Additional data in progressive familial intrahepatic cholestasis (PFIC)

Significant serum bile acid (sBA) improvements

Half of patients treated with LIVMARLI in the All-PFIC cohort met the NAPPED threshold for transplant-free survival (n=15/30)²

sBA responders³

≥75% reduction or sBA <102 μmol/L

A graph of patients who achieved sBA control.

MARCH-PFIC was a 26-week, Phase 3, randomized, placebo-controlled study that assessed efficacy and safety of treatment with LIVMARLI in patients who were 12 months to <18 years old with cholestatic pruritus in PFIC.^1,2*

sBA control (relative decrease in sBA to <102 µmol/L or ≥75% reduction) after surgical biliary diversion is associated with native liver survival  ≥15 years.

CI=confidence interval; NAPPED=NAtural course and Prognosis of PFIC and Effect of biliary Diversion consortium.
*The average sBA value from Weeks 18, 22, and 26 values were used.

The only IBAT inhibitor with bilirubin data in cholestatic pruritus responders with PFIC

An exploratory analysis of the MARCH-PFIC and MARCH-ON studies analyzed bilirubin levels in patients who achieved a cholestatic pruritus response with LIVMARLI.⁴

MARCH-ON is an open-label, long-term extension study for patients who completed the MARCH-PFIC study and continued treatment with LIVMARLI.⁵

Responders were those who saw improvement in their cholestatic pruritus. This was defined as either an improvement ≥1 point from baseline or a score of ≤1 on the Itch Reported Outcome (Observer) (ItchRO[Obs]) scale.

Patients with normal bilirubin levels (≤1.2 mg/dL) at baseline that remained within normal range⁴*

Mean change from baseline (CFB) in total bilirubin (mg/dL)⁴

A graph of change in baseline in total bilirubin.

In PFIC, elevated bilirubin is a common clinical finding and has been shown to be associated with worse long-term outcomes. Bilirubin and pruritic response in patients with PFIC warrants further investigation.^4,6-7

*Based on average total bilirubin value at Weeks 18, 22, and 26.

These data are based on an ongoing, exploratory analysis of MARCH-PFIC/MARCH-ON.

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The only IBAT inhibitor with growth data in cholestatic pruritus responders with PFIC

An exploratory analysis of the MARCH-PFIC and MARCH-ON studies analyzed height and weight in patients who achieved a cholestatic pruritus response with LIVMARLI.⁸

Height and weight increases in patients with PFIC who achieved a cholestatic pruritus response with LIVMARLI

Responders were those who saw relief from their cholestatic pruritus. This was defined as an improvement of ≥1 point from baseline or a score of ≤1 on the ItchRO(Obs) scale.³

Mean change from baseline in height Z-score over time⁸

LIVMARLI responders experienced increases through 70 weeks.⁸

Research has shown that pruritus may contribute to systemic issues that impair growth, including sleep disruptions, nutritional challenges, and increased inflammatory burden. Reducing pruritus severity has been associated with improved linear growth in children with chronic pruritic conditions.^9-12

MARCH-PFIC

In the pivotal MARCH-PFIC study, the primary endpoint was met³:

In the BSEP cohort, patients treated with LIVMARLI (n=14) had statistically significantly greater reductions in ItchRO(Obs) scores from baseline vs placebo (n=17) at 6 months (–1.7 vs –0.6, least squares mean change –1.1 [95% CI, –1.8 to –0.3]; P=0.0063)²*
—Similar results were observed in the All-PFIC cohort
In the All-PFIC cohort, 64% of participants who received LIVMARLI (n=33) were pruritus responders vs 29% who received placebo (n=31)³
LIVMARLI has a well-established safety and tolerability profile for cholestatic pruritus in patients with PFIC. The most common adverse reactions (≥5%) in the MARCH-PFIC clinical study were diarrhea, fat-soluble vitamin deficiency, abdominal pain, liver test abnormalities, hematochezia, and bone fractures. No new safety signals were observed in the exploratory analysis¹

BL=baseline; BSEP=bile salt export pump; CFB=change from baseline; IBAT=ileal bile acid transporter; SE=standard error.

