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-HT1A receptor agonist (sarizotan), and adenosine A2A 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.

A Historical Review of Brain Drug Delivery

“…Yet, CNS drug developers practice their craft by adhering to two conflicting beliefs: (a) drugs for CNS disease can be developed, and (b) CNS drug development can take place in the absence of any consideration of the blood-brain barrier. These contradictory beliefs are illustrated by recent reviews of drug development for AD [1202][1203][1204][1205], PD [755,1206], stroke [1207], brain cancer [1208], Huntington's disease [1209], ALS [1210], ataxia [1211], spinal cord injury [1212], traumatic brain injury [1213], or addiction [1214]. In none of these reviews on drug development for specific brain diseases was the BBB even mentioned, so the crucial issue of brain drug delivery was uniformly in absentia in the CNS drug development process.…”

The understanding of Parkinson's disease through genetics and new therapies

“…In addition, α‐synuclein is a neuronal protein that regulates synaptic vesicle trafficking and neurotransmitter release. A clinical trial showed that treatments that use small molecule α‐synuclein aggregation therapy, monoclonal antibody, or gene therapy could be better than other clinical trials/therapies for the treatment in the future (Prasad & Hung, 2021). Moreover, a real‐life study revealed a continued reduction in motor fluctuations in patients who received 2 years of continuous treatment with apomorphine as an under‐the‐skin infusion (Meira et al., 2021).…”

Overcoming barriers in non-viral gene delivery for neurological applications

“…Gene therapy is a rapidly growing market across the world with over 700 gene therapy clinical trials ongoing as of 2019, seeking to solve a variety of diseases and disorders, such as Parkinson's Disease, 1,2 Cystic Fibrosis 3,4 and various types of cancer 5,6 at the genomic level. Current clinical applications in gene therapy make use of adeno-associated viral vectors (AAVs) due to their unmatched gene delivery efficiency but limitations in max gene size, disputed safety, high cost of production and lack of ease in scalability has drawn the desire for an alternative for gene delivery applications.…”