How should future clinical trials be designed in the search for disease-modifying therapies for Parkinson’s disease?

ABSTRACT

Introduction

Although there has been substantial progress in research and innovations in symptomatic treatments, similar success has not been achieved in disease-modifying therapy (DMT) for Parkinson’s disease (PD). Considering the enormous motor, psychosocial and financial burden associated with PD, safe and effective DMT is of paramount importance.

Areas covered

One of the reasons for the lack of progress in DMT for PD is poor or inappropriate design of clinical trials. In the first part of the article, the authors focus on the plausible reasons why the previous trials have failed and in the latter part, they provide their perspectives on future DMT trials.

Expert opinion

There are several potential reasons why previous trials have failed, including broad clinical and etiopathogenic heterogeneity of PD, poor definition and documentation of target engagement, lack of appropriate biomarkers and outcome measures, and short duration of follow-up. To address these deficiencies, future trials may consider- (i) a more customized approach to select the most suitable participants and therapeutic approaches, (ii) explore combination therapies that would target multiple pathogenetic mechanisms, and (iii) moving beyond targeting only motor symptoms to also assessing non-motor features of PD in well-designed longitudinal studies.

KEYWORDS:

• Parkinson’s disease
• clinical trial
• disease-modification
• neuroprotection

Article highlights

• Clinical trials on disease-modifying therapy (DMT) for Parkinson’s disease (PD) have not been successful.

• It is crucial to obtain insights from previous DMT trials to understand why they failed.

• The many reasons for prior failed trials include broad clinical and etiopathogenic heterogeneity of PD, poor definition and documentation of target engagement, lack of appropriate biomarkers and outcome measures, and short duration of follow-up.

• Future trials may consider a more customized approach to select the most suitable participants and therapeutic approaches, explore combination therapies that would target multiple pathogenetic mechanisms, and should also assess non-motor features of PD as outcome measures.

• Governments, regulatory agencies, academic centers, and industry should emphasize the support for clinical trialists, statisticians, and other workforce trained in designing and conducting clinical trials.

Declaration of interes

A Lenka serves Frontiers in Neurology journal as an associate editor. J Jankovic has received research or training grants from: AbbVie Inc, CHDI Foundation, Dystonia Coalition, Emalex Biosciences Inc, Medtronic Neuromodulation, the Michael J Fox Foundation for Parkinson Research, the Parkinson’s Foundation, Revance Therapeutics, Inc and Teva Pharmaceutical Industries Ltd. He has also served as a consultant for AbbVie Inc, Aeon BioPharma, Neurocrine, Revance Therapeutics, Teva Pharmaceutical Industries Ltd and has received royalties from Cambridge University Press, Elsevier, Medlink: Neurology, Lippincott Williams and Wilkins, UpToDate and Wiley-Blackwell. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.