CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203858Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`
`

`

`Memo to the File
`
`203858
`NDA:
`Drug name: lomitapide
`Reviewer: James P. Smith, MD, MS
`Date:
`07 December 2012
`
`RE: Amendment to Clinical Review
`
`On page 175 of my clinical review, signed 27 November 2012, I provided brief
`narratives for five subjects in HoFH-pivotal who had at least one peak ALT ≥3x
`but <5x ULN. As enumerated in Table 86, however, six patients had a peak ALT
`in this range during HoFH-pivotal. A brief summary of the additional subject’s
`ALT elevation follows:
`
`Subject 02-001 (U.S.) had one isolated ALT 3.6x ULN on study day 202,
`detected at an unscheduled visit at a local laboratory between weeks 26 and 31.
`The subject was taking lomitapide 40 mg at the time. This resolved with
`continued dosing when next measured 8 days later (ALT 23 IU/L on study day
`210 at the week 31 visit). A reason for the unscheduled visit is not provided in the
`narrative, and the case report forms do not mention this visit. The only labs
`drawn on day 202 were ALT, AST, alkaline phosphatase, albumin, bilirubin, and
`total protein. No changes to lomitapide dose or concomitant medications were
`recorded.
`
`Reference ID: 3227399
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JAMES P SMITH
`12/07/2012
`
`ERIC C COLMAN
`12/07/2012
`
`Reference ID: 3227399
`
`

`

`CLINICAL REVIEW
`
`Application Type NDA
`Application Number(s) 203858
`Priority or Standard Standard
`
`
`Submit Date(s) 28 February 2012
`Received Date(s) 29 February 2012
`PDUFA Goal Date 29 December 2012
`Division / Office DMEP / ODE II / OND
`
`
`Reviewer Name(s)
`James P. Smith, MD, MS
`Review Completion Date 13 November 2012
`
`
`Established Name
`lomitapide mesylate
`(Proposed) Trade Name TRADENAME
`Therapeutic Class Microsomal triglyceride transfer protein
`(MTP) inhibitor
`Applicant Aegerion, Inc.
`
`
`Formulation(s) Capsules (5, 10, and 20 mg)
`Dosing Regimen Daily oral dose
`Indication(s) Reduce LDL-C, total cholesterol, apo B,
`and TG
`Intended Population(s) Homozygous familial
`hypercholesterolemia
`
`
`
`
`Template Version: March 6, 2009
`
`Reference ID: 3221657
`
`

`

`NDA 203858
`lomitapide mesylate
`
`
`
`
`
`James P. Smith, MD, MS
`Clinical Review
`
`2
`
`Table of Contents
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ....................................... 11
`1.1 Recommendation on Regulatory Action ........................................................... 11
`1.2 Risk Benefit Assessment.................................................................................. 11
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies . 17
`1.4 Recommendations for Postmarket Requirements and Commitments .............. 18
`INTRODUCTION AND REGULATORY BACKGROUND ...................................... 19
`2.1 Product Information .......................................................................................... 25
`2.2 Tables of Currently Available Treatments for Proposed Indications ................. 26
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 26
`2.4
`Important Safety Issues With Consideration to Related Drugs......................... 26
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 26
`2.6 Other Relevant Background Information .......................................................... 33
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 33
`3.1 Submission Quality and Integrity ...................................................................... 33
`3.2 Compliance with Good Clinical Practices ......................................................... 33
`3.3 Financial Disclosures........................................................................................ 34
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 34
`4.1 Chemistry Manufacturing and Controls ............................................................ 34
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 35
`4.4 Clinical Pharmacology...................................................................................... 39
`4.4.1 Mechanism of Action.................................................................................. 39
`4.4.2 Pharmacodynamics.................................................................................... 39
`4.4.3 Pharmacokinetics....................................................................................... 41
`5 SOURCES OF CLINICAL DATA............................................................................ 43
`5.1 Tables of Studies/Clinical Trials ....................................................................... 43
`5.2 Review Strategy ............................................................................................... 50
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 50
`6 REVIEW OF EFFICACY....................................................................................... 113
`6.1
`Indication ........................................................................................................ 115
`6.1.1 Methods ................................................................................................... 116
`6.1.2 Demographics.......................................................................................... 117
`6.1.3 Subject Disposition................................................................................... 121
`6.1.4 Analysis of Primary Endpoint(s) ............................................................... 124
`6.1.5 Analysis of Secondary Endpoints(s) ........................................................ 138
`6.1.6 Other Endpoints ....................................................................................... 141
`6.1.7 Subpopulations ........................................................................................ 146
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .. 146
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects............... 147
`
`Reference ID: 3221657
`
`2
`
`

