Hepatotoxicity of AKR1C3 Inhibitor BAY1128688: Findings from an Early Terminated Phase IIa Trial for the Treatment of Endometriosis

Jan Hilpert, Esther Groettrup‐Wolfers, Hristiyan Kosturski, Laura Bennett, Catriona L K Barnes, Kerstin Gude, Isabella Gashaw, Stefanie Reif, Thomas Steger‐Hartmann, Thomas Steger-Hartmann, Christian Scheerans, Alexander Solms, Antje Rottmann, Mao Guang-ping, Guangping Mao, Charles Chapron
Drugs in R&D · 2023 · vol. 23(3) , pp. 221–237 · doi:10.1007/s40268-023-00427-5 · PMID:37422772 · PMC10439066 · W4383682249
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

A phase IIa trial for endometriosis was terminated early due to dose-dependent hepatotoxicity from BAY1128688, which was not predicted by prior animal or healthy volunteer studies.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 ⓘ

This paper reports results from the placebo-controlled, multicenter phase IIa AKRENDO1 trial that randomized adult premenopausal women with endometriosis-related pain into five BAY1128688 dose groups or placebo for 12 weeks, assessing efficacy alongside safety and tolerability. The main finding was dose-/exposure-dependent hepatotoxicity, with serum alanine transferase (ALT) elevations clustering around week 12, which led to premature trial termination; pharmacokinetics and pharmacodynamics in participants were comparable to those previously seen in healthy volunteers and were not predictive of the later ALT increases. The authors note that the reduced number of valid completers prevents conclusions about treatment efficacy. This paper is centrally about endometriosis— it reports hepatotoxicity findings from an early terminated phase IIa trial of the AKR1C3 inhibitor BAY1128688 for endometriosis-related pain.

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Abstract

INTRODUCTION: BAY1128688 is a selective inhibitor of aldo-keto reductase family 1 member C3 (AKR1C3), an enzyme implicated in the pathology of endometriosis and other disorders. In vivo animal studies suggested a potential therapeutic application of BAY1128688 in treating endometriosis. Early clinical studies in healthy volunteers supported the start of phase IIa. OBJECTIVE: This manuscript reports the results of a clinical trial (AKRENDO1) assessing the effects of BAY1128688 in adult premenopausal women with endometriosis-related pain symptoms over a 12-week treatment period. METHODS: Participants in this placebo-controlled, multicenter phase IIa clinical trial (NCT03373422) were randomized into one of five BAY1128688 treatment groups: 3 mg once daily (OD), 10 mg OD, 30 mg OD, 30 mg twice daily (BID), 60 mg BID; or a placebo group. The efficacy, safety, and tolerability of BAY1128688 were investigated. RESULTS: Dose-/exposure-dependent hepatotoxicity was observed following BAY1128688 treatment, characterized by elevations in serum alanine transferase (ALT) occurring at around 12 weeks of treatment and prompting premature trial termination. The reduced number of valid trial completers precludes conclusions regarding treatment efficacy. The pharmacokinetics and pharmacodynamics of BAY1128688 among participants with endometriosis were comparable with those previously found in healthy volunteers and were not predictive of the subsequent ALT elevations observed. CONCLUSIONS: The hepatotoxicity of BAY1128688 observed in AKRENDO1 was not predicted by animal studies nor by studies in healthy volunteers. However, in vitro interactions of BAY1128688 with bile salt transporters indicated a potential risk factor for hepatotoxicity at higher doses. This highlights the importance of in vitro mechanistic and transporter interaction studies in the assessment of hepatoxicity risk and suggests further mechanistic understanding is required. CLINICAL TRIAL REGISTRATION: NCT03373422 (date registered: November 23, 2017).

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endometriosis

MeSH descriptors

Alanine Alanine Alanine Alanine Alanine Alanine Alanine Alanine Alanine Alanine Alanine Alanine Alanine Alanine Chemical and Drug Induced Liver Injury Chemical and Drug Induced Liver Injury Chemical and Drug Induced Liver Injury Chemical and Drug Induced Liver Injury Chemical and Drug Induced Liver Injury Chemical and Drug Induced Liver Injury

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