Restless Leg Syndrome

October 20, 2008

Neurogen reported positive results from two phase II studies of aplindore for the treatment of neurological indications. The first study was a placebo-controlled, single-blind, multi-center study in 27 subjects with restless legs syndrome. Each subject spent an adaptation night in the sleep laboratory followed by a placebo-dosed (baseline) night and then individual nights of sequentially increasing doses of aplindore from 0.05 mg to 0.2 mg. If a subject demonstrated less than a 50% reduction in PLMI (periodic limb movement index) from baseline at the 0.2 mg dose, the dose was escalated to a maximum of 0.7 mg. Results showed a significant reduction in the mean PLMI over placebo (p less than 0.0001). In the evaluable population the mean PLMI scores were 33.97, 13.88, 9.12, 8.24 and 8.20 for the placebo, 0.05 mg, 0.1 mg, 0.2 mg and the highest dose groups, respectively. On the basis of these significant results the study was terminated early. The second study was a dose-ranging, randomized, double-blind, placebo-controlled, parallel design study in 39 subjects with Parkinsons disease. The subjects were assigned to one of five cohorts, with each cohort consisting of a different dose escalation schedule and maximum dose. Following two weeks of titration to five different maximum daily doses, clinically and statistically significant improvement was observed in the Motor Score (Part III) of the Unified Parkinson Disease Rating Scale (UPDRS) in the cohorts dosed at 2 mg BID, 3 mg BID and 5 mg BID of aplindore compared to placebo. The subjects titrated to higher aplindore doses (9 mg BID and 15 mg BID) over the same two-week period of time showed improvements that did not separate statistically from placebo, suggesting a possible plateauing of the observed effect. Based on the data, Neurogen plans to move forward with the development of aplindore for both indications.

March 10, 2008

Xenoport and GlaxoSmithKline reported positive top-line results from a phase III trial of XP13512 for the treatment of moderate to severe restless legs syndrome. This twelve week, double-blind, placebo-controlled study, dubbed XP053, enrolled three hundred and twenty five subjects. The subjects received placebo or 600 mg or 1,200 mg of XP13512, given once per day. The primary endpoint were the change from baseline for the International Restless Legs Syndrome (IRLS) rating scale score at end of treatment and the percentage of subjects showing significant improvement on the Investigator Clinical Global Impression of Improvement (CGI-I) scale at end of treatment. The endpoints were met with statistical significance in both dose groups when compared to placebo. In the 600 mg dose group, the unadjusted mean reduction in the IRLS scale score was -13.8 (p less than 0.0001). At the end of treatment, 73% of subjects treated with 600 mg of XP13512 were reported as "much improved" or "very much improved" on the CGI-I scale (p less than 0.0001 compared to placebo). In the 1,200 mg dose group, the unadjusted mean reduction in the IRLS scale score was -13.0 versus -9.8 for placebo (p=0.0015). At the end of treatment, 78% of subjects treated with 1,200 mg XP13512 were reported as "much improved" or "very much improved" on the CGI-I scale compared to 45% treated with placebo (p less than 0.0001). Treatment was generally well tolerated, with adverse events mild to moderate in nature. Based on positive phase III findings, an NDA filing was planned for third quarter of 2008.

January 21, 2008

XenoPort and AstraZeneca released positive top-line results from a phase III trial of XP13512 for the treatment of Restless Legs Syndrome (RLS). This randomized, placebo-controlled trial enrolled three hundred and twenty seven subjects with primary moderate to severe RLS. The first portion of the study consisted of a single blind phase. All subjects were administered 1200 mg of XP13512, taken at approximately 5:00 p.m., for twenty four weeks. At the end of this phase, they were measured for treatment response based on the following criteria: a decrease in total International RLS (IRLS) rating scale score of six or more points compared to baseline score, a decrease in IRLS score to less than 15 and an assessment of "much improved" or "very much improved" on the Investigator Clinical Global Impression of Improvement (CGI-I). The subjects considered responders continued on to a double-blind phase whereby they received XP13512 (600 mg) for two weeks and then placebo for an additional ten weeks or XP13512 (1200 mg) for 12 weeks. Of the three hundred and twenty seven original subjects, one hundred and ninety four completed both treatment phases. The primary endpoint was achieved; XP13512 resulted in a statistically significant lower proportion of relapses compared to placebo during the double-blind treatment period (23% placebo compared to 9% XP13512; p= 0.0158). Treatment was determined to be safe and well tolerated over the nine month period, with no reported serious adverse events. Based on positive phase III results, XenoPort and AstraZeneca plan to file an NDA with the FDA in the third quarter of 2008.

January 22, 2007

Schwarz Pharma reported positive results from a phase III trial of rotigotine transdermal patch for the treatment of restless legs syndrome (RLS). This double-blind, placebo-controlled trial enrolled 505 subjects with moderate to severe RLS. Subjects began the four-week titration period at a daily dosage of 0.5 mg/24h rotigotine transdermal patch or placebo. During the six-month treatment duration, the subjects received rotigotine transdermal patch (0.5, 1, 2 or 3 mg/24h) or placebo daily. The co-primary endpoints were absolute change from baseline in the International Restless Legs Syndrome Study Group Rating Scale (IRLS) sum score and in the Clinical Global Impression (CGI) item 1 score (severity of illness) at the end of maintenance period. A statistically significant reduction in the IRLS and CGI 1 score was observed in the 2 and 3 mg/24h daily treatment groups when compared to placebo. The 0.5 and 1 mg/24h groups did not reached statistical significance. Based on the results, Schwarz plans for regulatory submission in Q4 2007.

