Statistically significant worsening on the Epworth Sleepiness Scale was observed in patients randomized to placebo compared to participants who received JZP-258.
Richard K. Bogan, MD, FCCP, FAASM
Results from a 12-week, open-label trial confirmed the efficacy of calcium, magnesium, potassium, and sodium oxybates (Xywav; Jazz Pharmaceuticals) oral solution to treat cataplexy and excessive daytime sleepiness (EDS), while also showing a safety profile consistent to what has been observed.1
Otherwise known as JZP-258, the treatment showed no median (first quartile [Q1], –0.49; third quartile [Q3], 1.75) change in weekly number of cataplexy attacks from the 2-week stable-dose period (SDP) to the double-blind, randomized withdrawal period (DBRWP; mean change, 0.12 [standard deviation (SD), 5.772]; P <.0001). In comparison, those on placebo showed statistically significant worsening of symptoms, with a median of 2.35 (Q1: 0.00; Q3: 11.61) change in weekly number of cataplexy attacks from SDP to DBRWP.
Median change in Epworth Sleepiness Scale (ESS) score, defined as a key secondary end point, was 2.0 (Q1: 0.0; Q3: 5.0) in the placebo group, compared to 0.0 (Q1: –1.0; Q3: 1.0) in the JZP-258 group (mean change: 3.0 [SD, 4.68] versus 0.0 [SD, 2.90]; P <.0001).
Richard K. Bogan, MD, FCCP, FAASM, associate clinical professor, University of South Carolina School of Medicine; medical officer, SleepMed, and colleagues assessed efficacy in 134 participants, aged 18 to 70 years with narcolepsy with cataplexy who received randomized treatment, and safety in all enrolled participants (n = 201). JZP-258 is an oxybate product that contains a unique composition of cations resulting in 92% less sodium, or approximately 1000 to 1500 mg/night, than sodium oxybate (Xyrem; Jazz), the only other approved agent for the treatment of cataplexy or EDS in patients with narcolepsy.
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The distribution of Patient Global Impression of Change (PGIC) ratings for narcolepsy overall demonstrated that more participants randomized to placebo experienced worsening symptoms compared to those randomized to continue JZP-258 treatment (nominal P <.0001). Furthermore, a greater percentage of participants rated their narcolepsy as “much worse” or “very much worse” on placebo compared to those randomized to JZP-258 (44.6% vs 4.3%; post hoc nominal P <.0001).
The safety profile was consistent with previous studies and with sodium oxybate. In total, treatment-emergent adverse events (TEAEs) were recorded in 76.1% of patients taking JZP-258, with headache (20.4%), nausea (12.9%), and dizziness (10.4%) rounding out the most common.
Similar results for narcolepsy were shown on the Clinical Global Impression of Change (CGIC), with a greater percentage of patients randomized to placebo who rated “much worse” or “very much worse” compared with the percentage of patients in the JZP-258 group (60.0% vs 5.9%; nominal P <.0001).
Researchers also documented a deterioration in quality of life at the end of SDP to the end of DBRWP in those randomized to placebo. Specifically, declines in the median Physical Component Summery and least squares mean Mental Component Summary scales of the 36-Item Short Form Health Survey Version 2 (SF-36) were greater (nominal P = .0174 and nominal P = .0331; respectively) in patients on placebo compared to those administered JZP-258.
The study design included a ≤30-day screening period and a 12-week, open-label, optimized treatment and titration period to transition to JZP-258 from previous cataplexy treatment medications. Patients were then placed in a 2-week SDP, a 2-week DBRWP, and a 2-week safety follow-up.
JZP-258 got its FDA approval in July 2020 for the treatment of cataplexy or EDS in patients 7 years of age or older with narcolepsy, making it the first treatment indicated for both cataplexy and EDS in 15 years. The basis of the approval came from data showing that the drug demonstrated statistically significant differences in the weekly number of cataplexy attacks and ESS scores compared to placebo in a phase 3 double-blind, placebo-controlled, randomized-withdrawal, multicenter study.2
Recently released top line data from a phase 3 study of JZP-258 suggested that the agent is effective and safe for adult patients with idiopathic hypersomnia. At the time, Jazz noted that they plan to use this data as part of its upcoming submission of a supplemental New Drug Application (sNDA), which is expected to be filed as early as the first quarter of 2021. Notably, the drug was granted fast track designation in September 2020.3