Endocrine Abstracts

Objectives: Endogenous Cushing’s Syndrome (CS) is a rare, chronic condition that results in high morbidity, caused by prolonged exposure to elevated levels of circulating free cortisol levels. Osilodrostat, a newly approved steroidogenesis inhibitor, has been shown to achieve fast and high rates of cortisol normalization, improving manifestations of hypercortisolism in patients with Cushing’s Disease (CD), a form of CS. We evaluated relative complete response (CR) outcomes at Weeks 12 and 36, and two discontinuation outcomes at Week 24 for osilodrostat vs metyrapone for patients with CS.

Methods: The LINC-4 and PROMPT clinical trials investigated osilodrostat and metyrapone, respectively, in patients with CS. All LINC-4 patients and 90% of PROMPT patients had CD; remaining PROMPT patients had other endogenous CS aetiologies. Efficacy endpoints of CR (mean urinary free cortisol [mUFC] ≤ 1.0 x the upper limit of normal) at Weeks 12 and 36, and safety endpoints of all cause discontinuation and discontinuation due to lack of efficacy or any adverse event at Week 24 were analysed. Unanchored matching-adjusted indirect comparisons were performed using LINC-4 patient-level data and published summary data for PROMPT. Four baseline characteristics identified as potential prognostic factors were adjusted for: age, sex, time since diagnosis, and mUFC. Estimated weights were applied to logistic regression models providing relative effect estimates through weighted odds ratios (ORs). Scenario analyses investigated a trade-off between the effective sample size of the matched population and inclusion/exclusion of baseline mUFC as a matching variable, a plausible but unconfirmed prognostic factor. For CR endpoints, two methods of imputing missing response observations were investigated: non-response imputation and last observation carried forward (LOCF).

Results: Non-response imputation results suggested treatment with osilodrostat was associated with significantly increased odds of CR compared with metyrapone at Week 12 (OR: 3.43; 95% confidence interval [CI]: 1.10, 10.65) and Week 36 (OR: 7.57; 95% CI: 2.22, 25.77). This implies osilodrostat patients have 3.43 and 7.57 times greater odds of experiencing normalized cortisol levels at Weeks 12 and 36, respectively. No significant differences between treatments were found for the discontinuation endpoints. Scenario analyses investigating the exclusion of baseline mUFC as a matching variable and the LOCF imputation method for missing observations had consistent results.

Conclusions: Our analyses suggest osilodrostat significantly increases the odds of achieving CR at Weeks 12 and 36 compared with metyrapone, implying osilodrostat is a more efficacious treatment option than metyrapone for reducing cortisol levels in patients with CS.