Levoketoconazole treatment in endogenous Cushing's syndrome: extended evaluation of clinical, biochemical, and radiologic outcomes

Author:

Fleseriu Maria1ORCID,Auchus Richard J2,Greenman Yona3ORCID,Zacharieva Sabina4,Geer Eliza B5,Salvatori Roberto6,Pivonello Rosario7ORCID,Feldt-Rasmussen Ulla8ORCID,Kennedy Laurence9,Buchfelder Michael10,Biller Beverly M K11,Cohen Fredric12,Heaney Anthony P13ORCID

Affiliation:

1. Oregon Health and Science University , Portland, OR, USA

2. University of Michigan Medical School , Ann Arbor, MI, USA

3. Tel Aviv University , Tel Aviv, Israel

4. Medical University-Sofia , Sofia, Bulgaria

5. Memorial Sloan Kettering Cancer Center , New York, NY, USA

6. Johns Hopkins University , Baltimore, MD, USA

7. Università Federico II di Napoli , Naples, Italy

8. Rigshospitalet, Copenhagen University Hospital , Copenhagen, Denmark

9. Cleveland Clinic , Cleveland, OH, USA

10. University Hospital Erlangen , Erlangen, Germany

11. Massachusetts General Hospital , Boston, MA, USA

12. Xeris Biopharma Holdings, Inc. , Chicago, IL, USA

13. University of California Los Angeles School of Medicine , Los Angeles, CA, USA

Abstract

Abstract Objective This extended evaluation (EE) of the SONICS study assessed the effects of levoketoconazole for an additional 6 months following open-label, 6-month maintenance treatment in endogenous Cushing's syndrome. Design/Methods SONICS included dose-titration (150–600 mg BID), 6-month maintenance, and 6-month EE phases. Exploratory efficacy assessments were performed at months 9 and 12 (relative to the start of maintenance). For pituitary MRI in patients with Cushing's disease, a threshold of ≥2 mm denoted change from baseline in the largest tumor diameter. Results Sixty patients entered EE at month 6; 61% (33/54 with data) exhibited normal mean urinary free cortisol (mUFC). At months 9 and 12, respectively, 55% (27/49) and 41% (18/44) of patients with data had normal mUFC. Mean fasting glucose, total and LDL-cholesterol, body weight, BMI, abdominal girth, hirsutism, CushingQoL, and Beck Depression Inventory-II scores improved from the study baseline at months 9 and 12. Forty-six patients completed month 12; four (6.7%) discontinued during EE due to adverse events. The most common adverse events in EE were arthralgia, headache, hypokalemia, and QT prolongation (6.7% each). No patient experienced alanine aminotransferase or aspartate aminotransferase >3× upper limit of normal, Fridericia-corrected QT interval >460 ms, or adrenal insufficiency during EE. Of 31 patients with tumor measurements at baseline and month 12 or follow-up, the largest tumor diameter was stable in 27 (87%) patients, decreased in one, and increased in three (largest increase 4 mm). Conclusion In the first long-term levoketoconazole study, continued treatment through a 12-month maintenance period sustained the early clinical and biochemical benefits in most patients completing EE, without new adverse effects.

Publisher

Oxford University Press (OUP)

Subject

Endocrinology,General Medicine,Endocrinology, Diabetes and Metabolism

Reference37 articles.

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