Cholic acid

12.1 Mechanism of Action Cholic acid is a primary bile acid synthesized from cholesterol in the liver. In bile acid synthesis disorders due to SEDs in the biosynthetic pathway, and in PDs including Zellweger spectrum disorders, deficiency of primary bile acids leads to unregulated accumulation of intermediate bile acids and cholestasis. Bile acids facilitate fat digestion and absorption by forming mixed micelles and facilitate absorption of fat-soluble vitamins in the intestine. Endogenous bile acids including cholic acid enhance bile flow and provide the physiologic feedback inhibition of bile acid synthesis. The mechanism of action of cholic acid has not been fully established; however, it is known that cholic acid and its conjugates are endogenous ligands of the nuclear receptor, farnesoid X receptor (FXR). FXR regulates enzymes and transporters that are involved in bile acid synthesis and in the enterohepatic circulation to maintain bile acid homeostasis under normal physiologic conditions.

1 INDICATIONS AND USAGE CHOLBAM is a bile acid indicated for: • Treatment of bile acid synthesis disorders due to single enzyme defects (SEDs). ( 1.1 ) • Adjunctive treatment of peroxisomal disorders (PDs) including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat-soluble vitamin absorption. ( 1.2 ) Limitations of use: The safety and effectiveness of CHOLBAM on extrahepatic manifestations of bile acid synthesis disorders due to SEDs or PDs including Zellweger spectrum disorders have not been established. ( 1.3 ). 1.1 Bile Acid Synthesis Disorders Due to Single Enzyme Defects CHOLBAM is indicated for the treatment of bile acid synthesis disorders due to single enzyme defects (SEDs). 1.2. Peroxisomal Disorders Including Zellweger Spectrum Disorders CHOLBAM is indicated for adjunctive treatment of peroxisomal disorders (PDs) including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat-soluble vitamin absorption. 1.3. Limitations of Use The safety and effectiveness of CHOLBAM on extrahepatic manifestations of bile acid synthesis disorders due to SEDs or PDs including Zellweger spectrum disorders have not been established.

