Time to Onset of Clinical Response During Treatment With Pitolisant
Craig Davis1, Jeffrey Dayno1, Ben Vaughn2, Yves Dauvilliers3
1Harmony Biosciences, 2Rho, 3Hopital Gui De Chaulliac
Objective:
To evaluate the time to onset of clinical response during treatment with pitolisant for EDS and cataplexy in adults with narcolepsy. 
Background:
Time to onset of response was evaluated in two short-term studies to further elucidate clinical features of pitolisant. 
Design/Methods:

Patients in both studies (HARMONY-1, HARMONY-CTP) experienced excessive daytime sleepiness (EDS) at baseline; patients in HARMONY-CTP experienced ≥3 cataplexy attacks/week. Pitolisant was titrated to a maximum dose of 35.6mg/day in both clinical trials. Change from baseline in mean Epworth Sleepiness Scale (ESS) score (2 studies) and mean weekly rate of cataplexy (WRC; 1 study) was compared for pitolisant versus placebo.

Results:
In the HARMONY-1 (pitolisant, n=31; placebo, n=30) and HARMONY-CTP (pitolisant, n=54; placebo, n=51) studies, ESS score improvement was significantly greater with pitolisant versus placebo beginning at Week 2 (least squares mean (LSM) difference, -2.8; P=0.015) and Week 3 (LSM difference, -2.0; P=0.005), respectively. This greater improvement for pitolisant-treated patients was maintained through the end of both trials; final visit LSM differences of -3.2 (P=0.026) and -4.0 (P<0.001), respectively.  In HARMONY-CTP, LSM weekly rate of cataplexy for pitolisant-treated patients was 11.7 at baseline, 4.6 at end-of-treatment, and 7.8 after a 1-week, placebo-washout period. Improvement in weekly rate of cataplexy was significantly greater with pitolisant versus placebo beginning at Week 2 (LSM difference, -5.3; P=0.004) and continued through end-of-treatment (LSM difference, -6.4; P<0.001); there was no evidence of rebound cataplexy after placebo-washout.
Conclusions:
During pitolisant treatment in which patients could be titrated to the maximum recommended dose of 35.6mg, improvement in EDS occurred within 2-3 weeks of treatment initiation when patients could be treated with up to 17.8mg daily. Improvement of cataplexy was seen at week two (treated with 8.9mg daily).  No evidence of rebound was seen for either symptom when pitolisant was withdrawn.