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To sleep: perchance to dream ... Ellen M Martin, from Kureczka/Martin Associates, explores Somnus Therapeutics' investigations into sleep: what it is, how the circadian disruptions of civilization lead to insomnia, and the possible solutions to the problem of poor sleep.

Ay, there's the rub. For while Shakespeare suggests that sleep is a healer and restorer of life, insomnia in modern life is an increasing problem for many people. Nearly all living organisms experience a circadian rest period, but sleep as we know it seems to have evolved only in the last few hundred million years. Birds and mammals (homeothermic animals with socially complex brains) all experience daily unconsciousness where episodes of REM (rapid eye movement) interrupt periods of non-REM (NREM) sleep. Despite growing research using an increasing number of animal models, including fruit flies, nematode worms and zebrafish, as well as mice, rats, cats and dogs, the neurological mechanisms and biochemical pathways of sleep are still poorly understood.

As is readily seen by observing pets, different species spend different amounts of time sleeping. Even apart from striking features like hibernation or aestivation, different species vary widely in the amount of time spent in sleep and show widely varying patterns of sleep architecture. For example, giraffes sleep less than 2 hours per day, while bats can sleep for as many as 20 hours.

With the invention of EEG (electroencephalography), most species were found to show distinctive REM and NREM brain-wave patterns. Total sleep time and patterns of sleep architecture also change through the lifespan--in general, younger animals sleep more and spend more sleep time in REM than adults, a pattern seen in most model species, even fruit flies.

Normal Sleep Architecture

In humans, "normal" sleep varies by individual, cultural and historical practice (for example, siestas are observed in most tropical cultures). However, the normal sleep pattern for a first-shift worker (or student) in industrialized countries starts in the late evening, and includes four stages of NREM sleep, interleaved with shorter periods of REM sleep (associated with dreaming) that increase in length as night progresses to morning.

Normally, diurnal adult humans spend 75-80% of sleep time (7-9 hours on average) in the four stages of NREM (see Table I) with little dreaming and a relatively quiet brain. Stages N3 and N4, also called "delta-wave" sleep, are the deepest sleep periods; delta sleep rebounds after deprivation, as does REM sleep. Usually, increasing periods of REM sleep follow delta sleep, followed by returns to N1 or N2, during which the sleeper is most likely to remember the preceding REM dream.

Adults spend about 90-120 minutes per night in REM sleep in 4-5 periods that lengthen through the night. Newborns, who spend 16 hours asleep, spend more than 80% of their sleep time in REM, but adults only 20-25%. While the elderly generally sleep fewer total hours and spend less time in delta sleep, it is not clear whether this is a normal pattern of aging or a side effect of accumulated ills associated with aging.

For psychopharmacological purposes, "normal sleep architecture" can be defined as getting sufficient REM and delta-wave sleep within a normal range of total sleep time (~7-9 hours/night--a "full night's sleep") to feel refreshed in the morning after a "good night's sleep."

Insomnia

Insomnia can be defined as any of the following: inadequate or non-restorative sleep; difficulty falling asleep; staying asleep; or once wakened, returning easily to sleep. Feeling drowsy, unrested or functionally impaired during waking hours is typical. Insomnia can be transient or mild (little wake-time impairment), short-term or moderate (impaired wake time for less than a month), chronic or severe (tired and irritable when awake, restless and anxious when trying to sleep, lasts more than a month).

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Insomnia is no doubt exacerbated by the circadian disruptions of civilization, such as artificial light, imposed school and work schedules, background noise, bedroom television, etc. Additional external influences include travel across time zones, poor sleep hygiene, personal stress, co-morbid mood disorders, and the widespread use of caffeine, alcohol, medications and other drugs.

Insomnia increases with age and is more common in females, although reasons are unclear. It is a hallmark of depression and anxiety disorders, and life stress is a common cause of acute insomnia. Insomnia may accompany other sleep disorders (apnea, bruxism, restless legs syndrome) yet many patients experience primary insomnia with no obvious cause.

With aging populations and global civilization, insomnia is a growing medical problem. The most significant public health risks of sleep deprivation are accidents on the road, on the job and, especially for the elderly, in the home. Insufficient or poor quality sleep is associated with higher rates of illness and absenteeism as well as less efficient job performance. Inadequate sleep is also associated with weight gain, diabetes and heart disease, perhaps by increasing secretion of the "hunger" hormone ghrelin. Prevention of these associated risks may also fuel the demand for better insomnia treatments.

Insomnia Treatments

Approaches to treating insomnia vary widely and include acupuncture, aromatherapy, cognitive behavior therapy, herbal remedies, sleep hygiene, relaxation techniques, OTC drugs (mostly antihistamines) and prescription pharmaceuticals.

There are more than two dozen prescription therapies approved for insomnia, in four drug classes:

* Barbiturates (once very popular, but largely supplanted by the newer drugs)

* Benzodiazepine sedatives (still the most used category of sleep drugs)

* Non-benzodiazepine "Z-drugs" (so called because the first three non-benzodiazepine drugs to enter the market were zopiclone, zolpidem and zaleplon) with faster onset of action and shorter half-lives than the benzodiazepines (this is the fastest growing drug class, including the three top-selling insomnia drugs)

* Sedating antidepressants are widely used for insomnia associated with mood disorders, but also used off-label for insomnia in the absence of a mood diagnosis.

