Case 1:20-cv-01630-RGA-JLH Document 17-22 Filed 01/25/21 Page 1 of 10 PageID #: 684
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`Exhibit U
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1023, p. 1 of 10
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`

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`Case 1:20-cv-01630-RGA-JLH Document 17-22 Filed 01/25/21 Page 2 of 10 PageID #: 685
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`Efficacy and Safety of Eicosapentaenoic Acid Ethyl Ester
`(AMR101) Therapy in Statin-Treated Patients With Persistent High
`Triglycerides (from the ANCHOR Study)
`Christie M. Ballantyne, MDa,*, Harold E. Bays, MDb, John J. Kastelein, MD, PhDc,
`Evan Stein, MD, PhDd, Jonathan L. Isaacsohn, MDd, Rene A. Braeckman, PhDe, and
`Paresh N. Soni, MD, PhDe
`AMR101 is an ␻-3 fatty acid agent containing >96% pure icosapent-ethyl, the ethyl ester of
`eicosapentaenoic acid. The efficacy and safety of AMR101 were evaluated in this phase 3,
`multicenter, placebo-controlled, randomized, double-blinded, 12-week clinical trial (ANCHOR)
`in high-risk statin-treated patients with residually high triglyceride (TG) levels (>200 and
`<500 mg/dl) despite low-density lipoprotein (LDL) cholesterol control (>40 and <100 mg/dl).
`Patients (n ⴝ 702) on a stable diet were randomized to AMR101 4 or 2 g/day or placebo. The
`primary end point was median percent change in TG levels from baseline versus placebo at 12
`weeks. AMR101 4 and 2 g/day significantly decreased TG levels by 21.5% (p <0.0001) and
`10.1% (p ⴝ 0.0005), respectively, and non-high-density lipoprotein (non-HDL) cholesterol by
`13.6% (p <0.0001) and 5.5% (p ⴝ 0.0054), respectively. AMR101 4 g/day produced greater TG
`and non-HDL cholesterol decreases in patients with higher-efficacy statin regimens and greater
`TG decreases in patients with higher baseline TG levels. AMR101 4 g/day decreased LDL
`cholesterol by 6.2% (p ⴝ 0.0067) and decreased apolipoprotein B (9.3%), total cholesterol
`(12.0%), very-low-density lipoprotein cholesterol (24.4%), lipoprotein-associated phospholipase
`A2 (19.0%), and high-sensitivity C-reactive protein (22.0%) versus placebo (p <0.001 for all
`comparisons). AMR101 was generally well tolerated, with safety profiles similar to placebo. In
`conclusion, AMR101 4 g/day significantly decreased median placebo-adjusted TG, non-HDL
`cholesterol, LDL cholesterol, apolipoprotein B, total cholesterol, very-low-density lipoprotein
`cholesterol, lipoprotein-associated phospholipase A2, and high-sensitivity C-reactive protein in
`statin-treated patients with residual TG elevations. © 2012 Elsevier Inc. All rights reserved.
`(Am J Cardiol 2012;xx:xxx)
`
`In association with an increasing prevalence of obesity
`and diabetes in recent decades, the number of patients with
`elevated serum triglycerides (TGs) has markedly increased.1
`In patients with fasting TG levels ⱖ200 and ⬍500 mg/dl,
`
`low-density lipoprotein (LDL) cholesterol is the primary
`lipid target, with statins being first-line therapy for prevent-
`ing atherosclerotic coronary heart disease.2 If TG levels
`remain ⱖ200 and ⬍500 mg/dl after optimization of LDL
`
`aBaylor College of Medicine and the Methodist DeBakey Heart and
`Vascular Center, Houston, Texas; bLouisville Metabolic and Atheroscle-
`rosis Research Center, Louisville, Kentucky; cAcademic Medical Center,
`eAmarin
`Amsterdam, The Netherlands; dMedpace, Cincinnati, Ohio;
`Pharma, Inc., Bedminster, New Jersey. Manuscript received March 2,
`2012; revised manuscript received and accepted May 23, 2012.
