Bempedoic Acid

1 INDICATIONS AND USAGE NEXLETOL is indicated: to reduce the risk of major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke, or coronary revascularization) in adults at increased risk for these events who are unable to take recommended statin therapy (including those not taking a statin). as an adjunct to diet and exercise, in combination with other low-density lipoprotein cholesterol (LDL-C) lowering therapies, or alone when concomitant LDL-C lowering therapy is not possible, to reduce LDL-C in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH). NEXLETOL, an adenosine triphosphate-citrate lyase (ACL) inhibitor, is indicated: to reduce the risk of major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke, or coronary revascularization) in adults at increased risk for these events who are unable to take recommended statin therapy (including those not taking a statin). ( 1 ) as an adjunct to diet and exercise, in combination with other low-density lipoprotein cholesterol (LDL-C) lowering therapies, or alone when concomitant LDL-C lowering therapy is not possible, to reduce LDL-C in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH). ( 1 )

2 DOSAGE AND ADMINISTRATION Administer 180 mg orally once daily with or without food. ( 2.1 ) 2.1 Recommended Dosage The recommended dosage of NEXLETOL is 180 mg administered orally once daily. NEXLETOL can be taken with or without food. After initiation of NEXLETOL, analyze lipid levels within 8 to 12 weeks.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hyperuricemia [see Warnings and Precautions (5.1) ] Tendon Rupture [see Warnings and Precautions (5.2) ] Common adverse reactions in the ( 6.1 ): Primary hypercholesterolemia trials (incidence ≥ 2% and more frequent than placebo) were upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, and elevated liver enzymes. Cardiovascular outcomes trial (incidence ≥ 2% and 0.5% greater than placebo) were hyperuricemia, renal impairment, anemia, elevated liver enzymes, muscle spasms, gout, and cholelithiasis. To report SUSPECTED ADVERSE REACTIONS, contact Esperion at 833-377-7633 (833 ESPRMED) 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 clinical practice. The data in Table 1 reflect exposure to NEXLETOL in two placebo-controlled primary hypercholesterolemia trials that included 2,009 patients treated with NEXLETOL for 52 weeks (median treatment duration of 52 weeks) [see Clinical Studies (14.2) ] . The mean age for NEXLETOL-treated patients was 65 years, 29% were female, 95% were White, 3% were Black or African American, 1% were Asian, and 1% were other races; 3% identified as Hispanic or Latino ethnicity. All patients received NEXLETOL 180 mg orally once daily plus maximally tolerated statin therapy alone or in combination with other lipid-lowering therapies. At baseline, 97% of patients had CVD and about 4% had a diagnosis of HeFH. Patients on simvastatin 40 mg/day or higher were excluded from the trials. In the primary hypercholesterolemia trials, adverse reactions led to discontinuation of treatment in 11% of NEXLETOL-treated patients and 8% of placebo-treated patients. The most common reasons for NEXLETOL treatment discontinuation were muscle spasms (0.5% versus 0.3% placebo), diarrhea (0.4% versus 0.1% placebo), and pain in extremity (0.3% versus 0.0% placebo). Adverse reactions reported in at least 2% of NEXLETOL-treated patients and more frequently than in placebo-treated patients are shown in Table 1. Table 1. Adverse Reactions (≥ 2% and greater than placebo) in NEXLETOL-Treated Patients with Primary Hypercholesterolemia and CVD or HeFH (Trials 2 and 3) Adverse Reaction Placebo Background therapy included statin and ± other lipid-lowering therapies (N = 999) % NEXLETOL (N = 2,009) % Upper respiratory tract infection 4.0 4.5 Muscle spasms 2.3 3.6 Hyperuricemia Grouped term that includes other related terms 1.1 3.5 Back pain 2.2 3.3 Abdominal pain or discomfort 2.2 3.1 Bronchitis 2.5 3.0 Pain in extremity 1.7 3.0 Anemia 1.9 2.8 Elevated liver enzymes 0.8 2.1 In the cardiovascular outcomes trial, in which 7,001 patients