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January 28, 2013
Vanda Pharmaceuticals released results from a phase III trial of tasimelteon for the treatment of non-24-hour sleep-wake disorder. This randomized, placebo-controlled, open-label, withdrawal study, RESET, enrolled 20 patients with non-24-hour sleep-wake disorder who were also blind. All subjects received 20mg of tasimelteon for three months, and then were randomized to receive 20mg of tasimelteon or placebo for two more months. Results showed the maintenance of effect as measured by entrainment of the melatonin (aMT6s) rhythm for tasimelteon-dosed patients was 90% (p=0.0026), versus 20% for patients receiving placebo. The study also assessed the maintenance of entrainment of the cortisol rhythm, which was found to be 80% (p=0.0118) in tasimelteon arm versus 20% in the placebo arm. The drug was well tolerated. Based on these data, Vanda Pharmaceuticals plans to submit a New Drug Application (NDA) to the FDA in mid-2013.
September 17, 2012
Merck issued results from a phase III trial of suvorexant for the treatment of insomnia. This long-term, randomized, double-blind study enrolled 781 patients with primary insomnia. Subjects 18-64 years of age received suvorexant 40mg per night, while subjects 65 or older received suvorexant 30mg per night, or placebo over a 12-month period. Results showed that patients who took suvorexant reported that they fell asleep significantly faster, stayed asleep significantly longer and spent significantly less time awake during the night compared to patients who received placebo (p<0.001). After 12 months, a two-month randomized, placebo-controlled, parallel-group discontinuation phase commenced, in which all subjects began a placebo regimen. Patients who had switched from suvorexant to placebo reported that it took them 14.9 minutes longer to fall asleep and that they slept 21.6 minutes less compared to patients who continued taking suvorexant (p<0.0001 for both measures). However, data showed that clinically meaningful withdrawal symptoms and rebound insomnia did not emerge. The drug was well tolerated. The most frequent adverse events were sleepiness, inflammation of the nasal passages, fatigue, upper respiratory tract infection and dry mouth. Based on these data, Merck plans to file a New Drug Application (NDA) for suvorexant with the FDA in 2012.
January 30, 2012
Vanda Pharmaceuticals released initial results from a phase III trial of tasimelteon for the treatment of Non-24-Hour Sleep-Wake Disorder. RESET is a randomized withdrawal, double-masked, placebo-controlled, parallel study and has enrolled four totally blind subjects with no light perception and diagnosed as having a body clock period of greater than 24 hours. The four subjects received tasimelteon for three months during a run-in phase. Tasimelteon was shown to reset and align the body clock to a constant 24-hour day. Enrollment of additional subjects is underway. The subjects will be randomized to either placebo or tasimelteon for two months.
June 14, 2010
Merck issued positive results from a phase IIb trial of MK-4305 for the treatment of insomnia. This multicenter, randomized, double-blind, placebo-controlled trial enrolled 254 subjects with primary insomnia. The subjects received MK-4305 (10, 20, 40 or 80 mg) tablets or placebo for four weeks. The primary endpoint was improvement in sleep efficiency (total sleep time divided by eight hours of time in bed), compared to placebo on night one and at the end of four weeks of treatment. Significant increases from baseline sleep efficiency versus placebo (p-values <0.005) were observed for all doses of MK-4305 at both time periods. Secondary endpoints were also reached. All doses of MK-4305 showed significant reductions in sleep maintenance, as measured by baseline-adjusted wake after sleep onset versus placebo (p-values <0.0005) as well as significant reductions in latency to persistent sleep versus placebo (p-values <0.05) both at night one and at the end of week four. Treatment with MK-4305 was generally well-tolerated with no reports of serious adverse events.