`The trial was designed and sponsored by Amarin Pharma, Inc., Bedmin-
`ster, New Jersey, and conducted by Medpace, Inc., Cincinnati, Ohio, with
`funding from Amarin Pharma, Inc. Writing assistance was provided to the
`authors by Peloton Advantage, LLC, Parsippany, New Jersey, and funded by
`Amarin Pharma, Inc. Dr. Ballantyne has received research grants from Abbott
`Laboratories, Abbott Park, Illinois, Amarin Pharma, Inc., AstraZeneca, Wil-
`mington, Delaware, Bristol-Myers Squibb, New York, New York, diaDexus,
`South San Francisco, California, GlaxoSmithKline, Research Triangle Park,
`North Carolina, Kowa Pharmaceuticals America, Inc., Montgomery, Alabama,
`Merck & Co., Whitehouse Station, New Jersey, Novartis Pharmaceuticals
`Corp., East Hanover, New Jersey, Roche, Basel, Switzerland, Sanofi-Syn-
`thelabo, Paris, France, Takeda, San Diego, California, National Institutes of
`Health, Bethesda, Maryland, American Diabetes Association, Alexandria, Vir-
`ginia, and American Heart Association, Dallas, Texas, speakers bureau fees
`from Abbott, GlaxoSmithKline, and Merck & Co.; honoraria from Abbott,
`Amarin, AstraZeneca, GlaxoSmithKline, Merck & Co., Sanofi-Synthelabo,
`and Takeda; and has provided consultancy services for Abbott, Adnexus,
`
`Waltham, Massachusetts, Amylin, San Diego, California, AstraZeneca, Bristol-
`Myers Squibb, Esperion, Plymouth, Michigan, Genentech, South San Francisco,
`California, GlaxoSmithKline,
`Idera Pharma, Cambridge, Massachusetts,
`Kowa, Novartis, Omthera, Princeton, New Jersey, Resverlogix, San Francisco,
`California, Roche, Sanofi-Synthelabo, and Takeda. Dr. Bays has received
`research grants from Amarin Pharma, Inc., GlaxoSmithKline, Trygg, Oslo,
`Norway,
`and Omthera;
`speakers bureau fees
`and honoraria
`from
`GlaxoSmithKline; and has provided consultancy services for Amarin Pharma,
`Inc. and GlaxoSmithKline. Dr. Kastelein has received speaker bureau fees
`from Merck & Co., Pfizer, New York, New York, Roche, and AstraZeneca
`and has provided consultancy services for Amarin Pharma, Inc., Merck & Co.,
`Roche, and AstraZeneca. Dr. Stein has received research grants from Regen-
`eron, Tarrytown, New York, Sanofi-Aventis, Bridgewater, New Jersey, Roche,
`AstraZeneca, Amarin Pharma, Inc., Omthera, GlaxoSmithKline, Amgen,
`Thousand Oaks, California, Genzyme, Cambridge, Massachusetts, and ISIS,
`Carlsbad, California; honoraria from Amgen, Roche, Bristol-Myers Squibb,
`Adnexus, Sanofi-Aventis, AstraZeneca, and Genzyme; and has provided con-
`sultancy services for Amgen, Roche, Bristol-Myers Squibb, Adnexus, Sanofi-
`Aventis, AstraZeneca, and Genzyme. Dr. Isaacsohn has received a research
`grant from Amarin Pharma, Inc. Dr. Soni is a stock shareholder of Amarin
`Pharma, Inc.
`*Corresponding author: Tel: 713-798-4951; fax: 713-798-3057.
`E-mail address: cmb@bcm.tmc.edu (C.M. Ballantyne).
`
`0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
`http://dx.doi.org/10.1016/j.amjcard.2012.05.031
`
`www.ajconline.org
`
`Hikma Pharmaceuticals
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`IPR2022-00215
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`2
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`The American Journal of Cardiology (www.ajconline.org)
`
`Figure 1. Study design. The screening period consisted of a 4- to 6-week lead-in period during which patients underwent diet and lifestyle stabilization and
`nonstatin lipid-altering treatment washout if necessary. At the first screening visit, patients not taking a statin were initiated on statin therapy and likely to
`achieve a low-density lipoprotein cholesterol goal of ⬍100 mg/dl and all patients received counseling on the National Cholesterol Education Program
`Therapeutic Lifestyle Changes diet.2 Patients then entered a 2- to 3-week qualifying period. Lipid qualifications included an average fasting triglyceride level
`ⱖ200 and ⬍500 mg/dl and an average fasting low-density lipoprotein cholesterol level ⱖ40 and ⬍100 mg/dl based on the average (arithmetic mean) of 2
`visits. If the average triglyceride and/or low-density lipoprotein cholesterol level was outside the required range, an additional measurement could be obtained
`at a third visit 1 week later, with eligibility determined based on the last 2 visits. Eligible patients were randomized 1 week later to AMR101 4 g/day (2
`AMR101 1-g capsules 2 times/day), AMR101 2 g/day (1 AMR101 1-g capsule plus 1 matching placebo capsule 2 times/day), or placebo (2 matching placebo
`capsules 2 times/day). Investigators and patients were blinded to treatment assignment throughout the double-blinded, placebo-controlled, 12-week treatment
`period. Visit 1 (V1) was 6 weeks for patients requiring washout and 4 weeks for patients not requiring washout. V2 to V7 ⫽ visits 2 to 7.
`
`cholesterol levels with statin therapy, adjunctive treatment
`options include lifestyle interventions, fibrates, niacin,
`ezetimibe, and ␻-3 fatty acids.3 AMR101 is an ␻-3 fatty
`acid investigational new drug containing ⱖ96% pure ico-
`sapent-ethyl
`(the ethyl ester of eicosapentaenoic acid
`[EPA]; United States Adopted Name [generic] and Interna-
`tional Nonproprietary Name). This study (ANCHOR) as-
`sessed the efficacy and safety of AMR101 in statin-treated
`patients at high cardiovascular risk with well-controlled
`LDL cholesterol and residually high TG levels (ⱖ200 and
`⬍500 mg/dl).
`
`Methods
`
`The ANCHOR study was a phase 3, multicenter, pla-
`cebo-controlled, randomized, double-blinded, 12-week
`clinical trial conducted at 97 sites in the United States
`from December 2009 through February 2011. The proto-
`col was approved by the appropriate institutional review
`boards, and all patients underwent the informed consent
`process before enrollment, as evidenced by their written
`informed consent. The clinical trial registration number
`was NCT01047501 (available at: http://clinicaltrials.gov/
`ct2/show/NCT01047501).
