CENTER FOR DRUG EVALUATION AND RESEARCH
APPLICATION NUMBER:
211617Orig1s000
INTEGRATED REVIEW Executive Summary Interdisciplinary Assessment Appendices NDA211617 Nexlizet I bempedoic acid and ezetimibe
Integrated Review Table 1. Administrative Application Information Category Application Information Application type NDA Application number 211617 Priority or standard Standard Submit date 2/26/2019 Received date 2/26/2019 PDUFA goal date 2/26/2020 Division/office Division of Metabolism and Endoc1inology Products (DMEP) Review completion date 2/25/2020 Established name Bempedoic acid and ezetimibe (Proposed) trade name Nexlizet Phannacologic class an adenosine triphosphate-citrate lyase (ACL) inhibitor and a cholesterol abso1ption inhibitor Code name ETC-I 002/ezetimibe Applicant Esperion Therapeutics, Inc. Dose form/formulation Tablets, 180 mg/10 mg One tablet dail Applicant proposed Adjunct to diet indication(s)/population(s)
Proposed SNOMED 55822004 (hyperlipidemia) indication Regulatory action Approval Approved adjunct to diet and maximally tolerated stat.in therapy for the indication(s)/population(s) treatment of adults with heterozygous familial (if applicable) hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C Approved SNOMED 55822004 (hyperlipidemia) indication
Integrated Review Template, version date 2019/06/14
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I. Executive Summary
1. Summary of Regulatory Action
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2. Benefit-Risk Assessment
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II. Interdisciplinary Assessment
3. Introduction
The Applicant, Esperion Therapeutics, Inc., submitted this New Drng Application (NDA) in suppo1t of the following indication:
NEXLIZET, which contains an ACL inhibitor and a cholesterol absor lion inhibitor, ;s indicated as an ad'unct to diet >rr4
w 10 require a itiona lowering ofLDL -C. Dmitations of Use: The effect of e=etimibe or bempedok acid on cardfovascular morbidity and morta/;ry has not been determined. Nexlizet contains bempedoic acid and ezetimibe. Bempedoic acid is an inhibitor of adenosine triphosphate-citrate lyase (ACL), an enzyme in the cholesterol and fatty acid biosynthesis pathways. Ezetimibe is an inhibitor of intestinal cholesterol abso1ption. The bempedoic acid ezetimibe fixed-dose combination (FDC) product is administered orally once daily as a 180 mg/10 mg tablet. Patients with elevated low-density lipoprotein cholesterol (LDL-C) are treated to reduce the risk of developing cardiovascular (CV) disease (prima1y prevention) or to reduce the risk of additional events in patients with established CV disease (secondaiy prevention). The 2018 American College of Cai·diology/ American Heait Association treatment guidelines for LDL-C reduction emphasize an individualized treatment approach to LDL-C reduction based on a patient's CV risk catego1y (primaiy versus secondary prevention) and calculated predicted risk for future CV events. Statins ai·e considered first-line therapy for all patients who require LDL-C reduction, regardless of CV risk catego1y. Ezetimibe and proprotein conve1tase subtilisin/kexin type 9 (PCSK9) inhibitors are recommended as second-line treatment options as add-on therapy to a background of optimized statin in patients at highest CV risk who require additional LDL-C reduction. Other approved treatment options include fenofibrates and niacin; however, these diug classes are not considered mainstays of therapy due to limited efficacy. Bempedoic acid (NDA 211616) was approved in the United States on Febrnai·y 21, 2020, for use as an adjunct to maximally tolerated statin therapy in patients with high-density lipoprotein cholesterol (HeFH) or established atherosclerotic cardiovascular disease (ASCVD). Postmarketing data are not yet available. Bempedoic acid is not marketed elsewhere worldwide. Ezetimibe is approved for the treatment of patients with prima1y hyperlipidemia as a monotherapy or in combination with statins or fenofibrates The bempedoic acid/ezetimibe fixed dose combination (FDC) IND was opened in June 201 6. Review issues relating to the evaluation of benefit include: • Data quality issue at three clinical sites
9 Integrated Review Template, version date 2019/06/ 14
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,QWHJUDWHG 5HYLHZ 7HPSODWH YHUVLRQ GDWH NDA211617 Nexlizet I bempedoic acid and ezetimibe
Characteristic Drug Information Absor tion Bioavailability Based on a radio-labelled PK study, at least 70% of the administered bempedoic acid dose was absorbed after oral administration. The absolute bioavailability of bempedoic acid was not determined in human. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for in·ection. Tmax T max of bempedoic acid and ezetimibe are 3.5 hours and 5 hours, respectively, following single-dose administration of the FDC tablet in healthy subjects. Food effect (fed/fasted) Table 7. Food Effect Geometric least square Component AU Co-int Cmax Tmax I mean and 90% Cl ETC-1002 0.95 (0.90, 1.00) 0.70 (0.61, 080) Prolonoed from 2 to 4 hours ESP15228 1.08 (1.00, 1.17) 0.91 (0.83, 0.99) Unchanged
Ezetimibe 0.91 (0.81, 1.02) 0.88 (0.70, 1.11) Prolonoed from 1.6 to 4 hours Ezetimibe-olucuronide 0.88 (0.75, 1.02) 0.6 (0.43, 0.78) Prolonoed from 0.8 to 2 hours Distribution Volume of distribution The bempedoic acid apparent volume of distribution (V/F) was 18 L. The volume of distribution for ezetimibe has not been re orted. Plasma protein binding Plasma protein binding of bempedoic acid, its glucuronide and its active metabolite, ESP15228, were 99.3%, 98.8% and 99.2%, respectively. Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins. Drug as substrate of ETC-1002 and ESP15228 were not substrates for cellular transporters. Ezetimibe is a substrate of P-gp. In a hamster transporters cell line, the Vmax was approximately 270% of basal activity and the Km was 21 µM. Elimination Mass balance results 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.
Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma. Approximately 78% and 11 % of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose. Clearance The steady-state clearance of bempedoic acid was 11.2 mUmin after once-daily dosing; renal clearance of unchanged bempedoic acid represented less than 2% of total clearance.The clearance of ezetimibe has not been re orted. Half-life The half-life of bempedoic acid and ezetimibe are 19.8 hr and 22 hr, respectively.
