更年期潮热非激素药物疗法的研发成败案例分析

Analysis of the success and failure of non-hormonal drug therapy development for menopausal hot flashes

本文深入分析了去甲文拉法辛缓释片、艾司米氮平片和甲磺酸帕罗西汀胶囊3种非激素药物治疗更年期潮热的临床研发历程。去甲文拉法辛缓释片和艾司米氮平片均由于疗效不足和存在安全性问题,被监管机构以获益风险平衡欠佳为理由拒绝批准。相比之下,甲磺酸帕罗西汀胶囊通过设置安慰剂导入期、更保守的样本量估计和预先规定对2项Ⅲ期试验的主要疗效指标进行荟萃分析等措施有效降低了药物研发失败的风险,不仅展示了对潮热频率和潮热程度的疗效,也通过多个Ⅱ期试验探索到耐受性最佳的剂量,最终获得了美国食品药品监督管理局的批准。非激素药物在更年期潮热治疗的研发中面临诸多挑战,包括药物安全性特征与在精神科疾病患者不同、药物疗效偏弱、临床前药效模型与临床症状缓解的关联度弱,以及剂量探索试验需要较大样本量等。以上案例分析为后续类似适应证的药物研发提供了优化试验设计、降低研发风险的策略借鉴。

This article provides an in-depth analysis of the clinical development process of three non-hormonal drugs,desvenlafaxine extended-release tablets,esmirtazapine tablets and paroxetine capsules,for the treatment of menopausal hot flashes.Both desvenlafaxine extended-release tablets and esmirtazapine tablets were rejected by regulators for poor benefit-risk balance due to inadequate efficacy and safety concerns.In contrast,paroxetine capsules effectively reduced the risk of drug development failure by setting placebo lead-in periods,more conservative sample size estimates,and pre-specifying meta-analyses of key efficacy measures in the two phaseⅢtrials,not only demonstrating efficacy in the frequency and degree of hot flashes,but also exploring the best-tolerated dose through multiple phaseⅡtrials,which was finally approved by the U.S.Food and Drug Administration.The development of non-hormonal drugs for the treatment of menopausal hot flashes faces many challenges,including drug safety characteristics that are different from those in patients with psychiatric diseases,weak drug efficacy,weak correlation between preclinical efficacy models and clinical symptom remission,and the need for large sample sizes for dose-finding trials.This case study provides a strategic reference for optimizing trial design and reducing the risk of drug development for subsequent drug development with similar indications.