Hickey Conor, Gueron Beatrice, Schmidt Fabian, Tyas Emma, Binowski Grzegorz, Pivonello Rosario
Lumanity, London, UK.
Recordati Rare Diseases, Puteaux, France.
Adv Ther. 2025 May 29. doi: 10.1007/s12325-025-03229-0.
Cushing's syndrome (CS) is a rare, chronic condition caused by prolonged exposure to elevated levels of circulating cortisol, and characterized by high morbidity and mortality. The primary treatment option for CS is surgery; however, medical therapy may be useful when surgery is unsuitable, refused, or has not been curative, or a rapid control of hypercortisolism is required. While osilodrostat and metyrapone are two treatments for controlling cortisol levels, they have not been compared directly in a clinical trial. This study evaluated the comparative efficacy and tolerability of osilodrostat versus metyrapone for the treatment of CS using indirect treatment comparison methods.
Unanchored matching-adjusted indirect comparison was used to synthesize relative treatment effects by reweighting patient-level data from two clinical trials for osilodrostat to published aggregate data for metyrapone. Efficacy endpoints included complete response (CR), defined as mean urinary free cortisol ≤ 1.0 × the upper limit of normal, at Weeks 12, 24, and 36. Tolerability endpoints included all-cause treatment discontinuation and treatment discontinuation due to lack of efficacy (LoE) or adverse events (AEs).
The base case analysis demonstrated that osilodrostat provides increased odds of CR versus metyrapone at Week 12 [odds ratio (OR) 2.75; 95% confidence interval (CI) 1.29, 5.88], Week 24 (OR 3.28; 95% CI 1.58, 6.84) and Week 36 (OR 10.50; 95% CI 1.84, 59.96), implying a greater proportion of patients experience normalized cortisol levels at these time-points. Although the base case analysis showed that the odds of all-cause discontinuation and discontinuation due to LoE or AEs were numerically lower for osilodrostat, the evidence was insufficient to show a statistically significant difference.
These analyses show that osilodrostat increases the odds of achieving CR at Weeks 12, 24, and 36 versus metyrapone, demonstrating that osilodrostat is a more efficacious treatment option for normalizing cortisol levels in CS patients.
库欣综合征（CS）是一种罕见的慢性疾病，由长期暴露于循环皮质醇水平升高引起，具有高发病率和死亡率。CS的主要治疗选择是手术；然而，当手术不合适、被拒绝或未治愈，或需要快速控制高皮质醇血症时，药物治疗可能会有所帮助。虽然奥西卓司他和甲吡酮是两种控制皮质醇水平的治疗方法，但它们尚未在临床试验中直接比较。本研究使用间接治疗比较方法评估了奥西卓司他与甲吡酮治疗CS的相对疗效和耐受性。
采用非锚定匹配调整间接比较方法，通过对奥西卓司他两项临床试验的患者水平数据进行重新加权，以匹配甲吡酮已发表的汇总数据，从而综合相对治疗效果。疗效终点包括在第12、24和36周时的完全缓解（CR），定义为平均尿游离皮质醇≤正常上限的1.0倍。耐受性终点包括全因治疗中断以及因疗效不佳（LoE）或不良事件（AE）导致的治疗中断。
基础病例分析表明，与甲吡酮相比，奥西卓司他在第12周[比值比（OR）2.75；95%置信区间（CI）1.29，5.88]、第24周（OR 3.28；95%CI 1.58，6.84）和第36周（OR 10.50；95%CI 1.84，59.96）实现CR的几率更高，这意味着在这些时间点有更大比例的患者皮质醇水平恢复正常。尽管基础病例分析显示奥西卓司他全因停药以及因LoE或AE停药的几率在数值上较低，但证据不足以显示出统计学上的显著差异。
这些分析表明，与甲吡酮相比，奥西卓司他在第12、24和36周实现CR的几率更高，这表明奥西卓司他是使CS患者皮质醇水平恢复正常的更有效治疗选择。
