LIVMARLI: Uses, Dosage & Side Effects

What Is LIVMARLI and What Is It Used For?

LIVMARLI contains the active substance maralixibat (as maralixibat chloride), a small molecule that selectively and reversibly inhibits the ileal bile acid transporter (IBAT), also known as the apical sodium-dependent bile acid transporter (ASBT). IBAT is a protein located on the surface of enterocytes (intestinal cells) in the terminal ileum that is responsible for reabsorbing bile acids from the intestinal lumen back into the portal circulation. Under normal physiological conditions, approximately 95% of bile acids secreted into the small intestine are reabsorbed through this transporter and returned to the liver via the portal vein, a process known as enterohepatic circulation. In cholestatic liver diseases, however, the impaired flow of bile leads to a toxic accumulation of bile acids in the liver and bloodstream, which in turn causes severe pruritus (itching), liver damage, and a range of systemic complications.

Alagille syndrome (ALGS) is a rare, autosomal dominant genetic disorder caused primarily by mutations in the JAG1 gene (approximately 94% of cases) or the NOTCH2 gene (approximately 2–4% of cases). These genes encode components of the Notch signaling pathway, which is essential for the normal development of multiple organ systems during embryogenesis. The syndrome is characterized by a paucity (reduction) of interlobular bile ducts in the liver, leading to chronic cholestasis (impaired bile flow). In addition to liver involvement, Alagille syndrome affects the heart (most commonly peripheral pulmonary artery stenosis), skeleton (butterfly vertebrae), eyes (posterior embryotoxon), kidneys (renal dysplasia), and facial features (broad forehead, deep-set eyes, pointed chin). The estimated prevalence of Alagille syndrome is approximately 1 in 30,000 to 1 in 50,000 live births, although milder cases may be underdiagnosed.

Cholestatic pruritus is one of the most burdensome symptoms of Alagille syndrome, frequently described as the symptom that most severely impairs quality of life for both patients and their families. The itching can be relentless and unresponsive to conventional antipruritic treatments such as antihistamines and topical emollients. In severe cases, pruritus leads to skin excoriations (self-inflicted scratches and wounds), sleep deprivation, behavioral disturbances, inability to attend school, and significant caregiver burden. Prior to the approval of LIVMARLI, there were no specifically targeted pharmacological treatments for cholestatic pruritus in Alagille syndrome, and surgical intervention such as partial external biliary diversion (PEBD) or liver transplantation was often considered for patients with refractory symptoms.

By inhibiting IBAT, maralixibat interrupts the enterohepatic circulation of bile acids at the level of the terminal ileum. This blockade prevents the reabsorption of bile acids from the intestinal lumen, resulting in increased fecal excretion of bile acids and a corresponding decrease in the total bile acid pool and serum bile acid concentrations. The reduction in circulating bile acids translates into clinical improvement of pruritus. Importantly, maralixibat acts locally within the gastrointestinal tract, with minimal systemic absorption. Plasma concentrations of the drug after oral administration are very low, which contributes to a safety profile characterized primarily by local gastrointestinal adverse effects rather than systemic toxicity.

The efficacy and safety of LIVMARLI in Alagille syndrome were evaluated in the ICONIC study (NCT02160782), a pivotal, multicenter, open-label trial that enrolled 31 patients with Alagille syndrome aged 1 to 17 years. The study included a 48-week open-label treatment period followed by a 4-week randomized, double-blind, placebo-controlled withdrawal period. During the open-label phase, patients received maralixibat at doses titrated up to 380 micrograms per kilogram once daily. Efficacy was assessed using validated instruments for pruritus severity, including the Itch Reported Outcome (ItchRO) Observer Scale and the Clinician Scratch Scale (CSS), as well as by monitoring serum bile acid levels.

