An Open-label Phase I/IIa Clinical Trial of 11β-HSD1 Inhibitor for Cushing's Syndrome and Autonomous Cortisol Secretion

• Published in: The journal of clinical endocrinology and metabolism 2021-09, Vol.106 (10), p.e3865-e3880
• Main Authors: Oda, Satoko, Ashida, Kenji, Uchiyama, Makiko, Sakamoto, Shohei, Hasuzawa, Nao, Nagayama, Ayako, Wang, Lixiang, Nagata, Hiromi, Sakamoto, Ryuichi, Kishimoto, Junji, Todaka, Koji, Ogawa, Yoshihiro, Nakanishi, Yoichi, Nomura, Masatoshi
• Format: Article
• Language: English
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors; Adult; Aged; Aged, 80 and over; Asymptomatic Diseases; Cushing Syndrome - drug therapy; Cushing Syndrome - metabolism; Databases, Factual; Enzyme Inhibitors - therapeutic use; Female; Humans; Hydrocortisone - metabolism; Japan; Male; Middle Aged; Organic Chemicals - therapeutic use; Paraneoplastic Endocrine Syndromes - drug therapy; Paraneoplastic Endocrine Syndromes - metabolism; Registries
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/clinem/dgab450

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors demonstrate antimetabolic and antisarcopenic effects in Cushing's syndrome (CS) and autonomous cortisol secretion (ACS) patients. To confirm the efficacy and safety of S-707106 (11β-HSD1 inhibitor) administered to CS and ACS patients. A 24-week single-center, open-label, single-arm, dose-escalation, investigator-initiated clinical trial on a database. Kyushu University Hospital, Kurume University Hospital, and related facilities. Sixteen patients with inoperable or recurrent CS and ACS, with mildly impaired glucose tolerance. Oral administration of 200 mg S-707106 after dinner, daily, for 24 weeks. In patients with insufficient improvement in oral glucose tolerance test results at 12 weeks, an escalated dose of S-707106 (200 mg twice daily) was administered for the residual 12 weeks. The rate of participants responding to glucose tolerance impairment, defined as those showing a 25% reduction in the area under the curve (AUC) of plasma glucose during the 75-g oral glucose tolerance test at 24 weeks. S-707106 administration could not achieve the primary endpoint of this clinical trial (>20% of responsive participants). AUC glucose decreased by -7.1% [SD, 14.8 (90% CI -14.8 to -1.0), P = 0.033] and -2.7% [14.5 (-10.2 to 3.4), P = 0.18] at 12 and 24 weeks, respectively. S-707106 administration decreased AUC glucose significantly in participants with a high body mass index. Body fat percentage decreased by -2.5% [1.7 (-3.3 to -1.8), P