PMID- 36958671 OWN - NLM STAT- MEDLINE DCOM- 20230504 LR - 20240226 IS - 1532-8600 (Electronic) IS - 0026-0495 (Linking) VI - 143 DP - 2023 Jun TI - Efficacy and safety of the ghrelin-O-acyltransferase inhibitor BI 1356225 in overweight/obesity: Data from two Phase I, randomised, placebo-controlled studies. PG - 155550 LID - S0026-0495(23)00153-1 [pii] LID - 10.1016/j.metabol.2023.155550 [doi] AB - 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/m(2) (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/m(2). 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 [C(max)]) 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, AUC(0-infinity) was slightly increased and C(max) 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. CI - Copyright (c) 2023 Boehringer Ingelheim International GmbH. Published by Elsevier Inc. All rights reserved. FAU - Bianzano, Susanna AU - Bianzano S AD - Boehringer Ingelheim International GmbH, 55216 Ingelheim am Rhein, Germany. Electronic address: susanna.bianzano@boehringer-ingelheim.com. FAU - Henrich, Andrea AU - Henrich A AD - Pharmetheus AB, 75237 Uppsala, Sweden; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA. FAU - Herich, Lena AU - Herich L AD - Staburo GmbH, 81549 Munchen, Germany. FAU - Kalsch, Brigitte AU - Kalsch B AD - CRS Clinical Research Services Mannheim GmbH, 68167 Mannheim, Germany. FAU - Sarubbi, Donald AU - Sarubbi D AD - Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA. FAU - Seitz, Friedeborg AU - Seitz F AD - CRS Clinical Research Services Mannheim GmbH, 68167 Mannheim, Germany. FAU - Forst, Thomas AU - Forst T AD - CRS Clinical Research Services Mannheim GmbH, 68167 Mannheim, Germany. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20230322 PL - United States TA - Metabolism JT - Metabolism: clinical and experimental JID - 0375267 RN - EC 2.3.- (Acyltransferases) RN - 0 (Ghrelin) RN - EC 2.3.- (MBOAT4 protein, human) SB - IM MH - Female MH - Male MH - *Acyltransferases/antagonists & inhibitors MH - Area Under Curve MH - Body Weight MH - Double-Blind Method MH - Ghrelin MH - Headache/chemically induced MH - *Obesity/drug therapy MH - *Overweight/drug therapy MH - Humans OTO - NOTNLM OT - Appetite OT - Ghrelin OT - Ghrelin-O-acyltransferase OT - Pharmacodynamics OT - Pharmacokinetics OT - Tolerability COIS- Declaration of competing interest SB and DS are employees of Boehringer Ingelheim. BK, FS and TF are employees of CRS Clinical Research Services. AH is external employee of Boehringer Ingelheim. LH was contracted by Boehringer Ingelheim as an external statistician. TF has provided advisory services to AstraZeneca, Atrogi, Bayer, Cipla, Eli Lilly, Eyesense, Fortbildungskolleg, Novo Nordisk, Pfizer, Sanofi, Remynd and Roche. TF has provided speaker activities to Amarin, AstraZeneca, Boehringer Ingelheim, Berlin Chemie, Cipla, Daiichi-Sankyo, Eli Lilly, Fortbildungskolleg, MSD, Novartis, Novo Nordisk, Sanofi and Santis. EDAT- 2023/03/24 06:00 MHDA- 2023/05/02 06:42 CRDT- 2023/03/23 20:32 PHST- 2022/09/27 00:00 [received] PHST- 2023/03/10 00:00 [revised] PHST- 2023/03/15 00:00 [accepted] PHST- 2023/05/02 06:42 [medline] PHST- 2023/03/24 06:00 [pubmed] PHST- 2023/03/23 20:32 [entrez] AID - S0026-0495(23)00153-1 [pii] AID - 10.1016/j.metabol.2023.155550 [doi] PST - ppublish SO - Metabolism. 2023 Jun;143:155550. doi: 10.1016/j.metabol.2023.155550. Epub 2023 Mar 22.