OR12-08 Safety and Efficacy of Once-Daily Osilodrostat in Cushing’s Syndrome to Improve Cortisol Circadian Rhythm and Quality of Life: A Multi-Center Study

Abstract Disclosure: A.M. Isidori: Neurocrine, HRA Pharma, Corcept, Recordati Rare Diseases. D. Ferrari: None. I. Bonaventura: None. A. Tomaselli: None. C. Simeoli: None. L. Vincenzi: None. D. De Alcubierre: None. L. Cerroni: None. N. Di Paola: None. M. Minnetti: None. E. Sbardella: None. M. Venneri: None. R. Pofi: None. R. Pivonello: Neurocrine, Recordati Rare Diseases, Corcept, HRA Pharma. D. Gianfrilli: None. V. Hasenmajer: None. Introduction: Current medical treatments for Cushing’s syndrome (CS) primarily aim to reduce daily cortisol levels but often neglect circadian rhythm restoration. No approved regimens are specifically designed for this purpose. We assessed the efficacy and safety of a once-daily, evening-dosed Osilodrostat regimen in optimizing the circadian cortisol profile in CS patients. Methods: In this prospective, multicenter study, patients with well-controlled CS on a stable twice-daily Osilodrostat regimen transitioned to an equivalent once-daily dose at 19:00 ± 1 hour. Frequent (4-to-6 hourly) sampling of circadian steroid profiles in saliva, serum, and urine was analyzed using UHPLC-MS/MS. Secondary outcomes included cardiometabolic markers, quality of life, sleep function, and safety. Results: Sixteen patients (4 males; 7 pituitary CS; mean age 53.3 ± 11.8 years) were enrolled. At baseline, CS was well controlled with a mean Osilodrostat dose of 4.2 mg (range 2–22 mg). Following the transition, salivary cortisol exposure significantly decreased from afternoon to early morning [AUC16:00-08:00: -6.1 (-0.15 to -12.1) ng/mL/h, p = .029; AUC16:00-04:00: -4.6 (-1.2 to -8.1) ng/mL/h, p=.009]. Quality of life and sleep improved [CushingQoL: +4.2 (-0.1-8.6), p=.029; PSQI: -1.7 (-3.7-0.4), p=.049]. Serum steroid precursors, including 11-deoxycorticosterone [AUC08:00-20:00 -3.1 ng/mL/h, p = .008] and 11-deoxycortisol [AUC08:00-20:00 -17.8 ng/mL/h, p = .005], along with total testosterone in women [AUC08:00-20:00 = -0.8 ng/mL/h, p=.039], showed reduced overall daytime exposure.In a subset of 8 patients who advanced dosing to 16:00 ± 1 hour, salivary cortisol reductions were comparable [cortisol AUC16:00-08:00: -5.5 ng/mL/h, p=.036]. Frequent salivary sampling proved effective for monitoring drug response in CS. The once-daily regimen was well tolerated, with 93.4% of patients preferring it over twice-daily dosing for convenience and adherence. No cases of adrenal insufficiency, liver toxicity, ECG abnormalities, or disease recurrence were observed during follow-up. Conclusions: This study provides the first evidence that once-daily evening Osilodrostat effectively and safely restores circadian cortisol rhythms in CS, improving quality of life and sleep. These findings support further investigation of chronotherapy-based strategies in CS management. Presentation: Sunday, July 13, 2025