The Qualification of an Enrichment Biomarker for Clinical Trials Targeting Early Stages of Parkinson's Disease

Abstract

As therapeutic trials target early stages of Parkinson's disease (PD), appropriate patient selection based purely on clinical criteria poses significant challenges. Members of the Critical Path for Parkinson's Consortium formally submitted documentation to the European Medicines Agency (EMA) supporting the use of Dopamine Transporter (DAT) neuroimaging in early PD. Regulatory documents included a comprehensive literature review, a proposed analysis plan of both observational and clinical trial data, and an assessment of biomarker reproducibility and reliability. The research plan included longitudinal analysis of the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) and the Parkinson's Progression Markers Initiative (PPMI) study to estimate the degree of enrichment achieved and impact on future trials in subjects with early motor PD. The presence of reduced striatal DAT binding based on visual reads of single photon emission tomography (SPECT) scans in early motor PD subjects was an independent predictor of faster decline in UPDRS Parts II and III as compared to subjects with scans without evidence of dopaminergic deficit (SWEDD) over 24 months. The EMA issued in 2018 a full Qualification Opinion for the use of DAT as an enrichment biomarker in PD trials targeting subjects with early motor symptoms. Exclusion of SWEDD subjects in future clinical trials targeting early motor PD subjects aims to enrich clinical trial populations with idiopathic PD patients, improve statistical power, and exclude subjects who are unlikely to progress clinically from being exposed to novel test therapeutics.

Keywords: Dopamine transporter; EMA; PPMI; PRECEPT; SWEDD; enrichment biomarker.

Fig.1

Proposed flow chart to apply DAT imaging as an enrichment biomarker in clinical trials targeting subjects with motor signs of early PD. Each of the four inclusion criteria / steps must be met for subjects to be successfully enrolled into the PD clinical trial. The clinical criteria must be met before subjects undergo DAT SPECT imaging (final step).

Fig.2

The proportion of subjects with absence of DAT deficit in clinical trials increases with earlier stages of PD. A number of PD clinical studies have identified subjects defined as SWEDD by employing DAT imaging at baseline and follow up. The proportion of subjects defined as SWEDD decreases with the time since diagnosis for those in specific PD clinical studies targeting early stages of the disease. The proportion of SWEDD subjects is lower in studies enrolling subjects with longer duration of disease. As sponsors enroll PD subjects earlier in the disease (i.e., sooner after diagnosis), the value (benefit) of DAT imaging for enrichment increases. References for PD clinical studies: [38, 39, 41, 59– 61]. ELLDOPA: Levodopa; PRECEPT: Mixed Lineage Kinase Inhibitor CEP 1347; REAL-PD: Ropinirole; CALM-PD: Pramipexole; GPI1485: Immunophilin; PPMI: Parkinson’s Progression Markers Initiative.