LOMITAPIDE
`
`FOR THE TREATMENT OF PATIENTS WITH
`HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HOFH)
`
`NDA #203858
`
`Sponsor’s Background Package
`
`For the
`Endocrinologic and Metabolic Drugs Advisory Committee Meeting
`17 October 2012
`
`
`
`Aegerion Pharmaceuticals, Inc.
`101 Main St., Suite 1850
`Cambridge, MA 02142
`
`
`
`ADVISORY COMMITTEE BRIEFING MATERIALS:
`AVAILABLE FOR PUBLIC RELEASE
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`Table of Contents
`1
`Executive Overview ...............................................................................................................11
`1.1 Homozygous Familial Hypercholesterolemia .................................................................11
`1.1.1 Overview of the Disease and the Impact of Elevated LDL-C Levels ......................11
`1.1.2
`Treatment Goals in Patients with HoFH and Current Treatment Options ...............13
`1.2 Lomitapide and Microsomal Triglyceride Transfer Protein Inhibition ...........................14
`1.3 Lomitapide Clinical Development Program ...................................................................14
`1.4 Efficacy and Safety of Lomitapide..................................................................................14
`1.4.1 Key Design Features of the Phase 3 Study UP1002/AEGR-733-005 .....................15
`1.4.2 Disposition, Baseline Characteristics and Exposure to Treatment in the
`Phase 3 Study UP1002/AEGR-733-005 .................................................................15
`Efficacy Results in the Phase 3 Study UP1002/AEGR-733-005 .............................16
`1.4.3
`Safety of Treatment with Lomitapide ......................................................................20
`1.4.4
`1.5 Risk Mitigation ................................................................................................................23
`1.6
`Future Clinical Development Plans ................................................................................24
`1.7 Benefits and Risks Conclusions ......................................................................................24
`Introduction ............................................................................................................................25
`2.1 Homozygous Familial Hypercholesterolemia .................................................................25
`2.1.1 Overview of the Disease ..........................................................................................25
`2.1.2
`Impact of Elevated LDL-C Levels on Atherosclerotic Cardiovascular
`Disease.....................................................................................................................26
`Treatment Goals in Patients with HoFH and Current Treatment Options ...............29
`2.1.3
`2.2 Rationale for Use of Lomitapide in HoFH ......................................................................31
`2.2.1 Overview of Microsomal Triglyceride Transfer Protein Inhibition ........................31
`2.2.2 Overview of Lomitapide ..........................................................................................32
`2.3 Lomitapide Clinical Development Program and Regulatory History .............................33
`2.3.1 Clinical Development Program ................................................................................33
`2.3.2 Key Regulatory History ...........................................................................................36
`2.4
`Proposed Indication, Dose and Administration...............................................................36
`3 Overview of Clinical Pharmacology and Dose Selection ......................................................37
`4 Overview of Study Designs for the Pivotal and Supportive Studies .....................................44
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`4.1 Key Design Features of the Pivotal Phase 3 Study UP1002/AEGR-733-005 in
`Subjects with HoFH .......................................................................................................44
`4.1.1 Overview ..................................................................................................................44
`4.1.2
`Study Design ............................................................................................................45
`4.2 Key Design Features of the Proof-of-Concept Phase 2 Study UP1001 in
`Subjects with HoFH .......................................................................................................47
`4.3 Key Design Features of the Supportive Phase 1 and 2 Studies in Subjects with
`Elevated LDL-C and Other Cardiovascular Risk Factors used to Support the
`Efficacy and Safety of Lomitapide ................................................................................48
`5 Overview of Clinical Efficacy ...............................................................................................50
`5.1 Overview of Efficacy Data Presentation and Pooling .....................................................50
`5.2 Choice of the Primary Endpoint ......................................................................................50
`5.3
`Statistical Methodology...................................................................................................50
`5.4
`Subject Disposition .........................................................................................................51
`5.4.1
`Subject Disposition: HoFH Studies ........................................................................51
`5.4.2
`Subject Disposition: Elevated LDL-C and Other Cardiovascular Risk
