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

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Let's take a closer look at bile acid buildup in Alagille syndrome. In normal anatomy, adequate enterohepatic circulation is crucial for homeostatic maintenance of the body's bile acid pool. This process starts with bile acid synthesis in hepatocytes and their subsequent biliary secretion, primarily mediated by the bile salt export pump, or BSEP. Bile acids then move through bile ducts to the gallbladder for storage and, later, for

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release into the small intestine to aid in lipid digestion and absorption.

Per cycle, approximately 95% of bile acids are reabsorbed by the ileal bile acid transporter, or IBAT, in the terminal ileal lumen for return to the liver through the hepatic portal vein. 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. In cholestatic liver disease, the flow of bile is impaired,

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leading to a buildup of bile acids in the liver. There is also spillover of bile acids into the bloodstream, resulting in an increase in serum bile acids systemically.

In Alagille syndrome, narrow, malformed, and/or a reduced number of bile ducts results in bile acid buildup in the liver and bloodstream. Symptoms associated with elevated serum bile acids may include debilitating cholestatic pruritus, which is considered to be the most troublesome symptom of Alagille syndrome. Accumulation of toxic serum bile

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acids may also lead to liver damage. With LIVMARLI, you can arm patients to battle bile acid buildup. A treatment for patients with cholestatic pruritus in Alagille syndrome who are 3 months of age and older…

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Narrator: …and the first FDA-approved treatment for cholestatic pruritus in Alagille syndrome. LIVMARLI helps battle bile acid buildup by inhibiting the IBAT.

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By interrupting the recirculation of bile acids to the liver, LIVMARLI increases the excretion of bile acids in feces in the terminal ileum, and decreases the bile acid pool in the body. Although the complete way by which LIVMARLI improves cholestatic pruritus in patients with Alagille syndrome is unknown, it may involve inhibition of the IBAT, which results in decreased reuptake of bile salts, as observed by a decrease in serum bile acid levels.

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In the ICONIC pivotal study, serum bile acid reductions correlated with reductions in cholestatic pruritus intensity, further supporting the potential causal relationship between the two.

INDICATION

LIVMARLI is indicated for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) 3 months of age and older.

IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Liver Test Abnormalities: Patients enrolled in clinical

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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

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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

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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

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(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

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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,

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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 a meal in the morning. The provided oral dosing dispenser must be used to accurately measure the dose. Any remaining LIVMARLI should be discarded 100 days after first opening the bottle.

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Narrator: [00:06:00]

It's time for your patients with Alagille syndrome to take aim against bile acid buildup. It's time for LIVMARLI.

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