Osilodrostat, a potent oral 11β-hydroxylase inhibitor: 22-week, prospective, Phase II study in Cushing’s disease

Pituitary Osilodrostat, a potent oral 11b-hydroxylase inhibitor: 22-week, prospective, Phase II study in Cushing's disease Maria Fleseriu 0 1 2 3 4 5 6 7 8 9 10 11 Rosario Pivonello 0 1 2 3 4 5 6 7 8 9 10 11 Jacques Young 0 1 2 3 4 5 6 7 8 9 10 11 Amir H. Hamrahian 0 1 2 3 4 5 6 7 8 9 10 11 Mark E. Molitch 0 1 2 3 4 5 6 7 8 9 10 11 Chikara Shimizu 0 1 2 3 4 5 6 7 8 9 10 11 Tomoaki Tanaka 0 1 2 3 4 5 6 7 8 9 10 11 Akira Shimatsu 0 1 2 3 4 5 6 7 8 9 10 11 Tracy White 0 1 2 3 4 5 6 7 8 9 10 11 Annie Hilliard 0 1 2 3 4 5 6 7 8 9 10 11 Chuan Tian 0 1 2 3 4 5 6 7 8 9 10 11 Nicholas Sauter 0 1 2 3 4 5 6 7 8 9 10 11 Beverly MK Biller 0 1 2 3 4 5 6 7 8 9 10 11 Xavier Bertagna 0 1 2 3 4 5 6 7 8 9 10 11 0 Department of Endocrinology, Centre de Re ́fe ́rence des Maladies Rares de la Surre ́nale, Hoˆpital Cochin, Faculte ́ de Me ́decine Paris Descartes, Universite ́ Paris 5 , Paris , France 1 Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita` Federico II di Napoli , Naples , Italy 2 Neuroendocrine Clinical Center, Massachusetts General Hospital , Boston, MA , USA 3 Northwest Pituitary Center, Departments of Medicine and Neurological Surgery, Oregon Health and Science University , Portland, OR , USA 4 Maria Fleseriu 5 Novartis Pharmaceuticals Corporation , East Hanover, NJ , USA 6 Clinical Research Institute, National Hospital Organization Kyoto Medical Center , Kyoto , Japan 7 Division of Endocrinology and Metabolism, Chiba University Hospital , Chiba-city , Japan 8 Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital , Sapporo , Japan 9 Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University , Chicago, IL , USA 10 Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic Foundation , Cleveland, OH , USA 11 Department of Endocrinology, Hoˆpital Biceˆtre, Universite ́ Paris-Sud, Assistance Publique Hoˆpitaux de Paris , Paris , France Purpose In a 10-week proof-of-concept study (LINC 1), the potent oral 11b-hydroxylase inhibitor osilodrostat (LCI699) normalized urinary free cortisol (UFC) in 11/12 patients with Cushing's disease. The current 22-week study (LINC 2; NCT01331239) further evaluated osilodrostat in patients with Cushing's disease. Methods Phase II, open-label, prospective study of two patient cohorts. Follow-up cohort: 4/12 patients previously enrolled in LINC 1, offered re-enrollment if baseline mean UFC was above ULN. Expansion cohort: 15 newly enrolled patients with baseline UFC [ 1.5 9 ULN. In the follow-up cohort, patients initiated osilodrostat twice daily at the penultimate efficacious/tolerable dose in LINC 1; dose was adjusted as needed. In the expansion cohort, osilodrostat was initiated at 4 mg/day (10 mg/day if baseline UFC [ 3 9 ULN), with dose escalated every 2 weeks to 10, 20, 40, and 60 mg/day until UFC B ULN. Main efficacy endpoint was the proportion of responders (UFC B ULN or C50 % decrease from baseline) at weeks 10 and 22. Results Overall response rate was 89.5 % (n/N = 17/19) at 10 weeks and 78.9 % (n/N = 15/19) at 22 weeks; at week 22, all responding patients had UFC B ULN. The most common AEs observed during osilodrostat treatment were nausea, diarrhea, asthenia, and adrenal insufficiency (n = 6 for each). New or worsening hirsutism (n = 2) and/ or acne (n = 3) were reported among four female patients, all of whom had increased testosterone levels. Conclusions Osilodrostat treatment reduced UFC in all patients; 78.9 % (n/N = 15/19) had normal UFC at week 22. Treatment with osilodrostat was generally well tolerated. - Maria Fleseriu and Rosario Pivonello are co-first authors. 7 8 9 10 11 Introduction Osilodrostat 11b-hydroxylase Cushing’s disease is caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor and is the most common cause of excess endogenous cortisol secretion [ 1– 3 ]. Hypercortisolism can lead to substantial morbidity and premature death compared with the general population [ 4 ]. The primary treatment goals for Cushing’s disease are to normalize cortisol levels and reverse the signs and symptoms of hypercortisolism [ 2, 3 ]. First-line treatment is transsphenoidal surgery [2], although this is not always successful [ 5 ] and patients may relapse many years after apparent surgical success [ 6 ]. A number of medical therapies are currently used in clinical practice for the treatment of Cushing’s disease. These include pasireotide (multireceptor-targeted somatostatin analogue), cabergoline (dopamine receptor agonist), metyrapone and ketoconazole (adrenal steroidogenesis inhibitors), mitotane (adrenolytic agent) and mifepristone (glucocorticoid receptor antagonist) [ 3, 5, 7– 18 ]. Since not all patients with Cushing’s disease achieve sufficient benefit with available therapies, there is a continuing need for new medical therapies. Osilodrostat (LCI699) is an oral inhibitor of 11b-hydroxylase, which catalyzes the final step of cortisol syn (...truncated)