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Efficacy and Safety of Triplet Therapy With

Efficacy and Safety of Triplet Therapy With

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Diane E. MacDougall, MS1; John Rubino, MD2; Lulu Ren Sterling, PhD1; Jeffrey C. Hanselman, MS1; Stephen J. Nicholls, MD, PhD3 Results & Methods 1Esperion Therapeutics Inc., Ann Arbor, MI; 2PMG Research of Raleigh, Raleigh, NC; Results 3Monash Cardiovascular Research Centre, Monash University, Melbourne, VIC, Australia Conclusions

INTRODUCTION METHODS • Patients with hypercholesterolemia often fail to achieve sufficient lowering, despite the use of guideline- recommended -lowering therapies1-3 STUDY DESIGN AND TREATMENT • Bempedoic acid is an oral, first-in-class ATP-citrate lyase inhibitor in development for treating hypercholesterolemia4,5 • Phase 2, randomized, double-blind, placebo-controlled study – The active form of bempedoic acid (bempedoyl-CoA) inhibits ATP-citrate lyase, an upstream of • The study consisted of 2 phases (Figure 1): HMG-CoA reductase (the target of ) in the cholesterol biosynthesis pathway – A 6-week screening/washout period during which patients – Bempedoic acid is a that is activated in the by very long-chain acyl-CoA synthetase 1 (ACSVL1) discontinued lipid-lowering drugs and nutritional supplements – A double-blind treatment period in which patients were – ACSVL1 expression is limited to the liver; therefore, bempedoic acid is not converted to bempedoyl-CoA in randomized 2:1 to treatment with triplet therapy (bempedoic acid skeletal muscle 180 mg + ezetimibe 10 mg + atorvastatin 20 mg) or placebo once • In phase 3 clinical trials, bempedoic acid significantly lowered low-density lipoprotein cholesterol (LDL-C) when daily for 6 weeks administered alone or as an add-on to background lipid-lowering therapy6-9 OBJECTIVE FIGURE 1. STUDY DESIGN • To evaluate the extent of LDL-C lowering achieved during triplet therapy with bempedoic acid 180 mg, ezetimibe 10 mg, and atorvastatin 20 mg Patients with Triplet therapy (BA 180 mg + LDL-C of 130-189 mg/dL Ezetimibe 10 mg + Atorvastatin 20 mg) following LLT washout Placebo REFERENCES 6-Week Screening 6-Week Treatment 1. Grundy et al. J Am Coll Cardiol. 2018. Epub ahead of print. 6. Ballantyne CM, et al. . 2018;277:195-203. 2. Gitt AK, et al. Atherosclerosis. 2016;255:200-209. 7. Ray KK, et al. N Engl J Med. 2019;380:1022-1032. BA, bempedoic acid; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy. 3. Menzin J, et al. J Manag Care Spec Pharm. 2017;23:1270-1276. 8. Laufs U, et al. J Am Heart Assoc. 2019;8:e011662. 4. Pinkosky SL, et al. J Lipid Res. 2013;54:134-151. 9. Goldberg AC, et al. Presented at the 2019 American College of Cardiology Scientific 5. Pinkosky SL, et al. Nat Commun. 2016;7:13457. Sessions. March 18, 2019.

Presented at the 2019 National Lipid Association Scientific Sessions • Miami, FL • May 16-19, 2019 Poster #321 Interactive! Click on any of Efficacy and Safety of Triplet Therapy With Bempedoic Acid, Ezetimibe, these bubbles to jump to each and Atorvastatin in Patients With Hypercholesterolemia section

Diane E. MacDougall, MS; John Rubino, MD; Lulu Ren Sterling, PhD; Jeffrey C. Hanselman, MS; Stephen J. Nicholls, MD, PhD Introduction Results Results & Conclusions