August 8, 2005

XenoPort has issued positive results of a phase IIb trial of their gabapentin Transported Prodrug XP13512, for the treatment of restless legs syndrome (RLS). Data indicated significant improvement in the trials primary efficacy endpoint at the highest dose, reducing symptom severity scores on the International Restless Legs Scale (IRLS) after 14 days compared to placebo (-16.1 points vs. -8.9 points, p<0.0001). Secondary efficacy endpoints were also met: improvements in IRLS symptom score were significant at 7 days; both Patient and Investigator Clinical Global Impression of Change improved vs. placebo (p<0.0001 for both scales); subjective measures of sleep quality (including overall quality of sleep, awakenings per night due to RLS, and number of hours awake per night due to RLS) all improved (p<0.005); and RLS symptom severity in the evenings was reduced significantly (p= 0.01). Results for the lower trial dose did not meet significance in primary or secondary endpoints. This multi-center, randomized, double-blind, placebo- controlled study enrolled 95 RLS patients, who received one of 2 doses of the drug (600 mg or 1200 mg) or placebo once daily at the evening meal for 14 days. Based on these results, the company announced plans to initiate phase III trials of the drug in the first half of 2006.

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.

January 3, 2005

GlaxoSmithKline reported results from a study with Requip (ropinirole), an approved non-ergoline dopamine agonist being investigated for the treatment of Restless Legs Syndrome (RLS). The placebo-controlled study enrolled 267 subjects with moderate-to-severe primary RLS. Results demonstrated that that Requip Tablets effectively treated the symptoms of primary Restless Legs Syndrome (RLS) as assessed by improvements in symptoms, over 12 weeks. Improvements were significantly better for Requip than placebo on the IRLS Scale (-11.2 vs. -8.7; p = 0.0197). In addition, the drug showed significant improvements in sleep and quality of life in RLS patients taking Requip versus placebo. The primary endpoint was the change in International RLS Rating Scale (IRLS Scale) score at week 12. On the CGI-I scale, 36.6% of subjects taking Requip (48/131) responded "much improved" or "very much improved" after one week compared with 16.4% (22/134) of subjects taking placebo. Subjects were randomized to Requip (0.25-4.0 mg/day) or placebo, 1-3 hours before bedtime. Full results were reported in the journal Movement Disorders. Requip is currently under FDA review for the treatment of the signs and symptoms of primary RLS.

Pharmos reported negative results from a phase III trial with dexanabinol (HU-211), a NMDA-receptor antagonist for the treatment of severe traumatic brain injury (TBI). The trial was one of the largest ever undertaken for the treatment of TBI. The pivotal, double-blind, randomized, placebo-controlled trial enrolled 861 subjects and was conducted in 86 trauma centers in European, Israeli, Australian and U.S. Results showed that dexanabinol did not demonstrate efficacy as measured by the primary clinical outcome endpoint, the Extended Glasgow Outcome Scale (GOSE). The study, however, did demonstrate an excellent safety profile with no evidence of excess side effects in the dexanabinol-treated patients. The primary endpoint was defined as a statistically significant increase in the number of dexanabinol-treated patients achieving a favorable outcome when compared to the placebo group at six months. To be enrolled, subjects must have sustained a severe brain injury as judged by both a Glasgow Coma Score between 4 and 8 and by a CT scan showing brain parenchymal damage. Subjects must have been administered a single dose of placebo or 150 mg of dexanabinol within 6 hours of injury. The company stated they will likely discontinue dexanabinol for TBI but plans to continue developing the drug for cognitive impairment in cardiac surgery. Dexanabinol is under license from the Hebrew University of Jerusalem as part of a series of tricyclic dextrocannabinoids.

July 14, 2003

GlaxoSmithKline reported positive results from a phase III trial investigating Requip (ropinirole HCL), a non-ergoline dopamine agonist for the treatment of restless leg syndrome (RLS). Results showed that Requip (up to 4 mg daily) was effective in the treatment of RLS and significantly improved symptoms as measured by The International RLS (IRLS) and Clinical Global Impression (CGI) scales compared with placebo. Treatment was generally well tolerated with Requip 5.3% of subjects withdrawing from the study before completion due to adverse events, as compared with 6.6% of the placebo group. The 12-week, randomized, double blind, placebo-controlled study enrolled 267 subjects and was conducted in 47 sites in six countries. Results were presented at the 17th Associated Professional Sleep Societies meeting in Chicago.

April 7, 2003

GlaxoSmithKline reported positive results from a phase III trial investigating Requip (ropinirole), an approved anti-Parkinson’s drug for the new indication of restless legs syndrome (RLS). Results showed the treatment significantly improved symptoms of RLS and was generally well tolerated. Subjects treated with Requip experienced a decrease in their RLS symptom scores that were 27% greater than those seen with subjects taking placebo (11 vs. 8 points). The most common adverse events related to Requip, compared to placebo, were nausea (37.7% vs. 6.5%), headache (19.9% vs. 16.7%) and vomiting (13% vs. 1.4%). The study international, randomized, double blind, placebo controlled trial examined the efficacy, safety and tolerability of Requip in 284 adults with RLS.

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