FDA Briefing Document
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`Endocrinologic and Metabolic Drugs
`Advisory Committee Meeting
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`October 16, 2013
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`DISCLAIMER STATEMENT
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`The attached package contains background information prepared by the Food and Drug Administration
`(FDA) for the panel members of the advisory committee. The FDA background package often contains
`assessments and/or conclusions and recommendations written by individual FDA reviewers. Such
`conclusions and recommendations do not necessarily represent the final position of the individual
`reviewers, nor do they necessarily represent the final position of the Review Division or Office. We have
`brought this supplemental application, VASCEPA (icosapent ethyl), NDA 202057/Supplement -005 to
`this Advisory Committee in order to gain the Committee’s insights and opinions, and the background
`package may not include all issues relevant to the final regulatory recommendation and instead is
`intended to focus on issues identified by the Agency for discussion by the advisory committee. The FDA
`will not issue a final determination on the issues at hand until input from the advisory committee process
`has been considered and all reviews have been finalized. The final determination may be affected by
`issues not discussed at the advisory committee meeting.
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`Table of Contents
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`1. Points to Consider
`2. Clinical Review
`3. Efficacy: Statistical Review
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`Draft Points to Consider
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`In ANCHOR, 12 weeks of treatment with Vascepa 4 g/day led to an estimated median
`-21.5% (95% CI, -26.7% to -16.2%; P<0.0001) change in fasting triglycerides, compared
`with the mineral oil placebo, among statin-treated patients with mixed dyslipidemia at
`high cardiovascular risk. Changes in other lipid/lipoprotein parameters (selected
`secondary and exploratory endpoints) are summarized in the table below.
`
`Median % Change from
`Baseline to Week 12
`Placebo
`Vascepa 4g/day
`+5.9
`-17.5
`+8.8
`+1.5
`+9.8
`-5.0
`+15.0
`-12.1
`+7.1
`-2.2
`+9.1
`-3.2
`+4.8
`-1.0
`+3.6
`-2.9
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`Median % Change
`(95% CI)
`Treatment Difference
`-21.5 (-26.7, -16.2)
`-6.2 (-10.5, -1.7)
`-13.6 (-17.2, -9.9)
`-24.4 (-31.9, -17.0)
`-9.3 (-12.3, -6.1)
`-12.0 (-14.9, -9.2)
`-4.5 (-7.4, -1.8)
`-6.9 (-8.9, -4.9)
`
`Fasting TG
`Direct LDL-C
`Non-HDL-C
`VLDL-C
`Apo B
`Tot. Chol.
`HDL-C
`Apo A-I
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`1. Please discuss the efficacy results from the ANCHOR trial, including the clinical
`significance of the observed changes in lipid/lipoprotein parameters and your
`level of confidence that these changes will translate into a meaningful reduction in
`cardiovascular risk among the target population.
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`2. Taking into account the described efficacy and safety data for Vascepa, do you
`believe that its effects on the described lipid/lipoprotein parameters are sufficient
`to grant approval for co-administration with statin therapy for the treatment of
`patients with mixed dyslipidemia and CHD or CHD risk equivalent prior to the
`completion of REDUCE-IT? Please provide the rationale underlying your
`recommendation.
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`VASCEPA (Icosapent Ethyl)
`NDA 202057
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`Clinical Review
`Endocrinologic and Metabolic Drugs Advisory Committee Meeting
`October 16, 2013
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`Page 1 of 94
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`Table of Contents
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`Table of Tables
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`Table of Figures
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`Executive Summary
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`1.