15 Integrated Review Template, version date 2019/06/ 14 Reference ID: 4566970
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The following summarizes DPMH 's conclusions. Pregnancy There are minimal human pregnancy data (and no outcome data) for bempedoic acid in the published literature and in the Applicant's PVDB. The findings in animal studies with minor skeletal variations at doses below the clinical exposure were not wonisome. The Applicant recommended a !bTC.il regarding the use in pregnancy based on the animal studies and mechanism of action. DPMH recommends removing the Jl.il and replacing it with a notice of the possibility of fetal harm based on mechanism of action in Section 8. Because there are insufficient human data available to info1m the safety of bempedoic acid use during pregnancy from clinical trial experience and the Applicant's phaimacovigilance database, DPMH recommends a PMR for a pregnancy exposure registry and a postmarketing pregnancy study of a different design to assess the safety ofbempedoic acid during pregnancy. Lactation Based on the high protein binding (99%), it is unlikely that significant amounts ofbempedoic acid would be present in human Inilk. However, because of theoretical concerns, DPMH proposes a PMR for a Inilk-only lactation study to confom a low level being present in human Inilk. Should a significant amount of bempedoic acid be found in the Inilk-only lactation study, a Inilk-plasma study should be considered. DPMH proposes the following for the "Risk SUillillaiy" labeling in Section 8.2: There ;s no informatfon about the presence ofe=etimibe in human 111;/k. E=etb11ibe ;s resent in rat 111;/k (see Data). When a drng is present in anb11al 111;/k, U i (6 likely that the drug w;J/ be present in human milk. There is no information about the effects of e=etb11ibe on the breastfed infant or the effects on milk productfon. (bJl.ill 57 Integrated Review Template, version date 2019/06/ 14 Reference ID 4566970 1'$ 1H[OL]HW EHPSHGRLF DFLG DQG H]HWLPLEH 9. 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GLVFUHSDQFLHV DQG HDFK VLWH KDG IROORZHG WKH SURWRFRO 7KH DVVXPSWLRQ WKDW VXEMHFWV PD\ KDYH EHHQ SHUSHWXDWLQJ VRPH OHYHO RI VXEMHFW PLVFRQGXFW LV OLNHO\ DQG WKHUHIRUH GDWD IURP WKHVH VLWHV DQG DUH VXVSHFW :H DJUHH ZLWK WKH Applicant’s GHFLVLRQ WR GR SRVW KRF VHQVLWLYLW\ DQDO\VHV RI NH\ VDIHW\ HIILFDF\ DQG 3. VWXG\ UHVXOWV ZLWK DOO GDWD IURP VLWHV DQG UHPRYHG ,Q JHQHUDO WKH $SSOLFDQW KDQGOHG WKLV LVVXH DSSURSULDWHO\ DQG KDG SURSHU RYHUVLJKW RI 7ULDO )'& 'DWD IURP WKLV $SSOLFDQW LQVSHFWLRQ DSSHDU DFFHSWDEOH WR VXSSRUW WKLV VXEPLWWHG DSSOLFDWLRQ )RU PRUH LQIRUPDWLRQ VHH 6HFWLRQ ,QWHJUDWHG 5HYLHZ 7HPSODWH YHUVLRQ GDWH Reference ID: 4566970 1'$ 1H[OL]HW EHPSHGRLF DFLG DQG H]HWLPLEH 11. Advisory Committee Summary 1$ ,QWHJUDWHG 5HYLHZ 7HPSODWH YHUVLRQ GDWH Reference ID: 4566970 NDA211617 Nexlizet I bempedoic acid and ezetimibe III. Appendices 12. Summary of Regulatory History IND 130707 was submitted May 27, 2016, for a fixed-dose combination (FDC)l tablet of bempedoic acid (180 mg) and ezetimibe (10 mg), an inhibitor of intestinal cholesterol (and related phytosterol) abso1p tion. Although the prefeITed description is "fixed-combination diug product" (FCDP), this document will use the te1m FDC for consistency with the Applicant's te1minology. An end-of-phase 2 meeting was requested March 15, 2017, and granted March 24, 2017. Prelimina1y responses were issued May 15, 2017, which the Applicant accepted as the final minutes, and the meeting was subsequently cancelled. A pre-NDA chemistiy, manufacturing, and conti·ols meeting, for both applications, was requested May 21 , 2018, granted May 31, 2018, and written responses issued August 1, 2018. fuitial agreement letters for the pediati·ic study plans were issued May 4, 2016, for bempedoic acid and January 11, 2018, for the FDC. The May 25, 2018, pre-NDA meeting request includes the following proposed indication for the initial submission: Bempedoic acid is indicated as an adjunct to diet and maximal~y tolerated statin therapy for treatment ofadults with Hetero=ygous Familial Hypercholesterolemia (HeFH) or Atherosclerotic Cardiovascular Disease (ASCVD) who require additional LDL-C lowering. According to the meeting package submitted June 29, 2018, the Applicant revised the proposed indication as follows: TRADENAME is indicated as an ad'unct to diet require a The Applicant is proposing to submit two NDAs simultaneously: one for the bempedoic acid tablet and one for the FDC tablet. The NDA for bempedoic acid will contain results from the following phase 3 ti·ials: • 1002-040: A randomized, double-blind, placebo-conti-olled, multicenter long-te1m safety and tolerability study of ETC-1 002 in patients with hyperlipidemia at high cardiovascular risk who are not adequately conti·olled by their lipid-modifying therapy • 1002-046: A randomized, double-blind, parallel group, multicenter study to evaluate the efficacy and safety ofbempedoic acid (ETC-1002) 180 mg compared to placebo added to background lipid-modifying therapy in patients with elevated low-density lipoprotein cholesterol (LDL-C) who are statin intolerant 61 Integrated Review Template, version date 2019/06/ 14 Reference ID 4566970 1'$ 1H[OL]HW EHPSHGRLF DFLG DQG H]HWLPLEH x $ ORQJWHUP UDQGRPL]HG GRXEOHEOLQG SODFHERFRQWUROOHG PXOWLFHQWHU VWXG\ WR HYDOXDWH WKH HIILFDF\ RI EHPSHGRLF DFLG (7& LQ SDWLHQWV ZLWK K\SHUOLSLGHPLD DW KLJK FDUGLRYDVFXODU ULVN QRW DGHTXDWHO\ FRQWUROOHG E\ WKHLU OLSLGPRGLI\LQJ WKHUDS\ x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b) (4) WLWOHG $ 5DQGRPL]HG 'RXEOH%OLQG 3ODFHER&RQWUROOHG 6WXG\ WR $VVHVV WKH (IIHFWV RI %HPSHGRLF $FLG (7& RQ WKH 2FFXUUHQFH RI 0DMRU &DUGLRYDVFXODU (YHQWV LQ 3DWLHQWV :LWK RU DW +LJK 5LVN IRU &DUGLRYDVFXODU 'LVHDVH :KR $UH 6WDWLQ ,QWROHUDQW (b) (4) 13. 