`Factors Studies ........................................................................................................52
`5.5 Demographics and Baseline Characteristics ...................................................................53
`5.5.1 Demographics and Baseline Characteristics: HoFH Studies ..................................53
`5.5.2 Demographics and Baseline Characteristics: Elevated LDL-C and Other
`Cardiovascular Risk Factors Studies .......................................................................55
`5.6 Results for the Primary Efficacy Endpoint: Change From Baseline in LDL-C .............56
`5.6.1 Change from Baseline in LDL-C: HoFH Studies ...................................................56
`5.6.2 Responder Analyses Based on Change from Baseline in LDL-C: Phase 3
`HoFH Study .............................................................................................................60
`5.6.3 Change from Baseline in LDL-C: Elevated LDL-C and Other
`Cardiovascular Risk Factors Study Pool .................................................................62
`Secondary Efficacy Variables .........................................................................................64
`5.7
`5.7.1 Change from Baseline in Total Cholesterol, Apo B, Non-HDL-C, and
`Triglycerides: HoFH Studies ..................................................................................64
`5.7.2 Change from Baseline in Total Cholesterol, Non-HDL-C, Apo B and
`Triglycerides: Elevated LDL-C and Other Cardiovascular Risk Factors
`Study Pool ...............................................................................................................67
`5.8 Other Efficacy Variables .................................................................................................67
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`5.8.1 Change from Baseline in VLDL-C, HDL-C, Apo AI, Total
`Cholesterol/HDL-C Ratio, and Lp(a): HoFH Studies ............................................67
`5.8.2 Change from Baseline in VLDL-C, HDL-C, Apo AI, Total
`Cholesterol/HDL-C Ratio, and Lp(a): Elevated LDL-C and Other
`Cardiovascular Risk Factors Study Pool .................................................................68
`5.9 Analysis of Efficacy Results in Subgroups .....................................................................69
`5.10 Efficacy Conclusions.......................................................................................................70
`6 Overview of Safety ................................................................................................................71
`6.1 Nonclinical Findings .......................................................................................................71
`6.1.1 General and Safety Pharmacology ...........................................................................71
`6.1.2 Repeat-Dose Toxicity: Target Organs .....................................................................71
`6.1.3 Genotoxicity .............................................................................................................73
`6.1.4 Carcinogenicity ........................................................................................................73
`6.1.5 Reproductive and Developmental Toxicity .............................................................74
`6.2
`Safety Monitoring in Clinical Trials ...............................................................................74
`6.3
`Pooling of Data for Analyses of Safety ...........................................................................76
`6.4 Disposition and Exposure for Subjects in the Safety Population ....................................77
`6.4.1 Disposition and Exposure: HoFH Studies ..............................................................77
`6.4.2 Disposition and Exposure: Elevated LDL-C and Other CV Risk Factors
`Study Pool ...............................................................................................................78
`6.5 Demographic and Baseline Characteristics of the Safety Population .............................79
`6.6 Common Adverse Events ................................................................................................81
`6.6.1 Common Adverse Events: HoFH Studies...............................................................81
`6.6.2 Common Adverse Events: Elevated LDL-C and Other Cardiovascular Risk
`Factors Study Pool...................................................................................................83
`Treatment-Related Adverse Events .........................................................................85
`6.6.3
`6.7 Other Adverse Events of Interest ....................................................................................85
`6.7.1
`Ischemic Heart Disease ............................................................................................85
`6.7.2 Myopathy Events .....................................................................................................86
`6.7.3 Asthma/Bronchospasm ............................................................................................87
`6.8 Deaths and Other Serious Adverse Events ......................................................................87
`6.8.1 Deaths and Other Serious Adverse Events: HoFH Studies ....................................87
`6.8.2 Major Adverse Cardiac Events: HoFH Subjects ....................................................88
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`6.8.3 Deaths and Other Serious Adverse Events: Elevated LDL-C and Other
`Cardiovascular Risk Factors Study Pool .................................................................89