More than 30 drugs are in clinical development, at least a dozen in the non-benzodiazepine GABA (gamma-aminobutyric acid) agonist class, plus a few novel agents active at receptors for the pineal gland hormones melatonin and orexin (sleep/wake-specific targets). Also in development are Histamine H1 antagonists and sedating antidepressants that are being tested specifically for insomnia indications licensing.

Most of these drugs are only approved for short-term use; even the current generation of Z-drugs is not well suited for chronic, maintenance and duration treatment, as reflected in the lack of regulatory approvals for chronic or long-term insomnia treatment.

Insomnia Market Opportunity

Although insomnia is the most highly prevalent (~10-50% of population, depending on how defined and in which country) sleep disorder, only a fraction of patients pursue pharmaceutical treatments. Worldwide, the prescription insomnia therapeutics market is estimated at $3.3 billion; in the United States, approximately 70 million prescriptions are written annually for insomnia, representing a $1.8 billion market, with a 5-10% annual growth rate. But of the 40-70 million American adults who suffer from insomnia (of which 25 million are chronic or severe cases), only 20% take prescription sleep aids. In fact, alcoholic beverages and OTC sleep aids are more widely used than prescription medications.

The ideal therapeutic would quickly induce sleep, maintain normal sleep architecture and allow timely awakening without hangover. However, many patients and physicians avoid drugs because of perceived risks of inefficacy, dependence, hangover, rebound and other side effects (memory impairment, confusion, sedation, falls). An additional market complexity concerns prescribing physicians. While most insomnia patients first complain to their primary care practitioner, the most sophisticated prescribing group are psychiatrists, who are frequently the specialists to which insomnia patients are referred by other doctors, and who are more likely to diagnose insomnia among their patients already in treatment for mood or other co-morbid disorders, possibly confounding the statistics.

Chronic insomniacs are particularly in need of improved therapeutics that allow long-term use without fear of dependence or hangover. Additionally, people with extrinsic circadian sleep disorders, such as shift-workers and frequent time-zone travellers, as well as those who are unable to co-ordinate their intrinsic sleep-wake patterns with the demands of normal life (for example those with Delayed and Advanced Sleep Phase Syndromes) may benefit from an improved therapeutic.

The Somnus Solution

Somnus sees a significant opportunity for new treatments in this underpenetrated multi-billion dollar market. Although there are many drugs on the market and in development for short-term insomnia, Somnus is aiming for a less-crowded target indication: the unmet need for sleep maintenance and duration treatment. Taking advantage of advances in preclinical and clinical sleep testing as well as in controlled-release formulation and technology, Somnus is developing a new product that more closely approaches the ideal sleep therapeutic.

SKP-1041 is a non-benzodiazepine hypnotic agent in-licensed from SkyePharma PLC. By using SkyePharma's patented GeoClock controlled-release technology to deliver a single oral dose at the beginning of the sleep cycle, the intent is to allow patients to experience a full period of sleep, preserve normal sleep architecture and avoid next-day hangover.

Using SkyePharma's formulation and manufacturing processes, the GeoClock technology allows the preparation of chronotherapeutic press-coated tablets. GeoClock tablets have active drug loaded within an outer tablet layer composed of hydrophobic wax and a brittle material that sets a pH-independent lag time before core drug delivery at a predetermined release rate. The company has already applied the GeoClock approach to a modified-release formulation of prednisone for rheumatoid arthritis, which was filed for EU approval in September 2006. Somnus is already pursuing clinical studies in Europe and plans to start additional clinical studies in the US later this year.

Further information

Gary Cupit founded Somnus Therapeutics in 2007 with funds from Care Capital, a life sciences venture capital firm based in Princeton, New Jersey. In June 2007, Somnus entered into an exclusive agreement with SkyePharma for the worldwide development and commercialization of a sleep therapeutic drug, SKP-1041. Under the agreement, SkyePharma will formulate and manufacture SKP-1041, a new controlled-release formulation of a non-benzodiazepine hypnotic agent, using SkyePharma's Geoclock technology. www.somnusthera.com.
Table I: The various stages of sleep.

Stage     Description                 Duration

W         Wakefulness                 ~16 hours

N1        Somnolence; "drowsy,"
          easily awakened             1-5%

N2        Asleep                      -50%

N3        Slow Wave Sleep             ~7%
(SWS)     Transition to deep sleep

N4        Slow Wave Sleep             ~20-25%
(SWS)     Deep sleep

REM1-4    Rapid Eye Movement          ~20-25%

Stage     EEG Brainwave pattern          Events and abnormalities

W         Alpha waves                    Daytime consciousness
N1
          Theta waves                    Hypnogogic twitches,
                                         hallucinations
N2        Slower waves,
          sleep spindles, K-complexes    Unconsciousness

N3        <50% delta waves               Melatonin peak,
(SWS)                                    night terrors, parasomnias

N4        >50% delta waves               Minimum core temperature,
(SWS)                                    rebounds after deprivation

REM1-4    Rapid low-voltage EEG          Dreaming, low muscle tone,
                                         rebounds after deprivation
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Title Annotation:drug development
Author:Martin, Ellen M.
Publication:Pharma
Geographic Code:1USA
Date:Nov 1, 2008
Words:1695
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