A Phase II Study to Evaluate the Safety and Efficacy of Prasinezumab in Early Parkinson's Disease (PASADENA): Rationale, Design, and Baseline Data

Abstract

Background: Currently available treatments for Parkinson's disease (PD) do not slow clinical progression nor target alpha-synuclein, a key protein associated with the disease. Objective: The study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD. Methods: The PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1,500 or 4,500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40-80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g., resting tremor, rigidity); DAT-SPECT imaging consistent with PD; and either treatment naïve or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson's Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naïve and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations. Results: Of the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. Mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society-Unified Parkinson's Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naïve PASADENA cohorts (MDS-UPDRS sum of Parts I + II + III [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naïve and 36.4% on MAO-B inhibitor) showed a similar severity in MDS-UPDRS scores (e.g., MDS-UPDRS sum of Parts I + II + III [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naïve). Conclusions: The PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD. Trial Registration: NCT03100149.

Keywords: MDS-UPDRS = Movement Disorder Society—Unified Parkinson's Disease Rating Scale; Parkinson's disease; Phase II clinical trial; alpha-synuclein (α-syn); disease modification treatments; disease progression; monoclonal antibodies; prasinezumab.

Figure 1

PASADENA study design schematic. ^*Low dose = 1,500 mg, ^†High dose = 4,500 mg for ≥65 kg; 3,500 mg for <65 kg. DaT-SPECT, dopamine transporter imaging with single-photon emission computerized tomography; IV, intravenous; Q4W, every month.

Figure 2

Schedule of activities in PASADENA Part 1. ^*Parkinson's Disease Questionnaire−39 (PDQ39) is at baseline, Week 20, and Week 48; ^†SCOPA-AUT (Scales for Outcomes in Parkinson's Disease—Autonomic Dysfunction) is at baseline, Weeks 16, 28, 40 and 52. ^‡Digital includes PASADENA Digital Motor Score, Patient Global Impression of Severity, Daily diary, Patient Assessment of Constipation Symptoms (PAC-SYM), EuroQol-5D (EQ-5D) and Hospital Anxiety and Depression Scale (HADS). ^§Magnetic resonance imaging (MRI) includes safety, diffusion tensor imaging (DTI), resting state and arterial spin labeling (ASL). CGI-C, Clinical Global Impression of Change; CGI-I, Clinical Global Impression of Improvement; DaT-SPECT, dopamine transporter imaging with single-photon emission computerized tomography; H&Y, Hoehn & Yahr; MDS-UPDRS, Movement Disorder Society—Unified Parkinson's Disease Rating Scale; MMSE, Mini Mental State Examination; MoCA, Montreal Cognitive Assessment; PDSS-2, Parkinson's Disease Sleep Scale Revised Version 2; PGI-C, Patient Global Impression of Change; RBDSQ, Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire; SE-ADL, Schwab and England Activities of Daily Living.

Figure 3

Schedule of activities in PASADENA Part 2. ^*Digital includes PASADENA Digital Motor Score, Patient Global Impression of Severity, Daily diary, Patient Assessment of Constipation Symptoms (PAC-SYM), EuroQol-5D (EQ-5D), and Hospital Anxiety and Depression Scale (HADS). ^†Magnetic resonance imaging (MRI) includes safety, diffusion tensor imaging (DTI), resting state and arterial spin labeling (ASL). CGI-I, Clinical Global Impression of Improvement; DaT-SPECT, dopamine transporter imaging with single-photon emission computerized tomography; MDS-UPDRS, Movement Disorder Society—Unified Parkinson's Disease Rating Scale; MoCA, Montreal Cognitive Assessment; PDQ39, Parkinson's Disease Questionnaire−39; PDSS-2, Parkinson's Disease Sleep Scale Revised Version 2; PGI-C, Patient Global Impression of Change; SCOPA-AUT, Scales for Outcomes in Parkinson's Disease—Autonomic Dysfunction; SE-ADL, Schwab and England Activities of Daily Living.

Figure 4

Table of digital measures included in the Roche Parkinson's Disease Mobile Application v2. SDMT, Symbol Digit Modalities Test.