FDA Approval of Maralixibat for Cholestatic Pruritus in PFIC Signals New Frontier for IBAT Inhibitor

Saeed Mohammed, MD, MS

Credit: Vanderbilt University Medical Center

The US Food and Drug Administration (FDA) approval of maralixibat (Livmarli) oral solution for the treatment of cholestatic pruritus in patients 5 years or older with progressive familial intrahepatic cholestasis (PFIC) marks the ileal bile acid transporter (IBAT) inhibitor’s second rare liver disease indication.¹

Announced by Mirum Pharmaceuticals on March 13, 2024, the decision is supported by data from the phase 3 MARCH PFIC study, the largest randomized trial conducted in PFIC. Among a cohort of 93 patients with a range of genetic PFIC subtypes including PFIC1, PFIC2, PFIC3, PFIC4, PFIC6, and unidentified mutational status, patients treated with maralixibat had statistically significant improvements in pruritus (P <.0001), serum bile acids (P <.0001), bilirubin (P = .0471), and growth as measured by weight z-score (P = .0391).^1,2

“Until the IBAT inhibitors came into play, we did not have any good medications for pruritis,” Saeed Mohammed, MD, MS, associate professor and director of the Pediatric Solid Organ Transplant Center at Vanderbilt University Medical Center, explained in an interview with HCPLive. “The number of patients is small, but I think their burden is pretty high. With the advent of IBAT inhibitors, it has changed the way that we treat these patients.”

An orally administered, once-daily IBAT inhibitor, maralixibat is the only FDA-approved medication for the treatment of cholestatic pruritus in patients with Alagille syndrome ≥ 3 months of age.³ It is also being evaluated in late-stage clinical studies in other rare cholestatic liver diseases including biliary atresia and has received Breakthrough Therapy designation for Alagille syndrome and PFIC type 2 and orphan designation for Alagille syndrome, PFIC, and biliary atresia.²

“Before, it was mostly supportive treatment. So we'd focus on nutrition so that they'd grow better, we'd give things like antihistamines, which blocked the itch, but don't really treat the itch. But giving an IBAT inhibitor helps to reduce bile acids and improve the pruritus in a lot of patients,” Mohammed explained.

Mirum Pharmaceuticals announced the submission of a supplemental New Drug Application (sNDA) for maralixibat on February 14, 2023, supported by data from MARCH PFIC as well as data from the phase 2 INDIGO study of PFIC2 patients demonstrating transplant-free survival in all serum bile acid responders after > 5 years of treatment with maralixibat.²

Of note, the FDA extended the review of the sNDA on October 17, 2023, to allow time for a full review of a submission provided in response to an FDA information request, which the FDA deemed a major amendment. However, no additional data or studies were requested with this extension.⁴

Although the exact mechanism behind pruritus is unknown, Mohammed noted that bile acids are one of the prime suspects: “So there's an idea that decreasing bile acids would decrease itching, and there's also theories that decreasing bile acids will improve liver health as well.”

While researchers know how IBAT inhibitors work for bile acids, little is known about its other interactions that may improve liver health and lead to the improved transplant-free survival observed in patients with Alagille syndrome: “I think that question will be answered with more usage of the medication and as we get more data.”

“I think the addition of IBAT inhibitors to the medications that we have for cholestatic liver disease, particularly PFIC, has been groundbreaking in the last 2 years,” Mohammed concluded.

References:

1. ^{Fitch J. FDA approves Maralixibat to treat cholestatic pruritus in PFIC patients 5 years and up. Contemporary Pediatrics. March 13, 2024. Accessed March 13, 2024. https://www.contemporarypediatrics.com/view/fda-approves-maralixibat-to-treat-cholestatic-pruritus-in-pfic-patients-2-months-and-up.}
2. ^{Mirum Pharmaceuticals. Mirum Pharmaceuticals Submits Supplemental New Drug Application to FDA for LIVMARLI in Patients with Cholestatic Pruritus in Progressive Familial Intrahepatic Cholestasis. February 14, 2023. Accessed ?. https://ir.mirumpharma.com/news-events/News/news-details/2023/Mirum-Pharmaceuticals-Submits-Supplemental-New-Drug-Application-to-FDA-for-LIVMARLI-in-Patients-with-Cholestatic-Pruritus-in-Progressive-Familial-Intrahepatic-Cholestasis/default.aspx}
3. ^{Walter, K. FDA Approves First Treatment for Rare Pediatric Liver Disease. HCPLive. September 29, 2021. Accessed ?. https://www.hcplive.com/view/fda-approves-first-treatment-rare-pediatric-liver-disease}
4. ^{Mirum Pharmaceuticals. Mirum Pharmaceuticals Announces New PDUFA Date for LIVMARLI for the Treatment of Cholestatic Pruritus in Progressive Familial Intrahepatic Cholestasis. October 17, 2023. Accessed ?. https://ir.mirumpharma.com/news-events/News/news-details/2023/Mirum-Pharmaceuticals-Announces-New-PDUFA-Date-for-LIVMARLI-for-the-Treatment-of-Cholestatic-Pruritus-in-Progressive-Familial-Intrahepatic-Cholestasis/default.aspx}