An open-label phase Ⅰ/Ⅱ a clinical trial of 11β-HSD1 inhibitor for Cushing's syndrome and autonomous cortisol secretion

Satoko Oda, Kenji Ashida, Makiko Uchiyama, Shohei Sakamoto, Nao Hasuzawa, Ayako Nagayama, Lixiang Wang, Hiromi Nagata, Ryuichi Sakamoto, Junji Kishimoto, Koji Todaka, Yoshihiro Ogawa, Yoichi Nakanishi, Masatoshi Nomura

Research output: Contribution to journalArticlepeer-review


CONTEXT: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors demonstrate anti-metabolic and anti-sarcopenic effects in Cushing's syndrome (CS) and autonomous cortisol secretion (ACS) patients.

OBJECTIVE: To confirm the efficacy and safety of S-707106 (11β-HSD1 inhibitor) administered to CS and ACS patients.

DESIGN: A 24-week single-center, open-label, single-arm, dose-escalation, investigator-initiated clinical trial on a database.

SETTING: Kyushu University Hospital, Kurume University Hospital, and related facilities.

PATIENTS: Sixteen patients with inoperable or recurrent CS and ACS, with mildly impaired glucose tolerance.

INTERVENTION: 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 BID) was administered for the residual 12 weeks.

MAIN OUTCOME MEASURES: 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.

RESULTS: 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- -1.0], P=0.033) and -2.7% (14.5 [-10.2-3.4], 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- -1.8], P<0.001), and body muscle percentage increased by 2.4% (1.6 [1.7-3.1], P<0.001).

CONCLUSIONS: S-707106 is an effective insulin sensitizer and anti-sarcopenic and anti-obesity medication for these patients.

Original languageEnglish
JournalThe Journal of clinical endocrinology and metabolism
Publication statusE-pub ahead of print - Jun 18 2021


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