Feasibility, safety and tolerability of the CREB-binding protein/β-catenin inhibitor OP-724 in patients with advanced primary biliary cholangitis: an investigator-initiated, open-label, non-randomised, two-centre, phase 1 study
Objective This study aimed to evaluate the safety and tolerability of OP-724, a CREB-binding protein/β-catenin inhibitor, in patients with advanced primary biliary cholangitis (PBC).Design An open-label, non-randomised, phase 1 trial was conducted at two hospitals in Japan. Patients with advanced PB...
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BMJ Publishing Group
2022-10-01
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| Series: | BMJ Open Gastroenterology |
| Online Access: | https://bmjopengastro.bmj.com/content/9/1/e001001.full |
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| author | Eiichi Ogawa Atsushi Tanaka Kenichi Harada Hiroshi Yatsuhashi Kazumoto Murata Masamichi Kimura Jun Imamura Masanao Saio Yoshihiro Ikura Kouichi Miura Ichiro Ieiri Kiminori Kimura |
| author_facet | Eiichi Ogawa Atsushi Tanaka Kenichi Harada Hiroshi Yatsuhashi Kazumoto Murata Masamichi Kimura Jun Imamura Masanao Saio Yoshihiro Ikura Kouichi Miura Ichiro Ieiri Kiminori Kimura |
| author_sort | Eiichi Ogawa |
| collection | DOAJ |
| description | Objective This study aimed to evaluate the safety and tolerability of OP-724, a CREB-binding protein/β-catenin inhibitor, in patients with advanced primary biliary cholangitis (PBC).Design An open-label, non-randomised, phase 1 trial was conducted at two hospitals in Japan. Patients with advanced PBC classified as stage III or higher according to the Scheuer classification by liver biopsy between 4 September 2019 and 21 September 2021 were enrolled. Seven patients received intravenous OP-724 infusions at escalating dosages of 280 and 380 mg/m2/4 hours two times weekly for 12 weeks. The primary endpoint was the incidence of serious adverse events (SAEs). The secondary endpoints were the incidence of AEs and the improvement in the modified Histological Activity Index (mHAI) score.Results Seven patients (median age, 68 years) were enrolled. Of these seven patients, five completed twelve cycles of treatment, one discontinued prematurely for personal reasons in the 280 mg/m2/4 hours cohort, and one in the 380 mg/m2/4 hours cohort was withdrawn from the study due to drug-induced liver injury (grade 2). Consequently, the recommended dosage was determined to be 280 mg/m2/4 hours. SAEs did not occur. The most common AEs were abdominal discomfort (29%) and abnormal hepatic function (43%). OP-724 treatment was associated with histological improvements in the fibrosis stage (2/5 (40%)) and mHAI score (3/5 (60%)) on histological analysis.Conclusion Administration of intravenous OP-724 infusion at a dosage of 280 mg/m2/4 hours two times weekly for 12 weeks was well tolerated by patients with advanced PBC. However, further evaluation of antifibrotic effects in patients with PBC is warranted.Trial registration number NCT04047160. |
| format | Article |
| id | doaj-art-cabfe85f53b94df4a8a96a71c3bfa66f |
| institution | Kabale University |
| issn | 2054-4774 |
| language | English |
| publishDate | 2022-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | BMJ Open Gastroenterology |
| spelling | doaj-art-cabfe85f53b94df4a8a96a71c3bfa66f2025-08-20T03:45:14ZengBMJ Publishing GroupBMJ Open Gastroenterology2054-47742022-10-019110.1136/bmjgast-2022-001001Feasibility, safety and tolerability of the CREB-binding protein/β-catenin inhibitor OP-724 in patients with advanced primary biliary cholangitis: an investigator-initiated, open-label, non-randomised, two-centre, phase 1 studyEiichi Ogawa0Atsushi Tanaka1Kenichi Harada2Hiroshi Yatsuhashi3Kazumoto Murata4Masamichi Kimura5Jun Imamura6Masanao Saio7Yoshihiro Ikura8Kouichi Miura9Ichiro Ieiri10Kiminori Kimura11Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan6 Saint Mother Hospital Infertility Clinic, Kitakyushu, Fukuoka, JapanDepartment of Urology, University of Occupational and Environmental Health, Kitakyushu, JapanClinical Research Center, National Hospital Organisation Nagasaki Medical Center, Omura, Nagasaki, JapanDivision of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine Graduate School of Medicine, Shimotsuke, Tochigi, JapanDepartment