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Insomnia

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.

June 20, 2011

Somnus issued results from a phase II trial of SKP-1041 for sleep maintenance insomnia. This four-way, double-blind, placebo-controlled, double-dummy crossover trial enrolled 67 non-elderly adults with primary insomnia characterized by middle of the night awakening. The subjects were randomly assigned to receive placebo or SKP-1041 at 10, 15 or 20 mg doses taken immediately before bedtime. Sleep-wake episodes were recorded by polysomnography for eight hours after lights-out. Residual cognitive effects were measured within one hour of awakening. At all three doses tested, SKP-1041 significantly reduced time spent awake during the night compared to placebo, with no evidence of next-morning adverse cognitive effects. For the 15 and 20 mg doses, there was a significant reduction in the number of middle-of-the-night awakenings during hours three through seven of the eight -hour sleep period, as well as increased total sleep time for hours three through seven. Blood levels of zaleplon were measured over eight hours and confirmed the release of active drug starting two hours after ingestion. SKP-1041 was well tolerated.

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.

March 16, 2009

Intra-Cellular Therapies issued positive top-line results from a phase II trial of ITI-007 for the treatment of sleep maintenance insomnia. This double-blind, placebo controlled, 4-way crossover design study enrolled 18 subjects who received one of three doses of ITI-1007 (1 mg, 5 mg or 10 mg) or placebo. The primary endpoints were an increase in slow wave sleep (SWS) and a decrease in wake after sleep onset (WASO), as measured by polysomnography (PSG), compared to baseline. ITI-007 significantly decreased WASO over baseline (p≡0.001) and showed a statistical trend to decrease the number of awakenings (p≡0.071). The decreases in WASO were reflected in the PSG recordings by increased total sleep time (p<0.001), decreased total time awake (p<0.001) and improved sleep efficiency (calculated by the proportion of the time spent sleeping while in bed, p<0.001). ITI-007 also significantly and dose-dependently increased the percent of SWS early in the night (p≡0.022 for the first quarter of the night, p≡0.029 for the second quarter of the night). Late in the night, towards morning, ITI-007 increased the percent of Stage 2 sleep (p≡0.048 for the third quarter of the night, p≡0.004 for the fourth quarter of the night). ITI-007 did not affect total duration of REM sleep (p≡0.124) and did not affect latency to the first episode of REM (p≡0.143). ITI-007 did not affect latency to persistent sleep (p≡0.455). The treatment was well tolerated and did not impair next day cognition, as measured by a battery of cognitive testing in the morning upon waking.

January 19, 2009

Intra-Cellular Therapeutics released positive results from a phase II trial of ITI-007 for the treatment of sleep maintenance insomnia. This double-blind, placebo controlled, 4-way crossover design study enrolled 18 subjects who received one of three doses of ITI-1007 1 mg, 5 mg or 10 mg, or placebo. The primary endpoints were an increase in slow wave sleep (SWS) and a decrease in wake after sleep onset (WASO), as measured by polysomnography, compared to baseline. All doses of ITI-007 significantly increased SWS (p≡0.002) and decreased WASO (p≡0.032) over baseline. These effects were maintained throughout the night. Doses of ITI-007 were safe and well-tolerated. Additional trials of ITI-007 are planned for the treatment of primary or comorbid insomnia.

