A phase 2, proof of concept, randomised controlled trial of berberine ursodeoxycholate in patients with presumed non-alcoholic steatohepatitis and type 2 diabetes

Abstract

Non-alcoholic steatohepatitis is frequently associated with diabetes and may cause progressive liver disease. Current treatment options are limited. Here we report on a prospective, randomised, double-blind, placebo-controlled trial of two doses of HTD1801 (berberine ursodeoxycholate, an ionic salt of berberine and ursodeoxycholic acid), versus placebo that was conducted in 100 subjects with fatty liver disease and diabetes (NCT03656744). Treatment was for 18 weeks with a primary endpoint of reduction in liver fat content measured by magnetic resonance imaging proton density fat fraction. Key secondary endpoints included improvement in glycemic control, liver-associated enzymes and safety. The pre-specified primary endpoint was met. Thus, subjects receiving 1000 mg twice a day of berberine ursodeoxycholate had significantly greater reduction in liver fat content than in placebo recipients (mean absolute decrease -4.8% vs. -2.0% (p = 0.011). Compared to placebo, subjects receiving this dose also experienced significant improvement in glycemic control as well as reductions in liver-associated enzymes and significant weight loss. Diarrhea and abdominal discomfort were the most frequently reported adverse events. We conclude that berberine ursodeoxycholate has a broad spectrum of metabolic activity in patients with presumed NASH and diabetes. It is relatively well tolerated and merits further development as a treatment for NASH with diabetes.

Conflict of interest statement

The authors listed below have the following competing interests: S.A.H.: Reports grant/research support from Axcella, BMS, Cirius, CiVi, Conatus, Cymabay, Enyo, Galectin, Galmed, Genentech, Genfit, Gilead, Hepion, Hightide, Intercept, Inventiva, Madrigal, NGM Bio, Northsea, Novartis, Novo Nordisk, Pfizer, Sagimet, and Viking. Consulting fees from Akero, Altimmune, Arrowhead, Axcella, Canfite, Cirius, CiVi, CLDF, Cymabay, Echosens, Fibronostics, Foresite Labs, Galectin, Genfit, Gilead, Hepion, Hightide, HistoIndex, Intercept, Kowa, Madrigal, Metacrine, NGM Bio, Novartis, Novo Nordisk, Poxel, Ridgeline, Sagimet, Terns, and Viking. N.G.: Research grants: Axcella, BMC, CymaBay, Genetech, Genfit, Gilead, High Tide, Madrigal, North Sea, NGM Bio, Novo Nordisk; Consultant/Speaker: AbbVie, Dova, Gilead, Intercept, Salix. G.W.N.: Grants: Ecosens, Intercept. Consultant/Speaker: Gilead, Intercept, Salix. A.K.: Grant/research support from Axcella, BMS, Cirius, Conatus, Cymabay, Enyo, Galectin, Genentech, Genfit, Gilead, Hightide, Intercept, Madrigal, NGM Bio, Northsea, Novartis, Novo Nordisk, Pfizer, Poxel, and Viking. Consulting fees from Intercept and Gilead. L.L.: employee of HighTide Therapeutics. A.F.: independent contractor to HighTide. L.G.: is a consultant to HighTide. A.M.D.: is a consultant to HighTide and Chief Medical Officer.

© 2021. The Author(s).

Figures

Fig. 1. Clinical study flow diagram.

Clinical study flow diagram showing the disposition of subjects with presumed NASH and diabetes screened and enrolled into a randomised controlled trial of berberine ursodeoxycholate (BUDCA).

Fig. 2. Waterfall plot of change in liver fat content and hemoglobin A1c in individual subjects.

Liver fat content in panels a [n = 30], b [n = 31] and c [n = 33], and hemoglobin A1c (HbA1C) in panels d [n = 26], e [n = 29] and f [n = 32]), among subjects receiving berberine ursodeoxycholate (BUDCA) 1000 mg twice a day (BID), 500 mg BID or placebo, respectively.