Compare excessive daytime sleepiness (EDS) profiles of P2B001 and Extended-Release pramipexole (ER-PPX) in untreated PD.

AAN guidelines do not recommend dopamine agonist (DA) monotherapy for early PD patients at risk for dopaminergic adverse events including EDS. P2B001 is an investigational, fixed, once daily ER combination of low-dose pramipexole (0.6mg) and rasagiline (0.75mg).

Untreated patients (time from diagnosis<3 years) were randomized (2:2:2:1) to 12-weeks double-blind treatment with P2B001, pramipexole-ER-0.6mg (PPX), rasagiline-ER-0.75mg (RAS), or marketed ER-PPX (6-week titration). EDS was assessed by Epworth Sleepiness Scale (ESS; key secondary endpoint) and treatment-emergent adverse event (TEAE) reporting. Rates of new-onset clinically-relevant EDS were assessed using shift analysis (from ESS ≤10 at baseline to >10 at Week 12).

519 patients were randomized/treated; P2B001 showed comparable efficacy to ER-PPX (~8 point reduction in UPDRS-Parts II&III; 95% CI: -1.67-2.42) yet had significantly less daytime sleepiness (p<0.0001).  At baseline, the percentage of patients without significant EDS (ESS≤10) was similar across groups (86.1–88.4%). Shift analysis showed rates of new-onset EDS greatest in patients treated with ER-PPX (mean dose 3.2mg; 35.7%) and PPX (15.6%), and lowest with P2B001 (8.5%) and RAS (6.6%). Adjusted odds ratio for developing EDS (P2B001 vs ER-PPX) was 0.17 (95% CI: 0.08-0.36; P<0.0001). Rates of somnolence reported as TEAEs were highest with ER-PPX (31.1%) followed by PPX (18.2%), P2B001 (14.7%) and RAS (4.8%). Temporally, 6-7% of patients treated with ER-PPX, PPX and P2B001 reported sleepiness-related TEAEs within the first days of treatment. While these rates remained relatively stable for PPX and P2B001, the proportion of patients experiencing sleepiness events steadily increased with ER-PPX titration and maintenance therapy (plateau ~24% Week 6).

EDS is a limiting factor for traditional dosing of DAs. With similar efficacy to ER-PPX monotherapy, patients treated with P2B001 developed significantly less new-onset EDS and fewer sleepiness-related TEAEs.