Expanding the Reach of Maralixibat in Rare Cholestatic Liver Diseases, With Mercedes Martinez, MD

For patients with rare cholestatic liver diseases, pruritus is a debilitating, often underrecognized symptom that can severely disrupt sleep, daily function, and quality of life. Frequently worsening at night and with heat or activity, it remains difficult to measure and does not reliably correlate with standard biomarkers like bile acids or bilirubin. As awareness grows and new therapies are being studied, there is increasing urgency to better recognize and more effectively treat this overlooked but life-altering burden.

In an interview with HCPLive, Mercedes Martinez, MD, a professor of pediatrics and medicine at CUMC, highlighted both the clinical burden of cholestatic pruritus and the growing promise of targeted therapies like maralixibat.

One of the central challenges, Martinez explained, is the lack of objective tools to quantify pruritus severity. Unlike laboratory markers such as bilirubin or bile acid levels, itch does not reliably correlate with measurable disease parameters. Some patients with markedly elevated bile acids report little to no pruritus, while others with only moderate elevations experience debilitating symptoms, a disconnect that can lead clinicians to underestimate the true burden of disease.

“That right there is a problem. We don't have an objective assessment of how much pruritus somebody can feel. It's a feeling, and because it's a feeling, sometimes people try to downplay it, and physicians don't recognize that this is a problem,” she explained. “Sometimes, when we don't understand something and we don't have an objective assessment or something, we try to downplay that.”

The consequences for patients, particularly children, can be profound. Martinez described cases of severe, relentless itching that disrupt sleep, limit physical activity, and significantly impair quality of life. In extreme instances, patients scratch to the point of bleeding or engage in harmful behaviors in an attempt to relieve symptoms. Pruritus is often worse at night, exacerbated by heat or physical exertion, and may go underreported because patients normalize the sensation over time. As a result, more proactive and specific questioning by clinicians is essential to fully capture symptom burden.

From a mechanistic standpoint, she says the role of bile acids is central. The body typically recycles approximately 95% of bile acids through reabsorption in the terminal ileum. In cholestatic disease, impaired bile acid handling contributes to symptom development.

Therapies that interrupt this recycling process can therefore help reduce pruritus. While older treatments such as bile acid sequestrants are poorly tolerated, newer ileal bile acid transporter (IBAT) inhibitors like maralixibat offer a more targeted approach by blocking bile acid reuptake and lowering systemic levels.

While it is already approved for conditions such as Alagille syndrome and progressive familial intrahepatic cholestasis (PFIC), where pruritus is a hallmark feature, Martinez noted that the underlying mechanism of cholestatic pruritus is shared across multiple liver diseases, suggesting broader therapeutic potential. In clinical practice, off-label use has shown benefit in conditions such as primary sclerosing cholangitis and biliary atresia, though access remains limited due to lack of formal approval.

She noted that this is where the ongoing EXPAND trial becomes critical. By evaluating maralixibat in a wider population of rare cholestatic liver diseases, the study aims to establish both efficacy and safety beyond its current indications. According to Martinez, expanding approval could alleviate not only the clinical burden of pruritus but also the financial and access barriers faced by families.

Ultimately, improving recognition of pruritus and broadening access to effective therapies may significantly transform care for patients living with these challenging conditions.

Editors’ Note: Martinez reports no relevant disclosures.

References

1. Brooks A. FDA Approves Maralixibat (Livmarli) Tablet for Alagille Syndrome, PFIC. HCPLive. April 14, 2025. Accessed March 24, 2026. https://www.hcplive.com/view/fda-approves-maralixibat-livmarli-tablet-alagille-syndrome-pfic

2. Mirum Pharmaceuticals. Mirum Pharmaceuticals Completes Enrollment in Phase 3 EXPAND Study of LIVMARLI® (maralixibat) in Additional Rare Cholestatic Liver Diseases. March 16, 2026. Accessed March 24, 2026. https://ir.mirumpharma.com/news/news-details/2026/Mirum-Pharmaceuticals-Completes-Enrollment-in-Phase-3-EXPAND-Study-of-LIVMARLI-maralixibat-in-Additional-Rare-Cholestatic-Liver-Diseases/default.aspx