THU032 Osilodrostat Is Effective And Well Tolerated In Patients Of Asian And Non-Asian Origin With Cushing's Disease: A Pooled Analysis From LINC 3 And LINC 4
Authors: Snyder Peter J , Biller Beverly M K , Fleseriu Maria , Pivonello Rosario , Lee Eun Jig , Leelawattana Rattana , Kim Jung Hee , Walia Rama , Yu Yerong , Liao Zhihong , Piacentini Andrea , Pedroncelli Alberto M , Shimatsu Akira 
Published: October 2023

Disclosure: P.J. Snyder: Consulting Fee; Self; Teva Pharmaceutical Industries Ltd. B.M. Biller: Consulting Fee; Self; HRA Pharmaceuticals, Recordati, Sparrow, Xeris Pharmaceuticals (Strongbridge). M. Fleseriu: Consulting Fee; Self; Recordati, Sparrow, Xeris Pharmaceuticals (Strongbridge), HRA Pharmaceuticals. Grant Recipient; Self; Recordati, Sparrow, Xeris Pharmaceuticals (Strongbridge). R. Pivonello: Consulting Fee; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Pfizer, Inc., Bresmed Health Solutions, Damor Farmaceutici, S&R Farmaceutici, Organon Italia, Siunergos Pharma, Biohealth Italia. Research Investigator; Self; Novartis Pharmaceuticals, Recordati, Xeris Pharmaceuticals (Strongbridge), Corcept Therapeutics, Takeda, Neurocrine Biosciences, Camurus AB, Pfizer, Inc., Merck Serono, IBSA. E.J. Lee: None. R. Leelawattana: None. J.H. Kim: None. R. Walia: None. Y. Yu: None. Z. Liao: None. A. Piacentini: Employee; Self; Recordati. A.M. Pedroncelli: Employee; Self; Recordati. A. Shimatsu: Consulting Fee; Self; Recordati. Speaker; Self; Recordati.

Introduction: Osilodrostat, a potent oral 11β-hydroxylase inhibitor, has demonstrated rapid and sustained normalization of cortisol in two Phase III studies (LINC 3, NCT02180217; LINC 4, NCT02697734) in patients (pts) with Cushing’s disease (CD). Relative osilodrostat bioavailability is estimated to be 20% higher in pts of Asian origin than other ethnicities, and body weight is not a major determinant of this difference. This analysis of the LINC 3 and LINC 4 studies evaluated the efficacy and safety of osilodrostat in pts of Asian and non-Asian origin with CD. Methods: Data were pooled from the LINC 3 and LINC 4 Phase III studies. LINC 3 comprised a 48-week (W) core phase, including an 8W randomized withdrawal for eligible pts. LINC 4 included a 12W, double-blind, placebo-controlled period and 36W of open-label osilodrostat. Both studies had an optional extension. Efficacy and safety outcomes were evaluated separately in pts of Asian and non-Asian origin. Periods where pts received placebo were excluded. Results: In total, 56/210 (27%) pts were of Asian origin, enrolled in China (n=16), South Korea (n=14), Japan (n=9), Thailand (n=9), India (n=7) and USA (n=1). Most non-Asian pts were Caucasian (n=138/154, 90%). Median (min−max) osilodrostat dose was 3.8 (1−25) and 7.3 mg/day (1−47) in pts of Asian and non-Asian origin, respectively. mUFC control was achieved at W48 and W72 in 64.3% and 68.1% of Asian pts and in 68.2% and 75.8% of non-Asian pts, respectively. Improvements from baseline in most cardiovascular and metabolic-related parameters and in physical manifestations of hypercortisolism were similar across both groups during osilodrostat treatment. Osilodrostat was well tolerated; the most common investigator-reported adverse events (AEs) in Asian pts were adrenal insufficiency (44.6%), nausea (33.9%) and decreased appetite (26.8%), and in non-Asian pts, nausea (45.5%), fatigue (40.9%) and headache (39.0%). The most common serious AE in Asian and non-Asian pts was adrenal insufficiency (5.4% and 5.2%, respectively). Hypocortisolism-related AEs occurred in 58.9% of Asian pts and 40.3% of non-Asian pts, most commonly reported by the investigator as adrenal insufficiency (44.6% and 22.1%). AEs related to pituitary tumor enlargement occurred in 21.4% of Asian and 9.1% of non-Asian pts. AEs related to arrhythmogenic potential and QT prolongation were infrequent in all pts. Conclusions: Osilodrostat demonstrated similar beneficial effects in Asian and non-Asian pts in terms of mUFC control and improvements in cardiovascular and metabolic-related parameters and physical manifestations of hypercortisolism. The mean dose to achieve beneficial effects was lower in pts of Asian than non-Asian origin. Osilodrostat was generally well tolerated in Asian and non-Asian pts; AEs related to hypocortisolism and pituitary enlargement were reported more frequently in Asian than non-Asian pts.

Presentation: Thursday, June 15, 2023