Maralixibat Chloride

1 INDICATIONS AND USAGE LIVMARLI is an ileal bile acid transporter (IBAT) inhibitor indicated for: • the treatment of cholestatic pruritus in patients 3 months of age and older with Alagille syndrome (ALGS). ( 1.1 ) • the treatment of cholestatic pruritus in patients 12 months of age and older with progressive familial intrahepatic cholestasis (PFIC). ( 1.2 ) o Limitations of Use: LIVMARLI is not recommended in a subgroup of PFIC type 2 patients with specific ABCB11 variants resulting in non-functional or complete absence of bile salt export pump (BSEP) protein. ( 14.2 ) 1.1 Treatment of Cholestatic Pruritus in Patients with Alagille Syndrome LIVMARLI ® is indicated for the treatment of cholestatic pruritus in patients 3 months of age and older with Alagille syndrome (ALGS). 1.2 Treatment of Cholestatic Pruritus in Patients with Progressive Familial Intrahepatic Cholestasis LIVMARLI is indicated for the treatment of cholestatic pruritus in patients 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 non-functional or complete absence of bile salt export pump (BSEP) protein [see Clinical Studies (14.2) ] .

2 DOSAGE AND ADMINISTRATION • Use LIVMARLI Oral Solution 9.5 mg/mL for treatment of ALGS. ( 2.1 ) • Use LIVMARLI Oral Solution 19 mg/mL for treatment of PFIC. ( 2.1 ) • LIVMARLI Tablets can be used for treatment of both ALGS and PFIC in patients weighing 25 kg and above who can swallow tablets. ( 2.1 ) ALGS: ○ The recommended dosage is 380 mcg/kg once daily, taken 30 minutes before a meal in the morning. ○ Starting dose is 190 mcg/kg orally once daily,and should be increased to 380 mcg/kg daily after one week, as tolerated and not to exceed a maximum daily dose of 28.5 mg per day for the oral solution and 30 mg per day for the tablets. ( 2.2 ) PFIC: ○ The recommended dosage is 570 mcg/kg twice daily before a meal. ○ Starting dose is 285 mcg/kg orally once daily in the morning and should be increased to 285 mcg/kg twice daily, 428 mcg/kg twice daily, and then to 570 mcg/kg twice daily, as tolerated and not to exceed a maximum daily dose of 38 mg per day for the oral solution and 40 mg per day for the tablets. ( 2.3 ) • See full prescribing information for additional dosage details for LIVMARLI oral solution and tablet formulations. ( 2.2 , 2.3 ) 2.1 Important Administration Information • Use LIVMARLI Oral Solution 9.5 mg/mL for treatment of ALGS. • Use LIVMARLI Oral Solution 19 mg/mL for treatment of PFIC. • The two strengths of LIVMARLI Oral Solution, 9.5 mg/mL and 19 mg/mL, should not be substituted for one another when treating PFIC patients [see Dosage and Administration (2.3) ]. • LIVMARLI tablets can be used for treatment of both ALGS and PFIC in patients weighing 25 kg and above who can swallow tablets. Select LIVMARLI Oral Solution or LIVMARLI Tablets based on the patient's weight and ability to swallow tablets [see Dosage and Administration (2.2 , 2.3 )]. 2.2 Recommended Dosage for Alagille Syndrome Use LIVMARLI Oral Solution 9.5 mg/ mL or LIVMARLI Tablets for the treatment of ALGS . The recommended dosage is 380 mcg/kg once daily, taken 30 minutes before a meal in the morning. Start dosing at 190 mcg/kg administered orally once daily; after one week, increase to 380 mcg/kg once daily, as tolerated. The maximum daily dose should not exceed 28.5 mg (3 mL) per day for LIVMARLI Oral solution and 30 mg per day for LIVMARLI tablets. Refer to the dosage by weight guidelines presented in Table 1 for LIVMARLI Oral Solution and Table 2 for LIVMARLI tablets. Table 1: 9.5 mg/mL LIVMARLI Oral Solution for Patients with ALGS: Volume per Dose (mL) by Weight Patient Weight (kg) Days 1-7 (190 mcg/kg once daily) Beginning Day 8 (380 mcg/kg once daily) 9.5 mg/mL Solution (for ALGS) Volume per Dose (mL) 5 to 6 0.1 0.2 7 to 9 0.15 0.3 10 to 12 0.2 0.45 13 to 15 0.3 0.6 16 to 19 0.35 0.7 20 to 24 0.45 0.9 25 to 29 0.5 1 30 to 34 0.6 1.25 35 to 39 0.7 1.5 40 to 49 0.9 1.75 50 to 59 1 2.25 60 to 69 1.25 2.5 70 or higher 1.5 3 Table 2: LIVMARLI Tablets for Patients with ALGS: Dosage by Weight* *Select the appropriate product based on the patient's weight and ability to swallow tablets. Patient Weight (kg) Days 1 to 7 (190 mcg/kg QD) Beginning Day 8 (380 mcg/kg QD) Less than 25 Use Oral Solution Use Oral Solution 25 to 