Safety, tolerability, pharmacodynamics and pharmacokinetics following once-daily doses of BI 187004, an inhibitor of 11 beta-hydroxysteroid dehydrogenase-1, over 28 days in patients with type 2 diabetes mellitus and overweight or obesity.

AIMS: To study the oral 11 beta-hydroxysteroid dehydrogenase-1 (11ß-HSD1) inhibitor BI 187004 (NCT02150824), as monotherapy and in combination with metformin, versus placebo in patients with type 2 diabetes mellitus (T2DM) affected by overweight or obesity. MATERIALS AND METHODS: This Phase II, randomized controlled trial investigated multiple rising doses of BI 187004 as monotherapy (Arm 1: 20, 80 or 240 mg) and in combination with metformin (Arm 2: 240 mg), in adults with T2DM and a body mass index of 28-40 kg/m2 . RESULTS: In total, 103 patients (Arm 1: n = 62, Arm 2: n = 41) were included in this study. BI 187004 was rapidly absorbed and exposure increased approximately dose-dependently. Target engagement of 11ß-HSD1 was observed with near-full inhibition of 11ß-HSD1 in the liver [decreased (5α-tetrahydrocortisol + 5ß-tetrahydrocortisol)/tetrahydrocortisone ratio]; hypothalamic-pituitary-adrenal axis activation was also seen (increased total urinary corticosteroids). No clinically relevant changes from baseline with BI 187004 treatment were observed for bodyweight or meal tolerance test parameters, or in most efficacy endpoints testing glucose and lipid metabolism; a significant increase was observed in weighted mean plasma glucose (p < .05 for 80 and 240 mg BI 187004) but not fasting plasma glucose. Drug-related adverse events were reported for 14 patients (22.6%) in Arm 1 and 10 patients (24.4%) in Arm 2, most frequently headache, diarrhoea, flushing and dizziness. A dose-dependent increase in heart rate was seen with BI 187004 treatment. CONCLUSIONS: BI 187004 was generally well tolerated in patients with T2DM. Despite complete 11ß-HSD1 inhibition, no clinically relevant effects were observed with BI 187004.

Efficacy and safety of the ghrelin-O-acyltransferase inhibitor BI 1356225 in overweight/obesity: Data from two Phase I, randomised, placebo-controlled studies.

BACKGROUND: Obesity is a complex disease associated with multiple concurrent complications, and the coordinated targeting of multiple pathways in pharmacological treatment may improve weight loss outcomes. During synthesis, ghrelin is converted from the 'inactive' unacylated ghrelin (UAG) to the active acylated ghrelin (AG) by the enzyme ghrelin-O-acyltransferase (GOAT), stimulating appetite and food intake. AIMS: To report the results of two Phase I studies investigating single rising doses (SRDs) or multiple rising doses (MRDs) of the novel oral GOAT inhibitor BI 1356225 versus placebo in male and postmenopausal/sterilised female subjects with overweight or obesity. METHODS: The SRD study investigated single doses of BI 1356225 (0.1-20.0 mg) in healthy male subjects with a BMI of 18.5-29.9 kg/m2 (SRD cohort) and assessed doses of 2.5 mg BI 1356225 under fed and fasted conditions (bioavailability [BA] cohort). The MRD study investigated multiple doses of BI 1356225 (0.2, 1.0, 2.5 or 10.0 mg) or 5.0 mg BI 1356225 with a single dose of midazolam and celecoxib (drug-drug interaction part) over 28 days in adults with a BMI of 27.0-39.9 kg/m2. RESULTS: Sixty-five subjects were treated in the SRD study. Drug-related adverse events (AEs) were reported for five subjects (9.1 %) in the SRD cohort and two subjects (20.0 %) in the BA cohort, with the most frequent being headache (SRD: n = 4, 9.8 %; BA: n = 1, 10.0 %). In the MRD study, two (2.3 %) of the 87 subjects treated discontinued treatment because of AEs. Drug-related AEs were reported for 18 subjects (20.7 %), did not increase with dose and were most frequently reported as headache (n = 5, 5.7 %) and gastrointestinal disorders (n = 5, 5.7 %). In both studies, exposure parameters (area under the concentration-time curve [AUC] and maximum plasma concentration [Cmax]) of BI 1356225 increased across dose groups, although this was less than dose-proportional across the entire dose range. In the BA cohort of the SRD study, AUC0-∞ was slightly increased and Cmax slightly decreased in fed versus fasted conditions, with fed/fasted ratios (90 % CI) of 101.10 % (92.42, 110.60) and 91.67 % (78.50, 107.05), respectively. In both studies, AG concentrations and the AG/UAG ratio were dose-dependently decreased after BI 1356225 treatment from baseline versus placebo. In the MRD study, UAG concentrations were increased from baseline, but not dose-dependently. No differences were observed in bodyweight, appetite, food cravings, ad libitum food uptake or obesity-related biomarkers after 28 days of treatment with BI 1356225. CONCLUSIONS: Treatment with SRDs and MRDs of BI 1356225 was well tolerated by healthy males and subjects with overweight/obesity. BI 1356225 treatment over 28 days reduced AG concentrations and the AG/UAG ratio by >80 %, but no effect was seen on bodyweight, hunger/satiety, control of eating or energy intake. Although, at 4 weeks, the MRD study was fairly short, a reduction in bodyweight would be expected to be evident by this time, suggesting that a reduction of AG via a GOAT inhibitor is not sufficient to induce clinically relevant bodyweight loss.

