Parkinson's Disease Drug Development Since 1999: A Story of Repurposing and Relative Success.

BACKGROUND: A global overview of drug development programs in Parkinson's disease over the last few decades is lacking, while such programs are challenging given the multifaceted and heterogeneous nature of the disease. OBJECTIVE: To indirectly assess drug development programs in Parkinson's disease, exploring some factors associated with compound attrition at different trial phases. METHODS: We assessed all Parkinson's disease trials in the WHO trials portal, from inception (1999) to September 2019. Independent authors selected trials and extracted data. The success rate was the number of compounds that progressed to the next drug development phase divided by the number of compounds in that phase. RESULTS: Overall, 357 trials (studying 152 compounds) fulfilled our inclusion criteria, with 62 (17.3%) phase 1 trials, 135 (37.8%) phase 2 trials, 85 (23.8%) phase 3 trials, and 53 (14.8%) phase 4 trials. The success rate was 42.4% from phase 2 to 3. Original compounds received regulatory approval by the FDA in 21.4% of cases, compared with 6.7% of repurposed compounds, representing an overall success rate of 14.9%. We found 172 trials (48.2%) conducted for repurposing previously licensed compounds. These figures were approximately the same regarding approval by the EMA. Most compounds were approved to treat parkinsonism and motor fluctuations. CONCLUSION: We found a moderate-to-high success rate in all phases of drug development. This was largely based on the success of original compounds, despite almost half of the identified trials attempting compound repurposing.

Risk of Developing Parkinson Disease in Bipolar Disorder: A Systematic Review and Meta-analysis.

Importance: Parkinson disease (PD) manifests by motor and nonmotor symptoms, which may be preceded by mood disorders by more than a decade. Bipolar disorder (BD) is characterized by cyclic episodes of depression and mania. It is also suggested that dopamine might be relevant in the pathophysiology of BD. Objective: To assess the association of BD with a later diagnosis of idiopathic PD. Data Sources: An electronic literature search was performed of Cochrane Controlled Register of Trials, MEDLINE, Embase, and PsycINFO from database inception to May 2019 using the terms Parkinson disease, bipolar disorder, and mania, with no constraints applied. Study Selection: Studies that reported data on the likelihood of developing PD in BD vs non-BD populations were included. Two review authors independently conducted the study selection. Data Extraction and Synthesis: Two review authors independently extracted study data. Data were pooled using a random-effects model, results were abstracted as odds ratios and 95% CIs, and heterogeneity was reported as I2. Main Outcome and Measures: Odds ratios of PD. Results: Seven studies were eligible for inclusion and included 4 374 211 participants overall. A previous diagnosis of BD increased the likelihood of a subsequent diagnosis of idiopathic PD (odds ratio, 3.35; 95% CI, 2.00-5.60; I2 = 92%). A sensitivity analysis was performed by removing the studies that had a high risk of bias and also showed an increased risk of PD in people with BD (odds ratio, 3.21; 95% CI, 1.89-5.45; I2 = 94%). Preplanned subgroup analyses according to study design and diagnostic certainty failed to show a significant effect. Conclusions and Relevance: This review suggests that patients with BD have a significantly increased risk of developing PD compared with the general population. Subgroup analyses suggested a possible overestimation in the magnitude of the associations. These findings highlight the probability that BD may be associated with a later development of PD and the importance of the differential diagnosis of parkinsonism features in people with BD.