April 13, 2009
Cephalon released positive results from a phase III trial of Nuvigil for the treatment of excessive sleepiness related to jet-lag disorder. This randomized, double-blind, placebo-controlled study enrolled 427 healthy adults who had experienced jet lag symptoms during the previous five years. The subjects traveled eastbound from the United States to France where they were then examined at a sleep facility. They received Nuvigil 150 mg or placebo. Efficacy was evaluated using two primary endpoints: an objective assessment, the Multiple Sleep Latency Test (MSLT), and a subjective assessment, the Patient Global Impression of Severity (PGI-S). Treatment with Nuvigil resulted in statistically significant improvements over placebo on both measurements: the MSLT [p<0.0001] and the PGI-S [p<0.05].
November 5, 2007
Vanda released positive results from a phase II trial of VSF-173 for the treatment of excessive sleepiness. This randomized, double-blind, placebo-controlled trial enrolled fifty-five subjects who received three doses of VSF-173 administered at 50 mg, 100 mg and 200 mg and placebo administered at 25 mg, 50 mg and 100 mg at the usual bedtime and at four hours after the first dose. Efficacy was measured via a series of six Maintenance of Wakefulness Tests (MWT) given two hours apart starting one hour after the first dose, as well as the scheduled daytime recovery sleep following the night time and morning evaluations. Although not statistically significant, VSF-173 demonstrated improvement over placebo on the primary endpoint, the effect of the compound on the first four series of MWT tests. The mean MWT sleep onset scores for the 50 mg, 100 mg and 200 mg, and placebo groups were 10.3, 12.9, 10.6 and 9.2 minutes, respectively. In a subset of 37 subjects with no observed impairment in pre-dose daytime wakefulness, the mean of all six MWT scores for the 50 mg, 100 mg and 200 mg groups showed improvements of 2.1, 3.4 and 2.1 minutes, respectively, compared to placebo. For the dose group of 100 mg, this observation of improvement was statistically significant (p < 0.05). During the scheduled daytime recovery sleep, statistically significant, dose-dependent correlations were observed with the following polysomnography (PSG) parameters: increased number of awakenings, decreased sleep efficiency and total sleep time for the first third of the sleep period, and increased wake time after sleep onset for the first 3 hours of the sleep period (p<.05). Based on the results, Vanda plans to move forward with the development of VSF-173.
October 22, 2007
Evotec announced positive results from a phase II trial of EVT201 for the treatment of insomnia. This randomized, double-blind, placebo-controlled parallel group study enrolled 149 elderly subjects with primary insomnia. The subjects received EVT201 (1.5 mg and 2.5) or placebo for seven nights. Polysomnography (PSG) data was analyzed on nights 1, 6 and 7. The primary endpoint, Total Sleep Time (TST), was reached with significance in both EVT201 dose groups compared to placebo. TST was improved by 30.9 minutes (9%) in the 1.5 mg arm and 56.4 minutes (17%) in the 2.5 mg arm (p=0.0001 and p=<0.0001 respectively). Secondary endpoints were reached as well. Wake After Sleep Onset (WASO) was improved by 15% in the 1.5 mg EVT201 arm and 36% in the 2.5 mg arm (p=0.0140 and p=<0.0001, respectively). Latency to Persistent Sleep (LPS) was improved by 34% and 43% in the 1.5 mg and 2.5 mg cohorts, respectively (p=0.0091 and p=0.0014). Treatment was determined to be safe and well tolerated. Based on the results, Evotec plans to move forward with the development of EVT201.
September 17, 2007
Actelion announced positive results from a phase II trial of almorexant for the treatment of insomnia. This dose-ranging trial enrolled 161 subjects in Israel and Australia. The subjects received 50, 100, 200 or 400 mg of almorexant, or placebo. Treatment was well tolerated, with no reported adverse events. Almorexant dose-dependently improved sleep efficiency, decreased latency to persistent sleep (LPS), decreased wake after sleep onset (WASO), increased or maintained the time spent in rapid-eye-movement (REM) sleep, and improved subjective sleep variables. Based on the results, Actelion plans to commence a phase III trial by the end of 2007.