`

`NDA 203858
`lomitapide mesylate
`
`
`
`
`
`James P. Smith, MD, MS
`Clinical Review
`
`6.1.10 Additional Efficacy Issues/Analyses......................................................... 149
`7 REVIEW OF SAFETY........................................................................................... 149
`7.1 Methods.......................................................................................................... 153
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ....................................... 153
`7.1.2 Categorization of Adverse Events............................................................ 154
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................. 154
`7.2 Adequacy of Safety Assessments .................................................................. 155
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations................................................................................... 155
`7.2.2 Explorations for Dose Response.............................................................. 157
`7.2.3 Special Animal and/or In Vitro Testing ..................................................... 157
`7.2.4 Routine Clinical Testing ........................................................................... 157
`7.2.5 Metabolic, Clearance, and Interaction Workup ........................................ 158
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class 158
`7.3 Major Safety Results ...................................................................................... 158
`7.3.1 Deaths...................................................................................................... 158
`7.3.2 Nonfatal Serious Adverse Events ............................................................ 159
`7.3.3 Dropouts and/or Discontinuations ............................................................ 166
`7.3.4 Significant Adverse Events ...................................................................... 169
`7.3.5 Submission Specific Primary Safety Concerns ........................................ 169
`7.4 Supportive Safety Results .............................................................................. 214
`7.4.1 Common Adverse Events ........................................................................ 214
`7.4.2 Laboratory Findings ................................................................................. 220
`7.4.3 Vital Signs ................................................................................................ 224
`7.4.4 Electrocardiograms (ECGs) ..................................................................... 229
`7.4.5 Special Safety Studies/Clinical Trials....................................................... 231
`7.5 Other Safety Explorations............................................................................... 233
`7.5.1 Dose Dependency for Adverse Events .................................................... 233
`7.5.2 Time Dependency for Adverse Events..................................................... 237
`7.5.3 Drug-Demographic Interactions ............................................................... 237
`7.5.4 Drug-Disease Interactions........................................................................ 237
`7.5.5 Drug-Drug Interactions............................................................................. 242
`7.6 Additional Safety Evaluations ......................................................................... 248
`7.6.1 Human Carcinogenicity............................................................................ 248
`7.6.2 Human Reproduction and Pregnancy Data.............................................. 248
`7.6.3 Pediatrics and Assessment of Effects on Growth .................................... 249
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound.................... 249
`7.7 Additional Submissions / Safety Issues.......................................................... 249
`8 POSTMARKET EXPERIENCE............................................................................. 249
`9 APPENDICES ...................................................................................................... 250
`9.1 Literature Review/References ........................................................................ 250
`9.2 Labeling Recommendations ........................................................................... 254
`9.3 Advisory Committee Meeting.......................................................................... 256
`
`Reference ID: 3221657
`
`3
`
`

`

`
`
`
`James P. Smith, MD, MS
`Clinical Review
`
`9.4 Supplemental Tables and Figures.................................................................. 258
`
`NDA 203858
`lomitapide mesylate
`
`
`
`
`Reference ID: 3221657
`
`4
`
`

