onset and / or duration of action, withdrawal and rebound effects, and adverse event profiles may provide these newer agents with the slight edge they need to compete with and eventually replace the current market leaders. Additionally, robust data from longer-term studies in chronic insomniacs and studies in select subpopulations of insomniacs could significantly expand not only these new agents’ potential markets but also the entire prescription drug market for insomnia.

Mechanism of Action

Unlike traditional benzodiazepines, which act nonselectively at two central receptor binding sites — benzodiazepine-1 (or omega 1) and benzodiazepine-2 (or omega 2) — located on the gamma aminobutyric acid-A receptor complex, non-benzodiazepine hypnotics interact preferentially with benzodiazepine-1 receptors, which researchers believe are responsible for these agents’ hypnosedative effects. Researchers hypothesize that activity at the benzodiazepine-2 receptors may be responsible for traditional benzodiazepines’ negative effects on psychomotor performance and memory, as well as their habit-forming effects.


U.S.-based Sepracor launched its non-benzodiazepine hypnotic eszopiclone (Estorra), the (S)-enantiomer of zopiclone (Sanofi-Aventis’s Imovane / Amoban), in the U.S. market in April 2005. The drug’s approval was for the 2mg and 3 mg tablets for the treatment of insomnia characterized by difficulty falling asleep and / or difficulty maintaining sleep during the night and early morning for adult and elderly patients, and for the 1 mg tablet for elderly patients whose primary complaint is difficulty falling asleep. Labeling that includes “sleep maintenance” will differentiate eszopiclone from its primary competitors in the U.S. Market — zolpidem (Sanofi-Aventis’s Ambien) and zaleplon (King Pharmaceuticals’ Sonata) — because these two marketed non-benzodiazepine hypnotics are indicated only for sleep onset (i.e., difficulty falling asleep), not sleep maintenance.

As mentioned, eszopiclone is the (S)-enantiomer of the currently marketed cyclopyrrolone hypnotic zopiclone. Eszopiclone has a 50-fold greater affinity for gamma aminobutyric acid-A receptors than the (R)-enantiomer of zopiclone, and investigators believe that eszopiclone is mainly responsible for the hypnotic effects of zopiclone. Like its predecessor zopiclone, eszopiclone is rapidly absorbed after oral administration and has a half-life of approximately five to seven hours.

Sepracor has conducted a total of 24 clinical trials including more than 2,700 nonelderly and elderly adults and 60 preclinical studies with eszopiclone; data from these trials were compiled and submitted to the FDA in the new drug application (NDA).

An sleep efficiency score of 80% is widely used as a cutoff for good versus poor sleep. Note: Clinical end points in insomnia trials can be measured objectively using polysomnographic recordings taken in a sleep lab or subjectively using patient- and physician-rated assessments. Entry criteria for chronic insomnia studies usually requires at least one month of chronic insomnia associated with difficulty initiating and / or maintaining sleep or nonrestorative sleep and resulting in clinically significant daytime impairment; patients must report a total sleep time (total sleep time) of > 3 hours and < 6 hours and at least one of the following: sleep latency >30 minutes, number of awakenings >3 per night, and wake time >30 minutes per night. In transient insomnia trials, the design usually involves a “first-night effect” model in healthy volunteers.

Six of the clinical trials were randomized, placebo-controlled, Phase III studies for the treatment of chronic or transient insomnia in both nonelderly and elderly patients. Data from these trials were presented at several conferences in 2003 and 2004, including annual meetings of the American Psychiatric Association (АРА), the Associated Professional Sleep Societies (APSS), and the International Psychogeriatric Association (IPA). In summary, the major Phase III trials incorporated the following parameters:

  • A two-week trial in 264 elderly patients (65-85 years) with chronic insomnia receiving 2 mg eszopiclone nightly; analysis included polysomnographic (polysomnographic) measurements.
  • A two-week trial in 160 elderly patients with chronic insomnia receiving 2 mg eszopiclone nightly; analysis did not include polysomnographic ().
  • A six-week trial in 204 nonelderly adults (21-64 years) with chronic insomnia receiving 3 mg eszopiclone nightly; analysis included polysomnographic.
  • A six-week trial in 308 nonelderly adults with chronic insomnia receiving 2mg or 3mg eszopiclone nightly; analysis included polysomnographic.
  • A six-month trial in 788 nonelderly adults with chronic insomnia receiving 3 mg eszopiclone nightly; analysis did not include polysomnographic. (A 12-month, open-label extension of this trial was also conducted in 471 of the original participants.)

