Volixibat Soothed the Itch in Primary Sclerosing Cholangitis

The investigational ileal bile acid transporter (IBAT) inhibitor volixibat delivered better itch relief than placebo in patients with primary sclerosing cholangitis (PSC), data from a phase II randomized clinical trial showed.

Among 111 patients with PSC and moderate to severe cholestatic pruritus, those randomized to volixibat had a mean 2.72-point reduction in their Adult Itch Reported Outcome (ItchRO) scores after 28 weeks, compared with a mean 1.08-point drop for those on placebo (P<0.0001).

More than half of volixibat patients (56%) saw at least a 2-point reduction in their itch scores — defined as a meaningful improvement for patients — compared with 26% of placebo patients (P=0.0019), while more than one-third of the volixibat group (37%) saw their scores drop by at least 3 points, a level achieved by only 11% of the placebo group (P=0.0011), reported Cynthia Levy, MD, of the University of Miami, at the European Association for the Study of the Liver annual meeting in Barcelona.

“Volixibat led to a rapid, sustained, and both clinically and statistically significant improvement in cholestatic pruritus,” Levy said during her presentation. “There were also improvements in quality of life, especially in sleep disturbance, which deserve further evaluation.”

Pruritus “is indeed one of the greatest unmet needs for people with PSC in their daily lives, and it was really encouraging to see the reduction in itch over the 28-week period,” said Martine Walmsley, head of research and policy at PSC Support in Manchester, England, during the presentation’s question and answer period.

Walmsley wondered about the durability of that effect, however, given that patients with PSC who receive anti-itch drugs often see the effects wear off over time. So far, the itch-reduction results have been sustained in the VISTAS trial’s open-label extension period, Levy explained.

PSC is a chronic, progressive disease in which inflammation and fibrosis damage the liver’s bile ducts, increasing risks of cirrhosis, portal hypertension, inflammatory bowel disease (IBD), and gastrointestinal cancers. Pruritus and fatigue are common PSC symptoms that substantially impair quality of life. There are no approved PSC treatments. IBAT inhibitors such as volixibat slow the reabsorption of bile acids into the liver and boost fecal bile acid excretion, which has the potential to improve clinical outcomes in PSC.

The VISTAS trial enrolled patients at 103 sites in 13 countries. Patients in the efficacy analysis were age 12 years or older with a confirmed diagnosis of PSC and had moderate to severe pruritus. Those who had IBD with stable treatment were allowed to participate. Patients were randomized to 28 weeks of either oral volixibat 20 mg twice daily or placebo.

The study’s primary endpoint was the change in pruritus by Adult ItchRO score from baseline to the last 12 weeks of the treatment period.

Mean ages in the volixibat and placebo groups were 45.2 years and 44.3 years, respectively, and 53.7% and 38.6% of the groups’ patients were male. Most patients in both groups had large-duct PSC (90.7% and 93.0%), and nearly three-quarters of both groups had IBD (74.1% and 73.7%). Mean ItchRO scores were 6.3 in the volixibat group and 6.1 in the placebo group.

Volixibat patients had significant improvement in serum bile acid levels, with levels declining by a mean of 33.7 μmol/L versus a 2.1-μmol/L increase with placebo (P=0.0324).

Improvements in patients’ PROMIS fatigue and sleep disturbance scores also favored volixibat over placebo, though only the sleep differences were significant. Fatigue scores fell an average of 4.22 points with volixibat and 1.89 points with placebo (P=0.1322), while sleep disturbance scores dropped by a mean 6.47 and 0.78 points, respectively (P=0.0011).

Unlike the efficacy analysis, which included only those with moderate or severe itch, the safety analysis included patients with mild itch. More volixibat patients experienced treatment-emergent adverse events than placebo patients (93.5% vs 84.0%). Drug-related discontinuation was more common in the volixibat group, primarily driven by diarrhea. While 40.3% of volixibat patients experienced that adverse event, only 8.6% of placebo patients did. Abdominal pain and nausea also were more common among volixibat patients.

Increased levels of alanine aminotransferase, blood bilirubin, and jaundice were more likely in volixibat patients than placebo patients, a safety profile that’s consistent with other IBAT inhibitor treatments, Levy said. In response to a question about the possibility that those increased levels may indicate volixibat worsened bile duct obstruction, she noted that “there was not excess need for procedures or interventions to relieve biliary strictures.”

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