June 12, 2017

Jazz Pharmaceuticals issued results of a phase III study of JZP-110 in adults with excessive sleepiness in narcolepsy. TONES 2 was a 12-week, four-arm, parallel-group, double-blind, placebo-controlled, randomized study. Patients (n=239) were randomized 1:1:1:1 to JZP-110 300mg (n=60), 150mg (n=60), 75mg (n=59) and placebo (n=60). The co-primary endpoints were the change in mean sleep latency on the Maintenance of Wakefulness Test (MWT) and in the Epworth Sleepiness Scale (ESS) score from baseline to week 12. The key secondary endpoint was the percentage of patients who reported improvement on the Patient Global Impression of Change (PGIc) scale, a patient-reported measure in overall condition from baseline to week 12. In patients with narcolepsy, JZP-110 150mg and 300mg doses significantly increased mean sleep latency relative to placebo at week 12 on the MWT and these effects were observed as early as week one and continued throughout the 12 weeks of the study (p<0.0001). JZP-110 significantly decreased ESS scores relative to placebo at all doses at week 12 (p<0.0001 for 150mg and 300mg doses and p<0.05 for 75mg dose). The JZP-110 75mg dose reached statistical significance on the co-primary endpoint of the ESS, but not the MWT. On the key secondary endpoint of PGIc, JZP-110 significantly increased the percentage of patients who reported improvement in their overall condition at all doses relative to placebo at week 12 (p<0.0001 for 150mg and 300mg doses and nominal p-value of p<0.05 at the 75mg dose as the co-primary endpoint of MWT was not met at this dose).

July 4, 2016

Jazz Pharmaceuticals reported results of a phase III study of JZP-110 for excessive sleepiness (ES) in adult patients with narcolepsy or with obstructive sleep apnea (OSA). The HAL study was a randomized, double-blind, placebo-controlled, six-sequence crossover study evaluating the abuse potential of JZP-110 relative to the Schedule IV stimulant phentermine in 43 adults with a recent history of recreational polydrug use. Subjects were randomized to one of six test sequences, in which they received a single treatment with one of the six study drugs (JZP-110 at 300mg, 600mg and 1200mg; phentermine at 45mg and 90mg; and placebo), with a two-day washout period between each treatment. On the primary endpoint, all doses of JZP-110 had significantly lower ratings of peak (Emax) Liking at the Moment compared to 90mg of phentermine (p<0.05) and had significantly greater ratings of peak Liking at the Moment compared to placebo (p<0.001). On the secondary endpoint of Overall Next Day Drug Liking, JZP-110 at 600mg and at 1200mg had significantly lower measures compared to both doses of phentermine (p<0.05). JZP-110 at 300mg was not statistically different from 45mg of phentermine (p=0.070). JZP-110 at 600mg and at 1200mg did not have any statistical difference in Overall Next Day Drug Liking measures compared to placebo. JZP- 110 at 300mg had higher measures of Overall Next Day Drug Liking at 24 hours compared to placebo (p=0.021). On the secondary endpoint of willingness to Take the Drug Again, JZP-110 at all doses had significantly lower measures compared to both doses of phentermine (p<0.05). All doses of JZP-110 had higher ratings of willingness to Take the Drug Again relative to placebo (p<0.05).

June 9, 2014

Jazz Pharmaceuticals issued results of a phase IIb study of JZP-110 (formerly known as ADX-N05) for the symptoms of excessive daytime sleepiness (EDS) in adults with narcolepsy. This phase IIb, double-blind, placebo- controlled, parallel-group, multicenter study evaluated the safety and efficacy of JZP-110 over 12 weeks in 93 subjects aged 18 to 70 years with an ICSD-2 diagnosis of narcolepsy. Subjects were randomized to once-daily placebo (n=49) or JZP-110 (n=44). JZP-110 was administered at a dose of 150mg/day during weeks one through four and at a dose of 300mg/day during weeks five through 12. Sleep Onset Latency on the Maintenance of Wakefulness Test showed improvement on the time to fall asleep for subjects receiving JZP-110 150mg of 9.5 minutes v. placebo in 1.4 minutes (N=40 v. N=45, respectively; p<0.0001). On the Clinical Global Impression- Change scale, symptoms were “much improved” or “very much improved,” with JZP-110 150mg showing an 80% improvement v. placebo at 51% (N=43v. N=47, respectively; p<0.0066). JZP-110 150mg also showed a decrease in overall sleepiness as measured by the Epworth Sleepiness Scale. JZP-110 150mg showed a -5.6 point change (N=43) compared to placebo of -2.4 points (N=47) for a statistically significant difference of p=0.0038. Jazz Pharmaceuticals plans to evaluate JZP-110 in phase III clinical studies in patients with EDS associated with narcolepsy and in patients with EDS associated with obstructive sleep apnea.

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.

September 20, 2004

Orphan Medical has announced the results of a phase III b study of Xyrem, for the treatment of excessive daytime sleepiness (EDS) associated with narcolepsy; Xyrem is currently approved for the treatment of cataplexy, another common symptom of narcolepsy. The study found that the study met its primary endpoint of improving wakefulness and alertness, with a significant improvement over placebo in objective wakefulness score, as measured on a standardized scale. Furthermore, the study also met its secondary endpoint of significantly reducing sleepiness score on another, similar objective standardized scale, compared with placebo. The study also found that while Xyrem was effective alone in limiting EDS, co-administration of Provigil (an approved EDS treatment) yielded greater efficacy than either agent alone. The multi-center, double-blind, placebo-controlled, parallel-group study randomized subjects with established EDS into one of four treatment arms for two weeks: Xyrem alone, Provigil alone, Xyrem and Provigil, or placebo. Orphan Medical announced plans to submit an sNDA for Xyrem for the treatment of EDS.

June 1, 2004

Orphan Medical reported positive results from a phase IIIb trial investigating Xyrem (sodium oxybate) for the treatment of narcolepsy. Results showed the study demonstrated a statistically significant change in the Epworth Sleepiness Score and Clinical Global Impressions of Change, the study’s primary endpoint measures. The double-blind, placebo-controlled, randomized study, called SXB-15, enrolled 228 subjects for eight weeks at 48 sites in North America and Europe. The study was designed to assess the improvement in the excessive daytime sleepiness of patients with narcolepsy. Subjects were administered Xyrem (4.5, 6.0 or 9.0 grams plus stimulant therapy. Secondary endpoints included changes in the Maintenance of Wakefulness Test (MWT), polysomnography recordings, as well as reductions in inadvertent daytime naps, nighttime awakenings and the number of cataplexy attacks. Additional data will be presented at the Associated Professional Sleep Societies meeting in Philadelphia in June 2004.

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