Endocrine Abstracts (2017) 49 EP1015 | DOI: 10.1530/endoabs.49.EP1015

Osilodrostat maintains normalized urinary free cortisol levels in a majority of patients with Cushing's disease: Long-term results from an extension to the LINC-2 study

Jacques Young1, Betul Hatipogulu2, Mark E Molitch3, Xavier Bertagna4, Nathalie Barbier5, Nicholas Sauter6, Beverly M K Biller7 & Rosario Pivonello8

1Department of Endocrinology, Hôpital Bicêtre, Université Paris-Sud, Assistance Publique Hôpitaux de Paris, Paris, France; 2Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, Ohio, USA; 3Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University, Chicago, IL, USA; 4Department of Endocrinology, Centre de Référence des Maladies Rares de la Surrénale, Hôpital Cochin, Faculté de Médecine Paris Descartes, Université Paris 5, Paris, France; 5Novartis Pharma AG, Basel, Switzerland; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 7Neuroendocrine Clinical Center, Massachusetts General Hospital, Boston, MA, USA; 8Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.

Background: In the 22-week LINC-2 study, osilodrostat (LCI699), a potent oral 11β-hydroxylase inhibitor, normalized urinary free cortisol (UFC) levels in 15 of 19 patients with Cushing’s disease (CD). The most common AEs were nausea, diarrhea, asthenia, and adrenal insufficiency (n=6 each). Here, we report the 31-month efficacy and safety results from LINC-2 extension.

Methods: Patients receiving clinical benefit at week 22 could enter two consecutive extensions and continue on the same dose of osilodrostat; dose adjustments were allowed. Response rate: proportion of patients with UFC≤ULN (controlled) or UFC>ULN but ≥50% decrease from baseline (partially controlled). The maximum safety follow-up from core baseline was 40.3 months.

Results: Sixteen patients entered the extension, 12 remained on treatment at month 31. Three patients discontinued during extensions (AEs, n=2; consent withdrawal, n=1). One patient decided not to continue on to extension-2. The response rate at month 31 was 100% (controlled, 14 (87.5%); partially controlled, 2 (12.5%)) when missing values were imputed using the last available measurements and 56.3% without imputation ((controlled, 8 (50.0%); partially controlled, 1 (6.3%)). No patient had escape from response (UFC>ULN at ≥2 consecutive visits on maximum tolerated dose after initial UFC normalization) during the extension. Mean (S.D.) changes in clinical signs of CD from baseline to month 31 (n=11) were: SBP (mmHg), −3.4 (18.5); DBP (mmHg), −5.4 (9.9); weight (kg), −4.5 (5.7); and BMI (kg/m2), −1.8 (2.3). The most common clinical AEs were diarrhea, hypocortisolism-related AEs (n=6 each), headache, asthenia, and nausea (n=5 each). Mean (S.D.) plasma ACTH (pmol/l; normal, 1.8–9.2) at baseline (n=15), week 22 (n=15) and month 31 (n=10) were 20.0 (10.4), 80.5 (145.5), and 54.0 (35.1), respectively.

Conclusion: In the majority of patients with CD, osilodrostat maintained normal UFC levels for >2.5 years with a long-term safety profile similar to that after 22 weeks; no new safety signals emerged. Two phase 3 studies are ongoing to further evaluate osilodrostat in patients with CD.