Pilot study with IBAT inhibitor A4250 for the treatment of cholestatic pruritus in primary biliary cholangitis

Abstract

Pruritus is a common complication of cholestatic liver diseases. Inhibition of the ileal bile acid transporter (IBAT/ASBT) may emerge as treatment option. Our aim was to assess tolerability and effect on pruritus of the selective IBAT inhibitor A4250 in patients with primary biliary cholangitis (PBC). Ten patients with PBC and bile acid sequestrant treatment of cholestatic pruritus were after a two-week wash out of the bile acid sequestrant treated with either 0.75 mg (n = 4) or 1.5 mg (n = 5) of A4250 for four weeks. Patients’ pruritus was assessed by Visual Analogue Scale (VAS), 5-D itch scale and the pruritus module of the PBC40 questionnaire. Plasma bile acids and 7α-hydroxy-4-cholesten-3-one were measured by UPLC-MS/MS, plasma fibroblast growth factor 19 by ELISA, and serum autotaxin activity by homemade assay. All nine patients exposed to A4250 reported a remarkable improvement in pruritus, until none or mild according to 5-D itch, VAS and PBC40 pruritus. Five patients finished the study prematurely due to abdominal pain (5/5) and diarrhoea (4/5). The high incidence of probably bile acid malabsorption-related diarrhoea and abdominal pain in the bile acid sequestrant pre-treated population indicates that the start dose of A4250 may have been too high for adult patients.

Autotaxin, bile acid profile and effect of ileal bile acid transporter inhibition in primary biliary cholangitis patients with pruritus

“…The treatment of pruritus in PBC is challenging because of the limited efficacy and poor tolerability of currently available drugs and lack of effective new therapies. Ileal bile acid transporter (IBAT) inhibitor agents are emerging as potential novel therapy for pruritus in PBC . Recently, we investigated GSK2330672, a novel, selective human IBAT inhibitor in a phase 2a, randomised controlled trial (RCT) and showed that PBC patients with pruritus receiving 2 weeks of oral treatment with GSK2330672 had significant improvement in their pruritus compared to placebo …”

“…Ileal bile acid transporter (IBAT) inhibitor agents are emerging as potential novel therapy for pruritus in PBC. [7][8][9][10] Recently, we investigated GSK2330672, a novel, selective human IBAT inhibitor in a phase 2a, randomised controlled trial (RCT) and showed that PBC patients with pruritus receiving 2 weeks of oral treatment with GSK2330672 had significant improvement in their pruritus compared to placebo. 11 Over the years, metabonomics has been applied to study the metabolic signatures in a variety of liver diseases.…”

Newer Approaches to the Management of Pruritus in Cholestatic Liver Disease

“…Only four patients finished the 4-week protocol and also reported a decrease in pruritic intensity. Five patients stopped their participation in the study early due to diarrhea and abdominal discomfort [27]. Odevixibat has also been investigated in pediatric cholestasis syndromes in a multiple dose (10-200-μg/kg bodyweight/day), open-label trial.…”

Bile Acid Receptor Therapeutics Effects on Chronic Liver Diseases

“…to increased BA deposition (75). IBAT/ASBT inhibitors are potential therapeutic candidates for this detrimental symptom (76). Pilot studies conducted with various synthetic IBAT/ASBT inhibitors have demonstrated variable results.…”