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`Introduction
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`2. VASCEPA
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`3. ANCHOR Rationale and Design/Conduct
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`4. ANCHOR Study Population
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`5. ANCHOR Efficacy Results
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`6. ANCHOR Safety Results
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`7. Benefit/Risk Assessment
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`8. Benefit/Risk Evaluation in Context of Current Scientific Knowledge
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`Appendix
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`Table of Tables
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`Table 1: Median percent change from baseline to week 12 endpoint – MARINE ITT
`population ......................................................................................................................... 11
`Table 2: ANCHOR Milestones........................................................................................ 13
`Table 3: Lipid Eligibility Requirements .......................................................................... 18
`Table 4: Schedule of Procedures...................................................................................... 20
`Table 5: Summary of Demographic and Baseline Characteristics – Randomized
`Population ......................................................................................................................... 25
`Table 6. Summary of Diabetes and Cardiovascular Disease – ANCHOR MITT
`population ......................................................................................................................... 27
`Table 7: Summary of Selected Concomitant Medications – Safety Population.............. 28
`Table 8: Summary of Statin Use at Randomization by Intensity – MITT population..... 28
`Table 9: Summary of Statin Use – MITT population....................................................... 30
`Table 10: Reasons Screened Patients Were Not Randomized.......................................... 31
`Table 11: Summary of Lipid Values at the End of the Qualifying Phase of Run-in Period
`........................................................................................................................................... 33
`Table 12: Patients Not Randomized at End of Screening Period due to Lipid Levels -
`Classified by LDL-C and TG Category............................................................................ 33
`Table 13: Patient Disposition During the Double-Blind Treatment Period – Randomized
`Population ......................................................................................................................... 34
`Table 14: Compliance with therapy – ANCHOR............................................................ 34
`Table 15: Summary of study medication compliance categories by visit and incidence of
`subjects with compliance <80% at one or more visits – Randomized population............ 35
`Table 16: Percent Change in Fasting TG (mg/dL) from Baseline to Week 12 Endpoint
`and Difference From Placebo– MITT Population ............................................................ 37
`Table 17: Percentage of Patients Achieving TG Treatment Goal (<150 mg/dL) at Week
`12 Endpoint....................................................................................................................... 38
`Table 18: Percent Change from Baseline and Difference from Placebo- Secondary
`Endpoints – MITT Population .......................................................................................... 41
`Table 19: Percent Change from Baseline and Difference from Placebo- Lipid
`Exploratory Endpoints – MITT Population ...................................................................... 42
`Table 20: Change from Baseline and Difference from Placebo - LDL Particle
`Concentration and Size - Exploratory Endpoints – MITT Population ............................. 44
`Table 21: Percent Change from Baseline and Difference from Placebo - Glucose
`Metabolism Exploratory Endpoints – MITT Population.................................................. 45
`Table 22: Percent Change from Baseline and Difference from Placebo- Inflammatory
`Biomarkers Exploratory Endpoints – MITT Population .................................................. 47
`Table 23: Changes in EPA Concentration From Baseline to Week 12 Endpoint – MITT
`Population ......................................................................................................................... 49
`Table 24. Summary of Adverse Events During the Randomized Treatment Period –
`Safety Population.............................................................................................................. 58
`Table 25: Listing of Patients with SAEs (fatal and non-fatal) During Randomized
`Treatment Period – Safety Population .............................................................................. 59
`Table 26: Listing of Patients with DAEs During Randomized Treatment Period – Safety
`Population ......................................................................................................................... 60
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`Table 27: Recent Omega-3 FA Cardiovascular Outcomes Trials ................................... 67
`Table 28: Primary and Secondary Endpoints – Risk and Prevention study .................... 71
`Table 29: Change in CV Risk Factors – Risk and Prevention study ............................... 72
`Table 30: Subgroup Analyses of the Efficacy of Omega-3 FA Supplements and Overall
