Emerging Therapies for Insomnia

By | March 23, 2015

Most of the late-stage compounds in clinical development for insomnia are non-benzodiazepine gamma-aminobutyric acid -acting agents. These drugs’ developers are hoping that their new compounds, once approved, will achieve less restrictive labeling from regulatory authorities than the currently marketed benzodiazepine and non-benzodiazepine hypnotics — most of which have short-term prescribing limits and all of which are classified as “controlled substances” because of their abuse potential (Table Important Drug Labeling Considerations That May Differentiate Emerging Hypnotics from Currently Marketed Agents shows how labeling may differentiate new GABA-acting hypnotics from currently marketed agents). While the newer compounds are unlikely to be “unscheduled” (i.e., devoid of the “controlled substance” classification) because of their class association (i.e., they are considered to be in the same class as zolpidem [Sanofi-Aventis’s Ambien / Stilnox, Fujisawa’s Myslee, generics], zopiclone [Sanofi-Aventis’s Imovane / Amoban, Chugai’s Amban, generics], and zaleplon [Wyeth and King Pharmaceuticals’ Sonata]), the relaxing of prescribing limits in terms of how long the drugs should be used is a definite possibility. More specifically, for chronic insomniacs, some of the newer drugs may be indicated for use for several months rather than just several weeks.

TABLE Important Drug Labeling Considerations That May Differentiate Emerging Hypnotics from Currently Marketed Agents

Hypnotic

Marketed

U.S. Labeling

Actual Labeling

Zolpidem Indication: sleep onset (but used for sleep maintenance)
Recommended treatment duration: 7-10 days
Controlled substance status: Schedule IV
Zopiclone (outside of U.S.) Indication: sleep onset / sleep maintenance
Recommended treatment duration: 7-10 days
Controlled substance status: Equivalent of Schedule IV in U.S.
Zaleplon Indication: sleep onset
Recommended treatment duration: 7-10 days
Controlled substance status: Schedule IV
In Development Potential Labeling
Indiplon immediate-release Indication: sleep onset
Recommended treatment duration: several weeks / months
Controlled substance status: Schedule IV
Zolpidem modified-release Indication: sleep onset / sleep maintenance
Recommended treatment duration: several weeks / months
Controlled substance status: Schedule IV
Zaleplon extended-release Indication: sleep onset / sleep maintenance
Recommended treatment duration: several weeks / months
Controlled substance status: Schedule IV
Eszopiclone Indication: sleep onset / sleep maintenance
Recommended treatment duration: several weeks / months
Controlled substance status: Schedule IV
Indiplon modified-release Indication: sleep onset / sleep maintenance
Recommended treatment duration: several weeks / months
Controlled substance status: Schedule IV
Gaboxadol Indication: sleep onset / sleep maintenance
Recommended treatment duration: several weeks / months
Controlled substance status: Schedule IV or possibly no restrictions
Tiagabine Indication: sleep onset / sleep maintenance
Recommended treatment duration: several weeks / months
Controlled substance status: no restrictions
TAK-375 Indication: sleep onset / sleep maintenance
Recommended treatment duration: several weeks / months
Controlled substance status: no restrictions
PD-6735 Indication: sleep onset / sleep maintenance
Recommended treatment duration: several weeks / months
Controlled substance status: no restrictions
M-100907 Indication: sleep maintenance
Recommended treatment duration: several months
Controlled substance status: no restrictions

A second and also important differentiating factor in terms of labeling for the newer compounds will be more-expansive labeling to cover “sleep maintenance” in addition to “sleep onset.” Neither zolpidem nor zaleplon is labeled for sleep maintenance because of these agents’ short duration of action. Zopiclone, the other marketed non-benzodiazepine hypnotic, is labeled for use in inducing and maintaining sleep, but this agent is not available on the U.S. market.

Aside from the fact that many of these next-generation non-benzodiazepine hypnotics have been studied for longer durations in clinical trials, there is little to differentiate them from the first generation of non-benzodiazepine hypnotics (i.e., zolpidem, zopiclone, and zaleplon) in terms of safety and efficacy. Nevertheless, robust data from longer-term (i.e., 3-, 6-, and 12-month) clinical trials along with aggressive marketing once these compounds reach the market may be enough to afford the newer non-benzodiazepine hypnotics a competitive edge over the current agents. Indeed, this new generation of non-benzodiazepine hypnotics may expand the overall prescription drug market for insomnia simply by providing physicians with a greater number of treatment choices for patients suffering from chronic insomnia.

