SAT-625 - Analysis of Cardiometabolic Effects from A Randomized, Placebo-Controlled, Clinical Trial of Clofutriben in Adults with Diabetes

Background
Clofutriben, a potent and selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor that lowers intracellular cortisol, is in clinical development for the improvement of glycemic control and metabolic health in patients with type 2 diabetes (T2D) and elevated cortisol (EC). A phase 2 trial of clofutriben in adults with painful diabetic peripheral neuropathy was discontinued for futility on the primary pain endpoint (NCT02372578). We report post-hoc analyses of cardiometabolic parameters.

Methods
Participants randomized to receive clofutriben 10 mg or placebo QD for 6 weeks were included in analyses of two populations: intent-to-treat (ITT; N=75, 72 T2D, 3 Type 1 Diabetes) and a subset of patients with clinical features associated with EC, i.e., baseline HbA1c ≥7.5% and treated with ≥2 antidiabetic medications (EC-enriched; N=25, all T2D). Treatment effects of clofutriben on HbA1c, glucose, total cholesterol (TC), triglycerides (TG), systolic blood pressure (SBP), diastolic blood pressure (DBP), and weight were analyzed using ANCOVA with baseline as the covariate. Safety was also evaluated.

Results
Mean baselines in the ITT population were HbA1c 7.36%, glucose 7.26 mM, TC 4.44 mM, TG 1.81 mM, weight 96.0 kg, SBP 133.8 mmHg, and DBP 77.6 mmHg. Placebo-adjusted changes from baseline to Week 6 (least-squares mean ± standard error) in the ITT population were nominally significant for HbA1c (−0.36 ± 0.029%), glucose (−1.64 ± 0.131 mM), and TC (−0.76 ± 0.029 mM), but not for TG (−0.25 ± 0.034 mM) or weight (−0.6 ± 0.10 kg). There were small, non-significant BP increases with clofutriben. Improvements in HbA1c (−0.51 ± 0.095%), glucose (−3.43 ± 0.533 mM), TC (−1.17 ± 0.152 mM), TG (−0.86 ± 0.190), and weight (−1.3 ± 0.28 kg) were numerically larger in the EC-enriched subset. In addition, small improvements in SBP and DBP (−2.4 ± 1.29 and −1.3 ± 0.76 mmHg) were observed. A participant with a history of idiopathic thrombocytopenic purpura developed serious thrombocytopenia after receiving clofutriben. In general, clofutriben was well tolerated.

Conclusion
In this short duration trial, HbA1c, glucose, TC, TG, and weight improvements were observed in participants who received clofutriben. For each parameter, observed clofutriben benefits were numerically larger in the EC-enriched subset. Our results support that clofutriben may provide more substantial cardiometabolic benefits in patients with T2D prospectively selected for EC.

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