`6.9 Other Significant Adverse Events ...................................................................................89
`6.9.1 Adverse Events of Severe Intensity .........................................................................89
`6.9.1.1 Adverse Events of Severe Intensity: HoFH Studies ....................................... 89
`6.9.1.2 Adverse Events of Severe Intensity: Elevated LDL-C and Other
`Cardiovascular Risk Factors Study Pool........................................................................... 90
`6.9.2 Adverse Events Leading to Treatment Modification ...............................................90
`6.9.2.1 Adverse Events Leading to Treatment Modification: HoFH Studies ............. 90
`6.9.2.2 Adverse Events Leading to Treatment Discontinuation: Elevated LDL-
`C and Other Cardiovascular Risk Factors Study Pool ...................................................... 91
`6.10 Clinical Laboratory Results .............................................................................................91
`6.10.1 Hematology and Clinical Chemistry ........................................................................92
`6.10.2 Coagulation Parameters ...........................................................................................92
`6.10.3 Liver Function Tests ................................................................................................92
`6.10.3.1 Liver Function Tests: HoFH Studies .............................................................. 92
`6.10.3.2 Liver Function Tests: Elevated LDL-C and Other Cardiovascular Risk
`Factors Study Pool ............................................................................................................ 96
`6.11 Hepatic Fat ......................................................................................................................97
`6.11.1 Hepatic Fat: HoFH Studies .....................................................................................97
`6.11.2 Hepatic Fat: Elevated LDL-C and Other Cardiovascular Risk Factors Study
`Pool ..........................................................................................................................98
`6.11.3 Potential for Insulin Resistance ...............................................................................99
`6.12 Analyses of Changes in Transaminase Levels with Changes in Lipids and
`Hepatic Fat .....................................................................................................................99
`6.13 Liver Histology Data .....................................................................................................101
`6.14 Fat Soluble Nutrients .....................................................................................................102
`6.15 Vital Signs, Weight, Body Mass Index and Pulmonary Function Tests .......................103
`6.16 Electrocardiograms........................................................................................................103
`6.17 Safety of Lomitapide in Subgroups ...............................................................................103
`Summary of the Sponsor’s Proposed Risk Mitigation Plan .................................................105
`7.1
`Future Clinical Development Plans ..............................................................................106
`8 Benefits and Risks Conclusions ...........................................................................................107
`
`7
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`9 References ............................................................................................................................114
`10 Appendices ...........................................................................................................................121
`10.1 Appendix Tables ...........................................................................................................121
`
`
`Table of Contents for In-Text Tables
`Table 1: Maximum Abnormal Liver Function Test Results Post First Dose, Study
`UP1002/AEGR-733-005 (Safety Population)..............................................................21
`Table 2: Overview of Clinical Studies in the Lomitapide Clinical Development
`Program ........................................................................................................................33
`Table 3: Overview of Clinical Pharmacology Results ...............................................................37
`Table 4: Mean Pharmacokinetic Parameters for Lomitapide across Studies at Similar
`Doses ............................................................................................................................40
`Table 5: Efficacy of Lomitapide (LDL-C reduction) from Phase 2 Studies in Subjects
`with Elevated LDL-C and Other Cardiovascular Risk Factors ...................................42
`Table 6: Subject Disposition in the HoFH Studies ....................................................................52
`Table 7: Subject Disposition in the Elevated LDL-C and Other Cardiovascular Risk
`Factors Studies .............................................................................................................53
`Table 8: Demographics and Baseline Characteristics, HoFH Studies .......................................54
`Table 9: Concomitant Lipid-Lowering Therapies, Study UP1002/AEGR-733-005 .................55
`Table 10: Summary of Results of the Primary Efficacy Endpoint, Change from Baseline
`in LDL-C using LOCF Methods, HoFH Studies (ITT Population) .............................57
`Table 11: Proportion of LDL-C Responders, Study UP1002/AEGR-733-005 (ITT
