Full MARCH-PFIC Data Offers Further Insight into Maralixibat in PFIC

Publication of phase 3 MARCH-PFIC trial demonstrate the use of maralixibat (LIVMARLI) oral solution was associated with improved pruritus and predictors of native liver survival among patients with progressive familial intrahepatic cholestasis (PFIC).

Full phase 3 data from the MARCH-PFIC published in The Lancet Gastroenterology and Hepatology provide the most comprehensive insight yet into the effects of maralixibat in patients with PFIC, which was approved for the treatment of cholestatic pruritus in patients 5 years or older with PFIC in March 2024.^1,2

“These data advance our understanding of LIVMARLI’s potential to provide meaningful improvements in pruritus and a number of parameters impacting patients with various PFIC types. The clinically meaningful reductions in serum bile acid and bilirubin levels also signify the potential for improvements in native liver survival in PFIC, a step forward in considering the long-term care and health of patients with PFIC,” said lead investigator Alexander Miethke, MD, of Cincinnati Children’s Hospital.³ “LIVMARLI presents a new non-surgical treatment option in PFIC with strong efficacy data and safety demonstrated across a range of PFIC types, which is important for patients with PFIC types previously unstudied.”

An ileal bile acid transporter (IBAT) inhibitor from Mirum Pharmaceuticals, maralixibat boasts a pair of rare liver disease indications, with its first indication being its approval for cholestatic pruritus in patients with Alagille syndrome 3 months of age or older. Used as the basis for the agent’s March 13, 2024 approval in PFIC, the MARCH-PFIC study was a phase 3 trial designed to examine the once-daily IBAT inhibitor against placebo therapy among patients aged 1 to 17 years with PFIC with persistent pruritus over 26 weeks.^1,2

Billed as the largest and most comprehensive dataset for an IBAT inhibitor in PFIC, the primary outcome of interest for the trial was mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15–26 among those with those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The secondary efficacy outcome of interest was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. For the purposes of analysis, the all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids.¹

A multicenter, randomized, double-blind, placebo-controlled trial, MARCH-PFIC was conducted at 29 sites in 16 countries across Europe, Asia, and North and South America. From July 9, 2019 through March 4, 2022, a total of 125 patients underwent screening. Among this cohort, 93 were randomized to maralixibat or placebo therapy and received at least 1 dose of study drug. This cohort had a median age of 3.0 years (Interquartile Range [IQR], 2.0 to 7.0), 55% participants were female, and 45% were male. Of the 47 patients randomized to maralixibat, 14 were included in there BSEP cohort and 33 were included in the all-PFIC cohort. Of the 46 patients randomized to placebo, 17 were included in the BSEP cohort and 31 were included in the all-PFIC cohort.¹

Upon analysis, results indicated the study met both the primary and secondary efficacy endpoints, with use of maralixibat associated, with statistically significant and clinically meaningful improvements observed with use by week 2 and sustained throughout the duration of the 26-week study for both the BESP and all-PFIC cohorts. Further analysis of data from the trial indicated use was associated with improvements in bilirubin concentrations, growth, and sleep disturbances relative to placebo therapy. Safety analyses from the trial indicated there were no new safety signals observed during the trial, with the most common adverse event being diarrhea and most of these events considered mild and transient in nature.¹

“We are pleased to see these data published and recognized by The Lancet as they demonstrate meaningful improvements in many clinical signs and symptoms seen in PFIC patients,” said Pam Vig, PhD, chief scientific officer and head of research at Mirum.² “Patients with PFIC suffer from cholestasis which can lead to debilitating cholestatic pruritus, as well as poor growth and progressive liver disease. These data demonstrate the significant impact LIVMARLI can have in this severe cholestatic setting.”

References:

1. ^{Miethke AG, Moukarzel A, Porta G, et al. Maralixibat in progressive familial intrahepatic cholestasis (March-PFIC): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Gastroenterology & Hepatology. Published online May 6, 2024. doi:10.1016/s2468-1253(24)00080-3}
2. ^{Mirum Pharmaceuticals. Mirum Announces Publication of Phase 3 MARCH Data in The Lancet Demonstrating Benefits of LIVMARLI (maralixibat) in patients with PFIC. Mirum Pharmaceuticals. May 7, 2024. Accessed May 7, 2024. https://ir.mirumpharma.com/news-events/News/news-details/2024/Mirum-Announces-Publication-of-Phase-3-MARCH-Data-in-The-Lancet-Demonstrating-Benefits-of-LIVMARLI-maralixibat-in-patients-with-PFIC/default.aspx.}
3. ^{Brooks A. FDA approval of Maralixibat for cholestatic pruritus in PFIC signals new frontier for IBAT inhibitor. HCP Live. March 14, 2024. Accessed May 7, 2024. https://www.hcplive.com/view/fda-approval-of-maralixibat-for-pfic-ibat-inhibitors.}