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

Abstract

ObjectiveThis 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).DesignAn 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.ResultsSeven 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prematurely for personal reasons in the 280 mg/m2/4 hours cohort, and one in the 380 mg/m2/4 hours cohort was withdrawn from the study due to drug-induced liver injury (grade 2).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.ConclusionAdministration 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 numberNCT04047160.

Safety and tolerability of OP-724 in patients with haemophilia and liver cirrhosis due to HIV/HCV coinfection: an investigator-initiated, open-label, non-randomised, single-centre, phase I study

“…Overall, the only AE reported was diarrhoea (1/5 patients, 20.0%). Diarrhoea is a side effect that also appeared as a gastrointestinal symptom in the previously conducted PRI-724-2101 study—a study conducted in patients with liver cirrhosis caused by HCV or HBV 12. This AE was manageable by monitoring the progress and administering appropriate symptomatic treatment.…”

“…To measure the plasma concentration of the investigational drug and determine changes in the PK parameters, the PK parameters obtained in this clinical trial were compared with those of a previous study, PRI-724-2101, and population PK parameters 12. The relationship between safety and PK was also assessed.…”

“…To measure the plasma concentration of the investigational drug and determine changes in the PK parameters, the PK parameters obtained in this clinical trial were compared with those of a previous study, PRI-724-2101, and population PK parameters. 12 The relationship between safety and PK was also assessed. The PK of OP-724 and C-82 in patients with cirrhosis due to HIV/HCV coinfection did not differ significantly from that of patients with cirrhosis due to HCV or HBV.…”

“…We previously reported that OP-724 is safe and well tolerated for the treatment of cirrhosis caused by hepatitis B virus (HBV) or HCV or primary biliary cirrhosis, and that it improves the liver stiffness measure (LSM) and increases albumin levels 11 12. Hence, OP-724 has potential as an antifibrotic treatment for cirrhosis.…”

Mechanism-based target therapy in primary biliary cholangitis: opportunities before liver cirrhosis?

“…An open-label phase 1 trial showed in patients with advanced PBC, intravenous OP-724 infusion was well tolerated. Although it did not significantly improve liver function, its anti-fibrotic effects were indicated by decreased in collagen in livers of PBC patients with advanced fibrosis ( 112 ).…”