`

`NDA 203858
`lomitapide mesylate
`
`
`
`
`
`James P. Smith, MD, MS
`Clinical Review
`
`Table of Tables
`
`Table 1. Lomitapide – Regulatory History ..................................................................... 29
`Table 2. Summary of Noteworthy Treatment-Related Effects from Nonclinical Studies 38
`Table 3. CV145-002 – Lomitapide Pharmacodynamics ................................................ 40
`Table 4. Clinical Pharmacology Studies ........................................................................ 41
`Table 5. Efficacy & Safety Trials in HoFH ..................................................................... 45
`Table 6. Phase 2 Efficacy & Safety Trials in Non-HoFH................................................ 46
`Table 7. Drug Interaction Trials ..................................................................................... 47
`Table 8. Dose-Finding, Bioavailability, Mass Balance................................................... 48
`Table 9. Special Safety / Special Populations ............................................................... 49
`Table 10. Enumeration of Subjects in Lomitapide Development ................................... 50
`Table 11. C-009 – Subject Disposition .......................................................................... 52
`Table 12. C-009 – Mean (SD) % Changes in Lipid Parameters at 4 weeks & Off-
`treatment....................................................................................................................... 53
`Table 13. C-009 – Extent of Exposure .......................................................................... 54
`Table 14. C-009 – Adverse Event Summary ................................................................. 55
`Table 15. C-009 – Selected Common Treatment-Emergent Adverse Events ............... 55
`Table 16. C-009 – Peak ALT Abnormalities .................................................................. 56
`Table 17. C-009 – Absolute Changes in % Hepatic Fat ................................................ 58
`Table 18. C-009 – Categorical Changes in % Hepatic Fat at End-of-Treatment ........... 58
`Table 19. C-009 – Hepatic Fat in Subjects with Insufficient Resolution at Follow-up .... 58
`Table 20. C-009 – Changes in Vitamin E ...................................................................... 61
`Table 21. C-009 – Absolute Changes in Pulmonary Function Parameters ................... 61
`Table 22. A-001 – Subject Disposition .......................................................................... 63
`Table 23. A-001 – Mean (SD) Baseline Lipid Parameters............................................. 64
`Table 24. A-001 – Mean (SD) % Changes in Lipid Parameters at 12 weeks ................ 64
`Table 25. A-001 – Mean (SD) % Changes in Lipid Parameters at Interim Visits........... 65
`Table 26. A-001 – Extent of Exposure (Duration by Dose)............................................ 65
`Table 27. A-001 – Adverse Event Summary ................................................................. 66
`Table 28. A-001 – Peak ALT Abnormalities .................................................................. 67
`Table 29. A-003b – Subject Disposition ........................................................................ 70
`Table 30. A-003b – Mean (SD) Baseline Lipid Parameters........................................... 71
`Table 31. A-003b – Mean % Changes in Lipid Parameters at Week 8 ......................... 71
`Table 32. A-003b – Extent of Exposure......................................................................... 73
`Table 33. A-003b – Adverse Event Summary ............................................................... 74
`Table 34. A-003b – Peak ALT Abnormalities ................................................................ 75
`Table 35. A-003b – Mean (SD) Vitamin A Levels Over 8 Weeks .................................. 76
`Table 36. A-003b – Mean (SD) Total Vitamin E Levels Over 8 Weeks ......................... 77
`Table 37. A-003b – Mean (SD) Safety Laboratory Values at Week 8 ........................... 77
`Table 38. A-003b – Mean (SD) Vital Sign Measurements............................................. 78
`Table 39. A-004 – Subject Disposition .......................................................................... 79
`Table 40. A-004 – Absolute Change in % Hepatic Fat at Week 12 ............................... 80
`Table 41. A-004 – Effect of Concomitant Lipid-lowering Therapy on Hepatic Fat ......... 82
`Table 42. A-004 – Correlations Between Changes in ALT and Change in % Hepatic Fat
`...................................................................................................................................... 83
`
`Reference ID: 3221657
`
`5
`
`

