Title: The D1/D5 Dopamine Partial Agonist PF-06412562 in Advanced-Stage Parkinson's Disease: A Feasibility Study.
Authors: Huang, Xuemei; Lewis, Mechelle M; Van Scoy, Lauren Jodi; De Jesus, Sol; Eslinger, Paul J; Arnold, Amy C; Miller, Amanda J; Fernandez-Mendoza, Julio; Snyder, Bethany; Harrington, William; Kong, Lan; Wang, Xi; Sun, Dongxiao; Delnomdedieu, Marielle; Duvvuri, Sridhar; Mahoney, Susan E; Gray, David L; Mailman, Richard B
Published In J Parkinsons Dis, (2020)
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.
PubMed ID: 32986682
MeSH Terms: Aged; Carbidopa/administration & dosage; Carbidopa/adverse effects; Carbidopa/pharmacology*; Cross-Over Studies; Dopamine Agonists/administration & dosage; Dopamine Agonists/adverse effects; Dopamine Agonists/pharmacology*; Double-Blind Method; Drug Combinations; Feasibility Studies; Female; Humans; Levodopa/administration & dosage; Levodopa/adverse effects; Levodopa/pharmacology*; Male; Middle Aged; Outcome Assessment, Health Care; Parkinson Disease/drug therapy*; Receptors, Dopamine D1/agonists*; Receptors, Dopamine D5/agonists; Severity of Illness Index