Also under investigation for insomnia are clinical-stage compounds with non-gamma aminobutyric acid mechanisms, such as the melatonin agonists and 5-HT2a antagonists. These novel agents hold the promise of offering sleep-enhancing effects without the potential for abuse and / or dependence associated with long-term use of benzodiazepine and even non-benzodiazepine hypnotics. However, these agents may prove useful in only certain segments of the insomnia population and may not be as effective as the benzodiazepine and non-benzodiazepine hypnotics, so their future in the insomnia market is less clear.

Table Emerging Therapies in Development for Insomnia summarizes the drug therapies in development for insomnia.

TABLE Emerging Therapies in Development for Insomnia

Compound Development Phase Marketing Company
Non-benzodiazepine GABA-A agonists
Eszopiclone
United States PR Sepracor
Europe
Japan
Zolpidem modified-release
United States III Sanofi-Aventis
Europe Sanofi-Aventis
Japan Sanofi-Aventis
Indiplon
United States III Pfizer / Neurocrine
Europe III Pfizer
Japan Pfizer
Gaboxadol
United States III Lundbeck / Merck
Europe III Lundbeck
Japan Lundbeck / Merck
Zaleplon extended-release
United States II King Pharmaceuticals
Europe
Japan
gamma aminobutyric acid reuptake inhibitors
Tiagabine
United States II Cephalon
Europe II Cephalon
Japan
Melatonin agonists / analogues
TAK-375 (Ramelteon)
United States III Takeda
Europe III Takeda
Japan II Takeda
PD-6735
United States II Phase 2 Discovery
Europe
Japan
5-HT2 antagonists
M-100907
United States IIb Sanofi-Aventis
Europe
Japan

Nonbenzodiazepine GABA-A Agonists

GABA Reuptake Inhibitors

Like non-benzodiazepine gamma aminobutyric acid-A agonists, gamma aminobutyric acid reuptake inhibitors essentially enhance the activity of the inhibitory neurotransmitter gamma aminobutyric acid and therefore possess sleep-enhancing properties. At present, the only gamma aminobutyric acid reuptake inhibitor under clinical investigation for insomnia is tiagabine (Cephalon’s Gabitril).

Mechanism Of Action

Gamma aminobutyric acid reuptake inhibitors enhance the activity of gamma aminobutyric acid. They do so by binding to recognition sites associated with the gamma aminobutyric acid uptake carrier and blocking uptake into presynaptic nerve cells. When gamma aminobutyric acid reuptake is blocked, more gamma aminobutyric acid is available to post-synaptic nerve cells, which leads to an inhibition of nerve impulses.

Tiagabine

Tiagabine was launched extensively for epilepsy by Novo Nordisk and Abbott in Europe and the United States by the end of 1997. In November 2000, Abbott licensed U.S. rights to the compound to Cephalon, which planned to pursue development for nonepilepsy indications, and by January 2002, Cephalon had acquired worldwide rights to tiagabine (excluding Canada, Latin America, and Japan). By 2004, Cephalon had announced positive preliminary data from Phase II trials in insomnia, generalized anxiety disorder, and neuropathic pain, and large Phase II trials for insomnia are underway.

As mentioned, tiagabine elicits its sedative effects via gamma aminobutyric acid reuptake blocking activity and subsequent potentiation of the inhibitory effects of gamma aminobutyric acid. More specifically, it produces an increase in extracellular gamma aminobutyric acid by inhibiting reuptake on the gamma aminobutyric acid-1 transporter (GAT-1). The drug has no effect on noradrenaline or dopamine reuptake and binds weakly to benzodiazepine, histamine HI, and 5-HT1 receptors. Tiagabine is rapidly absorbed (T-max of 45 minutes) and has a plasma half-life of seven to nine hours (longer in those with hepatic dysfunction); investigators have, however, noted substantial inter-individual variability (4.5-13 hours) when the drug has been used as an antiepileptic.

Cephalon presented clinical data from its initial insomnia trials at the 2004 annual meeting of the APSS. In the first double-blind, placebo-controlled, dose-response Phase II study, 58 subjects with primary insomnia were given 4, 8, 12, and 16 mg doses of tiagabine for two consecutive nights followed by a 5-12 day washout between treatment periods. Investigators assessed sleep using polysomnographic and next-day psychomotor performance using the Digit Symbol Substitution Test (DSST). Efficacy data were presented for treatment period one (11-12 subjects per group) and safety data were presented for all subjects who received at least one dose of tiagabine (n = 58).