Selective Inhibition of 11beta-Hydroxysteroiddehydrogenase-1 with BI 187004 in Patients with Type 2 Diabetes and Overweight or Obesity: Safety, Pharmacokinetics, and Pharmacodynamics After Multiple Dosing Over 14 Days.

OBJECTIVE: To assess safety, tolerability, pharmacokinetics, and pharmacodynamics of treatment with the selective 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1) inhibitor BI 187004 in male and female patients with type 2 diabetes and overweight or obesity. METHODS: Randomized, double-blind, parallel-group, placebo-controlled multiple rising dose study, with 10-360 mg BI 187004 once daily over 14 days in 71 patients. Assessments included 11beta-HSD1 inhibition in the liver and subcutaneous adipose tissue ex vivo (clinical trial registry number NCT01874483). RESULTS: BI 187004 was well tolerated and safe in all tested dose groups. The incidence of drug-related adverse events was 51.8% (n=29) for BI 187004 and 35.7% (n=5) for placebo. There were no clinically relevant deviations in laboratory or electrocardiogram parameters besides one patient on 360 mg discontinuing treatment due to moderate supraventricular tachycardia.BI 187004 was rapidly absorbed within 2 h; exposure increased non-proportionally. The oral clearance was low, apparent volume of distribution was moderate to large, and terminal half-life with 106-124 h was rather long. Urinary tetrahydrocortisol/tetrahydrocortisone ratio decreased, indicating liver 11beta-HSD1 inhibition. Median inhibition of 11beta-HSD1 in subcutaneous adipose tissue biopsies was 87.9-99.4% immediately after the second dose and 73.8-97.5% 24 h after the last dose of BI 187004. CONCLUSIONS: BI 187004 was safe and well tolerated over 14 days and could be dosed once daily. Targeted 11beta-HSD1 enzyme inhibition of≥80% could be shown for BI 187004 doses≥40 mg. This dose should be targeted in further studies to test blood glucose lowering in patients with type 2 diabetes and overweight or obesity.

Safety, tolerability, pharmacokinetics and pharmacodynamics of single oral doses of BI 187004, an inhibitor of 11beta-hydroxysteroid dehydrogenase-1, in healthy male volunteers with overweight or obesity.

BACKGROUND: The study characterizes safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single rising doses of the 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1) inhibitor BI 187004 in healthy men with overweight or obesity. METHODS: This was a randomized, double-blind, parallel group, placebo-controlled study with administration of 2.5-360 mg BI 187004 or placebo once daily as single dose in 72 healthy male volunteers with overweight or obesity. Assessments included 11beta-HSD1 inhibition in the liver (assessed indirectly by urinary tetrahydrocortisol/tetrahydrocortisone ratio) and in subcutaneous adipose tissue ex vivo and determination of hypothalamus-pituitary-adrenal axis hormones. RESULTS: BI 187004 was well tolerated and safe in all tested dose groups. The incidence of drug-related adverse events was 16.7% (n = 9) for all 9 BI 187004 dose groups and 5.9% (n = 1) for placebo. All treatment groups were similar concerning kind and intensity of adverse events. No clinically relevant deviations in clinical laboratory or ECG parameters were reported. Exposure of BI 187004 increased non-proportionally over the entire dose range tested. The geometric mean apparent terminal half-life decreased from 33.5 h (5 mg) to 14.5 h (160 mg) remaining stable up to 360 mg. Renal excretion of BI 187004 was low (3-5%). Urinary tetrahydrocortisol/tetrahydrocortisone ratio decreased, indicating liver 11beta-HSD1 inhibition. Median inhibition of 11beta-HSD1 in subcutaneous adipose tissue biopsies following single dosing ranged from 86.8% (10 mg) to 99.5% (360 mg) after 10 h and from 59.4% (10 mg) to 98.6% (360 mg) after 24 h. CONCLUSIONS: BI 187004 as single dose was safe and well tolerated and is suitable for once daily dosing. There was significant, sustained 11beta-HSD1 inhibition in liver and adipose tissue. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01587417 , registered on 26-Apr-2012.