`The study design is explained in Figure 1. Inclusion
`criteria included patients ⬎18 years of age and at high risk
`for cardiovascular disease as defined by the National Cho-
`lesterol Education Program Adult Treatment Panel III
`guidelines2 who were willing to maintain stable diet and
`exercise throughout the study; at the first TG-qualifying
`visit, patients were required to have been on ⱖ4 weeks of
`stable statin therapy (atorvastatin, rosuvastatin, or simvasta-
`tin; with or without ezetimibe) at doses likely to achieve
`“optimal” LDL cholesterol for high-risk patients (ⱖ40 and
`
`⬍100 mg/dl) and continue such treatment throughout the
`study. To facilitate enrollment, a protocol amendment was
`implemented after approximately 1/2 of patients were ran-
`domized: the hemoglobin A1c exclusion criterion was in-
`creased from 9.0% to ⬎9.5%; based on known within-
`patient variability for TG and LDL cholesterol, entry criteria
`were expanded so the mean of the 2 TG-qualifying values
`was ⱖ185 mg/dl with ⱖ1 of the 2 values ⱖ200 mg/dl; and
`the upper limit of the LDL cholesterol entry criteria was
`increased by 15% to ⱕ115 mg/dl.
`Exclusion criteria included body mass index ⬎45 kg/m2,
`a weight change ⬎3 kg from the first visit to the end of the
`qualifying period, non-high-density lipoprotein (non-HDL)
`cholesterol levels ⬍100 mg/dl, known nephrotic range (⬎3
`g/day) proteinuria, malignancy, bariatric surgery, long-term
`treatment with antihypertensive and antidiabetic medica-
`tions, treatment with weight-loss drugs, thyroid-stimulating
`hormone ⬎1.5 times upper limit of normal, alanine amino-
`transferase or aspartate aminotransferase ⬎3 times upper
`limit of normal, and unexplained creatine kinase concentra-
`tion ⬎3 times upper limit of normal or creatine kinase
`increase from known muscle disease.
`The primary end point was median placebo-adjusted
`percent change in TG levels from baseline to week 12
`(study end). Baseline TG level was calculated as the average
`of levels at randomization and 1 week previously. TG value
`at study end was calculated as the average of weeks 11 and
`12. Prespecified secondary efficacy end points included
`median placebo-adjusted percent change in non-HDL cho-
`lesterol, LDL cholesterol, apolipoprotein B, very-low-den-
`sity lipoprotein (VLDL), and lipoprotein-associated phos-
`pholipase A2. Exploratory end points included median
`placebo-adjusted percent change in total cholesterol, HDL
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`Hikma Pharmaceuticals
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`Preventive Cardiology/The ANCHOR Study
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`3
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`Figure 2. Patient disposition.
`
`cholesterol, VLDL-TG, and high-sensitivity C-reactive pro-
`tein. Safety assessments, blood and urine tests, and efficacy
`end-point assessments were analyzed as previously de-
`scribed; high-sensitivity C-reactive protein was measured
`with the same assay as previously described for lipoprotein-
`associated phospholipase A2.4
`A sample size of 194 completed patients per treatment
`arm was required to provide 90.6% power to detect a dif-
`ference of 15% between AMR101 4 g/day and placebo in
`percent change from baseline in fasting TG levels, assuming
`an SD of 45% in TG measurements and a significance level
`(p value) ⬍0.05, and 80% power to demonstrate noninferi-
`ority (p ⬍0.025, 1-sided) of the LDL cholesterol response
`between AMR101 4 g/day and placebo with a ⫹6% margin.
`To accommodate a 10% drop-out rate, recruitment was
`planned for 648 randomized patients.
`All efficacy analyses were performed on the intent-to-
`treat population (randomized patients who received ⱖ1
`dose of study drug and had baseline and ⱖ1 postrandom-
`ization efficacy measurements) using an analysis of covari-
`ance model with treatment, type of statin, gender, and pres-
`ence of diabetes as factors and baseline TG as a covariate.
`If no significant departure from normality was observed,
`parametric testing was planned for each comparison be-
`tween AMR101 and placebo. For each efficacy end point, if
`a significant departure from normality was observed
`(p ⬍0.01, Shapiro–Wilk test), the median and interquartile
`
`range would be calculated for each treatment group and
`median differences and Hodges–Lehmann 2-tailed 95%
`confidence interval would be calculated for each compari-
`son between AMR101 and placebo.
