PF-06649751 efficacy and safety in early Parkinson's disease: a randomized, placebo-controlled trial

Abstract

Background: PF-06649751 is a novel, oral, non-catechol-based, D1/D5 dopamine receptor partial agonist under investigation for the treatment of motor symptoms associated with Parkinson's disease.

Methods: A 15-week, phase II, double-blind, placebo-controlled clinical trial was conducted to assess the efficacy and safety of flexible-dose PF-06649751 in subjects with early stage Parkinson's disease (ClinicalTrials.gov identifier: NCT02847650).

Results: Enrollment was terminated early for reasons unrelated to the trial. Overall, 57 subjects received study medication (PF-06649751 = 29; placebo = 28) and 47 completed the study (PF-06649751 = 25; placebo = 22). Despite early termination, the study met its primary endpoint with the PF-06649751 group showing statistically significant improvement from baseline in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score at week 15 compared with placebo. Mean (SE) change in MDS-UPDRS Part III score was -9.0 (1.54) for PF-06649751 and -4.3 (1.65) for placebo. This corresponds to an improvement versus placebo of 4.8 for the PF-06649751 group (two-sided p = 0.0407; 90% CI = 1.0, 8.6). Statistically significant improvement in MDS-UPDRS-III score was also observed at all assessment time points prior to week 15. The safety profile of PF-06649751 was similar to that observed in prior studies, with the majority of adverse events (AEs) reported as mild or moderate. The most common AEs in the PF-06649751 group were nausea, headache, dry mouth, somnolence, and tremor.

Conclusions: Once-daily dosing of oral PF-06649751 resulted in significant improvement of motor symptoms and was generally well tolerated in subjects with early stage Parkinson's disease.

Keywords: D1/D5 receptor; PF-06649751; Parkinson’s disease; partial agonist; phase II clinical trial.

Conflict of interest statement

Conflict of interest statement: JW and YZ are full-time employees of, and own stock or stock options, in Pfizer Inc. DG and SD were full-time employees of Pfizer Inc. at the time the study was conducted, and own stock in Pfizer Inc. DG is named on the patent for PF-06649751 (though all rights are assigned to Pfizer Inc). RR has no potential conflicts to disclose. Medical writing support provided by Matt Soulsby of Engage Scientific was funded by Pfizer. RR reports no financial relationships with commercial interests. JW, and YZ have received salary as full-time employees of Pfizer Inc. and own stock in Pfizer Inc. SD and DG have received salary as full-time employees of Pfizer Inc., and subsequently Cerevel Therapeutics, and own stock in Pfizer Inc.

© The Author(s), 2020.

Figures

Figure 1.

Design of the study. aMaximum allowed dose at each interval of the dose optimization period is shown. Subjects initially received 0.25 mg PF-06649751 or matching placebo, with a mandatory increase to 0.75 mg at Visit 2. At Visits 3–10, the dose could be increased 1 level, decreased 1 level, or remain unchanged to achieve an optimum balance of tolerability and control of motor symptoms. Subjects received their optimized dose (up to 15 mg) from Visit 10–14. See methods for details. All visits were clinic except for V5, V7, V9, V11, V13, and V16, which were by phone. There was a +3 day window for Visits 2–9 and a ±3 day window for Visits 10–16, with the exception of Visit 14 which had a −3 day window.

Figure 2.

Subject disposition.

Figure 3.

Change in MDS-UPDRS Part III score over the course of the study. Data shown are mean ± SE. 2-sided p ⩽ 0.1 versus placebo; 2-sided p value at week 15 (primary endpoint) was 0.0407. MDS-UPDRS, Movement disorder society-unified Parkinson’s disease rating scale; SE, standard error.