*Baseline for the LIVMARLI-LIVMARLI group is from MARCH-PFIC and baseline for the Placebo-LIVMARLI group is from MARCH-ON, respectively. All data are mean unless otherwise indicated. Values are based on non-missing assessments. ItchRO(Obs) is the 4-week morning average severity score.

References:

1. LIVMARLI® (maralixibat). Prescribing Information. Mirum Pharmaceuticals, Inc. 2. Miethke A, Moukarzel A, Porta G, et al. Efficacy and safety of maralixibat in patients with progressive familial intrahepatic cholestasis (MARCH-PFIC): a randomized placebo-controlled phase 3 study. Presented at: North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) Annual Meeting: October 4-7, 2023; San Diego, CA. 3. 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. Lancet Gastroenterol Hepatol. 2024;9(7):620-631. doi:10.1016/S2468-1253(24)00080-3 4. Data on file. REF-01712. Mirum Pharmaceuticals, Inc.  5. Miethke A, Moukarzel A, Porta G, et al. Long-term maintenance of response and improved liver health with maralixibat in patients with progressive familial intrahepatic cholestasis (PFIC): data from the MARCH-ON Study. Presented at: American Association for the Study of Liver Diseases (AASLD) The Liver Meeting: November 10-14, 2023; Boston, MA. 6. Amirneni S, Haep N, Soto-Gutierrez A, Squires JE, Florentino RM. Molecular overview of progressive familial intrahepatic cholestasis. World J Gastroenterol. 2020;26(47):7470-7484. doi:10.3748/wjg.v26.i47.7470 7. Verkade HJ, Bezerra JA, Davenport M, et al. Biliary atresia and other cholestatic childhood diseases: advances and future challenges. J Hepatol. 2016;65(3):631-642. doi:10.1016/j.jhep.2016.04.032 8. Miethke AG, Aqul AA, Lin C-H, et al. Improvements in pruritus are associated with improvements in growth in patients with progressive familial intrahepatic cholestasis: data from the MARCH-ON trial. Presented at: American Association of the Study of the Liver Diseases (AASLD) The Liver Meeting: November 15-19, 2024; San Diego, CA. 9. Nicholas MN, Keown-Stoneman CD, Maguire JL, Drucker AM. Association between atopic dermatitis and height, body mass index, and weight in children. JAMA Dermatol. 2022;158(1):26-32. doi:10.1001/jamadermatol.2021.4529 10. Gerard G, Ng WWV, Koh JKJ, et al. The association between atopic dermatitis and linear growth in children-a systematic review. Eur J Pediatr. 2024;183(12):5113-5128. doi:10.1007/s00431-024-05804-z 11. Zhang M, He M, Tang T. The effect of atopic dermatitis in pediatric patients on height: reflections triggered by a real-life case report. Medicine (Baltimore). 2023;102(47):e36150. doi:10.1097/MD.0000000000036150 12. Melter M, Rodeck B, Kardorff R, et al. Progressive familial intrahepatic cholestasis: partial biliary diversion normalizes serum lipids and improves growth in noncirrhotic patients. Am J Gastroenterol. 2020;95(12):3522-3528. doi:10.1111/j.1572-0241.2000.03380

Indications

LIVMARLI (maralixibat) oral solution and tablets are indicated for the treatment of cholestatic pruritus in patients who are 3 months of age and older with Alagille syndrome.

LIVMARLI (maralixibat) oral solution and tablets are indicated for the treatment of cholestatic pruritus in patients who are 12 months of age and older with progressive familial intrahepatic cholestasis (PFIC).