`Nonparametric analysis p values were planned using
`Wilcoxon rank-sum test for each comparison between
`AMR101 and placebo. Missing data were imputed using the
`last-observation-carried-forward method. To control
`the
`family-wise error rate when performing multiple pairwise
`tests between the 2 dose levels of AMR101 and placebo, a
`prespecified step-down testing procedure was followed for
`the primary end point: differences in TG-lowering between
`AMR101 4 g/day and placebo were tested; if this first
`comparison showed a statistically significantly greater de-
`crease in TG at the prespecified significance level of 0.05,
`the TG-lowering effects of AMR101 2 g/day versus placebo
`were also analyzed. For all end points, comparisons be-
`tween AMR101 and placebo were made using a significance
`level of 0.05. The Hommel procedure was used to test the
`adequate control of type 1 error for multiple secondary end
`points. For non-HDL cholesterol, VLDL cholesterol, lipo-
`protein-associated phospholipase A2, and apolipoprotein B,
`treatment groups were compared using the Dunnett test to
`control the type I error rate within each parameter. Changes
`in TG and non-HDL cholesterol were analyzed by select
`baseline characteristics in prespecified (TG) and post hoc
`(non-HDL cholesterol) analyses. All safety analyses were
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`Hikma Pharmaceuticals
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`4
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`The American Journal of Cardiology (www.ajconline.org)
`
`Table 1
`Baseline characteristics
`
`Characteristic
`
`AMR101 Dose
`
`4 g/day
`(n ⫽ 233)
`
`2 g/day
`(n ⫽ 236)
`
`Placebo
`(n ⫽ 233)
`
`Age (years),
`mean ⫾ SD
`Age ⱖ65 years
`Men
`White
`Weight (kg),
`mean ⫾ SD
`Body mass index (kg/
`m2), mean ⫾ SD
`Diabetes mellitus
`Fasting plasma glucose
`(mg/dl), mean ⫾ SD
`(n ⫽ 225, 234, 227)
`Hemoglobin A1c (%),
`mean ⫾ SD
`(n ⫽ 226, 234, 227)
`Statin use
`Atorvastatin
`Simvastatin
`Rosuvastatin
`Statin efficacy regimens*
`Lower
`Medium
`Higher
`
`61.1 ⫾ 10.03
`
`61.8 ⫾ 9.42
`
`61.2 ⫾ 10.05
`
`91 (39%)
`142 (61%)
`226 (97%)
`94.5 ⫾ 18.30
`
`95 (40%)
`144 (61%)
`226 (96%)
`95.5 ⫾ 18.29
`
`87 (37%)
`145 (62%)
`224 (96%)
`97.0 ⫾ 19.14
`
`32.7 ⫾ 4.99
`
`32.9 ⫾ 4.98
`
`33.0 ⫾ 5.04
`
`171 (73%)
`133.0 ⫾ 37.1
`
`172 (73%)
`135.4 ⫾ 43.2
`
`171 (73%)
`130.1 ⫾ 35.8
`
`6.6 ⫾ 0.9
`
`6.7 ⫾ 1.1
`
`6.5 ⫾ 0.9
`
`44 (19%)
`134 (58%)
`55 (24%)
`
`16 (7%)
`148 (64%)
`69 (30%)
`
`43 (18%)
`136 (58%)
`57 (24%)
`
`17 (7%)
`148 (63%)
`71 (30%)
`
`45 (19%)
`133 (57%)
`55 (24%)
`
`15 (6%)
`144 (62%)
`74 (32%)
`
`Data are reported for the randomized population, with the exception of
`fasting plasma glucose and hemoglobin A1c, which are reported for the
`intent-to-treat population.
`* Lower-efficacy statin regimens ⫽ simvastatin 5 to 10 mg; medium-
`efficacy statin regimens ⫽ rosuvastatin 5 to 10 mg, atorvastatin 10 to 20
`mg, simvastatin 20 to 40 mg, simvastatin 10 to 20 mg plus ezetimibe 5 to
`10 mg; higher-efficacy statin regimens ⫽ rosuvastatin 20 to 40 mg, ator-
`vastatin 40 to 80 mg, simvastatin 80 mg, simvastatin 40 to 80 mg plus
`ezetimibe 5 to 10 mg.
`
`performed in the safety population (randomized patients
`who received ⱖ1 dose of study medication). For hemoglo-
`bin A1c and fasting plasma glucose, differences in change
`from baseline between AMR101 and placebo were analyzed
`using an analysis of covariance model with treatment as a
`factor and baseline value as a covariate using a significance
`level of 0.05.
`
`Results
`
`Figure 2 shows the patient disposition; 663 patients
`(⬎90% in each treatment group) completed the 12-week
`double-blinded treatment phase. Baseline characteristics of
`randomized patients are listed in Table 1 and were compa-
`rable across treatment groups (p ⬎0.14 for all comparisons;
`not presented in Table 1). Patients with diabetes had well-
`controlled diabetes with mean baseline hemoglobin A1c
`⬍7% and fasting plasma glucose ⬍136 mg/dl for all groups.
`Median LDL cholesterol level was 83.0 mg/dl and 21% of
`patients had baseline LDL cholesterol levels ⬍70 mg/dl.
`Most patients (93.2%) were taking medium- or high-effi-
`cacy statin regimens (as defined a priori) and 90.2% were on
`statin therapy before screening. Median baseline TG level
`was 259.0 mg/dl.
`
`AMR101 produced significant decreases in TG and var-
`ious efficacy end points in placebo-adjusted changes from
`baseline to study end (Figure 3 and Table 2). Because a
`significant departure from normality was observed for all
`efficacy end points (p ⬍0.01, Shapiro–Wilk test), nonpara-
`metric statistics were used. For the 2 AMR101 treatment
`groups, the maximum TG-lowering effect was reached by
`approximately week 4 (data not shown). AMR101 did not
`significantly increase LDL cholesterol at either dose. The
`noninferiority criterion for LDL cholesterol was met for the
`2 AMR101 doses because the prespecified upper boundary
`(⫺1.7 to ⫹0.5 for
`of
`the 97.5% confidence interval
`AMR101 4 and 2 g/day, respectively) did not cross the
`⫹6% noninferiority threshold (data not shown).
`Analysis of subgroups by prespecified statin efficacy
`regimen indicated that patients treated with more effective
`statin regimens exhibited greater TG and non-HDL choles-
`terol decreases with AMR101 compared to lower-efficacy
`regimens (Table 3). Statistically significant decreases in TG
`levels with AMR101 4 g/day were observed for patients
`treated with atorvastatin, simvastatin, and rosuvastatin and
`with AMR101 2 g/day for patients treated with simvastatin.
