Case 1:20-cv-01630-RGA-JLH Document 17-23 Filed 01/25/21 Page 1 of 13 PageID #: 694
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`Exhibit V
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1024, p. 1 of 13
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`Case 1:20-cv-01630-RGA-JLH Document 17-23 Filed 01/25/21 Page 2 of 13 PageID #: 695
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`established in 1812
`
`January 3, 2019
`
`vol. 380 no. 1
`
`Cardiovascular Risk Reduction with Icosapent Ethyl
`for Hypertriglyceridemia
`Deepak L. Bhatt, M.D., M.P.H., P. Gabriel Steg, M.D., Michael Miller, M.D., Eliot A. Brinton, M.D.,
`Terry A. Jacobson, M.D., Steven B. Ketchum, Ph.D., Ralph T. Doyle, Jr., B.A., Rebecca A. Juliano, Ph.D.,
`Lixia Jiao, Ph.D., Craig Granowitz, M.D., Ph.D., Jean-Claude Tardif, M.D., and Christie M. Ballantyne, M.D.,
`for the REDUCE-IT Investigators*
`
`a bs tr ac t
`
`BACKGROUND
`Patients with elevated triglyceride levels are at increased risk for ischemic events. Icosapent
`ethyl, a highly purified eicosapentaenoic acid ethyl ester, lowers triglyceride levels, but data
`are needed to determine its effects on ischemic events.
`METHODS
`We performed a multicenter, randomized, double-blind, placebo-controlled trial involving
`patients with established cardiovascular disease or with diabetes and other risk factors, who
`had been receiving statin therapy and who had a fasting triglyceride level of 135 to 499 mg
`per deciliter (1.52 to 5.63 mmol per liter) and a low-density lipoprotein cholesterol level of
`41 to 100 mg per deciliter (1.06 to 2.59 mmol per liter). The patients were randomly assigned
`to receive 2 g of icosapent ethyl twice daily (total daily dose, 4 g) or placebo. The primary
`end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal
`stroke, coronary revascularization, or unstable angina. The key secondary end point was a
`composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
`RESULTS
`A total of 8179 patients were enrolled (70.7% for secondary prevention of cardiovascular
`events) and were followed for a median of 4.9 years. A primary end-point event occurred in
`17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients
`in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.68 to 0.83; P<0.001);
`the corresponding rates of the key secondary end point were 11.2% and 14.8% (hazard ratio,
`0.74; 95% CI, 0.65 to 0.83; P<0.001). The rates of additional ischemic end points, as assessed
`according to a prespecified hierarchical schema, were significantly lower in the icosapent
`ethyl group than in the placebo group, including the rate of cardiovascular death (4.3% vs.
`5.2%; hazard ratio, 0.80; 95% CI, 0.66 to 0.98; P = 0.03). A larger percentage of patients in
`the icosapent ethyl group than in the placebo group were hospitalized for atrial fibrillation
`or flutter (3.1% vs. 2.1%, P = 0.004). Serious bleeding events occurred in 2.7% of the patients
`in the icosapent ethyl group and in 2.1% in the placebo group (P = 0.06).
`CONCLUSIONS
`Among patients with elevated triglyceride levels despite the use of statins, the risk of ische-
`mic events, including cardiovascular death, was significantly lower among those who re-
`ceived 2 g of icosapent ethyl twice daily than among those who received placebo. (Funded
`by Amarin Pharma; REDUCE-IT ClinicalTrials.gov number, NCT01492361.)
`
`From Brigham and Women’s Hospital
`Heart and Vascular Center and Harvard
`Medical School, Boston (D.L.B.); FACT
`(French Alliance for Cardiovascular Trials),
`Département Hospitalo-Universitaire FIRE
`(Fibrose, Inflammation, and Remodeling),
`Assistance Publique–Hôpitaux de Paris,
`Hôpital Bichat, Université Paris-Diderot,
`INSERM Unité 1148, Paris (P.G.S.); Na-
`tional Heart and Lung Institute, Imperial
`College, Royal Brompton Hospital, Lon-
`don (P.G.S.); the Department of Medi-
`cine, University of Maryland School of
`Medicine, Baltimore (M.M.); the Utah
`Lipid Center, Salt Lake City (E.A.B.); the
`Office of Health Promotion and Disease
`Prevention, Department of Medicine,
`Emory University School of Medicine,
` Atlanta (T.A.J.); Amarin Pharma, Bedmin-
`ster, NJ (S.B.K., R.T.D.J., R.A.J., L.J., C.G.);
`Montreal Heart Institute, Université de
`Montréal, Montreal (J.-C.T.); and the De-
`partment of Medicine, Baylor College of
`Medicine, and the Center for Cardiovas-
`cular Disease Prevention, Methodist De-
`Bakey Heart and Vascular Center, Hous-
`ton (C.M.B.). Address reprint requests to
`Dr. Bhatt at Brigham and Women’s Hos-
`pital Heart and Vascular Center, Harvard
`Medical School, 75 Francis St., Boston, MA
`02115, or at dlbhattmd@ post . harvard . edu.
