A Proposed Roadmap for Parkinson’s Disease Proof of Concept Clinical Trials Investigating Compounds Targeting Alpha-Synuclein

Abstract

The convergence of human molecular genetics and Lewy pathology of Parkinson’s disease (PD) have led to a robust, clinical-stage pipeline of alpha-synuclein ( α -syn)-targeted therapies that have the potential to slow or stop the progression of PD and other synucleinopathies. To facilitate the development of these and earlier stage investigational molecules, the Michael J. Fox Foundation for Parkinson’s Research convened a group of leaders in the field of PD research from academia and industry, the Alpha-Synuclein Clinical Path Working Group. This group set out to develop recommendations on preclinical and clinical research that can de-risk the development of α -syn targeting therapies. This consensus white paper provides a translational framework, from the selection of animal models and associated end-points to decision-driving biomarkers as well as considerations for the design of clinical proof-of-concept studies. It also identifies current gaps in our biomarker toolkit and the status of the discovery and validation of α -syn-associated biomarkers that could help fill these gaps. Further, it highlights the importance of the emerging digital technology to supplement the capture and monitoring of clinical outcomes. Although the development of disease-modifying therapies targeting α -syn face profound challenges, we remain optimistic that meaningful strides will be made soon toward the identification and approval of disease-modifying therapeutics targeting α -syn.

Toward a Regulatory Qualification of Real-World Mobility Performance Biomarkers in Parkinson’s Patients Using Digital Mobility Outcomes

“…This was recently confirmed by the call for proposals “IMI2-2017-13-07—Linking digital assessment of mobility to clinical endpoints to support regulatory acceptance and clinical practice” that funded the Mobilise-D project [ 8 ]. Mobility is particularly important for diseases involving a significant burden of mobility disability, such as Parkinson’s Disease (PD) [ 9 , 10 ], Chronic Obstructive Pulmonary Disease (COPD) [ 11 ], Multiple Sclerosis (MS) [ 12 ], and the recovery after a fragility Proximal Femur Fracture (PFF) [ 13 ].…”

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

“…For therapeutic trials in patients with PD, drug developers have an urgent need for effective biomarkers to enrich study patients and assess target engagement, disease prognosis, and clinical response . There is not yet a reliable biofluid or imaging biomarker of ␣-synuclein to enrich PD clinical trial populations [19,20,30,57]. However, neuroimaging biomarkers, particularly ones probing the dopaminergic system in the brain, have been employed in PD clinical trials for many years [31,32].…”

Synucleinopathies: Where we are and where we need to go

“…We will also need to develop PET‐tracers that can detect aSyn, to enable longitudinal studies in patients, and even in individuals at risk (based on genetic factors, for example). Attempts to develop radioligands able to bind to different forms of aSyn are ongoing, but we still face major challenges such as selectivity, or blood–brain barrier penetration (Cairns et al, ; Merchant et al, ; Verdurand et al, ). However, the coming years may bring novel developments in this area.…”