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VOLUME 31, ISSUE 12

ADP125 EFFECTS ON PRIMARY INSOMNIA
APD125, a Selective Serotonin 5-HT2A Receptor Inverse Agonist, Significantly Improves Sleep Maintenance in Primary Insomnia

Russell Rosenberg, PhD1; David J. Seiden, MD2; Steven G. Hull, MD3; Milton Erman, MD4; Howard Schwartz, MD5; Christen Anderson, MD, PhD6; Warren Prosser, MBA6; William Shanahan, MD6; Matilde Sanchez, PhD6; Emil Chuang, MD6; Thomas Roth, PhD7

1NeuroTrials Research and Atlanta School of Sleep Medicine, Atlanta, GA; 2Broward Research Group, Pembroke Pines, FL; 3Vince and Associates, Overland Park, KS; 4Avastra USA, San Diego, CA; 5Miami Research Associates, Miami, FL; 6Arena Pharmaceuticals, San Diego, CA; 7Henry Ford Hospital, Detroit, MI



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Introduction:

Insomnia is a condition affecting 10% to 15% of the adult population and is characterized by difficulty falling asleep, difficulty staying asleep, or nonrestorative sleep, accompanied by daytime impairment or distress. This study evaluates APD125, a selective inverse agonist of the 5-HT2A receptor, for treatment of chronic insomnia, with particular emphasis on sleep maintenance. In phase 1 studies, APD125 improved sleep maintenance and was well tolerated.

Methodology:

Adult subjects (n = 173) with DSM-IV defined primary insomnia were randomized into a multicenter, double-blind, placebo-controlled, 3-way crossover study to compare 2 doses of APD125 (10 mg and 40 mg) with placebo. Each treatment period was 7 days with a 7- to 9-day washout period between treatments. Polysomnographic recordings
were performed at the initial 2 screening nights and at nights (N) 1/2 and N 6/7 of each treatment period.

Results:

APD125 was associated with significant improvements in key sleep maintenance parameters measured by PSG. Wake time after sleep onset decreased (SEM) by 52.5 (3.2) min (10 mg) and 53.5 (3.5) min (40 mg) from baseline to N 1/2 vs. 37.8 (3.4) min for placebo, (P < 0.0001 for both doses vs placebo), and by 51.7 (3.4) min (P = 0.01) and 48.0 (3.6) min (P = 0.2) at N 6/7 vs. 44.0 (3.8) min for placebo. Significant APD125 effects on wake time during sleep were also seen (P < 0.0001 N 1/2, P < 0.001 N 6/7). The number of arousals and number of awakenings decreased significantly with APD125 treatment compared to placebo. Slow wave sleep showed a statistically significant dose-dependent increase. There was no significant decrease in latency to persistent sleep. No serious adverse events were reported, and no meaningful differences in adverse event profiles were observed between either dose of APD125 and placebo. APD125 was not associated with next-day psychomotor impairment as measured by Digit
Span, Digit Symbol Copy, and Digit Symbol Coding Tests.

Conclusions:

APD125 produced statistically significant improvements in objective parameters of sleep maintenance and sleep consolidation and was well tolerated in adults with primary chronic insomnia.

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