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Introduction <p>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.</p> Methods <p>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&#xa0;≤&#xa0;1.0&#xa0;×&#xa0;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).</p> Results <p>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.</p> Conclusion <p>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.</p>

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Matching-Adjusted Indirect Comparison of Osilodrostat Versus Metyrapone for the Treatment of Cushing’s Syndrome

  • 期刊论文

  • 发表日期：

    2025年5月29日

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  • Conor Hickey,
  • Beatrice Gueron,
  • Fabian Schmidt,
  • Emma Tyas,
  • Grzegorz Binowski,
  • Rosario Pivonello

摘要

Introduction

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.

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).

Results

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.

Conclusion

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.