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Lipid Lowering with Bempedoic Acid Added Interactive! Click on any of Lipid Lowering With Bempedoic Acid Added to Proprotein Convertase TAP TO RETURN these bubbles to TO KIOSK MENU jump to each Subtilisin/Kexin Type 9 Inhibitor Therapy: A Randomized Controlled Trial section James M. McKenney, PharmD1; Diane E. MacDougall, MS2; Lulu Ren Sterling, PhD2; Stephanie Kelly, BS2; John Rubino, MD3 Results & Methods 1Virginia Commonwealth University and National Clinical Research Inc., Richmond, VA; Results 2Esperion Therapeutics Inc., Ann Arbor, MI; 3PMG Research of Raleigh, Raleigh, NC Conclusions INTRODUCTION FIGURE 1. BEMPEDOIC ACID • Combination therapy is often required to reach optimal lipid levels in patients with elevated low-density MECHANISM OF ACTION lipoprotein cholesterol (LDL-C) despite lipid-lowering monotherapy1,2 • Bempedoic acid is an oral, once daily, first-in-class ATP-citrate lyase inhibitor3,4 – Activated bempedoic acid inhibits ATP-citrate lyase (ACL), an enzyme that acts upstream of HMG-CoA reductase (the target of statins) in the cholesterol biosynthesis pathway (Figure 1) Bempedoyl-CoA – Bempedoic acid, a prodrug, is converted to its active form (bempedoyl-CoA) in the liver by very long-chain acyl-CoA synthetase 1 (ASCVL1), which is not present in skeletal muscle – Importantly, activated bempedoic acid is not found in skeletal muscle • Bempedoic acid has been shown to provide additional LDL-C lowering when added to background treatment with a statin and/or ezetimibe5-8 OBJECTIVES • To assess the efficacy and safety of bempedoic acid added to stable proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i; evolocumab) background therapy in patients with elevated LDL-C REFERENCES 1. Menzin J, et al. J Manag Care Spec Pharm. 2017;23:1270-1276. 5. Ballantyne CM, et al. Atherosclerosis. 2018;277:195-203. 2. Fox KM, et al. Clin Res Cardiol. 2018;107:380-388. 6. Ray KK, et al. N Engl J Med. 2019;380:1022-1032. 3. Pinkosky SL, et al. J Lipid Res. 2013;54:134-151. 7. Laufs U, et al. J Am Heart Assoc. 2019;8:e011662. ACSVL1, very long-chain acyl-CoA synthetase 1; BA, bempedoic acid; CoA, coenzyme A; 4. Pinkosky SL, et al. Nat Commun. 2016;7:13457. 8. Goldberg AC, et al. Presented at the 2019 American College of Cardiology HMG-CoA, 3-hydroxy-3-methylglutaryl CoA; LDL-C, low-density lipoprotein cholesterol; Scientific Sessions. March 18, 2019 LDL-R, low-density lipoprotein receptor. Reproduced from Ray et al.6 Presented at the 2019 National Lipid Association Scientific Sessions • Miami, FL • May 16-19, 2019 Poster #323 Interactive! Click on any of Lipid Lowering With Bempedoic Acid Added to Proprotein Convertase these bubbles to jump to each Subtilisin/Kexin Type 9 Inhibitor Therapy: A Randomized Controlled Trial section James M. McKenney, PharmD; Diane E. MacDougall, MS; Lulu Ren Sterling, PhD; Stephanie Kelly, BS; John Rubino, MD Introduction Results Results & Conclusions STUDY DESIGN AND TREATMENT PATIENTS STATISTICAL ANALYSIS • Phase 2, randomized, double-blind, placebo-controlled study • Adult men and women with fasting LDL-C ≥160 mg/dL • The primary endpoint was the percent change from • The study consisted of 3 phases (Figure 2): prior to initiating the PCSK9i run-in period and LDL-C baseline in LDL-C at month 2 – A 1.5-month screening/washout period during which all lipid-modifying drugs and ≥70 mg/dL prior to randomization • Efficacy analyses were performed using the modified nutritional supplements were discontinued, if applicable • Patients were excluded from the study if they had: intention-to-treat (mITT) population, which was defined – A 3-month lipid stabilization period wherein patients initiated background therapy – Homozygous or heterozygous familial as all randomized patients with a baseline lipid value with subcutaneous evolocumab 420 mg/3.5 mL administered via the Pushtronex® hypercholesterolemia and ≥1 postbaseline lipid value who took study drug system (Amgen, Thousand Oaks, CA) once monthly – Fasting triglycerides ≥500 mg/dL at month –3 within 2 days before the lipid measurement and PCSK9i within 30 ± 3 days before the lipid measurement – A double-blind treatment period in which patients were randomized 1:1 to – Known cardiovascular disease, peripheral arterial treatment with bempedoic acid 180 mg or placebo once daily added to disease, or cerebrovascular disease • Changes from baseline for efficacy endpoints were analyzed using analysis of covariance, with treatment background PCSK9i for 2 months – History of type 1 or type 2 diabetes, or laboratory group as a factor and baseline value as a covariate evidence of diabetes at month –4.5 – Statistical testing was 2-sided and conducted at the – Use of a PCSK9i within 16 weeks of first screening visit 5% level of significance FIGURE 2. STUDY DESIGN – Missing values were imputed using the last- ASSESSMENTS observation-carried-forward procedure, with only Screening/ Lipid Stabilization