were exposed to NEXLETOL and 6,964 patients were exposed to placebo for a median of 3.1 years [see Clinical Studies, (14.1) ] , adverse reactions led to discontinuation of treatment in 11% of NEXLETOL-treated patients and 10% of placebo-treated patients. Adverse reactions reported in at least 2% of NEXLETOL-treated patients and 0.5% greater than placebo are shown in Table 2. Table 2. Adverse Reactions (≥ 2% and 0.5% greater than placebo) in NEXLETOL-Treated Patients with CVD or at High Risk for CVD (Trial 1) Adverse Reaction Placebo (N=6,964) % NEXLETOL (N=7,001) % Hyperuricemia Grouped term that includes other related terms 8 16 Renal impairment Renal impairment includes laboratory related terms including glomerular filtration rate decreased, blood creatinine increased and hematuria 9 11 Anemia 4 5 Elevated liver enzymes 3 4 Muscle spasms 3 4 Gout 2 3 Cholelithiasis 1 2 Other Adverse Reactions Tendon Rupture In the hypercholesterolemia trials, tendon rupture occurred in 0.5% of NEXLETOL-treated patients versus 0% of placebo-treated patients. In the cardiovascular outcomes trial, tendon rupture events occurred in 1.2% of NEXLETOL-treated patients versus 0.9% of placebo-treated patients. Gout In the hypercholesterolemia trials, gout occurred in 1.5% of NEXLETOL-treated patients versus 0.4% of placebo-treated patients. In the cardiovascular outcomes trial, gout occurred in 3.2% of NEXLETOL-treated patients versus 2.2% of placebo-treated patients. Laboratory Tests NEXLETOL was associated with persistent changes in multiple laboratory tests that occurred within the first 4 weeks of treatment and returned to baseline following discontinuation of treatment. Increase in Creatinine and Blood Urea Nitrogen In the hypercholesterolemia trials, there was a mean increase in serum creatinine of 0.05 mg/dL compared to baseline with NEXLETOL at Week 12. Approximately 3.8% of patients treated with NEXLETOL had blood urea nitrogen values that doubled (versus 1.5% placebo), and about 2.2% of patients had creatinine values that increased by 0.5 mg/dL (versus 1.1% placebo). In the cardiovascular outcomes trial, 7.1% of patients had creatinine values that increased by 0.5 mg/dL (versus 5.5% placebo) and 9.5% of patients in the NEXLETOL group had BUN values that increased ≥ 2× baseline (versus 6.2% placebo). Decrease in Hemoglobin and Leukocytes In the hypercholesterolemia trials, approximately 5.1% of patients treated with NEXLETOL (versus 2.3% placebo) had decreases in hemoglobin levels of 2 or more g/dL and below the lower limit of normal on one or more occasion. Anemia was reported in 2.8% of patients treated with NEXLETOL and 1.9% of patients treated with placebo. Approximately 9.0% of NEXLETOL-treated patients with normal baseline leukocyte count had a decrease to less than the lower limit of normal on one or more occasion (versus 6.7% placebo). Leukocyte decrease was generally asymptomatic and did not require medical intervention. In the hypercholesterolemia trials, there was a small imbalance in skin or soft tissue infections, including cellulitis (0.8% versus 0.4%), but there was no imbalance in other infections. In the cardiovascular outcomes trial, 10.8% of patients (versus 7.4% placebo) had a decrease in hemoglobin of 2 or more g/dL and below the lower limit of normal. Anemia was reported in 4.7% of patients treated with NEXLETOL and 3.9% of patients treated with placebo. There were 9.3% of NEXLETOL-treated patients with a leukocyte count below the lower limit of normal (and normal at baseline) at any point (versus 6.8% placebo). Increase in Platelet Count In the hypercholesterolemia trials, approximately 10.1% of patients (versus 4.7% placebo) had increases in platelet counts of 100× 10 9 /L or more on one or more occasion. In the cardiovascular outcomes trial, 18.6% of patients in the NEXLETOL-treated group (versus 10.2% placebo) had an increase in platelet count of 100 × 10 9 /L or more. Platelet count increase was asymptomatic and did not result in increased risk for thromboembolic events. Increase in Liver Enzymes In the hypercholesterolemia