Update on emerging drugs for insomnia

Abstract

In recent years, there has been no evidence that the problem of chronic insomnia has faded in the least in US adults; on the contrary, a recent estimate of annual lost productivity due to insomnia was $63.2 billion dollars. However, the proportion of insomniacs who are treated continues to be low, indicating the need for continued development and dissemination of effective therapies. Hypnotic drug development has arguably become more focused in recent years, particularly upon the highly anticipated novel target, the orexin (hypocretin) system. Merck's suvorexant (MK-4305) is the first compound of the so-called dual orexin receptor antagonist (DORA) class expected to be submitted for FDA approval, with a new drug application anticipated in 2012. While there has also been some new activity in the modulation of well-characterized targets with well-characterized agents, such as CNS histamine receptors with low-dose doxepin, a decades-old antidepressant and GABA_A with sublingual zolpidem, experience with melatonin and serotonin modulators suggests that other targets also exist. Diversifying insomnia drug targets may expand possibilities for customizing hypnotic administration to individualized patient presentation and mechanistic underpinnings. In addition, it may offer improved avenues for combining medications with non-drug treatments such as cognitive behavioral therapy for insomnia (CBT-I).

Keywords::

• DORA
• hypnotics
• insomnia
• orexin

1. Introduction

Since the publication of our original review in 2009 [1], there has been no evidence that the problem of chronic insomnia has faded in the least in the adult US population. In fact, adding to estimates of the staggering impact of insomnia on the US workforce are recently published data using the America Insomnia Survey to assess prevalence and work-related impacts of insomnia [2]. Among 7428 employed health plan subscribers, the prevalence of broadly defined insomnia was 23.2%, higher than previous, generally accepted prevalence estimates, with an annual lost productivity of $63.2 billion dollars in the US alone due to insomnia-related lost work performance – and that is after controlling for comorbidity. They further calculated a $2280 – 3274 individual-level estimate of the value to the employer loss due to insomnia – a striking finding, with ‘presenteeism' (attending work while ill) accounting for about two-thirds of lost work performance and absenteeism (missed work due to illness) accounting for about one-third. This adds to growing evidence in Europe that insomnia is a risk factor for sickness absence and disability retirement [3].

The proportion of insomniacs in treatment is relatively low, and progress toward effectively disseminating proven cognitive and behavioral treatments is too slow to meet demand. While benzodiazepine receptor agonists (BzRAs), which are positive allosteric modulators of GABA_A signaling that function to inhibit neuronal activity and promote sleep, are popular among prescribers, they are associated with rebound insomnia at discontinuation and a variety of well-described side effects such as morning sedation, amnesia, confusion, possible interaction with abnormal nocturnal breathing and possible dependence/tolerance. Off-label use of sedating antidepressants is sometimes perceived to be safer and/or induce less dependence; however, there is a paucity of clinical data establishing their efficacy and safety in insomnia and side effects can be limiting.

No new drugs with novel mechanisms have been launched to treat chronic insomnia since publication of our review. However, continued hypnotic drug development has arguably become more focused in recent years, particularly upon the highly anticipated novel target, the orexin (hypocretin) system. Furthermore, insomnia indications for new formulations of already-existing drugs have recently occurred, including approvals for low-dose doxepin, a decades-old antidepressant with anti-histaminergic activity, and sublingual zolpidem, a GABA_A agonist. A brief update regarding selected recent and emerging therapies and targets is provided below.

2. Dual acting orexin antagonists

Probably the most anticipated area of novel drug development involves the so-called dual acting orexin antagonists (DORAs), target modulation/antagonism of the orexin/hypocretin system. Orexin A and orexin B (also known as hypocretin-1 and hypocretin-2) are neuropeptides produced in the lateral hypothalamus that regulate sleep and wakefulness. One clinical example of this system's importance is narcolepsy with cataplexy, a condition of deficient orexin signaling that leads to hallmark excessive daytime sleepiness, disrupted nocturnal sleep and impaired regulation of REM sleep. Scammell and Winrow [4] recently published an excellent review of orexin/hypocretin receptors and pathways, which include not just sleep/wake signaling, but also neural regulation of reward, emotion, stress, appetite and, perhaps importantly, autonomic control. The orexin peptides bind selectively to OX1 and OX2 receptors, and preclinical and clinical studies have demonstrated that antagonism of OX2 or both OX1 and OX2 dose dependently promote REM sleep and non-REM sleep [5-8]. While there is not yet evidence that people with insomnia have elevated orexin tone, insomnia has been associated with elevated sympathetic tone, which has been implicated in the delay of sleep onset. Given proposed roles of the orexin peptides in appetite, reward and autonomic control, it is possible that future investigation of utility of OX1/OX2 receptor antagonists may reach beyond sleep [4].

Several groups have pursued development of orexin receptor antagonists, with OX1/OX2 antagonists almorexant (ACT-078573) and suvorexant (MK—4305) in Phase III trials and several others in preclinical trials [9,10]. Actelion, GlaxoSmithKline (GSK) and Merck all reported clinical development of orexin antagonists for insomnia in recent years, and others have also identified orexin antagonists. While Merck has recently announced that they will submit a new drug application to the FDA by the end of 2012 [11], GSK placed development of their OX1/OX2 antagonist SB-649868 on hold in late 2007 due to undescribed preclinical toxicity [4], and Actelion and GSK announced discontinuation of the development of almorexant in 2011 due to undisclosed tolerability concerns [12]. It remains to be seen the extent to which other compounds in this class will be pursued.