In all of the aforementioned studies, eszopiclone produced sustained improvements in sleep onset, duration of sleep, and maintenance of sleep compared with placebo with no evidence of tolerance when administered at the 2 mg and 3 mg doses (2 mg in the elderly and 3 mg in nonelderly adults). The drug was also shown to improve next-day functioning in both elderly and nonelderly adults. In a comparison of data from three of the previously mentioned studies (two-week [n = 160] and six-week [n = 204] trials in elderly and a six-month [n = 788] trial in nonelderly adults), investigators found that patients consistently reported improvements in measures of daytime functioning, including daytime alertness, morning sleepiness, sense of well-being, and daytime ability to function. An additional pooled analysis of data from two studies in which elderly participants received eszopiclone 2mg for two weeks revealed that the cumulative number of naps and the duration of naps over the two-week period was significantly reduced in those receiving eszopiclone compared with those receiving placebo (naps being an indicator of daytime sleepiness); of those who napped (about 50% in both groups), those taking placebo typically napped three times a week and those taking eszopiclone decreased to two naps per week .

Investigators also conducted a subgroup analysis of the six-month trial data from nonelderly adults (n = 788) to evaluate whether eszopiclone is effective in those with substantial sleep maintenance problems and to estimate the effects of eszopiclone in patients with difficulties in staying asleep. Two subgroups were defined by baseline wake time after sleep onset (WASO): group 1 (n = 336) was the low-WASO group (>60 minutes of wake time after sleep onset) and group 2 (n = 340) was the high-WASO group (>60 minutes of wake time after sleep onset). Final six-month analysis revealed statistically significant differences in WASO between eszopiclone-treated and placebo-treated patients in both groups (19 versus 30 minutes in the low-WASO group and 39 versus 60 minutes in the high-WASO group for eszopiclone versus placebo, respectively).

Data from the six-month open-label extension of the initial six-month trial in nonelderly adults with chronic insomnia provided additional support for eszopiclone’s safety and efficacy when used over the long term (i.e., 12 months). This study represents the longest insomnia treatment study successfully conducted to date. In the six-month extension phase, 471 patients (111 who had been treated with placebo and 360 who had been treated with eszopiclone) received 3 mg eszopiclone nightly; at the end of the six-month extension, 86 of the original 111 placebo-treated patients and 296 of the original 360 eszopiclone-treated patients who had entered the extension phase of the trial had received eszopiclone for 6 months or 12 months, respectively. Overall, eszopiclone was well tolerated, and there was no evidence of tolerance or adverse withdrawal effects upon discontinuation. In addition, patients switched from placebo to eszopiclone reported rapid and significant improvement in sleep and daytime functioning that persisted throughout the six-month duration of the extension phase. The most common side effects associated with eszopiclone are unpleasant taste, headache, and dry mouth.

Sepracor is currently conducting additional Phase Illb trials in specific sub-populations of patients with secondary insomnia, including those suffering from depression, patients with rheumatoid arthritis, and women experiencing symptoms of perimenopause. These trials were initiated in late 2003 and include the following components:

  • A double-blind, placebo-controlled, eight-week trial in depressed patients with insomnia (target enrollment of 600 patients).
  • A double-blind, placebo-controlled, four-week trial in patients with rheumatoid arthritis and insomnia (target enrollment of 440 patients).
  • A double-blind, placebo-controlled, four-week study in women experiencing insomnia associated with perimenopause (target enrollment of 440 patients).

Zolpidem MR

Sanofi-Aventis launched Ambien CR, a modified-release version of its best-selling non-benzodiazepine hypnotic zolpidem Ambien in the U.S. market in late 2005. Like its predecessor zolpidem, Ambien CR (zolpidem modified-release) elicits its hypnotic effect via selective binding to the benzodiazepine-1 subtype of the benzodiazepine receptor located on the alpha subunit of the gamma aminobutyric acid-A receptor complex. The modified-release formulation, however, specifically addresses the short duration of action of the original formulation of the drug in individuals who metabolize zolpidem faster than normal; in these patients, zolpidem does not provide a full night’s duration of effect but rather loses efficacy after three to four hours, resulting in middle-of-the-night and early morning awakening. Pharmacokinetic studies comparing zolpidem and zolpidem modified-release in healthy volunteers suggest that higher plasma concentrations of zolpidem modified-release are maintained three to six hours post-dose, and there is no loss of bioavailability with the modified-release formulation.

In February 2004, Sanofi presented an overview of results from the ZOLADULT study. In this study, individuals with primary insomnia (defined by the DSM-IV) received either 12.5 mg zolpidem modified-release (Ambien CR) (n = 102) or placebo (n = 110) nightly for a period of three weeks. According to the company, zolpidem modified-release provided statistically significant improvements on objective polysomnographic measures of sleep maintenance (WASO, within six hours of sleep onset), sleep efficiency, and sleep induction (latency to persistent sleep, or LPS). Mean changes from baseline were approximately — 10 minutes for placebo and — 33 minutes for zolpidem modified-release on WASO; + 5.5 minutes for placebo and + 13 minutes for zolpidem modified-release on sleep efficiency; and — 13 minutes for placebo and — 23 minutes for zolpidem modified-release for LPS. Subjective measurements were reportedly consistent with polysomnographic measurements, and the drug was well tolerated.

