Evaluation of D₁/D₅ Partial Agonist PF-06412562 in Parkinson’s Disease following Oral Administration

Background: PF-06412562 is a moderately potent, highly selective oral D₁/D₅ dopamine receptor partial agonist. Objective: To study the efficacy and safety of a single, oral, split dose of PF-06412562 in patients with Parkinson’s disease. Methods: Following overnight levodopa (L-dopa, Sinemet®) washout, subjects received a single dose of levodopa in open-label period 1. Periods 2 and 3 had a double-blinded, sponsor-open, randomized, 2-way cross-over, placebo-controlled design, during which subjects were randomized to PF-06412562 30 mg (+ 20 mg 4 h later) or placebo. Maximum percent improvement from baseline in finger-tapping speed (measure of bradykinesia) measured using Kinesia^TM technology (as the primary end point) and change from baseline in the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS-III) motor section scores (the preferred exploratory end point) were evaluated. Results: Nineteen subjects received levodopa; 13 met the period 2/3 entry criteria and received PF-06412562, 30 + 20 mg, or placebo. The prespecified primary efficacy criterion for significant improvement in finger-tapping was not met due to inconsistencies in the task leading to large between-period fluctuations of within-patient baseline values. Change from baseline in MDS-UPDRS-III score with PF-06412562 resulted in a placebo-adjusted point estimate of –10.59 with a one-sided 90% upper CI of PF-06412562 versus placebo model-based contrast of (–inf, –7.44) at 1.5–2.5 h after the dose (p < 0.0001). All adverse events were mild-to-moderate. Conclusions: We report the first evidence of potential anti-parkinsonian efficacy of the oral selective D₁/D₅ partial agonist PF-06412562 without the significant acute changes in cardiovascular parameters reported with previous D₁ agonists.