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.

1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 损伤的普通狨猴已被广泛用于模拟帕金森病，l -3,4-二羟基苯丙氨酸 ( l-DOPA) 引起的运动障碍，以及最近的多巴胺能精神病。虽然已经在这种灵长类动物中测试了几种实验药物，其中许多随后进行了临床试验，但在狨猴中缺乏可以预测临床疗效的疗效阈值。在这里，我们旨在确定此类疗效终点，这些终点将指示临床研究中的可能疗效。为此，我们使用国际帕金森和运动障碍协会 (IPMDS) 发表的循证医学评论来选择被评为临床有效、可能有效或无效的药物，用于治疗帕金森病、运动障碍和精神病。然后我们回顾了有关 MPTP 损伤的狨猴的文献，并确定了报告 IPMDS 建议中包含的药物影响的文章，之后，我们估计了狨猴的功效阈值，该阈值将在临床水平上预测功效。我们建议，当药物作为单一疗法给药时，可能需要使整体帕金森综合征减少 ≥ 50% 才能预测临床疗效的可能性。作为小剂量的辅助l -DOPA，我们建议整体帕金森综合征的额外减少 ≥ 25% 可能预测临床疗效。作为最佳剂量l 的辅助-DOPA，我们建议额外的抗帕金森病获益 ≥ 20%，以全球帕金森病为终点，可能预测临床疗效。对于运动障碍的治疗，我们建议将可预测阈值设置为峰值剂量运动障碍减少 ≥ 25%，而我们认为该阈值应为精神病相关终点的峰值剂量精神病样行为减少 50% 以上。本文代表了在自信地将药物推向临床试验之前，确定在 MPTP 损伤的狨猴的临床前研究中可能需要达到何种疗效的第一步。我们希望它有助于药物发现和开发过程，特别是通过避免将患者暴露于基于临床前实验几乎没有临床疗效的药物。