Improved Clinical Outcomes During Long-term Osilodrostat Treatment of Cushing Disease With Normalization of Late-night Salivary Cortisol and Urinary Free Cortisol

John Newell-Price; Maria Fleseriu; Rosario Pivonello; Richard A Feelders; Mônica R Gadelha; André Lacroix; Przemysław Witek; Anthony P Heaney; Andrea Piacentini; Alberto M Pedroncelli; Beverly M K Biller

doi:10.1210/jendso/bvae201

Improved Clinical Outcomes During Long-term Osilodrostat Treatment of Cushing Disease With Normalization of Late-night Salivary Cortisol and Urinary Free Cortisol

J Endocr Soc. 2024 Nov 12;9(1):bvae201. doi: 10.1210/jendso/bvae201. eCollection 2024 Nov 26.

Affiliations

¹ The School of Medicine and Population Health, University of Sheffield, Sheffield S10 2RX, UK.
² Pituitary Center, Departments of Medicine and Neurological Surgery, Oregon Health & Science University, Portland, OR 97239, USA.
³ Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, 80138 Naples, Italy.
⁴ Department of Internal Medicine, Endocrine Section, Erasmus Medical Center, 3015 GD Rotterdam, Netherlands.
⁵ Neuroendocrinology Research Center, Endocrinology Section, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-617, Brazil.
⁶ Department of Medicine, Centre hospitalier de l'Université de Montréal, Montreal, QC H2X 0A9, Canada.
⁷ Department of Internal Medicine, Endocrinology and Diabetes, Medical University of Warsaw, 02-091 Warsaw, Poland.
⁸ Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
⁹ Recordati SpA, 20148 Milan, Italy.
¹⁰ Recordati AG, 4057 Basel, Switzerland.
¹¹ Neuroendocrine and Pituitary Tumor Clinical Center, Massachusetts General Hospital, Boston, MA 02114, USA.

Abstract

Purpose: To assess whether simultaneous normalization of late-night salivary cortisol (LNSC) and mean urinary free cortisol (mUFC) in patients with Cushing disease treated with osilodrostat is associated with better clinical outcomes than control of mUFC or LNSC alone.

Methods: Pooled data from two phase III osilodrostat studies (LINC 3 and LINC 4) were analyzed. Both comprised a 48-week core phase and an optional open-label extension. Changes in cardiovascular/metabolic-related parameters, physical manifestations of hypercortisolism, and quality of life (QoL) were evaluated across the following patient subgroups: both LNSC and mUFC controlled, only mUFC controlled, only LNSC controlled, and neither controlled.

Results: Of 160 patients included in the analysis, 85.0% had both LNSC and mUFC uncontrolled at baseline. At week 72, 48.6% of patients had both LNSC and mUFC controlled; these patients generally exhibited greater improvements in cardiovascular/metabolic-related parameters than those with only mUFC controlled or both LNSC and mUFC uncontrolled: systolic/diastolic blood pressure, -7.4%/-4.9%, -6.0%/-5.5%, and 2.3%/0.8%, respectively; fasting plasma glucose, -5.0%, -4.8%, and 1.9%; glycated hemoglobin, -5.1%, -4.8%, and -1.3%. Weight, waist circumference, and body mass index improved with control of LNSC and/or mUFC; physical manifestations of hypercortisolism generally improved regardless of LNSC/mUFC control. Patients with both LNSC and mUFC controlled or only mUFC controlled had the greatest improvement from baseline to week 72 in QoL.

Conclusion: In osilodrostat-treated patients with Cushing disease, normalization of LNSC and mUFC led to improvements in long-term outcomes, indicating that treatment should aim for normalization of both parameters for optimal patient outcomes.

Clinical trial identifiers: NCT02180217 (LINC 3); NCT02697734 (LINC 4).

Keywords: Cushing disease; cortisol normalization; hypercortisolism; long-term treatment; osilodrostat.

Associated data

ClinicalTrials.gov/NCT02697734
ClinicalTrials.gov/NCT02180217