Compared with zolpidem 10 mg, the DORAs have less attenuation of treatment effect on wake after sleep onset (WASO) at 2 weeks of use [13], and suvorexant efficacy was shown to be maintained for 1 year in a Phase III clinical trial of primary insomnia. Unlike the benzodiazepine receptor agonists, which arguably may demonstrate rebound insomnia (depending on how defined) with discontinuation, there is reportedly evidence for lack of rebound with almorexant. Similar to other non-GABA hypnotics, DORAs have been reported to cause less confusion, amnesia and unsteady gait and have been proposed to have lower abuse liability than benzodiazepine receptor agonists. A further proposed benefit of this class of compounds is the lack of expected cross-tolerance to GABA_A agonists, which opens the door for multi-drug regimens when clinically indicated. Importantly, because orexins modulate REM sleep, parameters measuring REM sleep phenomena, such as sleep paralysis, latency to REM sleep and so on, are of special interest and there are at least some data to suggest that these may be affected in compound-specific or class-specific ways, which undoubtedly has received a good deal of attention in the development process [14].

3. Histamine receptor antagonism

One of the few newly indicated drugs in the treatment of insomnia in the last 5 years, the histamine (H1) receptor antagonist ‘low dose' doxepin (Silenor®) achieved FDA approval for the treatment of sleep maintenance insomnia in 2010. Doxepin has potentially vexatious anticholinergic activity at higher doses and has been available for many years, which presents an interesting and unique situation in terms of gaining traction among prescribers. Recently, Somaxon announced a meeting with FDA regarding an over-the-counter (OTC) development program [15].

4. Other targets for hypnotic development

Since 2009, a host of compounds have discontinued development for an insomnia indication but continued for other indications or have ceased development altogether. This includes tasimelteon, a melatonin (MT1/MT2) receptor agonist (though tasimelteon is in development for circadian rhythm disorders, which may present with insomnia among other symptoms). It also includes a host of serotonin 5-HT₂ receptor modulators, including 5HT_2A modulators eplivanserin and pimavanserin (the latter is in Phase III development for Parkinson's disease), Lilly's LY-2624803, a 5-HT_2A and histamine H1 antagonist, which reached Phase II trials, as well as paliperidone and ITI-007, which have 5HT₂ and dopamine receptor modulation but are aimed at schizophrenia. Development of serotonin antagonists for insomnia, especially those with activity at other sleep-modulating targets such as the histamine receptor, remains an intriguing but not fully developed area.

On the other hand, there is some activity among GABA_A agonists for insomnia. EVT-201, a partial positive allosteric modulator of GABA_A, developed by Roche, which had progressed to Phase II trials, was licensed to Jingxin Pharma in China with Phase II clinical development to ensue reportedly in late 2011 [16]. As noted above, in November 2011, Transcept Pharmaceuticals received FDA approval for a sublingual version of the GABA_A agonist zolpidem, for the treatment of middle-of-the-night awakening with at least 4 h of sleep time remaining [17].

5. Expert opinion

The need for effective pharmacological therapies for insomnia continues to be strong. The same challenges that have been described previously still exist: therapies that have been well studied and are impactful in both primary and comorbid insomnia (insomnia associated with conditions such as mood disorders, pain syndromes, other sleep disorders and post-traumatic stress disorder, for example), and in light of age, sex and other factors, are needed. Recent approvals for new formulations of long-available drugs such as doxepin and zolpidem may offer some benefit for some insomnia sufferers, but the true frontier in novel targets in the field may presently be regarded as modulation of the orexin/hypocretin system. With agents having made it to Phase III clinical trials, and one other OX1/OX2 modulators in the development pipeline, anticipation regarding the so-called DORA class is growing. Prescribers have not had the choice of a novel-class drug for insomnia in recent years, so demand may be predicted to be high if these agents are efficacious and safe.

Whether DORA compounds can be developed to have customizable clinical impact by controlling differential activity/modulation at OX1 and OX2 remains to be seen, but doing so could open up a new paradigm in hypnotic treatment altogether. At present, there is little customization of the most frequently used hypnotics based on individual insomnia symptoms and comobidities. Therapy chosen on the basis of an individual's specific symptoms and clinical either with dose titrations or by using combinations of agents (within or outside the DORA class), may provide a type of customized insomnia therapy that heretofore has not been emphasized. Importantly, since agents in this class seems to have less dependence and little rebound insomnia, the DORAS may uniquely pair with cognitive-behavioral therapy for insomnia (CBT-I), which is widely regarded as an effective and lasting non-pharmacological treatment for both primary and comorbid insomnia. As more novel modalities for CBT-I become more widely available, such as via Web-based applications, individual and group teletherapy and others, the role of customizable, titratable hypnotics may be highly complementary. In an era when personalized medical therapy is becoming increasingly realistic, such advances may help put insomnia to bed.

Declaration of interest

The author states no conflict of interest and has received no payment in preparation of this manuscript.