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.

Conflict of interest statement

GP, FB, KT, BR, JA-C, AV, MM, TN, HS, MB, SO, RD, DU, and ABon are employees of F. Hoffmann-La Roche Ltd. ABou is an employee of Idorsia Pharmaceuticals Ltd. AP is an employee of Feetme SAS. JS is an employee of Prevail Therapeutics. GK, WZ, DN, and MK are employees of Prothena Biosciences Inc. The authors declare that F. Hoffmann-La Roche Ltd was the sponsor of the study. F. Hoffmann-La Roche Ltd and Prothena Corporation plc were the funders of the study. F. Hoffmann-La Roche Ltd and Prothena Corporation plc were involved in the study design, collection, analysis, interpretation of data, the writing of this article and the decision to submit it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Pagano, Boess, Taylor, Ricci, Mollenhauer, Poewe, Boulay, Anzures-Cabrera, Vogt, Marchesi, Post, Nikolcheva, Kinney, Zago, Ness, Svoboda, Britschgi, Ostrowitzki, Simuni, Marek, Koller, Sevigny, Doody, Fontoura, Umbricht, Bonni and PASADENA Investigators and Prasinezumab Study Group.

Figures

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.