July 7, 2008

Vanda released positive results from a phase III trial of tasimelteon for the treatment of insomnia. This multi-center, placebo-controlled, randomized trial enrolled 322 subjects with chronic primary insomnia. The subjects received either 20 mg or 50 mg of tasimelteon or placebo over the course of four weeks. The primary endpoint, the immediate and short-term ability (average of Nights 1 and 8) of tasimelteon to improve sleep onset as measured by Latency to Persistent Sleep (LPS) through polysomnography (PSG), was reached. Mean LPS at baseline was 78.8 minutes in the 20mg group, 76.4 minutes in the 50mg group, and 78.2 minutes in the placebo group. On Nights 1 and 8 of treatment, mean LPS improved over baseline by 45.0 minutes in the 20mg group (p<.001), by 46.4 minutes in the 50mg group (p<.001), and by 28.3 minutes in the placebo group. On Nights 22 and 29 of treatment, mean LPS improved by 49.4 minutes in the 20mg group (p<.001), by 45.1 minutes in the 50mg group (p=.016), and by 33.9 minutes in the placebo group. Secondary endpoints were reached as well; including improvements on sleep onset after long-term (average of Nights 22 and 29) use of the compound as well as measures of sleep duration (Total Sleep Time, TST) and sleep maintenance (Wake After Sleep Onset, WASO). On Nights 1 and 8 of treatment, mean TST improved by 51.4 minutes in the 20mg group (p=.089), by 52.0 minutes in the 50mg group (p=.074), and by 40.0 minutes in the placebo group. On Nights 22 and 29 of treatment, mean TST improved by 60.3 minutes in the 20mg group (p=.057), by 48.6 minutes in the 50mg group (not statistically significant), and by 47.4 minutes in the placebo group. WASO times improved as well, however these did not reach statistical significance. On Nights 1 and 8 of treatment, mean WASO improved by 12.2 minutes in the 20mg group, by 14.1 minutes in the 50mg group and by 11.7 minutes in the placebo group. On Nights 22 and 29 of treatment, mean WASO improved by 17.7 minutes in the 20mg group, by 10.2 minutes in the 50mg group and by 20.3 minutes in the placebo group. Based on the results Vanda plans to continue with the development of tasimelteon.

December 10, 2007

Takeda reported positive results from a trial of ramelteon for the treatment of insomnia in subjects with Chronic Obstructive Pulmonary Disease (COPD). This double-blind, placebo-controlled trial enrolled twenty-five subjects with moderate to severe COPD. The subjects were randomized to receive ramelteon 8 mg or placebo thirty minutes before overnight monitoring of oxygen saturation (SaO2) by pulse oximetry and sleep by polysomnography. After a five- to ten-day washout, subjects crossed over to the alternate treatment and repeated the procedure. The primary endpoint was mean SaO2 for the entire night. Data revealed that ramelteon did not exacerbate respiratory depressant effects; there was no statistically significant difference in SaO2 for the entire night observed between the ramelteon arm and the placebo arm (92.2% versus 92.4%, p=0.576). Secondary endpoints were reached as well. There was no statistically significant difference in the number of minutes in the night that SaO2 was <80% and <90% (p=0.927 and p=0.653, respectively). A significant increase in total sleep time (389.0 minutes versus 348.4 minutes, p=0.019) and sleep efficiency (81.0% versus 72.6%, p=0.019) was observed with ramelteon compared to placebo. Latency to persistent sleep was shorter with ramelteon (23.1 minutes) compared to placebo (56.9 minutes; p=0.051). Based on the results, Takeda plans to continue with the development of ramelteon for this indication.

October 29, 2007

Amicus reported positive results from two phase I trials of AT2220 for the treatment of Pompe Disease. These double-blind, placebo-controlled, dose escalation studies were designed to evaluate the safety, tolerability and pharmacokinetics of AT2220. In a single ascending dose study, 32 subjects received oral doses of AT2220 (50, 150, 300, or 600 mg) or placebo. In a multiple ascending dose study, 24 subjects received oral doses of AT2220 (50, 150, or 450 mg/day) or placebo for 7 days. Treatment was determined to be safe and well tolerated at all doses tested. In the multiple ascending dose study all possible drug-related adverse events were mild and resolved spontaneously. AT2220 was orally bioavailable with a plasma half-life of 4 to 5 hours. Based on the results, Amicus plans to initiate phase II trials early in 2008.

