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, the main pathology 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. The study rationale, design, and baseline characteristics of enrolled subjects are presented here. 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 (1500 mg or 4500 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 naive 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 Parkinson1s Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naive 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. The 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-naive PASADENA cohorts (MDS-UPDRS Total score [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naive and 36.4% on MAO-B inhibitor) also showed a similar severity in MDS-UPDRS scores (e.g. MDS-UPDRS Total score [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naive). Conclusions The PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD.

Self‐Report versus Clinician Examination in Early Parkinson's Disease

“…The study was approved by the IRB or IEC. Further information on the protocol and eligibility criteria can be found at https://clinicaltrials.gov/ct2/show/NCT03100149 and in Pagano et al 17 At baseline, data from 316 individuals with recently diagnosed PD (ie, disease duration <2 years) were available. All patients were either treatment naïve or treated with a stable dose of monoamine oxidase‐B inhibitors (36.4%) and had HY stages 1 and 2, with a diagnosis of PD confirmed by the dopamine transporter single‐photon emission computed tomography (DaT‐SPECT).…”

Hoehn and Yahr Stage and Striatal Dat-SPECT Uptake Are Predictors of Parkinson’s Disease Motor Progression

“…The key inclusion criteria for PASADENA included: patients that were diagnosed with idiopathic PD with bradykinesia and one of rigidity or resting tremor and no other known or suspected cause of PD; patients aged between 40 and 80 years old; a visual evaluation of Dat-SPECT consistent with PD; a body weight in the range of 45–110 kg; a body mass index between 18 and 34 kg/m2; and either treatment naïve or on a stable dose of MAO-B inhibitor for at least 90 days ( Pagano et al, 2021 ).…”

“…Prasinezumab is a humanized immunoglobulin G1 monoclonal antibody designed to selectively bind aggregated alpha-synuclein at the C-terminus. PASADENA is a Phase II, randomized, double blind, placebo controlled trial that investigates the efficacy and safety of prasinezumab in early PD ( Pagano et al, 2021 ). Here, the placebo arm from PASADENA was used to investigate the progression of the disease in individuals with early PD and to identify prognostic factors that can predict PD progression.…”

A Mouse Model to Test Novel Therapeutics for Parkinson's Disease: an Update on the Thy1-aSyn (“line 61”) Mice

“…Transfer of misfolded alpha-synuclein and thus propagation of pathology across the brain is targeted via active (alpha-synuclein mimicking peptides) and passive (antibodies against human alpha-synuclein) immunotherapies. Thy1-aSyn mice accumulate disease-relevant C-terminally cleaved alpha-synuclein in neurons and neuropil [108], and several antibodies against the C-terminus have been tested in Thy1-aSyn mice [155,156], including prasinezumab (RO7046015) which is far advanced in clinical trials [157]. The murine form of prasinezumab (9E4; syn aa 118-126) was administered weekly intraperitoneally over 5-6 months and showed reduced neuronal and synaptic loss and a reduction in intraneuronal build-up of alpha-synuclein pathology, reduction of gliosis, and an improvement in both cognitive and motor behaviors.…”