`Analysis of subgroups by median baseline TG tertiles indi-
`cated that higher baseline TG levels resulted in greater TG
`decreases. Median decreases in TG levels were statistically
`significant versus placebo and similar in patients with and
`without diabetes mellitus.
`During the double-blinded treatment period, 46.2% of
`patients had ⱖ1 treatment-emergent adverse event regard-
`less of cause: 106 patients (45.5%) in the AMR101 4 g/day
`group, 106 patients (44.9%) in the AMR101 2 g/day group,
`and 112 patients (48.1%) in the placebo group. Most treat-
`ment-emergent adverse events were mild or moderate in
`severity and considered unrelated to study drug. Diarrhea,
`nausea, nasopharyngitis, and arthralgia occurred in ⬎3% of
`patients, and only arthralgia occurred in a larger percentage
`of patients treated with AMR101 versus placebo (Table 4).
`The most common treatment-emergent adverse events were
`gastrointestinal disorders, which occurred in a larger per-
`centage of patients in the placebo group. Eructations were
`reported by 2, 1, and 4 patients receiving AMR101 4 g/day,
`AMR101 2 g/day, and placebo, respectively. Twenty-five
`patients (3.6%) discontinued treatment during the double-
`blinded treatment phase because of a treatment-emergent
`adverse event (5 patients in AMR101 4 g/day group, 8
`patients in AMR101 2 g/day group, and 12 patients in
`placebo group). In total, 18 serious adverse events were
`reported during the study (7 patients in AMR101 4 g/day
`group, 6 patients in AMR101 2 g/day group, and 5 patients
`in placebo group including 1 death related to myocardial
`infarction). No serious adverse events were considered re-
`lated to study drug. No clinically significant increases in
`alanine aminotransferase, aspartate aminotransferase, and
`creatine kinase were observed in the AMR101 treatment
`groups. One patient in the AMR101 4 g/day group had an
`increase in alanine aminotransferase ⬎3 times the upper
`limit of normal detected at week 12, which decreased during
`follow-up after the study. No statistically significant in-
`creases in fasting plasma glucose or hemoglobin A1c were
`observed in either treatment group compared to placebo. No
`clinically meaningful changes in safety laboratory parame-
`
`Hikma Pharmaceuticals
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`IPR2022-00215
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`Preventive Cardiology/The ANCHOR Study
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`5
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`Figure 3. Median placebo-adjusted percent change from baseline to week 12 for efficacy end points (intent-to-treat population). *p ⬍0.0001; †p ⬍0.001;
`‡p ⬍0.01; §p ⬍0.05. apo B ⫽ apolipoprotein B; HDL-C ⫽ high-density lipoprotein cholesterol; hsCRP ⫽ high-sensitivity C-reactive protein; LDL-C ⫽
`⫽ lipoprotein-associated phospholipase A2; non-HDL-C ⫽ non-high-density lipoprotein cholesterol; NS ⫽ not
`low-density lipoprotein cholesterol; Lp-PLA2
`significant; TC ⫽ total cholesterol; TG ⫽ triglyceride; VLDL-C ⫽ very-low-density lipoprotein cholesterol; VLDL-TG ⫽ very-low-density lipoprotein
`triglyceride.
`
`ters, electrocardiographic parameters, vital signs, or physi-
`cal examination findings were noted.
`
`Discussion
`
`In this randomized trial of statin-treated patients at high
`risk of coronary artery disease with optimized LDL choles-
`terol levels and residually elevated TG levels, AMR101 4
`and 2 g/day significantly decreased median placebo-ad-
`justed TG levels from baseline by 21.5% and 10.1%, re-
`spectively. Although LDL cholesterol levels were well con-
`trolled at baseline and most patients were taking medium- or
`high-efficacy statin regimens (93.2%), AMR101 4 g/day
`significantly decreased median placebo-adjusted LDL
`cholesterol levels by an additional 6.2%. Furthermore,
`AMR101 decreased non-HDL cholesterol (13.6%) and apo-
`lipoprotein B (9.3%). Patients treated with more effective
`statin regimens showed greater decreases in TG and non-
`HDL cholesterol with AMR101 4 g/day compared to less-
`effective regimens. AMR101 decreased TG levels similarly
`in patients regardless of diabetes mellitus status or statin
`type, with the greatest TG decreases seen in higher-tertile
`baseline TG (31% in 4 g/day group compared to placebo).
`Based on this study, AMR101 4 g/day appears to be a more
`effective dose than 2 g/day because changes in efficacy end
`points were greater with the higher dose.
`One of the potential explanations for the continued in-
`crease of cardiovascular risk in high-risk patients with per-
`sistent high TG elevations despite statin therapy may be due
`to increased inflammation. AMR101 4 g/day decreased me-
`dian placebo-adjusted lipoprotein-associated phospholipase
`A2 by 19% and decreased high-sensitivity C-reactive pro-
`tein by 22.0%.