`Population) ...................................................................................................................62
`Table 12: Summary of Results of the Secondary Efficacy Variables, Percent Change
`from Baseline to Week 16 in Study UP1001 and Week 26/LOCF in Study
`UP1002/AEGR-733-005 (ITT Population)..................................................................65
`Table 13: Estimated Differences in Percent Change from Baseline in Lipid and
`Lipoprotein Levels for Subjects Receiving and Not Receiving Apheresis,
`Study UP1002/AEGR-733-005 (ITT Population, N=29) ............................................69
`Table 14: Summary of Exposure to Lomitapide in Studies UP1002/AEGR-733-005 and
`AEGR-733-012, and Overall (Safety Populations) .....................................................78
`Table 15: Subject Disposition, Elevated LDL-C and Other Cardiovascular Risk Factors
`Study Pool ....................................................................................................................79
`Table 16: Summary of Demographic Characteristics: Elevated LDL-C and Other
`Cardiovascular Risk Factors Study Pool (Safety Population) .....................................80
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`Table 17: Treatment-Emergent Adverse Events Reported in ≥10% of Subjects in Studies
`UP1002/AEGR-733-005 and AEGR-733-012 (Safety Population) ............................82
`Table 18: Incidence per Subject Exposure Years of Commona Treatment-Emergent
`Adverse Events in Study UP1002/AEGR-733-005 and Overall (Safety
`Population) ...................................................................................................................83
`Table 19: Treatment-Emergent Adverse Events Reported in ≥5% of Subjects in a
`Treatment Group: Studies that Evaluated Lomitapide Monotherapy in the
`Elevated LDL-C and Other Cardiovascular Risk Factors Study Poola (Safety
`Population) ...................................................................................................................84
`Table 20: Maximum Abnormal Liver Function Test Results Post First Dose: HoFH
`Indication (Safety Population) .....................................................................................94
`Table 21: Baseline Value and Absolute Change from Baseline in Hepatic Fat Percent
`Based on NMRSa HoFH Studies (Safety Population) .................................................98
`Table 22: Dosage Adjustment and Monitoring in Patients Developing Liver
`Aminotransferase Elevations >3×ULN .....................................................................112
`Table 23: Percent Change from Baseline in LDL-C using LOCF, Elevated LDL-C Study
`Pool (Full Analysis Set) .............................................................................................122
`Table 24: Percent Change from Baseline to Week 4 in Total Cholesterol, Non-HDL-C,
`Apo B and Triglycerides Based on LOCF, Elevated LDL-C Study Pool (Full
`Analysis Set) ..............................................................................................................123
`Table 25: Treatment-Emergent Adverse Events Reported in 5% or More of Subjects in a
`Treatment Group: Elevated LDL-C and Other Cardiovascular Risk Factors
`Study Pool (Safety Population) ..................................................................................125
`
`Table of Contents for In-Text Figures
`Figure 1: Mean (95% CI) Percent Changes from Baseline in LDL-C in the Phase 3
`Study UP1002/AEGR-733-005 through the Primary Endpoint of Week 26
`using LOCF (ITT Population, N=29) ..........................................................................17
`Figure 2: Waterfall Plot of Percent Change from Baseline in LDL-C at Week 26/LOCF
`by Subject (ITT Population) ........................................................................................18
`Figure 3: Mean (95% CI) Absolute Percent Hepatic Fat Based on NMRS in Study
`UP1002/AEGR-733-005 (Subjects with Baseline and Post-baseline Data
`Available) .....................................................................................................................23
`Figure 4: Conceptual Relationship Between Cumulative LDL-C Exposure,
`Cardiovascular Disease Risk and Age .........................................................................27
`Figure 5: Mechanism of Action of Lomitapide ...........................................................................32
`Figure 6: Geometric Mean Percent Change from Baseline in LDL-C following Multiple
`Doses of Lomitapide and Placebo, Study CV145-002 (Pharmacokinetic
`Population, N=54) ........................................................................................................42
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`Figure 7: Dose Response: Mean Percent Change from Baseline in LDL-C by Mean
`Lomitapide Dose Level in the HoFH Studies ..............................................................43
`Figure 8: Overview of Study Design, Study UP1002/AEGR-733-005 .......................................46
`Figure 9: Mean (95% CI) Percent Changes from Baseline in LDL-C in the Phase 3
`Study UP1002/AEGR-733-005 through the Primary Endpoint of Week 26
`using LOCF to Each Assessment (ITT Population, N=29) .........................................58
`Figure 10: Mean (95% CI) Percent Changes from Baseline in LDL-C in the Phase 2
`Study UP1001 (ITT Population, N=6) .........................................................................59
`Figure 11: Mean (95% CI) Percent Change from Baseline in LDL-C Over Time during
`the Efficacy and Safety Phases, Study UP1002/AEGR-733-005 (Subjects who
