Volixibat improves fatigue and sleep in PBC alongside pruritus

Presenting the findings at AASLD The Liver Meeting in Washington, DC, USA, Kris Kowdley (Liver Institute Northwest, Seattle, Washington, USA)  began by underlining that pruritus and fatigue are the “most debilitating symptoms in PBC,” and affect up to 80% of patients, but that sleep disturbance, which can be moderate to severe and associated with fatigue, anxiety, depression, and pruritus, also occurs in approximately 60%.

Moreover, these symptoms, he continued, are “major determinants of impaired health-related quality of life” in PBC, and have a multifaceted and incompletely understood pathophysiology, underscoring the need for novel, effective, and safe treatments that manage the overall symptom burden.

The phase 2 VANTAGE study involves patients aged at least 18 years with a confirmed diagnosis of PBC, and chronic pruritus. It is divided into two parts, the first a 28-week dose selection phase, with patients randomly assigned to receive volixibat 20 mg or 80 mg, or placebo.

Previously reported results from this first phase demonstrated that volixibat reached its primary endpoint, with a significant placebo-adjusted reduction on the 10-point Adult ItchRO scale of 2.4 points with the 20 mg dose.

With the benefit similar in both the low- and high-dose groups, the 20 mg dose was taken forward into the second, confirmatory phase of the study, in which patients are being assigned to receive volixibat 20 mg or placebo for 28 weeks. This second phase is ongoing and patients who complete either phase will be eligible to enter an open-label extension study.

The current analysis looked at changes in health-related quality of life on the Patient-Reported Outcomes Measurement Information System (PROMIS) scale in the first phase of the study, focusing on the 7-item Fatigue and 8-item Sleep subscales. Data from the 20 mg and 80 mg volixibat groups were combined.

Thirty-one patients were included, 20 of whom received volixibat. Kowdley highlighted that the average age at enrollment was 56.3 years, and 87.1% of the participants were women. The mean baseline PROMIS Fatigue score was 57.6 points, while that for PROMIS Sleep was 57.8 points.

At week 28, fatigue scores among patients with data available had decreased by an average of 3.8 points in 14 patients receiving volixibat versus 1.0 point in the six patients treated with placebo, while the reductions in sleep scores were 4.3 points versus 1.0 point.

The minimum clinically important difference (MCID) in PROMIS scores was set at a decrease of at least 3 points from baseline, and the results showed that 57.1% of volixibat-treated patients reached this milestone on the Fatigue subscale, alongside 42.9% on the Sleep subscale. The proportion of patients in the placebo group achieving this MCID improvement in scores was 16.7% for both subscales.

Kowdley reported that the volixibat group also saw an increase in the proportion of patients achieving normal scores of below 55 points on the PROMIS Fatigue subscale. At baseline, 28.6% of volixibat-treated patients met these criteria, rising to 42.9% at 28 weeks. There was no change in the placebo group, with 33.3% having normal scores at both timepoints.

A similar pattern was seen with volixibat for the PROMIS Sleep subscale, with the proportion having normal scores increasing from 50.0% at baseline to 64.3% at week 28, while the opposite was observed in patients assigned to placebo, decreasing from 66.7% at baseline to 50.0% at the end of treatment.

Kowdley showed that there was significant correlation between PROMIS Fatigue and average weekly ItchRO scores at week 16, at a Spearman correlation coefficient of 0.66, although this relationship was no longer significant at week 28, “because of the smaller number of subjects.” A similar pattern was seen for PROMIS Sleep scores.

He concluded: “The impact of volixibat on fatigue and sleep will be further evaluated in the ongoing part two phase of the study, which will include a larger number of participants and those with milder and less intense pruritus, and we look forward to those results.”