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. 2019;9(1):31-61.
doi: 10.3233/JPD-181471.

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

Kalpana M Merchant  1 , Jesse M Cedarbaum  2 , Patrik Brundin  3 , Kuldip D Dave  4 , Jamie Eberling  4 , Alberto J Espay  5 , Samantha J Hutten  4 , Monica Javidnia  6 , Johan Luthman  7 , Walter Maetzler  8 , Liliana Menalled  4 , Alyssa N Reimer  4 , A Jon Stoessl  9 , David M Weiner; The Michael J. Fox Foundation Alpha Synuclein Clinical Path Working Group
Affiliations

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

Kalpana M Merchant et al. J Parkinsons Dis. 2019.

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.

Keywords: Alpha-synuclein; animal models; biomarkers; digital endpoints; experimental therapies; immunotherapies; neuroimaging.

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Conflict of interest statement

KMM is a Senior Advisor to The Michael J. Fox Foundation for Parkinson’s Research. She serves on the Scientific Advisory Board and/or provides consulting services to AbbVie, Acumen Pharmaceuticals, Epiodyne, Lysosomal Therapeutics, Neuroinitiative, Pfizer, Sinopia Biosciences and private equity investors. She also serves on the NCATS Advisory Council and CAN Review Board, NIA’s Division of Neuroscience Review Committee, and Wellcome Trust Review Board.

JC is an employee and shareholder of Biogen.

PB has received commercial support as a consultant from Renovo Neural, Inc., Cellular Dynamics International, Axial Biotherapeutics, Roche, Teva Inc, Lundbeck A/S, NeuroDerm, AbbVie, ClearView Healthcare, FCB Health, IOS Press Partners and Capital Technologies, Inc. He is conducting sponsored research on behalf of Roche and Lundbeck A/S. He has ownership interests in Acousort AB.

KDD is an employee of The Michael J. Fox Foundation for Parkinson’s Research and has no conflicts of interest to report.

JE is an employee of The Michael J. Fox Foundation for Parkinson’s Research and has no conflicts of interest to report.

AJE has received grant support from the NIH, Great Lakes Neurotechnologies and The Michael J. Fox Foundation for Parkinson’s Research; personal compensation as a consultant/scientific advisory board member for Abbvie, TEVA, Impax, Acadia, Acorda, Cynapsus/Sunovion, Lundbeck, and USWorldMeds; publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer; and honoraria from Abbvie, UCB, USWorldMeds, Lundbeck, Acadia, the American Academy of Neurology, and the Movement Disorders Society.

SJH is an employee The Michael J. Fox Foundation for Parkinson’s Research and has no conflicts of interest to report.

MJ has no conflicts of interest to report.

JL is a full time employee of Eisai Inc, USA. He owns shares in AstraZeneca and Merck Co.

WM receives or received funding from the European Union, The Michael J. Fox Foundation for Parkinson’s Research, Robert Bosch Foundation, Neuroalliance, Lundbeck and Janssen, and holds part of a patent for the assessment of dyskinesias (German patent office, 102015220741.2). He received speaker honoraria from GlaxoSmithKline, Abbvie, UCB, Licher MT and Rölke Pharma, and was invited to Advisory Boards of Market Access & Pricing Strategy GmbH and Abbvie.

LM is an employee The Michael J. Fox Foundation for Parkinson’s Research and has no conflicts of interest to report.

ANR is an employee of The Michael J. Fox Foundation for Parkinson’s Research and has no conflicts of interest to report.

AJS is an employee of the University of British Columbia and is supported by a Canada Research Chair and by research grants from the Michael J. Fox Foundation and Weston Brain Institute. He is Deputy Editor of Movement Disorders. He has received consulting and speaking honoraria from AbbVie and is an advisor for Cellular Dynamics International and on a Data Safety Monitoring Board for Voyager Inc.

DMW is an Advisor to The Michael J. Fox Foundation for Parkinson’s Research.

Figures

Fig. 1.
Fig. 1.
Key Stages of Therapeutic Discovery and Development. Key stages of therapeutic discovery and development and associated objectives aimed at improving the probability of technical success. Note the specific utility of biomarkers to inform preclinical and clinical decisions during each stage. DMPK, drug metabolism and pharmacokinetics; ID, identification; PK, pharmacokinetics; PoC, proof of concept; PoM, proof of mechanism; TE, target engagement.
Fig. 2.
Fig. 2.
Adapted Illustration of the International Classification of Functioning, Disability and Health Model of the World Health Organization. A) The description (and treatment) of a disease, dysfunction or symptom require(s) consideration of multiple domains of an individual (more specifically, body/organ structure and function, activity, social participation, as well as personal and environmental factors), and the corresponding interactions across domains. B) Traditional outcome measures, such as clinical scales, body fluid parameters and imaging (green circles) document variables about the body/organ (here: brain) structure and function domain and to some extent about the activity domain. Mobile technology (orange) has the potential to collect information over most of the ICF domains. ICF, International Classification of Functioning, Disability, and Health; UPDRS, Unified Parkinson’s Disease Rating Scale.
See this image and copyright information in PMC

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