Mechanism of Action (MOA) for the First and Only FDA-Approved Treatment for Cholestatic Pruritus in Alagille Syndrome1

Mechanism of Disease (MOD)

Bile Acid Buildup in Alagille Syndrome

Ileal bile acid transporter (IBAT) Terminal ileal lumen Ileal bile acid transporter (IBAT) Impaired bile flow between liver and duodenum Bile acid buildup
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Normally, adequate enterohepatic circulation is crucial for homeostatic maintenance of the body’s bile acid pool.2

  • This process starts with bile acid synthesis in hepatocytes and its subsequent biliary secretion, primarily mediated by the bile salt export pump2
  • Bile acids then move through bile ducts to the gallbladder for storage2
  • Later, bile acids are released into the small intestine to aid in lipid digestion and absorption2

Per cycle, approximately 95% of bile acids are reabsorbed from the terminal ileal lumen…

…by the ileal bile acid transporter (IBAT) for return to the liver through the hepatic portal vein.2

Bile acids that are not reabsorbed from the intestine via the IBAT are lost in feces…

…and, under steady-state conditions, are replaced by hepatic de novo synthesis.2

In cholestatic liver disease, bile flow is impaired between the liver and the duodenum, leading to a buildup of bile acids in the liver.3,4

There is also spillover of bile acids into the bloodstream, resulting in an increase in serum bile acids (sBA) systemically.3,4

In Alagille syndrome, bile ducts are narrow, malformed, and/or reduced in number.2,5

This results in bile acid buildup in the liver and bloodstream.2,5

Related to elevated serum bile acid (sBA) levels, cholestatic pruritus in Alagille syndrome is among the worst of any cholestatic liver disease.2,6-8

Boy playing pirate
Hey, Extra Bile—Keep Out!

Mechanism of Action

LIVMARLI Helps Battle Bile Acid Buildup

Ileal bile acid transporter (IBAT) IBAT inhibitor IBAT inhibitor
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Ileal bile acid transporter (IBAT)

LIVMARLI is an ileal bile acid transporter (IBAT) inhibitor and the first and only approved treatment for cholestatic pruritus in patients with Alagille syndrome who are ≥1 year old.1

IBAT inhibitor

LIVMARLI interrupts recirculation of bile acids to the liver and increases fecal excretion of bile acids to reduce serum bile acid (sBA) levels in the body, with minimal systemic absorption.1,9,10

IBAT inhibitor

Although the complete mechanism by which LIVMARLI improves cholestatic pruritus in patients with Alagille syndrome is unknown, it may involve inhibition of the ileal bile acid transporter (IBAT), which results in decreased reuptake of bile salts, as observed by a decrease in sBA.1

  • In the ICONIC study, sBA reductions correlated with reductions in cholestatic pruritus intensity, further supporting the potential causal relationship between the two11

During the first year of treatment, 83% (n=24/29) of patients with Alagille syndrome experienced a ≥20% reduction in sBA levels vs baseline with LIVMARLI.9,12

the Scratch

Significant improvements in cholestatic pruritus from baseline were achieved as early as Week 3 and maintained through 1 year in patients with Alagille syndrome taking LIVMARLI (P<0.0001).9,13

See the Efficacy Data

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LIVMARLI is indicated for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) 1 year of age and older.

Important Safety Information

Warnings and Precautions

Liver Test Abnormalities: Patients enrolled in clinical trials had abnormal liver tests at baseline. In the main clinical trial, treatment-emergent elevations or worsening of liver tests (ALT, AST or T/DB) relative to baseline were observed. Obtain baseline liver tests and monitor during treatment. 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. Discontinue permanently if a patient progresses to portal hypertension or experiences a hepatic decompensation event.

GI Adverse Reactions: Diarrhea, abdominal pain and vomiting were reported as the most common adverse reactions. If diarrhea, abdominal pain and/or vomiting occur and no other etiologies are found, consider reducing the dose or interrupting LIVMARLI. For diarrhea or vomiting, monitor for dehydration and treat promptly. Consider interrupting LIVMARLI dosing if a patient experiences persistent diarrhea or has diarrhea with accompanying signs and symptoms such as bloody stool, vomiting, dehydration requiring treatment, or fever. Restart LIVMARLI at 190 mcg/kg/day when diarrhea, abdominal pain or vomiting resolve, and increase the dose as tolerated. If they recur upon re-challenge, consider stopping LIVMARLI treatment.

Fat-Soluble Vitamin Deficiency: ALGS patients can have fat-soluble vitamin (FSV) deficiency (vitamins A, D, E, and K) at baseline, and LIVMARLI may affect absorption of FSV. In the main clinical trial, treatment emergent FSV deficiency was reported in 3 (10%) patients during 48 weeks of treatment. Obtain baseline serum levels and monitor during treatment, along with any clinical manifestations. Supplement if deficiency is observed. Consider discontinuing LIVMARLI if FSV deficiency persists or worsens despite adequate FSV supplementation.

Adverse Reactions

The most common adverse reactions (≥5%) are diarrhea, abdominal pain, vomiting, fat-soluble vitamin deficiency, liver test abnormalities, gastrointestinal bleeding and bone fractures.

Drug Interactions

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

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

LIVMARLI should be taken 30 minutes before the first meal of the day. The provided oral dosing dispenser must be used to accurately measure the dose. Any remaining LIVMARLI should be discarded 45 days after first opening the bottle.

Please see full Prescribing Information for LIVMARLI.