MediciNova issued negative results from a phase IIa trial of MN-305 for the treatment of insomnia. This randomized, double-blind, placebo-controlled, four-period crossover dose-response study enrolled 90 subjects with primary insomnia in the US. Each subject received three doses of MN-305 (1 mg, 3 mg and 6 mg) and placebo, administered orally approximately 60 minutes before bedtime, for seven consecutive nights. The primary endpoint, statistical significance in the reduction of Wake (time) After Sleep Onset (WASO), was not met. Treatment was well tolerated at all doses tested. Based on the results, MediciNova plans to discontinue the development of MN-305 for insomnia and focus on other potential indications.

TorreyPines reported positive results from a phase IIb trial of tezampanel for the treatment of migraine headaches. This randomized, double-blind, placebo-controlled, parallel-group study enrolled 306 subjects in the US. The subjects were equally randomized to one of four treatment arms: tezampanel 40 mg, 70 mg, or 100 mg or placebo administered as a single, subcutaneous dose. The primary endpoint was headache pain response at two hours post-dose. Statistical significance was observed in the 40 mg arm, with improvement in headache response reported in 78.2% of the subjects versus 58.7% in the placebo arm (p=0.033). This response was sustained through 24 hours post-dose. Statistical significance was not reached in the 70 mg arm (63.5%; p=0.890) or the 100 mg arm (57.1%; p=0.890). The 40 mg arm achieved the secondary endpoints as well, with improvements over placebo in nausea (p=0.014), photophobia (p=0.056) and phonophobia (p=0.227). Treatment was well tolerated, with no reports of serious adverse events. Based on the results, TorreyPines plans to commence phase III trials in 2008.

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.

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.

October 30, 2006

AstraZeneca reported negative results from a phase III trial, dubbed SAINT II, of Cerovive (NXY-059) for the treatment of stroke related disabilities. This multinational, multi-centre, double-blind, randomized, placebo-controlled parallel-group trial enrolled 3,200 subjects. Each subject received Cerovive or placebo up to six hours after the onset of stroke symptoms. Subjects were then measured using the modified Rankin Scale. The primary endpoint, statistical significance in the reduction of stroke related disability in the subjects treated with Cerovive versus placebo, was not met (p=0.33, odds ratio 0.94). Secondary endpoints were not met as well with no statistically significant improvement in neurological status versus placebo on the National Institute of Health Stroke Scale (p=0.70). In addition, Cerovive, when administered with the approved thrombolytic agent, rt-PA, showed no evidence of lowering the incidence of symptomatic intracranial hemorrhage (p=0.56). Based on the results AstraZeneca has discontinued development of Cerovive.

Somaxin released positive results from a phase III trial of Silenor for the treatment of transient insomnia. This randomized, double-blind, placebo-controlled, multi-center, parallel group trial enrolled 565 subjects who received 6 mg of Silenor or placebo. Treatment was well tolerated with the incidence of serious adverse events low and mild in nature. Efficacy data revealed that treatment with Silenor led to statistically significant results when compared to placebo in a number of endpoints, including: latency to persistent sleep with an improvement of 13 minutes (p<0.0001), latency to sleep onset, an improvement of 16 minutes (p<0.0001), wake after sleep an improvement of 40 minutes (p<0.0001) and total sleep time with an improvement of 51 minutes (p<0.0001). Somaxin is currently conducting two other phase III trials of Silenor and plans to file a NDA in the third quarter of 2007.

September 25, 2006

Johnson & Johnson and Jenssen released positive results from a phase III trial of paliperidone ER for the treatment of schizophrenia- related insomnia. This multi-center, double-blind, randomized, placebo- controlled trial enrolled 36 subjects who received 9 mg of paliperidone ER or placebo, every morning for two weeks. The most commonly reported adverse effects were mild and included involuntary movements and headaches. Efficacy data revealed that those subjects in the treatment arm achieved a mean reduction of over half an hour in the time required to first fall asleep and a reduction of more than 40 minutes in the time required to remain asleep, compared to placebo. Treated subjects also had enhanced sleep duration and continuity, with the treated subjects increasing their time in stage two sleep by 51 minutes. In addition, time spent in rapid eye movement (REM) increased by 18 minutes for the treated arm versus placebo. Johnson & Johnson submitted a NDA to the FDA for paliperidone ER in the treatment of schizophrenia in November of 2005. The drug is currently in phase III trials for the treatment of bipolar disorder.