`CV Events ......................................................................................................................... 73
`Table 31: Demographic and Baseline Characteristics of Subgroup with Dyslipidemia:
`ACCORD-Lipid................................................................................................................ 80
`Table 32: Lipid Changes by Baseline Dyslipidemic Status – ACCORD-Lipid .............. 81
`Table 33: Between Group Lipid Treatment Differences – HPS2 THRIVE .................... 86
`Table 34: Summary of Lipid Changes in Selected Clinical Trials .................................. 87
`Table 35: Change in lipid parameters –by statin type – MITT Population ..................... 88
`Table 36: Change in lipid parameters – by statin regimen intensity – MITT Population 89
`Table 37: Change in lipid parameters – by TG tertile – MITT Population ..................... 90
`Table 38: Changes in Lipid Parameters - by Non-Statin Washout Status – MITT
`Population ......................................................................................................................... 91
`Table 39: Changes in Lipid Parameters – by Diabetes Status – MITT Population ......... 92
`Table 40: Lipid Changes in Placebo-treated Patients – Selected Trials .......................... 93
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`Table of Figures
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`Figure 1: Change from Baseline in Selected Endpoints .................................................... 8
`Figure 2: ANCHOR Study Design .................................................................................. 15
`Figure 3: Summary of Subject Disposition...................................................................... 31
`Figure 4: Box-and-Whisker Plot of Median Percent Change in Fasting TG From
`Baseline to Week 12 Endpoint – MITT Population.......................................................... 38
`Figure 5: Percent Change in Fasting TG versus Percent Change in EPA Concentration
`from Baseline to Week 12 Endpoint – MITT Population................................................. 50
`Figure 6: Change from Baseline in Selected Endpoints .................................................. 62
`Figure 7: JELIS: Estimated Hazard Ratios of Clinical Endpoints.................................. 65
`Figure 8: Primary and Secondary Outcomes – ORIGIN trial.......................................... 70
`Figure 9: Primary outcome in subgroups – ORIGIN trial ............................................... 70
`Figure 10: Efficacy of Omega-3 FA Supplements in the Secondary Prevention of Overall
`Cardiovascular Events – Kwak et al. ................................................................................ 73
`Figure 11: Efficacy of Omega-3 FA Supplements and Cardiovascular Events – Delgado-
`Lista et al........................................................................................................................... 74
`Figure 12: Efficacy of Omega-3 FA Supplements on Mortality and CV Outcomes....... 74
`Figure 13: Subgroup Analyses for the Omega-3 FA Supplements Effect........................ 75
`Figure 14: Effect of Omega-3 FA on Composite Cardiovascular Outcomes .................. 76
`Figure 15: Subgroup Analyses for the Effect of Omega-3 FA on the Primary CV
`Outcome............................................................................................................................ 77
`Figure 16: ACCORD-Lipid Study Design....................................................................... 78
`Figure 17: Hazard ratios for the primary outcome in prespecified subgroups –
`ACCORD-Lipid................................................................................................................ 79
`Figure 18: Effect of Treatment on Cardiovascular Events by Baseline Lipoprotein/lipid
`Tertiles – AIM-HIGH ....................................................................................................... 84
`Figure 19: Primary Endpoint Result in HPS-2 THRIVE................................................. 85
`Figure 20: Effect of Treatment on Cardiovascular Events by Baseline Lipid– HPS2-
`THRIVE............................................................................................................................ 86
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`Clinical Review
`Endocrinologic and Metabolic Drugs Advisory Committee Meeting
`October 16, 2013
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`New Drug Application 202057: AMR101 VASCEPA (icosapent ethyl)
`Applicant: Amarin Pharma, Inc.
`Clinical Reviewer: Mary Dunne Roberts, MD
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`
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`Executive Summary
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`VASCEPA, herein referred to as AMR101, is a purified ethyl ester of eicosapentaenoic
`acid (EPA) derived from fish oil. In July 2012, AMR101 was approved as an adjunct to
`diet to reduce triglyceride (TG) levels in adult patients with severe hypertriglyceridemia
`(defined as TG (cid:149) 500 mg/dL) at a dose of 4 grams per day. On February 21, 2013, the
`applicant, Amarin Pharma Inc., submitted an efficacy supplement seeking to substantially
`expand the treatment population of AMR101 to include patients with mixed dyslipidemia
`who are at high risk for coronary heart disease and who are already being treated with
`HMG-CoA reductase inhibitors (statins). It is estimated that approximately 21% of U.S.
`adults have mixed dyslipidemia, defined as the presence of high LDL-C combined with at
`least one other lipid abnormality.1 Data from one pivotal efficacy trial, ANCHOR, was
`submitted to support the expanded treatment indication.
