Parrish Marcus C, Hanson-Kahn Andrea, Srinivasan V, Grimes Kevin V
SPARK Translational Research Program, Stanford University School of Medicine, Stanford, CA, USA.
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
J Clin Transl Sci. 2022 Mar 1;6(1):e35. doi: 10.1017/cts.2022.372. eCollection 2022.
This research examined the perspective of the Huntington's disease (HD) community regarding the use of predictive biomarkers as endpoints for regulatory approval of therapeutics to prevent or delay the onset of clinical HD in asymptomatic mutation carriers.
An online, choice-based conjoint survey was shared with HD community members including untested at-risk individuals, presymptomatic mutation carriers, and symptomatic individuals. Across 15 scenarios, participants chose among two proposed therapies with differing degrees of biomarker improvement and side effects or a third option of no treatment.
Two hundred and thirty-eight responses were received. Attributes reflecting biomarker efficacy (e.g., prevention of brain atrophy on magnetic resonance imaging, reduced mutant huntingtin, or reduced inflammation biomarkers) had 3- to 7-fold greater importance than attributes representing side effects (e.g., increased risk of heart disease, cancer, and stroke over 20 years) and were more influential in directing choice of treatments. Reduction in mutant huntingtin protein was the most valued attribute overall. Multinomial logit model simulations based on survey responses demonstrated high interest among respondents (87-99% of the population) for drugs that might prevent or delay HD solely based upon biomarker evidence, even at the risk of serious side effects.
These results indicate a strong desire among members of the HD community for preventive therapeutics and a willingness to accept significant side effects, even before the drug has been shown to definitively delay disease onset if the drug improves biomarker evidence of HD progression. Preferences of the HD community should inform regulatory policies for approving preventive therapies.
本研究探讨了亨廷顿舞蹈症（HD）群体对于使用预测性生物标志物作为治疗药物监管批准的终点指标的看法，这些治疗药物旨在预防或延缓无症状突变携带者临床HD的发病。
向HD群体成员开展了一项基于选择的在线联合调查，其中包括未经检测的高危个体、症状前突变携带者和有症状个体。在15种情景中，参与者在两种提出的治疗方法中进行选择，这两种治疗方法具有不同程度的生物标志物改善和副作用，或者选择第三种不治疗的选项。
共收到238份回复。反映生物标志物疗效的属性（例如，磁共振成像显示脑萎缩的预防、突变亨廷顿蛋白减少或炎症生物标志物减少）的重要性比代表副作用的属性（例如，20年内患心脏病、癌症和中风的风险增加）高3至7倍，并且在指导治疗选择方面更具影响力。突变亨廷顿蛋白的减少是总体上最受重视的属性。基于调查回复的多项logit模型模拟表明，即使存在严重副作用的风险，受访者（87-99%的人群）对仅基于生物标志物证据可能预防或延缓HD的药物仍有很高兴趣。
这些结果表明，HD群体成员强烈希望获得预防性治疗，并且愿意接受重大副作用，即使在药物尚未被证明能明确延缓疾病发作之前，只要该药物能改善HD进展的生物标志物证据。HD群体的偏好应为预防性治疗的监管政策提供参考。