`Completed the Efficacy Phase, N=23) .........................................................................60
`Figure 12: Waterfall Plot of Percent Change from Baseline in LDL-C at Week 26/LOCF
`by Subject, Study UP1002/AEGR-733-005 (ITT Population, N=29) .........................61
`Figure 13: Mean LDL-C Levels by Study Week and Treatment Group Using LOCF,
`Phase 2 Studies in Subjects with Elevated LDL-C and Other Cardiovascular
`Risk Factors (Full Analysis Set) ..................................................................................63
`Figure 14: Mean Percent Changes from Baseline to Week 8a in LDL-C by Treatment
`Group and Study, Phase 2 Studies in Subjects with Elevated LDL-C and Other
`Cardiovascular Risk Factors ........................................................................................64
`Figure 15: Mean (95% CI) Percent Change from Baseline in Total Cholesterol, Apo B,
`non-HDL-C and Triglycerides in the Phase 3 Study UP1002/AEGR-733-005
`Over Time During the Efficacy and Safety Phases (Subjects who Completed
`the Efficacy Phase, N=23) ...........................................................................................66
`Figure 16: Mean (95% CI) Percent Change from Baseline in Total Cholesterol, Apo B,
`non-HDL-C and Triglycerides in the Phase 2 Study UP1001 Over Time (ITT
`Population, N=6) ..........................................................................................................67
`Figure 17: Mean (95% CI) Change from Baseline in HDL-C and Apo AI in the Phase 3
`Study UP1002/AEGR-733-005 Over Time During the Efficacy and Safety
`Phases (Subjects who Completed the Efficacy Phase, N=23) .....................................68
`Figure 18: Peak ALT and Corresponding Total Bilirubin Levels during Studies
`UP1002/AEGR-733-005 and AEGR-733-012 (Safety Population) ............................93
`Figure 19: Subjects with ALT and/or AST Elevations >5×ULN during Study
`UP1002/AEGR-733-005 ..............................................................................................95
`Figure 20: Peak ALT and Corresponding Total Bilirubin Levels by Treatment Group:
`Elevated LDL-C and Other Cardiovascular Risk Factors Study Pool (Safety
`Population) ...................................................................................................................96
`Figure 21: Regression Analysis of Time-Averageda AUC for ALT and AST and
`Maximum Hepatic Fat Measurement, Phase 3 HoFH Study .....................................100
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`Abbreviation
`AE
`ALA
`ALP
`ALT
`ANCOVA
`apo AI
`apo B
`ARH
`AST
`AUC
`BL
`BMI
`BMS
`CABG
`CHD
`CI
`Cmax
`CAD
`CV
`CVD
`DHA
`DSMB
`ECG
`eDISH
`EPA
`ER
`ESRD
`FC
`FDA
`FEV1
`FVC
`GI
`HCP
`HDL
`HDL-C
`HeFH
`HMG-CoA
`HOMA-IR
`HoFH
`IC50
`IND
`INR
`
`List of Abbreviations
`Term
`Adverse event
`α-linolenic acid
`Alkaline phosphatase
`Alanine aminotransferase
`Analysis of covariance
`Apolipoprotein AI
`Apolipoprotein B
`Autosomal recessive hypercholesterolemia
`Aspartate aminotransferase
`Area under the curve
`Baseline
`Body mass index
`Bristol-Myers Squibb
`Coronary artery bypass graft
`Coronary heart disease
`Confidence interval
`Maximum concentration
`Coronary artery disease
`Cardiovascular
`Cardiovascular disease
`Docosahexaenoic acid
`Data Safety Monitoring Board
`Electrocardiogram
`Evaluation of drug-induced serious hepatotoxicity
`Eicosapentaenoic acid
`Emergency room
`End-stage renal disease
`Familial chylomicronemia
`Food and Drug Administration
`Forced expiratory volume in 1 second
`Forced vital capacity
`Gastrointestinal
`Healthcare providers
`High-density lipoprotein
`High-density lipoprotein cholesterol
`Heterozygous familial hypercholesterolemia
`3-hydroxy-3-methylglutaryl coenzyme A
`Homeostasis model assessment-insulin resistance
`Homozygous familial hypercholesterolemia
`Inhibitory concentration, 50%
`Investigational New Drug Application
`International normalized ratio
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`Abbreviation
`ITT
`IV
`LDL
`LDL-C
`LDL-R
`LFT
`LLD
`LLT
`LOCF
`Lp(a)
`LSM
`Max
`MACE
`MedDRA
`MI
`Min
`MOA
`MRI
`MTP
`NASH
`NCEP-ATP III
`NDA
`NMRS
`NYHA
`PFT
`PK
`PT
`QTc
`REMS
`SAE
`SD
`SEM
`TEAE
`ULN
`US
`VLDL
`VLDL-C
`
`
`Term
`Intent-to-treat
`Intravenous
`Low-density lipoprotein
`Low-density lipoprotein cholesterol
`Low-density lipoprotein receptor
`Liver function test
`Lipid-lowering drug
`Lipid-lowering therapy
`Last observation carried forward
`Lipoprotein(a)
`Least square means
`Maximum
`Major adverse cardiac events
`Medical Dictionary for Regulatory Activities
`Myocardial infarction
`Minimum
`Mechanism of action
`Magnetic resonance imaging
`Microsomal triglyceride transfer protein
`Non-alcoholic steatohepatitis
`National Cholesterol Education Program Adult Treatment Panel III
`New Drug Application
`Nuclear magnetic resonance spectroscopy
`New York Heart Association
`Pulmonary function test
`Pharmacokinetic(s)
`Prothrombin time
`Corrected QT interval
`Risk Evaluation and Mitigation Strategy
`Serious adverse event
`Standard deviation
`Standard error of the mean
`Treatment-emergent adverse event
`Upper limit of normal
`United States
`Very low-density lipoprotein
`Very low-density lipoprotein cholesterol
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`1 EXECUTIVE OVERVIEW
`Aegerion is seeking approval for lomitapide as an adjunct to a low-fat diet and other lipid-
`lowering drugs (LLDs) with or without low-density lipoprotein (LDL) apheresis to reduce LDL
`cholesterol (LDL-C), total cholesterol, apolipoprotein B (apo B) and triglycerides in patients
`with homozygous familial hypercholesterolemia (HoFH).