Sanofi continues to put considerable resources into the currently marketed formulation of zolpidem; the company recently released results from a clinical trial in primary insomniacs (n = 199) in which zolpidem was administered on an asneeded basis over a period of 12 weeks. Data from this trial (as well as an earlier trial in which the drug was used intermittently)suggest that zolpidem is beneficial when used intermittently over the long term (i.e., three months).

Indiplon immediate-release and modified-release

Neurocrine Biosciences and Pfizer are codevelop-ing indiplon (NBI-34060), a non-benzodiazepine sedative hypnotic that Wyeth originally licensed to DOV Pharmaceuticals and that DOV then sublicensed to Neurocrine. In early 2004, Neurocrine acquired Wyeth’s position in the DOV / Wyeth license agreement for indiplon. According to the restructured license agreement, DOV will continue to receive $3.5 million in aggregate milestones upon Neurocrine’s NDA filing and approval of the drug, and a 3.5% royalty on worldwide sales. Neurocrine’s development and commercialization agreement with Pfizer for indiplon provides the two companies with copromotion rights in the United States and gives Pfizer exclusive development and marketing rights outside the United States. (Pfizer and Neurocrine are also codeveloping NGD-96-3, a gamma aminobutyric acid-A modulator in Phase Italy development for insomnia.)

Data from Phase III trials with both the immediate-release and modified-release formulations of indiplon were released by Neurocrine and Pfizer in early 2004 in preparation for the submission of NDAs for the two compounds. Both agents are pre-registered for approval in the United States. The immediate-release version is in Phase III in Europe. The companies are hoping for broad approval of the two drugs for use in both elderly and nonelderly adults with transient or chronic insomnia who suffer from difficulty falling asleep, middle-of-the-night awakening, and / or short total sleep duration.

Like the other non-benzodiazepine gamma aminobutyric acid-A agonists, indiplon elicits its sedative effects via the benzodiazepine-1 site on the alpha subunit of the gamma aminobutyric acid-A receptor. What differentiates indiplon from the currently marketed agents — at least pharmacologically — is its potency at this receptor. Indiplon has been shown to have binding affinity 10-50 times greater than zolpidem or zaleplon.

Neurocrine completed enrollment in Phase III clinical trials with indiplon in early 2004; by that time, the clinical program for indiplon encompassed more than 60 clinical trials involving approximately 7,000 patients (the largest clinical program for any insomnia drug by far). The Phase III program involves both elderly and nonelderly adults with chronic or transient insomnia and includes five double-blind studies with the immediate-release formulation (one in transient and four in chronic insomniacs) and three with the modified-release formulation (all in chronic insomniacs). Studies completed to date suggest that both the immediate-release and modified-release formulations of indiplon are safe and efficacious in both elderly and nonelderly adults, with no evidence of next-day impairment.

Preliminary data from two of the largest Phase III trials with the longest duration (i.e., three months) were released by Neurocrine in March 2004 (Neurocrine, press release). The first of these — the RESTFUL trial — included 700 nonelderly adults with chronic insomnia who were treated with either indiplon immediate-release (10 mg or 20 mg) or placebo nightly. The second — the SLEEP trial — included 740 nonelderly adults with chronic insomnia who were treated with either indiplon modified-release (20 mg or 30 mg) or placebo nightly.

In the RESTFUL trial, both the 10 mg and 20 mg doses of indiplon immediate-release demonstrated a highly statistically significant improvement in patient-reported latency to sleep onset (LSO) at all time points compared with placebo (a 30% improvement over placebo and more than 27 minutes over baseline). On the secondary end points of total sleep time (total sleep time), WASO, number of awakenings after sleep onset (NAASO), and sleep quality (SQ), both doses of indiplon immediate-release also reportedly showed statistically significant improvements compared with placebo. Similarly, in the SLEEP trial, both doses of indiplon modified-release provided statistically significant improvements compared with placebo on all primary (total sleep time) and secondary (total wake time [TWT], WASO, NAASO, and LSO) end points at all time points. On the primary end point of total sleep time, indiplon-treated patients reported an increase of up to 75 minutes compared with placebo and up to 90 minutes compared with baseline. In both the RESTFUL and SLEEP studies, patient- and investigator-reported outcomes, as measured by the Insomnia Severity Index and the Global Rating for Severity of Insomnia and Change (respectively), showed statistically significant differences between indiplon and placebo in favor of indiplon.