April 17, 2006

NeuroVax announced positive results of a clinical trial of NeuroVax for the treatment of multiple sclerosis (MS) at the AAN Annual Meeting. This open-label study enrolled 25 subjects, 17 of whom had not previously received NeuroVax. The untreated patient subset showed significantly lower levels of FOXP3+ regulatory T-cells (as measured by FOXP3+ mRNA (p=0.03) and protein expression (p=0.02)). Trial data indicated that NeuroVax significantly increased FOXP3 expression in 14 of 17 subjects, including levels of both FOXP3+ mRNA (p=0.01) and FOXP3 protein (p=0.02). Based on these results, the company confirmed plans to initiate a phase II trial of NeuroVax for the treatment of MS across sites in the US and Eastern Europe later in 2006; this study was designed to investigate the effect of the drug on MRI measures and relapse rates.

Sangamo announced positive results of a phase I trial of SB-509, for the treatment of diabetic neuropathy, at the 58th Annual Meeting of the American Academy of Neurology (AAN) in San Diego. Primary safety data were positive, with no serious adverse events reported and mild injection site reactions the only noted all-severity adverse events. Dose limiting toxicities were not observed. Single administrations of the drug produced improvements in severity of pain, numbness and neurological symptoms in roughly 50% of subjects. Additional preliminary efficacy was noted in neurologic exam scores and electrophysiological testing. This single blind, single-dose dose-escalation study enrolled 12 subjects with mild to moderate disease, who received intramuscular injections of the drug. Based on these results, the company announced plans to initiate a phase II trial of SB-509 in the second half of 2006.

Somaxon reported positive results of their first phase III trial of Silenor (doxepin HCl), for the treatment of chronic insomnia. The drug was shown to significantly reduce 8-hour Wake After Sleep Onset (WASO), with a mean improvement of 26 minutes for the low dose and 31 minutes for the high dose groups, vs. placebo (p<0.0001). Improvement in secondary measures was also noted: Total Sleep Time was 415 min. and 421 min. for the two Silenor doses (respectively), vs. 374 min. for placebo (p<0.0001); Latency to Persistent Sleep during the initial treatment period was 27 minutes for both doses, vs. 45 minutes for placebo (p=0.011, p=0.0018); these improvements were not maintained at subsequent timepoints (due in part to improvements in the placebo group). This randomized, double-blind, placebo-controlled, parallel-group, multi-center study enrolled 229 patients, who received one of two doses of the drug (3 mg or 6 mg) or placebo nightly for 35 days.

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 22, 2005

Neurocrine Biosciences has issued positive results of a phase III study of indiplon MR, the long acting formulation of their non-benzodiazepine sedative for the treatment of insomnia. Results from the study met their primary efficacy endpoint, producing a significant and clinically relevant improvement in patient-reported total sleep time over the 4 weeks of treatment, versus placebo (p=0.0002). Mean increase in sleep time with indiplon was roughly one hour from baseline. No unexpected safety or tolerability concerns were raised. This randomized, double-blind, placebo-controlled, parallel-group, multi-center, out-patient study enrolled 248 patients with sleep maintenance difficulties across 50 US sites. Subjects received either 15 mg of indiplon MR tablets or placebo nightly for 4 weeks. Neurocrine anticipated including the results of this trial in their upcoming NDA submission, planned for Q2 2005.

