Elafibranor

1 INDICATIONS AND USAGE IQIRVO is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have had an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. This indication is approved under accelerated approval based on reduction of alkaline phosphatase (ALP) [see Clinical Studies (14) ] . Improvement in survival or prevention of liver decompensation events have not been demonstrated. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). IQIRVO is a peroxisome proliferator-activated receptor (PPAR) agonist indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. This indication is approved under accelerated approval based on reduction of alkaline phosphatase (ALP). Improvement in survival or prevention of liver decompensation events have not been demonstrated. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). ( 1 ) Limitations of Use Use of IQIRVO is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy). ( 8.7 , 12.3 ) Limitations of Use Use of IQIRVO is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy) [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ] .

12.1 Mechanism of Action Elafibranor and its main active metabolite GFT1007 are peroxisome proliferator-activated receptor (PPAR) agonists, both of which activate PPAR-alpha, PPAR-gamma, and PPAR-delta in vitro. However, the mechanism by which elafibranor exerts its therapeutic effects in patients with PBC is not well understood. Pharmacological activity that is potentially relevant to therapeutic effects includes inhibition of bile acid synthesis through activation of PPAR-alpha and PPAR-delta. The signaling pathway for PPAR-delta was reported to include Fibroblast Growth Factor 21 (FGF21)-dependent downregulation of CYP7A1, the key enzyme for the synthesis of bile acids from cholesterol. An in vitro PPAR functional assay showed that both elafibranor and GFT1007 produced activation of PPAR-alpha (EC 50 = 46 nM and 14 nM, respectively, and E max = 56% and 61%, respectively, relative to reference agonists). The potency of elafibranor and GFT1007 for PPAR-alpha activation exceeded the respective potencies for PPAR-gamma and PPAR-delta activation by approximately 3- to 8-fold. Although the in vitro pharmacology studies detected PPAR-gamma activation by elafibranor and its metabolite GFT1007, toxicology studies in rats and monkeys (species with plasma metabolite profiles comparable to human) showed none of the adverse effects that are associated with PPAR-gamma activation.

2 DOSAGE AND ADMINISTRATION Before treatment, evaluate for muscle pain or myopathy, and/or verify that females of reproductive potential are not pregnant. ( 2.1 ) The recommended dosage is 80 mg orally once daily with or without food. ( 2.2 ) 2.1 Recommended Evaluation Before Initiating IQIRVO Before initiating IQIRVO: Evaluate for muscle pain or myopathy [see Warnings and Precautions (5.1) ] . Verify that females of reproductive potential are not pregnant prior to initiating treatment with IQIRVO [ see Warnings and Precautions (5.3) , Use in Specific Populations (8.1 , 8.3) ] . 2.2 Recommended Dosage and Administration The recommended dosage of IQIRVO is 80 mg taken orally once daily with or without food [see Clinical Pharmacology (12.3) ] . 2.3 Administration Modification for Bile Acid Sequestrants Administer IQIRVO at least 4 hours before or 4 hours after administering the bile acid sequestrant, or at as great an interval as possible [see Drug Interactions (7.2) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Myalgia, Myopathy, and Rhabdomyolysis [see Warnings and Precautions (5.1) ] Fractures [see Warnings and Precautions (5.2) ] Drug-Induced Liver Injury [see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Warnings and Precautions (5.5) ] Most common adverse reactions with IQIRVO (reported in ≥ 5% and higher compared to placebo) are weight gain, diarrhea, abdominal pain, nausea, vomiting, arthralgia, constipation, muscle injury, fracture, gastroesophageal reflux disease, dry mouth, weight loss, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at 1-855-463-5127 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. The safety of IQIRVO is based on Study 1 consisting of 161 patients who were randomized to receive IQIRVO 80 mg (n=108) or placebo (n=53) once daily with a median duration of exposure during the double-blind period of 62 weeks (inter quartile range: 52, 84) [see Clinical Studies (14) ] . IQIRVO or placebo was administered in combination with UDCA in 95% of patients and as monotherapy in 5% of patients who were unable to tolerate UDCA. The most common adverse reaction leading to treatment discontinuation was increased CPK (4%). Common Adverse Reactions Table 1 presents common adverse reactions that occurred in Study 1. Table 1: Common Adverse Reactions Occurring During the Double-Blind Period in Adult Patients with PBC (Study 1) Included 8 patients (5%) who were intolerant to UDCA and initiated treatment as monotherapy: 6 patients (5%) in the IQIRVO arm and 2 patients (4%) in the placebo arm. Adverse Reaction Occurring in greater than or equal to 5% of patients in the IQIRVO treatment arm and at an incidence greater than or equal to 1% higher than in the placebo treatment arm. IQIRVO 80 mg Once Daily N = 108 % (n) Placebo N = 53 % (n) Weight gain Weight gain, abdominal pain, muscle pain, fracture, and rash include other related terms. 23% (25) 21% (11) Diarrhea 11% (12) 9% (5) Abdominal pain 11% (12) 6% (3) Nausea 11% (12) 6% (3) Vomiting 11% (12) 2% (1) Arthralgia 8% (9) 4% (2) Constipation 8% (9) 2% (1) Muscle pain 7% (8) 2% (1) Fracture 6% (7) 0 Gastroesophageal reflux disease 6% (7) 2% (1) Dry mouth 5% (5) 2% (1) Weight loss 5% (5) 0 Rash 5% (5) 4% (2) Gastrointestinal Adverse reactions Gastrointestinal symptoms were observed in 35 (32%) IQIRVO-treated patients compared to 6 (11%) in the placebo-treated patients. The severity of gastrointestinal events was mild in 43% of events and was moderate in 51% of events. The median time to onset was 13 (0.3 to 92) weeks for diarrhea, 4 (0.1 to 26) weeks for nausea, and 23 (4 to 55) weeks for vomiting. The median duration of events was 0.6 (0.3 to 86) weeks for diarrhea, 2 (0.1 to 89) weeks for nausea and 0.3 (0.1 to 51) weeks for vomiting without requiring discontinuation of IQIRVO. Myalgia, Myopathy, and Rhabdomyolysis Muscle injury included rhabdomyolysis, CPK elevation with or without myalgia, and myopathy. Rhabdomyolysis and acute kidney injury (AKI) occurred in one IQIRVO-treated patient who had cirrhosis at baseline and was also on a stable dose of an HMG-CoA reductase inhibitor for a year. Median time to development of myalgia was 85.5 days (interquartile range: 29, 291). CPK elevation and/or myalgia occurred in patients on IQIRVO monotherapy as well as in patients who were concomitantly treated with an HMG-CoA reductase inhibitor. Table 2 presents the frequency of muscle injury related adverse reactions in Study 1. Table 2: Muscle Injury Related Adverse Reactions During the Double-Blind Period in Adult Pati