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`EPA, along with (cid:302)-linolenic acid and docosahexaenoic acid (DHA), are collectively
`referred to as omega-3 fatty acids (FA). EPA and DHA are also the major constituents of
`fish oils derived from cold water fish. Over forty years ago, investigation into the dietary
`habits of Greenland Eskimos suggested an inverse association between the consumption
`of omega-3 fatty acids from fish and the incidence of ischemic heart disease.2 Several
`mechanisms have been proposed to explain the putative cardioprotective effect of EPA
`and DHA, including triglyceride (TG) reduction, platelet aggregation inhibition, plaque
`stabilization, anti-inflammatory effects, and improvements in cardiac hemodynamics.3
`
`There are currently two FDA-approved prescription products derived from fish oil
`indicated for the treatment of severe hypertriglyceridemia: (1) LOVAZA, herein referred
`to as omega-3 fatty acid ethyl ester (omega-3 EE), available in 1 g capsules containing,
`among other things, purified ethyl esters of EPA and DHA of approximately 465 mg and
`375 mg, respectively; and (2) AMR101, which contains approximately 1 g per capsule of
`purified ethyl ester of EPA derived from fish oil and no DHA. While the dosing units for
`omega-3 EE and AMR101 are alike (i.e., 1 g capsule), the composition is not; the EPA
`
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`1 Toth P et al. Prevalence of lipid abnormalities in the United States: The National Health and Nutrition
`Examination Survey 2003-2006. Journal of Clinical Lipidology 2012;6:325-330.
`2 Bang HO, Dyerberg J. Plasma lipids and lipoproteins in Greenlandic west coast Eskimos. Acta Med
`Scand 1972;192:85-94
`3 Adkins Y, Kelley DS. Mechanisms underlying the cardioprotective effects of omega-3 polyunsaturated
`fatty acids. Journal of Nutritional Biochemistry 2010;21:781-92
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`content within a 1 g AMR101 capsule is approximately twice that of a 1 g omega-3 EE
`capsule.
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`ANCHOR was a randomized, double-blind, placebo-controlled, 12-week study of
`AMR101 in patients with persistently high TG levels on statin background therapy. After
`a 6- to 8-week lead-in period for dietary instruction, washout of non-statin lipid-
`modulating drugs, and stabilization of statin therapy, 702 individuals still meeting lipid
`eligibility requirements were randomized to either placebo (mineral oil), AMR101
`2 g/day, or AMR101 4 g/day. The primary endpoint was the percent change in TG levels
`from baseline to week 12. The treatment groups were well matched for baseline
`characteristics. The mean age was 61 years, most were male (61%), Caucasian (96%),
`and diabetic (73%); the mean HbA1c in patients with diabetes was 6.9%. Approximately
`one-third had a history of cardiovascular disease. The average baseline BMI was 32.9
`kg/m2. At entry into the study, 90% of subjects were taking a statin with an average
`treatment duration of approximately 3 years. After the lead-in and statin stabilization
`period, the baseline mean LDL-C was 85 mg/dL, with 21% having an LDL-C less than
`70 mg/dL; mean non-HDL-C was 132 mg/dL; median TG was 259 mg/dL; mean HDL-C
`was 39 mg/dL, with 55% having an HDL-C less than 40 mg/dL; and 53% had a hsCRP (cid:149)
`2 mg/L.
`
`After 12 weeks of therapy, statistically significant differences were observed between
`placebo and AMR101 4g with respect to TG (-21.5%; p<0.0001) and with respect to
`secondary endpoints such as LDL-C (-6.2%; p=0.007) and non-HDL-C (-13.6%;
`p=0.0001). Notably, despite a lead-in period that is quite typical for trials with lipid
`parameter endpoints, within-group changes in lipid parameters and biomarkers of
`inflammation from baseline to 12 weeks were highly statistically significant in the
`mineral oil placebo group (all p<0.001). Although it is recognized that the effect of an
`intervention (e.g., mineral oil capsules) cannot be isolated when one only considers
`within-group changes over time, these results at least suggest the possibility that mineral
`oil may not be biologically inert. If true, this complicates the interpretation of between-
`group differences. For example, LDL-C increased a median 9% in the placebo group,
`despite statin therapy, and only increased a median of 1.5% in the AMR101 4g group
`(Figure 1), but does this reflect an LDL-lowering effect of AMR101, an LDL-raising
`effect of mineral oil in statin-treated individuals, or some combination?
