SALT LAKE CITY, June 21 /PRNewswire-FirstCall/ -- Arena Pharmaceuticals, Inc. announced that it is presenting favorable results from Phase 1 clinical studies of APD125, a novel insomnia compound, today at the 20th Anniversary Meeting of the Associated Professional Sleep Societies (APSS) in Salt Lake City, UT. In the Phase 1 clinical trials, APD125:
* Demonstrated an excellent safety and tolerability profile; * Significantly improved sleep parameters in normal healthy volunteers, including slow wave, or deep, sleep which is associated with better sleep maintenance; and * Did not impair next-day psychomotor skills or memory.
The abstract entitled "Pharmacokinetic and Pharmacodynamic Effects of the Selective 5-HT2A Inverse Agonist APD125 in Healthy Adults" includes data from three clinical trials, APD125-001, APD125-002 and APD125-003, designed to evaluate the single and multiple dose safety and pharmacokinetics and single dose pharmacodynamics of APD125 in normal volunteers.
"Not only did we find an excellent safety and tolerability profile, the trial results suggest that APD125 significantly improved parameters associated with better sleep maintenance," said William Shanahan, M.D., Arena's Vice President and Chief Medical Officer. "With about 30 to 40 percent of U.S. adults complaining about some level of insomnia, the majority of whom report of sleep maintenance issues that are less than optimally treated by GABA-A directed therapy, these data are encouraging and suggest that APD125 may help address an unmet medical need."
Discovered through Arena's proprietary platform, APD125 is a potent and selective inverse agonist for 5-HT2A receptors. Unlike the hypnotic drugs being marketed today for insomnia, which activate GABA-A receptors and cause generalized central nervous system (CNS) suppression, APD125 inhibits one of several CNS activating pathways, namely the serotonergic system, and may improve sleep maintenance and lack hangover effects, including detrimental effects on daytime functioning, and the potential for abuse.
"We are pleased to see the favorable Phase 1 clinical data demonstrating that APD125 has the potential to improve sleep maintenance and reduce insomnia symptoms," said Jack Lief, Arena's President and CEO. "We believe APD125 merits further evaluation as a novel therapy to promote sleep maintenance, and we look forward to initiating a Phase 2 clinical trial of APD125 in patients with chronic insomnia."
APD125 Phase 1 Study Design & Results
The Phase 1 program consisted of three clinical trials, APD125-001, APD125-002 and APD125-003, which were randomized, double blinded and placebo controlled. APD125 was safe and well-tolerated at single doses up to 160 mg and repeated doses up to 80 mg. At doses from 10-40 mg APD125 showed improvements related to slow wave, or deep, sleep, sleep continuity (the number of shifts in stages of sleep and number of awakenings), sleep architecture (time spent in the different stages of sleep), and continuous bouts of sleep. These improvements suggest that APD125 potentially improves sleep maintenance. Adverse events were infrequent and similar to placebo.
APD125 was rapidly absorbed after a single dose (tmax=1-1.5 hr). Plasma half-life was 3.9-10.7 hour at 10-40 mg; exposure was dose-proportional up to 40 mg, with Cmax plateauing at 40 mg and AUC at 80 mg.
APD125-001
The APD125-001 trial enrolled 45 healthy male volunteers with normal sleep patterns in a randomized, double-blinded, placebo-controlled study evaluating the safety, tolerability and pharmacokinetics of single escalating morning doses of APD125 in five cohorts of nine volunteers each. Six volunteers in each cohort received one dose of APD125 while three volunteers received placebo. The first cohort was administered 10 mg of APD125, which was subsequently increased to 20 mg, 40 mg, 80 mg and 160 mg in each successive cohort after safety and pharmacokinetics were evaluated in the prior cohort. In addition to safety and pharmacokinetic evaluation, this trial included waking 4-lead electroencephalographic (EEG) readings taken after dosing to examine brain wave activity to help guide dose selection in the 002 trial.
Results demonstrated that APD125 was well tolerated at all doses investigated, and the incidence of adverse events was similar to placebo.