`
`*A complete list of the REDUCE-IT trial in-
`vestigators is provided in the Supplemen-
`tary Appendix, available at NEJM.org.
`
`This article was published on November
`10, 2018, and updated on November 12,
`2018, at NEJM.org.
`
`N Engl J Med 2019;380:11-22.
`DOI: 10.1056/NEJMoa1812792
`Copyright © 2018 Massachusetts Medical Society.
`
`n engl j med 380;1 nejm.org
`
`January 3, 2019
`
`11
`
`The new england
`journal of medicine
`
`The New England Journal of Medicine
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`Downloaded from nejm.org on November 19, 2020. For personal use only. No other uses without permission.
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`Case 1:20-cv-01630-RGA-JLH Document 17-23 Filed 01/25/21 Page 3 of 13 PageID #: 696
`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`A Quick Take
`is available at
`NEJM.org
`
`A mong patients with cardiovascular
`
`risk factors who are receiving treatment
`for secondary or primary prevention, the
`rates of cardiovascular events remain high.1-3 Even
`in patients receiving appropriate treatment with
`statins, a substantial residual cardiovascular risk
`remains.4 In such patients, an elevated triglyceride
`level serves as an independent marker for an in-
`creased risk of ischemic events, as shown in epi-
`demiologic and mendelian randomization stud-
`ies.5-9 In randomized trials, medications that
`reduce triglyceride levels, such as extended-release
`niacin and fibrates, have not reduced the rates of
`cardiovascular events when administered in ad-
`dition to appropriate medical therapy, including
`statins.10 Contemporary trials and recent meta-
`analyses of n−3 fatty acid products have not shown
`a benefit in patients receiving statin therapy.11-13
`In the Japan EPA Lipid Intervention Study
`(JELIS), 18,645 Japanese patients with hypercho-
`lesterolemia were randomly assigned to receive
`either low-intensity statin therapy plus 1.8 g of
`eicosapentaenoic acid (EPA) daily or statin ther-
`apy alone (there was no placebo group). The risk
`of major coronary events was significantly low-
`er, by 19%, in the group that received EPA plus
`statin therapy than in the group that received
`statin therapy alone.14
`These considerations led to the design of the
`Reduction of Cardiovascular Events with Icosa-
`pent Ethyl–Intervention Trial (REDUCE-IT).15 Icosa-
`pent ethyl is a highly purified and stable EPA
`ethyl ester that has been shown to lower triglyc-
`eride levels and is used as an adjunct to diet in
`adult patients who have triglyceride levels of at
`least 500 mg per deciliter (5.64 mmol per liter).16,17
`In addition, icosapent ethyl may have antiinflam-
`matory, antioxidative, plaque-stabilizing, and
`membrane-stabilizing properties.18-21 We hypoth-
`esized that the risk of cardiovascular events would
`be lower with icosapent ethyl therapy than with
`placebo among patients in whom elevated triglyc-
`eride levels served as a marker of residual risk
`despite statin therapy.
`
`Me thods
`
`Trial Design
`The design of REDUCE-IT has been published
`previously.15 In brief, REDUCE-IT was a phase 3b
`randomized, double-blind, placebo-controlled trial
`comparing icosapent ethyl (2 g twice daily with
`food [total daily dose, 4 g]) with a placebo that
`
`contains mineral oil to mimic the color and
`consistency of icosapent ethyl. Randomization
`was stratified according to cardiovascular risk
`stratum (secondary-prevention cohort or primary-
`prevention cohort, with primary prevention capped
`at 30% of enrolled patients), use or no use of
`ezetimibe, and geographic region. Further details
`of the study design are provided in Figure S1 in
`the Supplementary Appendix, available with the
`full text of this article at NEJM.org. Patients were
`enrolled and followed at 473 participating sites in
`11 countries. The first patient underwent ran-
`domization on November 28, 2011, and the last
`on August 4, 2016.
`The trial was sponsored by Amarin Pharma.
`The steering committee, which consisted of aca-
`demic physicians (see the Supplementary Appen-
`dix), and representatives of the sponsor developed
`the protocol, available at NEJM.org, and were re-
`sponsible for the conduct and oversight of the
`study, as well as the interpretation of the data.
