Osilodrostat Can Provide Control of Urinary Free Cortisol for over 2.5 Years in Patients with Cushing's Disease: Results from an Extension to the Linc-2 Study
Presentation Number: OR22-5
Date of Presentation: April 1st, 2017
Rosario Pivonello*1, Betul Hatipoglu2, Mark E Molitch3, Xavier Bertagna4, Nathalie Barbier5, Nicholas Sauter6, Beverly M.K. Biller7 and Jacques Young8
1Università Federico II di Napoli, Naples, Italy, 2Cleveland Clinic, Cleveland, OH, 3Northwestern University, Chicago, IL, 4Hôpital Cochin, Paris, France, 5Novartis Pharma AG, Basel, Switzerland, 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, 7Massachusetts General Hospital, Boston, MA, 8Assistance Publique Hôpitaux de Paris, Paris, France
Background: Osilodrostat (LCI699) is a potent oral 11β-hydroxylase inhibitor. In the 22-week (wk) LINC-2 study, osilodrostat normalized urinary free cortisol (UFC) levels in 78.9% (15/19) of patients (pts) with Cushing’s disease (CD). Sixteen pts entered an extension to LINC-2, with 68.8% (11/16) achieving normalized UFC at month (mo) 19. The most common AEs during the 22-wk study were nausea, diarrhea, asthenia, and adrenal insufficiency (n=6 each). This work reports 31-mo efficacy and safety results from the extension.
Methods: Pts receiving clinical benefit at wk 22 could enter the extension and continue on the same dose of osilodrostat. Dose adjustments were permitted during the extension. Response rate (RR; defined as the proportion of pts with UFC≤ULN [controlled; C] or UFC>ULN but ≥50% decrease from baseline [BL] [partially controlled; PC]) was assessed with last observation carried forward (LOCF; imputation of missing values using the last available measurements) and observed measurements at 31 mo. Safety was assessed from core BL until the last pt reached mo 31 (maximum follow-up = 40.3 mo).
Results: Of the 16 pts (11 females) who entered the extension, 12 remained on treatment at mo 31. The overall RR (LOCF) for pts who entered the extension was 93.8% (C, 93.8% [15/16]) at wk 22 and 100% (C, 87.5% [14/16]; PC, 12.5% [2/16]) at mo 31. RR was lower at mo 31 when missing values were not imputed: 56.3% (C, 50.0% [8/16]; PC, 6.3% [1/16]). No pts had escape from response (UFC>ULN at ≥2 consecutive visits on maximum tolerated dose after initial UFC normalization) during the extension. Mean (SD) changes in clinical signs of CD from BL to mo 31 (n=11) were: SBP, –3.4 (18.5) mmHg; DBP, –5.4 (9.9) mmHg; weight, –4.5 (5.7) kg; and BMI, –1.8 (2.3) kg/m2. The most common clinical AEs were diarrhea (n=6), headache, asthenia, and nausea (n=5 each). Six pts reported hypocortisolism-related AEs. Three pts discontinued from the extension; 1 other patient did not wish to participate. Mean (SD) plasma ACTH increased from 20.0 (10.4) pmol/L (normal 1.8–9.2; n=15) at BL to 80.5 (145.5) pmol/L (n=15) at wk 22 and 54.0 (35.1) pmol/L (n=10) at mo 31. Mean (SD) 11-deoxycortisol and 11-deoxycorticosterone increased from 4.5 (5.3) nmol/L (normal 0–3.92; n=15) and 0.3 (0.3) nmol/L (normal 0.1–0.4; n=13), respectively, at BL to 44.7 (39.5) nmol/L (n=15) and 4.8 (6.6) nmol/L (n=13) at wk 22, and 24.5 (18.8) nmol/L (n=9) and 2.0 (1.5) nmol/L (n=6) at mo 31. Mean (SD) aldosterone decreased from 168.1 (255.4) pmol/L (normal 55–250; n=15) at BL to 44.5 (72.0) pmol/L (n=15) at wk 22 and 19.0 (35.4) pmol/L (n=8) at mo 31.
Conclusion: Osilodrostat maintained normal UFC levels for >2.5 years in a majority of pts with CD, with a long-term safety profile similar to that after 22 wks; no new safety signals emerged. Osilodrostat is being evaluated in two ongoing Phase III studies in pts with CD.
Disclosure: RP: Principal Investigator, Novartis Pharmaceuticals, Coinvestigator, Novartis Pharmaceuticals, Clinical Researcher, Shire, Consultant, Shire, Speaker, Novartis Pharmaceuticals, Speaker, Novartis Pharmaceuticals, Speaker, Shire, Principal Investigator, Ipsen, Principal Investigator, Pfizer, Inc.. BH: Consultant, Merck & Co., Speaker, Merck & Co., Consultant, Novo Nordisk, Speaker, Novo Nordisk. MEM: Investigator, Novartis Pharmaceuticals, Investigator, Chiasma, Investigator, Ipsen, Investigator, Novo Nordisk, Investigator, Bayer, Inc., Consultant, Novartis Pharmaceuticals, Consultant, Chiasma, Consultant, Novo Nordisk, Consultant, Pfizer, Inc., Consultant, Merck Janssen. XB: Advisory Group Member, Novartis Pharmaceuticals. NB: Employee, Novartis Pharmaceuticals. NS: Employee, Novartis Pharmaceuticals. BMKB: Principal Investigator, Novartis Pharmaceuticals, Principal Investigator, Cortendo, Ad Hoc Consultant, Cortendo, Ad Hoc Consultant, Ipsen, Ad Hoc Consultant, Novartis Pharmaceuticals. JY: Investigator, Novartis Pharmaceuticals, Investigator, Jansen Pharmaceuticals, Investigator, HRA Pharma.