Mirum Pharmaceuticals' volixibat has been granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) for the treatment of cholestatic pruritus in patients with primary biliary cholangitis (PBC). This regulatory milestone, announced on October 10, 2024, is based on positive interim data from the Phase 2b VANTAGE study, which demonstrated a statistically significant improvement in pruritus compared to placebo in patients treated with volixibat.
The Breakthrough Therapy Designation is designed to accelerate the development and review of drugs intended to treat serious or life-threatening diseases, provided preliminary clinical evidence indicates substantial improvement over existing therapies on at least one clinically significant endpoint.
VANTAGE Study: Interim Results
The Phase 2b VANTAGE study (NCT05050136) enrolled patients aged 18 years and older with a confirmed diagnosis of PBC, according to AASLD guidelines, and PBC-associated pruritus. Participants were randomized to receive volixibat 20 mg twice daily, volixibat 80 mg twice daily, or placebo for 28 weeks. The primary endpoint was the mean change in daily itch scores using the Adult ItchRO questionnaire from baseline to week 28.
Interim results from the VANTAGE study demonstrated a statistically significant improvement in pruritus among patients treated with volixibat (-3.82, P < .0001) and a placebo-adjusted difference of -2.32 points in the primary endpoint (P = .0026). Additionally, 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.
Safety and Tolerability
No new safety signals were observed during the VANTAGE study. 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, four patients experienced serious adverse events, including one in the placebo arm. There were no clinically meaningful changes in liver biomarkers.
Mechanism of Action
Volixibat is an oral, minimally absorbed agent designed to selectively inhibit the ileal bile acid transporter (IBAT). By blocking the recycling of bile acids through inhibition of IBAT, volixibat reduces bile acids systemically and in the liver. This mechanism may offer a novel approach in the treatment of adult cholestatic diseases.
Expert Commentary
"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," said Joanne Quan, MD, chief medical officer at Mirum. "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."
Ongoing Studies and Future Directions
The confirmatory portion of the VANTAGE study is ongoing, with completion of enrollment expected in 2026. Volixibat is also being evaluated in the Phase 2 VISTAS study for primary sclerosing cholangitis (PSC).