Double-blind • Blood samples for analysis of basic fasting lipids (total postbaseline values carried forward Washout Treatment cholesterol, calculated LDL-C, high-density lipoprotein – No adjustment was performed for multiple testing; PCSK9i + BA cholesterol [HDL-C], non-HDL-C, and triglycerides) were P values for secondary endpoints are considered PCSK9i Run-in collected at each study visit descriptive only PCSK9i + Placebo • Additional biomarkers (apolipoprotein B, high-sensitivity • Safety analyses included all randomized patients who C-reactive protein [hsCRP], and lipoprotein[a]) were received ≥1 dose of study drug; descriptive summaries measured before the PCSK9i run-in period and at were produced for safety endpoints Month–M4.5 –M3 –M2 –M1 Day 1 M1 M2 (Baseline) baseline, month 1, and month 2 Basic lipids X X XX X X X • Safety was evaluated via treatment-emergent adverse Additional XXXXevents (TEAEs), clinical laboratory findings, physical biomarkers examination findings, and vital sign measurements BA, bempedoic acid; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor. Interactive! Click on any of Lipid Lowering With Bempedoic Acid Added to Proprotein Convertase these bubbles to jump to each Subtilisin/Kexin Type 9 Inhibitor Therapy: A Randomized Controlled Trial section James M. McKenney, PharmD; Diane E. MacDougall, MS; Lulu Ren Sterling, PhD; Stephanie Kelly, BS; John Rubino, MD Introduction Methods Results & Conclusions PATIENTS EFFICACY • A total of 59 patients were randomized at 16 sites in the US: 28 to bempedoic acid and 31 to placebo • Addition of bempedoic acid to background PCSK9i therapy lowered LDL-C significantly more than – 1 patient in the placebo group did not receive any study drug and was excluded from the safety placebo at month 2 (P <.001; Figure 3) population – 5 patients in the placebo group and 1 patient in the bempedoic acid group were excluded from the FIGURE 3. PERCENT CHANGE FROM BASELINE IN LDL-C AT MONTH 2, mITT population MITT POPULATION • Baseline characteristics were similar between treatment groups (Table 1) PCSK9i + Placebo PCSK9i + Bempedoic Acid TABLE 1. PATIENT DEMOGRAPHICS AND BASELINE CHARACTERISTICS, SAFETY POPULATION PCSK9i + Placebo PCSK9i + Bempedoic Acid (n=26) (n=27) 10 Characteristic (n=30) (n=28) 2.8% a Age, years 58.4 ± 11.2 62.0 ± 9.4 5 Female, % (n) 50.0 (15) 75.0 (21) Race, % (n) 0 White 93.3 (28) 85.7 (24) Black or African American 6.7 (2) 14.3 (4) -5 2a BMI, kg/m 28.2 ± 5.5 29.6 ± 4.7 -10 History of hypertension, % (n) 26.7 (8) 35.7 (10) Difference Between Groups: Baseline lipid parameters -15 LDL-C, mg/dLa 104.1 ± 32.1 102.1 ± 29.0 –30.3% (95% CI: –41.3%, –19.2%) Non-HDL-C, mg/dLa 133.0 ± 36.6 129.7 ± 36.3 -20 P <.001 a in LDL-C Baseline Total cholesterol, mg/dL 190.3 ± 39.4 186.2 ± 38.3 -25 Apolipoprotein B, mg/dLa 87.9 ± 23.8 87.5 ± 27.1 b Triglycerides, mg/dL 129 (101, 191) 130 (93, 177) From Change Percent Mean -30 HDL-C, mg/dLa 57.3 ± 15.5 56.5 ± 12.3 –27.5% Baseline hsCRP, mg/Lb 2.1 (1.1, 4.7) 3.1 (1.3, 4.6) -35 BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor. aData are means ± standard deviations. bData are medians (Q1, Q3). CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; mITT, modified intention-to-treat; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor. Data are least-squares means ± standard errors. Interactive! Click on any of Lipid Lowering With Bempedoic Acid Added to Proprotein Convertase these bubbles to jump to each Subtilisin/Kexin Type 9 Inhibitor Therapy: A Randomized Controlled Trial section James M. McKenney, PharmD; Diane E. MacDougall, MS; Lulu Ren Sterling, PhD; Stephanie Kelly, BS; John Rubino, MD Introduction Methods Results EFFICACY (CONTINUED) SAFETY CONCLUSIONS • Nominally significant lowering of apolipoprotein B, non-HDL-C, • Rates of TEAEs were similar in the bempedoic acid and placebo • Bempedoic acid 180 mg once daily provided significant additional total cholesterol, and hsCRP were also observed with addition of treatment groups (Table 2) lipid lowering when added to background PCSK9i therapy bempedoic acid vs placebo to PCSK9i therapy (P <.05; Figure 4) • TEAEs were generally mild or moderate in severity throughout a 2-month treatment period • Changes in lipoprotein(a), HDL-C, and triglycerides were similar • No patients discontinued treatment due to a TEAE • Addition of bempedoic acid to a PCSK9i was well tolerated, with a safety profile similar to that observed in the PCSK9i plus placebo between treatment groups • No difference was found in the number of patients experiencing group FIGURE 4. PERCENT CHANGES FROM BASELINE IN KEY TEAEs related to study drug SECONDARY ENDPOINTS AT MONTH 2, MITT POPULATION TABLE 2. SUMMARY OF ADVERSE EVENTS, SAFETY POPULATION Total PATIENTS WITH A TEAE, % (N) DISCLOSURES AND ACKNOWLEDGMENTS ApoB Non-HDL-C Cholesterol hsCRP PCSK9i + Placebo PCSK9i + BA 10 This study was funded by Esperion Therapeutics, Inc.
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