ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 8.9 | DOI: 10.1530/ey.18.8.9

ESPEYB18 8. Adrenals Clinical Trials – New Treatments (2 abstracts)

8.9. Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase

Pivonello R , Fleseriu M , Newell-Price J , Bertagna X , Findling J , Shimatsu A , Gu F , Auchus R , Leelawattana R , Lee EJ , Kim JH , Lacroix A , Laplanche A , O’Connell P , Tauchmanova L , Pedroncelli AM & Biller BMK; LINC 3 investigators

Lancet Diabetes Endocrinol. 2020; 8(9): 748–761.

The authors report the outcomes from the pivotal phase 3 trial in patients with Cushing’s disease of osilodrostat (a potent oral inhibitor of cytochrome P450 11B1, [mitochondrial 11β-hydroxylase]). Twice-daily osilodrostat rapidly reduced mean 24-h urine free cortisol (UFC) and sustained this reduction alongside improvements in clinical signs of hypercortisolism.

Cushing’s disease is a rare endocrine disorder characterised by increased cortisol secretion and severe complications. Therapies for cortisol reduction are often necessary.

This prospective, multicentre, open-label study, included a double-blind randomised withdrawal phase after a 24-week, open-label, single-arm treatment period. Patients with active Cushing’s disease of pituitary origin were recruited from 66 hospitals in 19 countries. The study protocol included 3 separate periods. In period 1, open-label osilodrostat was initiated in all participants and adjusted every 2 weeks on the basis of mean 24-h UFC concentration and safety until week 12. In period 2, all participants continued on osilodrostat at the therapeutic dose determined by period 1. In period 3, participants with mean 24-h UFC concentration <= ULN at week 24, were randomly assigned (1:1, stratified by osilodrostat dose and history of pituitary irradiation) to continue osilodrostat or switch to placebo for 8 weeks. In a final period, all participants were given open-label osilodrostat until core-study end (week 48). The primary objective was to compare the efficacy of osilodrostat versus placebo at the end of period 3.

The study enrolled 137 patients (median age: 40 years; 77% female), of whom 72 (53%) were eligible for randomisation to continuation or withdrawal (phase 3). Patients who continued osilodrostat were more likely to maintain a complete response at week 34 (P<0.0001). Most common adverse events (in >25% of patients) included nausea, headache, fatigue and adrenal insufficiency. Hypocortisolism occurred in 70 (51%) patients and adverse events related to adrenal hormone precursors occurred in 58 (42%) patients. One patient died, unrelated to study drug, after the core study phase. Regarding clinical benefits, patients on osilodrostat showed significant improvement in weight, BMI, fasting plasma glucose, systolic and diastolic blood pressure, and total cholesterol concentrations, apparent soon after initiation of treatment, and sustained until the end of the study. Therefore, osilodrostat is an effective new treatment option for the management of Cushing’s disease.

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