Endocrine Abstracts

JOINT2654

Introduction: Tissue-specific 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) reactivates glucocorticoids increasing binding to intracellular receptors. HSD-1 deficiency suppresses Cushing syndrome (CS) phenotype despite hypercortisolism.^1-3 Treatment with clofutriben (C), a potent and specific inhibitor of HSD-1, might improve CS comorbidities by decreasing intracellular cortisol.

Methods: Seventeen adults with ACTH-dependent CS (16 pituitary, 1 ectopic), and type 2 diabetes (T2D), impaired glucose tolerance (IGT), hypertension (HTN), hyperlipidemia, or osteopenia were randomized to a total of 12 weeks of oral C 6mg/d and 12 weeks of matching placebo (P) in 2 blinded sequences (PCCP, CCPP; “P” or “C” representing 6-week periods). Patients were offered open-label C treatment on completion. Primary endpoint was urinary ratio of cortisol and cortisone metabolites at Week 6 (hepatocellular HSD-1 activity biomarker). Key exploratory endpoints (and applicable population) at Week 6 were HbA1c (T2D), systolic blood pressure (>120 mmHg), LDL cholesterol (>100 mg/dl), osteocalcin (<7.5 mg/l), and normalization of elevated (>1.5&times;ULN) urinary free cortisol.

Results: Mean baseline HSD-1 ratio was 1.95±0.171. At Week 6, mean ratio was 0.21±0.091 with C and 2.01±0.263 with P. HbA1c decreased by 0.6% for C and 0.2% for P. Systolic blood pressure in C and P decreased by 8 and 3 mmHg. LDL in C decreased by 25 mg/dl but increased in P by 29 mg/dl. Osteocalcin increased by 6 mg/l for C and by 0.1 mg/l for P. Urinary free cortisol normalized with C in 3 of 8 patients, but in none of 6 patients with P. Concomitant medications for T2D were reduced in 4 C-treated, but increased in 2 P-treated patients. For HTN there were also 4 reductions for C-treated and 1 increase for P-treated patients. One patient succumbed to ectopic Cushing’s due to cervical carcinoma after trial discontinuation. Four patients discontinued for non-adverse event (AE) reasons. One serious AE of vomiting (possible glucocorticoid withdrawal syndrome per investigator) led to temporary drug interruption. Common AEs (≥ 3 patients) included Arthralgia, Fatigue, Headache, and Nausea, but only Headache was more common in C during the P-controlled period. There was no evidence of adrenal insufficiency, clinically or biochemically (low cortisol). All 13 patients completers elected to enter the open-label extension (current treatment duration 3-15 months).

Conclusions: Clofutriben decreased hepatic HSD-1 activity adequately to confer clinical benefit while maintaining safety and overall tolerability. These limited data support clofutriben’s potential for clinical improvement without adrenal insufficiency.References1. Tomlinson JW 2002.2. Arai H 2008.3. Weber RJ 2024.