SAN DIEGO, June 30, 2005 /PRNewswire-FirstCall via COMTEX/ -- Arena Pharmaceuticals, Inc. (Nasdaq: ARNA) announced today top-line results from its Phase 1 clinical trials of APD125, Arena's orally administered, internally discovered drug candidate for the treatment of insomnia. APD125 was well tolerated at all doses investigated. The data demonstrated a robust and statistically significant increase in the amount of deep, or slow wave, sleep and a positive signal in other sleep maintenance parameters, which may distinguish APD125 from currently available sleep therapeutics. APD125 may have extended sleep onset latency in normal volunteers. APD125 is a novel and highly selective inverse agonist of the 5-HT2A serotonin receptor.
"These preliminary results met our expectations for safety and provided evidence of efficacy consistent with this mechanism," stated William R. Shanahan, Jr., M.D., Arena's Vice President and Chief Medical Officer. "As we plan our Phase 2 trial, we are very optimistic and look forward to evaluating the potential benefits of APD125 in chronic insomnia patients."
The Phase 1 program consisted of three clinical trials, APD125-001, APD125-002 and APD125-003, designed to evaluate the single and multiple dose safety and pharmacokinetics of APD125 in normal volunteers. Additionally, it evaluated the pharmacodynamics of nighttime dosing using polysomnography to assess effects on sleep patterns in normal volunteers.
The APD125-001 trial enrolled 45 healthy male volunteers in a randomized, double-blinded, placebo-controlled study evaluating the safety, tolerability and pharmacokinetics of single escalating doses of APD125 in five cohorts of nine volunteers each. Six volunteers in each cohort received one daytime 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 electroencephalographic (EEG) readings taken after dosing to examine brain wave activity to help guide dose selection in the 002 trial.
Top-line results demonstrated that APD125 was well tolerated at all doses investigated. 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; there were no significant differences in Cmax among the 40 mg, 80 mg and 160 mg doses. At 80 mg, the total overall exposure, or AUC (0-inf), of APD125 also plateaued; the pharmacokinetics at the 160 mg dose were generally similar to the 80 mg dose. The maximum tolerated dose was not defined in the trial and higher doses were not tested because of the similar pharmacokinetics observed at the 80 mg and 160 mg doses. At the 40 mg dose the drug plasma half life was 10.8 hours and the mean residence time, or the average time the drug resided in the blood, was 6.8 hours.
An effect promoting delta, or slow, wave activity was observed in the waking EEGs. The effect peaked at the 40 mg dose.
The incidence of adverse events was similar to placebo. System Organ Class Placebo 10 mg 20 mg 40 mg 80 mg 160 mg Total Adverse Event Term (N=15) (N=6) (N=6) (N=6) (N=6) (N=6) (N=45) Total # of Adverse Events 14 5 2 3 2 5 31 Total # of Volunteers With at Least One Adverse Event 7 4 2 3 2 3 21 Blood and Lymphatic Epistaxis 2 2 Hematoma 2 2 1 5 Cardiovascular Orthostatic 1 1 hypotension Vasovagal syncope 2 2 Gastrointestinal Abdominal pain 1 1 Constipation 1 1 Nausea 1 1 General disorders and administrative site conditions Ears buzzing 1 1 Electrode irritation 1 1 Veinitis 1 1 Venipuncture site 1 1 pain Investigations CPK increased 1 1 Nervous System Headache 4 4 Somnolence 2 3 1 6 Respiratory Dry cough 1 1 Rhinitis 1 1 2 APD125-002
The APD125-002 trial was a randomized, double-blinded, placebo-controlled study evaluating the safety, pharmacodynamics and efficacy of nighttime dosing in 24 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.
Top-line results demonstrated a robust improvement in slow wave sleep at all doses investigated. The improvement at the 40 mg dose was an increase of 60 percent, which was highly statistically significant (p=.0002). The trial also provided a positive signal on other sleep maintenance parameters. APD125 may have extended sleep onset latency by up to an average of about 12 minutes in these healthy volunteers with normal sleep/wake patterns. The apparent effect on sleep onset latency did not affect total sleep time between the APD125 and placebo groups, and it contradicts a sleep induction effect reported by volunteers in the 001 trial. This sleep onset latency effect is believed to be an anomaly, but will be studied in future trials along with other common sleep evaluation measures.
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 appear related to APD125.
System Organ Class Placebo 10 mg 20 mg 40 mg Total Adverse Event Term (N=26) (N=24) (N=24) (N=25) (N=29) Total # of Adverse Events 5 14 4 6 29 Total # of Volunteers With at Least One Adverse Event 4 9 2 4 19 Blood and Lymphatic Epistaxis 1 1 Hematoma 2 1 3 Cardiovascular Ventricular extrasystoles* 1 1 Gastrointestinal Abdominal pain 1 1 Colitis/diverticulitis* 1 1 Constipation 1 1 General disorders and administrative site conditions Sore throat 1 1 Tooth decay 1 1 Veinitis 1 1 2 Infections and inflammations Conjunctivitis 1 1 Pharyngitis 1 1 Investigations GGT increased* 1 1 Musculoskeletal Back pain 1 1 2 Left superior limb locking/muscular contraction 2 2 Nervous System Dizziness 1 1 Headache 2 1 1 4 Insomnia 2 2 Leg restlessness 1 1 Orthostatic malaise 1 1 2 *Discontinued from the trial 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 at all doses investigated in this trial and pharmacokinetics, dose proportionality and side effects 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.
