Exposure-Response Modeling From the CLARITY Trial of Pimavanserin for Adjunctive Treatment of Major Depressive Disorder

Pimavanserin, a selective serotonin inverse agonist/antagonist at the 5-HT2A/C receptors, is being actively studied for multiple indications. The CLARITY clinical trial program is evaluating pimavanserin as adjunctive therapy in major depressive disorder (MDD); a Phase 2 trial in patients with MDD and inadequate response to SSRIs or SNRIs met its primary endpoint of change in 17-item Hamilton Depression Rating Scale (HDRS-17) and Sheehan Disability Scale (SDS) scores. The randomized, placebo controlled, 10-week trial of pimavanserin (34mg QD), CLARITY, employed a sequential, parallel comparison design. Exposure measures, (peak plasma concentration [Cmax]) were estimated for each patient, based on population-pharmacokinetic empirical Bayesian estimates. Using data from patients with consistent study treatment, exposure-response (E-R) models were developed to describe exposure-efficacy (HDRS-17 and SDS) and exposure-safety (probability of adverse effects [AEs]: headache, sedation, and somnolence) relationships. The E-R model predicted change from baseline in HDRS-17 scores at weeks 5 and 10. A sigmoid maximum efficacy (Emax) time course with a linear function for exposure was statistically significant. HDRS-17 scores decreased steadily over time with placebo and pimavanserin; separation from placebo increased as Cmax increased. At median pimavanserin Cmax (34mg dose), the change from baseline was -11.1 and -13.5 at weeks 5 and 10, respectively. Relative to placebo, the model predicted comparable reductions in HDRS-17 scores at weeks 5 and 10 (3.9 and 4.8 points over placebo, respectively). Similar results were observed with SDS scores. No E-R relationship was found for AEs of headache, sedation, or somnolence in the safety analysis.