`The sponsor was responsible for the collection
`and management of the data. The protocol was
`approved by the relevant health authorities, in-
`stitutional review boards, and ethics commit-
`tees. All the data analyses were performed by the
`sponsor, and the primary, secondary, and tertiary
`adjudicated end-point analyses were validated by
`an independent statistician from the data and
`safety monitoring committee. The first author
`vouches for the completeness and accuracy of the
`data and analyses and for the fidelity of the trial
`to the protocol.
`
`Eligibility
`Patients could be enrolled if they were 45 years
`of age or older and had established cardiovascu-
`lar disease or were 50 years of age or older and
`had diabetes mellitus and at least one additional
`risk factor. Eligible patients had a fasting triglyc-
`eride level of 150 to 499 mg per deciliter (1.69 to
`5.63 mmol per liter) and a low-density lipopro-
`tein (LDL) cholesterol level of 41 to 100 mg per
`deciliter (1.06 to 2.59 mmol per liter) and had been
`receiving a stable dose of a statin for at least 4
`weeks; because of the intraindividual variability
`of triglyceride levels, the initial protocol allowed
`for a 10% lower triglyceride level from the target
`lower limit, which permitted patients to be en-
`rolled if they had a triglyceride level of at least
`135 mg per deciliter (1.52 mmol per liter). The
`first protocol amendment in May 2013 changed
`the lower limit of the acceptable triglyceride level
`
`12
`
`n engl j med 380;1 nejm.org
`
`January 3, 2019
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on November 19, 2020. For personal use only. No other uses without permission.
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`Case 1:20-cv-01630-RGA-JLH Document 17-23 Filed 01/25/21 Page 4 of 13 PageID #: 697
`Cardiovascular Risk Reduction with Icosapent Ethyl
`
`from 150 mg per deciliter to 200 mg per deciliter
`(2.26 mmol per liter), with no allowance for vari-
`ability. Patients were excluded if they had severe
`heart failure, active severe liver disease, a glycated
`hemoglobin level greater than 10.0%, a planned
`coronary intervention or surgery, a history of acute
`or chronic pancreatitis, or known hypersensitivity
`to fish, shellfish, or ingredients of icosapent ethyl
`or placebo. Further details regarding inclusion and
`exclusion criteria are provided in Tables S1 and
`S2 in the Supplementary Appendix. Written in-
`formed consent was obtained from all patients.
`
`End Points
`The primary efficacy end point was a composite
`of cardiovascular death, nonfatal myocardial in-
`farction (including silent myocardial infarction),
`nonfatal stroke, coronary revascularization, or
`unstable angina in a time-to-event analysis. While
`the steering committee and the sponsor remained
`unaware of the trial-group assignments, a sec-
`ond protocol amendment in July 2016 designated
`the key secondary end point as a composite of
`cardiovascular death, nonfatal myocardial infarc-
`tion, or nonfatal stroke in a time-to-event analy-
`sis. After the primary efficacy end-point analysis
`was performed, the prespecified secondary effi-
`cacy end points were examined in a hierarchical
`fashion in the following order: the key second-
`ary efficacy end point; a composite of cardiovas-
`cular death or nonfatal myocardial infarction;
`fatal or nonfatal myocardial infarction; emer-
`gency or urgent revascularization; cardiovascular
`death; hospitalization for unstable angina; fatal
`or nonfatal stroke; a composite of death from
`any cause, nonfatal myocardial infarction, or
`nonfatal stroke; and death from any cause. Pre-
`specified tertiary end points are listed in the
`Supplementary Appendix. Adjudication of all the
`above events was performed by an independent
`clinical end-point committee whose members
`were unaware of the trial-group assignments
`and lipid levels.
`
`Statistical Analysis
`In this event-driven trial, it was estimated that
`approximately 1612 adjudicated primary end-point
`events would be necessary to provide the trial with
`90% power to detect a 15% lower risk of the pri-
`mary composite end point in the icosapent ethyl
`group than in the placebo group. We estimated
`that a sample size of approximately 7990 patients
`would be required to reach that number of pri-
`
`mary end-point events. The primary efficacy analy-
`sis was based on the time from randomization
`to the first occurrence of any component of the
`primary composite end point. If the risk of the
`primary composite end point was significantly
`lower with icosapent ethyl than with placebo at
`a final two-sided alpha level of 0.0437 (as deter-
`mined with the use of O’Brien–Fleming bound-
`aries generated with the Lan–DeMets alpha-
`spending function approach after accounting for
`two prespecified interim efficacy analyses), the
`key secondary end point and other prespecified
`secondary end points were to be tested in a hi-
`erarchical fashion at the same final alpha level
`of 0.0437. All analyses were performed accord-
`ing to the intention-to-treat principle. Hazard
`ratios and 95% confidence intervals were gener-
`ated with the use of a Cox proportional-hazards
`model that included trial-group assignment as a
`covariate, stratified according to cardiovascular
`risk category, geographic region, and use of ezeti-
`mibe. Log-rank P values from a Kaplan–Meier
`analysis that was stratified according to the three
`randomization factors are reported to evaluate
`the timing of events in the two trial groups. With
`respect to the tertiary and subgroup efficacy
`analyses, 95% confidence intervals (which were
`not adjusted for multiple comparisons) are re-
`ported. An independent data and safety monitor-
`ing committee oversaw the study and performed
`two prespecified interim efficacy reviews.
