Sleep Apnea Syndromes

March 27, 2017

Jazz Pharmaceuticals released results of two global multicenter phase III studies of JZP-110 for excessive sleepiness associated with obstructive sleep apnea (OSA). TONES 3 was a 12-week, five-arm, parallel-group, double-blind, placebo-controlled, randomized study evaluating JZP-110 at 300mg, 150mg, 75mg and 37.5mg compared to placebo. TONES 4 was a six-week study comprising a two-week flexible-dose titration phase followed by two weeks at stable dose, and then a two-week, placebo-controlled, double-blind randomized withdrawal phase. TONES 3 demonstrated highly statistically significant improvement in the co-primary endpoints of Maintenance of Wakefulness test (MWT) and Epworth Sleepiness scale (ESS) at all doses. In addition, the key secondary endpoint of Patient Global Impression of Change (PGIc) scale demonstrated a highly statistically significant improvement. On the co-primary endpoints of MWT and ESS, the study demonstrated that treatment with JZP-110 significantly increased the patients’ ability to stay awake and significantly decreased patients’ subjective levels of sleepiness, respectively, compared to placebo. These effects were maintained throughout the course of the study. In the TONES 4 study, at the end of week four, 126 patients who reported “much” or “very much” improvement on the PGIc scale and who had numerical improvements on the MWT and ESS at week four were then randomized 1:1 to receive either the same dose of JZP-110 received in the stable dose phase, or placebo, for two weeks in the randomized withdrawal phase. In TONES 4, patients randomized to continue on JZP-110 maintained efficacy, while those randomized to placebo experienced a loss of efficacy, as measured by the co-primary and key secondary endpoints.

January 9, 2017

RespireRx Pharmaceuticals released results of a phase IIb study of dronabinol for the treatment of obstructive sleep apnea (OSA). In a dose-dependent fashion, treatment with 2.5mg and 10mg dronabinol once a day at night significantly reduces the Apnea Hypopnea Index (AHI), a measure of breathing abnormalities during sleep, in 56 patients with moderate to severe OSA who completed the study. Of these, 17 received placebo, 19 received the 2.5mg dose and 20 received the 10mg dose. Compared to average baseline AHI values of 26 + 12, six weeks of dronabinol administration to moderate to severe OSA patients reduced AHI values, compared to placebo, by 9.7 + 4 for the 2.5mg dose and 13.2 + 4 for the 10mg dose (p=0.02 and p=0.001, respectively, compared to control). Furthermore, treatment with 10mg dronabinol significantly improved daytime sleepiness as measured by the ESS (p=0.0001, compared to placebo) and achieved the greatest overall patient satisfaction with treatment (p=0.02) as measured by the Treatment Satisfaction Questionnaire for Medications . Dronabinol is approved in the U.S. in 2.5mg, 5mg and 10mg capsules for the treatment of anorexia associated with AIDS and chemo-therapy induced nausea and vomiting. The company plans to move forward with the development of dronabinol in OSA, and plans to meet with the FDA for a Special Protocol Assessment to finalize the phase III study required for approval using both Fast Track and Breakthrough designations from the FDA to facilitate the development path. 

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).

January 18, 2010

Vivus released positive results from a phase II trial of Qnexa for obstructive sleep apnea (OSA). This single-center, randomized, double-blind, placebo-controlled parallel group trial (OB-204) enrolled 45 obese subjects who underwent a four-week dose titration followed by 24 weeks of additional treatment with full dose Qnexa or placebo. The primary endpoint was the change in apnea/hypopnea index (AHI) between baseline and Week 28. The AHI is a standard measure of OSA severity, indicating the number of apnea/hypopnea events per hour of sleep. The subjects treated with Qnexa had a 69% reduction in sleep apnea events. The number of apnea/hypopnea events was reduced from a mean of 46 events per hour of sleep to 14 hours, compared to a reduction from a mean 44 events per hour of sleep to 27 for the placebo arm (p<0.001). Secondary endpoints included weight loss, oxygen saturation and changes in blood pressure, were all reached with significant results over placebo.

April 21, 2008

BTG issued positive results from a phase II trial of BGC20-0166 for the treatment of obstructive sleep apnea (OSA). This study enrolled thirty nine subjects with mild to severe OSA who received placebo, a single agent or one of two doses of BGC20-0166 daily for a period of twenty eight days. Each subject's apnea-hypopnea index (AHI) was measured in overnight sleep laboratory polysomnograph studies on days fourteen and twenty eight. The primary endpoint was a reduction in the AHI at day twenty eight. The treatment group receiving the high-dose demonstrated a statistically significant reduction in AHI compared to subjects receiving placebo at both day fourteen and twenty eight. AHI was reduced by a mean of 40% in this treatment group, with individual responses ranging between 10% and 85%. Three of ten subjects in the high-dose group were considered complete responders, with a reduction in AHI of 50% or more and an AHI below 10 at day twenty eight. This group also showed reduced AHI in both REM and non-REM sleep stages and independent of sleep position and a trend towards improved oxygen saturation levels relative to placebo. Treatment was well tolerated. Based on the results, BTG plans to continue with the development of BGC20-0166.

Genentech and Biogen released negative results from a phase II/III trial of Rituxan for the treatment of primary-progressive multiple sclerosis. This randomized, double-blind, placebo-controlled study enrolled four hundred and thirty nine subjects in the US and Canada. The subjects received either four treatment courses of Rituxan six months apart or placebo. MRI evaluations were conducted at baseline, weeks six, forty-eight, ninety-six and one hundred and twenty-two. The study did not meet its primary endpoint as measured by the time to confirmed disease progression during the ninety six-week treatment period. The incidence of overall adverse events was comparable between Rituxan and placebo treatment groups. The companies plan to fully analyze the data in order to determine the best path forward.

Santhera reported positive results from a phase II trial of SNT-MC17 for the treatment of Duchenne Muscular Dystrophy (DMD). This double-blind, randomized, controlled study was dubbed DELPHI (Duchenne Efficacy Study In Long-Term Protocol Of High Dose Idebenone). A total of twenty-one pediatric subjects, aged eight to sixteen years, with DMD and cardiac dysfunction were enrolled in Belgium. The subjects received SNT-MC17 450 mg/day or placebo for twelve months. The primary endpoint was the percent change from baseline on the peak systolic radial strain of the left ventricular (LV) inferolateral cardiac wall. In the group treated with SNT-MC17, this was improved by 104%, a significant difference over the placebo group who improved by 29% (p=0.03). In addition, peak systolic longitudinal strain of the LV lateral-mid cardiac region also improved significantly, indicating a beneficial effect of SNT-MC17 on early and systolic myocardial dysfunction in DMD. Secondary endpoints included respiratory function tests. Direct measures of respiratory weakness, including peak expiratory flow, improved in subjects on SNT-MC17. Peak flow expressed as percentage of the predicted value for subjects on SNT-MC17 improved by 2.8% while those on placebo deteriorated by 8.5% (p=0.042). Treatment was determined to be safe and well tolerated. Additional phase II studies are currently underway.