of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo, JapanDepartment of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo, JapanDepartment of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, JapanDepartment of Pathology, Takatsuki General Hospital, Takatsuki, Osaka, JapanDivision of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, JapanDepartment of Clinical Pharmacokinetics, Division of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, JapanDepartment of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo, JapanObjective This study aimed to evaluate the safety and tolerability of OP-724, a CREB-binding protein/β-catenin inhibitor, in patients with advanced primary biliary cholangitis (PBC).Design An open-label, non-randomised, phase 1 trial was conducted at two hospitals in Japan. Patients with advanced PBC classified as stage III or higher according to the Scheuer classification by liver biopsy between 4 September 2019 and 21 September 2021 were enrolled. Seven patients received intravenous OP-724 infusions at escalating dosages of 280 and 380 mg/m2/4 hours two times weekly for 12 weeks. The primary endpoint was the incidence of serious adverse events (SAEs). The secondary endpoints were the incidence of AEs and the improvement in the modified Histological Activity Index (mHAI) score.Results Seven patients (median age, 68 years) were enrolled. Of these seven patients, five completed twelve cycles of treatment, one discontinued prematurely for personal reasons in the 280 mg/m2/4 hours cohort, and one in the 380 mg/m2/4 hours cohort was withdrawn from the study due to drug-induced liver injury (grade 2). Consequently, the recommended dosage was determined to be 280 mg/m2/4 hours. SAEs did not occur. The most common AEs were abdominal discomfort (29%) and abnormal hepatic function (43%). OP-724 treatment was associated with histological improvements in the fibrosis stage (2/5 (40%)) and mHAI score (3/5 (60%)) on histological analysis.Conclusion Administration of intravenous OP-724 infusion at a dosage of 280 mg/m2/4 hours two times weekly for 12 weeks was well tolerated by patients with advanced PBC. However, further evaluation of antifibrotic effects in patients with PBC is warranted.Trial registration number NCT04047160.https://bmjopengastro.bmj.com/content/9/1/e001001.full |
| spellingShingle | Eiichi Ogawa Atsushi Tanaka Kenichi Harada Hiroshi Yatsuhashi Kazumoto Murata Masamichi Kimura Jun Imamura Masanao Saio Yoshihiro Ikura Kouichi Miura Ichiro Ieiri Kiminori Kimura Feasibility, safety and tolerability of the CREB-binding protein/β-catenin inhibitor OP-724 in patients with advanced primary biliary cholangitis: an investigator-initiated, open-label, non-randomised, two-centre, phase 1 study BMJ Open Gastroenterology |
| title | Feasibility, safety and tolerability of the CREB-binding protein/β-catenin inhibitor OP-724 in patients with advanced primary biliary cholangitis: an investigator-initiated, open-label, non-randomised, two-centre, phase 1 study |
| title_full | Feasibility, safety and tolerability of the CREB-binding protein/β-catenin inhibitor OP-724 in patients with advanced primary biliary cholangitis: an investigator-initiated, open-label, non-randomised, two-centre, phase 1 study |
| title_fullStr | Feasibility, safety and tolerability of the CREB-binding protein/β-catenin inhibitor OP-724 in patients with advanced primary biliary cholangitis: an investigator-initiated, open-label, non-randomised, two-centre, phase 1 study |
| title_full_unstemmed | Feasibility, safety and tolerability of the CREB-binding protein/β-catenin inhibitor OP-724 in patients with advanced primary biliary cholangitis: an investigator-initiated, open-label, non-randomised, two-centre, phase 1 study |
| title_short | Feasibility, safety and tolerability of the CREB-binding protein/β-catenin inhibitor OP-724 in patients with advanced primary biliary cholangitis: an investigator-initiated, open-label, non-randomised, two-centre, phase 1 study |
| title_sort | feasibility safety and tolerability of the creb binding protein β catenin inhibitor op 724 in patients with advanced primary biliary cholangitis an investigator initiated open label non randomised two centre phase 1 study |
| url | https://bmjopengastro.bmj.com/content/9/1/e001001.full |
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