`
`R esults
`
`Patients
`A total of 19,212 patients were screened, of whom
`8179 (43%) underwent randomization. At the
`time of database lock, vital status was available
`for 99.8% of the patients; 152 patients (1.9%) did
`not complete the final study visits, and 578 pa-
`tients (7.1%) withdrew consent. Details regard-
`ing the disposition of the patients are provided
`in Figure S2 in the Supplementary Appendix.
`The baseline characteristics of the patients
`are shown in Table 1. Among the patients who
`underwent randomization, 70.7% were enrolled
`on the basis of secondary prevention (i.e., patients
`had established cardiovascular disease) and 29.3%
`on the basis of primary prevention (i.e., patients
`had diabetes mellitus and at least one additional
`risk factor). The median age of the patients was
`64 years; 28.8% were female, and 38.5% were
`from the United States. At baseline, the median
`
`n engl j med 380;1 nejm.org
`
`January 3, 2019
`
`13
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`Case 1:20-cv-01630-RGA-JLH Document 17-23 Filed 01/25/21 Page 5 of 13 PageID #: 698
`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`Table 1. Characteristics of the Patients at Baseline.*
`
`Characteristic
`Age
`Median (IQR) — yr
`≥65 yr — no. (%)
`Male sex — no. (%)
`White race — no. (%)†
`Body-mass index‡
`Median (IQR)
`≥30 — no. (%)
`Geographic region — no. (%)§
`United States, Canada, the Netherlands, Australia, New Zealand,
`and South Africa
`Eastern European
`Asia–Pacific
`Cardiovascular risk stratum — no. (%)
`Secondary-prevention cohort
`Primary-prevention cohort
`Ezetimibe use — no. (%)
`Statin intensity — no. (%)
`Low
`Moderate
`High
`Data missing
`Diabetes — no. (%)
`Type 1
`Type 2
`No diabetes at baseline
`Data missing
`Median high-sensitivity CRP level (IQR) — mg/liter
`Median triglyceride level (IQR) — mg/dl
`Median HDL cholesterol level (IQR) — mg/dl
`Median LDL cholesterol level (IQR) — mg/dl
`Distribution of triglyceride levels — no./total no. (%)
`<150 mg/dl
`≥150 to <200 mg/dl
`≥200 mg/dl
`Triglyceride level ≥200 mg/dl and HDL cholesterol level ≤35 mg/dl — no. (%)
`Median eicosapentaenoic acid level (IQR) — μg/ml
`
`Icosapent Ethyl (N = 4089)
`
`Placebo (N = 4090)
`
`64.0 (57.0–69.0)
`1857 (45.4)
`2927 (71.6)
`3691 (90.3)
`
`30.8 (27.8–34.5)
`2331 (57.0)
`
`2906 (71.1)
`
`1053 (25.8)
`130 (3.2)
`
`2892 (70.7)
`1197 (29.3)
`262 (6.4)
`
`254 (6.2)
`2533 (61.9)
`1290 (31.5)
`12 (0.3)
`
`27 (0.7)
`2367 (57.9)
`1695 (41.5)
`0
`2.2 (1.1–4.5)
`216.5 (176.5–272.0)
`40.0 (34.5–46.0)
`74.0 (61.5–88.0)
`
`412/4086 (10.1)
`1193/4086 (29.2)
`2481/4086 (60.7)
`823 (20.1)
`26.1 (17.1–40.1)
`
`64.0 (57.0–69.0)
`1906 (46.6)
`2895 (70.8)
`3688 (90.2)
`
`30.8 (27.9–34.7)
`2362 (57.8)
`
`2905 (71.0)
`
`1053 (25.7)
`132 (3.2)
`
`2893 (70.7)
`1197 (29.3)
`262 (6.4)
`
`267 (6.5)
`2575 (63.0)
`1226 (30.0)
`22 (0.5)
`
`30 (0.7)
`2363 (57.8)
`1694 (41.4)
`3 (0.1)
`2.1 (1.1–4.5)
`216.0 (175.5–274.0)
`40.0 (35.0–46.0)
`76.0 (63.0–89.0)
`
`429/4089 (10.5)
`1191/4089 (29.1)
`2469/4089 (60.4)
`794 (19.4)
`26.1 (17.1–39.9)
`
`* Median low-density lipoprotein (LDL) cholesterol level at baseline differed significantly between the trial groups (P = 0.03); there were no
`other significant between-group differences in baseline characteristics. To convert the values for triglycerides to millimoles per liter, multiply
`by 0.01129. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. In general, the baseline value was defined as
`the last nonmissing measurement obtained before randomization. The baseline LDL cholesterol value as measured by means of preparative
`ultracentrifugation was used in our analyses; however, if the preparative ultracentrifugation value was missing, the LDL cholesterol value
`measured by another method was used in the following order of priority: the value obtained by means of direct measurement of LDL choles-