`Although other studies in hypertriglyceridemic patients on
`statin therapy have suggested EPA and docosahexaenoic acid
`(DHA) combinations may decrease non-HDL cholesterol,5,6
`lipoprotein-associated phospholipase A2,7 and possibly apoli-
`poprotein B,5 AMR101 not only decreased these parameters
`
`but also decreased LDL cholesterol and high-sensitivity C-re-
`active protein levels. Decreases in non-HDL cholesterol, lipo-
`protein-associated phospholipase A2, and apolipoprotein B in
`the present study were greater than expected. In the Combina-
`tion of Prescription Omega-3 with Simvastatin (COMBOS)
`study,5 which enrolled patients without regard to coro-
`nary heart disease risk on stable simvastatin therapy and
`with similarly elevated TGs, 4 g/day of a prescription ␻-3
`combination EPA and DHA ethyl ester formulation de-
`creased median TG levels by 29.5% versus 6.3% with
`placebo (p ⬍0.001). Omega-3 acid ethyl esters combined
`with simvastatin significantly decreased the primary end
`point of median change in non-HDL cholesterol (9.0% vs
`2.2%; p ⬍0.001) and median change in apolipoprotein B
`(4.2% vs 1.9%; p ⫽ 0.023) compared to simvastatin alone.
`In this trial, the combined EPA and DHA prescription prep-
`aration resulted in a nonsignificant increase in LDL choles-
`terol levels of 0.7%, compared to a 2.8% decrease in pa-
`tients treated with placebo (p ⫽ 0.052).
`The LDL cholesterol effect seen in the present trial with
`AMR101 is supported by the Multi-center, Placebo-con-
`trolled, Randomized, Double-blind, 12-week Study with an
`Open-label Extension (MARINE),4 which enrolled patients
`with very high TGs (ⱖ500 and ⱕ2,000 mg/dl). In the
`MARINE study, AMR101 significantly decreased TG lev-
`els but did not increase LDL cholesterol compared to pla-
`cebo. This contrasts with the effect on LDL cholesterol with
`combination EPA and DHA preparations wherein adminis-
`tration to patients with very high TG levels increased LDL
`cholesterol as much as 49% compared to placebo.8 Defini-
`tive differences between EPA and EPA plus DHA await
`head-to-head clinical trials. However, a previous double-
`blinded, randomized, parallel-design controlled trial in 121
`healthy men and women showed that the DHA group had
`significant increases in LDL cholesterol, whereas the pure
`EPA group had significant decreases in small dense LDL
`cholesterol and lipoprotein-associated phospholipase A2.
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1023, p. 6 of 10
`
`

`

`Case 1:20-cv-01630-RGA-JLH Document 17-22 Filed 01/25/21 Page 7 of 10 PageID #: 690
`
`Table 2
`Changes in efficacy end points from baseline to week 12 (intent-to-treat population)
`
`Variable
`
`AMR101 Dose
`
`4 g/day
`(n ⫽ 226)
`
`2 g/day
`(n ⫽ 234)
`
`Baseline
`
`Baseline
`
`End of
`Treatment
`
`Change From
`Baseline (%)
`
`Baseline
`
`End of
`Treatment
`
`Change From
`Baseline (%)
`
`6
`
`Placebo
`(n ⫽ 227)
`
`End of
`Treatment
`
`Median Placebo-Adjusted Change From
`Baseline
`
`Change
`From
`Baseline
`(%)
`
`AMR101
`4 g/day vs
`Placebo
`(%)
`
`p
`Value
`
`p
`Value
`
`AMR101
`2 g/day vs
`Placebo
`(%)
`
`264.8 (93.0) 220.8 (92.0) ⫺17.5 (31.0) 254.0 (92.5) 244.3 (117.0) ⫺5.6 (34.5)
`
`259.0 (81.0) 269.5 (149.5) 5.9 (44.9)
`
`⫺21.5
`
`⬍0.0001
`
`⫺10.1
`
`0.0005
`
`82.0 (25.0)
`
`83.0 (31.0)
`
`1.5 (26.6)
