The MPTP-lesioned marmoset model of Parkinson's disease: proposed efficacy thresholds that may potentially predict successful clinical trial results.

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset has been used extensively to model Parkinson's disease, L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and, more recently, dopaminergic psychosis. Whereas several experimental drugs have been tested in this primate, many of which subsequently underwent clinical trials, efficacy thresholds in the marmoset that would predict efficacy in the clinic are lacking. Here, we aimed to determine such efficacy end points that would be indicative of likely efficacy in clinical studies. To do so, we used the evidence-based medicine reviews published by the International Parkinson and Movement Disorder Society (IPMDS) to select drugs that were rated as clinically efficacious, likely efficacious or not efficacious for the treatment of parkinsonism, dyskinesia and psychosis. We then reviewed the literature in the MPTP-lesioned marmoset and identified articles reporting the effects of drugs that were included in the IPMDS recommendations, following which we estimated efficacy thresholds in the marmoset that would predict efficacy at the clinical level. We propose that, when drugs are administered as monotherapy, ≥ 50% reduction of global parkinsonism may be necessary to predict the possibility of clinical efficacy. As adjunct to a low dose of L-DOPA, we propose that an additional reduction of global parkinsonism ≥ 25% might predict clinical efficacy. As adjunct to an optimal dose of L-DOPA, we propose that additional anti-parkinsonian benefit ≥ 20%, with global parkinsonism as the end point, might predict clinical efficacy. For the treatment of dyskinesia, we suggest that the predictability threshold be set at ≥ 25% reduction of peak dose dyskinesia, while we believe that this threshold should be > 50% reduction of peak dose psychosis-like behaviours for psychosis-related end points. This article represents the first step in determining what efficacy might be necessary to achieve in pre-clinical studies in the MPTP-lesioned marmoset prior to confidently advancing drugs to clinical trials. We hope that it will help in the drug discovery and development process, notably by avoiding exposing patients to drugs that have little probability of clinical efficacy based upon pre-clinical experiments.