`terol, the value derived with the use of the Friedewald equation (only for patients with a triglyceride level <400 mg per deciliter), and the val-
`ue derived with the use of the calculation published by Johns Hopkins University investigators.22 At the first and second screening visits, the
`LDL cholesterol value obtained by direct measurement was used if at the same visit the triglyceride level was higher than 400 mg per decili-
`ter. At all remaining visits, the LDL cholesterol value was obtained by means of direct measurement or preparative ultracentrifugation if at
`the same visit the triglyceride level was higher than 400 mg per deciliter. For all other measures of lipid and lipoprotein markers, whenever
`possible, the baseline value was derived as the arithmetic mean of the value obtained at visit 2 (day 0) and the value obtained at the preced-
`ing screening visit. If only one of these values was available, that single value was used as the baseline value. CRP denotes C-reactive pro-
`tein, HDL high-density lipoprotein, and IQR interquartile range. Percentages may not total 100 because of rounding.
`† Race was reported by the investigators.
`‡ Body-mass index is the weight in kilograms divided by the square of the height in meters.
`§ Eastern European region includes Poland, Romania, Russia, and Ukraine, and Asia–Pacific region includes India.
`
`14
`
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`
`January 3, 2019
`
`The New England Journal of Medicine
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`Downloaded from nejm.org on November 19, 2020. For personal use only. No other uses without permission.
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` Copyright © 2019 Massachusetts Medical Society. All rights reserved.
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`Hikma Pharmaceuticals
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`Ex. 1024, p. 5 of 13
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`

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`Case 1:20-cv-01630-RGA-JLH Document 17-23 Filed 01/25/21 Page 6 of 13 PageID #: 699
`Cardiovascular Risk Reduction with Icosapent Ethyl
`
`30
`
`20
`
`10
`
`0
`
`0
`
`Hazard ratio, 0.75 (95% CI, 0.68–0.83)
`P<0.001
`
`Placebo
`
`Icosapent ethyl
`
`1
`
`2
`
`3
`
`4
`
`5
`
`0
`
`1
`
`2
`3
`4
`YearssinceRandomization
`
`5
`
`A PrimaryEndPoint
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`PatientswithanEvent(%)
`
`No.atRisk
`Placebo
`Icosapent ethyl
`
`4090
`4089
`
`3743
`3787
`
`3327
`3431
`
`2807
`2951
`
`2347
`2503
`
`1358
`1430
`
`B KeySecondaryEndPoint
`100
`
`30
`
`20
`
`10
`
`0
`
`0
`
`Hazard ratio, 0.74 (95% CI, 0.65–0.83)
`P<0.001
`
`Placebo
`
`Icosapent ethyl
`
`1
`
`2
`
`3
`
`4
`
`5
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`PatientswithanEvent(%)
`
`0
`
`1
`
`2
`3
`4
`YearssinceRandomization
`
`5
`
`No.atRisk
`Placebo
`Icosapent ethyl
`
`4090
`4089
`
`3837
`3861
`
`3500
`3565
`
`3002
`3115
`
`2542
`2681
`
`1487
`1562
`
`Figure 1. Cumulative Incidence of Cardiovascular Events.
`Panel A shows the Kaplan–Meier event curves for the primary efficacy com-
`posite end point of cardiovascular death, nonfatal myocardial infarction, non-
`fatal stroke, coronary revascularization, or unstable angina in the icosapent
`ethyl group and the placebo group, in a time-to-event analysis. Panel B shows
`the Kaplan–Meier event curves for the key secondary efficacy composite end
`point of cardiovascular death, nonfatal myocardial infarction, or nonfatal
`stroke in the two trial groups, in a time-to-event analysis. In each panel, the
`inset shows the same data on an expanded y axis. The curves were visually
`truncated at 5.7 years because a limited number of events occurred beyond
`that time point; all patient data were included in the analyses.