`
`82.0 (24.0)
`
`87.0 (27.0)
`
`2.4 (26.1)
`
`84.0 (27.0)
`
`88.5 (31.0)
`
`8.8 (31.0)
`
`⫺6.2
`
`0.0067
`
`⫺3.6
`
`0.0867
`
`128.0 (32.0) 122.0 (39.0) ⫺5.0 (21.3) 128.0 (33.0) 134.0 (41.0)
`
`2.4 (26.1)
`
`128.0 (34.0) 138.0 (43.0)
`
`9.8 (27.6)
`
`⫺13.6
`
`⬍0.0001
`
`⫺5.5
`
`0.0054
`
`44.0 (21.0)
`
`38.0 (22.0) ⫺12.1 (47.9)
`
`43.0 (21.0)
`
`44.0 (25.0)
`
`1.6 (54.6)
`
`42.0 (21.0)
`
`49.0 (28.0) 15.0 (58.8)
`
`⫺24.4
`
`⬍0.0001
`
`⫺10.5
`
`0.0093
`
`The American Journal of Cardiology (www.ajconline.org)
`
`⫺1.8 (23.1)
`
`185.0 (58.0) 200.0 (71.0)
`
`6.7 (24.0)
`
`⫺19.0
`
`⬍0.0001
`
`⫺8.0 ⬍0.0001
`
`1.6 (20.7)
`
`91.0 (24.0)
`
`98.0 (25.0)
`
`7.1 (23.2)
`
`⫺9.3
`
`⬍0.0001
`
`⫺3.8
`
`0.0170
`
`2.1 (19.6)
`
`168.0 (38.0) 181.0 (46.0)
`
`9.1 (20.8)
`
`⫺12.0
`
`⬍0.0001
`
`⫺4.8
`
`0.0019
`
`0.0 (19.5)
`
`39.0 (12.0)
`
`40.0 (14.0)
`
`4.8 (22.0)
`
`⫺4.5
`
`0.0013
`
`⫺2.2
`
`0.1265
`
`⫺2.1 (48.9)
`
`183.0 (94.0) 196.0 (136.0) 8.9 (63.8)
`
`⫺26.5
`
`⬍0.0001
`
`⫺11.3
`
`0.0049
`
`10.3 (88.6)
`
`2.2 (4.0)
`
`2.6 (4.7)
`
`17.1 (108.0) ⫺22.0
`
`0.0005
`
`⫺6.8
`
`0.2889
`
`Primary end point
`Triglycerides (mg/dl)
`(n ⫽ 226, 234, 227)
`Secondary end points
`Low-density lipoprotein
`cholesterol (mg/dl)
`(n ⫽ 225, 233, 226)
`Non-high-density
`lipoprotein cholesterol
`(mg/dl)
`(n ⫽ 226, 234, 227)
`Very-low-density
`lipoprotein cholesterol
`(mg/dl)
`(n ⫽ 225, 233, 226)
`Lipoprotein-associated
`phospholipase A2
`(ng/ml)
`(n ⫽ 217, 224, 213)
`Apolipoprotein B (mg/dl)
`(n ⫽ 217, 227, 219)
`Selected exploratory end points
`167.0 (38.0) 162.0 (38.0) ⫺3.2 (16.8) 169.0 (34.0) 175.0 (44.0)
`Total cholesterol (mg/dl)
`(n ⫽ 226, 234, 227)
`High-density lipoprotein
`cholesterol (mg/dl)
`(n ⫽ 226, 234, 227)
`Very-low-density
`lipoprotein triglycerides
`(mg/dl)
`(n ⫽ 225, 233, 226)
`High-sensitivity C-reactive
`protein (mg/l)
`(n ⫽ 217, 227, 219)
`
`180.0 (56.0) 160.0 (57.0) ⫺12.8 (18.5) 190.0 (55.5) 183.5 (57.5)
`
`93.0 (23.0)
`
`90.0 (25.0) ⫺2.2 (16.4)
`
`91.0 (22.0)
`
`95.0 (24.0)
`
`37.0 (12.0)
`
`37.0 (13.0) ⫺1.0 (18.2)
`
`38.0 (13.0)
`
`38.0 (11.0)
`
`190.0 (99.0) 147.0 (88.0) ⫺19.2 (46.2) 185.0 (86.0) 168.0 (98.0)
`
`2.2 (2.7)
`
`2.0 (3.0)
`
`⫺2.4 (62.8)
`
`1.9 (2.9)
`
`2.5 (3.4)
`
`Data are presented as median (interquartile range) for end point values.
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1023, p. 7 of 10
`
`

`

`Case 1:20-cv-01630-RGA-JLH Document 17-22 Filed 01/25/21 Page 8 of 10 PageID #: 691
`
`Table 3
`Changes in triglyceride and non-high-density lipoprotein cholesterol end points from baseline to week 12 (intent-to-treat population subgroups)
`
`Variable
`
`AMR101 Dose
`
`Placebo
`(n ⫽ 227)
`
`4 g/day
`(n ⫽ 226)
`
`2 g/day
`(n ⫽ 234)
`
`Baseline
`
`End of
`Treatment
`
`Change From
`Baseline (%)
`
`Baseline
`
`End of
`Treatment
`
`Change From
`Baseline (%)
`
`Baseline
`
`End of
`Treatment
`
`Change From
`Baseline (%)
`
`Median Placebo-Adjusted Change
`
`AMR101
`4 g/day vs
`Placebo
`(%)
`
`p
`Value
`
`p
`Value
`
`AMR101
`2 g/day vs
`Placebo
`(%)
`
`208.5 (162.0) ⫺18.8 (46.3)
`248.0 (116.0) ⫺5.3 (34.0)
`
`315.0 (148.5) 304.5 (158.5)
`257.3 (83.5)
`268.3 (131.3)
`
`19.4 (61.0)
`4.6 (44.4)
`
`0.5467 ⫺13.8
`⫺13.1
`⫺20.1 ⬍0.0001
`⫺8.7
`
`0.6784
`0.0139
`
`257.5 (76.5)
`
`266.0 (160.0)
`
`6.5 (45.0)
`
`⫺26.0 ⬍0.0001 ⫺11.7
`
`0.0200
`
`⫺2.2 (28.7)
`1.7 (23.5)
