Regulatory Decision Summary for Xywav

This New Drug Submission (NDS) was submitted to seek approval for Xywav, a mixture of oxybate cations (calcium, magnesium, potassium and sodium) in a solution formulation for oral administration. The sponsor was seeking an indication for the treatment of cataplexy in patients with narcolepsy.

Xywav (mixed salts oxybate) was developed as a lower sodium alternative to Xyrem (sodium oxybate) for the treatment of cataplexy in patients with narcolepsy. To support its authorization, 2 phase I pharmacokinetic (PK) studies, a phase I taste test study assessing the applicability of the chosen placebo for phase 3 testing, and a single phase 3 double-blind, placebo-controlled, randomized-withdrawal study assessing the efficacy and safety of Xywav were provided. In addition, 3 Pharmacokinetic (PK)/Pharmacodynamic (PD), Population PK (PopPK) and Exposure-Response models were submitted that explored potential modeled differences in Xywav and Xyrem formulations, as well as potential impacts of intrinsic and extrinsic factors on Xywav use.

The PK studies showed comparable bioavailability of the two formulations with respect to the overall plasma exposure when administered at equivalent doses.

The Phase 3 study (Study 15-006) consisted of two parts, the main study, followed by an optional 24-week open-label extension (OLE). The main study consisted of a 12-week Open-Label Optimized Treatment and Titration Period (OL OTTP) where all subjects were treated with Xywav titrated to an optimal, effective and tolerable dose, while simultaneously discontinuing any previous narcolepsy/cataplexy therapies (stimulants excluded). The OL OTTP was followed by a 2-week stable-dose period (SDP), where no further dose titrations were permitted; and finally, a 2-week double-blind randomized-withdrawal period (DB RWP), where half the subjects were randomized (1:1) to switch to placebo, or to remain on Xywav, with no dose changes permitted.

Results from Study 15-006 demonstrated efficacy as assessed by the change in the average number of cataplexy attacks (primary endpoint) and change in scores on the Epworth Sleepiness Scale (key secondary endpoint), from the end of the SDP to the end of the DB RWP. Subjects randomized to placebo saw a statistically significant and clinically meaningful return of cataplexy and narcolepsy symptoms in comparison to those randomized to remain on Xywav. Other secondary endpoints assessing patient- and clinician-rated improvements of symptoms supported these findings. Thus, Xywav met its primary and key secondary objectives and demonstrated an efficacy profile similar to that previously observed in clinical trials of Xyrem.

A broad range of participants were enrolled for both ease of enrollment and to study efficacy across the range of participants (i.e., patients currently taking: Xyrem, Xyrem + another anticataplectic, other anticataplectic alone, or subjects who were treatment-naïve at study entry). Although not powered for statistical analysis, the range of participants allowed further information to be gleaned from the trends in the sub-group data. For example, treatment-naïve subjects showed a trend of attenuation of cataplexy symptoms across the open-label titration and stabilization periods, and reinstatement of symptoms when randomized to placebo. These trends support efficacy of Xywav upon initiating treatment. Further, 70% of subjects previously treated with Xyrem were switched to Xywav at a 1:1 dose and trends suggested stable cataplexy symptoms across the open-label periods, with increased cataplexy attacks observed in patients randomized to placebo. These trends suggest continued efficacy after switching from Xyrem to Xywav, and the minimal need for titration supports the interchangeability of products and dose.

Xywav also exhibited a similar safety profile to the known safety profile of Xyrem. No new safety issues were raised from the clinical trials of Xywav. The most frequently (≥ 5% of subjects overall) reported clinical trial adverse reactions during treatment with Xywav were headache, dizziness, nausea, vomiting, diarrhea, decreased appetite, somnolence, parasomnia, anxiety, and hyperhidrosis. Most adverse events were mild or moderate in severity and occurred with greater frequency during the first few weeks of treatment.

Given the similar efficacy and safety profile observed in clinical trials of Xywav and Xyrem, interchangeability of Xywav/Xyrem dose in Study 15-006, and lack of formulation effect in statistical modeling to indicate differences between the two formulations, Xyrem safety information and market experience was considered to supplement the Xywav clinical trial and post-marketing safety data. Thus, similar contraindications, dosing recommendations, drug interactions, warnings, precautions, and adverse events were applied to the Xywav Product Monograph (PM) from the Xyrem PM. Importantly, Xywav contains the same potential for abuse, misuse and diversion. To mitigate these risks, Xywav will be added to the controlled distribution program already in place for Xyrem.

The 92% reduction in sodium results in a favorable safety profile with no added concerns related to calcium, magnesium or potassium content. Taken together, in conjunction with the known safety profile of Xyrem, the benefit-harm-uncertainty assessment for Xywav is considered favorable for the recommended indication and when used as described in the PM.

The chemistry and manufacturing information submitted for Xywav has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Following review of the labelling components submitted, the final labelling and PM were considered to be acceptable.

An updated Risk Management Plan (RMP) for Xywav was reviewed by Health Canada and considered acceptable.

For further details about Xywav, please refer to the PM, approved by Health Canada and available through the Drug Product Database.