32 10 mg 33 to 43 15 mg 44 to 65 10 mg 20 mg 66 or higher 15 mg 30 mg 2.3 Recommended Dosage for Progressive Familial Intrahepatic Cholestasis Use LIVMARLI Oral Solution 19 mg/mL or LIVMARLI Tablets for the treatment of PFIC . The two strengths of LIVMARLI, 9.5 mg/mL and 19 mg/mL, should not be substituted for one another when treating PFIC patients. Special attention should be given to the accurate calculation of the dose volume of LIVMARLI. This is especially important for pediatric patients less than 5 years old as LIVMARLI oral solution contains the excipient propylene glycol (364.5 mg/mL) [see Warnings and Precautions (5.4) and Overdosage (10) ]. The recommended dosage is 570 mcg/kg twice daily 30 minutes before a meal. The starting dose is 285 mcg/kg orally once daily in the morning, and should be increased to 285 mcg/kg twice daily, 428 mcg/kg twice daily, and then to 570 mcg/kg twice daily, as tolerated. The maximum daily dose should not exceed 38 mg (2 mL) per day for LIVMARLI oral solution and 40 mg per day for LIVMARLI tablets. Refer to the dosing by weight guidelines presented in Table 3 for LIVMARLI oral solution and Table 4 for LIVMARLI tablets. Table 3: 19 mg/mL LIVMARLI Oral Solution for Patients with PFIC: Volume per Dose (mL) by Weight Patient Weight (kg) 285 mcg/kg (once daily titrated to twice daily) 428 mcg/kg (twice daily) 570 mcg/kg (twice daily as tolerated) 19 mg/mL Solution (for PFIC) Volume per Dose (mL) 5 0.1 0.1 0.15 6 to 7 0.1 0.15 0.2 8 0.1 0.2 0.25 9 0.15 0.2 0.25 10 to 12 0.15 0.25 0.3 13 to 15 0.2 0.3 0.4 16 to 19 0.25 0.4 0.5 20 to 24 0.3 0.5 0.6 25 to 29 0.4 0.6 0.8 30 to 34 0.45 0.7 0.9 35 to 39 0.6 0.8 1 40 to 49 0.6 0.9 1 50 to 59 0.8 1 1 60 or higher 0.9 1 1 Table 4: LIVMARLI Tablets for Patients with PFIC: Dosage by Weight* *Select the appropriate product based on the patient's weight and ability to swallow tablets. Patient Weight (kg) 285 mcg/kg BID 428 mcg/kg BID 570 mcg/kg BID Less than 25 Use Oral Solution Use Oral Solution Use Oral Solution 25 to 32 15 mg 33 to 43 10 mg 15 mg 20 mg 44 or higher 15 mg 20 mg 20 mg 2.4 Missed Dose For once daily dosing: If a dose is missed, it should be taken as soon as possible within 12 hours of the time it is usually taken, and the original dosing schedule should be resumed. If a dose is missed by more than 12 hours, the dose can be omitted and the original dosing schedule resumed. For twice daily dosing: If a dose is missed, it should be taken as soon as possible within 6 hours of the time it is usually taken, and the original dosing schedule should be resumed. If a dose is missed by more than 6 hours, the dose can be omitted and the original dosing schedule resumed. 2.5 Important Administration Instructions Administer LIVMARLI oral solution and tablets 30 minutes before a meal [see Clinical Pharmacology (12.3) ] . A calibrated measuring device (0.5 mL, 1 mL or 3 mL oral dosing dispenser) for LIVMARLI oral solution will be provided by the pharmacy to measure and deliver the prescribed dose accurately. After opening the LIVMARLI oral solution bottle, store below 30°C (86°F) and discard any remaining LIVMARLI oral solution after 100 days. 2.6 Dosage Modification for Management of Adverse Events Establish the baseline pattern of variability of liver tests prior to starting LIVMARLI, so that potential signs of liver injury can be identified. Monitor liver tests (e.g., ALT [alanine aminotransferase], AST [aspartate aminotransferase], TB [total bilirubin]), DB [direct bilirubin], and International Normalized Ratio [INR]) during treatment with LIVMARLI. Reduce the dosage or interrupt LIVMARLI if new onset liver test abnormalities occur. Once the liver test abnormalities either return back to baseline values or stabilize at a new baseline value, consider restarting LIVMARLI at the last tolerated dose, and increase the dose as tolerated. Consider discontinuing LIVMARLI permanently if liver test abnormalities recur or symptoms consistent with clinical hepatitis are observed [see Warnings and Precautions (5.1) ] . LIVMARLI has not been studied in patients with hepatic decompensation. Discontinue LIVMARLI permanently if a patient experiences a hepatic decompensation event (e.g., variceal hemorrhage, ascites, hepatic encephalopathy). 