Pharmacokinetics were related to dose at the 10 mg, 20 mg and 40 mg doses, demonstrating good dose proportionality. At 40 mg, the maximum concentration in the body, or Cmax, of APD125 plateaued, without further increases at the 40 mg, 80 mg and 160 mg doses. At 80 mg, the total overall exposure, or AUC (0-inf), of APD125 also plateaued. Maximal effects on waking EEG delta power were observed at the 40 mg dose. Because of the similar pharmacokinetics observed at the 80 mg and 160 mg doses, higher doses were not tested and the maximum tolerated dose was, therefore, not defined in the trial.
APD125-002
The APD125-002 trial was a randomized, double-blinded, placebo-controlled study evaluating the safety, pharmacodynamics and efficacy of a single nighttime dose in 29 healthy male and female volunteers, ages 45 to 65, with normal sleep/wake patterns. This trial employed a cross-over design, meaning that each volunteer randomly received each of three treatment doses (10 mg, 20 mg and 40 mg) in addition to placebo, separated by at least one week to allow for wash out of the study drug. Polysomnography was used to evaluate the effects on sleep patterns in these normal volunteers.
APD125 was well tolerated at all doses investigated in this trial and the incidence of adverse events was similar to placebo. Three volunteers were discontinued for adverse events, none of which were deemed related to APD125 by the investigator.
The results demonstrated a robust improvement in measurements associated with sleep maintenance, including statistically significant increases in the minutes of slow wave sleep (p<0.0001 for treatment effect). Slow wave sleep is comprised of Stage 3 and Stage 4 sleep, and is essential for restoring energy and releasing important growth hormones. The increases in slow wave sleep were not associated with changes in the percentage of time in REM sleep. REM sleep is an active period of sleep marked by intense brain activity and dreams. Regions of the brain that are used in learning, thinking and organizing are stimulated during REM sleep.
Additionally, the results demonstrated statistically significant decreases in the number of shifts between different stages of sleep (p<0.0001) and the number of awakenings during sleep (p<0.0001). Statistically significant decreases in the number of sleep bouts were found in volunteers (p<0.0001) and there was also a trend towards a decrease in wake after sleep onset at all three doses. Fewer sleep stage shifts and fewer sleep bouts are additional factors that may be associated with improved sleep maintenance, reflecting fewer sleep cycle interruptions.
APD125 did not impair next-day psychomotor skills or memory. Sleep onset latency was not decreased.
APD125-003
The APD125-003 trial enrolled 27 healthy male volunteers in a randomized, double-blinded, placebo-controlled study evaluating the safety, tolerability and pharmacokinetics of escalating daytime doses of APD125 given once daily for seven consecutive days in three cohorts of nine volunteers each. Six volunteers in each cohort received APD125, while three volunteers received placebo. The first cohort received once daily 20 mg doses of APD125 for seven consecutive days, which was subsequently increased to 40 mg and 80 mg in each successive cohort after safety and pharmacokinetics were evaluated in the prior cohort. The doses evaluated were chosen based on the results of the APD125-001 trial.
APD125 was well tolerated, and the pharmacokinetic and side effect profiles were consistent with the findings from the 001 trial. The results indicate that APD125 given once daily over seven consecutive days was well tolerated at all doses investigated, and there were no serious adverse events.
About Insomnia
Insomnia is characterized by inadequate or poor sleep due to nonrefreshing sleep, frequent wakening with difficulty falling back to sleep, difficulty falling asleep or waking too early. Most insomnia complaints relate to sleep maintenance issues, such as waking frequently or awakening too early, as opposed to problems with sleep latency (i.e. falling asleep). About 30 to 40 percent of U.S. adults complain about some level of insomnia in the course of a year, and about 10 to 15 percent of U.S. adults indicate that their condition is severe or chronic. Generally, insomnia is termed chronic when it persists for at least one month, and acute when lasting for one or several days. The prevalence of insomnia increases with age and is more common in women.
Insomnia has a variety of causes. It is often a symptom of some other disease or condition (e.g. life stress, psychiatric and medical disorders, or use of certain medications), but it can also be a distinct disorder. Common symptoms of acute insomnia are sleepiness, negative mood and impairment of performance. Chronic insomnia is often associated with fatigue, mood changes, difficulty concentrating and impaired daytime functioning.