Results from the ICONIC study demonstrated that treatment with LIVMARLI led to clinically meaningful and statistically significant improvements in pruritus. At week 48, patients treated with maralixibat showed a mean reduction of 2.2 points on the ItchRO Observer Scale (on a 0–4 scale) compared to baseline, and a 49% mean reduction in serum bile acid levels. During the randomized withdrawal phase, patients who were rerandomized to placebo experienced a worsening of pruritus and an increase in serum bile acid levels compared with those who continued on maralixibat, confirming the treatment effect. Additionally, improvements in growth parameters (height z-scores) were observed in some patients, potentially reflecting enhanced fat and nutrient absorption due to improved bile acid homeostasis.

LIVMARLI was first approved by the U.S. Food and Drug Administration (FDA) in September 2021, making it the first medicine specifically approved for the treatment of cholestatic pruritus in patients with Alagille syndrome aged 1 year and older (subsequently extended to 2 months and older). The European Medicines Agency (EMA) granted conditional marketing authorization for LIVMARLI in 2022 for the treatment of cholestatic pruritus associated with Alagille syndrome in patients aged 2 months and older. LIVMARLI represents a paradigm shift in the management of Alagille syndrome, offering a non-surgical, oral therapeutic option that specifically addresses the underlying pathophysiology of cholestatic pruritus by targeting bile acid reabsorption.

What Should You Know Before Taking LIVMARLI?

Contraindications

The primary contraindication to LIVMARLI use is known hypersensitivity (allergy) to maralixibat or to any of the excipients in the formulation. The oral solution contains the following inactive ingredients: propylene glycol, water, citric acid, sodium citrate, sucralose, grape flavoring, and other standard pharmaceutical excipients. If you have a known allergy to any of these substances, you must inform your healthcare provider before starting treatment.

LIVMARLI should not be used in patients with complete biliary obstruction (complete blockage of bile flow). The mechanism of action of maralixibat depends on the presence of bile acids in the intestinal lumen, which are delivered from the liver via the biliary system. In patients with complete biliary atresia where no bile acids reach the intestine, LIVMARLI would not be expected to provide clinical benefit because there would be no substrate for IBAT inhibition. Patients with Alagille syndrome who have progressed to complete biliary obstruction or end-stage liver disease may require alternative treatments including liver transplantation.

Warnings and Precautions

Before starting LIVMARLI and during treatment, the following considerations are important:

• Liver function monitoring: Liver function tests (ALT, AST, total bilirubin, and direct bilirubin) should be checked at baseline, during dose escalation, and at regular intervals during treatment. While changes in liver biochemistry may reflect the natural course of Alagille syndrome rather than drug effect, clinically significant elevations in liver enzymes or signs of hepatic decompensation (worsening jaundice, ascites, coagulopathy, hepatic encephalopathy) require immediate medical evaluation and potential discontinuation of LIVMARLI.
• Fat-soluble vitamin deficiency: LIVMARLI reduces bile acid levels in the intestine, which can impair the absorption of fat-soluble vitamins (A, D, E, and K). Patients with cholestatic liver disease are already at risk for fat-soluble vitamin deficiency due to reduced bile flow. Treatment with LIVMARLI may further reduce fat absorption. Fat-soluble vitamin levels should be monitored before starting treatment and periodically thereafter, and supplementation should be provided as needed.
• Diarrhea and gastrointestinal effects: Diarrhea is the most common adverse reaction with LIVMARLI and is a pharmacological consequence of increased bile acid excretion into the colon. In most patients, diarrhea is mild to moderate and tends to improve over time. However, severe or persistent diarrhea may require dose reduction, temporary treatment interruption, or additional supportive measures including oral rehydration. Monitor hydration status, particularly in young children.
• Gastrointestinal obstruction: Use LIVMARLI with caution in patients with a history of gastrointestinal obstruction or those at risk for gastrointestinal complications.

