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Arena Pharmaceuticals, Inc. (Nasdaq: ARNA) announced today results from a Phase 1 clinical trial of APD916, a novel drug candidate discovered by Arena that targets the histamine H3 receptor for the treatment of narcolepsy with cataplexy.

The randomized, double-blind and placebo-controlled trial evaluated the safety, tolerability and pharmacokinetics of 1 mg, 3 mg and 5 mg single doses of APD916. The trial evaluated 24 healthy volunteers in three cohorts of eight participants each, six randomized to APD916 and two to placebo. APD916 demonstrated dose-proportional pharmacokinetic exposure over the tested dose range. The terminal half-life was approximately 50 hours.

Dose-limiting CNS adverse events occurred at the 5 mg dose, including insomnia, abnormal dreams and a nightmare. Adverse events of insomnia, nausea, headache, parosmia, alterations in perception of body temperature, abnormal dreams and visual and tactile hallucinations were commonly reported at the 3 mg and 5 mg doses, and adverse events of insomnia were commonly reported at the 1 mg dose. All adverse events in the trial were mild or moderate in nature. No serious adverse events were reported nor were there any significant safety issues with respect to vital signs, ECGs or laboratory testing.

"APD916 is a highly potent compound, and we believe that exposures of 1 mg or less could be sufficient for the intended patient population," said William R. Shanahan, M.D., Arena's Senior Vice President and Chief Medical Officer. "We are currently evaluating next steps for this program."

APD916, a potent and selective inverse agonist of the histamine H3 receptor, is Arena's internally discovered drug candidate for the treatment of narcolepsy with cataplexy. The histamine H3 receptor is predominantly expressed in the brain, and inverse agonists of the H3 receptor increase the synthesis and release of histamine through inhibition of presynaptic autoreceptors. Enhanced histamine release plays an important role in arousal, and the histaminergic system is at least partly under the control of orexin/hypocretin neurons. Narcolepsy with and without cataplexy have been associated with orexin/hypocretin deficiency and low levels of histamine in cerebrospinal fluid. Therefore, an H3 inverse agonist, by increasing central histamine activity, may potentially be effective in the treatment of these conditions.

Narcolepsy is a chronic neurological disorder caused by the brain's inability to regulate sleep-wake cycles normally. At various times throughout the day, people with narcolepsy experience fleeting urges to sleep. If the urge becomes overwhelming, individuals will fall asleep for periods lasting from a few seconds to several minutes. Cataplexy, or the sudden loss of muscle tone often triggered by emotional factors, is a symptom of narcolepsy and can cause a range of physical changes, from slurred speech to complete weakness of most muscles.

According to the National Institutes of Health, or NIH, narcolepsy affects about one in every 2,000 Americans. Treatments are limited and consist of stimulant drugs to suppress daytime sleepiness and antidepressants for cataplexy. The only approved treatment for cataplexy in the United States is Xyrem (sodium oxybate), a DEA Schedule III drug.

Arena is a clinical-stage biopharmaceutical company focused on discovering, developing and commercializing oral drugs that target G protein-coupled receptors, an important class of validated drug targets, in four major therapeutic areas: cardiovascular, central nervous system, inflammatory and metabolic diseases. Arena's most advanced drug candidate, lorcaserin, is intended for weight management and has completed a pivotal Phase 3 clinical trial program. Arena has filed an NDA for lorcaserin with the FDA, and the FDA has assigned a PDUFA date of October 22, 2010, for review of the application. Arena's wholly owned subsidiary, Arena Pharmaceuticals GmbH, has granted Eisai Inc. exclusive rights to market and distribute lorcaserin in the United States.

Arena Pharmaceuticals(R) and Arena(R) are registered service marks of the company. SOURCE Arena Pharmaceuticals, Inc.

Researchers from the University of Tokyo have identified a genetic variant linked to a much higher risk of narcolepsy, which may explain the cause of the condition.

Narcolepsy is a rare condition which causes extreme daytime sleepiness, impaired vision and sudden muscle weakness. Sufferers suddenly fall asleep without any warning during a normal activity, and some of them also suffer from "cataplexy", where strong emotions such as anger, surprise, or laughter can trigger loss of muscle strength or lead to collapse.

Scientists believe the cause of narcolepsy may be related to a shortage of a chemical called hypocretin which sends signals to the brain about sleeping and waking up. The condition occurs in 1 in every 2,500 people in the United States and Europe, but is at least four times more common in Japan.

The Japanese researchers analyzed the genomes, or DNA, of 222 narcoleptic Japanese and 389 others who did not have that condition, as well as 424 Koreans, 785 people of European descent and 184 African Americans.

The research found one gene variant occurred with significant frequency among those with narcolepsy and it was linked to an 79% higher chance of narcolepsy in Japanese people, and a 40% increased chance in other ethnic groups - it occurred with significant frequency among narcoleptic Koreans, but the association was not evident in the Europeans and African Americans.

The culprit gene is found close to two genes, CPT1B, and CHKB, which have already been identified as candidates for involvement in the disorder as they both have a role in regulating sleep.

This research could be vital because treatments usually focus on dealing with the symptoms of narcolepsy, but knowing the genetic cause may help to understand underlying cause - in particular what was causing the shortage of hypocretin.

The National Sleep Foundation’s “Sleeptionary” site provides the following information about Narcolepsy. (Sleeptionary content reviewed by Emmanuel Mignot, MD, PhD)

Narcolepsy is a neurological disorder caused by the brain's inability to regulate sleep-wake cycles normally. The main features of narcolepsy are excessive daytime sleepiness and cataplexy. The disease is also associated with sudden sleep attacks, insomnia, dream-like hallucinations, and a condition called sleep paralysis.

Normal sleep happens in cycles. When we fall asleep, we initially enter a light stage of sleep and then progress into increasingly deeper stages. After about 90 minutes, we enter the first stage of REM sleep, which is the dreaming portion of sleep, and throughout the night we alternate between stages of REM and non-REM sleep. For people with narcolepsy, sleep begins almost immediately with REM sleep and fragments of REM occur involuntarily throughout the waking hours. As during REM sleep our muscles are paralyzed and dreaming occurs, it is not surprising that narcolepsy is associated with paralysis and hallucinations.

Narcolepsy is considered a "state boundary" control abnormality. That is, narcolepsy patients sleep a normal amount but cannot control the timing of sleep. 

Narcolepsy affects both sexes equally and develops with age; symptoms usually first develop in adolescence or young adulthood. A combination of genetic and environmental factors may be at the root of this sleep disorder. 

Narcolepsy is often undiagnosed as  sleepiness is not thought to be indicative of disease. Yet the potential dangers of this disorder is reflected in studies showing that narcoleptic patients are more accident-prone and have difficulty with interpersonal relationships.

Researchers believe that narcolepsy may be caused by a deficiency in hypocretin production in the brain. The results of one recent study, in which hypocretin was directly administered to the brain, suggest that using hypocretin derivatives may be an effective way to prevent cataplexy and improve wakefulness.

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