About APD125
Discovered by Arena, APD125 is a novel and orally bioavailable, highly selective inverse agonist of the 5-HT2A serotonin receptor. Currently marketed drugs for insomnia generally activate the GABA-A receptor in the brain, triggering a general CNS-suppressive effect. These drugs are DEA-scheduled controlled substances due to their potential for abuse. Common side effects of GABA activating drugs include the risk of developing tolerance to the drug, impaired functioning when the drug is at therapeutic levels, and the potential for causing a sensation of dullness and lethargy upon awakening, often referred to as the "hangover effect."
By selectively targeting the 5-HT2A receptor, APD125 acts through a different mechanism than currently marketed insomnia drugs and inhibits one of several CNS activating pathways. Because of the different mechanism of action, APD125 may not have the side effects generally associated with currently marketed GABA-A drugs. APD125 has the potential to reduce insomnia symptoms and improve sleep maintenance by decreasing the number of awakenings during the night and the amount of wake time after initial sleep onset, and by increasing total sleep time.
About Arena Pharmaceuticals
Arena is a clinical-stage biopharmaceutical company focusing its research and development efforts on small molecule drugs in four major therapeutic areas: metabolic, central nervous system, cardiovascular and inflammatory diseases. Arena is developing a broad pipeline of compounds targeting an important class of drug targets called G protein-coupled receptors, or GPCRs, using its knowledge of GPCRs and its technologies, including CART(TM) and Melanophore. Arena has four internally discovered, clinical-stage drug candidates for major diseases. The most advanced, lorcaserin, is under investigation for the treatment of obesity. Arena's lead drug candidate for the treatment of insomnia, APD125, is a compound with a novel mechanism of action. Arena also has two clinical-stage collaborations with major pharmaceutical companies: Merck & Co., Inc. and Ortho-McNeil, Inc.
Arena Pharmaceuticals(R) and Arena(R) are registered service marks of the company. CART(TM) is an unregistered service mark of the company. "APD" is an abbreviation for Arena Pharmaceuticals Development.
Forward-Looking Statements
Certain statements in this press release are forward-looking statements that involve a number of risks and uncertainties. Such forward-looking statements include statements about the results of Arena's clinical trials of APD125, the tolerability, side effects and efficacy of APD125, the expected clinical trial of APD125, the potential for APD125 to satisfy an unmet medical need, and other statements about Arena's strategy, technologies, preclinical and internal and partnered clinical programs, and ability to develop compounds and commercialize drugs. For such statements, Arena claims the protection of the Private Securities Litigation Reform Act of 1995. Actual events or results may differ materially from Arena's expectations. Factors that could cause actual results to differ materially from the forward-looking statements include, but are not limited to, Arena's planned clinical trials may not proceed at the time Arena expects or at all, the results of preclinical studies or clinical trials may not be predictive of future results, Arena's ability to partner lorcaserin, APD125 or other of its compounds or programs, the timing, success and cost of Arena's research, out-licensing endeavors and clinical trials, Arena's ability to obtain additional financing, Arena's ability to obtain and defend its patents, and the timing and receipt of payments and fees, if any, from Arena's collaborators. Additional factors that could cause actual results to differ materially from those stated or implied by Arena's forward-looking statements are disclosed in Arena's filings with the Securities and Exchange Commission. These forward-looking statements represent Arena's judgment as of the time of this release. Arena disclaims any intent or obligation to update these forward-looking statements, other than as may be required under applicable law.
Contacts: Jack Lief President and CEO David Walsey Director, Corporate Communications Arena Pharmaceuticals 858.453.7200, ext. 1682 E. Blair Schoeb WeissComm Partners Media Relations 760.365.1857 www.arenapharm.com
Arena Pharmaceuticals, Inc.CONTACT: Jack Lief, President and CEO, or David Walsey, Director,Corporate Communications, both of Arena Pharmaceuticals, Inc.,+1-858-453-7200, ext. 1682; or Media Relations, E. Blair Schoeb ofWeissComm Partners, +1-760-365-1857, for Arena Pharmaceuticals, Inc.
Web site: http://www.arenapharm.com//