Teva, Eisai, and H. Lundbeck have reported positive data from their phase III “PRESTO” study of Agilect (rasagiline), in the treatment of Parkinson’s disease (PD). Trial results indicated that the addition of the drug to standard optimized levodopa therapy produced significant decreases in both symptom severity and the total amount of daily time when treatment did not sufficiently ameliorate symptoms (“off” time). Specifically, patients receiving Agilect demonstrated significant improvements symptom severity score, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS) and Clinical Global Improvement (CGI) scales at both trial doses, and a non-significant trend towards improvement on the PDQUALIF quality of life assessment scale at the lower trial dose. Further, the average reduction in "off" time was 1.85 hours daily for the high dose group and 1.41 hours daily in the low dose group, vs. 0.91 hours for placebo. This randomized, placebo-controlled, double-blind, parallel group study enrolled 427 moderate-to-severe PD patients on optimized levodopa therapy experiencing at least 2.5 hours of “off” time daily across 57 investigative sites in the US and Canada. Patients received one of two doses of Agilect (0.5 mg. or 1 mg.) or placebo in addition to their current therapeutic regimen. An NDA for Agilect, including these data, is currently under review by the FDA.

January 18, 2005

Amarin Corporation has announced positive results of a phase IIa study of Miranox (LAX-101c), for the treatment of unresponsive major depression. Data from the first exploratory trial found that among subjects experiencing a new episode of depression, the drug produced a statistically significant improvement in symptoms on the Bech-Depression Scale over placebo, a standardized rating system for primary depressive symptomology. Retrospective analysis of a similar subset of patients from a previously completed trial with this methodology demonstrated a similarly significant efficacy profile. The placebo-controlled study randomized 77 subjects to receive either Miranox or placebo for 6 weeks; the previously completed study was a randomized, placebo-controlled trial which enrolled 70 subjects for 12 weeks.

Sepracor announced positive preliminary results of a phase IIIb/IV trial of their recently approved drug Lunesta (eszopiclone), for the treatment of insomnia in patients with co-morbid major depression. These data indicated that co-administration of Lunesta and fluoxetine (Prozac) significantly improved primary and secondary symptoms of insomnia vs. fluoxetine plus placebo, including sleep onset, wake time after sleep onset, and total sleep time (p<0.05). Furthermore, patients receiving Lunesta and fluoxetine experienced significant improvements in depression symptom severity and the proportion of patients achieving symptom response or remission vs. fluoxetine plus placebo, as measured by changes in total score on the HAM- D17 standardized scale. This double-blind, placebo-controlled ten-week study evaluated the efficacy and safety the drug in 545-patients who met DSM-IV(1) criteria for both insomnia and Major Depressive Disorder (depression). Subjects were randomized to receive either 3 mg Lunesta (n=270) or placebo (n=275) for eight weeks in addition to nightly fluoxetine, followed by a two-week Lunesta washout (fluoxetine treatment continued). Sepracor announced plans to present these data to the FDA, to discuss further development and expanded indications for the drug.

January 10, 2005

Somaxon issued positive results of a phase II study of low-dose doxepin, for the treatment of insomnia. Doxepin is currently approved for the treatment of depression under the trade name Sinequan, with a typical dose range of 75-100 mg. Results indicated that the 3 mg and 6 mg doses achieved their primary endpoint, demonstrating a statistically significant improvement in PSG-defined wake time during sleep vs. placebo (p = 0.0004, p=0.0025, respectively). All three trial doses achieved significance in the secondary endpoints, including PSG-defined wake after sleep onset, sleep efficiency and total sleep time vs. placebo. A non significant improvement was seen in latency to persistent sleep time. This multi-center, double-blind, placebo-controlled, four-way cross-over dose-response study randomized 61 patients with confirmed primary sleep maintenance insomnia to receive one of three regimens of doxepin (1, 3, or 6 mg) for two nights, followed by 5-12 days of drug-free interval. The company announced that based on these results, they expected to initiate their pivotal phase III trials by mid-year.

XenoPort has issued positive results of a phase IIa study of XP13512 for the treatment of restless legs syndrome. Study results indicated that the drug produced a highly significant improvement (p<0.0001) in IRLS symptom severity score after 14 days, vs. placebo. The drug also produced improvements in Patient and Investigator Clinical Global Impression scales and a number of objective sleep measures, including an increase in total sleep time, total slow-wave sleep, a reduction in the amount of time awake after sleep onset, and a reduction in the number of times periodic limb movements woke patients from sleep. The drug was well tolerated. This double-blind, placebo-controlled, cross-over, multicenter study randomized 38 RLS patients to receive one of three doses of XP13512 or placebo twice daily for two weeks, followed by a one-week washout and re-randomization into a second 2 week treatment arm.