Data from several other studies were presented at the 2004 annual meetings of the АРА and the APSS. In summary, both formulations of indiplon have shown efficacy in elderly and nonelderly adults with chronic or transient insomnia with a low occurrence of side effects, no residual next-day effects, and no evidence of withdrawal effects in studies ranging from 2 to 12 weeks. More recently, the two companies reported sustained efficacy and safety for both indiplon formulations in chronic insomniacs taking either drug for up to 12 months (detailed data from 6-month double-blind and 12-month open-label extension trials have yet to be published).

It is unclear whether either of the formulations will offer meaningful improvements in efficacy and / or tolerability over drugs such as zolpidem, zopiclone, zaleplon, or the newer eszopiclone. Nevertheless, given the wealth of positive clinical data and the marketing muscle of Pfizer behind them, the two new formulations of indiplon may pose a significant competitive threat to other marketed non-benzodiazepine hypnotics once they reach the market.


Lundbeck is currently conducting Phase III trials in insomnia with its direct-acting gamma aminobutyric acid-A agonist gaboxadol. In early 2004, the company signed an exclusive U.S. development and commercialization deal with Merck, the terms of which call for joint completion of the Phase III clinical program for gaboxadol. Merck will fund the majority of the remaining development, with plans to file an NDA in the United States by 2007. Upon approval, the two companies will copromote the drug in the United States, with Lundbeck focusing on psychiatrists and other specialists who treat sleep disorders. This codevelopment deal was extended to include the Japanese market in mid 2004.

Unlike other investigational gamma aminobutyric acid-acting hypnotics like eszopiclone and indiplon, gaboxadol does not elicit its hypnotic effects via benzodiazepine-1 receptors. Rather, the drug may act as a gamma aminobutyric acid mimetic, exerting its sleep-promoting effects by increasing the inhibitory activity of gamma aminobutyric acid in the synaptic space (similar to the gamma aminobutyric acid reuptake inhibitor tiagabine, discussed later). Studies suggest that gaboxadol interacts directly with the gamma aminobutyric acid receptor site and mediates its effects via a gamma aminobutyric acid receptor population that is insensitive to modulation by benzodiazepines. At this time, it is too early to determine whether the drug’s novel mechanism will, in fact, clinically differentiate it from other gamma aminobutyric acid-acting hypnotics. Importantly, however, its lack of activity at benzodiazepine receptors suggests a potential lack of abuse potential.

At present, gaboxadol’s efficacy and tolerability in the broader insomnia population are difficult to determine because few data have been published for the drug. While a Phase III, randomized, double-blind, multicenter trial that will evaluate three doses of gaboxadol in 650 adults with primary chronic insomnia is ongoing, results have yet to be reported. In an earlier Phase II trial conducted in 100 subjects in a transient insomnia model, gaboxadol reportedly elicited positive effects on measures of sleep maintenance and sleep induction without suppressing rapid eye movement (rapid eye movement) sleep. In another small study involving healthy human subjects, a single dose of gaboxadol increased slow-wave sleep by more than 20 minutes, and electroencephalographic (EEG) analysis revealed that, during non-rapid eye movement (non-rapid eye movement) sleep, the slow-wave frequencies were enhanced compared with placebo. No difference in rapid eye movement sleep was detected between drug-treated subjects and the placebo group, nor was there any difference in sleep onset latency.

Zaleplon extended-release

U.S.-based King Pharmaceuticals is developing an extended-release formulation of the currently marketed zaleplon (Sonata) using Elan’s Spheroidal Oral Drug Absorption System. In mid 2003, King acquired the primary care business of Elan, which included the rights to zaleplon and potential new formulations of the drug. Elan had previously acquired rights to the drug from Wyeth.

Zaleplon extended-release, like its predecessor zaleplon, is a pyrazolopyrimidine hypnotic that binds selectively to the benzodiazepine-1 site on the gamma aminobutyric acid-A receptor complex. Because of the original molecule’s short elimination half-life (1 — 1.5 hours), drug developers have formulated an extended release version of the drug in the hopes that it will improve not only sleep onset, but also sleep maintenance.

Phase II trials designed to determine which extended-release formulation of zaleplon is the most efficacious in increasing total sleep time and reducing the potential for premature awakening, while retaining the rapid onset of the original formulation of zaleplon, were initiated in mid 2004. Although no human data are yet available, the extended-release formulation will probably be at least safe (assuming there are no drug accumulation issues) and effective in reducing sleep latency in insomniacs who have difficulty falling asleep, given that the original formulation does as much. The challenge will be to show that zaleplon extended-release can, in fact, improve sleep maintenance and overall sleep duration because the drug has such a short half-life (1 — 1.5 hours).

Nevertheless, King is pursuing the clinical development an extended-release formulation of zaleplon with the expectation that the addition of this formulation to the current product line will expand zaleplon’s market reach. This strategy is similar to Pfizer’s strategy with the immediate-release and modified-release formulations of indiplon, which the company hopes will address both sleep onset difficulties and middle-of-the-night and early morning awakenings.