FDA Grants Volixibat Breakthrough Therapy, Orphan Designations for PSC

The US Food and Drug Administration (FDA) has granted volixibat, an investigational ileal bile acid transporter (IBAT) inhibitor, Breakthrough Therapy and Orphan Drug Designations for the treatment of cholestatic pruritus due to primary sclerosing cholangitis (PSC).

Mirum Pharmaceuticals announced in a press release on August 5, 2026, and if eventually approved, volixibat would be the first FDA-approved therapy specifically targeting cholestatic pruritus in PSC, a symptom for which no PSC-specific treatment currently exists.

The designations rest on topline results from the phase 2b VISTAS trial, in which volixibat produced a statistically significant, placebo-adjusted improvement in itch severity in patients with moderate-to-severe pruritus, along with a reduction in serum bile acids. But the same announcement carried a more complicated regulatory signal: at a pre-NDA meeting, the FDA recommended that Mirum run an additional phase 3 study before submission, even though the company had designed VISTAS, with agency input, as a pivotal trial.

"VISTAS was designed with FDA input as a pivotal study and met its primary endpoint with highly significant results. However, at our recent pre-NDA meeting, the agency recommended conducting a Phase 3 study," Chris Peetz, chief executive officer of Mirum, said in the company's announcement. "We intend to hold further discussions with the FDA before a potential NDA submission in the first half of 2027 based on VISTAS."

That timeline is later than the second-half 2026 submission Mirum had previously outlined.

Why the Efficacy Signal Matters Beyond Its Size

Pruritus is one of the most common and burdensome symptoms of PSC, closely tied to impaired sleep and reduced quality of life, and existing management leans on off-label options such as bile acid sequestrants, rifampin, opioid antagonists, and selective serotonin reuptake inhibitors, with inconsistent results. IBAT inhibition, the mechanism behind volixibat and already-approved agents like maralixibat and odevixibat, works by reducing enterohepatic recirculation of bile acids; accumulated bile acids are thought to drive cholestatic itch in part through activation of sensory pathways including MRGPRX4 and TGR5.

Speaking with HCPLive after full VISTAS data were presented at the European Association for the Study of the Liver meeting, Gideon Hirschfield, FRCP, PhD, Director of the Autoimmune and Rare Liver Disease Programme, discussed early signals of pruritus relief.

After all, patients in VISTAS separated from placebo within 1 to 2 weeks, alongside placebo-adjusted improvements in sleep disturbance and a numerical, non-significant trend toward improved fatigue, a symptom affecting an estimated 70% to 75% of patients with PSC.

"If I told you that you have a headache and I'm going to give you Tylenol, but you have to wait a month for the Tylenol to work, you're not going to take it," Hirschfield said. "It's exactly the same if I tell a patient who's got cholestatic pruritus due to PSC that I have a treatment that, within 1 to 2 weeks, they'll be able to tell immediately that it's helping them. That's patient-centered care."

For clinicians managing PSC-related itch with limited and often poorly tolerated options, that combination, a real effect size paired with rapid, noticeable relief, is likely what distinguishes this data from prior attempts to treat the symptom.

Parallel Development Continues in PBC

Volixibat is also being evaluated in the phase 2b VANTAGE study in cholestatic pruritus due to primary biliary cholangitis (PBC), a program that has separately reported positive interim results and received its own FDA Breakthrough Therapy designation. Mirum said enrollment in VANTAGE has been completed, with topline data expected in the first quarter of 2027, roughly the same window in which the company hopes to have clarity on its PSC submission path.

References

1. Mirum Pharmaceuticals, Inc. Mirum Pharmaceuticals reports second quarter 2026 financial results and provides business update. News release. August 5, 2026. Accessed August 10, 2026. https://ir.mirumpharma.com/news/news-details/2026/Mirum-Pharmaceuticals-Reports-Second-Quarter-2026-Financial-Results-and-Provides-Business-Update/default.aspx

2. Brooks A. Volixibat improves pruritus in phase 2b PSC trial, with GI and liver safety signals. HCPLive. May 4, 2026. Accessed August 10, 2026. https://www.hcplive.com/view/volixibat-improves-pruritus-in-phase-2b-psc-trial-with-gi-and-liver-safety-signal

3. Hirschfield G. Volixibat improves itch, fatigue in PSC, supporting "patient-centered" care. HCPLive. July 1, 2026. Accessed August 10, 2026. https://www.hcplive.com/view/volixibat-itch-fatigue-psc-patient-centered-care