September 13, 2004

Neurocrine Biosciences issued positive results of their phase III study of the modified release formulation of indiplon, their investigational treatment for insomnia. Data indicated that the study met its primary endpoint, with a highly significant increase in total sleep time (p<0.0001), compared with placebo. The study also met its secondary endpoints with significant improvements in all parameters: total wake time, wake after sleep onset, number of awakenings after sleep onset, latency to sleep onset, and sleep quality. The double-blind, placebo-controlled, multi-center, parallel-group outpatient study randomized a total of 229 elderly patients with a history of sleep disturbances; all subjects received nightly doses of either indiplon modified-release or placebo for 14 days. Neurocrine announced plans to submit an NDA for indiplon modified-release bases upon these results.

Schwarz Pharma has reported positive results of a phase II b study of their anti-epileptic investigational drug harkoseride. Trial data demonstrated that the drug produced a significant observed reduction in seizure frequency, and a greater than 50% response rate among participants, compared with placebo. Harkoseride treatment was also found to be safe and generally well tolerated. The multi-center, double-blind, placebo-controlled trial enrolled a total of 497 subjects suffering from partial seizures suffering due to treatment-refractory epilepsy. Subjects were randomized to receive either harkoseride or placebo twice daily for 12 weeks, adjunct to standard anticonvulsant treatment. Schwarz is currently conducting an open-label extension study in this patient population, in addition to an ongoing phase III investigation.

June 7, 2004

Phase 2 Discovery reported results from a phase II trial investigating PD-6735, a melatonin analog for the treatment of insomnia. Results demonstrated that PD-6735 produced statistically significant improvements in sleep latency. Data showed subjects who were administered 20 mg of PD-6735 had a sleep performance improvement, measured using polysomnography, of 31%. Subjects administered 50mg and 100mg of PD-6735 experienced a sleep performance improvement of 32% and 41% respectively. Subjects with more severe insomnia showed greater improvements as compared to those with mild insomnia. The randomized, placebo-controlled, cross-over study enrolled 40 subjects with moderate primary insomnia Subjects received three doses of PD-6735 at 20 mg, 50 mg, and 100 mg or placebo.

April 12, 2004

Neurocrine Biosciences reported preliminary positive results from two phase III trials investigating an immediate release (IR) and a modified release (MR) formulation of indiplon for the treatment of insomnia. Results from the MR study demonstrated highly statistically significant improvements as measured by polysomnography in Wake After Sleep Onset after the first two nights of dosing. The randomized, double-blind, placebo-controlled, parallel-group study enrolled 340 elderly subjects with chronic insomnia. Results from the IR saftey study demonstrated that the incidence of adverse events were similar to long-term studies conducted previously with indiplon. The double-blind, out-patient extension study enrolled 120 subjects. Based on these results, Neurocrine plans to submit NDAs for both formulations shortly.

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.

February 23, 2004

Neurocrine Biosciences reported positive results from a phase III trial investigating an immediate release formulation of indiplon for the treatment of chronic insomnia. Results demonstrated statistical significance in the primary endpoint, Latency to Sleep Onset (LSO). The LSO measures the time it took for subjects to fall asleep with indiplon compared to placebo. Data showed indiplon (5 and 10mg) shortened the LSO by more than 40%. Secondary endpoints, including patient self-reported total sleep time, wake after sleep onset, and number of awakenings after sleep onset were also statistically significant compared with placebo. The randomized, placebo-controlled, double-blind, parallel-group study enrolled 360 elderly subjects at 50 sites in North America. Subjects were eligible to continue in a six-month open-label extension trial.

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.

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.