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This is not of safety concern considering the absence of additive or synergetic toxicological interaction upon coadministration ofbempedoic acid and ezetimibe. Table 37. Summary of TK Data From Combination 90-Day General Tox icity and EFD Study With Bempedoic Acid and Ezetimibe Study/Study No. Major Findings General Toxicology Studies RR 1002-500-061: 90-day Table 38. TK Parameters for ETC-1002 and ESP15228 in the Rat 90-Day repeat dose oral Co m b ·ma f ion StU d I V combination toxicity study ETC-1002 + Bempedoic ETC-1 002 ESP15228 ESP15288 in rats Ezetimibe Acid Cmax AUC Cmax AUC Cm •• AUC (mg/kg/ (mg/kg/ (ng/ (ng.hr/ (ng/ (ng.hr/ (ng/ (ng.hr/ Sample collection times: Sex day} day} mLI m LI m LI mLI mLI m LI 0 30 58,400 356,000 4,950 31,000 63,350 387,000 predose and at 1, 2, 4,8, 150 30 74,600 511 ,000 5,850 45,700 80,450 556,700 M 12 and 24 hours post dose 375 30 87,200 447,000 5,090 35,600 92,290 482,600 750 30 89 300 475 000 5230 38300 94 530 513 300 0 30 108,000 925,000 6,430 62,700 17,230 987,700 Accumulation: none 50 30 91 ,200 730,000 4,740 53,900 95,940 783,900 F 125 30 86,800 698,000 4,490 43,300 91,290 741 ,300 Dose Proportionality: 250 30 125 000 800 000 5450 47 400 130 450 847 400 greater than Table 39. TK Parameters for Ezetimibe and Ezetimibe-Glucuronide in the NOAEL: Ra t 90. D a v C om bmat1. on Stu d I V Bempedoic acid: Ezetimibe + Ezetimibe Ezetimibe <30 mg/kg/day Bempedoic Ezeti mibe Glucuronide Glucuronide Ezetimibe Acid Cm.. AUC Cmax AUC Cmax AUC Ezetimibe: (mg/kg/ (m g/kg/ (ng/ (ng.hr/ (ng/ (ng.hr/ (ng/ (ng.hr/ Sex daYl daYl mLl mLl mLl mLI mLI mLI M: 750 mg/kg/day 750 0 59.8 416 506 6,110 566 6,526 150 30 18.7 103 1,470 10,700 1,489 10,803 F: 250 mg/kg/day M 375 30 33.9 264 1,230 13,800 1,264 14,064 750 30 57.4 333 1 660 15 300 17 717 15 633 Safety margin: 250 0 13.3 154 1,780 14,200 1,793 14,354 50 30 14.1 113 4,900 63,300 4,914 63,413 Bempedoic acid: <2 F 125 30 15.3 138 9,780 66,800 9,795 66,938 250 30 27.5 297 18500 130 000 18 528 130 297 Ezetimibe: M: 22, F: 186 65 Integrated Review Template, version date 2019/06/ 14 Reference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SKDUPDFRNLQHWLFV 6' VWDQGDUG GHYLDWLRQ ,QWHJUDWHG 5HYLHZ 7HPSODWH YHUVLRQ GDWH Reference ID: 4566970 NDA211617 Nexlizet I bempedoic acid and ezetimibe Figure 7. Arithmetic Mean Plasma Bempedoic Acid Concentration in Healthy Subjects Following Single Oral Dose of Bempedoic Acid 180 mg Coadministered With Ezetimibe 10 mg as Individual Tablets or Fixed-Dose Combination 25 ::::? E 20 'Ol 2 c .Q cu -...... c 15 ltil (ill <1> FDC ab let u -e- 11 c < 0 -fr- FDC n" Tablet u 0 0 so 100 150 200 250 Time (hr) Source: Reviewer's analysis from data submitted in CSR (Study 1002FDC-034) Abbreviations: BA, Bempedoic acid; FDC, fixed-dose combination 79 Integrated Review Template, version date 2019/06/ 14 Reference ID 4566970 NDA211617 Nexlizet I bempedoic acid and ezetimibe Figure 8. Arithmetic Mean Plasma Ezetimibe Concentration in Healthy Subjects Following Single Oral Dose of Bempedoic Acid 180 mg Coadministered With Ezetimibe 10 mg as Individual Tablets or Fixed-Dose Combination 6 ::::; ...... E O'l 5 c 0 ·.;:::; 4 ~c Q) u ~ c 0 ...... fr .... FDC Tablet u Q) ----6--- FDC ~Tablet .0 E ~ Individual Tablet ·.;:::; Q) N Q) 2 C1l E Vl C1l 0. c C1l Q) ~ :::::::::::::::::-::::::------ 0 50 100 150 Time (hr) Source: Reviewer's analysis from data submitted in CSR (Study 1002FDC-034) Abbreviations: FDC, fixed-dose combination Table 48. Geometric Mean T/R Ratio (90% Cl) for PK Parameters of Bempedoic Acid and Ezetimibe, Study 1002FDC-034 Parameter (unit) Bempedoic Acid Ezetimibe Cmax 0.93 (0.86, 1.01) 0.87(0.74, 1.03) AUC1 0.99 (0.95, 1.04) 1.00 (0.86, 1.16) AUC;nt 0.99 (0.95, 1.03) Source NOA 211617, Module 5.3.1. CSR Study 1002FDC-034 T/R: FDC ~Cb-m?tab l etlindividual tablet Abb rev i at 1~. confidence interval; FDC, fixed-dose combination; PK, pharmacokinetic; T/R, test/reference While the systemic exposure ofbempedoic acid was similar between the bempedoic acid tablet and the to-be-marketed FDC tablet, the bempedoic acid tablet used in this study was not the to be-marketed foimulation for NDA 211616. The Applicant provided the following evidence to support the PK bridging evaluation: physicochemical prope1iies ofbempedoic acid, foim ulation composition, in vitro release profiles, population phaimacokinetic analysis. Given the minor difference in foimulation composition and in vitro dissolution profiles between foimulation to to-be-mai·keted and the foimulation used in this study, no clinical meaningful difference between foimulation 2A and foimulation 2 would be expected. Refer to the Integrated Review ofNDA 211616 for additional details. 80 Integrated Review Template, version date 2019/06/ 14 Reference ID 4566970 1'$ 1H[OL]HW EHPSHGRLF DFLG DQG H]HWLPLEH Is there a drug-drug interaction between bempedoic acid and ezetimibe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eference ID: 4566970 NDA211617 Nexlizet I bempedoic acid and ezetimibe Figure 10. Arithmetic Mean (+SD) Plasma Bempedoic Acid Concentrations in Healthy Subjects Following Administration of Single Oral Dose of Bempedoic Acid 180 mg Alone and With Steady State Ezetimibe ::J" 30 E di 2. c: 0 24 ·;::; ~ ....c: Q) u c: 8 18 ·u ~ Bempedoic Acid + Ezetimibe " 0 25 so 75 100 125 Time (hr) Source: Reviewer's analysis from data submitted in CSR (Trial 1002FDC-049) Abbreviations: SD, standard deviation Figure 11 . Arithmetic Mean (+SD) Plasma Unconjugated Ezetimibe in Healthy Subjects Following Administration of Single Oral Dose of Ezetimibe 10 mg Alone and With Steady-State Bempedoic Acid s ::J" ...... E Cl .s 4 c: 0 ·;::; ~ ....c: ~ 3 c: 0 u ~ Bempedoic Acid + Ezetimibe Q) .E..c ·-tr- Ezetimibe Alone ·;::; 2 Q) ' N '' Q) '' RJ ' E '' VI 0 24 48 72 96 Time (hr) Source: Reviewer's analysis from data submitted in CSR (Trial 1002FDC-049) Abbreviations: SD, standard deviation 82 Integrated Review Template, version date 2019/06/ 14 Reference ID 4566970 NDA211617 Nexlizet I bempedoic acid and ezetimibe Table 49. Geometric Mean T/R Ratio (90% Cl) for PK Parameters of Bempedoic Acid and Ezetimibe, Trial 1002FDC-049 Parameter (unit) Bempedoic Acid Ezetimibe Cmax 1.08 (0.98, 1.18) 1.16 (0.99, 1.36) AUC1 1.05 (1.01 , 1.08) 1.20 (1.02, 1.41) AUC;nt 1.05 (1.02, 1.09) Source NOA 211617, Module 5.3.3. CSR Trial 1002FDC-049 T/R for bempedoic acid: Bempedoic acid alone/Bempedoic acid +SS ezetim be T/R for ezetimibe: Ezetimibe alone/Ezetimibe +SS bempedoic acid Abbreviations: Cl, confidence interval; FDC, fixed-dose combination; PK, pharmacokinetic; T/R, test/reference Trough plasma concentration ofbempedoic acid and ezetimibe were also measured following administration of the FDC tablet and the individual component products. Data suggest that the trough concentrations at various weekly intervals were generally comparable between the FDC and both bempedoic acid and ezetimibe alone, suggesting no drng interaction between the two components (Figure 12 and Figure 13). Figure 12. Box Plot for Trough Plasma Bempedoic Acid Concentration at Various Weekly Intervals in Patients With Hyperlipidemia WEEK 4 W EEKS WEEK 12 so so so 0 0 0 0 a0. & -r - -r:- · r---L---• : ' ! ~-~~~-~ t=-_r_-:.,:-; ·---.