`

`
`
`
`James P. Smith, MD, MS
`Clinical Review
`
`NDA 203858
`lomitapide mesylate
`
`Table 43. A-004 – Associations Between Changes in Lipids and Hepatic Fat .............. 83
`Table 44. A-004 – Mean (SD) Baseline Lipid Parameters............................................. 85
`Table 45. A-004 – Mean (SD) Placebo-subtracted % Changes in Lipids at Week
`12/LOCF........................................................................................................................ 86
`Table 46. A-004 – Extent of Exposure........................................................................... 88
`Table 47. A-004 – Adverse Event Summary ................................................................. 88
`Table 48. A-004 – Selected Common Treatment-Emergent Adverse Events ............... 89
`Table 49. A-004 – Peak ALT Abnormalities .................................................................. 90
`Table 50. A-004 – Mean (SD) Safety Laboratory Values at Week 12/LOCF................. 91
`Table 51. A-004 – Mean (SD) Vital Sign Measurements............................................... 92
`Table 52. A-004 – Mean (SD) % Change in Body Weight at Week 12/LOCF ............... 93
`Table 53. A-004 – Mean (SD) Values for Pulmonary Function Parameters at Week
`12/LOCF........................................................................................................................ 93
`Table 54. A-006 – Summary of Effect on Lipids ............................................................ 94
`Table 55. Timing of Selected Assessments in HoFH-pivotal......................................... 99
`Table 56. HoFH-pivotal – Protocol Actions in Response to Potential Liver-related Events
`.................................................................................................................................... 101
`Table 57. Baseline Characteristics of HoFH Trials...................................................... 117
`Table 58. HoFH-pivotal – Evidence for HoFH ............................................................. 118
`Table 59. HoFH-pivotal – Baseline Lipid-Lowering Therapy ....................................... 119
`Table 60. HoFH – Baseline Lipid, Lipoprotein, hsCRP Values.................................... 120
`Table 61. HoFH-pivotal – Enrollment by Site .............................................................. 120
`Table 62. HoFH-pivotal – Subject Disposition ............................................................. 121
`Table 63. Reasons for Early Withdrawal from HoFH-pivotal and Extension................ 122
`Table 64. HoFH-pivotal – Analysis Populations .......................................................... 122
`Table 65. HoFH-pivotal – Distribution of Achieved Doses........................................... 123
`Table 66. HoFH-pivotal – Direct LDL-C (Primary Endpoint) at Week 26..................... 124
`Table 67. HoFH-pivotal – LDL-C Changes from Baseline to Week 26 (Sensitivity
`Analyses) .................................................................................................................... 124
`Table 68. HoFH-pivotal – LDL-C by Study Visit .......................................................... 125
`Table 69. HoFH-pivotal – Days from Apheresis to LDL-C Assessment....................... 130
`Table 70. HoFH-pilot – Changes in LDL-C.................................................................. 137
`Table 71. HoFH-pivotal – Secondary Efficacy Parameters at Week 26/LOCF............ 138
`Table 72. HoFH-pilot – Mean (SD) % Changes in Lipids after Each Dosing Period.... 141
`Table 73. HoFH-pilot – % Changes in Select Lipid Parameters after Lomitapide 1.0
`mg/kg .......................................................................................................................... 141
`Table 74. HoFH-pivotal – HDL-C and ApoAI at Week 26/LOCF (ITT/Safety) ............. 142
`Table 75. HoFH-pivotal – HDL-C and ApoAI at Weeks 26 & 56 (Completers) ............ 143
`Table 76. HoFH-pivotal – LDL-C During Safety Period through Week 56................... 148
`Table 77. HoFH-pivotal – Secondary Efficacy Parameters at Weeks 26 & 56
`(Completers) ............................................................................................................... 149
`Table 78. Applicant's "Elevated LDL-C" Safety Pool ................................................... 153
`Table 79. Duration of Exposure to Lomitapide (HoFH-pivotal and extension)............. 155
`Table 80. Exposure to Lomitapide in HoFH-pivotal ..................................................... 155
`Table 81. Exposure to Lomitapide in HoFH-extension ................................................ 156
`Table 82. Exposure to Lomitapide in Applicant’s "Elevated LDL" Safety Pool ............ 156
`
`Reference ID: 3221657
`
`6
`
`

`

`
`
`
`James P. Smith, MD, MS
`Clinical Review
`
`NDA 203858
`lomitapide mesylate
`
`Table 83. HoFH-pivotal – Treatment-emergent AE Summary..................................... 158
`Table 84. Serious Adverse Events in HoFH Trials ...................................................... 161
`Table 85. HoFH-pivotal – Dropouts............................................................................. 167
`Table 86. HoFH Population – Peak ALT Abnormalities............................................... 170
`Table 87. HoFH Population – Peak AST Abnormalities .............................................. 170
`Table 88. Phase 2 – Incidence of ALT Elevations....................................................... 177
`Table 89. HoFH-pivotal – Absolute Change in % Hepatic Fat From Baseline............. 178
`Table 90. HoFH Phase 3 – Maximum Categorical Changes in % Hepatic Fat............ 178
`Table 91. HoFH-pivotal – Selected Subject-level % Hepatic Fat & Dose.................... 181
`Table 92. HoFH-pivotal – Correlation of Transaminases and % Hepatic Fat .............. 183
`Table 93. Exploration of ALT ≥3x ULN as Screen for Hepatic Fat .............................. 184
`Table 94. HoFH-pivotal – Reversibility of Hepatic Fat................................................. 185
`Table 95. HoFH-pivotal – Hepatic Biomarker Descriptive Statistics ............................ 188
`Table 96. HoFH-pivotal – Correlations with Hepatic Biomarkers at Week 56.............. 189
`Table 97. HoFH-pivotal – Median Changes in Fat-soluble Nutrients........................... 192
`Table 98. HoFH-pivotal – Fat-Soluble Vitamin Shift Table .......................................... 193
`Table 99. HoFH-pivotal – Fatty Acid Shift Table ......................................................... 193
`Table 100. HoFH-pivotal Subject-Level Weight Changes ........................................... 204
`Table 101. HoFH-pivotal – Pulmonary Function Descriptive Statistics........................ 207
`Table 102. HoFH-pivotal – INR and Warfarin Dosages for Relevant Subjects............ 209
`Table 103. HoFH-pivotal – Broad & Narrow Cardiovascular SMQs ............................ 210
`Table 104. Elevated LDL-C Phase 1/2 Pool – Broad & Narrow Cardiovascular SMQs
`.................................................................................................................................... 211
`Table 105. HoFH-pivotal & -extension – Common Treatment-emergent AEs (≥5%
`incidence).................................................................................................................... 215
`Table 106. Most Commonly Reported AEs by Type of Concomitant Statin ................ 218
`Table 107. HoFH-pilot - AEs Reported by Two or More Subjects ............................... 219
`Table 108. HoFH-pivotal – Hematology Trends .......................................................... 220
`Table 109. HoFH-pivotal – Hematology Shift Tables................................................... 221
`Table 110. HoFH-pivotal – Clinical Chemistry Descriptive Statistics........................... 222
`Table 111. HoFH-pivotal – Vital Sign Descriptive Statistics ........................................ 224
`Table 112. HoFH-pilot – Mean (SD) Vital Signs Over Time ........................................ 227
`Table 113. HoFH-pivotal – Mean Changes in ECG Intervals (Central Read).............. 230
`Table 114. HoFH-pivotal – QTcF Outliers (Central Read)........................................... 230
`Table 115. Thorough QT Study – Summary of QTcI Results ...................................... 231
`Table 116. Thorough QT Study – Max Changes in HR, PR, QRS .............................. 232
`Table 117. HoFH-pivotal – AEs in ≥10% of Subjects by Dose at Onset (through Week
`56)............................................................................................................................... 234
`Table 118. "Elevated LDL-C" Safety Pool – Incidence of Common AEs..................... 236
`Table 119. "Elevated LDL-C" Safety Pool – Incidence Rates of Common AEs........... 236
`Table 120. Child-Pugh Scoring System....................................................................... 238
`Table 121. Effect of Low- and High-Fat Breakfast on Lomitapide PK (CV145-005) .... 242
`Table 122. CV145-005 – Gastrointestinal Adverse Events ......................................... 243
`Table 123. A-003b – Adverse Events Leading to Discontinuation............................... 269
`Table 124. A-003b – Selected Common Treatment-Emergent Adverse Events ......... 269
`Table 125. “Elevated LDL-C” Safety Pool – AEs Leading to Discontinuation.............. 271
`
`Reference ID: 3221657
`
`7
`
`

