Quantitative Clinical Pharmacology, Takeda Pharmaceuticals, Cambridge, Massachusetts, USA.
Division of Pharmacometrics, Food and Drug Administration, Silver Spring, Maryland, USA.
J Clin Pharmacol. 2020 Aug;60(8):1051-1060. doi: 10.1002/jcph.1598. Epub 2020 May 16.
Development of effective therapeutics that slow Huntington's disease progression is a research priority that requires an understanding of natural disease progression. We applied a population-modeling approach to describe the progression of 2 routinely used rating scales - the total motor score and the total functional capacity score. Models were fitted to data from research participants aged ≥ 18 years with Huntington's disease stage I or II at study entry (total functional capacity score ≥ 7), from a controlled clinical trial (CARE-HD) and 2 observational studies (COHORT and Registry). A logistic model without shape factors was selected as the base model based on placebo data from CARE-HD and validated using data from the CARE-HD active-treatment arms. Albeit with a smaller progression rate constant than was found in CARE-HD, the proposed models provided reasonable predictions for both rating scales in the pooled data from COHORT and Registry and were considered suitable for use in clinical trial simulations. Results also showed that disease burden score (a product of age and expanded CAG length) is a significant covariate on both the progression rate constant and the baseline score in the total motor score model. These findings suggest that total motor score and total functional capacity progress fastest near their half-maximal score, implying that the efficiency of clinical trials evaluating disease-modifying therapeutics for Huntington's disease could be enhanced by enrolling patients with faster disease progression or evaluating treatment effect near their half-maximal score, provided that the evaluated therapy is expected to be efficacious at this disease stage.
开发能够减缓亨廷顿病进展的有效疗法是一项研究重点，这需要我们了解疾病的自然进展过程。我们应用了一种群体模型方法来描述两种常用的评分量表——总运动评分和总功能能力评分的进展情况。模型基于研究参与者的数据进行拟合，这些参与者在研究入组时（总功能能力评分≥7）患有亨廷顿病 I 期或 II 期，且来自一项对照临床试验（CARE-HD）和两项观察性研究（COHORT 和 Registry）。基于 CARE-HD 的安慰剂数据，我们选择了没有形状因素的逻辑模型作为基础模型，并使用 CARE-HD 活性治疗臂的数据进行验证。虽然提出的模型的进展率常数比 CARE-HD 中的发现小，但它们为 COHORT 和 Registry 合并数据中的两种评分量表提供了合理的预测，并且被认为适合用于临床试验模拟。研究结果还表明，疾病负担评分（年龄和扩展 CAG 长度的乘积）是总运动评分模型中进展率常数和基线评分的重要协变量。这些发现表明，总运动评分和总功能能力在接近其半最大值评分时进展最快，这意味着，通过招募疾病进展较快的患者或在接近其半最大值评分时评估治疗效果，可以提高评估治疗亨廷顿病的疾病修饰疗法的临床试验效率，前提是评估的治疗方法在该疾病阶段预期有效。