2.7 Administration Modification for Drug Interaction Bile Acid Binding Resins Administer LIVMARLI at least 4 hours before or 4 hours after administering the bile acid binding resins [see Drug Interactions (7.1) ] when used concomitantly .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Hepatotoxicity [see Warnings and Precautions (5.1) ] • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.2) ] • Fat Soluble Vitamin (FSV) Deficiency [see Warnings and Precautions (5.3) ] Most common adverse reactions (≥5%) are: • ALGS: diarrhea, abdominal pain, vomiting, fat-soluble vitamin deficiency, liver test abnormalities, and bone fractures. ( 6.1 ) • PFIC: diarrhea, fat soluble vitamin deficiency, abdominal pain, liver test abnormalities, hematochezia, and bone fractures. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mirum Pharmaceuticals at 1-855-MRM-4YOU or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. ALGS: In the Alagille syndrome clinical development program, which includes five clinical studies comprising 86 patients, patients received doses of LIVMARLI up to 760 mcg/kg per day with a median duration of exposure of 32.3 months (range: 0.03 – 60.9 months). In Trial 1, the 4-week placebo control period occurred after 18 weeks of LIVMARLI treatment. In two supportive studies that included long-term open‑label extensions, only 13 weeks of placebo-controlled treatment occurred which evaluated doses lower than 380 mcg/kg/day. The majority of LIVMARLI exposure in the development program occurred without a placebo control in open-label trial extensions. The most common adverse reactions (≥5%) for ALGS patients treated with LIVMARLI are presented in Table 5 below. Treatment interruptions or dose reductions occurred in 5 (6%) patients due to diarrhea, abdominal pain, or vomiting. Table 5: Adverse Reactions Occurring in ≥ 5% of Patients Treated with LIVMARLI in the ALGS Clinical Development Program *Terms were defined as: Fat-Soluble Vitamin deficiency includes: A, D, E, or K deficiency, or 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 Fracture includes: tibia fracture, rib fracture, hand fracture, humerus fracture, pathological fracture, forearm fracture, clavicle fracture 1 Exposure adjusted incidence rate for each adverse reaction type was calculated using the first occurrence of this adverse reaction per patient LIVMARLI (n=86) Adverse Reaction Any Grade n (%) Number of events per 100 person‑years 1 Diarrhea 48 (55.8%) 41.6 Abdominal pain* 46 (53.5%) 38.6 Vomiting 35 (40.7%) 19.8 Nausea 7 (8.1%) 2.9 Fat-Soluble Vitamin deficiency* 22 (25.6%) 11.1 Transaminases increased (ALT, AST)* 16 (18.6%) 6.9 Bone Fractures* 8 (9.3%) 3.3 Liver Test Abnormalities Increase in Transaminases In a pooled analysis of patients with ALGS (N=86) administered LIVMARLI, increases in hepatic transaminases (ALT) were observed. Seven (8.1%) patients discontinued LIVMARLI due to ALT increases. Three (3.5%) patients had a decrease in dose or interruption of LIVMARLI in response to ALT increases. In the majority of cases, the elevations resolved or improved after discontinuation or dose modification of LIVMARLI. In some cases, the elevations resolved or improved without change in LIVMARLI dosing. Increases to more than three times baseline in ALT occurred in 26% of patients treated with LIVMARLI and increases to more than five times baseline occurred in 3%. AST increases to more than three times baseline occurred in 16% of patients treated with LIVMARLI, and an increase to more than five times baseline occurred in one patient. Elevations in transaminases were asymptomatic and not associated with bilirubin elevations or other laboratory abnormalities. Increases in Bilirubin Four (4.6%) patients in the pooled analysis experienced bilirubin increases above baseline, and LIVMARLI was subsequently withdrawn in two of these patients, who had elevated bilirubin at baseline. PFIC: In Trial 2, which enrolled 93 patients, 47 patients received doses of LIVMARLI up to 570 mcg/kg BID, with a median duration of exposure of 6 months (range: 0.3-6.7 months). The most common adverse reactions (≥5%) for PFIC patients treated with LIVMARLI at a rate greater than placebo are presented in Table 6 below. Diarrhea was the most frequent adverse reaction; the majority of episodes were mild and