Clinical Trial to Assess the Safety and Efficacy of 11ß-HSD1 Inhibitor in Japanese Patients with the Refractory Cushing Syndrome and Subclinical Cushing Syndrome

Presentation Number: LB SAT 51
Date of Presentation: April 1st, 2017

Hiromi Nagata*1, Satoko Oda1, Makiko Uchiyama2, Kenji Ashida1, Eriko Terada1, Shohei Sakamoto1, Koji Todaka2, Yoichi Nakanishi2 and Masatoshi Nomura1
1Kyushu University Hospital, 2Center for Clinical and Translational Research of Kyushu University Hospital

Abstract

The refractory Cushing syndrome (CS) and subclinical Cushing syndrome (SCS) show poor-prognosis due to hypercortisolemia leading to the complications such as diabetes, hypertension, dyslipidemia and osteoporosis. Although the intervention for these complications has been effective, improvement of the prognosis was incomplete and far from expectation unless causative tumor can be successfully resected. Aiming to improve patient prognosis and develop a novel treatment for these refractory diseases, we have been constructing a patient registry that founded on a multicenter database for CS and SCS from 2001 at Kyushu University hospital and related facilities. CS included pituitary Cushing’s disease, adrenal Cushing syndrome and ectopic ACTH syndrome. The proposed diagnostic criteria for adrenal SCS was described (1). Using this registry, we first conducted a prognostic survey. Among total of 81 patients, CS and SCS accounted for 49% and 51%, respectively. The prevalence of complications; diabetes, hypertension, dyslipidemia was 58%, 86%, 69% in CS, and 55%, 58%, 60% in SCS, respectively. The percentage of patients who underwent surgical intervention in CS and SCS was 78% and 53%, respectively. Despite surgery, 54% of CS patients were not cured. In addition, 47% of SCS patients have not undergone surgery. Consequently, a considerable number of patients still need treatment for hypercortisolemia. Based on these results, we have started the investigator-initiated phase I/IIa clinical trial to assess the safety and efficacy of 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor in patients with the refractory CS and SCS from 2016 (2). 11β-HSD1 interconverts the inactive glucocorticoid cortisone and its active form cortisol. Although bidirectional, it functions predominantly as an oxoreductase in vivo and generates active glucocorticoid, allowing glucocorticoid receptor to be activated. In this clinical trial, target sample size is 16 patients. The subjects are the patients of CS and SCS with impaired glucose tolerance or type 2 diabetes who are treated with α glucosidase inhibitor and/or diet exercise therapy. The patients with HbA1c less than 8.0 % and with no change in the diabetes drug for at least 2 months prior to the study will be enrolled. 11β-HSD1 inhibitor (200mg/day) will be orally administered once a day for 12 weeks. After confirming the safety, oral administration continues for another 12 weeks. In case of the subjects with insufficient effect, administration dose will be increased to 400mg for further 12 weeks. The primary outcome is to assess the response rate in AUCglucose during oral glucose tolerance test at Week 24. The progress in this trial will be introduced. Therapeutic inhibition of 11β-HSD1 is an exciting prospect for the treatment of the diseases such as refractory CS and SCS.

 

Nothing to Disclose: HN, SO, MU, KA, ET, SS, KT, YN, MN