System Organ Class Placebo 20 mg 40 mg 80 mg Total Adverse Event Term (N=9) (N=6) (N=6) (N=6) (N=27) Total # of Adverse Events 9 12 8 1 30 Total # of Volunteers With at 6 6 3 1 16 Least One Adverse Event 6 6 3 1 16 Blood and Lymphatic Epistaxis 1 1 2 Hematoma 2 1 3 Neutropenia 1 1 Cardiovascular Orthostatic hypotension 2 2 Vasovagal syncope 1 1 Ventricular extrasystole 1 1 Gastrointestinal Constipation 1 1 Diarrhea 1 1 Epigastralgia (gastritis) 2 2 General disorders and administrative site conditions Electrode irritation 1 1 Veinitis 1 1 Skin inflammation due to insect bite 1 1 Investigations ALT Increased 1 2 3 Musculoskeletal Dorsalgia 1 1 Nervous System Headache 1 1 Insomnia 2 2 Orthostatic malaise 2 2 Somnolence 1 3 4
"We are excited and encouraged by the top-line evidence of safety, improved slow wave sleep, and the positive signal on sleep maintenance parameters. We expect they will provide a solid foundation to start our Phase 2 APD125 trial by the end of the year," stated Jack Lief, Arena's President and Chief Executive Officer. "The results announced today are also important because, in combination with the positive Phase 2a obesity results announced in May for APD356, they clearly demonstrate our ability to independently discover promising drug candidates and our capability to move those candidates into successful clinical development."
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. 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. 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 be a disorder in its own right. 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.
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 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 blocks a general CNS activating effect. Because of the different mechanism of action, APD125 may not have the side effects generally associated with currently marketed drugs. Additionally, APD125 has the potential to improve sleep quality by increasing time spent in slow wave sleep and also improve sleep maintenance. Slow wave sleep, also known as Stage 3 and 4 sleep, and often called deep sleep, is the deepest and most restorative sleep; blood pressure drops, breathing slows and energy is regained. As we age we spend less time in slow wave sleep. Increased time in slow wave sleep may decrease insomnia symptoms.
Conference Call & Webcast
Arena will host a conference call today at 11:00 a.m. EDT (8:00 a.m. PDT) to discuss the APD125 Phase 1 clinical results and to provide a corporate update. The conference call can be accessed by dialing 800.299.9086 for domestic callers and 617.786.2903 for international callers. Please specify to the operator that you would like to join the "Arena APD125 conference call," or use the passcode: 89358604. Additionally, the conference call will be webcast live under the investor relations section of Arena's website at http://www.arenapharm.com, and will be archived there for 30 days following the call. Please connect to Arena's website several minutes prior to the start of the conference call to ensure adequate time for any software download that may be necessary.
About Arena Pharmaceuticals
Arena is a clinical-stage biopharmaceutical company focusing on the discovery, development and commercialization of small molecule drugs in four major therapeutic areas: metabolic, cardiovascular, inflammatory and central nervous system diseases. Arena is developing a broad pipeline of compounds that act on an important class of drug targets called G protein-coupled receptors, or GPCRs, using its proprietary technologies, including CART (Constitutively Activated Receptor Technology) and Melanophore. Arena's most advanced clinical compound, APD356, a selective 5-HT2C serotonin receptor agonist for the treatment of obesity, is in Phase 2b. Arena has completed Phase 1 clinical trials of APD125, a compound with a novel mechanism of action (a selective 5-HT2A receptor inverse agonist) for the treatment of insomnia. Arena has active collaborations with two major pharmaceutical companies, Ortho-McNeil Pharmaceutical, Inc., a Johnson & Johnson company, for the treatment of type 2 diabetes, and Merck & Co., Inc., for the treatment of atherosclerosis and related disorders.
Arena Pharmaceuticals® and Arena® are registered service marks of the company. CART is an unregistered service mark of the company.
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 APD125's safety profile, efficacy and pharmaceutical behavior, including differences between APD125 and currently marketed drugs, APD125's effect on sleep onset latency, expectations for future studies of APD125, and other statements about Arena's strategy, technologies, preclinical and 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, the risk that the results of clinical trials may not be predictive of future results, Arena's ability to partner APD125, the results of any future studies of APD125, the timing, success and cost of Arena's research, out-licensing endeavors and clinical studies, Arena's ability to obtain additional financing, and the timing and receipt of payments and fees, if any, from Arena's collaborators, including Ortho-McNeil and Merck. 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.
SOURCE Arena Pharmaceuticals, Inc.
Jack Lief, President and CEO
or David Walsey, Director, Corporate Communications,
both of Arena Pharmaceuticals, +1-858-453-7200, ext. 1682;
or Susan Neath, Media & Investor Relations of Atkins + Associates, +1-858-527-3486
for Arena Pharmaceuticals, Inc.