---.J : L:]BA180mg c:J BA 180 mg + EZE 10 mg FDC Source: Reviewer's analysis from data submitted in CSR (Trial 1002FDC-053) Abbreviations: BA, bempedoic acid; EZE, ezetimibe; FDC, fixed-dose combination Figure 13. Box Plot for Trough Plasma Ezetimibe Concentration at Various Weekly Intervals in Patients With Hyperlipidemia WEEK 4 WEEK S WEEK 12 30 30 30 0 :::1 :::1 :::1 &. E &. E 0 &. E OI ....._ OI ....._ OI ....._ 0 :::J OI :::J OI :::J OI 0 c 20 0 c 20 0 c 20 ::: ~c ::: ~c ::: ~c ., 0 ., 0 ., 0 ..0 ·.;::: • ..0 ·.;::: 0 .0 ·.;::: 0 6 6 ·-E "'~ ·-E "'~ :§ ~ • 0 .,c 10 ·.;:::., c., 10 ·.;:::., c., 10 v v v v .'.;:! c .'.;:! c • .'.;:! c 0 l _.L. 0 0 v y ~ v v 0 0 ~ ~ 0 CJ BA 180 mg + EZE 10 mg FDC C] EZElO mg Source: Reviewer's analysis from data submitted in CSR (Trial 1002FDC-053) Abbreviations: BA, bempedoic acid; EZE, ezetimibe; FDC, fixed-dose combination 83 Integrated Review Template, version date 2019/06/ 14 Reference ID 4566970 NDA211617 Nexlizet I bempedoic acid and ezetimibe Does food affect the systemic exposure ofbempedoic acid and ezetimibe from the FDC tablet? The effect of food on the systemic exposure ofbempedoic acid and ezetimibe from the FDC tablet was investigated in Study 1002FDC-055. This was a randomized, open-label, 2-sequence, 2-period, crossover study in which healthy subjects (n=1 6) were given a single dose of the FDC tablet in a fasted state and after consumption of a standardized high-fat, high-calorie meal. The treatments were separated by a washout period of 14 days. PK samples were collected predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96 and 120 hr postdose. There was no effect of a high-fat meal on the extent of bempedoic acid absorption based on the fed-to-fasted AUC ratio and the 90% Cls. However, there was an effect on the rate of abso1ption as indicated by a 30% reduction in mean Cmax and a 2-hour delay in median Tmax for bempedoic acid. Similarly, a high-fat meal did not affect the extent of ezetimibe exposure as measured by fed-to-fasted AUC ratio and its 90% CI. The mean ezetimibe Cma.x was reduced by 12%, and the median Tmax was prolonged by 2.5 hours under fed conditions relative to fasted conditions, in a manner similar to bempedoic acid. In the pivotal phase 3 study (1002FDC-053), the to-be marketed FDC product was administered with or without food. Hence, the observed difference in Cmax under fed condition does not appear to impact the efficacy of the diu g product. Figure 14. Arithmetic Mean (+SD) Plasma Bempedoic Acid Concentrations in Healthy Subjects Following Administration of Single Oral Dose of FDC Tablet Under Faster and Fed Conditions ::i' 25 E ...... CJl 2. c 0 ·.;:::; 20 ro ...... '- c Q) v c 8 15 :g v ~ Fas t ed ro v ----6.- Fed ·5 -g 10 Q. E \ Q) \ .0 ro E Vl 5 ro Q. 0 24 48 72 96 120 Time (hr) Source: Reviewer's analysis from data submitted in CSR (Trial 1002FDC-049) Abbreviations: FDC, fixed-dose combination; SD, standard deviation 84 Integrated Review Template, version date 2019/06/ 14 Reference ID 4566970 NDA211617 Nexlizet I bempedoic acid and ezetimibe Figure 15. Arithmetic Mean (+SD) Plasma Ezetimibe Concentrations in Healthy Subjects Following Administration of Single Oral Dose of FDC Tablet Under Fasted and Fed Conditions 10 ::::J E ...... O'l 5 8 c 0 ·.;::; ...,r: c ~ 6 c 0 u ~ Fasted Q) ...0E ··--fr- Fed ·.;::; 4 Q) N Q) cu E cuV'l 0. 2 c cu Q) ~ 0 24 48 72 96 120 Time (hr) Source: Reviewer's analysis from data submitted in CSR (Trial 1002FDC-049) Abbreviations: FDC, fixed-dose combination; SD, standard deviation Table 50. Geometric Mean Fed/Fasted Ratio (90% Cl) for PK Parameters of Bempedoic Acid and Ezetimibe, Study 1002FDC-055 Parameter (unit) Bempedoic Acid Ezetimibe Cmax 0.70 (0.61, 0.80) 0.88(0.70, 1.11) AUC1 0.95 (0.90, 1.00) 0.97 (0.83, 1.14) AUCint 0.95 (0.91. 1.00) Source NOA 211617, Module 5.3.1. CSR Study 1002FDC-055 Abbreviations: Cl, confidence interval; FDC, fixed-dose combination; PK, pharmacokinetic How is the proposed to-be-marketed formulation linked to the clinical formulation? The to-be-marketed foimulation was used in the pivotal phase 3 study (1002FDC-053) as well as the relative bioavailability study (1002FDC-034) and the food effect study (1002FDC-055). What are the bioanalytical methods used to measure bempedoic acid and ezetimibe in plasma? Liquid chromatography-tandem mass spectrometiy (LC-MS/MS) methods were developed and validated for quantitation ofETC-1002 (bempedoic acid parent molecule) and ESP15228 (active metabolite) in human plasma, as well as for unconjugated ezetimibe (parent molecule) and ezetimibe-glucuronide (active metabolite). 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VDPSOHV ZHUH VWRUHG DQG DQDO\]HG ZLWKLQ WKH YDOLGDWHG VWRUDJH VWDELOLW\ SHULRG DQG FRQGLWLRQV 3KDUPDFRNLQHWLF VDPSOHV IRU EHPSHGRLF DFLG DQG H]HWLPLEH ZHUH UHDQDO\]HG DV SDUW RI LQFXUUHG VDPSOH UHSURGXFLELOLW\ DVVHVVPHQW $SSUR[LPDWHO\ RI WKH ILUVW VDPSOHV DQG RI WKH UHPDLQLQJ VDPSOHV WKDW PHW WKH DFFHSWDQFH FULWHULD RI RI LQFXUUHG VDPSOH UHVXOWV EHLQJ ZLWKLQ RI WKH RULJLQDO UHVXOW ZHUH UHDVVHVVHG ,QWHJUDWHG 5HYLHZ 7HPSODWH YHUVLRQ GDWH Reference ID: 4566970 NDA211617 Nexlizet I bempedoic acid and ezetimibe 15. Trial Design: Additional Information and Assessment Tirtle of Smdy: A Randomized, Do11ble-Blmd, Parallel Group Study to E..-aluate tihe Efficacy md Safety of B empedo.tc ~~cid 180 mg+ Ez.etimibe 10 mg Fixed Dose Combinartion Compared to Bempedoic Acid. Ezeb:mibe, and !Placebo Alone in Patients 'freated with :!\llaximally Tolexated Sbtin Therapy {1002FDC-053) (ClinicalTrials.gov No. NCT01337308) lndi.ca tion:I (bT!1 1n,-e In1.