Findings presented by study investigators showed that the 8 mg and 12 mg doses achieved a significant reduction in WASO. A dose-related decrease in number of awakenings was noted, as was a dose-related increase in percentage of sleep time in slow-wave sleep (with dose-related reductions in all other stages of sleep). Tolerability was also dose-related, with the two highest doses causing residual effects. The most common adverse effects (adverse events) were dizziness, nausea, and daytime somnolence.

Additional findings from a smaller dose-response analysis (n = 26) of older adults (i.e., 60-80 years) revealed that the 4 mg and 8 mg doses of tiagabine have positive effects on sleep maintenance with minimal adverse effects. Larger trials examining these doses in elderly insomniacs are being planned.

Although it is clear that tiagabine has sleep-enhancing properties, it remains to be seen whether the drug provides comparable efficacy and tolerability to the non-benzodiazepine hypnotics on the market and in clinical development. If not, tiagabine will have little chance of carving out a niche in the insomnia marketplace. In addition, its status as an antiepileptic drug may limit its acceptance among GPs and PCPs, who might perceive the drug as one that falls within the realm of the specialist.

Cephalon could potentially capitalize on two important factors: (1) tiagabine’s status as a nonscheduled drug, and (2) specialists’ familiarity with the drug — some already prescribe it on occasion for insomnia. Cephalon has an increasing presence in the sleep disorders arena with its recently marketed drug modafanil (Provigil) — which is now marketed for excessive sleepiness associated with narcolepsy, obstructive sleep apnea / hypopnea syndrome, and moderate to severe chronic shift work sleep disorder — and will have an established sales-force with expertise in this arena by the time tiagabine is approved for insomnia (if it is, in fact, approved). That said, based on its current pricing for epilepsy, tiagabine may be considerably more expensive than other available sleep aids.

Melatonin Agonists / Analogues

5-НТ2 Antagonists

Drugs that act as 5-НТ2a and / or 5-НТ2c antagonists are under investigation for insomnia because they have exhibited sedative effects when used as treatments for anxiety and depression. For example, NV Organon has initiated Phase II trials with the single enantiomer version (Spain-isomer) of its widely marketed antidepressant mirtazapine (Organon’s Remeron / Remergil, generics) — a 5-НТ2c and alpha-2 adrenergic antagonist — because the parent drug has been shown to promote sleep in depressed patients. Similarly, Sanofi’s investigational 5-НТ antagonist eplivanserin — which was originally being developed for depression and anxiety — is reportedly back in development for insomnia. Sanofi-Aventis also has a 5-HT2A antagonist called M-100907 in Phase II trials for anxiety, depression, and insomnia. Because there are scant available data for any of these compounds in treating insomnia, only one of them is profiled in detail in the following section — Sanofi-Aventis’s M-100907.

Mechanism of Action

Investigators suspect that 5-HT2 antagonists exert their sedative effects by enhancing slow-wave sleep. In particular, 5-НТ2 antagonists may tone down serotonin-induced arousal, which is part of the sleep-wake cycle.

M-100907

Sanofi-Aventis’s highly selective 5-HT2a antagonist M-100907 is in Phase IIb trials for insomnia. The drug was originally being developed for schizophrenia and had reached Phase III trials for that indication, but development ceased in 1999 following interim analysis of results that suggested a lack of efficacy.

According to Sanofi-Aventis, M-100907 significantly increased slow-wave sleep and reduced the number of nighttime awakenings in a small crossover trial in elderly adults (n = 13). These findings were reportedly confirmed in another small trial. Based on the drug’s half-life of eight hours, it is reasonable to assume that it will provide a full night’s effect in individuals with insomnia. However, it could also cause residual sedative effects. In schizophrenia trials, the most common adverse effects were headache and constipation.

One potential benefit of the drug compared with other sedative hypnotics could be its lack of gamma aminobutyric acid-related effects such as the propensity to be habit-forming or to cause rebound insomnia upon discontinuation. However, in the absence of more evaluable data from clinical trials in insomniacs, it is too early to determine whether the drug will even provide meaningful sedative effects in this population.