`HoFH is a rare genetic disease caused by mutations in the LDL receptor gene or in genes
`affecting LDL receptor function, leading to extreme elevations of LDL-C causing premature
`atherosclerosis and early death. The primary goal of therapy for patients with HoFH involves
`lowering LDL-C levels, thereby delaying the progression of cardiovascular disease (CVD).
`Current treatment options are inadequate and leave patients at high risk of cardiovascular (CV)
`events due to continuous exposure to high levels of LDL-C. Lomitapide is a first-in-class small
`molecule inhibitor of microsomal triglyceride transfer protein (MTP). MTP plays a key role in
`the assembly and release of apo B-containing lipoproteins into the circulation and inhibition of
`this protein significantly lowers plasma lipid levels. Lomitapide is administered orally once a
`day with dose level individualized according to safety and tolerability.
`The lomitapide clinical development program includes a comprehensive series of Phase 1 studies
`in healthy subjects, Phase 2 studies in subjects with hypercholesterolemia and other CV risk
`factors, and Phase 3 studies in subjects with HoFH that provide clinical data demonstrating
`significant reductions in LDL-C with an acceptable safety profile.
`Studies with lomitapide have shown that it is now feasible for some subjects with HoFH to reach
`target LDL-C goals and maintain these levels during chronic treatment. The safety profile has
`been consistent across studies; treatment with lomitapide is primarily associated with
`gastrointestinal (GI) side effects, elevations in liver transaminase levels, and increases in hepatic
`triglyceride content. Dosing with lomitapide is escalated to each patient’s individually-defined
`maximum tolerated dose from 5 mg up to a maximum dose of 60 mg. With appropriate risk
`mitigation activities to ensure safe and appropriate use, lomitapide is expected to represent a
`major advance in the treatment options for patients with HoFH.
`
`1.1 Homozygous Familial Hypercholesterolemia
`
`1.1.1 Overview of the Disease and the Impact of Elevated LDL-C Levels
`HoFH is a rare, life-threatening, autosomal co-dominant genetic disease characterized by marked
`elevations in plasma levels of LDL-C and markedly premature atherosclerotic CVD. The disease
`is typically caused by homozygosity or compound heterozygosity for loss-of-function mutations
`in the LDLR gene encoding the LDL receptor protein, leading to markedly reduced or absent
`LDL receptor function. The prevalence of loss-of-function mutations in both alleles of the LDL
`receptor (HoFH) has been calculated to occur in ~1 in 1 million persons (Moorjani, 1993). This
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`calculation is based on the estimated prevalence of 1 in 500 for HeFH (Goldstein, 2001), which
`is caused by a mutation in one allele of the LDL receptor gene and is associated with plasma
`LDL-C levels and CVD risk intermediate between HoFH and normal individuals.
`Patients with HoFH have markedly impaired removal of LDL-C from the circulation resulting
`from reduced or absent hepatic LDL receptor activity. The hepatic LDL receptor plays a critical
`role in regulating the concentration of LDL-C in the blood by binding apo B to LDL and
`mediating its uptake, internalization, and lysosomal degradation. In the absence of functional
`LDL receptors, the uptake of LDL from the blood is impaired and concentrations are extremely
`elevated.
`As a direct consequence of absent or severely reduced LDL receptor function leading to
`markedly elevated LDL-C blood levels, patients with HoFH develop dramatically early and
`severe atherosclerotic CVD and often, early cardiac-related death. Symptomatic CVD often
`presents during the first 2 decades of life, and includes atherosclerosis in the coronary arteries,
`the carotid arteries, the aorta and aortic valve, and the peripheral vasculature, often leading to
`heart attack, stroke, and death (Kwiterovich, 1974; Buja, 1979; Moorjani, 1993; Marais, 2004).
`Early onset of atherosclerosis is generally accompanied by accelerated di