THU041 Clinical Improvements In Patients With Cushing’s Disease Treated With Osilodrostat According To Urinary And Late-night Salivary Cortisol Levels: Pooled Analysis From LINC 3 And LINC 4

Abstract Disclosure: B.M. Biller: Consulting Fee; Self; HRA Pharmaceuticals, Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Research Investigator; Self; served on the LINC 3 steering committee. M. Fleseriu: Consulting Fee; Self; HRA Pharmaceuticals, Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Grant Recipient; Self; Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Research Investigator; Self; served on the LINC 3 steering committee. R. Pivonello: Consulting Fee; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Pfizer, Inc., Bresmed Health Solutions, Damor farmaceutici, S&R Farmaceutici SpA, Organon Italia Srl, Siunergos Pharma, Biohealth Italia Srl. Research Investigator; Self; Novartis Pharmaceuticals, Recordati, Xeris Pharmaceuticals (Strongbridge), Corcept Therapeutics, Takeda, Neurocrine Biosciences, Camurus AB, Pfizer, Inc., Merk Serono, Ibsa. R. Feelders: Consulting Fee; Self; HRA Pharmaceuticals, Recordati. Grant Recipient; Self; Corcept Therapeutics. M. Gadelha: Advisory Board Member; Self; Novo Nordisk, Recordati, Crinetics Pharmaceuticals. Speaker; Self; Recordati, Ipsen, Pfizer, Inc., Crinetics, Novo Nordisk. A. Lacroix: Consulting Fee; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Ipsen, Novo Nordisk. Grant Recipient; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Ipsen, Novo Nordisk. P. Witek: Grant Recipient; Self; Novartis Pharmaceuticals, Ipsen, Recordati, Novo Nordisk, Xeris Pharmaceuticals (Strongbridge), Lilly. Speaker; Self; Novartis Pharmaceuticals, Ipsen, Recordati, Novo Nordisk, Xeris Pharmaceuticals (Strongbridge), Lilly. A.P. Heaney: Advisory Board Member; Self; Xeris Pharmaceuticals (Strongbridge), Novo Nordisk, Lundbeck Pharma. Speaker; Self; Chiasma, Ipsen. A. Piacentini: Employee; Self; Recordati. A.M. Pedroncelli: Employee; Self; Recordati. J. Newell-Price: Consulting Fee; Self; Crinetics, Diurnal, HRA Pharmaceuticals, Recordati Rare Diseases. Grant Recipient; Self; Crinetics, Diurnal, HRA Pharmaceuticals, Recordati Rare Diseases. Introduction: In two Phase III studies (LINC 3, NCT02180217; LINC 4, NCT02697734), osilodrostat, a potent oral 11β-hydroxylase inhibitor, led to rapid, sustained reductions in mean urinary free cortisol (mUFC) and late-night salivary cortisol (LNSC), as well as improvements in clinical signs of hypercortisolism and health-related quality of life (HRQoL), in patients (pts) with Cushing’s disease (CD). mUFC and LNSC are recommended for monitoring treatment response. Objective: We assessed if pts with control of both mUFC and LNSC experienced greater improvements in clinical signs of hypercortisolism and HRQoL, compared to control of mUFC alone. Methods: LINC 3 comprised a 48-week (W) core phase, including an 8W randomized-withdrawal period. LINC 4 included a 12W, double-blind, placebo-controlled period followed by 36W of open-label osilodrostat. Both studies had an optional extension. mUFC (mean of 2–3 samples; normal range [NR] 11–138 nmol/24h [4–50 µg/24h]) and LNSC (one sample; NR ≤2.5 nmol/L [≤0.9 µg/L]) were measured by liquid chromatography-tandem mass spectrometry. Changes in cardiovascular/metabolic-related parameters, physical manifestations of hypercortisolism and HRQoL were assessed in the pooled population according to mUFC and LNSC control status: both controlled (C) mUFC + LNSC (mUFC ≤ULN + LNSC ≤ULN), C-mUFC (mUFC ≤ULN + LNSC >ULN) and uncontrolled (UC) mUFC + LNSC (mUFC >ULN + LNSC >ULN). Pts with C-LNSC (mUFC >ULN + LNSC ≤ULN) were not analyzed as very few pts had control of LNSC without UFC control. This analysis includes pts in core and extension phases with both mUFC and LNSC assessments available. Periods where pts received placebo were excluded. Results: 136 (85.0%) of 160 pts with available assessments had UC mUFC + LNSC at baseline (BL). At W48 (n=133) and W72 (n=111), respectively, 59 (44.4%) and 54 (48.6%) pts had C mUFC + LNSC, 49 (36.8%) and 44 (39.6%) had C-mUFC, and 19 (14.3%) and 11 (9.9%) had UC mUFC + LNSC. Pts with C mUFC + LNSC had greater percentage improvements from BL to W72 in cardiovascular/metabolic-related parameters than pts with C-mUFC or UC mUFC + LNSC, respectively: fasting plasma glucose, –5.0%, –4.8%, 1.9%; glycated hemoglobin, –5.1%, –4.8%, –1.3%; weight, –6.5%, –6.5%, –4.5%; waist circumference, –7.2%, –6.3%, –4.9%. Physical manifestations of hypercortisolism generally improved from BL to W72 regardless of mUFC/LNSC control. Pts with C mUFC + LNSC or C-mUFC had the greatest improvement from BL to W72 in HRQoL. Conclusions: The greatest improvements in cardiovascular/metabolic-related parameters and HRQoL were observed in pts with C mUFC + LNSC or C-mUFC, compared to pts with UC mUFC + LNSC. Improvements in most physical manifestations of hypercortisolism were observed regardless of mUFC/LNSC control. Data are limited by small patient numbers in some groups. Normalization of both mUFC and LNSC can improve long-term treatment outcomes in pts with CD. Presentation: Thursday, June 15, 2023

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