2 DOSAGE AND ADMINISTRATION • The recommended dosage is 10 to 15 mg/kg once daily or in two divided doses, in pediatric patients and adults. See prescribing information for weight-based dosing tables. ( 2.1 ) • The recommended dosage in patients with concomitant familial hypertriglyceridemia is 11 to 17 mg/kg once daily or in two divided doses and is adjusted based on clinical response. ( 2.1 ) • Monitor AST, ALT, GGT, alkaline phosphatase, bilirubin and INR every month for the first 3 months, every 3 months for the next 9 months, every 6 months during the next three years and annually thereafter. Administer the lowest dose that effectively maintains liver function. ( 2.2 ) • Discontinue CHOLBAM if liver function does not improve within 3 months of starting treatment, if complete biliary obstruction develops, or if there are persistent clinical or laboratory indicators of worsening liver function or cholestasis; continue to monitor liver function and consider restarting at a lower dose when parameters return to baseline. ( 2.2 , 5.1 ) Administration Instructions: • Take with food. ( 2.3 ) • Do not crush or chew the capsules. For patients unable to swallow the capsules, the capsules can be opened and the contents mixed with drink/food ( 2.3 ) 2.1. Dosage Regimen for Bile Acid Synthesis Disorders Due to SEDs and PDs Including Zellweger Spectrum Disorders The recommended dosage of CHOLBAM is 10 to 15 mg/kg administered orally once daily or in two divided doses, in pediatric patients and adults. Table 1 and Table 2 show the number of capsules that should be administered daily to approximate a dosage of 10 mg/kg/day and 15 mg/kg/day, respectively, using the available 50 mg and 250 mg capsules alone or in combination. Table 1: Number of CHOLBAM Capsules Needed to Achieve a Recommended Dosage of 10 mg/kg/day 10 mg/kg/day Dosage Body Weight (kg) Number of 50 mg capsules Number of 250 mg capsules 4 to 6 1 0 7 to 10 2 0 11 to 15 3 0 16 to 20 4 0 21 to 25 0 1 26 to 30 1 1 31 to 35 2 1 36 to 40 3 1 41 to 45 4 1 46 to 50 0 2 51 to 55 1 2 56 to 60 2 2 61 to 65 3 2 66 to 70 4 2 71 to 75 0 3 76 to 80 1 3 Table 2: Number of CHOLBAM Capsules Needed to Achieve a Recommended Dosage of 15 mg/kg/day 15 mg/kg/day Dosage Body Weight (kg) Number of 50 mg capsules Number of 250 mg capsules 4 to 5 1 0 6 to 9 2 0 10 to 13 3 0 14 to 16 4 0 17 to 19 0 1 20 to 23 1 1 24 to 26 2 1 27 to 29 3 1 30 to 33 4 1 34 to 36 0 2 37 to 39 1 2 40 to 43 2 2 44 to 46 3 2 47 to 49 4 2 50 to 53 0 3 54 to 56 1 3 57 to 59 2 3 60 to 63 3 3 64 to 66 4 3 67 to 69 0 4 70 to 73 1 4 74 to 76 2 4 77 to 79 3 4 80 4 4 Patients with newly diagnosed, or a family history of, familial hypertriglyceridemia may have poor absorption of CHOLBAM from the intestine and require a 10% increase in the recommended dosage to account for losses due to malabsorption. The recommended dosage of CHOLBAM in patients with concomitant familial hypertriglyceridemia is 11 to 17 mg/kg orally once daily, or in two divided doses. Adequacy of the dosage regimen can be determined by monitoring the patient’s clinical response including steatorrhea and laboratory values of serum transaminases, bilirubin, and prothrombin time/international normalized ratio (PT/INR). 2.2. Treatment Monitoring Treatment with CHOLBAM should be initiated and monitored by an experienced hepatologist or pediatric gastroenterologist. Monitor serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), serum gamma glutamyltransferase (GGT), alkaline phosphatase, bilirubin, and INR every month for the first 3 months, every 3 months for the next 9 months, every 6 months during the subsequent three years, and annually thereafter. Monitor more frequently during periods of rapid growth, concomitant disease, and pregnancy. Administer the lowest dose of CHOLBAM that effectively maintains liver function [see Warnings and Precautions ( 5.1 )] . Discontinue treatment with CHOLBAM if liver function does not improve within 3 months of the start of treatment or if complete biliary obstruction develops. Discontinue treatment with CHOLBAM at any time if there are persistent clinical or laboratory indicators of worsening liver function or cholestasis [see Warnings and Precautions ( 5.1 )] . Concurrent elevations of serum GGT and serum ALT may indicate CHOLBAM overdose [see Overdosage ( 10 )] . Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when parameters return to baseline. Assessment of serum or urinary bile acid levels using mass spectrometry is used in the diagnosis of bile acid synthesis disorders due to SEDs and PDs including Zellweger spectrum disorders. The utility of bile acid measurements in monitoring the clinical course of patients and in decisions regarding dose adjustment has not been demonstrated. 2.3 Administration Instructions • Take CHOLBAM with food. • Take CHOLBAM at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after

