Therapeutic strategies for Parkinson’s disease: promising agents in early clinical development

ABSTRACT

Introduction

To date, no drug has demonstrated clinically indisputable neuroprotective efficacy in Parkinson’s disease (PD). We also have no effective symptomatic treatment for disabling symptoms such as balance problems, and dementia, and we need to improve the efficacy and safety profile of drugs currently used in the management of motor complications.

Areas covered

We examine the agents which appear to have most therapeutic promise based on concepts, feasibility in a reasonable time frame, and available clinical data and place an emphasis on disease-modifying treatments. PUBMED and Clinicaltrials.gov databases were searched for Phase I and II randomized trials for symptomatic or disease-modifying treatments considering only studies that began since 2010 or that were completed after 2015, up to 30 April 2020.

Expert opinion

Encouraging progress has been made in our understanding of molecular pathways. We find passive immunization approaches against α-synuclein, LRRK2 kinase inhibitors, and treatment that can increase GCase activity, which have shown some efficacy on both GBA-mutated and non-mutated PD patients. The recognition of non-dopaminergic impairment and the prominent role of non-motor symptoms have prompted the development of trials on compounds that could tackle different neurotransmitter systems. Future approaches will encompass more personalized medicine strategies based on molecular signatures and non-motor phenotypes.

KEYWORDS:

• Clinical trials
• disease-modifying
• dopaminergic treatment
• non-dopaminergic treatment Parkinson’s disease
• personalized medicine
• symptomatic treatment

Article highlights

• There is a need for the development of disease-modifying interventions and symptomatic treatment for dopaminergic unresponsive symptoms for patients with Parkinson’s disease (PD);

• The efficacy demonstrated in preclinical models for several disease-modifying therapies and symptomatic treatments for dyskinesias management has proved difficult to translate in human clinical trials;

• Passive immunization approaches against α-synuclein, LRRK2 kinase inhibitors, and agents that can increase GCase activity may offer promising disease-modifying approaches for both hereditable and idiopathic PD patients;

• New longer-acting or more rapid-acting dopaminergic agents have been recently marketed or are under Phase II-III trials evaluation, offering a better management of PD motor symptoms;

• New compounds tackling the glutamatergic, serotoninergic, cholinergic, and noradrenergic systems have been recently evaluated, but negative or still inconclusive results have been obtained concerning the management of dyskinesias and axial symptoms, while positive results have been obtained with pimavanserin for the treatment of psychosis and in Phase II trials on noradrenergic compounds for excessive daytime treatment;

• A personalized approach combining different disease-modifying and symptomatic treatments based on patients’ disease stage, genetic signatures, and troublesome symptoms, may be warranted.

This box summarizes the key points contained in the article.

Declaration of interest

M Fabbri has received research grants from AbbVie. O Rascol has Advisory Board and Consultancy roles with AbbVie, Adamas, Acorda, Addex, AlzProtect, Apopharma, Astrazeneca, Axovant, Bial, Biogen, Britannia, Buckwang, Cerespir, Clevexel, Denali, INC Reasearch, Lundbeck, Lupin, Merck, MundiPharma, Neuratris, Neuroderm, Novartis, ONO Pharma, Osmotica, Parexel, Pfizer, Prexton Therapeutics, Quintiles, Roche, Sanofi, Servier, Sunovion, Théranexus, Takeda, Teva, UCB, Vectura, Watermark Research, XenoPort, XO, Zambo. He has also received grants from Agence Nationale de la Recherche (ANR), CHU de Toulouse, France-Parkinson, INSERM-DHOS Recherche Clinique Translationnelle, MJFox Foundation, Programme Hospitalier de Recherche Clinique, European Commission (FP7, H2020), Cure Parkinson UK and a grant to participate in a symposium at International Parkinson and Movement disorder society (IPMDS). 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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