May 26, 2003

Cephalon reported positive results from two-phase II trials investigating Provigil (modafinil), a previously approved wake-promoting agent for the new indication of attention deficit/hyperactivity disorder (ADHD). During one 4-week study, 248 children with ADHD were randomized to Provigil in different combinations of 300 mg doses or placebo. Results showed that the 300 mg regimen of Provigil significantly improved symptoms as measured by the teacher- rated ADHD Rating scale. In a second four-week double blind, placebo-controlled, crossover study, 48 children were randomized to receive placebo or Provigil 100, 200, 300, or 400 mg. The most significant improvements were seen in subjects receiving the 300 or 400 mg dose of Provigil as assessed in the home environment by the parent-rated ADHD Rating Scale.

Sepracor reported positive results from a phase III trial investigating Estorra (eszopiclone), a non-benzodiazepine compound for the treatment of insomnia. Results showed that the eszopiclone arm demonstrated statistically significant improvements in sleep maintenance measures, sleep latency, total sleep time and sleep quality relative to placebo. Data showed no evidence of tolerance was observed over the course of the trial and eszopiclone was well tolerated. The randomized, multi-center, placebo-controlled study enrolled 788 subjects 21-69 years of age with chronic insomnia. Subjects received nightly treatment of either eszopiclone or placebo (3 mg) for 6 months. The results were presented at the American Psychiatric Association meeting in San Francisco.

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.

July 8, 2002

Phase II trial results indicate that treatment with Neurocrine Biosciences' indiplon-MR (modified release formulation) tablets improves sleep maintenance in elderly subjects with primary insomnia characterized by sleep maintenance difficulties. The randomized, multicenter, double-blind, dose-response trial evaluated four dose levels of indiplon-MR (10, 20, 30 and 35 mg). Results showed that the 20, 30 and 35 mg indiplon-MR doses produced a highly statistically significant improvement in the primary endpoint of sleep efficiency - defined as total sleep time divided by total bed time - compared to placebo. Total sleep time was also statistically significant compared to placebo, in addition to secondary sleep maintenance endpoints, including wake time after sleep onset and wake time during sleep.

June 3, 2002

Positive results were reported from a phase II trial of Theratechnologies' ThGRF peptide (TH 9507) in insomnia subjects affected by poor daytime performance. The randomized, double-blind, multicenter trial included 83 subjects between the ages of 35 and 50 with sleep maintenance insomnia. Subjects received 0.1 mg ThGRF, 1.0 mg ThGRF or placebo daily via subcutaneous injection for 14 days. Results indicated that sleep efficiency (as measured by polysomnography) improved 5.7% with the 0.1 mg dose compared to treatment with placebo. In terms of daytime vigilance, a clinically and statistically significant improvement was observed in mean reaction time with the 0.1 mg dose versus placebo. Improved short-term memory was also noted with the 0.1 mg dose as assessed by the Digit Span Test.

January 7, 2002

Neurocrine Biosciences announced positive results from a phase II placebo-controlled, double-blind study comparing three doses of NBI-34060 Immediate Release (IR) in 42 elderly subjects with chronic insomnia. The study endpoint was Latency to Persistent Sleep (LPS) compared to placebo as measured by polysomnography (PSG). At all dose levels, NBI-34060 IR had a statistically significant effect on LPS as compared to placebo, with 61% improvement. Secondary efficacy, also measured by PSG, demonstrated statistically significant improvements on Total Sleep Time and Sleep Efficiency in subjects receiving the two higher doses. These results support data from three previously conducted phase II trials that found the drug highly effective in reducing LPS, and therefore provide confidence in the expansion of the current phase III program.

Phase I/II results suggest that PTI-801, a novel narcotic painkiller, is well tolerated in volunteer subjects and those with chronic, moderate-to-severe pain. The studies enrolled 22 subjects and were designed to analyze the safety and pharmacokinetic properties of orally administered PTI-801. Results showed no treatment-related or unexpected adverse events. PTI-801 is being developed by Pain Therapeutics.