6 ADVERSE REACTIONS The following clinically significant adverse reaction is described elsewhere in the labeling: • Exacerbation of Liver Impairment [see Warnings and Precautions ( 5.1 )] Most common adverse reactions (≥1%) are diarrhea, reflux esophagitis, malaise, jaundice, skin lesion, nausea, abdominal pain, intestinal polyp, urinary tract infection, and peripheral neuropathy. ( 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. Clinical safety experience with CHOLBAM consists of: • Trial 1: a non-randomized, open-label, single-arm trial of 50 patients with bile acid synthesis disorders due to SEDs and 29 patients with PDs including Zellweger spectrum disorders. Safety data are available over the 18 years of the trial. • Trial 2: an extension trial of 12 new patients (10 SED and 2 PD) along with 31 (21 SED and 10 PD) patients who rolled over from Trial 1. Safety data are available for 3 years and 11 months of treatment. Adverse events were not collected systematically in either of these trials. Most patients received an oral dose of 10 to 15 mg/kg/day of CHOLBAM. Deaths In Trial 1, among the 50 patients with SEDs, 5 patients aged 1 year or less died, which included three patients originally diagnosed with AKR1D1 deficiency, one with 3β-HSD deficiency and one with CYP7A1 deficiency. The cause of death was attributed to progression of underlying liver disease in every patient. Of 29 patients in Trial 1 with PDs including Zellweger spectrum disorders, 12 patients between the ages of 7 months and 2.5 years died. In the majority of these patients (8/12), the cause of death was attributed to progression of underlying liver disease or to a worsening of their primary illness. Two additional patients in Trial 1 (1 SED and 1 PD) died who had been off study medication for more than one year with the cause of death most likely being a progression of underlying liver disease. Of the patients who died with disease progression, laboratory testing showed abnormal serum transaminases, bilirubin, or cholestasis on liver biopsy suggesting worsening of their underlying cholestasis. In Trial 2, among the 31 patients with SED, two patients (1 new patient and 1 who rolled over from Trial 1) died. The cause of death in both cases was unrelated to their primary treatment or progression of their underlying liver disease. Of the 12 patients with PD in Trial 2, four patients died between the ages of 4 and 8 years (1 new patient and 3 who rolled over from Trial 1). The cause of death in three of these patients was attributed to progression of underlying liver disease or to a worsening of their primary illness. Worsening of Liver Impairment Seven patients in Trial 1 (4 SED and 3 PD) and 3 patients in Trial 2 (1 SED and 2 PD) experienced worsening serum transaminases, elevated bilirubin values, or worsening cholestasis on liver biopsy during treatment [see Warnings and Precautions ( 5.1 )] . Common Adverse Reactions There were 12 adverse reactions reported across 9 patients in the trials, with diarrhea being the most common reaction in approximately 2% of the patient population. All other adverse reactions represented 1% of the patient population. The breakdown by trial follows: Table 3: Most Common Adverse Reactions in Trials 1 and 2 *Adverse reactions that occurred in new patients Adverse Reactions Trial 1 Trial 2* Overall n (%) Diarrhea 1 2* 3 (2) Reflux Esophagitis 1 0 1 (1) Malaise 1 0 1 (1) Jaundice 1 0 1 (1) Skin lesion 1 0 1 (1) Nausea 0 1* 1 (1) Abdominal Pain 0 1* 1 (1) Intestinal Polyp 0 1* 1 (1) Urinary Tract Infection 0 1* 1 (1) Peripheral Neuropathy 0 1 1 (1) Only one of the reactions (peripheral neuropathy) resulted in discontinuation of medication for a patient in Trial 2. An additional five SED patients (3 from Trial 1 and 2 from Trial 2) and 1 PD patient (Trial 1) discontinued medication and withdrew from the study due to a worsening of their primary disease. The development of symptomatic cholelithiasis requiring cholecystectomy has been reported in a single patient with 3β-HSD deficiency. 6.2. Postmarketing Experience The following adverse reactions have been identified during post-approval use of CHOLBAM. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their relative frequency or to establish a causal relationship to CHOLBAM exposure: • Gastrointestinal disorders : discomfort and distention, emesis, constipation • General disorders and administrative site conditions : pyrexia/fever • Skin and subcutaneous tissue disorders : rash

7 DRUG INTERACTIONS • Bile Salt Efflux Pump (BSEP) Inhibitors (e.g., cyclosporine): Avoid concomitant use; if concomitant use is necessary, monitor serum transaminases and bilirubin ( 7.1 ) • Bile Acid Resins and Aluminum-Based Antacids: Take CHOLBAM at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after a bile acid binding resin or aluminum-based antacids. ( 2.3 , 7.1 ) 7.1. Effects of Other Drugs on CHOLBAM Drug interactions with CHOLBAM mainly relate to agents capable of interrupting the enterohepatic circulation of bile acids. Inhibitors of Bile Acid Transporters Avoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine. Concomitant medications that inhibit canalicular membrane bile acid transporters such as the BSEP may exacerbate accumulation of conjugated bile salts in the liver and result in clinical symptoms. If concomitant use is deemed necessary, monitoring of serum transaminases and bilirubin is recommended. Bile Acid Binding Resins Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce the efficacy of CHOLBAM. Take CHOLBAM at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after a bile acid binding resin [see Dosage and Administration ( 2.3 )] . Aluminum-Based Antacids Aluminum-based antacids have been shown to adsorb bile acids in vitro and can reduce the availability of CHOLBAM. Take CHOLBAM at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after an aluminum-based antacid [see Dosage and Administration ( 2.3 )] .