`
`95% CI, 0.65 to 0.83; P<0.001), corresponding to
`an absolute between-group difference of 3.6 per-
`centage points (95% CI, 2.1 to 5.0); the number
`needed to treat to avoid one key secondary end-
`
`LDL cholesterol level was 75.0 mg per deciliter
`(1.94 mmol per liter), the median high-density
`lipoprotein cholesterol level was 40.0 mg per
`deciliter (1.03 mmol per liter), and the median
`triglyceride level was 216.0 mg per deciliter (2.44
`mmol per liter).22
`
`Follow-up and Effects on Lipids
`The median duration of follow-up was 4.9 years
`(maximum, 6.2 years). The median change in
`triglyceride level from baseline to 1 year was a
`decrease of 18.3% (−39.0 mg per deciliter [−0.44
`mmol per liter]) in the icosapent ethyl group and
`an increase of 2.2% (4.5 mg per deciliter [0.05
`mmol per liter]) in the placebo group; the me-
`dian reduction from baseline (as estimated with
`the use of the Hodges–Lehmann approach) was
`19.7% greater in the icosapent ethyl group than
`in the placebo group (a 44.5 mg per deciliter
`[0.50 mmol per liter] greater reduction; P<0.001).
`The median change in LDL cholesterol level
`from baseline was an increase of 3.1% (2.0 mg
`per deciliter [0.05 mmol per liter]) in the icosa-
`pent ethyl group and an increase of 10.2% (7.0 mg
`per deciliter [0.18 mmol per liter]) in the placebo
`group — a 6.6% (5.0 mg per deciliter [0.13 mmol
`per liter]) lower increase with icosapent ethyl than
`with placebo (P<0.001). The results with respect
`to levels of EPA and lipid, lipoprotein, and in-
`flammatory biomarkers are provided in Table S4
`in the Supplementary Appendix.
`
`Clinical End Points
`A total of 1606 adjudicated primary end-point
`events occurred. A primary end-point event oc-
`curred in 17.2% of the patients in the icosapent
`ethyl group, as compared with 22.0% of the pa-
`tients in the placebo group (hazard ratio, 0.75;
`95% confidence interval [CI], 0.68 to 0.83; P<0.001),
`an absolute between-group difference of 4.8 per-
`centage points (95% CI, 3.1 to 6.5); the number
`needed to treat to avoid one primary end-point
`event was 21 (95% CI, 15 to 33) over a median
`follow-up of 4.9 years.23,24 The event curves based
`on a Kaplan–Meier analysis of the primary effi-
`cacy end point are provided in Figure 1A. The
`results of time-to-event analyses of each compo-
`nent of the primary end point are provided in
`Figure S3 in the Supplementary Appendix. A key
`secondary efficacy end-point event (Fig. 1B) oc-
`curred in 11.2% of the patients in the icosapent
`ethyl group, as compared with 14.8% of the pa-
`tients in the placebo group (hazard ratio, 0.74;
`
`n engl j med 380;1 nejm.org
`
`January 3, 2019
`
`15
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on November 19, 2020. For personal use only. No other uses without permission.
`
` Copyright © 2019 Massachusetts Medical Society. All rights reserved.