Evotec issued positive top-line results from a phase II trial of EVT 201 for the treatment of insomnia. This randomized, double-blind trial enrolled 67 subjects in a three way cross-over design, Subjects received two dose levels of EVT 201 (1.5 mg and 2.5 mg) and placebo for two consecutive nights, with a 5-12 day washout between each period. The co-primary endpoints were to assess Wake After Sleep Onset (WASO) as well as Total Sleep Time (TST) determined by polysomnography (PSG). The endpoints reached statistical significance for both doses of EVT 201 compared to placebo. The WASO time in minutes was 63.9, 47.2 and 38.2 for placebo, EVT 1.5 mg and EVT 2.5 mg, respectively (p<0.0001). The TST in minutes was 379, 412 and 424 for placebo, EVT 1.5 mg and EVT 2.5 mg, respectively (p<0.0001). Improvements were also seen in the secondary endpoints. Latency to persistent sleep was decreased by 40% and 49% for EVT low dose and high dose respectively, compared to placebo (p<0.001). In addition, subjects reported significant improvements in subjectively assessed quality of sleep (p<0.001 both doses). Additional phase II trials are currently underway.
June 11, 2007
Evotec issued positive results from a phase II trial of EVT 201 for the treatment of chronic primary insomnia. This randomized, double-blind trial enrolled 67 subjects in a three way cross-over design, Subjects received two dose levels of EVT 201 (1.5 mg and 2.5 mg) and placebo for two consecutive nights, with a 5-12 day washout between each period. The primary endpoints were to assess Wake After Sleep Onset (WASO) as well as Total Sleep Time (TST) determined by polysomnography (PSG). Secondary endpoints included additional PSG-based measures such as latency to persistent sleep, number of awakenings and effects on sleep architecture, as well as sleep quality and quantity. Statistical significance was reached in the co-primary endpoints between both doses of EVT 201 and placebo (p<0.001). Improvements were also seen in the secondary endpoints. Latency to persistent sleep was decreased by both doses of EVT 201 (p<0.001) and subjects reported significant improvements in subjectively assessed quality of sleep (p<0.001 both doses). In addition, treatment with EVT 201 had no effect on residual sedation the following day. Additional phase II trials are currently underway.
May 28, 2007
Neurogen issued positive results from a phase IIa trial of NG2-73 for the treatment of insomnia. This double-blind, placebo-controlled, randomized trial enrolled 369 healthy subjects aged 24-63. The primary endpoint was sleep onset as measured by Latency to Persistent Sleep (LPS). The study design incorporated a single-night polysomnography (PSG) model of transient insomnia which measures physiologic variables during sleep. Subjects received 1,3,10 and 20 mg of NG2-73 or placebo, dosed in a sleep laboratory 2.5 hours prior to median habitual bedtime. PSG recording started 30 minutes later. LPS was statistically significantly reduced all doses of NG2-73 when compared to placebo, and demonstrated a dose-response relationship. The mean times for LPS were 17.8, 10.6, 7.8, and 6.6 minutes for the 1, 3, 10, and 20 mg NG2-73 groups, respectively, versus 30.8 minutes for the placebo group. NG2-73 also had a statistically significant effect on Total Sleep Time and Sleep Efficiency at doses of 3mg and above. Neurogen is currently conducting phase IIb trials with NG2-73 for the treatment of chronic insomnia.
February 5, 2007
Actelion issued positive results from a phase I trial of ACT-078573 for the treatment of sleep disorders. This randomized, placebo-controlled, double-blind, single-ascending dose trial enrolled 70 healthy male subjects with no history of neurological, psychiatric or sleep disorders. Subjects received either a single dose of ACT-078573, in doses ranging from 1mg to 1000mg, placebo or 10mg of Zolpidem, an FDA approved insomnia medication. Treatment was well tolerated up to 1000 mg with no serious adverse events reported. Within one hour of taking a single dose of ACT-078573 at 200 mg or higher, all subjects displayed signs of sleep. In addition, there were no signs of cataplexy, a sudden loss of muscle tone, which is a frequent symptom of narcolepsy syndrome. Phase II trials are currently underway evaluating further safety and efficacy profiles of ACT-078573 for this indication.
