Alexander Miethke, MD: Maralixibat for Progressive Familial Intrahepatic Cholestasis

Ileal bile acid transporter (IBAT) inhibitor maralixbat was associated with significantly reduced pruritus and serum bile acid, as well as benefits to hepatic levels, in pediatric patients with progressive familial intrahepatic cholestasis (PFIC).¹

New findings from the phase 3 MARCH trial, presented in an abstract at the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) 2023 Annual Meeting in San Diego this week, show significant benefit with maralixibat to treat a multitude of symptoms and serum levels in patients with the rare, progressive, genetic liver disease.

In an interview with HCPLive leading up to NASPGHAN 2023, study author Alexander Miethke, MD, medical director of the Liver Transplant Program and associate professor in the department of pediatrics at Cincinnati Children's Hospital, discussed the significance of the findings from what is currently the largest clinical trial of pediatric PFIC to date.

“Several endpoints related to the control of itching and bile acids showed an improvement in the treatment group, and that was across all the different genotypes and one of the largest studies were performed in this rare disorder to date,” Miethke explained. “The most common clinical treatment-emergent adverse event was diarrhea and abdominal pain—it did happen in almost 50% of patients, but it was usually limited in duration, lasting between 3 - 5 days.”

A key characteristic of a family of rare liver diseases driven by bile duct acid retention—including PFIC and Alagille syndrome, the latter of which maralixibat has been approved by the US Food and Drug Administration to treat²—is the presence of persistent pruritus, or itching.

It’s still not well understood how the retention of bile duct acids in the liver results in significant symptoms of pruritus, but it remains a key target for clinical benefit in the development of agents like maralixibat. In many cases, patients with these rare forms of liver disease can begin experiencing a severe, constant sense of itching by 6 months’ age that eventually resolves clinicians to pursue a liver transplant.

“How they exactly cause itching we don't quite know yet, but we know that conditions which lead to cholestasis are often associated with severe itching, which is often so severe that it's refractory to medical therapies, surgical therapy and even requires transplantation that leads to fibrosis of the liver and sometimes types of liver cancer,” Miethke said. “And that leads to a lack of bile acids in the intestine; that leads to malnutrition and fat-soluble vitamin deficiency.”

With these latest findings primarily providing promise for prospective management of pediatric PFIC, Miethke noted the growing confidence he and fellow investigators are developing for the IBAT inhibitor drug class in general for patients in this family of rare diseases.

“I think the class of IBAT inhibitors, of which maralixibat is one of them, it has been a very important intervention over the last 5 - 10 years in various cholestatic diseases—diseases which are related to retention of bile acids,” Miethke said. “They are very important from a nutritional aspect, and they actually are also important signaling molecules.”

Reference

1. ^{Miethke A, Moukarzel A, Porta G, Esquer JC, et al. Efficacy and Safety of Maralixibat in Patients with Progressive Familial Intrahepatic Cholestasis (MARCH): A Randomized Placebo-Controlled Phase 3 Study. Paper presented at: North American Society for Pediatric Gastroenterology, Hepatology and Nutrition 2023 Annual Meeting; October 4 - 7; San Diego, CA. Accessed October 4, 2023.}
2. ^{Walter K. FDA Approves First Treatment for Rare Pediatric Liver Disease. HCPLive. Published September 29, 2021. https://www.hcplive.com/view/fda-approves-first-treatment-rare-pediatric-liver-disease}