Current Therapies in Clinical Trials of Parkinson's Disease: A 2021 Update

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder that currently has no cure, but treatments are available to improve PD symptoms and maintain quality of life. In 2020, about 10 million people worldwide were living with PD. In 1970, the United States Food and Drug Administration approved the drug levodopa as a dopamine replacement to manage PD motor symptoms; levodopa-carbidopa combination became commercialized in 1975. After over 50 years of use, levodopa is still the gold standard for PD treatment. Unfortunately, levodopa therapy-induced dyskinesia and OFF symptoms remain unresolved. Therefore, we urgently need to analyze each current clinical trial's status and therapeutic strategy to discover new therapeutic approaches for PD treatment. We surveyed 293 registered clinical trials on ClinicalTrials.gov from 2008 to 16 June 2021. After excluded levodopa/carbidopa derivative add-on therapies, we identified 47 trials as PD treatment drugs or therapies. Among them, 19 trials are in phase I (41%), 25 trials are in phase II (53%), and 3 trials are in phase III (6%). The three phase-III trials use embryonic dopamine cell implant, 5-HT_1A receptor agonist (sarizotan), and adenosine A_2A receptor antagonist (caffeine). The therapeutic strategy of each trial shows 29, 5, 1, 5, 5, and 2 trials use small molecules, monoclonal antibodies, plasma therapy, cell therapy, gene therapy, and herbal extract, respectively. Additionally, we discuss the most potent drug or therapy among these trials. By systematically updating the current trial status and analyzing the therapeutic strategies, we hope this review can provide new ideas and insights for PD therapy development.

Keywords: Parkinson’s disease; clinical trials; dopamine receptor agonists; gene therapy; levodopa; plasma therapy; α-synuclein.

Figure 1

The pathological hallmarks of PD and the interplay of aging, environmental hazards, and genetics in the pathogenesis of PD. (A) The pathological hallmarks of Parkinson’s disease include dopaminergic neuronal death, α-synuclein aggregates, mitochondrial dysfunction, reactive oxygen species, apoptosis, and neuroinflammation. (B) PD is a multifactorial disorder involving aging, genetics, and environmental factors, associated with dopaminergic neuronal death. Gene mutations associate with PD includes DJ-1, PTEN-induced putative kinase-1 (PINK1), parkin, leucine-rich repeat serine/threonine kinase-2 (LRRK2), Synuclein alpha (SNAC), and ubiquitin carboxyl-terminal hydrolase-L1 (UCHL1). Neurotoxins (e.g., rotenone, paraquat) and gene mutations of DJ-1, PINK1, parkin, LRRK2, and SNAC induce mitochondria complex I inhibition, ATP depletion, reactive oxygen species (ROS) accumulation, mitochondria depolarization, and mitochondrial dysfunction in dopaminergic neurons to promote neuronal death in the substantia nigra of PD patients. Overexpression of SNAC gene mutations enhance α-synuclein aggregation in Lewy bodies of PD brain. UCHL1 gene mutations impair ubiquitin-proteasome systems and further induce autophagy lysosomal pathway dysfunction, contributing to Lewy body formation in dopaminergic neurons.

Figure 2

Flow diagram of the method used to select and analyze the clinical trial data for PD treatment from ClinicalTrials.gov (https://clinicaltrials.gov, accessed on 16 June 2021).

Figure 3

The type of therapeutic strategies, mechanism, and the current drugs/therapies in the clinical trials of PD treatment.

Figure 4

The trial phases and therapeutic strategies in the clinical trials for PD treatment. (A) A pie chart shows the individual percentage of phase I, phase II, and phase III trials to the total. The phase I/II or II/III trials on ClinicalTrials.gov are showed as phase I or II, respectively. (B) A pie chart shows the proportions of each therapeutic strategy to the total PD clinical trials.

Figure 5

The drug or therapy with its therapeutic strategy and trial status in the clinical trials for PD treatment. The blue and red text color indicates the trial status is unknown and discontinued, respectively (active as of 16 June 2021).