January 15, 2007
Somaxon issued positive results from a phase III trial of Silenor for the treatment of insomnia in elderly subjects. This randomized, double-blind, placebo-controlled, multi-center, parallel group trial enrolled 240 elderly subjects who received placebo or Silenor at 1 mg or 3 mg, for 12 weeks. Treatment was well tolerated, with adverse events similar to placebo. Statistically significant improvement was seen in the primary endpoint, Wake After Sleep Onset (WASO) measured at night one, for both doses studied (1mg: p=0.0053, 3mg: p less than 0.0001). Statistical significance for this endpoint was also achieved at the end of the twelve week treatment period for both doses studied (1mg: p=0.0330, 3mg: p less than 0.0001) . In addition, both doses resulted in statistical significance over placebo in Total Sleep Time (TST), Sleep Efficiency (SE) and subjective Total Sleep Time (sTST). Both doses of Silenor demonstrated improvements relative to baseline in Latency to Persistent Sleep (LPS), but statistical significance versus placebo was not observed. Based on positive phase III results, Somaxon planned to file a NDA with the FDA in Q3 of 2007.
June 26, 2006
Auris Medical issued positive results of a phase I/II trial of AM-111, for the treatment of acute sensorineural hearing loss (ASNHL). This open-label study enrolled 11 subjects experiencing ASNHL associated with acute acoustic trauma (>30 dB in worst affected ear, <20 dB in other ear) across 2 sites in Germany. Subjects received single 250 mcl transtympanic injections of either 2 mg/ml or 0.4 mg/ml concentrations of the drug in a gel formulation in their worst affected ear only, with follow-up at 30 days. Trial data indicated that the drug was well tolerated, with the majority of adverse events deemed unrelated or not likely related to treatment. Preliminary evidence of efficacy was also noted: subjects improved from a baseline hearing loss of 35.9 dB to 24.5dB at 30 days, compared to an improvement from 20.0 dB to 17.6 dB for the untreated ear.
Cortex Pharmaceuticals reported mixed results of a pair of phase II trials of CX717, for the treatment of poor cognitive performance due to night-shift-work sleep disruption, at the Sleep 2006 meeting in Salt Lake City. The first trial, a randomized, double-blind, placebo-controlled, parallel group study conducted in 50 healthy male volunteers over 4 nights at the Walter Reed Army Institute of Research, found no significant improvements in measures of cognitive performance, compared to placebo. In a separate study of the drug in a sleep-deprivation model conducted in the UK, preliminary data indicated that CX717 dose-dependently altered recovery sleep architecture, as measured by EEG polysomnography. The highest trial dose (1000 mg) significantly reduced the amount of slow wave sleep during each of four recovery sleep periods (p<0.05), and increased wake time after sleep onset during 2 of the 4 recovery sleep periods (p<0.05). The company indicated that differences in trial design may have contributed to the disparity between results, and additional data analysis was planned.
December 12, 2005
Neurogen has issued positive results of a phase I trial of their investigational GABA modulator NG2-73, for the treatment of insomnia. Pharmacokinetic data indicated a linear dose response profile, with no evidence of plasma drug accumulation. Safety data were also positive, with no serious adverse events reported and a positive overall tolerability profile. Preliminary evidence of hypnotic efficacy was also noted in several subjective measures of sedation. This randomized, double-blind, placebo-controlled study enrolled 32 healthy volunteers, who received one of four ascending oral doses of the drug (5 mg to 20 mg) for 5 days. These data served to support plans for an upcoming phase II trial.
February 14, 2005
Axonyx announced top-line results of their first phase III trial of phenserine, their acetylcholinesterase inhibitor under investigation for the treatment of mild-to-moderate Alzheimer’s disease (AD). Trial data indicated that the neither trial dose of the drug met the primary endpoint, improvement in score on the ADAS-cog and CIBIC diagnostic scales, vs. placebo after 26 weeks of treatment. Non-significant trends towards improvement were noted in both metrics at both dose regimens, and no serious safety or tolerability concerns were raised. This double-blind, placebo-controlled study enrolled 384 subjects across 16 sites in Spain, the United Kingdom, Croatia, and Austria. Subjects were randomized to receive one of two doses of phenserine (10mg or 15mg) or placebo twice daily for 6 months. Axonyx announced that the planned interim analysis of their ongoing phase II b trials of the drug, investigating phenserine’s ability to lower levels of beta-amyloid precursor protein and beta-amyloid in the plasma and cerebrospinal fluid (CSF), would not be affected by these results.