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`Figure 1: Change from Baseline in Selected Endpoints
`
`*^
`
`*+
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`*^
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`*^
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`*+
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`*^
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`*(cid:121)
`
`Pbo + statin
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`AMR 101 4g + statin
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`TG
`
`LDL-C
`non-HDL-C
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`VLDL-C
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`HDL-C
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`Apo B
`Selected Endpoints
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`hsCRP
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`20
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`10
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`0
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`-10
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`-20
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`Median percent change from baseline
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`* p<0.001 for within group changes in placebo group
`^ p<0.0001 between group changes
`· p<0.001 between group change
`+ p<0.01 between group change
`Source: FDA reviewer graph of submitted data
`
`The 702 patients exposed to at least one dose of study drug experienced relatively low
`and similar numbers of treatment-emergent adverse events (TEAEs), serious adverse
`events (SAEs), and discontinuations due to adverse events. Only one adverse event led to
`a fatality due to a myocardial infarction (MI) in a placebo-treated patient. There were no
`instances of rhabdomyolysis, and CK elevations >5x ULN were infrequent and similar
`between treatment groups. Elevations in ALT and/or AST >3x ULN occurred in three
`patients (1 placebo-treated patient and 2 AMR101 4g-treated patients). No patients
`developed laboratory or clinical findings consistent with drug-induced liver injury
`defined by Hy’s Law. No new safety signals were identified. The safety profile of
`AMR101 in ANCHOR was consistent with current labeling and post-market safety
`reports.
`
`In considering the results of the ANCHOR trial, the presumption has been that improving
`various lipid parameters will translate into a reduction in cardiovascular risk. With rare
`exception, FDA has historically considered granting approval for lipid-altering drugs
`based on favorable changes in the lipid profile, with the assumption that these changes
`would translate into a benefit on clinical outcomes. Both epidemiological studies and
`controlled interventional trials of lipid-lowering agents, including omega-3 FA, supported
`the hypothesis that pharmacologically-induced improvements in the lipid profile are
`cardioprotective. These studies also informed professional society guidelines that
`promoted the consumption of EPA and DHA with the goal to reduce cardiovascular risk.4
`
`4 Kris-Etherton PM et al. American Heart Association Nutrition Committee. Fish consumption, fish oil,
`omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747-2757.
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`Recent clinical trials and meta-analyses have failed to confirm definitive cardiovascular
`benefit with EPA and DHA supplementation, however.5,6,7
`
`During a pre-IND meeting with the applicant in July 2008, however, the Division noted
`that there was a lack of prospective, controlled clinical trial data demonstrating that
`pharmacological reduction of non-HDL-C (or TG) with a second drug, in patients with
`elevated TG levels at LDL goal on statin therapy, significantly reduces residual
`cardiovascular risk. The Division referenced trials ongoing at the time (e.g., AIM-HIGH,
`ACCORD-Lipid) that, while not able to assess the effect of specifically lowering
`non-HDL-C (or TG) on clinical outcomes, would be expected to provide important
`information on the incremental benefit of adding a second lipid-active drug to statin
`therapy. It was stated that before an indication would be entertained for Ethyl-EPA as
`add-on to statin therapy in patients with elevated TG levels, the applicant at a minimum
`would have to provide results from a 12-week study with lipid endpoints as well as
`initiate an appropriately designed cardiovascular outcomes study. This outcomes study,
`known as REDUCE-IT, is ongoing and is investigating whether the addition of AMR101
`4 g daily ameliorates residual cardiovascular risk among patients at high CV risk who
`have moderate hypertriglyceridemia at LDL-C goal on statin therapy. The study designs
`for both ANCHOR and REDUCE-IT were agreed to by the Division under special
`protocol assessments.
`
`Several cardiovascular outcome trials of non-statin lipid-modulating therapy, such as
`those referenced by the Division in 2008, have since completed. ACCORD-Lipid, AIM-
`HIGH, and HPS2-THRIVE, which were designed to target residual cardiovascular risk
`by improving lipid parameters other than LDL-C (e.g., HDL-C and/or TG) in patients
`optimally treated with statin therapy, failed to demonstrate unequivocally additional
`cardiovascular benefit from non-statin lipid-modulating drugs. Several hypotheses could
`be put forward regarding the failures of these large, carefully designed trials to
`demonstrate benefit on their primary endpoints, but the evidence to date certainly
`challenges the hypothesis that adding lipid-modulating therapies to patients optimally
`treated with statins will reduce residual cardiovascular risk. Although it can be argued
`that lipid and/or lipoprotein parameters can be used to define subpopulations of statin-
`treated patients who would be expected to benefit from various non-statin lipid-
`modulating agents, contemporary trials have not yet prospectively tested this hypothesis.
