FDA Grants Breakthrough Therapy Designation to Volixibat for Cholestatic Pruritus in PBC

The US Food and Drug Administration has granted Breakthrough Therapy Designation to Mirum Pharmaceuticals’ volixibat as a potential treatment for cholestatic pruritus in patients with primary biliary cholangitis (PBC).¹

Announced on October 10, 2024, the regulatory designation is based on a positive interim analysis of the phase 2b VANTAGE study demonstrating statistically significant improvement versus placebo in pruritus for patients treated with volixibat.¹

“Breakthrough Therapy Designation for volixibat in PBC underscores the importance and urgency for a treatment to address one of the most burdensome impacts of this rare liver disease,” Joanne Quan, MD, chief medical officer at Mirum, said in a press release.¹ “We look forward to advancing our VANTAGE study with the goal of making volixibat available to patients living with PBC-related itch as quickly as possible.”

An oral, minimally absorbed agent designed to selectively inhibit the ileal bile acid transporter (IBAT), volixibat is thought to offer a potential novel approach in the treatment of adult cholestatic diseases by blocking the recycling of bile acids through inhibition of IBAT, reducing bile acids systemically and in the liver. It is currently being evaluated in phase 2b studies for primary sclerosing cholangitis (VISTAS), and PBC (VANTAGE), with interim results from both studies announced on June 17, 2024.¹

VANTAGE, the trial supporting volixibat’s Breakthrough Therapy Designation in PBC, 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 VANTAGE demonstrated a statistically significant (-3.82, P <.0001) improvement in pruritus among patients treated with volixibat and a placebo-adjusted difference of -2.32 points in the primary endpoint (P = .0026). 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.²

No new safety signals were observed, and adverse events were similar between the 20 mg and 80 mg treatment groups with the most common adverse event being mild to moderate diarrhea. 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.²

According to a press release from Mirum, the confirmatory portion of the VANATGE study is ongoing with completion of enrollment expected in 2026.¹

References

1. ^{Mirum Pharmaceuticals. Volixibat Granted Breakthrough Therapy Designation for Cholestatic Pruritus in Primary Biliary Cholangitis. October 10, 2024. Accessed October 10, 2024. https://ir.mirumpharma.com/news-events/News/news-details/2024/Volixibat-Granted-Breakthrough-Therapy-Designation-for-Cholestatic-Pruritus-in-Primary-Biliary-Cholangitis/default.aspx}
2. ^{Brooks, A. Positive Interim Analyses of Phase 2b Studies Show Promise for Volixibat in PBC, PSC. HCPLive. June 17, 2024. Accessed October 10, 2024. https://www.hcplive.com/view/positive-interim-analyses-of-phase-2b-studies-show-promise-for-volixibat-in-pbc-psc}