Jan Hilpert, Esther Groettrup-Wolfers, Hristiyan Kosturski, Laura Bennett, Catriona L K Barnes, Kerstin Gude, Isabella Gashaw, Stefanie Reif, Thomas Steger-Hartmann, Christian Scheerans, Alexander Solms, Antje Rottmann, Guangping Mao, Charles Chapron
{"title":"AKR1C3抑制剂BAY1128688的肝毒性：治疗子宫内膜异位症的早期 IIa 期临床试验结果","authors":"Jan Hilpert, Esther Groettrup-Wolfers, Hristiyan Kosturski, Laura Bennett, Catriona L K Barnes, Kerstin Gude, Isabella Gashaw, Stefanie Reif, Thomas Steger-Hartmann, Christian Scheerans, Alexander Solms, Antje Rottmann, Guangping Mao, Charles Chapron","doi":"10.1007/s40268-023-00427-5","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Clinical trial registration: </strong>NCT03373422 (date registered: November 23, 2017).</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 3","pages":"221-237"},"PeriodicalIF":2.2000,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/58/73/40268_2023_Article_427.PMC10439066.pdf","citationCount":"0","resultStr":"{\"title\":\"Hepatotoxicity of AKR1C3 Inhibitor BAY1128688: Findings from an Early Terminated Phase IIa Trial for the Treatment of Endometriosis.\",\"authors\":\"Jan Hilpert, Esther Groettrup-Wolfers, Hristiyan Kosturski, Laura Bennett, Catriona L K Barnes, Kerstin Gude, Isabella Gashaw, Stefanie Reif, Thomas Steger-Hartmann, Christian Scheerans, Alexander Solms, Antje Rottmann, Guangping Mao, Charles Chapron\",\"doi\":\"10.1007/s40268-023-00427-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>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.</p><p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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. 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Hepatotoxicity of AKR1C3 Inhibitor BAY1128688: Findings from an Early Terminated Phase IIa Trial for the Treatment of Endometriosis.
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).
期刊介绍：
Drugs in R&D is an international, peer reviewed, open access, online only journal, and provides timely information from all phases of drug research and development that will inform clinical practice. Healthcare decision makers are thus provided with knowledge about the developing place of a drug in therapy.
The Journal includes:
Clinical research on new and established drugs;
Preclinical research of direct relevance to clinical drug development;
Short communications and case study reports that meet the above criteria will also be considered;
Reviews may also be considered.
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