-ie.stig:1to.rs and Study S i t~: This study was con:ducted at 78 stu.dy sites in dte Unit!:!d States. Study sites and i.m-estigatoTs. ar;e listed in Appendix 16.L4. Phao; e ofDu«elopmeot: 3 Shld~- Period: Date rust patient emolled: 23 Oe,t 2017 Date last patient rom]>!ered: 03 Jul 2018 iB:ukg_round and Rnti'On:1le for the Study: This Phase 3, 4-arm. study '\\ras designed to direetiy estim.1te the o.-exall treatment effect oflit e FDC product by assessing the 12-weel efficacy 1ofthe bempedoic acid 180 mg; +- ezetimibe 10 mg rnc vs bempedoie acid 18-0 mg alone, ezetimibe 10 m,g alone, or placebo, in deereas,ing low-density ilipoprotein ch.olesterol (LDL-C) a.:; added on f:o maxnnally tolerated strtin therapy (which may include no statin:; at all). Based on data from an integrated analysis of Phas.e 2 safety and efficacy, observed va.lue.s md percent change from baseline in the primary efficacy endpoint, LDI.-C, together- with. a po~tn;e safe:ty profile, support the choice of dte 180-mg dose for- the Phase 3 studies.. Th:e target population for- this study comprues patien~ \\iith docmnenred .a.therosdei-otic cardioli.-a~ diseases (ASCVD) md/or lt.et:e:rozygous. familial hypercholestero!emia (HefH) and/or multiple cardio'l.-as.c:ular risk factors who required additional l.DL-C-lowering therapy despite already being o:n maximally tolented sbtin ba:clgnnmd therapy . This de:fulltion mclude.s patients for whom mamnally tolerated sfatins may mean no stirtin at all '[he treatment duration of ] 2 weeks and brgeted study po:pul were designed to provide e:fticacy data for LDL-C !owerin,g, safety, and tolerability of bempedoic acid +- E!2Etiimibe :in patients v.-idi hi,gb ca:rdioi.·ascub:r risl requiring a::dditiooal LDL-lo"ii:i"ering therapy desprte receirv.iin,g mnimum. tolerated strtin ·therapy. A placebo ,group la.dis included to 1en:able accurafe charade:riz.ation of the magnitude ofLUL-C lo\\reimg of the FDC, while the active 'comparator ,groups of bempedoic acid alon:e and 1ez~timibe a!one e1ubled compiare.on of both incm;idual components to the FDC unde:r well-conn-oiled, 1·eali.sb.c conditions._ This study provides an ass.es5lllellt of the lDL-C- lo1"ering effect of the ili-x:ed combinartion drug produd with concomitant strtin use. 88 Integrated Review Template, version date 2019/06/ 14 Reference ID 4566970 1'$ 1H[OL]HW EHPSHGRLF DFLG DQG H]HWLPLEH Objecti,·es: C:O-primaty: To assess LDL-C lo\vering efficacy in patients receiving maximally b lerated statin thet'apy and b-eated for 12 \\'Hh with bempedoic acid 180 mg+ ezetimibe 10 mg FDC vs each of the follo\\'1ng. • Placebo • Bempedoic acid 180 mg • Ezetimibe 10 mg Secondaty: • To assess the efficacy ofbempedoic acid 180 mg+ ezetimibe 10 mg FDC\-s placebo alone, bempedoic acil alone, and ezetiuribe alone on bigh-sensiti\it}' C-reactive ?rotein (hsCRP), non -high-density lipoprotein cholesterol (non· HDL-C), total cho!esterol (TC), apolipoprotein B (apo B), high-density tipoprotein cholesterol (HDL-C), aod triglycerides (TGs) atler 12 weeks of treatment • To chal'acterize the safety and tolerability ofbempedoic acid 180 mg+ ezetimibe 10 mg FDC vs bempedoic aciC. alone, ezetimibe alone, and placebo alone through 12 weeks of b-eatment ~fethodo logy : This was a Phase 3, randomized, double-blind, paral!el group, muhicenter study of bempedoic acid + ezefunibe \-S its individual components and placebo . The study consisted of an appro:rimate 2 -\\·eek screening period and 12 \\•eds of treatment. Sct-eening Pe1iod Patients: started screening at Week -2 (Visit Sl), approximate!)• 2 weeks ptior to randomization. Patients \\ ,QWHJUDWHG 5HYLHZ 7HPSODWH YHUVLRQ GDWH Reference ID: 4566970 NDA211617 Nexlizet I bempedoic acid and ezetimibe dysfunction, renal dysnmction or gilomeru.lonephritis, hematologic or roagulatio:n dis.orders (or a kemoglobin level <10.0 g/dl.) at Week -2 (Visit Sl), or UD.elQ>lained creatine kinase >3 x ULN at any time prior to :ran:doullz3tio11. The complete list of eligibility criteria is provided in Protocol Amendment 1, Sedion 7. lnYestig3tional Prochut, No!11-m•·es tig3doual P rod!uct, Diose ::in d! l\!ode- of .\dmiufatntioo, Batch !Numbe~: Each daily allotment ofTh-1iP comprised 2 tablets a.n.d 1. capsule pro\i.ded in a blister package. • Tl:te bempedoic acid 180 m,~ + ezetimibe 10 mg fDC V.1.15 supplied as a :6.lm-coak!d tablet. The placebo.-to-mateh FDC was a film-coated tablet of identical physical appea!r.UlCe· and packagin,g. Tke fomiula.tion used in thi:; study V.'a.S the to-be-maikected fonnulation (a.ho ki!!:own as the FDC I 1i>mltablet). • .Rempedoic acid 1ao mg wars supplied as a film-coated tablet. The placebo-to-match banpedoic acid was a film-coated tablet ofidentical physical appe;uai!!:ce and pacb..ging . • Ezetimibe lO mg was supplied a5 over-encapsulated rablets. The placebo-fo-matcb ellleltimibe was a capsule of identical ph:ysmcal appearance md packaging. Lot number:; are pwvided in Appendix 16. l .6. Du:ntiou ofTl'e::ttme.ot: Duxailioe 1oftr:eatment for an indni.dual pati.em.t was up to•approximately 14 weEks (2 weeks for- screening aed 12 w eeks of treatment). Study Endpoint ~ : :Effic:tC'}" Ile co-pr.imai1· efficacy endpoints consiste. • Patient incidence oftreatmem~emergent ad\·erse e'lients (including adverse e'\-enfs iofspecial interest [AESJ]) • Clinical safefy booraio:ry (mcluding hematology, blood chemistry, and m:inalysis) resuhs • Vital s ign>, e!ectroc::antiogi'aID.S. (ECG s), and physical exa.mination findim.~ Stnti~tical M~thodg: Study populations were· defined. for malysis as follows. ·• Full Analysis Set (FAS) : also known as the intention-to-treat (ITT) set, wa.:; U5ed for all efficacy a.nal)•ses .and w ars defined ais all randomized patients • Treatment Completer Analysis Set: used as a. sensitivity analysis for th.e primary and secondacy efficacy an.;l::p"SeS, was a subset of the PAS and mduded patients who completed the 12-week treabnent md had non-missing LDL-C data at Week 12 ·• Safety Population: used for aD th.e safefy SWJ:llll.aries, was defined a.s all rmdomized patients who racei'i; ed .at least l dose oHMP • Pbanna:cokmetic (PK) Anal)·sis Set mduded ill patients in the Safety Analysis Set "iko had at least l PK assessment 90 Integrated Review Template, version date 2019/06/ 14 Reference ID 4566970 1'$ 1H[OL]HW EHPSHGRLF DFLG DQG H]HWLPLEH Ptiuulv E ffic3cy Anal"rsis .!