METHODS (CONTINUED) RESULTS TATISTICAL NALYSIS • Sixty-three patients were enrolled at 14 sites in the United States: PATIENTS S A 43 patients were randomized to triplet therapy and 20 patients to • Adult men and women with fasting LDL-C of 130 to 189 mg/dL • The primary endpoint was the percent change from baseline in placebo after washout of lipid-lowering therapies and nutritional LDL-C at week 6 – 2 patients in the triplet-therapy group were excluded from the supplements (measured on week –1) • Efficacy analyses were performed using the modified intention- modified intention-to-treat population due to lack of sufficient • Patients were excluded from the study if they had: to-treat population, which was defined as all randomized patients postbaseline efficacy measurements – History of clinically significant who received ≥1 dose of study drug and who had a baseline and • Patient demographics and baseline characteristics were generally ≥1 postbaseline assessment, excluding any assessment taken – Body mass index >50 kg/m2 similar between treatment groups (Table 1) more than 2 days after a dose of study drug – Fasting >400 mg/dL at week –1 Table 1. Patient Demographics and Baseline Characteristics • Percent changes from baseline for most efficacy endpoints were Placebo Triplet Therapy – History of type 1 or type 2 , or fasting glucose analyzed using analysis of covariance, with treatment group as a >125 mg/dL at week –6 Characteristic (n=20) (n=43) factor and baseline value as a covariate. Age, yearsa 61.2 ± 7.8 61.2 ± 12.3 – Uncontrolled hypothyroidism – Statistical testing was 2-sided and conducted at the 5% level Female, % (n) 70.0 (14) 60.5 (26) of significance Race, % (n) ASSESSMENTS – Missing values were imputed using the last-observation- White 80.0 (16) 79.1 (34) • Blood samples for analysis of basic fasting (total cholesterol, carried-forward procedure, with only postbaseline values Black or African American 15.0 (3) 16.3 (7) 2a calculated LDL-C, high-density lipoprotein cholesterol [HDL-C], carried forward BMI, kg/m 28.4 ± 5.9 29.3 ± 6.6 non-HDL-C, and triglycerides) were collected during screening and – No adjustment was performed for multiple testing; P values History of hypertension, % (n) 35.0 (7) 53.5 (23) predose at baseline and on weeks 3 and 6 for secondary endpoints are considered descriptive only Lipid parameters LDL-C, mg/dLa 155.9 ± 13.7 154.3 ± 17.9 – If triglycerides were >400 mg/dL or calculated LDL-C was • Percent change from baseline for hsCRP was analyzed using a Non-HDL-C, mg/dLa 183.1 ± 18.4 183.6 ± 27.3 <50 mg/dL, direct measurement of LDL-C was performed non-parametric approach, with the P value derived from the Total cholesterol, mg/dLa 235.1 ± 21.2 235.7 ± 27.0 Wilcoxon rank sum test and median treatment difference • Additional biomarkers ( and high-sensitivity Apolipoprotein B, mg/dLa 119.2 ± 15.3 118.0 ± 19.9 (location shift) and 95% confidence interval derived from C-reactive protein [hsCRP]) were measured at baseline and week 6 Triglycerides, mg/dLb 125 (73, 295) 127 (59, 400) Hodges-Lehmann estimates • Safety was evaluated via treatment-emergent adverse events HDL-C, mg/dLa 52.0 ± 13.0 52.1 ± 12.9 (AEs), clinical laboratory findings, physical examination findings, • Safety analyses included all randomized patients who received hsCRP, mg/Lb 1.6 (0.1, 9.5) 1.9 (0.3, 29.2) and vital sign measurements ≥1 dose of study drug; descriptive summaries were produced BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; hsCRP, high-sensitivity for safety endpoints C-reactive protein; LDL-C, low-density lipoprotein cholesterol. aData are means ± standard deviations. bData are medians (range). Interactive! Click on any of Efficacy and Safety of Triplet Therapy With Bempedoic Acid, Ezetimibe, these bubbles to jump to each and Atorvastatin in Patients With Hypercholesterolemia section

Diane E. MacDougall, MS; John Rubino, MD; Lulu Ren Sterling, PhD; Jeffrey C. Hanselman, MS; Stephen J. Nicholls, MD, PhD Introduction Methods Results & Conclusions

PRIMARY ENDPOINT SECONDARY ENDPOINTS

• At week 6, LDL-C lowering with triplet therapy (bempedoic acid • Nominally significant reductions with triplet therapy vs placebo were • More than 90% of patients in the triplet-therapy group and no 180 mg + ezetimibe 10 mg + atorvastatin 20 mg) was significantly also observed for non-HDL-C, total cholesterol, apolipoprotein B, patients in the placebo group achieved LDL-C targets at week 6 greater than placebo (P <.001; Figure 2) hsCRP, and triglycerides (P <.001; Figure 3) (P <.001 for both comparisons; Figure 4) • No appreciable treatment effect on HDL-C was observed FIGURE 2. PERCENT CHANGE FROM BASELINE IN FIGURE 3. PERCENT CHANGE FROM BASELINE IN FIGURE 4. ACHIEVEMENT OF LDL-C TARGETS LDL-C AT WEEK 6 SECONDARY ENDPOINTS AT WEEK 6 Placebo Triplet Therapy LDL-C Reduction >50% LDL-C <70 mg/dL (n=20) (n=41) Non-HDL-C TC apoB hsCRP TGs HDL-C 10 20 100 95.1%* 8.9% 90.2%* 90 0 10 0.6% 0.4% 80 0 -10 –3.1% –1.3% –1.1% –2.7% –1.1% 70 -10 -20 60 -20 50 -30 Difference Between Groups: -30 40 –60.5% (95% CI: –68.0%, –53.0%) –27.4% -40 Baseline in in LDL-C Baseline P <.001 -40 * 30 -50 Patients of Percentage