`Members of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC)
`are asked to consider the results of the ANCHOR trial in the context of the available
`science when recommending whether to approve the proposed treatment indication for 4
`grams AMR101 daily to be co-administered with statin therapy for the treatment of
`patients with mixed dyslipidemia and coronary heart disease (CHD) or its risk equivalent.
`
`
`5 Kotwal S et al. Omega 3 Fatty Acids and Cardiovascular Outcomes: Systematic review and Meta-
`analysis. Circ Cardiovasc Qual Outcomes 2012;5:808-18.
`6 The Risk and Prevention Study Collaborative Group. N-3 Fatty Acids in Patients with Multiple
`Cardiovascular Risk Factors. NEJM 2013;368:1800-8.
`7 Rizos EC et al. Association between Omega-3 Fatty Acid Supplementation and Risk of Major
`Cardiovascular Disease Events. JAMA 2012;308 (10):1024-33.
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`1. INTRODUCTION
`
`Over a decade ago, the National Cholesterol Education Program’s (NCEP) Third Adult
`Treatment Panel (ATP III) recognized the relationship between elevated TG and coronary heart
`disease (CHD) observed in epidemiological studies and meta-analyses from the late 1990s.8 A
`high TG level ((cid:149)200 to <500 mg/dL) is considered a biomarker of atherogenic potential due to its
`association with increased levels of cholesterol-enriched lipoproteins, such as very-low-density
`lipoprotein cholesterol (VLDL-C). Collectively, atherogenic lipoprotein cholesterol is a
`secondary target of therapy, referred to as non-HDL-C and calculated as total cholesterol minus
`HDL-C. The NCEP ATP III guidelines recommend statin therapy as initial pharmacotherapy for
`lowering LDL-C and non-HDL-C in patients with high TG levels. If elevated TG persists, the
`guidelines discuss further intervention such as fibrates, niacin, and dietary intake of omega-3 FA
`(although no specific level of intake is recommended). In 2002, the American Heart Association
`made recommendations that were more explicit: patients with elevated TG could be considered
`for additional treatment with EPA plus DHA at a dose of 2 to 4 g per day.9
`
`Despite treatment recommendations based on robust clinical data and acceptance of statins as
`first-line standard-of-care for cardiovascular risk reduction, substantial risk for major adverse
`cardiovascular events still exists for many patients optimally treated with statins.10 Therefore,
`several investigators have hypothesized that favorably altering other lipid, lipoprotein, or
`inflammatory biomarkers in addition to optimizing LDL-C may further reduce CV risk. Recent
`cardiovascular outcome trials testing these hypotheses, however, have failed to establish that
`improvements in secondary lipid targets such as HDL-C and/or TG translate into cardiovascular
`benefit, causing further controversy regarding effective cardioprotective lipid management.
`Within this context, AMR101, an FDA-approved, commercially available EPA prescription
`product, seeks an expanded treatment indication as add-on to statin therapy in high risk
`cardiovascular patients with mixed dyslipidemia based on a 12-week lipid-altering trial.
`
`2. VASCEPA (Icosapent Ethyl)
`
`
`2.1. VASCEPA
`
`
`VASCEPA (icosapent ethyl), referred to as AMR101 in this review, is a purified ethyl ester of
`eicosapentaenoic acid (EPA) derived from fish oil. In July 2012, AMR101 was approved as an
`adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe
`hypertriglyceridemia (defined as triglycerides (cid:149) 500 mg/dL) at the recommended dose of 4
`grams per day. The clinical rationale underlying the support of approval based on TG levels for
`patients with severe hypertriglyceridemia is the expected reduction in the risk for acute
`pancreatitis.
`
`8 Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of
`the third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection evaluation and
`treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486-97.
`9 Kris-Etherton PM et al. American Heart Association Nutrition Committee. Fish consumption, fish oil, omega-3
`fatty acids, and cardiovascular disease [published correction appears in Circulation. 2003;107:512]. Circulation.
`2002;106:2747-2757.
