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Clinical Trial
. 2023 Mar;25(3):832-843.
doi: 10.1111/dom.14932. Epub 2022 Dec 22.

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

Susanna Bianzano  1 , Matias Nordaby  1 , Leona Plum-Mörschel  2 , Barbara Peil  3 , Tim Heise  2
Affiliations
Clinical Trial

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

Susanna Bianzano et al. Diabetes Obes Metab. 2023 Mar.

Abstract

Aims: To study the oral 11 beta-hydroxysteroid dehydrogenase-1 (11β-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 11β-HSD1 was observed with near-full inhibition of 11β-HSD1 in the liver [decreased (5α-tetrahydrocortisol + 5β-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 11β-HSD1 inhibition, no clinically relevant effects were observed with BI 187004.

Keywords: antidiabetic drug; antiobesity drug; clinical trial; metformin; phase I-II study.

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Conflict of interest statement

SB, MN and BP are employees of Boehringer Ingelheim. LPM has received travel grants and speaker fees from Novo Nordisk A/S, Eli Lilly and Gan & Lee Pharmaceuticals. TH is shareholder of Profil, which received research funds from Adocia, AstraZeneca, Biocon, Boehringer Ingelheim, Crinetics, Eli Lilly, Gan & Lee Pharmaceuticals, Genova, Nestlé, Neuraly, Novo Nordisk, Sanofi and Zealand Pharma, has received speaker honoraria from Eli Lilly, Gan & Lee Pharmaceuticals and Novo Nordisk, and is a member of advisory panels for Novo Nordisk.

Figures

FIGURE 1
FIGURE 1
Experimental design showing the allocation of patients to each treatment arm and dosing group and patient disposition. met, metformin; OAD, oral antidiabetic drug
FIGURE 2
FIGURE 2
Changes from baseline in glucose metabolism parameters. Mean change from baseline in FPG measured throughout treatment (up to day 28) and for 11 days post‐treatment in A, Arm 1 and B, Arm 2 with BI 187004 treatment or placebo. C, Mean change from baseline in WMG at day 28 with BI 187004 treatment or placebo. D, Changes in mean plasma glucose following a meal (meal tolerance test) at baseline and at day 28 with BI 187004 treatment or placebo. Data are presented as mean ± standard deviation. FPG, fasting plasma glucose; met, metformin; WMG, weighted mean daily glucose
See this image and copyright information in PMC

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