5 WARNINGS AND PRECAUTIONS Myalgia, Myopathy, and Rhabdomyolysis : Assess for muscle pain and myopathy prior to IQIRVO initiation. Consider periodic assessment (clinical exam, CPK measurement). Interrupt IQIRVO if there is new onset or worsening of muscle injury, or muscle pain. ( 5.1 ) Fractures: The risk of fracture should be considered in the care of patients treated with IQIRVO. Apply current standards of care for assessing and maintaining bone health. ( 5.2 ) Adverse Effects on Fetal and Newborn Development : May cause fetal harm. Verify that a female of reproductive potential is not pregnant prior to initiating IQIRVO. Advise females of reproductive potential to avoid use of hormonal contraceptives containing ethinyl estradiol and to use alternative contraception. ( 5.3 , 8.1 , 8.3 ) Drug-Induced Liver Injury : Obtain clinical and laboratory assessments at treatment initiation and monitor thereafter according to routine patient management. Interrupt the treatment if liver tests worsen, or patients develop signs and symptoms consistent with clinical hepatitis. Consider permanent discontinuation if liver tests worsen after restarting IQIRVO. ( 5.4 ) Hypersensitivity Reactions : If severe hypersensitivity reactions occur, permanently discontinue IQIRVO. If a mild or moderate hypersensitivity reaction occurs, interrupt IQIRVO and treat promptly. Monitor until signs and symptoms resolve. ( 5.5 ) Biliary Obstruction : Avoid use in patients with complete biliary obstruction. If biliary obstruction is suspected, interrupt IQIRVO and treat as clinically indicated. ( 5.6 ) 5.1 Myalgia, Myopathy, and Rhabdomyolysis Rhabdomyolysis resulting in acute kidney injury occurred in one IQIRVO-treated patient who had cirrhosis at baseline and was also taking a stable dose of an HMG-CoA reductase inhibitor (statin). Myalgia or myopathy, with or without CPK elevations, occurred in patients treated with IQIRVO alone or treated concomitantly with a stable dose of an HMG-CoA reductase inhibitor [see Adverse Reactions (6.1) ] . Assess for myalgia and myopathy prior to IQIRVO initiation. Consider periodic assessment (clinical exam, CPK measurement) during treatment with IQIRVO, especially in those who have signs and symptoms of new onset or worsening of muscle pain or myopathy. Interrupt IQIRVO treatment if there is new onset or worsening of muscle pain, or myopathy, or rhabdomyolysis. IQIRVO may be restarted if an alternative etiology for these signs and symptoms has been identified and resolved. However, discontinue IQIRVO if signs and symptoms recur. Patients concomitantly taking peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonists (e.g., fenofibrate, fenofibric acid) may have an increased risk of muscle injury. Monitor for signs and symptoms of muscle injury during concomitant use with IQIRVO [see Drug Interactions (7.2) ] . 5.2 Fractures Fractures occurred in 6% of IQIRVO-treated patients compared to no placebo-treated patients [see Adverse Reactions (6.1) ] . Consider the risk of fracture in the care of patients treated with IQIRVO and monitor bone health according to current standards of care. 5.3 Adverse Effects on Fetal and Newborn Development Based on findings from animal reproduction studies, IQIRVO may cause fetal harm when administered during pregnancy. Treatment of pregnant rats with elafibranor at maternal plasma drug exposures lower than or approximately equal to human exposure at the recommended dose resulted in stillbirths, reduced survival, decrease in pup body weight, and/or blue/black discoloration of the caudal section of body [see Use in Specific Populations (8.1) ] . For females of reproductive potential, verify that the patient is not pregnant prior to initiation of therapy. IQIRVO may reduce the effectiveness of hormonal contraceptives containing ethinyl estradiol. Advise females of reproductive potential to avoid use of hormonal contraceptives containing ethinyl estradiol and to use alternative contrace

4 CONTRAINDICATIONS None. None.