`10 Sampson UK et al. Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the
`evidence, etiology, and therapeutic challenges. Curr Atheroscler Rep 2012;14:1-10.
`Page 10 of 94
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`DFNDTS(ICO)_DE_00005886
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1029, p. 14 of 115
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`

`

`
`The clinical development program for AMR101 includes studies designed to assess effects on
`the lipid profile of patients with severe hypertriglyceridemia (TG (cid:149) 500 mg/dL) as well as in
`patients with persistent hypertriglyceridemia (TG (cid:149)200 to <500 mg/dL) despite LDL-C control
`on statin therapy, and a cardiovascular outcomes trial in patients at high risk for cardiovascular
`disease.
`
`FDA approval of AMR101 for the treatment of severe hypertriglyceridemia was based on
`MARINE, a Phase 3, international, double-blind, randomized, placebo (mineral oil)-controlled
`trial. Following diet stabilization, 229 patients with very high TG defined as (TG (cid:149) 500 mg/dL
`and (cid:148)2000 mg/dL) with or without background statin therapy were randomized to placebo,
`AMR101 2g/day, or AMR101 4g/day for 12 weeks of therapy. The primary endpoint was
`median percent change in TG from baseline. The following table summarizes the lipid changes
`across the three treatment arms in MARINE. Compared with placebo, AMR101 4g/day reduced
`TG levels by an estimated median of 33%. Although the reduction in fasting TG levels was
`statistically significant in the AMR101 2g/day group compared with the placebo group, TG
`reduction was more substantial in the AMR101 4g/day group, and the magnitude of effects on
`other lipid parameters was consistently lower in the AMR101 2g/day group. During the review,
`the applicant submitted a formal request to remove the 2g/day dose from the proposed indication,
`and the request was granted.
`
`Table 1: Median percent change from baseline to week 12 endpoint – MARINE ITT
`population
`
`
`
`2.2. VASCEPA Development Program
`
`Median [Q1, Q3] % Change from Baseline to Wk 12
`AMR101 2g/d
`AMR101 4g/d
`Placebo
`(n=73)
`(n=76)
`(n=75)
`-7.0 [-30.1, 18.6]
`-26.6 [-41.1, 0.0]
`+9.7 [-19.2, 42.3]
`
`TG
`
`LDL-C
`
`-2.5 [-9.8, 23.5]
`
`-4.5 [-23.3, 17.2]
`
`-3.0 [-21.3, 23.3]
`
`Non-HDL-C
`
`0.0 [-9.0, 14.1]
`
`-7.7 [-21.6, -0.1]
`
`+7.8 [-4.1, 26.6]
`
`VLDL-C
`
`0.0 [-22.5, 29.2]
`
`-19.5 [-35.7, 19.6]
`
`+13.7 [-13.5, 55.3]
`
`ApoB
`
`HDL-C
`
`+2.1 [-4.7, 7.6]
`
`-3.8 [-11.9, 3.8]
`
`+4.3 [-4.5, 17.5]
`
`0.0 [-11.8, 14.8]
`
`-3.5 [-13.2, 9.1]
`
`0.0 [-10.0, 11.5]
`
`<0.0001
`
`0.68
`
`<0.0001
`
`0.0002
`
`0.002
`
`0.22
`
`AMR101 4g/d vs. Placebo
`Estimated Median
`P
`Difference (95% CI)
`-33.1
`(-46.6, -21.5)
`-2.3
`(-12.9, 8.1)
`-17.7
`(-25.0, -11.3)
`-28.6
`(-43.4, -13.9)
`-8.5
`(-13.5, -3.2)
`-3.6
`(-9.1, 2.0)
`-16.3
`(-22.4, -11.0)
`
`<0.0001
`
`+0.7 [-8.5, 10.8]
`
`-7.3 [-17.7, 0.5]
`
`+7.7 [-3.6, 24.2]
`
`Tot. chol.
`
`Source: NDA 202057 MARINE Clinical Study Report, Tables 8, 10, 12-16. 95% CI estimated with the Hodges-Lehmann method; P values from
`Wilcoxon rank-sum.
`
`During the review of the MARINE data, the Division noted that several lipid parameters
`(including TG) increased from baseline to week 12 in the placebo group, treated with mineral oil.
`The avai