The D₁/D₅ Dopamine Partial Agonist PF-06412562 in Advanced-Stage Parkinson’s Disease: A Feasibility Study

Article type: Research Article

Authors: Huang, Xuemei^{a; b; c; d; e; k; *} | Lewis, Mechelle M.^{a; b; k} | Van Scoy, Lauren Jodi^{f; g; h} | De Jesus, Sol^{a; k} | Eslinger, Paul J.^{a; c; f; i; j; k} | Arnold, Amy C.ⁱ | Miller, Amanda J.ⁱ | Fernandez-Mendoza, Julioⁱ | Snyder, Bethany^a | Harrington, William^a | Kong, Lan^j | Wang, Xi^j | Sun, Dongxiao^b | Delnomdedieu, Marielle^l | Duvvuri, Sridhar^m | Mahoney, Susan E.^l | Gray, David L.^m | Mailman, Richard B.^{a; b; k}

Affiliations: [a] Department of Neurology, Penn State College of Medicine, Hershey, PA, USA | [b] Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA | [c] Department of Radiology, Penn State College of Medicine, Hershey, PA, USA | [d] Department of Neurosurgery, Penn State College of Medicine, Hershey, PA, USA | [e] Department of Kinesiology, Penn State University, University Park, PA, USA | [f] Department of Medicine, Penn State College of Medicine, Hershey, PA, USA | [g] Department of Humanities, Penn State College of Medicine, Hershey, PA, USA | [h] Department of Psychiatry, Penn State College of Medicine, Hershey, PA, USA | [i] Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, USA | [j] Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA | [k] Translational Brain Research Center, Penn State Hershey Medical Center, Hershey, PA, USA | [l] Pfizer Inc., Cambridge, MA, USA | [m] Cerevel Neurosciences LLC., Boston, MA, USA

Correspondence: [*] Correspondence to: Xuemei Huang, MD, PhD, University Distinguished Professor of Neurology, Penn State Hershey Medical Center, 500 University Dr., H-037, Hershey, PA 17033-0850, USA. E-mail: [email protected].

Abstract: Background:Current drug treatments have little efficacy in advanced-to-end-stage Parkinson’s disease (advPD), yet there are no reports of interventional trials in advPD. D1 dopamine agonists have the potential to provide benefit. Objective:To determine the feasibility and safety of the selective D1/D5 dopamine partial agonist PF 06412562 in advPD. Methods:A two-week, randomized, double blind, crossover phase Ib study in advPD patients compared standard-of-care (SoC) carbidopa/levodopa with PF 06412562. Each week, there was a Day 1 baseline evaluation with overnight levodopa washout, then treatment on Days 2 and 3 with either SoC or PF-06412562 (split dose 25 + 20 mg), followed by discharge on Day 4. Primary endpoints were safety and tolerability. Secondary endpoints were global clinical impression of change (GCI-C) rated by clinicians and caregivers. Results:Eight advPD patients and their caregivers consented to participate and six were randomized (average disease duration: 22 y). None withdrew voluntarily. One participant with baseline Day 1 dehydration, pre-renal kidney injury, and autonomic dysfunction experienced symptomatic and serious hypotension after receiving PF-06412562 in Week 1 and was discontinued from the study. All other adverse events were rated mild (PF-06412562: n = 1, SoC: n = 0), moderate (PF-06412562: n = 1, SoC: n = 1), or severe but non-serious (PF-06412562: n = 3, SoC: n = 2). No clinically meaningful laboratory changes were observed. Among the five participants who completed the study, GCI-C favored PF-06412562 in two per clinicians’ and four participants per caregivers’ rating. Conclusion:PF-06412562 was tolerated in advPD patients. This study provides the feasibility for future safety and efficacy studies in this population with unmet needs.

Keywords: D₁ dopamine receptor, dopamine D₁ agonists, advanced Parkinson’s disease, levodopa, safety, feasibilityTrial Registration#: ClinicalTrials.gov:NCT03665454

DOI: 10.3233/JPD-202188

Journal: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1515-1527, 2020