Cephalon has reported positive combined results from four phase III trials of Nuvigil (armodafinil) for the treatment of excessive sleepiness associated with narcolepsy (1 study), shift work sleep disorder (1 study) or obstructive sleep apnea/hypopnea syndrome (2 studies). Compiled data demonstrated significant efficacy in improving measures of objective sleep latency, including the Maintenance of Wakefulness Test and the Multiple Sleep Latency Test, and in the physician rating of Clinical Global Impression-Change, vs. placebo (p<0.05). The drug was also shown to promote wakefulness late in the day when administered in the morning, confirming a long duration of action. All 4 trials were 12-week, double-blind, randomized, placebo-controlled studies, which enrolled a combined total of roughly 1,000 patients. Subjects received one of two doses of the drug (150 or 250 mg) or placebo once daily. Cephalon announced that these results were in line with their intention to submit and NDA for the drug before the end of Q1 2005.
Repligen announced preliminary results of a phase II trial of secretin, for the treatment of refractory schizophrenia. Data from the study yielded no significant improvements in symptom severity scores on either the Clinical Global Impression (CGI) or the Positive And Negative Syndrome Scale (PANSS), which were assessed at baseline and 6 times during the study. Responders on the CGI scale were noted in both the low dose (n=3, 20% response rate) and high dose (n=4, 29% response rate) secretin group and in the placebo group (n=2, 13% response rate), but the difference between these rates was also non-significant, possibly due to the small cohort size. A non-significant trend towards improvement was seen in a sub-section analysis of the PANSS dysphoric mood scale (anxiety, tension, etc.) in the secretin group (p=0.06), and several clinical investigators were reported to have noted transient changes in the social interaction at the time of the treatment, though these responses were not quantified. This double-blind trial enrolled 44 subjects, who received one of two doses of secretin (2 CU/kg, n=15; or 5 CU/kg, n=14) or placebo (n=15) in 4 intravenous doses over 2 weeks. The company announced that they were preparing a follow-up study to statistically measure the transient changes in mood noted by investigators.
March 29, 2004
Neurocrine Biosciences reported positive results from their seventh phase III trial investigating immediate release indiplon for the treatment of insomnia. Results showed a highly statistically significant enhancement in sleep initiation, Latency to Sleep Onset (LSO) and sleep quality, sustained over a three-month period. Data demonstrated subjects taking indiplon immediate release achieved rapid sleep onset and slept longer with minimal sleep disturbances. The randomized, double-blind, placebo-controlled, parallel- group, multi-center study, called RESTFUL, enrolled 700 subjects with chronic insomnia at 67 sites worldwide. Subject received administration of indiplon immediate release (10 mg or 20 mg) over a three-month period.
December 15, 2003
Neurocrine reported positive results from a phase II/III trial investigating an immediate release formulation of indiplon, a non-benzodiazapone agent for the treatment of insomnia. Results demonstrated that subjects suffering from middle of the night (MOTN) awakenings who took indiplon were able to return to sleep rapidly with fewer awakenings and a better quality of sleep. Data showed subjects on indiplon demonstrated no evidence of next morning residual effects and more next day alertness than those who took placebo did. The randomized, placebo-controlled, double blind, parallel group, multi-center study enrolled 264 subjects with chronic primary insomnia with a history of frequent and prolonged (MOTN) awakenings. It was designed to assess the efficacy and safety of MOTN administration of indiplon compared to placebo. The primary endpoint was Latency to Sleep Onset (LSO) reported by subjects.
