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

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.

Trial registration: ClinicalTrials.gov NCT03665454.

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

Conflict of interest statement

Drs. Huang (PI) and Mailman declared a potential conflict of interest (COI) due to existing patents related due to the discovery or use of D1 agonists, although neither has any financial interest that are affected by the results of this study. Drs. Huang and Mailman did not participate in consenting subjects, were not involved with the Data Safety Board (DSB, composed of three investigators and three clinicians), and did not participate in data analysis until the data were locked. Dr. Huang worked closely with Drs. De Jesus (a movement disorder specialist) and Van Scoy (a pulmonary and critical care physician) to provide the best care for the participants throughout the study. Drs. Huang or De Jesus provided blinded ratings for the clinician global impression of change based on their availability.

Figures

Figure 1.

Chemical structure of PF-06412562: (4-[4-(4,6-dimethyl-5-pyrimidinyl)-3-methylphenoxyl]-1H-pyrazolo[4,3-c]pyridine

Figure 2.. Schematic of the overall design of the study

Subjects were randomized to receive PF-06412562 followed by levodopa (Sequence A, top) or levodopa followed by PF-06412562 (Sequence B). PF-06412562 (5 mg) or placebo tablets were provided by Pfizer. Sinemet (carbidopa/levodopa, 25/100 mg) tablets were encapsulated to preserve study blind. The bottom part of the schematic shows the events that occurred on each day. Abbreviations: SoC = Standard of Care. Some subjects received a fourth dose of levodopa if that was required according to their pretrial regimen.

Figure 3.. Vital signs and cardiovascular autonomic test results.

There were no apparent overall differences in baseline vital signs or cardiovascular autonomic data between testing periods.