transient with a median duration of 5.5 days. Nineteen (40.4%) LIVMARLI-treated subjects had diarrhea greater than or equal to 7 days. Placebo-treated subjects had a median duration of 3 days of diarrhea and two subjects (4.3%) experienced diarrhea with a duration greater than or equal to 7 days. There were no severe events reported. The majority of abdominal pain events were mild based on AE grading, and associated with concurrent diarrhea. One LIVMARLI-treated patient with an event of mild diarrhea discontinued treatment. Treatment interruptions or dose reductions occurred in 3 (6.4%) LIVMARLI-treated patients due to diarrhea or abdominal pain. No placebo-treated subjects discontinued treatment or had dose reductions or interruptions due to diarrhea. Table 6: Adverse Reactions (any grade) Occurring in ≥5% and at a Rate Greater Than Placebo in Patients Treated with LIVMARLI in the PFIC Trial † Terms were defined as: Abdominal Pain includes : abdominal pain, abdominal pain upper, abdominal distension Transaminases increased includes : Hypertransaminasaemia, ALT abnormal, ALT increased, AST abnormal, AST increased, Transaminases increased, Hepatic enzyme increased. Bone Fracture includes : upper limb fracture, lower limb fracture, radius fracture, ulna fracture, femur fracture, foot fracture Adverse Reaction (Any Grade) Placebo n=46 LIVMARLI n=47 Diarrhea 9 (19.6%) 27 (57.4%) Abdominal pain † 7 (15.2%) 13 (27.7%) Transaminases increased (ALT or AST) † 3 (6.5%) 8 (17%) Hematochezia or rectal hemorrhage 1 (2.2%) 4 (8.5%) Bone Fractures † 0 3 (6.4%) Hepatotoxicity LIVMARLI treatment is associated with a potential for drug-induced liver injury. In PFIC patients in Trial 2, treatment-emergent elevations of liver tests or worsening of liver tests, relative to baseline values, and hepatic decompensation events were observed. Two patients experienced drug-induced liver injury (DILI) attributable to LIVMARLI; one patient received 570 mcg/kg twice daily and the second patient required dose interruption and reduction. Two additional patients experienced DILI in the open-label extension portion of the trial. Of these four patients, one patient required liver transplant and another patient died. Biliary Complications In the placebo-controlled portion of Trial 2, two LIVMARLI-treated patients developed cholangitis or cholecystitis within 3-weeks of drug discontinuation (after 84 days and 130 days after initiating LIVMARLI treatment, respectively). Four LIVMARLI-treated patients developed cholecystitis or cholangitis in the open-label extension portion of Trial 2; the average time to onset was 281 days. Bone Fracture In PFIC patients in Trial 2, treatment-emergent bone fracture events were observed. Three receiving LIVMARLI experienced bone fractures relative to none in placebo-treated patients. The median time to onset of fractures was 73 days. Two LIVMARLI-treated patients developed bone fractures in the open-label portion of Trial 2, with average time to onset of fracture was 204 days. Bleeding In PFIC patients in Trial 2, treatment-emergent events of hematochezia (4 [8.5%] versus 1 [2.2%]), decrease in hemoglobin greater than or equal to 2 grams/dL from baseline (8 [17%] versus 1 [2.2%]), were reported more frequently in LIVMARLI-treated patients relative to placebo-treated patients 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of LIVMARLI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders: hematemesis, liver transplant, post-endoscopy hemorrhage, post-liver biopsy hemorrhage General disorders and administration site conditions: drug ineffective Injury, poisoning and procedural complications : off label use Investigations : gamma-glutamyltransferase increased Nervous system disorders : intracranial hemorrhage

