MON-012 - Safety and Efficacy of A Standardized Osilodrostat Block-and-Replace Protocol with Cortisol Suppression and Methylprednisolone Replacement

Introduction: Osilodrostat (Osi) is a potent inhibitor of P450 11B1 (11-hydroxylase) used for treatment of Cushing syndrome. To avoid adrenal insufficiency during titration, a block-and-replace strategy has been used with inconsistent protocols.

Methods: We developed a standardized block-and-replace protocol, which adds methylprednisolone 4 mg the morning after the first evening dose of Osi. The Osi dose is gradually increased based on glucocorticoid withdrawal symptoms (fatigue, myalgias, anorexia) until the AM cortisol is < 5 μg/dL. A urine free cortisol (UFC) is then obtained, with a target < 5 μg/24 h; Osi is further up-titrated if UFC is not at goal. Excess serum at baseline and during treatment was assayed for 11β-hydroxyandrostenedione (11OHA4) as a secondary biomarker of Osi efficacy. The primary endpoint is the number of participants who experience an adrenal crisis during Osi titration.

Results: We consented 7 participants, 5 of whom have received Osi treatment. Maximal Osi doses ranged from 6-26 mg/d distributed evenly or a higher dose in the evening. Of 3 participants who reached goal AM cortisol and UFC, 2 have discontinued Osi with persistently low serum and urine cortisol. Osi titration is in process for 3 participants, and 1 withdrew prior to receiving Osi. Serum 11OHA4 was 17.8-384 ng/dL (median 113) at baseline and fell to 6.5-22.8 ng/dL (median 12.8) in the 3 participants who achieved an AM cortisol < 5 μg/dL. Although glucocorticoid withdrawal symptoms were common, including emergency room visits for nausea or unrelated acute illnesses, no episodes of hypoglycemia and/or hypotension consistent with adrenal crises were observed.

Conclusions: We have developed a safe, easily implemented, and effective protocol for Osi block-and-replace using once daily methylprednisolone, which does not interfere with modern cortisol immunoassays and restores approximately circadian glucocorticoid exposure. No episodes of adrenal crises occurred, and 3 of 5 treated participants were titrated to goal, with 2 having prolonged cortisol deficiency after stopping Osi. Aggressive adrenal suppression with sufficient Osi to sustain cortisol deficiency might favor development of a long-term adrenolytic response to Osi. Serum 11OHA4 is a useful biomarker of Osi efficacy and an alternative to cortisol.

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