The investigational ileal bile acid transporter (IBAT) inhibitor volixibat provides rapid and sustained improvement in pruritus in patients with primary sclerosing cholangitis, according to the topline results of the VISTAS study.
Over 28 weeks of treatment, patients who received volixibat had a 2.72-point reduction in Adult Itch Reported Outcome (ItchRO) scores from baseline, whereas those who received placebo only had a 1.08-point decrease. [EASL 2026, abstract LB26-5075]
The 1.64-point difference in Adult ItchRO scores between volixibat and placebo at week 28 was both “clinically meaningful and statistically significant (p<0.0001),” reported lead investigator Dr Cynthia Levy from the University of Miami Miller School of Medicine, Miami, Florida, US.
The improvements in pruritus with volixibat were observed as early as week 2 and maintained over time, Levy said.
Significantly more patients in the volixibat group than in the placebo group achieved a ≥2-point reduction (56 percent vs 26 percent; p=0.0019) or a ≥3-point reduction (37 percent vs 11 percent; p=0.0011) in their itch scores.
Levy noted that a ≥2-point reduction in itch scores from baseline was considered a meaningful improvement for patients.
Largest study to date
“VISTAS is the largest investigation into the efficacy and safety of an IBAT inhibitor in PSC and is the first controlled evidence of a potential therapy addressing the cholestatic symptom burden in this population,” Levy said.
Conducted across 103 sites in 13 countries, VISTAS involved 158 PSC patients aged 12 years or older with moderate to severe pruritus. Those who had concomitant inflammatory bowel disease (IBD) on stable medication were allowed to participate.
The patients were randomly assigned to receive 28 weeks of treatment with either volixibat 20 mg or placebo (n=57), administered orally twice daily. Upon treatment completion, the patients were invited to participate in the open-label extension study.
Of the patients, 111 had moderate-to-severe pruritus at baseline and comprised the primary cohort, which was included in both the efficacy and safety analyses. The remaining 47 patients with mild pruritus at baseline comprised the secondary cohort and were included only in the safety analysis.
In the primary cohort, 54 patients were in the volixibat group (mean age 45.2 years, 53.7 percent male, 74.1 percent had IBD) and 57 were in the placebo group (mean age 44.3 years, 38.6 percent male, 73.7 percent had IBD). The mean ItchRO scores at baseline were 6.3 points in the volixibat group and 6.1 points in the placebo group, while the mean serum bile acid levels were 109.6 and 61.4 μmol/L, respectively.
The primary endpoint was change in Adult ItchRO score from baseline to the last 12 weeks of the double-blind treatment period.
Secondary and safety outcomes
Compared with placebo, volixibat was associated with improvements in quality of life at week 28. PROMIS domain scores for sleep disturbance decreased by 6.47 with volixibat vs 0.78 with placebo (difference, –5.69 points; p=0.0011), while scores for fatigue dropped by 4.22 vs 1.89 (difference, –2.33 points; p=0.1322), respectively.
As expected, volixibat-treated patients had a 33.7-μmol/L reduction in serum bile acid levels, whereas those who received placebo had a 2.1-μmol/L increase (difference, –35.8 μmol/L; p=0.0324), according to Levy. No significant between-group differences were observed in alkaline phosphatase and total bilirubin levels.
In terms of safety, treatment-emergent adverse events (TEAEs) considered related to the study drug were more common in the volixibat vs placebo group (44.2 percent vs 19.8 percent). The most common TEAEs were diarrhoea, abdominal pain, and nausea.
No significant between-group differences were observed in the frequency of grade ≥3 TEAEs (13 percent vs 11.1 percent) and serious TEAEs (10.4 percent vs 6.2 percent). Serious TEAEs in the volixibat group included acute cholangitis, infection, abdominal pain, cholangiocarcinoma, sclerosing cholangitis progression, biliary colic, pyrexia, back pain, and procedure-related pancreatitis, none of which were related to the study drug.
TEAEs led to premature treatment discontinuation in 9.1 percent of patients in the volixibat group and in 2.5 percent in the placebo group. One patient in the placebo group died due to spontaneous bacterial peritonitis.
“The safety of volixibat is generally consistent with the known effects of IBAT inhibition,” according to Levy.