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1024, p. 6 of 13
`
`

`

`Case 1:20-cv-01630-RGA-JLH Document 17-23 Filed 01/25/21 Page 7 of 13 PageID #: 700
`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`Subgroup
`
`All patients
`Risk stratum
`Secondary-prevention cohort
`Primary-prevention cohort
`Region
`United States, Canada,
`the Netherlands, Australia,
`New Zealand, and South Africa
`Eastern Europe
`Asia–Pacific
`Ezetimibe use
`No
`Yes
`Sex
`Male
`Female
`Race
`White
`Other
`Age
`<65 yr
`≥65 yr
`From the United States
`Yes
`No
`Diabetes at baseline
`Yes
`No
`Baseline estimated GFR
`<60 ml/min/1.73 m2
`≥60 to <90 ml/min/1.73 m2
`≥90 ml/min/1.73 m2
`Baseline triglycerides
`≥200 mg/dl
`<200 mg/dl
`Baseline triglycerides
`≥150 mg/dl
`<150 mg/dl
`Baseline triglycerides ≥200 mg/dl and
`HDL cholesterol ≤35 mg/dl
`Yes
`No
`Baseline statin intensity
`High
`Moderate
`Low
`Baseline LDL cholesterol (derived)
`in thirds
`≤67 mg/dl
`>67 to ≤84 mg/dl
`>84 mg/dl
`Baseline high-sensitivity CRP
`≤2 mg/liter
`>2 mg/liter
`
`Placebo
`IcosapentEthyl
`no. of patients with event/total no. of patients (%)
`705/4089 (17.2)
`901/4090 (22.0)
`
`559/2892 (19.3)
`146/1197 (12.2)
`
`738/2893 (25.5)
`163/1197 (13.6)
`
`551/2906 (19.0)
`
`713/2905 (24.5)
`
`143/1053 (13.6)
`11/130 (8.5)
`
`167/1053 (15.9)
`21/132 (15.9)
`
`649/3827 (17.0)
`56/262 (21.4)
`
`834/3828 (21.8)
`67/262 (25.6)
`
`551/2927 (18.8)
`154/1162 (13.3)
`
`715/2895 (24.7)
`186/1195 (15.6)
`
` 646/3691 (17.5)
`59/398 (14.8)
`
`812/3688 (22.0)
`89/401 (22.2)
`
`322/2232 (14.4)
`383/1857 (20.6)
`
`460/2184 (21.1)
`441/1906 (23.1)
`
`281/1548 (18.2)
`424/2541 (16.7)
`
`394/1598 (24.7)
`507/2492 (20.3)
`
`433/2394 (18.1)
`272/1695 (16.0)
`
`536/2393 (22.4)
`365/1694 (21.5)
`
`197/905 (21.8)
`380/2217 (17.1)
`128/963 (13.3)
`
`263/911 (28.9)
`468/2238 (20.9)
`170/939 (18.1)
`
`430/2481 (17.3)
`275/1605 (17.1)
`
`559/2469 (22.6)
`342/1620 (21.1)
`
`640/3674 (17.4)
`65/412 (15.8)
`
`811/3660 (22.2)
`90/429 (21.0)
`
`149/823 (18.1)
`554/3258 (17.0)
`
`214/794 (27.0)
`687/3293 (20.9)
`
`232/1290 (18.0)
`424/2533 (16.7)
`48/254 (18.9)
`
`310/1226 (25.3)
`543/2575 (21.1)
`45/267 (16.9)
`
`244/1481 (16.5)
`248/1347 (18.4)
`213/1258 (16.9)
`
`302/1386 (21.8)
`307/1364 (22.5)
`292/1339 (21.8)
`
`288/1919 (15.0)
`417/2167 (19.2)
`
`407/1942 (21.0)
`494/2147 (23.0)
`
`HazardRatio(95%CI)
`
`PValuefor
`Interaction
`
`0.75 (0.68–0.83)
`
`0.73 (0.65–0.81)
`0.88 (0.70–1.10)
`
`0.74 (0.66–0.83)
`
`0.84 (0.67–1.05)
`0.49 (0.24–1.02)
`
`0.75 (0.67–0.83)
`0.82 (0.57–1.16)
`
`0.73 (0.65–0.82)
`0.82 (0.66–1.01)
`
`0.77 (0.69–0.85)
`0.60 (0.43–0.83)
`
`0.65 (0.56–0.75)
`0.87 (0.76–1.00)
`
`0.69 (0.59–0.80)
`0.80 (0.71–0.91)
`
`0.77 (0.68–0.87)
`0.73 (0.62–0.85)
`
`0.71 (0.59–0.85)
`0.80 (0.70–0.92)
`0.70 (0.56–0.89)
`
`0.73 (0.64–0.83)
`0.79 (0.67–0.93)
`
`0.75 (0.68–0.83)
`0.79 (0.57–1.09)
`
`0.62 (0.51–0.77)
`0.79 (0.71–0.88)
`
`0.69 (0.58–0.82)
`0.76 (0.67–0.86)
`1.12 (0.74–1.69)
`
`0.72 (0.61–0.85)
`0.81 (0.68–0.96)
`0.74 (0.62–0.89)
`
`0.68 (0.58–0.79)
`0.81 (0.71–0.93)
`
`0.14
`
`0.30
`
`0.64
`
`0.33
`
`0.18
`
`0.004
`
`0.14
`
`0.56
`
`0.41
`
`0.45
`
`0.83
`
`0.04
`
`0.12
`
`0.62
`
`0.07
`
`0.2
`
`0.6
`
`1.0
`
`1.4
`
`1.8
`
`IcosapentEthyl
`Better
`
`Placebo
`Better
`
`16
`
`n engl j med 380;1 nejm.org
`
`January 3, 2019
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on November 19, 2020. For personal use only. No other uses without permission.