Pregnancy and Breastfeeding

Although Alagille syndrome is predominantly a pediatric condition and the primary patient population for LIVMARLI is children, some patients with ALGS survive into adulthood and may require continued treatment. There are no adequate and well-controlled studies of maralixibat in pregnant women. Animal reproductive toxicity studies with maralixibat have not shown direct harmful effects on fertility, embryo-fetal development, or postnatal development at clinically relevant exposures. However, as a precautionary measure, LIVMARLI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether maralixibat or its metabolites are excreted in human breast milk. Given the minimal systemic absorption of maralixibat after oral administration, the likelihood of significant exposure to a breastfed infant is considered low. Nevertheless, the decision to continue breastfeeding during LIVMARLI treatment should be made in consultation with a healthcare provider.

Use in Pediatric Patients

LIVMARLI is specifically indicated for pediatric patients aged 2 months and older with Alagille syndrome. The safety and efficacy of LIVMARLI have been established in pediatric patients through the ICONIC clinical trial and open-label extension studies. Special attention should be paid to growth monitoring, nutritional status, hydration, and fat-soluble vitamin levels in pediatric patients. The oral solution formulation and the supplied dosing syringe are specifically designed to allow precise measurement of small volumes for accurate dosing in infants and young children.

Driving and Operating Machinery

No studies on the effects of LIVMARLI on the ability to drive or operate machinery have been performed. Given the minimal systemic absorption of maralixibat and its known side effect profile (predominantly gastrointestinal), LIVMARLI is not expected to impair the ability to drive or use machines.

How Does LIVMARLI Interact with Other Drugs?

Understanding potential drug interactions with LIVMARLI is important for optimizing treatment outcomes, particularly in patients with Alagille syndrome who may be taking multiple medications for the management of their liver disease and associated comorbidities. Maralixibat acts primarily within the gastrointestinal tract with minimal systemic absorption, which means that traditional systemic drug-drug interactions mediated by hepatic cytochrome P450 (CYP) enzymes are not expected to be clinically significant. However, several important pharmacokinetic and pharmacodynamic interactions should be considered.

The most clinically relevant interaction involves bile acid binding resins (also known as bile acid sequestrants), which include cholestyramine, colestipol, and colesevelam. These resins work by binding bile acids in the intestinal lumen, which is the same compartment where maralixibat exerts its pharmacological effect. Co-administration of bile acid binding resins with LIVMARLI may theoretically bind maralixibat in the gut and reduce its efficacy. Therefore, if bile acid binding resins must be used concurrently with LIVMARLI, it is recommended that LIVMARLI be administered at least 4 hours before or 4 hours after the bile acid binding resin to minimize the potential for interaction.

In vitro studies have shown that maralixibat is a substrate and inhibitor of the organic anion transporting polypeptides OATP1B1 and OATP1B3, which are hepatic uptake transporters involved in the disposition of many drugs including statins, certain antibiotics, and hormonal therapies. However, because systemic exposure to maralixibat is very low following oral administration, the clinical significance of OATP-mediated interactions at clinically relevant doses is considered to be low. Nevertheless, caution is advised when co-administering LIVMARLI with sensitive OATP1B1/1B3 substrates.

Patients with Alagille syndrome frequently receive multiple concomitant medications, including ursodeoxycholic acid (UDCA), fat-soluble vitamin supplements, antipruritic agents (such as hydroxyzine or rifampicin), and immunosuppressants (in post-transplant patients). While maralixibat is not expected to have significant systemic drug interactions with most of these agents, the altered bile acid milieu in the intestine may affect the absorption of lipophilic (fat-soluble) medications. Healthcare providers should monitor drug levels and clinical responses accordingly, particularly for medications with narrow therapeutic indices.

What Is the Correct Dosage of LIVMARLI?

LIVMARLI should always be used exactly as prescribed by your healthcare provider. The medication is supplied as an oral solution with a concentration of 9.5 mg/mL, and it is administered using the provided oral dosing syringe to ensure accurate measurement. The dose is individualized based on the patient's body weight and is gradually titrated upward to the target dose over several weeks to minimize gastrointestinal side effects.

