10.6084/m9.figshare.7358432.v1 Papapetropoulos S. Papapetropoulos S. Liu W. Liu W. Duvvuri S. Duvvuri S. Thayer K. Thayer K. Gray D.L. Gray D.L. Supplementary Material for: Evaluation of D<sub>1</sub>/D<sub>5</sub> Partial Agonist PF-06412562 in Parkinson’s Disease following Oral Administration Karger Publishers 2018 Parkinson’s disease D1/D5 partial agonist Levodopa Bradykinesia 2018-11-19 11:00:26 Dataset https://karger.figshare.com/articles/dataset/Supplementary_Material_for_Evaluation_of_D_sub_1_sub_D_sub_5_sub_Partial_Agonist_PF-06412562_in_Parkinson_s_Disease_following_Oral_Administration/7358432 <b><i>Background:</i></b> PF-06412562 is a moderately potent, highly selective oral D<sub>1</sub>/D<sub>5</sub> dopamine receptor partial agonist. <b><i>Objective:</i></b> To study the efficacy and safety of a single, oral, split dose of PF-06412562 in patients with Parkinson’s disease. <b><i>Methods:</i></b> 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<sup>TM</sup> 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. <b><i>Results:</i></b> 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 (<i>p</i> < 0.0001). All adverse events were mild-to-moderate. <b><i>Conclusions:</i></b> We report the first evidence of potential anti-parkinsonian efficacy of the oral selective D<sub>1</sub>/D<sub>5</sub> partial agonist PF-06412562 without the significant acute changes in cardiovascular parameters reported with previous D<sub>1</sub> agonists.