October 27, 2003
Sepracor reported positive results from a phase III trial investigating Estorra (eszopiclone), a non-benzodiazepine compound for the treatment of insomnia. Results showed that use of Estorra demonstrated statistically significant improvements of sleep onset, sleep maintenance, sleep quality and next-day function compared with placebo. In addition, subjects treated with eszopiclone reported improved daytime alertness, improved daytime functioning, and improved sense of physical well being compared with subjects on placebo. Eszopiclone was well tolerated over the treatment period. The six-month, randomized, double-blind, placebo-controlled study enrolled nearly 800 subjects who received nightly treatments with either placebo or eszopiclone 3 mg. Results were published in October 2003, in the journal SLEEP.
October 6, 2003
Neurocrine Biosciences reported positive results from a phase III trial investigating indiplon, in a modified release formulation for the treatment of insomnia. Statistically significant results showed that subjects with insomnia that took indiplon (30 mg) fell asleep faster and stayed asleep longer. Data demonstrated that indiplon showed statistically significant results in sleep maintenance as compared to placebo on multiple secondary endpoints. The 30 mg dose of the modified release formulation was well tolerated. The multicenter, randomized, double-blind, placebo-controlled, parallel group study enrolled 211 subjects at 32 sites in the U.S.
August 11, 2003
Acadia Pharmaceuticals reported positive results from a phase I trial investigating ACP-103, a 5-HT2A inverse agonist for the treatment of various neuropsychiatric conditions. Results demonstrated that ACP-103 was safe and well tolerated with dose proportional pharmacokinetics and a long half-life. Data also demonstrated that ACP-103 was well tolerated with no changes in cardiovascular and neurological function and no serious adverse events. The randomized, double blind, placebo-controlled, dose-escalation study enrolled 49 subjects and used both single-dose and multiple-dose regimens. The single-dose study evaluated five doses ranging from 20 to 300 mg and the multiple dose-escalation study evaluated oral doses of 50, 100, and 150 mg given once-daily for 14-days.
June 2, 2003
Neurocrine reported positive results from a phase III trial investigating indiplon, a non-benzodiazepine compound for the treatment of chronic insomnia. Results showed no evidence of rebound insomnia or withdrawal with two doses of indiplon (10/20 mg) in immediate release formulation. The primary measure compared subject’s Latency to Persistent Sleep (LPS) to LPS during the pretreatment visit. Both doses of indiplon were well tolerated and side effects for the treatment groups were no different from placebo. The study enrolled 200 subjects and was designed to evaluate the potential for rebound insomnia or withdrawal effects after discontinuation of indiplon. Subjects were evaluated by using continuous eight hours of polysomnography (PSG) recordings in sleep laboratories for 35 consecutive nights of treatment.
April 28, 2003
Neurocrine Biosciences reported positive results from a phase III trial investigating indiplon, in immediate release formulation, for the treatment of chronic primary insomnia. Results demonstrated the study achieved statistically significant results in both primary and secondary endpoints of sleep initiation with no evidence of next day residual effects. Data also showed that the formulation was safe, well tolerated, and effective throughout the 35-day treatment period. The randomized, double blind, placebo-controlled study enrolled 200 subjects at 19 sleep centers and was designed to assess the safety and efficacy of immediate release indiplon capsules in subjects with Chronic Primary Insomnia.
October 28, 2002
Cephalon reported positive results from a phase IV clinical study investigating Provigil (modafinil) in subjects with shift work sleep disorder (SWSD). The 12-week, randomized, double blind, placebo-controlled study included 209 subjects with confirmed diagnosis of SWSD. Subjects were randomly given either Provigil (200 mg) or placebo prior to the start of their night shift. The study showed the drug significantly improved wakefulness compared to placebo, as measured by the Multiple Sleep Latency Test (MSLT). In addition, subjects treated with Provigil showed significant improvement in their clinical condition as measured by the Clinical Global Impression of Change (CGI-C) when compared to subjects treated with placebo. Provigil was found to be well tolerated with reported adverse events consistent with those described on the current label.