Development of disease-modifying drugs for Parkinson's disease. Is it a tough road?

Abstract

The treatment of diseases can be broadly classified into causal and symptomatic therapies. All the drugs currently on the market for Parkinson's disease are symptomatic treatments. Levodopa, a dopamine precursor, is the mainstay of treatment for Parkinson's disease to correct the malfunction of basal ganglia circuits caused by dopamine deficiency in the brain. In addition, dopamine agonists, anticholinergics, NMDA receptor antagonists, adenosine A2A receptor antagonists, COMT inhibitors, and MAO-B inhibitors have been marketed. With regard to the causal therapies, 57 out of 145 clinical trials for Parkinson's disease registered on ClinicalTrials.gov in January 2020 were related to disease-modifying drugs. Anti-α-synuclein antibodies, GLP-1 agonists, and kinase inhibitors have been examined in clinical trials as disease-modifying drugs, but no drug has been obviously demonstrated to inhibit the progression of Parkinson's disease to date. It is not easy to prove the beneficial results obtained from basic research in clinical trials. Especially for neurodegenerative disorders such as Parkinson's disease, it is more difficult to demonstrate clinical efficacy of disease-modifying drugs because there is no useful biomarker to quantify the degree of neuronal degeneration in clinical practice. In addition, the difficulty of using placebos for long periods in a clinical trial also makes proper assessment difficult.