Dose Escalation Schedule

Treatment with LIVMARLI begins at a low dose and is gradually increased to the target dose. This dose escalation strategy is important for minimizing gastrointestinal adverse effects, especially diarrhea. The recommended dose escalation schedule is as follows:

If a patient experiences intolerable gastrointestinal side effects during dose escalation, the dose may be reduced to the previously tolerated dose for at least one week before reattempting escalation. In some cases, the healthcare provider may decide that a lower maintenance dose is appropriate based on the individual patient's tolerability and clinical response.

Adults

While Alagille syndrome is predominantly diagnosed in childhood, a growing number of patients survive into adulthood with ongoing cholestatic liver disease. Adult patients with ALGS who weigh 19.5 kg or more should follow the fixed-dose regimen of 7.2 mg once daily (after completing dose escalation). Limited data are available specifically in adult patients with Alagille syndrome, but the pharmacological mechanism and dosing principles remain the same.

Children and Infants

LIVMARLI is approved for use in pediatric patients aged 2 months and older. The weight-based dosing regimen (micrograms per kilogram) ensures appropriate dose adjustments for the wide range of body weights seen in pediatric patients, from young infants to adolescents. The oral solution formulation and the supplied dosing syringe are specifically designed to allow precise measurement of small volumes for accurate dosing in infants and young children. As children grow, their dose should be periodically recalculated based on current body weight. Caregivers should be trained on the proper use of the oral dosing syringe.

Elderly Patients

There is very limited clinical experience with LIVMARLI in elderly patients, as Alagille syndrome rarely presents for the first time in old age. Elderly patients with ALGS who continue treatment should follow the same dosing guidelines as younger adults. Given the minimal systemic absorption of maralixibat, age-related changes in renal or hepatic function are not expected to significantly alter drug exposure.

Missed Dose

If a dose of LIVMARLI is missed, it should be skipped and the next dose taken at the regularly scheduled time. Do not take a double dose to make up for a missed dose. If doses are missed frequently, contact your healthcare provider for guidance. Consistent daily dosing is important for maintaining the therapeutic effect of bile acid reduction and pruritus control.

Overdose

There is limited experience with overdose of LIVMARLI. In clinical studies, doses up to 600 micrograms/kg/day were explored, with gastrointestinal effects (primarily diarrhea and abdominal pain) being the dose-limiting adverse reactions. Given the minimal systemic absorption of maralixibat, significant systemic toxicity from an oral overdose is unlikely. In the event of overdose, treatment should be symptomatic and supportive, with particular attention to hydration status and electrolyte balance if severe diarrhea occurs. There is no specific antidote for maralixibat.

How to Use the Oral Solution

LIVMARLI is supplied as a clear to slightly yellow oral solution with a grape flavor. Follow these instructions for proper administration:

1. Timing: Take LIVMARLI once daily in the morning, approximately 30 minutes before the first meal of the day.
2. Measuring the dose: Use only the oral dosing syringe provided with the medication. Draw up the prescribed volume as indicated by your healthcare provider. Do not use household spoons.
3. Administering: Place the tip of the oral syringe inside the mouth, against the inner cheek, and slowly push the plunger to deliver the medication. For infants and young children, deliver the solution slowly to prevent choking or spitting.
4. After dosing: Replace the bottle cap tightly. Rinse the oral dosing syringe with clean water after each use and allow it to air dry.

What Are the Side Effects of LIVMARLI?

Like all medicines, LIVMARLI can cause side effects, although not everybody gets them. The side effect profile of LIVMARLI is largely predictable from its pharmacological mechanism of action. By inhibiting the ileal bile acid transporter and increasing the delivery of bile acids to the colon, maralixibat can cause gastrointestinal symptoms. In the ICONIC clinical trial and its open-label extension, the safety profile of LIVMARLI was comprehensively evaluated over extended treatment periods.