\Ji anal)rsis of covariance (ANCOV A) \\eith tre J.nd baseline LDL4 C as a covariate \\·ere peifonned to compare b-e of the comparisons \\'1th.in the co4 primat) ' endpoint family w If all 3 tests \\'1th.in the co4 prim;uy endpoint family achie\'ed statistical significance, the hypothesis testing continued to the second.aty endpoints; other\\iise, all statistical compa.tlsotl$ for secondJ.ly endpoints \\·ere to be considered descriptive only. Seconda.ty Effie.an • Jlnalyses Key seconchry effic3C)' endpoints, which included percent change from baseline to \Ved 12 in LDL4 C, non ·HDL4 C, TC, hsCR.P, 3 non ·para.metric (\Vilcoxon rank 4 swn test) an:tl)"Sis \\·ith Hodges-Lehmann estimates a.nd confidence intet'\:als (CI) \\'et-e perfotmed. High-densit)• lipoprotein and TGs \\·e1-e summarized using descriptive statistics for the observed \•alue and the change/percent eh:tnge from b3seline at each protocol4 scheduled visit. PMrm.acokinetic Analyses Descriptive statistics of b'Ougb plasma concentrations of bempedoic acid (ETC 4 1002), its metabolite (ESP l 5228), ezetimibe (unconjugated), and ezetimibe4 glucuronide and.for ezetimibe \\'et-e provided ,QWHJUDWHG 5HYLHZ 7HPSODWH YHUVLRQ GDWH Reference ID: 4566970 1'$ 1H[OL]HW EHPSHGRLF DFLG DQG H]HWLPLEH Demographi(' and Ba'l:eline Chara('teristi('s Sex: 180 (47.1%) m en, 202 (52.9%) \\'omen ~ lean (standard deli."1.tion (SD)) age: 64.4 (9.68) years Ra('e: 314 (82.2%) white, 62 (16.2%) black or African American, 4 (1.0%) Asian, 1 (0.3%) Native Hawaiian o r other Pacific Islander, and 1 (0.3%) American Indian or Alaskan native Ethni('ity: 117 (30.6%) Hispanic or Latino; 265 (69.4%) not Hispanic or Latino ~le•• (SD) LDL-C: 149.17 (385S3) mg/clL In the post hoc sensitivity analysis, patient characteristics generally are similar e~cept that the percentage of randomized patients of Hispanic and Latino ethnicity decreased from 30.6% to 12.0% of the randomized population (FAS). A large proportion of the patients eru:olled at the 3 Miami sites that \\·ere removed from the sensitivity analysis were of Hispanic or Latino ethnicity. I ffi('acy Results : In the co-primary efficacy anal)"Sis: • T reahnent with the FDC resulted in significant!)• greater reductiotlS from baseline for least squares (LS) mean LDL-C (-31.5%) compared \\ri.th placebo (-2.5%). The difference from placebo for LS means (-29.oe/o) was statistically significant (p <0.001). • T reahnent with the FDC resulted in significantly greater reductiotlS from baseline for LS mean LDL-C (-31.5%) compared with ezetimibe (-21.0%). The difference from ezetimibe for LS means (-10.5%) was statistically significant (p = 0.001). • T reahnent with the FDC resulted in significant!)• greater reductiotlS from baseline for LS mean LDL-C (-31.5%) compared with bempedoic acid (·17.7%). The difference from ezetimibe for LS means (-13.8%) was statistically significant (p <0.001). Mean absolute changes from baseline to Week 12 in LDL·C we.re ·51.26, ·27.44, ·33.75, and -5.11 mg/dL for the FDC, bempedoic acid, ezetimibe, and placebo groups, respectively (observed data) . In the key secondary efficacy analyses: • The location shift comparing the FD C and placebo \\tas statistical!)• significantly different for bsCRP (-37.2%), and the LS mean difference \\·as statistically significantly different for non-HDL-C (-25.4%), TC (-20.6%), and apo B (-2 1.7%) . • The location shift comparing the FD C and ezetimibe was statistically significantly different for bsCRP (-19.0%), and the LS mean difference \\·as statistically significantly different for non-HDL-C (-10.9%), TC (-9.1%), and apo B (-6.9%). • The location shift comparing the FD C and bempedoic acid 180 mg was not statistically significantly different for hsCRP (-7.2%, p = 0.321); and the LS mean difference \\tas statistically significantly different for non-HDL-C (-12.3%), TC (-9.8%), and apo B (-S.4%). Priuury and secondary efficacy anal)>ses in the FAS population based on the percent change from baseline at Week 12 are summarized below: ,QWHJUDWHG 5HYLHZ 7HPSODWH YHUVLRQ GDWH Reference ID: 4566970 1'$ 1H[OL]HW EHPSHGRLF DFLG DQG H]HWLPLEH Paramtttr Btmpedoic ..\ c:id Percent Change From FDC' l SOmg Eztlimibt 10 mg Placebo B:a.stti.Dt :at WHk 12 (N = 108) (N = 110) (N = 109) (N = 55) LDL-C. o 108 110 109 55 Least squares meao" (SE) -315 (2.50) -11.7 (2.28) -21.0 (2.04) -2.5 (3.07) Noo-HDL.C, o 108 110 109 55 Least squares meao• (SE) -212 (22 4) -14.9 (2.01) -16.3 (2.02) -1.8 (2.82) TC, o 108 110 109 55 Least squares meao• (SE) -22.6 0 .89) -12.8 (l.68) -13.5 (l .54) -2.0 (2.17) apoB. o 104 107 107 52 Least squares meao• (SE) -20.l (128) -11.7 (2.15) -13.l (l.76) 1.6 (2.75) luCRP, o 102 101 102 52 Medfan' (IQR) -34.0 (61.4) -20.0 (84.4) -8.5 (64.5) 4.0 (82.2) .WCO\'. ~ = analysis of co\'ariaoce; apo B = apolipoproteio B; FDC = fi.~ dose combination; bsCRP = high- seosiri\ity C-reactive protein; LDL-C = lO\\•-density lipoprotein cholesterol; noo-HDL.C = ooa-bigh~ensity lipopro::ein cholesterol; SE = standard mor; TC = tot:tl cbolesta ol. • Bempedoic acid 180 mg+ ez.erimfbe 10 mg_fi.o:ed dose combin:nion " Percent chmg_e from baseline io LDL.C " ·as analyzed using: .WCO\'A \\tith treanuent group and rando:nlizarion strati.ficarioo as a f:actors aod baseline LDL-C as a covariate. Baseline ~-as delmed as the meao of tbe \:alues from Week -2 (Visit Sl) and predose Day 11\\ieek O(V isit Tl). For LDL-C, ifm easured LDL.C \·alue "·a; a\·:tilable, measured LDL.C " ·as used • .""1lalyzed using an .WCO\'A \\tith treaaue.nt group and nndomiz:arioo stratification as factors aod baseline \"altte as a co\·aria;e dObsen:eddat:t Source: Tables 14.2.1.1.1, 14.2.2.1, 14.2.1.2.l, 14.2.l.3.l, 14.2.1.5.l, 14.2.l.4.l, 14.2.2.7, 14.2.2.3, 14.2.2.4, 14.2.2.6 Phnrmoeokinelir Results: In the initial analysis, mean and median trough plasma concentratiotl$ o f ETC-1002 (bempedoic acid parent compound) and ESP15228 (activ·e metabolite) for patients in the FDC group and the bempedoic acid group \\·ere similar at Wee.ks 4, 8, and 12 . The same is true in the post hoc: sensitivity analysis, but as expected, mean and median trough PK !e\rels \\·ere slightly higher in the post hoc analysis. Safetr Result'i: • Patients t\'ho received active b-e.abnent bad an incidence of adverse e\rents o f 58.9%, 6 1.8'/o, and 53.2o/. for FDC, bempedoic acid, and ezetimibe, respectively, compared l\'1.th patients in the placebo group (43.6%). The percentage o f patients l\·bo bad IMP·related adverse events \\'as 12.1o/. , 11.8%, 8.3o/., and 7.3% in the rnc. bempedoic acid, ezetimibe, and placebo groups, respectively. • The percentage o f patients who had a serious adverse e\rent \\ ,QWHJUDWHG 5HYLHZ 7HPSODWH YHUVLRQ GDWH Reference ID: 4566970 1'$ 1H[OL]HW EHPSHGRLF DFLG DQG H]HWLPLEH • Mean changes from baseline to Wed 4, S, and 12 in ere.a.tine kinase \\' ere not clinically meaningful in any o f the b-e.atment gi·oups. In the initial an.al)-sis, mean increases in creatinine \\' ere seen in each b-eatment p ·oup: 2.4% FDC, 7.0 bempedoic acid, 2.6% ezetimibe, and 0.2o/. for placeboat Week 12. • Hepatic AESJ occun-ed in 2 patients (1.9%) in the FDC group, 1 patient (0.99/o) in the bempedoic acid p ·oup, and no patients in the ezetimibe or placebo groups. ?-.fuscular .!\ES] occm1-ed in 6 patients (5.6%) in the FDC p ·oup, 7 patients (6.4%) in the bempedoic acid group, 7 patients (6.4%) in the ezetimibe group, and 3 patients (5.5%) in the placebo p ·oup. Ne\\' onset or \\'or:sening of diabetes AESJ occurred in 4 patients (3.7%) in the FDC group, 1 patient (0.9%) in the bempedoic acid group, 2 patients (1.8%) in the ezetimibe group, and no patients in the placebo group. Renal disorder AESJ occurred in 4 patients (3.7%) in the FDC group, 2 patients (1.8%) in the bempedoic acid p -oup , and no patients in the ezetimibe and placebo groups. Three patients (2.8%) in the FDC group and 2 patients (1.8%) in the bempedoic acid group had adverse events of blood wic acid increased. No patient in any treatment group t-eported new Otl$et of gout or exacerbation of gout as an adverse event and no patient discontinued from the study due to an adverse ev·ent of uric acid inct-eased. • At \\'eek 12, tre.atment \\:ith bempedoic acid (either alone in the FDC group) ivas associated wifh slight!)• gre_ate.r increases than obsen:ed in the ezetimibe alone or p lacebo treatment groups in mean change from baseline for ct-eatinine and uric acid. • Mean heal't rate, SBP and D BP, weight, and body mass index were essentially unchanged from baseline across all b-e.abnent groups at all time points. • One patient each (0.9%) in the FDC and ezetimibe groups \\'ent from having a nonnal ECG at baseline to an " abnotm al, clinical!)• significant" E CG at Week 12, and 2 patients (1.8%) in the bempedoic acid group went from having "abnomtal, not clinical!)• significant" ECGs: at baseline to "abnormal, clinically significant" ECGs at \Ved 12. No patient in the placebo group had an "'abnorma~ clinically significant" ECG at \Veek 12. A post hoc sensitivity analysis was perfomted in which all pa tients fi:-om 3 sites \\'et-e removed. C:O mpared to the initial overvieiv, and \\-ith the exception o f the number of patients \\rho had at !east 1 tre.atment 4 emergent advet'Se event, the numbers o f patients who had particular types o f ev·ents in the post hoc s.e.nsitn:ity analysis are generally the same or similar in all tre.atment groups, but because the ntwlbers of patients in each b-e.atment group at-e lower, the percentages at-e slightly higher. CONCLUSI0 1'S: Results from this 124week, Phase 3, randomized, double4blind, placebo4 and ac6ve<0ntrol!ed study of the bempedoic acid + ezetimibe FDC compared with ezetimibe, bempedoic acid, or placebo a!one in patients \\'1th elevated LDL~ treated with maximally tolerated statin therapy demonstrate the follo\\iing. • Treatment with the FDC results in both clinically meaningful and statistically significant greater redu ctions in LDL 4 C at Week 12 (LS mean; 4 31.5% from baseline) compared \\'1.th ezetimibe (LS mean 421.0%), bempedoic acid (LS mean 417.7%), or placebo (LS mean 42.5%) on a background of maximally tolerated statin use. The LS mean differences from placebo (-29.0%), ezetimibe 4 4 ( 10.5%), and bempedoic acid ( 13.8%), \\'et-e statistically significant (p '!:0.001). The mean absolute change fi:-om baseline to Week 12 in the FDC p ·oup \\'as 4 51.26 mg/dl. • The results in the FDC group at-e suggestive of an additive effect of its 2 components on a backgrotllld o f maximally tolerated statin use, as there did not seem to be any loss of effect of either component \\then administet-ed as the combination. This is supported b)• the kno\\'D diffet-e.nce in m ee:hanisms o f action of the 2 chugs. • The overall treatment benefit of the FDC on a background of maximally tolerated statin use \\·as also obsen·ed across all key secon dary endpoints. The tre.atment diffet-e.nce between the FDC :mcl pbecib o in L S m ci :m p cirecin f eh::a.ngci &-om b:lf;cilinci :lt W cicik 12 U'":lf; -25.4%, 420.6%, ,QWHJUDWHG 5HYLHZ 7HPSODWH YHUVLRQ GDWH Reference ID: 4566970 1'$ 1H[OL]HW EHPSHGRLF DFLG DQG H]HWLPLEH 6RXUFH $SSOLFDQW ,QWHJUDWHG 5HYLHZ 7HPSODWH YHUVLRQ GDWH Reference ID: 4566970 1'$ 1H[OL]HW EHPSHGRLF DFLG DQG H]HWLPLEH 16. 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Mechanism of Action/Drug Resistance: Additional Information and Assessment 1$ 19. Other Drug Development Considerations: Additional Information and Assessment 1$ ,QWHJUDWHG 5HYLHZ 7HPSODWH YHUVLRQ GDWH Reference ID: 4566970 NDA211617 Nexlizet I bempedoic acid and ezetimibe 20. Data Integrity-Related Consults (Office of Scientific Investigations, Other Inspections) Clinical inspe<-tion Summary NOA 21 1617 be,m~oio acid+ euti.mibe Clinical Inspection Summary Dart- 1m on o19 Cynthia F. Kleppinger, M.D., Senior Medical Officer Anthony Orencia, M.D., Ph.D., Acting Team Leader Ka~ Ayalew, M.D., MP.H , Branch Chief From Good Clinical Practice Assessment Branch (GCPAB) Division of Oinic.al Compliance Evaluation (DCCE) Office of Scientific lnvestie.ations (OSD Laura Higginbotham, MD., M.P.H., Clinical Reviewer John Sharretts, M.D., Clinical Team Leader To Kati Johnson., Senior Regulatory Project Manager Division of Metabolism and Endocrinolo~ Products ffi:MEP) r\DA 211617 •-U>olicant Esperion Theraoeutics, Inc. D1112 Bemt>edoic acid + ezetimibe l\~IE Yes Tuerapeutk Classification (Ii) ('I~ Proposed Indication I Consulrarion