12.3 Pharmacokinetics Because of the low systemic absorption of maralixibat, pharmacokinetic parameters cannot be reliably calculated at the recommended doses. Concentrations of maralixibat in the pediatric ALGS and PFIC patients were below the limit of quantification (0.25 ng/mL) in the majority of plasma samples. Following single dose administration of maralixibat oral solution in healthy adults at doses ranging from 1 mg to 500 mg, plasma concentrations of maralixibat were below the limit of quantification (0.25 ng/mL) at doses less than 20 mg and PK parameters could not be reliably estimated. Following single dose administration of 30 mg maralixibat oral solution under fasted condition, median Tmax was 0.75 hour and mean (SD) Cmax and AUClast were 1.65 (1.10) ng/mL and 3.43 (2.13) ng·h/mL, respectively. Absorption Maralixibat is minimally absorbed and plasma concentrations are often below the limit of quantification (0.25 ng/mL) after single or multiple doses at recommended doses. Oral Solution : Following a single oral administration of maralixibat 30, 45, and 100 mg liquid formulation under fasted condition, AUClast and Cmax increased in a dose-dependent manner with increase of 4.6-and 2.4-fold, respectively, following a 3.3-fold dose increase from 30 to 100 mg. No accumulation of maralixibat was observed following repeated oral administration of maralixibat in healthy adults at doses up to 100 mg once-daily. Tablet: After a single 100 mg dose of maralixibat tablet under fasted condition, mean (SD) AUCinf and Cmax were 13.2 (8.2) ng·h/mL and 3.0 (2.2) ng/mL, respectively. Following a single dose of maralixibat oral solution (99.75 mg) under the same conditions, mean (SD) AUCinf and Cmax were 18.4 (13.2) ng·h/mL and 4.3 (2.7) ng/mL, respectively. Given the local site of action of maralixibat, the slightly lower exposure afforded by the tablet compared to the oral solution is not clinically meaningful. Effect of Food Concomitant administration of a high-fat meal with a single dose of maralixibat oral solution decreased both the rate and extent of absorption. AUC and Cmax of maralixibat values in the fed state were 64.8% to 85.8% lower relative to oral administration of 30 mg in fasted conditions. The effect of food on the changes of systemic exposures to maralixibat is not clinically significant [see Dosage and Administration (2.1 , 2.3 )] . Distribution Maralixibat shows high binding (91%) to human plasma proteins in vitro. Elimination Following a single dose of 30 mg maralixibat oral solution in healthy adults, the mean half-life (t 1/2 ) was 1.6 hours. Metabolism No maralixibat metabolites have been detected in plasma. Three minor metabolites, accounting for <3% of maralixibat-associated fecal radioactivity in total, were identified following administration of [ 14 C]maralixibat as an oral solution. Excretion Fecal excretion was found to be the major route of elimination. Following a single dose of 5 mg 14 C-maralixibat as an oral solution, 73% of the dose was excreted in the feces with 0.066% excreted in the urine. 94% of the fecal excretion was as unchanged maralixibat. Specific Populations Patients with Renal Impairment The pharmacokinetics of maralixibat were not studied in patients with impaired renal function, including those with end-stage renal disease (ESRD) or those on hemodialysis. Drug Interaction Studies Effect of Other Drugs on Maralixibat Maralixibat is not a substrate of the drug transporters MDR1 (P-gp), BCRP, OATP1B1, OATP1B3, or OATP2B2; therefore, concomitant drug products are not predicted to affect the disposition of maralixibat. Effect of Maralixibat on Other Drugs In vitro, maralixibat did not induce CYP isoforms 1A2, 2B6, or 3A4, nor inhibit CYP isoforms 1A2, 2B6, 2C8, 2C9, 2C19 or 2D6 at clinically relevant concentrations. Maralixibat inhibits CYP3A4 in vitro, however clinically relevant effects on the pharmacokinetics of CYP3A4 substrates are unlikely. In vitro, maralixibat did not inhibit the transporters MDR1 (P-gp), BCRP, OAT1, OAT3, OATP1B1, OATP1B3, PEPT1, OCT1, OCT2, OCT3, OCTN1, OCTN2, MRP2, MATE1, or MATE2-K at clinically relevant concentrations. Maralixibat inhibits the drug transporter OATP2B1 in vitro, which can potentially result in reduced absorption of drugs that rely on OATP2B1-mediated uptake in the GI tract. In clinical studies coadministration of 4.75 mg maralixibat (once daily in the morning) with daily doses of either simvastatin, or lovastatin in the evening, did not have a clinically relevant effect on the pharmacokinetics of these statins and their metabolites. Coadministration of 4.75 mg maralixibat did not affect pharmacokinetics of atorvastatin. However, the effect of maralixibat on the pharmacokinetics of OATP2B1 substrates at higher doses has not been evaluated in a clinical study.