trials, increases in hepatic transaminases (AST and/or ALT) were observed with NEXLETOL. In most cases, the elevations were transient and resolved or improved with continued therapy or after discontinuation of therapy. Increases to more than 3× the upper limit of normal (ULN) in AST occurred in 1.4% of patients treated with NEXLETOL versus 0.4% of placebo patients, and increases to more than 5× ULN occurred in 0.4% of NEXLETOL-treated versus 0.2% of placebo-treated patients. Increases in ALT occurred with similar incidence between NEXLETOL- and placebo-treated patients. Elevations in transaminases were generally asymptomatic and not associated with elevations ≥ 2× ULN in bilirubin or with cholestasis. In the cardiovascular outcomes trial, the incidence of repeated and confirmed ALT and/or AST >3× ULN was 1.6% in the NEXLETOL-treated group (versus 1.0% placebo). A higher percentage of patients in the NEXLETOL-treated group had hepatic enzyme elevations versus placebo (4.5% versus 3.0%, respectively). Increase in Creatine Kinase In the hypercholesterolemia trials, approximately 1.0% of patients (versus 0.6% placebo) had elevations of CK levels of 5 or more times the normal value on one or more occasions, and 0.4% of patients (versus 0.2% placebo) had elevations of CK levels of 10 or more times. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of NEXLETOL. 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. Immune System Disorders: Hypersensitivity reactions including: angioedema, wheezing, rash, and urticaria.

12.3 Pharmacokinetics Bempedoic acid pharmacokinetic parameters are presented as the mean [± standard deviation (SD)] unless otherwise specified. The steady-state maximum plasma concentration (C max ) and area under the curve (AUC) following multiple-dose administration of bempedoic acid at 180 mg/day were 20.6 ± 6.1 µg/mL and 289.0 ± 96.4 µg∙h/mL, respectively. Bempedoic acid steady-state pharmacokinetics were generally linear over a range of > 60 mg to 220 mg (approximately 33% to 122% of the recommended dosage of 180 mg daily). There were no time-dependent changes in bempedoic acid pharmacokinetics following repeat administration at the recommended dosage, and bempedoic acid steady-state was achieved after 7 days. The mean accumulation ratio was approximately 2.3-fold. The steady-state C max and AUC of the active metabolite (ESP15228) of bempedoic acid were 2.8 ± 0.9 µg/mL and 51.2 ± 17.2 µg∙h/mL, respectively. ESP15228 likely made a minor contribution to the overall clinical activity of bempedoic acid based on systemic exposure, relative potency, and pharmacokinetic properties. Absorption Pharmacokinetic data indicate that bempedoic acid is absorbed with a median time to maximum concentration of 3.5 hours when administered as NEXLETOL 180 mg tablets. Effect of Food Concomitant food administration had no effect on the oral bioavailability of bempedoic acid. Distribution The bempedoic acid apparent volume of distribution (V/F) was 18 L. Plasma protein binding of bempedoic acid, its glucuronide and its active metabolite, ESP15228, were 99.3%, 98.8% and 99.2%, respectively. Bempedoic acid does not partition into blood cells. Elimination The steady-state clearance (CL/F) of bempedoic acid was 11.2 mL/min after once-daily dosing; renal clearance of unchanged bempedoic acid represented less than 2% of total clearance. The mean ± SD half-life for bempedoic acid in humans was 21 ± 11 hours at steady-state. Metabolism The primary route of elimination for bempedoic acid is through metabolism of the acyl glucuronide. Bempedoic acid is also reversibly converted to an active metabolite (ESP15228) based on aldo-keto reductase activity observed in vitro from human liver. Mean plasma AUC metabolite/parent drug ratio for ESP15228 following repeat-dose administration was 18% and remained constant over time. Both compounds are converted to inactive glucuronide conjugates in vitro by UGT2B7. Bempedoic acid, ESP15228 and their respective conjugated forms were detected in plasma with bempedoic acid accounting for the majority (46%) of the AUC 0-48h and its