Endocrine Abstracts

Introduction: Osilodrostat decreases cortisol production by inhibiting 11β-hydroxylase, increasing adrenal hormones above the blockade. Here, we describe these effects of osilodrostat and associated adverse events (AEs). The efficacy and safety of osilodrostat in patients with Cushing’s disease (CD) were confirmed in the published Phase III, prospective LINC 3 study (NCT02180217).

Methods: 137 patients with CD (mUFC >1.5x upper limit of normal) were enrolled in a 48-week (W) core phase including an 8W double-blind, randomised-withdrawal period for eligible patients. 106/113 patients who completed W48 entered an optional extension, ending when all ongoing patients completed ≥72W of treatment or discontinued. Testosterone, 11-deoxycortisol, 11-deoxycorticosterone and aldosterone were assessed centrally at baseline and regular intervals by liquid chromatography-tandem mass spectrometry, and dehydroepiandrosterone sulfate (DHEAS) by chemiluminescence immunoassay. Hirsutism (females; rated on a semi-quantitative scale: 0=absent; 1=mild; 2=moderate; 3=severe), blood pressure, oedema and serum potassium were assessed regularly.

Results: Median osilodrostat exposure was 130W (range 1–245); median osilodrostat dose was 7.4 mg/day (range 0.8–46.6). Following an increase during the core phase, mean testosterone levels stabilised in males and decreased towards baseline levels in females during long-term treatment. Of females with baseline, W48 (n=76) and W72 (n=64) assessments, hirsutism score improved from baseline in 26 and 22 patients at W48 and W72, respectively, and remained unchanged in 37 and 33 patients. Mean (SD) DHEAS levels decreased during the core phase to within the normal range, then stabilised during the extension (W48 and W72; females: 1.6 [1.6] and 1.0 [0.9] μmol/l; males: 3.4 [3.3] and 3.0 [3.1] μmol/l). Aldosterone levels also decreased and then stabilised during long-term treatment. Overall, mean potassium levels remained stable throughout the study. AEs related to accumulation of adrenal hormone precursors were reported in 58.4% (n=80/137) of patients, regardless of study drug relationship, and managed with additional therapy in 36.5% (n=50/137) of patients. The most common AEs were hypertension (n=24), peripheral oedema (n=22) and hypokalaemia (n=18), managed with concomitant medication in 17, 6 and 4 patients, respectively. They mostly occurred during the first 26W of treatment (females: 35.5%; males: 49.1%) at different osilodrostat doses (1–60 mg), with no discernable dose-related effect. Few patients discontinued treatment because of these AEs (1.5%; n=2/137).

Conclusions: Adrenal hormone levels frequently change when initiating osilodrostat but stabilise during long-term treatment. AEs associated with these changes are manageable without osilodrostat discontinuation; they should be closely monitored and treatment initiated as needed to achieve optimal patient outcomes.