ALGS Safety | LIVMARLI® (maralixibat) oral solution and tablets

LIVMARLI has well-established safety and tolerability in patients with cholestatic pruritus in Alagille syndrome (ALGS).^1,2

In the ICONIC study, there were no discontinuations of LIVMARLI due to ineffectiveness.³

* The majority of exposure occurred without a placebo control in open-label extensions.

Common adverse reactions

Adverse reactions occurring in patients in the ALGS clinical development program.

ALT=alanine transaminase; AST=aspartate aminotransferase; FSV=fat-soluble vitamin.

^†Integrated safety profile from multiple clinical trials, including the ICONIC study.¹
^‡Terms were defined as: FSV deficiency includes vitamins A, D, E, and/or K deficiency or International Normalized Ratio (INR) increase; abdominal pain includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper; transaminases increased includes ALT abnormal, ALT increased, AST abnormal, AST increased; bone fractures include tibia fracture, rib fracture, humerus fracture, pathological fracture, forearm fracture, and clavicle fracture.¹
^§Exposure-adjusted incidence rate for each adverse reaction type was calculated using the first occurrence of this adverse reaction per patient.^1,2

Additional
safety

The most common adverse reactions seen with LIVMARLI in the ALGS clinical development program, which included 5 clinical studies comprising 86 patients, were diarrhea, abdominal pain, vomiting, nausea, FSV deficiency, liver test abnormalities, and bone fractures.¹

Most gastrointestinal side effects were transient, and the majority resolved in <1 week.⁴

Data from an integrated safety analysis of 86 patients treated with LIVMARLI for up to 5 years.¹

Five patients experienced treatment interruptions or dose reductions due to diarrhea, abdominal pain, or vomiting.^1,4 Among those taking LIVMARLI, no patients discontinued due to diarrhea, abdominal pain, or vomiting.⁵

In a pooled analysis of patients with ALGS (n=86), 7 patients discontinued LIVMARLI due to increases in hepatic transaminases (ALT) and 3 patients had a decrease in dose or interruption of LIVMARLI in response to these increases; elevations in transaminases were asymptomatic and not associated with bilirubin or other laboratory abnormalities.¹

In the majority of cases, the elevations resolved or improved after discontinuation or dose modification of LIVMARLI¹

In some cases, the elevations resolved or improved without change in LIVMARLI dosing¹
Four patients experienced bilirubin increases above baseline, and LIVMARLI was subsequently withdrawn in 2 of these patients (those who had elevated bilirubin at baseline)¹

Patients with ALGS can have fat-soluble vitamin (FSV) deficiency (vitamins A, D, E, and/or K) at baseline¹

LIVMARLI may affect absorption of FSV¹

References:

1. LIVMARLI® (maralixibat). Prescribing Information. Mirum Pharmaceuticals, Inc. 2. Raman RK, Garner W, Vig P, Tucker E. An integrated analysis of long-term clinical safety in maralixibat-treated participants with Alagille syndrome. Poster presented at: European Association for the Study of the Liver (EASL): International Liver Congress; June 23-26, 2021. 3. 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 4. Kamath BM, Raman RK, Garner W, Tucker E, Vig P, Gonzales E. Gastrointestinal tolerability of maralixibat in patients with Alagille syndrome: an integrated analysis of short- and long-term treatment. Poster presented at: The 6th World Congress of Pediatric Gastroenterology, Hepatology and Nutrition; June 2-5, 2021; Vienna, Austria. 5. Data on file. REF-00180. Mirum Pharmaceuticals, Inc.

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.

Grounded by a well-characterized safety and tolerability profile