Limitations of Use: LIVMARLI is not recommended in a subgroup of PFIC type 2 patients with specific ABCB11 variants resulting in nonfunctional or complete absence of bile salt export pump (BSEP) protein.

Important Safety Information

CONTRAINDICATIONS

LIVMARLI (maralixibat) oral solution and tablets are contraindicated in patients with prior or active hepatic decompensation events (eg, variceal hemorrhage, ascites, or hepatic encephalopathy).

WARNINGS AND PRECAUTIONS

Hepatotoxicity: LIVMARLI treatment is associated with a potential for drug-induced liver injury (DILI). In the PFIC trial, treatment-emergent hepatic decompensation events and elevations of liver tests or worsening of liver tests occurred. Two patients experienced DILI attributable to LIVMARLI. Two additional patients experienced DILI in the open-label extension portion of the trial. Of these 4 patients, 1 patient required liver transplant and another patient died.

In the Alagille syndrome trial, treatment-emergent elevations of liver tests or worsening of liver tests occurred.

Obtain baseline liver tests and monitor during treatment. Liver-related adverse reactions and physical signs of hepatic decompensation should also be monitored. Dose reduction or treatment interruption may be considered if abnormalities occur in the absence of other causes. For persistent or recurrent liver test abnormalities, consider treatment discontinuation. Permanently discontinue LIVMARLI if a patient experiences the following: persistent or recurrent liver test abnormalities, clinical hepatitis, or a hepatic decompensation event.

Gastrointestinal Adverse Reactions: Diarrhea and abdominal pain were reported as the most common adverse reactions. Monitor for dehydration and treat promptly. Consider reducing the dosage or interrupting LIVMARLI treatment if a patient experiences persistent diarrhea or diarrhea with bloody stool, vomiting, dehydration requiring treatment, or fever.

Fat-Soluble Vitamin (FSV) Deficiency: Patients can have FSV deficiency (vitamins A, D, E, and K) at baseline, and LIVMARLI may adversely affect absorption of FSVs. Treatment-emergent bone fracture events have been observed more frequently with patients treated with LIVMARLI compared with patients treated with placebo. If bone fractures or bleeding occurs, consider interrupting LIVMARLI and supplement with FSVs. LIVMARLI can be restarted once FSV deficiency is corrected and maintained at corrected levels.

Risk of Propylene Glycol Toxicity (Pediatric Patients Less Than 5 Years of Age): LIVMARLI oral solution contains propylene glycol. Total daily intake of propylene glycol should be considered for managing the risk of propylene glycol toxicity. Monitor patients for signs of propylene glycol toxicity. Discontinue LIVMARLI if toxicity is suspected.

ADVERSE REACTIONS

Alagille syndrome: The most common adverse reactions are diarrhea, abdominal pain, vomiting, FSV deficiency, liver test abnormalities, and bone fractures.

PFIC: The most common adverse reactions are diarrhea, FSV deficiency, abdominal pain, liver test abnormalities, hematochezia, and bone fractures.

DRUG INTERACTIONS

Administer LIVMARLI at least 4 hours before or 4 hours after administration of bile acid binding resins.

A decrease in the absorption of OATP2B1 substrates (eg, statins) due to OATP2B1 inhibition by LIVMARLI in the GI tract cannot be ruled out. Consider monitoring the drug effects of OATP2B1 substrates as needed.

DOSING INFORMATION

In patients with Alagille syndrome, LIVMARLI is taken once daily, 30 minutes before a meal in the morning. In patients with PFIC, LIVMARLI is taken twice daily, 30 minutes before a meal. Refer to the dosing by weight guidelines in the full Prescribing Information for complete details on dosing for the oral solution and tablet formulations. The provided oral solution dosing dispenser must be used to accurately measure the dose. Any remaining LIVMARLI oral solution should be discarded 100 days after first opening the bottle. LIVMARLI tablets can be used in patients weighing ≥25 kg who can swallow tablets.

Please see full Prescribing Information for LIVMARLI.