`
` Copyright © 2019 Massachusetts Medical Society. All rights reserved.
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1024, p. 7 of 13
`
`

`

`Case 1:20-cv-01630-RGA-JLH Document 17-23 Filed 01/25/21 Page 8 of 13 PageID #: 701
`Cardiovascular Risk Reduction with Icosapent Ethyl
`
`Figure 2 (facing page). Primary Efficacy Composite
`End Point in Selected Prespecified Subgroups.
`Shown are the hazard ratios and 95% confidence in-
`tervals for the primary efficacy composite end point of
`cardiovascular death, nonfatal myocardial infarction,
`nonfatal stroke, coronary revascularization, or unsta-
`ble angina, as assessed in a time-to-event analysis, in
`selected prespecified subgroups of the intention-to-
`treat population (all patients who underwent random-
`ization). The confidence intervals shown for the sub-
`group analyses have not been adjusted for multiple
`testing, and inferences drawn from the intervals may
`not be reproducible. Race was reported by the investi-
`gators. Eastern European region includes Poland, Ro-
`mania, Russia, and Ukraine, and Asia–Pacific region
`includes India. To convert the values for triglycerides
`to millimoles per liter, multiply by 0.01129. To convert
`the values for cholesterol to millimoles per liter, multi-
`ply by 0.02586. CRP denotes C-reactive protein, GFR
`glomerular filtration rate, HDL high-density lipoprotein,
`and LDL low-density lipoprotein. The LDL cholesterol
`value obtained by means of preparative ultracentrifu-
`gation was used. If the preparative ultracentrifugation
`value was missing, the LDL cholesterol value mea-
`sured by another method was used in the following
`order of priority: the nonmissing value obtained by
`means of direct measurements of LDL cholesterol, the
`value derived with the use of the Friedewald equation,
`and the value derived with the use of the calculation
`published by Johns Hopkins University investigators.22
`
`point event was 28 (95% CI, 20 to 47) over a me-
`dian follow-up 4.9 years.23,24
`The rates of the primary and key secondary
`efficacy end points in selected prespecified sub-
`groups are provided in Figures 2 and 3; the find-
`ings show a consistent benefit with icosapent
`ethyl. Baseline triglyceride levels (≥150 vs. <150 mg
`per deciliter or ≥200 or <200 mg per deciliter)
`had no influence on the primary or key second-
`ary efficacy end points (Figs. 2 and 3). The at-
`tainment of triglyceride levels of 150 mg per
`deciliter or higher or below 150 mg per deciliter
`at 1 year after randomization also had no influ-
`ence on the efficacy of icosapent ethyl as com-
`pared with placebo with respect to the primary
`or key secondary efficacy end point (Fig. S4 in
`the Supplementary Appendix). In a post hoc
`analysis, we found no substantial difference in
`the benefit of icosapent ethyl as compared with
`placebo with respect to the primary end point
`according to whether the patients who received
`placebo had an increase in LDL cholesterol levels
`at 1 year or had no change or a decrease in LDL
`cholesterol levels.
`In the prespecified hierarchical testing of end
`
`points (Fig. 4), the rates of all individual and
`composite ischemic end points (except for death
`from any cause — the last secondary end point
`in the hierarchy) were significantly lower in the
`icosapent ethyl group than in the placebo group,
`including the rate of cardiovascular death (4.3%
`vs. 5.2%; hazard ratio, 0.80; 95% CI, 0.66 to 0.98;
`P = 0.03). The rate of death from any cause was
`6.7% in the icosapent ethyl group and 7.6% in
`the placebo group (hazard ratio, 0.87; 95% CI,
`0.74 to 1.02). The results for selected prespeci-
`fied tertiary end points, which were not adjusted
`for multiple comparisons, are provided in Table
`S3 in the Supplementary Appendix. Among these
`results, the rates of adjudicated sudden cardiac
`death were 1.5% in the icosapent ethyl group and
`2.1% in the placebo group (hazard ratio, 0.69;
`95% CI, 0.50 to 0.96), and the rates of cardiac
`arrest were 0.5% and 1.0%, respectively (hazard
`ratio, 0.52; 95% CI, 0.31 to 0.86).
`
`Safety and Adverse Events
`The overall rates of adverse events that occurred
`while the patients were in the trial and the rates
`of serious adverse events leading to discontinua-
`tion of the trial drug or placebo did not differ
`significantly between the trial groups (Table S5
`in the Supplementary Appendix). The only serious
`adverse event that occurred at a frequency of at
`least 2% was pneumonia (2.6% in the icosapent
`ethyl group and 2.9% in the placebo group,
`P = 0.42). Adverse events that occurr