Re-0ut-sr Date 4/1712019 Summary Goal Dare 12.n l/2019 Action Goal Date 212112020 PDUFADare 212612020 I. OYERALL ASSESS:\IEl'fT OF fl~~GS Al\"D REC0:\11\lEl\"DA TIO:\"S The inspection for this new drug application (NDA) consisted of five domestic si1es in addition to the sponsor. In general, based on the inspections of the five clinical sites, the inspectional findings support validity ofdata as reported by the sponsor under this NDA. The Esperion Therapeutics, Inc. (sponsor) site inspection included a focu.s on the lack ofan y drug product found by the sponsor after database lock in phannacokinetic (PK) blood samples from certain subjects at certain clinical sites who bad reported that they took the investigational drug product The inspections did not reveal a definitive root cause. The clinical investigators and their staff did not appear to be aware of the PK discrepancies and each site had followed the protocol. The assumption that subjects may have been perpetuating some level of subject misconduct is likely and. therefore, data from these sites (1028. 1058, and 1068) are suspect We agree with the sponsor's decision to do post hoc sensiti\iity analyses ofke y safe.ty, efficacy, and PK snldy results wi th all data from Sites l 028, 1058, and 1068 removed. In general. the sponsor handled this issue appropriately, and had proper oversight ofSnldy 1002FDC--053. Data from this sponsor inspection appear acceptable to support this submitted application. l THErO[ COWING 11 PA GES'HAVE-SEEN WITHHECDA-S~UPCTC7ffEl>AGE PLEASE SEE THE CLINICAL INSPECTION SUMMARY DOCUMENT IN THE Re,ference ID: 453802 1 OTHER REVIEWS SECTION OF THIS APPROVAL PACKAGE 116 Integrated Review Template, version date 2019/06/ 14 Reference ID 4566970 1'$ 1H[OL]HW EHPSHGRLF DFLG DQG H]HWLPLEH 21. Labeling Summary of Considerations and Key Additional Information 7KH IROORZLQJ PDMRU ODEHOLQJ GHFLVLRQV ZHUH FRPPXQLFDWHG WR WKH $SSOLFDQW x $OLJQPHQW RI 6HFWLRQ $GYHUVH 5HDFWLRQV ZLWK EHPSHGRLF DFLG DQG H]HWLPLEH ODEHOLQJ x $GGLWLRQ RI H]HWLPLEH GDWD WR 6HFWLRQ 3UHJQDQF\ DQG /DFWDWLRQ x ,Q 6HFWLRQ &OLQLFDO 6WXGLHV UHPRYDO RI (b) (4) x ,Q 6HFWLRQ &OLQLFDO 6WXGLHV DGGLWLRQ RI GDWD IURP H]HWLPLEH ODEHOLQJ 22. 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Review Team 7DEOH 5HYLHZHUV RI ,QWHJUDWHG $VVHVVPHQW 5ROH 1DPH V 5HJXODWRU\ 3URMHFW 0DQDJHU .DWL -RKQVRQ 1RQFOLQLFDO 5HYLHZHU /\GLD +DLOH 1RQFOLQLFDO 7HDP /HDGHU &DOYLQ /HH (OPRUH 2IILFH RI &OLQLFDO 3KDUPDFRORJ\ 0RKDPPDG $ELU $EVDU 5HYLHZHU V 2IILFH RI &OLQLFDO 3KDUPDFRORJ\ 6XU\DQDUD\DQD 6LVWD 7HDP /HDGHU V &OLQLFDO 5HYLHZHU /DXUD +LJJLQERWKDP &OLQLFDO 7HDP /HDGHU -RKQ 6KDUUHWWV 6WDWLVWLFDO 5HYLHZHU -LZHL +H 6WDWLVWLFDO 7HDP /HDGHU )HQJ /L &URVV'LVFLSOLQH 7HDP /HDGHU -RKQ 6KDUUHWWV 'HSXW\ 'LYLVLRQ 'LUHFWRU $FWLQJ 7DEOH $GGLWLRQDO 5HYLHZHUV RI $SSOLFDWLRQ 2IILFH RU 'LVFLSOLQH 1DPH V 234 /HH]D 5DKLPL-RKQ $PDUWH\3DUPHVD 3DWHO0XWKXNXPDU 5DPDVZDP\'RQQD &KULVWQHU&KULVWLQD &DSDFFL'DQLHO ,QWHJUDWHG 5HYLHZ 7HPSODWH YHUVLRQ GDWH Reference ID: 4566970 1'$ 1H[OL]HW EHPSHGRLF DFLG DQG H]HWLPLEH 7DEOH 6LJQDWXUHV RI 5HYLHZHUV 6HFWLRQV $XWKRUHG 'LVFLSOLQH DQG 7LWOH RU 5ROH 5HYLHZHU 1DPH 2IILFH'LYLVLRQ $SSURYHG ,$ &OLQLFDO 3KDUPDFRORJ\ 0RKDPPDG $EVDU 3K' 2762&3'30 ܈ $XWKRUHG տ $SSURYHG Digitally signed by Mohammad Absar -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, 3ULPDU\ 5HYLHZHU 6LJQDWXUH ou=People, cn=Mohammad Absar -S, Mohammad Absar -S 0.9.2342.19200300.100.1.1=2001438751 Date: 2020.02.26 12:18:52 -05'00' 6HFWLRQV $XWKRUHG 'LVFLSOLQH DQG 7LWOH RU 5ROH 5HYLHZHU 1DPH 2IILFH'LYLVLRQ $FNQRZOHGJHG $SSURYHG ,$ &OLQLFDO 3KDUPDFRORJ\ 6XU\DQDUD\DQD 6LVWD 3K' 2762&3'&(3 տ $XWKRUHG ܈ $SSURYHG Digitally signed by Suryanarayana M. Sista -S Suryanarayana M. Sista DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, 6HFRQGDU\ 5HYLHZHU 6LJQDWXUH ou=People, 0.9.2342.19200300.100.1.1=2001007118, cn=Suryanarayana M. Sista -S -S Date: 2020.02.26 12:09:13 -05'00' 6HFWLRQV $XWKRUHG 'LVFLSOLQH DQG 7LWOH RU 5ROH 5HYLHZHU 1DPH 2IILFH'LYLVLRQ $FNQRZOHGJHG $SSURYHG ,$ 3KDUPDFRORJ\7R[LFRORJ\ /\GLD +DLOH 3K' 21'2'('0(3 ܈ $XWKRUHG տ $SSURYHG Digitally signed by Lydia A. Haile -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, cn=Lydia A. Haile -S, 3ULPDU\ 5HYLHZHU 6LJQDWXUH Lydia A. Haile -S 0.9.2342.19200300.100.1.1=2000470805 Date: 2020.02.26 11:56:00 -05'00' 6HFWLRQV $XWKRUHG 'LVFLSOLQH DQG 7LWOH RU 5ROH 5HYLHZHU 1DPH 2IILFH'LYLVLRQ $FNQRZOHGJHG $SSURYHG ,$ 3KDUPDFRORJ\7R[LFRORJ\ & /HH (OPRUH 3K' 21'2'('0(3 տ $XWKRUHG ܈ $SSURYHG Digitally signed by Calvin L. Elmore -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, 6HFRQGDU\ 5HYLHZHU 6LJQDWXUH ou=People, 0.9.2342.19200300.100.1.1=2000356615, Calvin L. Elmore -S cn=Calvin L. Elmore -S Date: 2020.02.26 12:25:50 -05'00' 6HFWLRQV $XWKRUHG 'LVFLSOLQH DQG 7LWOH RU 5ROH 5HYLHZHU 1DPH 2IILFH'LYLVLRQ $FNQRZOHGJHG $SSURYHG ,$ 6WDWLVWLFDO -LZHL +H 3K' 2762%,'% ܈ $XWKRUHG տ $SSURYHG Digitally signed by Jiwei He -S 3ULPDU\ 5HYLHZHU 6LJQDWXUH Date: 2020.02.26 12:02:05 Jiwei He -S -05'00' ,QWHJUDWHG 5HYLHZ 7HPSODWH YHUVLRQ GDWH Reference ID: 4566970 1'$ 1H[OL]HW EHPSHGRLF DFLG DQG H]HWLPLEH 6HFWLRQV $XWKRUHG 'LVFLSOLQH DQG 7LWOH RU 5ROH 5HYLHZHU 1DPH 2IILFH'LYLVLRQ $SSURYHG ,$ 6WDWLVWLFDO )HQJ /L 3K' 2762%,'% տ $XWKRUHG ܈ $SSURYHG Digitally signed by Feng Li -S DN: c=US, o=U.S. Government, ou=HHS, 6HFRQGDU\ 5HYLHZHU 6LJQDWXUH ou=FDA, ou=People, cn=Feng Li -S, Feng Li -S 0.9.2342.19200300.100.1.1=2000332337 Date: 2020.02.26 12:35:31 -05'00' 6HFWLRQV $XWKRUHG 'LVFLSOLQH DQG 7LWOH RU 5ROH 5HYLHZHU 1DPH 2IILFH'LYLVLRQ $FNQRZOHGJHG $SSURYHG (6,$ /DXUD +LJJLQERWKDP 0' &OLQLFDO 21'2'('0(3 03+ ܈ $XWKRUHG Digitally signed by Laura B. Higginbotham -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 3ULPDU\ 5HYLHZHU 6LJQDWXUH 0.9.2342.19200300.100.1.1=2002617854, cn=Laura B. Laura B. Higginbotham -S Higginbotham -S Date: 2020.02.26 11:50:19 -05'00' $EEUHYLDWLRQV ,$ ,QWHUGLVFLSOLQDU\ $VVHVVPHQW (6 ([HFXWLYH 6XPPDU\ ,QWHJUDWHG 5HYLHZ 7HPSODWH YHUVLRQ GDWH Reference ID: 4566970 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------ KATI JOHNSON 02/26/2020 02:26:47 PM JOHN M SHARRETTS 02/26/2020 02:28:51 PM I co-authored the executive summary and approved the integrated assessment. I concur with the conclusions. Reference ID: 4566970