Positive Interim Analyses of Phase 2b Studies Show Promise for Volixibat in PBC, PSC

Mirum Pharmaceuticals has announced interim results from a pair of phase 2b studies assessing volixibat in patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).¹

Interim analyses of the VANTAGE PBC study in patients with PBC and the VISTAS PSC study in patients with PSC confirm the potential of volixibat in targeting bile acids in both conditions, with VANTAGE analysis showing a 3.8-point reduction from baseline and 2.3 point placebo-adjusted reduction in the primary endpoint of pruritus and VISTAS analysis exceeding the efficacy threshold for study continuation.¹

“The results of the interim analyses are very impressive as they confirm the potential of volixibat in targeting bile acids in PBC and PSC,” Kris Kowdley, MD, Washington State University and an investigator for VANTAGE and VISTAS, said in a press release.¹ “I look forward to seeing the final data with the goal of having additional therapies available to address the burden of disease in adult cholestasis."

An oral ileal bile acid transporter (IBAT) inhibitor, volixibat is a minimally absorbed agent potentially offering a novel approach in the treatment of adult cholestatic diseases by blocking the recycling of bile acids to reduce bile acids in the liver systematically. Findings from phase 1 and phase 2 studies have demonstrated on-target fecal bile acid excretion, a pharmacodynamic marker of ASBT inhibition, in addition to decreases in LDL cholesterol and increases in 7αC4, markers of bile acid synthesis. Volixibat has been evaluated in more than 400 individuals across multiple clinical trials and is currently being evaluated in phase 2b studies for PBC and PSC.¹

VANTAGE

VANTAGE enrolled patients ≥ 18 years of age with a confirmed diagnosis of PBC in line with AASLD guidance and qualified pruritus associated with PBC as assessed by Adult ItchRO. Participants were randomly assigned to receive volixibat 20 mg twice daily, volixibat 80 mg twice daily, or placebo for 28 weeks.²

The primary endpoint is the mean change in the daily itch scores using the Adult ItchRO questionnaire from baseline to week 28. Secondary outcomes include the proportion of patients with itch response, changes in alkaline phosphatase, changes in total bilirubin, changes in serum bile acid levels, and quality of life measures.²

Interim results from the VANTAGE study demonstrated a statistically significant (-3.82, P <.0001) improvement in pruritus for volixibat and a placebo-adjusted difference of -2.32 points in the primary endpoint (P = .0026), as measured by the Adult ItchRO scale. In total, 75% of patients on volixibat achieved a > 50% reduction in serum bile acids, and investigators noted a significant improvement in fatigue at week 16 with volixibat compared to placebo.¹

No new safety signals were observed, and adverse events were similar between the 20 mg and 80 mg treatment groups. The most common adverse event was diarrhea (77%) with all cases mild to moderate and mostly transient, although a single case resulted in discontinuation. Across the study population, 4 patients experienced serious adverse events, including 1 in the placebo arm. There were no clinically meaningful changes in liver biomarkers.¹

Based on these results, the VANTAGE PBC trial will continue with a volixibat dose of 20 mg twice daily.¹

“The interim data from the VANTAGE study provide outstanding results in relation to what has been shown for treatment of pruritus in PBC,” Joanne Quan, MD, chief medical officer at Mirum, said in a press release.¹ “With both VISTAS and VANTAGE advancing to enroll their confirmatory portions, we are excited about volixibat as a potential future option to help patients overcome one of the most prevalent and burdensome symptoms of these rare liver diseases.”

VISTAS

VISTAS enrolled patients ≥12 years of age for eligible regions (otherwise ≥ 18 years of age) with a confirmed diagnosis of large duct or small duct PSC based on AASLD guidelines and pruritus associated with PSC as assessed by Adult ItchRO.³

Participants were randomly assigned to receive volixibat 20 mg twice daily, volixibat 80 mg twice daily, or placebo for 28 weeks, after which all patients will receive volixibat through the open-label extension phase of the study.⁴

The primary endpoint is change in pruritus from baseline for volixibat versus placebo using the Adult ItchRO tool. Secondary endpoints include safety and tolerability, quality of life measures, and serum bile acids, while exploratory endpoints include assessments of liver fibrosis and other markers of PSC progression.⁴

Interim analysis results from VISTAS PSC were reviewed by an independent data review committee who recommended the study continue with the selected volixibat dose of 20 mg twice daily, with no changes to the study. The criteria for continuation included safety as well as a predefined threshold for efficacy. The sponsor and investigators are blinded to the interim results and analysis.¹

References:

1. ^{Mirum Pharmaceuticals. Mirum’s Volixibat Achieves Positive Interim Analyses in VANTAGE PBC and VISTAS PSC Studies. June 17, 2024. Accessed June 17, 2024. https://ir.mirumpharma.com/news-events/News/news-details/2024/Mirums-Volixibat-Achieves-Positive-Interim-Analyses-in-VANTAGE-PBC-and-VISTAS-PSC-Studies/default.aspx}
2. ^{Clinicaltrials.gov. A Study to Evaluate Efficacy and Safety of an Investigational Drug Named Volixibat in Patients With Itching Caused by Primary Biliary Cholangitis (VANTAGE). April 25, 2024. Accessed June 17, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05050136}
3. ^{Clinicaltrials.gov. A Study to Evaluate Efficacy and Safety of an Investigational Drug Named Volixibat in Patients With Itching Caused by Primary Sclerosing Cholangitis (PSC) (VISTAS). June 17, 2024. Accessed June 17, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04663308}
4. ^{Mirum Pharmaceuticals. Mirum Pharmaceuticals Announces First Patient Enrolled in Phase 2b VISTAS Clinical Study Evaluating Volixibat in Adult Patients With Primary Sclerosing Cholangitis. January 14, 2021. Accessed June 17, 2024. https://ir.mirumpharma.com/news-events/News/news-details/2021/Mirum-Pharmaceuticals-Announces-First-Patient-Enrolled-in-Phase-2b-VISTAS-Clinical-Study-Evaluating-Volixibat-in-Adult-Patients-With-Primary-Sclerosing-Cholangitis/default.aspx}