glucuronide being the next most prevalent (30%). ESP15228 and its glucuronide represented 10% and 11% of the plasma AUC 0-48h , respectively. Excretion Following single oral administration of 240 mg of bempedoic acid (1.3 times the approved recommended dose), approximately 70% of the total dose (bempedoic acid and its metabolites) was recovered in urine, primarily as the acyl glucuronide conjugate of bempedoic acid, and approximately 30% was recovered in feces. Less than 5% of the administered dose was excreted as unchanged bempedoic acid in feces and urine combined. Specific Populations No clinically significant differences in the pharmacokinetics of bempedoic acid were observed based on age, gender, race, weight, renal impairment (mild, moderate, and severe renal impairment or renal failure), or mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment. The effect of severe (Child-Pugh Class C) hepatic impairment on bempedoic acid pharmacokinetics is unknown. Drug Interaction Studies Cytochrome P450 Substrates In vitro metabolic interaction studies suggest that bempedoic acid, as well as its active metabolite and glucuronide forms are not metabolized by and do not interact with cytochrome P450 enzymes. Transporter-mediated Drug Interactions In vitro drug interaction studies suggest bempedoic acid, as well as its active metabolite and glucuronide form, are not substrates of commonly characterized drug transporters with the exception of bempedoic acid glucuronide, which is an OAT3 substrate. Bempedoic acid weakly inhibits OAT3 at high multiples of clinically relevant concentrations, and bempedoic acid and its glucuronide weakly inhibit OATP1B1, and OATP1B3 at clinically relevant concentrations. Bempedoic acid weakly inhibits OAT2 in vitro , which is likely the mechanism responsible for minor elevations in serum creatinine and uric acid [see Adverse Reactions (6.1) ] . Probenecid Administration of bempedoic acid 180 mg with steady-state probenecid resulted in a 1.7- and a 1.2-fold increase in bempedoic acid AUC and C max , respectively. AUC and C max for bempedoic acid active metabolite (ESP15228) were increased 1.9- and 1.5-fold, respectively. These elevations are not clinically meaningful and do not impact dosing recommendations. Statins The pharmacokinetic interactions between bempedoic acid (at systemic exposure relevant to the indicated CVD population) and simvastatin 20 mg, atorvastatin 10 mg, pravastatin 40 mg, and rosuvastatin 10 mg were evaluated in clinical trials. Simvastatin: Administration of simvastatin 20 mg with 240 mg of bempedoic acid or 40 mg with 180 mg of bempedoic acid in healthy subjects at steady-state resulted in approximately 2-fold (91% for 20 mg and 96% for 40 mg) and 1.5-fold (54% for 20 mg and 52% for 40 mg) increases in simvastatin acid AUC and C max , respectively [see Drug Interactions (7) ] . Pravastatin: Administration of pravastatin 40 mg with steady-state bempedoic acid 240 mg in healthy subjects resulted in 99% (2-fold) and 104% (2-fold) increases in pravastatin acid AUC and C max , respectively [see Drug Interactions (7) ] . Atorvastatin and Rosuvastatin: Elevations of 1.7-fold in AUC of atorvastatin, and rosuvastatin and/or their major metabolites were observed, suggesting a weak interaction. These elevations were generally within the individual statin exposures and do not impact dosing recommendations. Ezetimibe Increases in AUC and C max for ezetimibe were less than 20% when a single dose of ezetimibe was taken with steady-state bempedoic acid. Total ezetimibe (ezetimibe and its glucuronide form) and ezetimibe glucuronide AUC and C max increased approximately 1.6- and 1.8-fold, respectively. These elevations are not clinically meaningful and do not impact dosing recommendations. Warfarin In vitro studies indicate that bempedoic acid is not an inhibitor or inducer of CYP2C9. Because warfarin is primarily eliminated through CYP2C9, its pharmacokinetics is not expected to be altered by bempedoic acid. Other Bempedoic acid had no effect on the pharmacokinetics of metformin or the oral contraceptive Ortho-Novum 1/35.