`
`149.5 (50.0)
`128.0 (35.0)
`
`152.0 (45.0)
`139.5 (42.5)
`
`1.5 (31.1)
`10.5 (25.1)
`
`0.6326
`2.4
`⫺13.9 ⬍0.0001
`
`3.3
`⫺7.1
`
`0.7107
`0.0031
`
`⫺6.3 (19.9) 128.0 (31.0)
`
`142.0 (47.0)
`
`5.4 (28.4)
`
`126.0 (27.0)
`
`134.0 (41.0)
`
`12.3 (28.6)
`
`⫺15.8 ⬍0.0001
`
`⫺3.5
`
`0.3266
`
`245.0 (125.0) ⫺0.5 (34.0)
`
`247.0 (71.0)
`
`266.0 (142.5)
`
`7.8 (44.6)
`
`⫺28.4 ⬍0.0001
`
`⫺2.4
`
`0.6642
`
`6.0 (43.2)
`
`⫺18.8 ⬍0.0001 ⫺14.3
`
`0.0004
`
`Changes in triglyceride value by statin efficacy regimen*
`Lower (n ⫽ 16, 15, 14) 267.8 (87.0)
`256.8 (131.5)
`0.5 (38.2) 256.0 (64.0)
`221.0 (91.0) ⫺15.8 (30.3) 253.8 (83.0)
`Medium
`269.0 (96.5)
`(n ⫽ 141, 148, 140)
`214.5 (87.0) ⫺20.2 (20.8) 256.5 (103.5) 239.5 (115.0) ⫺5.8 (31.2)
`High (n ⫽ 69, 71, 73)
`254.5 (92.5)
`Changes in non-high-density lipoprotein cholesterol value by statin efficacy regimen*†
`Lower (n ⫽ 16, 15, 14) 128.0 (24.0)
`⫺1.4 (29.3) 139.0 (20.0)
`131.0 (36.5)
`135.0 (28.0)
`⫺4.3 (24.2) 126.5 (35.5)
`Medium
`129.0 (35.0)
`124.0 (40.0)
`133.0 (40.0)
`(n ⫽ 141, 148, 140)
`High (n ⫽ 69, 71, 73)
`118.0 (38.0)
`128.0 (31.0)
`Changes in triglyceride value by statin type
`216.0 (82.5) ⫺23.9 (18.6) 235.0 (89.0)
`Atorvastatin
`281.5 (59.0)
`(n ⫽ 41, 43, 45)
`Simvastatin
`(n ⫽ 131, 134, 128)
`Rosuvastatin
`(n ⫽ 54, 57, 54)
`Changes in triglyceride value by diabetes status
`216.5 (88.0) ⫺18.7 (31.9) 253.5 (87.0)
`Diabetes
`262.0 (92.0)
`(n ⫽ 165, 171, 165)
`No diabetes
`(n ⫽ 61, 63, 62)
`Changes in triglyceride value by baseline triglyceride tertile‡
`183.5 (67.5) ⫺10.9 (33.5) 205.8 (33.0)
`First tertile
`207.8 (28.0)
`(n ⫽ 68, 84, 72)
`Second tertile
`(n ⫽ 81, 76, 80)
`Third tertile
`(n ⫽ 77, 74, 75)
`
`262.0 (106.0) 228.0 (114.5) ⫺14.7 (31.8) 256.5 (102.0) 241.3 (133.0) ⫺8.8 (33.2)
`
`250.8 (85.5)
`
`204.0 (77.0) ⫺20.5 (39.1) 258.0 (93.5)
`
`252.5 (99.0)
`
`⫺5.8 (30.8)
`
`271.5 (114.5) 234.5 (90.0) ⫺15.0 (29.1) 256.5 (96.0)
`
`245.0 (121.5) ⫺12.1 (24.7)
`
`244.0 (116.5) ⫺1.5 (36.9)
`
`261.5 (26.0)
`
`205.0 (74.5) ⫺19.3 (32.0) 257.0 (30.5)
`
`228.3 (83.5) ⫺13.0 (30.7)
`
`346.5 (75.5)
`
`260.0 (110.5) ⫺21.8 (25.9) 348.5 (75.0)
`
`320.3 (119.0) ⫺8.7 (35.4)
`
`207.8 (74.5)
`
`0.7 (36.4)
`
`Preventive Cardiology/The ANCHOR Study
`
`7
`
`262.0 (97.8)
`
`274.5 (148.3)
`
`258.3 (69.0)
`
`268.3 (147.0) ⫺0.6 (46.2)
`
`⫺23.4 ⬍0.0001
`
`⫺5.7
`
`0.2512
`
`259.0 (78.0)
`
`275.5 (153.5)
`
`6.2 (43.4)
`
`⫺23.2 ⬍0.0001
`
`⫺9.8
`
`0.0074
`
`258.8 (123.5) 258.5 (138.0)
`
`4.3 (43.0)
`
`⫺16.8
`
`0.0005 ⫺10.8
`
`0.0261
`
`203.8 (31.5)
`
`214.5 (71.5)
`
`7.9 (36.4)
`
`⫺14.4
`
`0.0020
`
`⫺4.1
`
`0.3694
`
`257.8 (30.3)
`
`263.5 (112.3)
`
`3.3 (39.7)
`
`⫺17.9 ⬍0.0001
`
`⫺9.9
`
`0.0324
`
`340.5 (94.0)
`
`380.5 (165.5)
`
`5.2 (56.2)
`
`⫺31.1 ⬍0.0001 ⫺16.9
`
`0.0043
`
`Data are presented as median (interquartile range) for end point values; triglyceride and non-high-density lipoprotein values are milligrams per deciliter.
`* Lower-efficacy statin regimens ⫽ simvastatin 5 to 10 mg; medium-efficacy statin regimens ⫽ rosuvastatin 5 to 10 mg, atorvastatin 10 to 20 mg, simvastatin 20 to 40 mg, simvastatin 10 to 20 mg plus
`ezetimibe 5 to 10 mg; higher-efficacy statin regimens ⫽ rosuvastatin 20 to 40 mg, atorvastatin 40 to 80 mg, simvastatin 80 mg, simvastatin 40 to 80 mg plus ezetimibe 5 to 10 mg.
`† Post hoc analysis.
`‡ First ter