Safety and Dosing Study of a Cholecystokinin Receptor Antagonist in Non‐alcoholic Steatohepatitis

Abstract

High saturated fat diets have been shown to raise blood levels of cholecystokinin (CCK) and induce nonalcoholic steatohepatitis (NASH). CCK receptors are expressed on stellate cells and are responsible for hepatic fibrosis when activated. The purpose of this study was to test the safety and dose of a CCK receptor antagonist, proglumide, in human participants with NASH. An open‐label single ascending dose study was conducted in 18 participants with clinical NASH based upon steatosis by liver ultrasound, elevated hepatic transaminases, and a component of the metabolic syndrome. Three separate cohorts (N = 6 each) were treated with oral proglumide for 12 weeks in a sequential ascending fashion with 800 (Cohort 1), 1,200 (Cohort 2), and 1,600 (Cohort 3) mg/day, respectively. Blood hematology, chemistries, proglumide levels, a biomarker panel for fibrosis, and symptom surveys were determined at baseline and every 4 weeks. Abdominal ultrasounds and transient elastography utilizing FibroScan were obtained at baseline and at Week 12. Proglumide was well tolerated at all doses without any serious adverse events. There was no change in body weight from baseline to Week 12. For Cohorts 1, 2, and 3, the median percent change in alanine aminotransferase was 8.42, −5.05, and −22.23 and median percent change in fibrosis score by FibroScan was 8.13, −5.44, and −28.87 (kPa), respectively. Hepatic steatosis as measured by controlled attenuation parameter score significantly decreased with proglumide, (P < 0.05). Blood microRNA biomarkers and serum 4‐hydroxyproline were consistent with decreased fibrosis at Week 12 compared with baseline. These findings suggest proglumide exhibits anti‐inflammatory and anti‐fibrotic properties and this compound is well tolerated in participants with NASH.

Treatment with a Cholecystokinin Receptor Antagonist, Proglumide, Improves Efficacy of Immune Checkpoint Antibodies in Hepatocellular Carcinoma

“…CCK-BRs have been reported on fibroblasts [ 27 ] and in pancreatic stellate cells [ 28 ] but never in hepatic stellate cells. However, we have previously noted this anti-fibrotic effect of proglumide in mouse models of nonalcoholic steatohepatitis (NASH) [ 29 ] and also in human subjects with NASH treated with proglumide [ 30 ]. In this investigation, we further described the effects of proglumide on genes involved in fibrogenesis or fibrinolysis using RNA sequencing.…”

The Role of a Cholecystokinin Receptor Antagonist in the Management of Chronic Pancreatitis: A Phase 1 Trial

“…This subject's liver AST improved with proglumide therapy. We previously reported that proglumide decreases inflammation and hepatic transaminase levels in nonalcoholic fatty liver disease [14]. The C-reactive protein (CRP) values decreased compared to the baseline values during the course of the study, suggesting decreased inflammation, but this difference was not significant.…”

“…Proglumide was dispensed from the investigational pharmacy at baseline and at the week 4 and week 8 visits and prescribed as one capsule by mouth three times daily for a total daily dose of 1200 mg. The dose and dosing schedule were based upon the results of a prior study involving subjects with metabolic-associated hepatic steatosis [14] and a pharmacokinetic study involving healthy controls and subjects with hepatic impairment [15]. The protocol allowed for the dose to be reduced from 1200 mg/day to 800 mg/day for drug-related side effects.…”

“…However, the commercialization of proglumide was halted with the development of proton pump inhibitors that were much more effective in decreasing gastric acid. In a Phase 1 clinical study in subjects with metabolic syndrome, hepatic steatosis, and fibrosis, three doses were tested, including 800 mg per day, 1200 mg per day, and 1600 mg per day [14]. In this study, both the 1200 mg per day and 1600 mg per day doses were effective and well tolerated; however, the subjects who were taking the higher dose had not yet achieved Cmax proglumide blood levels and steady states by week 12.…”