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LEVOKETOCONAZOLE IN THE TREATMENT OF ENDOGENOUS CUSHING'S SYNDROME: IMPROVEMENTS IN CLINICAL SIGNS AND SYMPTOMS, PATIENT-REPORTED OUTCOMES, AND ASSOCIATED BIOCHEMICAL MARKERS IN THE PHASE 3 SONICS STUDY


Authors:

Maria Fleseriu, MD – Professor of Medicine and Neurological Surgery, Oregon Health and Science University

Rosario Pivonello, MD, PhD – Professor, Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli

Atanaska Elenkova, MD, PhD – Assoc. Professor Clinical Centre of Endocrinology and Gerontology, Medical University Sofia

Roberto Salvatori, MD – Professor of Medicine, Johns Hopkins University

Richard Auchus, PhD – Professor of Internal Medicine; Professor of Pharmacology, University of Michigan Medical School

Richard Feelders, MD, PhD – Associate Professor of Endocrinology, Erasmus Medical Center

Eliza Geer, MD – Medical Director, Pituitary & Skull Base Tumor Center, Memorial Sloan Kettering Cancer Center

Yona Greenman, MD – Senior Deputy Director, Institute of Endocrinology and Metabolism, Tel Aviv University

Przemyslaw Witek, MD, PhD – Associate Professor of Endocrinology and Diabetes, Military Institute of Medicine

Beverly Biller, MD – Professor of Medicine, Harvard Medical School, Massachusetts General Hospital

Fredric Cohen

Abstract:

Objective : Secondary endpoints in SONICS include investigator-assessed clinical signs and symptoms and patient-reported outcomes for the treatment of endogenous Cushing’s syndrome (CS).

Methods : In a phase 3, multicenter, open-label, dose-titration study, adults with confirmed CS and mean 24-hour urinary free cortisol (mUFC) ≥1.5 × upper limit of normal (ULN) were treated with levoketoconazole in 3 phases: 2- to 21-week dose-titration phase (150 to 600 mg BID, as needed, to target mUFC normalization), 6-month maintenance (M) phase (primary endpoint), and 6-month extended evaluation phase. The end of M phase (EoM) findings focused on reductions in mUFC and safety have been presented (Fleseriu M, et al. Presented at ENEA; 2018). Secondary endpoints include changes from baseline (BL) to EoM in investigator-assessed CS clinical signs and symptoms (acne score [range: 0-44]; hirsutism score [women only; range: 0-36]; and peripheral edema score [range: 0-12]), and patient-reported outcomes of quality-of-life (QoL; Cushing QoL questionnaire score [range: 0-100]) and depression (Beck Depression Inventory II score [range: 0-63]). Hormones including free testosterone levels were also assessed. Statistical significance of the mean changes from BL to EOM for all measures was inferred from paired t-tests.

Results : 94 patients were enrolled and treated with ≥1 dose of levoketoconazole; 77 entered M phase (secondary endpoint population). The majority of enrolled patients were female (82%) and white (96%), mean (SD) age 44 (13) years, and mean BL mUFC 243.3 μg/day (4.9 × ULN). Significant mean improvements from BL to EoM were observed in acne (mean BL score: 2.8; ∆ -1.8; P=0.0063 vs BL), hirsutism (women only; mean BL score: 7.8; ∆ -2.6; P=0.0008 vs BL), and peripheral edema (mean BL score: 1.0; ∆ -0.4; P=0.0295 vs BL) scores. Significant mean improvements were observed from BL to EoM in QoL (mean BL score: 44.3; ∆ +10.6 [+∆ = improvement]; P<0.0001 vs BL) and depression (mean BL score: 17.1; ∆ -4.3; P=0.0043 vs BL). Mean free testosterone levels increased non-significantly from BL to EoM in men (5.1 to 5.8 ng/dL; reference: 4.6-22.4 ng/dL) and decreased significantly in women (0.3 to 0.1 ng/dL; P<0.0001; reference: 0.02-0.5 ng/dL). Overall, 33 patients (35%) discontinued by EoM; 12 (13%) due to adverse events.

Discussion :   

Conclusion : Clinical signs and symptoms of CS including acne, hirsutism, and peripheral edema, and patient-reported outcomes of QoL and symptoms of depression improved following 6 months of levoketoconazole therapy. Improvements in biochemical markers of efficacy including reduction in urinary cortisol and free testosterone (in women) were also observed.

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