PFIC Relief | LIVMARLI® (maralixibat) oral solution and tablets

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

Statistically significant improvements in cholestatic pruritus vs placebo at 6 months. Improvements were seen as early as Week 2^2,3

A graph showing the change from baseline and cholestatic pruritus score from weeks 15 to 26.

A graph of the primary endpoint weekly change.

See the ALGS data

*The primary efficacy endpoint was the mean change in the average morning ItchRO(Obs) severity score between baseline and the last 12 weeks of treatment (Weeks 15-26) in the BSEP cohort, as reported by caregivers. In the BSEP cohort, treatment with LIVMARLI led to significantly greater reductions in LS mean change from baseline in the morning ItchRO(Obs) score vs placebo (–1.7 [95% CI, –2.3 to –1.2]; P<0.0001 vs –0.6 [–1.1 to –0.1]; P=0.017), with a difference in LS mean change from baseline between groups of –1.1 (95% CI, –1.8 to –0.3; P=0.0063).

64%

of patients in the All-PFIC cohort were considered cholestatic pruritus responders and experienced clinically meaningful improvements in cholestatic pruritus vs 29% of patients treated with placebo (P=0.0064) in the MARCH-PFIC study.¹

Cholestatic pruritus responders had a ≥1-point ItchRO(Obs) improvement or a score of ≤1.0

Quick and consistent improvements over 2 years^2-4

Meaningful improvements in
cholestatic pruritus were
seen as early as

2weeks

and sustained
through

2years

MARCH-PFIC: The broadest population of PFIC subtypes studied

The MARCH-PFIC study was a 26-week, Phase 3, randomized, placebo-controlled study that assessed efficacy and safety of treatment with LIVMARLI.^2,3

Participants aged ≥12 months to <18 years with a clinical diagnosis of PFIC with persistent (>6 months) pruritus and biochemical abnormalities, pathological evidence of progressive liver disease, or both were included.^2,3

The study populations for MARCH-PFIC included¹:

BSEP cohort (n=31)

Nontruncated BSEP (n=31)

All-PFIC cohort (n=64)

Nontruncated BSEP (n=31), FIC1 (n=13), MDR3 (n=9), TJP2 (n=7), MYO5B (n=4)

Full cohort (N=93)^‡§

Nontruncated BSEP (n=36), Truncated BSEP (n=9), FIC1 (n=17), MDR3 (n=9), TJP2 (n=8), MYO5B (n=4), heterozygous variant (n=2), no pathogenic variant (n=8)

A study design chart of the ICONIC study

Primary efficacy endpoint: Mean change in the average morning ItchRO(Obs) severity score between baseline and the last 12 weeks of treatment (Weeks 15-26) in the BSEP cohort, as reported by caregivers.^†

Key secondary efficacy endpoint: The mean change in total serum bile acid concentration between baseline and the average of Weeks 18, 22, and 26 in the BSEP cohort.^†

Additional secondary efficacy endpoints: The primary and key secondary endpoints analyzed in the All-PFIC cohort and the proportions of participants with improvements in pruritus and serum bile acids (pruritus and serum bile acid responders, respectively) in both the BSEP and All-PFIC cohorts.^†

Exploratory efficacy endpoints: The mean change from baseline in additional parameters of pruritus (highest daily, evening, and morning frequency ItchRO[Obs] and Clinician Scratch Scale scores), EDQ(Obs) sleep disturbance score, liver chemistry, and growth (height and weight Z-scores).^†

Safety endpoints: The incidence of adverse events, adverse events by severity, and adverse events by relationship to study drug.^†

Cholestatic pruritus was assessed at baseline using the ItchRO scale. ItchRO is a 0–4 scale, where 0 is none and 4 is very severe. This scale takes itch-related symptoms into consideration, including patients’ skin damage, sleep, and irritability.^5-7

Participants’ baseline scores were calculated as the average of the daily ItchRO scores over the 2 consecutive weeks during the screening period

MARCH-ON was an open-label, long-term extension study for patients who completed the MARCH-PFIC study and continued treatment with LIVMARLI^1,2

The study populations for MARCH-PFIC included¹:

BSEP cohort (n=31)

Nontruncated BSEP (n=31)

All-PFIC cohort (n=64)

Nontruncated BSEP (n=31), FIC1 (n=13), MDR3 (n=9), TJP2 (n=7), MYO5B (n=4)

Full cohort (N=93)^‡§

Nontruncated BSEP (n=36), Truncated BSEP (n=9), FIC1 (n=17), MDR3 (n=9), TJP2 (n=8), MYO5B (n=4), heterozygous variant (n=2), no pathogenic variant (n=8)

A table listing patient characteristics in the MARCH-PFIC clinical study.

ALT=alanine transaminase; BID=twice daily; BL=baseline; BSEP=bile salt export pump; CI=confidence interval; DB=direct bilirubin; EDQ(Obs)=Exploratory Diary Questionnaire (Observer); FIC1=familial intrahepatic cholestasis associated protein 1; ItchRO=Itch Reported Outcome; ItchRO(Obs)=Itch Reported Outcome for Observer; LS=least squares; MMRM=mixed model for repeated measures; MDR3=multidrug resistance class III; MYO5B=myosin VB; TB=total bilirubin; TJP2=tight junction protein 2.

*In the dose escalation period, the dose was increased weekly starting at 142.5 mcg/kg twice daily to a maximum dose of 570 mcg/kg twice daily.¹
^† Endpoints were analyzed using a repeated measures model (MMRM) considering data from all study visits.³
^‡ 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 BSEP protein.²
^§ The full study cohort included 8 patients with prior surgery to treat PFIC. Surgery participants had the following PFIC types: nontruncated BSEP (LIVMARLI: 3; placebo: 0), FIC1 (LIVMARLI: 2; placebo: 2), and TJP2 (LIVMARLI: 0; placebo: 1).¹

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. Lancet Gastroenterol Hepatol. 2024;9(7):620-631. doi:10.1016/S2468-1253(24)0080-3 2. LIVMARLI® (maralixibat). Prescribing Information. Mirum Pharmaceuticals, Inc. 3. Miethke A, Moukarzel A, Porta G, et al. Efficacy and safety of maralixibat in patients with progressive familial intrahepatic cholestasis (MARCH-PFIC): a randomised 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. 4. 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. 5. Kamath BM, Abetz-Webb L, Kennedy C, et al. Development of a novel tool to assess the impact of itching in pediatric cholestasis. Patient. 2018;11(1):69-82. doi:10.1007/s40271-017-0266-4 6. Gonzales E, Hardikar W, Stormon M, et al. Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study. Lancet. 2021;398(10311):1581-1592. doi:10.1016/S0140-6736(21)01256-3 7. Kamath BM, Spino C, McLain R, et al. Unraveling the relationship between itching, scratch scales, and biomarkers in children with Alagille syndrome. Hepatol Commun. 2020;4(7):1012-1018. doi:10.1002/hep4.1522

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.

Early improvements with long-term impact in progressive familial intrahepatic cholestasis (PFIC)

Statistically significant improvements in cholestatic pruritus vs placebo at 6 months. Improvements were seen as early as Week 22,3