Seladelpar Lysine

1 INDICATIONS AND USAGE LIVDELZI 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 a 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). LIVDELZI is a peroxisome proliferator-activated receptor (PPAR)-delta 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 a 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 LIVDELZI is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy). ( 8.7 ) Limitations of Use Use of LIVDELZI 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) ] .

2 DOSAGE AND ADMINISTRATION The recommended dosage of LIVDELZI is 10 mg orally once daily. Administer LIVDELZI with or without food. ( 2.1 ) 2.1 Recommended Dosage and Administration The recommended dosage of LIVDELZI is 10 mg orally once daily. Administer LIVDELZI with or without food [see Clinical Pharmacology (12.3) ] . 2.2 Administration Modification for Bile Acid Sequestrants Administer LIVDELZI at least 4 hours before or 4 hours after taking bile acid sequestrants, or at as great an interval as possible [see Drug Interactions (7.1) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: Fractures [see Warnings and Precautions (5.1) ] Liver Test Abnormalities [see Warnings and Precautions (5.2) ] Most common adverse reactions (reported in ≥5% and higher compared to placebo) are headache, abdominal pain, nausea, abdominal distension, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial 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. In Trial 1, 193 patients were randomized to receive either LIVDELZI 10 mg (N=128) or placebo (N=65) once daily for 12 months [see Clinical Studies (14) ] . LIVDELZI or placebo was administered in combination with UDCA in 94% of patients and as monotherapy in 6% of patients who were unable to tolerate UDCA. Common Adverse Reactions Table 1 presents common adverse reactions that occurred in Trial 1. Table 1: Common Adverse Reactions Occurring Through Week 52 in Adult Patients with PBC (Trial 1) Included 12 patients (6%) who were intolerant to UDCA and initiated treatment as monotherapy: 8 patients (6%) in the LIVDELZI 10 mg arm and 4 patients (6%) in the placebo arm. Adverse Reaction Occurring in greater than or equal to 5% of patients in the LIVDELZI treatment arm and at an incidence greater than or equal to 1% higher than in the placebo arm. LIVDELZI 10 mg Once Daily (N=128) % (n) PLACEBO (N=65) % (n) Headache 8% (10) 3% (2) Abdominal pain The gastrointestinal adverse reactions were mild to moderate without the need for discontinuation of LIVDELZI. 7% (9) 2% (1) Nausea 6% (8) 5% (3) Abdominal distension 6% (8) 3% (2) Dizziness 5% (6) 2% (1) Fractures In Trial 1, fractures occurred in 4% (n=5) of LIVDELZI-treated patients compared to no placebo-treated patients. Baseline bone mineral density was not obtained. The median time to fracture after receiving LIVDELZI was 295 days (range: 89–349). Less Common Adverse Reactions Additional adverse reactions that occurred more frequently in the LIVDELZI-treated patients compared to placebo, but in less than 5% of patients, included dyspepsia, rash, alopecia, anemia, and cough. Laboratory Abnormalities Estimated Glomerular Filtration Rate In Trial 1, LIVDELZI-treated patients developed decreased estimated glomerular filtration rate (eGFR) (serum creatinine elevations) more frequently compared to placebo-treated patients. Ten percent (n=12) of LIVDELZI-treated patients had a decline in eGFR of at least 25%, compared to 2% (n=1) of placebo-treated patients. None of the patients experienced an eGFR decline of 50% or more. The decline in eGFR stabilized or returned towards baseline with ongoing LIVDELZI treatment. None of the patients required discontinuation of LIVDELZI and there were no clinical findings associated with the observed changes in eGFR.