Mean Percent Change From Change Percent Mean 20 -50 –47.1% –47.7% Percent Change From Baseline From Change Percent * –53.5% * 10 -60 -60 0% 0% –60.0% * Placebo (n=20) Triplet Therapy (n=41) 0 -70 –63.6% -70 * Placebo Triplet Therapy Placebo Triplet Therapy (n=20) (n=41) (n=20) (n=41) Data for non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B CI, Confidence interval; LDL-C, low-density lipoprotein cholesterol. (apoB), triglycerides (TGs), and high-density lipoprotein cholesterol (HDL-C) are least-squares means LDL-C, low-density lipoprotein cholesterol. Data are least-squares means ± standard errors. ± standard errors. Data for high-sensitivity C-reactive protein (hsCRP) are medians. *P <.001 for the comparison of triplet therapy and placebo. *P <.001 for the comparison of triplet therapy and placebo. Interactive! Click on any of Efficacy and Safety of Triplet Therapy With Bempedoic Acid, Ezetimibe, these bubbles to jump to each and Atorvastatin in Patients With Hypercholesterolemia section

Diane E. MacDougall, MS; John Rubino, MD; Lulu Ren Sterling, PhD; Jeffrey C. Hanselman, MS; Stephen J. Nicholls, MD, PhD Introduction Methods Results

EFFICACY (CONTINUED) SAFETY CONCLUSIONS • All patients who received triplet therapy experienced a reduction • Treatment-emergent AE rates were comparable in the 2 treatment • Oral, once-daily, combination therapy with bempedoic acid from baseline in LDL-C at week 6 (Figure 5) groups (Table 2) 180 mg, ezetimibe 10 mg, and atorvastatin 20 mg lowered LDL-C • Most AEs were mild or moderate in severity; 1 patient experienced by 64% FIGURE 5. PERCENT CHANGE FROM BASELINE IN an AE considered by the investigator to be severe • Triplet therapy was well tolerated, with an AE profile similar to that of the placebo group LDL-C AT WEEK 6: PATIENT-LEVEL ANALYSIS FOR • No patients experienced clinically relevant aminotransferase or elevations • More than 90% of patients who received triplet therapy THE TRIPLET-THERAPY GROUP • No clinically relevant changes were observed in clinical laboratory experienced >50% LDL-C lowering from baseline and achieved LDL-C <70 mg/dL 25 results, vital sign measurements, or physical examination findings Table 2. Summary of Adverse Events Patients, % (n) DISCLOSURES AND ACKNOWLEDGMENTS 0 Placebo Triplet Therapy Parameter (n=20) (n=43) This study was funded by Esperion Therapeutics, Inc. Esperion Overview of AEs participated in the study design, research, data collection, analysis -25 Any AE 35.0 (7) 34.9 (15) and interpretation of data, writing, reviewing, and approving the Discontinuation due to an AE 5.0 (1) 7.0 (3) poster for presentation. Esperion and the authors thank the study Serious AE 0 0 investigators, clinical site staff, and patient volunteers who -50 Deaths 0 0 participated in the study. Diane E. MacDougall, Lulu Ren Sterling, Common AEsa and Jeffrey C. Hanselman are past or present employees of Esperion. John Rubino has no disclosures to report. Stephen J. -75 Headache 5.0 (1) 4.7 (2) 0 4.7 (2) Nicholls has received research support from and has been a 0 4.7 (2) consultant for Esperion. Medical writing assistance, funded by Percent change from baseline in LDL-C in baseline from change Percent Esperion, was provided by Crystal Murcia, PhD, of JB Ashtin. -100 Hepatic enzyme increased 0 4.7 (2) LDL-C, low-density lipoprotein cholesterol. Osteoarthritis 0 4.7 (2) Pain in extremity 0 4.7 (2) Rash 0 4.7 (2) Muscle spasms 10.0 (2) 2.3 (1) AE, adverse event. aOccurring in 2 or more patients in either treatment group.

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