BYLVAY

1 INDICATIONS AND USAGE BYLVAY is an ileal bile acid transporter (IBAT) inhibitor indicated for: Progressive Familial Intrahepatic Cholestasis (PFIC) the treatment of pruritus in patients 3 months of age and older with progressive familial intrahepatic cholestasis (PFIC). ( 1.1 ) Limitation of Use : BYLVAY is not recommended in a subgroup of PFIC type 2 patients with specific ABCB11 variants resulting in non-functional or complete absence of the bile salt export pump protein. ( 12.5 , 14.1 ) Alagille Syndrome (ALGS) the treatment of cholestatic pruritus in patients 12 months of age and older with Alagille syndrome (ALGS). ( 1.2 ) 1.1 Progressive Familial Intrahepatic Cholestasis (PFIC) BYLVAY is indicated for the treatment of pruritus in patients 3 months of age and older with PFIC. Limitations of Use BYLVAY is not recommended in a subgroup of PFIC type 2 patients with specific ABCB11 variants resulting in non-functional or complete absence of the bile salt export pump (BSEP) protein [see Clinical Pharmacology (12.5) and Clinical Studies (14.1) ]. 1.2 Alagille Syndrome (ALGS) BYLVAY is indicated for the treatment of cholestatic pruritus in patients 12 months of age and older with ALGS.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Hepatotoxicity [ see Warnings and Precautions (5.1) ] Diarrhea [see Warnings and Precautions (5.2) ] Fat-Soluble Vitamin Deficiency [see Warnings and Precautions (5.3) ] PFIC: Most common adverse reactions (>2%) are liver test abnormalities, diarrhea, abdominal pain, vomiting, and fat-soluble vitamin deficiency. ( 6.1 ) ALGS: Most common adverse reactions (>5%) are diarrhea, abdominal pain, hematoma, and decreased weight. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Albireo Pharma, Inc. at +1-855-252-4736, 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. PFIC Clinical Studies Trial 1 is a randomized, double-blind, placebo-controlled, 24-week study of two dose levels of BYLVAY (40 mcg/kg and 120 mcg/kg) administered once daily [see Clinical Studies (14.1) ] . Sixty-two patients were randomized (1:1:1) to receive one of the following: BYLVAY 40 mcg/kg/day (n=23), BYLVAY 120 mcg/kg/day (n=19), or Placebo (n=20). Table 3 summarizes the frequency of adverse reactions reported in ≥2% and at a rate greater than placebo in patients treated with BYLVAY in Trial 1. The most common adverse reactions observed in Trial 1 included diarrhea, liver test abnormalities, vomiting, abdominal pain, and fat-soluble vitamin deficiency. Table 3. Common Adverse Reactions Adverse reactions that occurred in ≥2% of BYLVAY-treated patients from a Clinical Study of BYLVAY in Patients with Progressive Familial Intrahepatic Cholestasis (Trial 1) Adverse Reaction Placebo N=20 n (%) BYLVAY 40 mcg/kg/day N=23 n (%) BYLVAY 120 mcg/kg/day N=19 n (%) Diarrhea 2 (10%) 9 (39%) 4 (21%) Transaminases increased (ALT, AST) 1 (5%) 3 (13%) 4 (21%) Vomiting 0 4 (17%) 3 (16%) Abdominal pain 0 3 (13%) 3 (16%) Blood bilirubin increased 2 (10%) 3 (13%) 2 (11%) Fat-soluble vitamin deficiency (A, D, E) 1 (5%) 0 3 (16%) Splenomegaly 0 0 2 (11%) Cholelithiasis 0 0 1 (5%) Dehydration 0 0 1 (5%) Fracture 0 1 (4%) 0 Trial 2 is an open-label, single-arm study in 116 patients with PFIC types 1, 2, 3, 4 and 6; four patients with benign recurrent intrahepatic cholestasis (BRIC) were also enrolled. BYLVAY 40 or 120 mcg/kg/day was administered once daily for 72 weeks, with the option to continue treatment beyond 72 weeks. Adverse reactions were similar to those observed in Trial 1. However, fractures were reported in a total of 6 patients (5%) in Trial 2. Adverse reactions observed in Trial 2 in addition to those described in Table 3 included increased INR (16%), epistaxis (9%), constipation (8%), coagulopathy (3%), headache (3%), nausea (3%), rash (3%), iron deficiency anemia (3%), gastroesophageal reflux disease (2%), prolonged prothrombin time (2%); and variceal hemorrhage, stoma hemorrhage, hematochezia, and rectal hemorrhage (<1% each). Adverse reactions leading to treatment discontinuation were increased bilirubin levels, diarrhea, progression of disease, increased INR, irritability, and decreased weight. There was a total of 19 (16%) patients who underwent surgical intervention in Trial 2, with one patient who had surgical biliary diversion (SBD) followed by liver transplant, 15 patients who underwent liver transplant alone, and three patients who underwent SBD alone. Overall, 11 of the 19 patients had these surgical interventions prior to Week 72. ALGS Clinical Studies Trial 3 is a randomized, double-blind, placebo-controlled, 24-week study of a single dose level of BYLVAY (120 mcg/kg) administered once daily [see Clinical Studies (14.2) ] . Fifty-two patients were randomized (2:1) to receive one of the following: BYLVAY 120 mcg/kg/day (n=35), or Placebo (n=17). Table 4 summarizes the frequency of adverse reactions in patients with ALGS, reported in ≥5% and at a rate greater than placebo in patients treated with BYLVAY in Trial 3. No patients discontinued study treatment due to an adverse reaction. The most common adverse reactions observed in Trial 3 included diarrhea, abdominal pain, hematoma, and decreased weight. Table 4. Common Adverse Reactions Adverse reactions that occurred in ≥5% of BYLVAY-treated patients from a Clinical Study of BYLVAY in Patients with Alagille Syndrome (Trial 3) Adverse Reaction Placebo N=17 n (%) BYLVAY 120 mcg/kg/day N=35 n (%) Diarrhea 1 (6%) 10 (29%) Abdominal Pain 1 (6%) 5 (14%) Hematoma 0 3 (9%) Weight decreased 0 2 (6%) Trial 4 is an open-label, single-arm study in 50 pediatric patients with ALGS. BYLVAY 120 mcg/kg/day was administered once daily for 72 weeks, with the option to continue beyond 72 weeks. Adverse reactions observed in Trial 4 in addition to those described in Table 4 included FSV deficiency (vitamin D deficiency [14%], vitamin E deficiency [10%], vitamin K deficiency [6%]), ALT increased (6%), headache (6%), increased INR (6%), increased blood bilirubin (4%), increased AST (4%), coagulopathy (4%), fracture (4%); nausea, vomiting, hematemesis, hematochezia, epistaxis, and constipation (2% each). The most common reason for BYLVAY treatment discontinuation was increased bilirubin levels. One patient underwent liver transplant in Trial 4 prior to Week 72 with no patients underwent SBD. Hepatotoxicity BYLVAY treatment is associated with a potential for DILI. In the PFIC and ALGS trials, treatment-emergent elevations of liver tests or worsening of liver tests occurred. Of the six patients who experienced DILI, two underwent liver transplant. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of BYLVAY. 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 : gastrointestinal hemorrhage, gingival hemorrhage, liver transplant Investigations : gamma-glutamyltransferase increased, hemoglobin decreased Nervous system disorders: extra-axial hemorrhage (subdural hemorrhage) Respiratory, thoracic, and mediastinal disorders: epistaxis