12.3 Pharmacokinetics Following a single dose administration, seladelpar systemic exposure increased dose-proportionally from 2 mg (0.2 times the recommended dosage) to 15 mg (1.5 times the recommended dosage) and greater than dose proportionally at higher doses. For a dose increase from 10 mg to 200 mg (20 times the recommended dosage), mean C max and mean AUC for seladelpar increased 70-fold and 27-fold, respectively. Following once daily dosing, seladelpar steady-state was achieved by day 4 and AUC increase was less than 30%. In PBC patients, median (CV) C max and AUC for seladelpar was 90.5 (42.5%) ng/mL and 817 (44%) ng*h/mL, respectively at steady state following once daily dosing of 10 mg. Absorption The median time to peak concentration (T max ) was 1.5 hours for seladelpar. Effect of Food No clinically significant differences in seladelpar pharmacokinetics were observed following administration of a high-fat meal in healthy subjects. Distribution Seladelpar steady state apparent volume of distribution was approximately 110.3 L. Seladelpar plasma protein binding is greater than 99%. Elimination The apparent oral clearance of seladelpar is 12.6 L/h. Following administration of a single dose of 10 mg seladelpar in healthy subjects, mean elimination half-life was 6 hours for seladelpar. In PBC patients, the half-life range was 3.8 to 6.7 hours for seladelpar. Metabolism Seladelpar is primarily metabolized in vitro by CYP2C9 and to a lesser extent by CYP2C8 and CYP3A4, resulting in the three major metabolites: seladelpar sulfoxide (M1), desethyl-seladelpar (M2), and desethyl-seladelpar sulfoxide (M3). The metabolite-to-parent AUC ratios were 0.36, 2.32 and 0.63 for M1, M2 and M3, respectively. Median T max for metabolites were 10 hours for M1 and 4 hours for M2 and M3. None of the major metabolites have pharmacological activity. Excretion Seladelpar is primarily eliminated in urine as metabolites. Following a single oral dose of 10 mg radiolabeled seladelpar in humans, approximately 73.4% of the dose was recovered in urine (less than 0.01% unchanged) and 19.5% in feces (2.02% unchanged) within 216 hours. Biliary excretion of seladelpar was suggested by an animal study. Specific Populations No clinically significant differences in the pharmacokinetics of seladelpar were observed based on age (19 to 79 years old), body mass index (BMI) (17.6 to 45.0 kg/m 2 ), weight (45.8 to 127.5 kg), sex, and race (White, Black, or other). Patients with Renal Impairment In subjects with mild (eGFR ≥60 to <90 mL/min/1.73 m 2 , MDRD), moderate (eGFR ≥30 to <60 mL/min/1.73 m 2 ), and severe (<30 mL/min/1.73 m 2 and not on dialysis) renal impairment, the AUC inf of seladelpar was 10% higher, 54% higher, and similar to that in subjects with normal renal function, respectively, after administration of a single 10 mg dose of seladelpar. The difference in C max of seladelpar was less than 18% in subjects with renal impairment compared to subjects with normal renal function [see Use in Specific Populations (8.6) ] . The pharmacokinetics of seladelpar have not been studied in patients requiring hemodialysis. Patients with Hepatic Impairment Hepatic Impairment of various etiologies: Following a single oral dose of 10 mg seladelpar, seladelpar AUC increased 1.1-fold in subjects with mild (Child-Pugh A), 2.5-fold in moderate (Child-Pugh B), and 2.1-fold in severe (Child-Pugh C) hepatic impairment. Seladelpar C max increased 1.3-fold in subjects with mild (Child-Pugh A), 5.2-fold in moderate (Child-Pugh B), and 5-fold in severe (Child-Pugh C) hepatic impairment. Hepatic Impairment in patients with PBC: Compared to PBC patients with mild hepatic impairment (Child-Pugh A) without portal hypertension, seladelpar exposures (C max , AUC) were 1.7 to 1.8-fold higher in PBC patients with mild hepatic impairment with portal hypertension, 1.6 to 1.9-fold higher in PBC patients with moderate hepatic impairment (Child-Pugh B), and 2.1 to 2.5-fold higher in PBC patients with severe hepatic impairment (Child-Pugh C) after a single oral dose of 10 mg seladelpar. Accumulation ratios were less than 1.2-fold in PBC patients with mild hepatic impairment with portal hypertension and PBC patients with moderate hepatic impairment following 10 mg seladelpar once daily dosing for 28 days. Drug Interaction Studies Effect of Other Drugs on Seladelpar Carbamazepine Seladelpar AUC 0–inf decreased by approximately 44% and C max by 24% following administration of a single 10 mg seladelpar dose after carbamazepine 300 mg twice daily for 8 days in healthy subjects. The carbamazepine (CYP3A and CYP2C9 inducer) dose was escalated from 100 mg twice daily for 3 days followed by 200 mg twice daily for 4 days to 300 mg twice daily. Fluconazole Seladelpar AUC 0–inf increased by 2.4-fold and C max by 1.4-fold following concomitant use of a single 10 mg seladelpar dose with 400 mg fluconazole (moderate CYP2C9 and CYP3A4 inhibitor) in healthy subjects. Cyclosporine Seladelpar AUC 0–inf increased by 2.1-fold and C max by 2.9-fold following concomitant use of a single 10 mg seladelpar dose with 600 mg cyclosporine (OATP1B1, OATP1B3, and BCRP inhibitor) in healthy subjects. Probenecid Seladelpar AUC 0–inf increased by 2-fold and C max by 4.69-fold following concomitant use of a single 10 mg seladelpar dose with 500 mg probenecid in healthy subjects . Quinidine Seladelpar exposures were not significantly altered when a single dose of 600 mg quinidine (P-gp inhibitor) was coadministered in healthy subjects. Other Drugs: No clinically significant differences in seladelpar pharmacokinetics were predicted when used concomitantly with strong CYP3A4 inhibitors or CYP2C8 inhibitors. In Vitro Studies Seladelpar is a substrate of CYP2C9, CYP2C8, CYP3A4, and the transporters BCRP, P-gp, OATP1B1, OATP1B3, and OAT3. Seladelpar is not a substrate of MATE1, MATE2-K, OAT1, OCT1, or OCT2 transporters. Effects of Seladelpar on other drugs In clinical studies, no clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with seladelpar: tolbutamide (CYP2C9 substrate), midazolam (CYP3A4 substrate), simvastatin (CYP3A4 and OATP substrate), atorvastatin (CYP3A4 and OATP substrate), or rosuvastatin (BCRP and OATP substrate). In Vitro Studies Based on in vitro studies, 10 mg seladelpar does not significantly affect the pharmacokinetics of concomitant drugs that are substrates of CYP enzymes (1A2, 2B6, 2C8, 2C19, 2D6, 3A4), UGTs, P-gp, MATEs, OCT1, OCT2, OAT1, or OAT3.