The following summary organizes side effects by frequency category according to standard medical conventions. Very common means the side effect occurs in more than 1 in 10 patients; common means it occurs in 1 in 10 to 1 in 100 patients; uncommon means 1 in 100 to 1 in 1,000; and rare means fewer than 1 in 1,000 patients.

The gastrointestinal side effects of LIVMARLI, particularly diarrhea, are a direct pharmacological consequence of the drug's mechanism of action. When IBAT is inhibited, a greater proportion of bile acids passes from the terminal ileum into the colon. In the colon, bile acids act as secretagogues, stimulating fluid and electrolyte secretion by colonocytes and accelerating colonic transit. Clinical experience has shown that these gastrointestinal effects tend to diminish over time as the body adjusts, and the gradual dose escalation strategy is specifically designed to minimize severity.

Fat-soluble vitamin deficiency is an important consideration during LIVMARLI treatment. Bile acids play a critical role in the emulsification and absorption of dietary fats and fat-soluble vitamins in the small intestine. By reducing bile acid levels in the intestinal lumen, LIVMARLI may impair the absorption of vitamins A, D, E, and K. Patients with cholestatic liver disease are already predisposed to fat-soluble vitamin deficiency due to reduced bile flow, and LIVMARLI may exacerbate this predisposition. Regular monitoring of fat-soluble vitamin levels is essential, and supplementation should be provided proactively. Vitamin K deficiency is of particular concern because it can lead to coagulopathy (impaired blood clotting).

It is important to distinguish between adverse events that are directly caused by LIVMARLI and those that reflect the natural history and complications of Alagille syndrome itself. Some adverse events reported in clinical trials, such as hepatic decompensation, gastrointestinal bleeding, and bone fractures, may reflect disease progression rather than a direct effect of the study drug.

How Should You Store LIVMARLI?

Proper storage of LIVMARLI is essential to maintain the stability and efficacy of the medication. The following storage conditions should be observed:

• Temperature: Store at controlled room temperature between 20°C and 25°C (68°F to 77°F). Temporary excursions between 15°C and 30°C (59°F to 86°F) are permitted. Do not refrigerate or freeze.
• Light protection: Keep the bottle in the original carton to protect from light.
• Bottle closure: Keep the bottle tightly closed when not in use.
• In-use shelf life: Once opened, use within 100 days. Write the date of opening on the bottle label.
• Do not use after the expiration date printed on the bottle and carton.
• Keep out of the reach and sight of children.

Do not dispose of unused medication in household waste or wastewater. Ask your pharmacist how to dispose of medicines you no longer use. Proper disposal helps protect the environment and prevents accidental ingestion.

What Does LIVMARLI Contain?

Each milliliter of LIVMARLI oral solution contains 9.5 mg of maralixibat (as maralixibat chloride). The active substance maralixibat is a small organic molecule with the empirical formula C₃₂H₄₆N₂O₅·HCl. It is a selective, reversible inhibitor of the ileal bile acid transporter (IBAT/ASBT), designed to act locally in the gastrointestinal tract with minimal systemic absorption.

The oral solution is a clear to slightly yellow liquid with a grape flavor, formulated to facilitate administration in pediatric patients. The other ingredients (excipients) are:

• Propylene glycol: A solvent and viscosity-adjusting agent.
• Citric acid monohydrate: A pH buffer to maintain solution stability.
• Sodium citrate dihydrate: A pH buffering agent working with citric acid.
• Sucralose: A non-caloric sweetener for improved palatability.
• Grape flavoring: Added to improve taste acceptance in children.
• Purified water: The primary solvent.

LIVMARLI oral solution does not contain alcohol, gluten, or lactose. The formulation is free from common allergens. The medication is supplied in a high-density polyethylene (HDPE) bottle with a child-resistant cap. Each package includes the bottle of oral solution and an oral dosing syringe calibrated for accurate volume measurement.