In a phase 3 double-blind placebo-controlled randomized-withdrawal study (NCT03030599) a novel oxybate (JZP-258; Jazz Pharmaceuticals, Philadelphia, PA) was effective for treatment of cataplexy and excessive daytime sleepiness (EDS) in narcolepsy. In randomized-withdrawal studies, efficacy is measured as maintenance of effect for participants continuing on active therapy vs those switching to placebo.
Those who continued active treatment with the novel oxybate the median change in cataplexy attacks was 0.00 (quartile 1 [Q1]: -0.49; quartile 3 [Q3]: 1.75). In contrast, those who were switched from active treatment to placebo had a median increase in cataplexy attacks of 2.35 (Q1: 0.00; Q3: 11.61] (P < .0001). Median ESS scores increased by 2.0 points (Q1: 0.0; Q3: 5.0) after withdrawal from oybate vs 0.0 (Q1: −1.0; Q3: 1.0) with continued treatment with oxybate (P < 0.0001). Clinician and participant rating on global indication of changes measures also indicated worsening of symptoms in those who were randomized to receive placebo.
“We are pleased with the positive results from the Phase 3 study of JZP-258, which demonstrate the efficacy of JZP-258 for the treatment of cataplexy and excessive daytime sleepiness in narcolepsy,” said Jed Black, M.D., senior vice president, Sleep and Neuroscience at Jazz Pharmaceuticals and adjunct professor, Stanford University Medical Center, Stanford Center for Sleep Sciences and Medicine. “These data support the efficacy and overall safety profile of a lower-sodium oxybate formulation for people living with narcolepsy, a chronic condition that may require lifelong therapy. There is broad consensus among health care organizations, like the National Academy of Sciences and American Heart Association, that lowering sodium intake lowers the risk of cardiovascular disease. We believe that JZP-258, if approved, will provide a clinically meaningful benefit to patients prescribed oxybate.”
Serious adverse events, considered treatment-related by the investigator, occurred in 2 participants. In 1 individual, a confusional state and visual hallucinations occurred after accidental overdose, and in 1 person taking placebo, muscle enzymes increased 1 day after treatment. The most common adverse events reported by 5% or more participants who took the oxybate compound were headache, nausea, and dizziness. Overall, the safety profile was similar to that seen for sodium oxybate in clinical trials.
In this study, a heterogeneous population of 134 participants previously treated with or naïve to sodium oxybate (Xyrem; Jazz Pharmaceuticals) were all treated with the novel oxybate for 12 weeks and then randomized to be switched to the novel oxybate or placebo for another 2 weeks. After the completion of the double-blind, placebo-controlled treatment period, patients had the opportunity to receive JZP-258 in an optional 24 week open-label safety extension period.
Data from the study were presented in at World Sleep 2019 in Vancouver, Canada.
Shruti Bhandari, MD; Rohit Kumar, MD; Megan Nelson, MD; Donald Miller, MD; and Brian J. Williams, MD
Ilana E. Green; Andrew M. Southerland, MD, MSc; and Bradford B. Worrall, MD, MSc