`

`
`
`
`James P. Smith, MD, MS
`Clinical Review
`
`NDA 203858
`lomitapide mesylate
`
`Table 126. Safety Assessments in Lomitapide Clinical Trials ..................................... 276
`Table 127. HoFH-pivotal – Subject 01-004 Transaminase Trend ............................... 279
`Table 128. HoFH-pivotal – Subject 02-002 Transaminase Trend ............................... 279
`Table 129. HoFH-pivotal – Subject 12-004 Transaminase Trend ............................... 280
`Table 130. HoFH-pivotal – Subject 32-001 Transaminase Trend ............................... 280
`Table 131. "Elevated LDL-C" Safety Pool – Common AEs by Sex ............................. 288
`Table 132. AEGR-733-002 DDI Study – Geometric Mean Ratios for Cmax and AUC .. 289
`
`
`Reference ID: 3221657
`
`8
`
`

`

`NDA 203858
`lomitapide mesylate
`
`
`
`
`
`James P. Smith, MD, MS
`Clinical Review
`
`Table of Figures
`
`Figure 1. Chemical Structure of Lomitapide .................................................................. 34
`Figure 2. CV145-002 – Lomitapide Dose-Response for LDL-C .................................... 41
`Figure 3. C-009 – Lipid Parameters Over Time............................................................. 54
`Figure 4. C-009 – ALT Profiles for Subjects with Peak ALT ≥3x ULN ........................... 57
`Figure 5. C-009 – Baseline Hepatic Fat vs. Peak ALT Observed.................................. 59
`Figure 6. C-009 – Peak ALT (x ULN) vs. Change in Hepatic Fat .................................. 60
`Figure 7. A-001 – ALT Profiles for Subjects with Peak ALT ≥3x ULN ........................... 68
`Figure 8. A-003b - Mean % Change in LDL-C Over Time............................................. 73
`Figure 9. A-003b – ALT Profiles for Subjects with Peak ALT ≥3x ULN ......................... 76
`Figure 10. A-004 – Placebo-subtracted Mean Changes in % Hepatic Fat .................... 81
`Figure 11. A-004 – Median % Hepatic Fat at Each Visit................................................ 82
`Figure 12. A-004 – Change in % Hepatic Fat vs. % Change in LDL-C ......................... 83
`Figure 13. A-004 - Change in % Hepatic Fat vs. % Change in C-peptide ..................... 84
`Figure 14. A-004 – Max Change in % Hepatic Fat vs. Change in HOMA-IR................. 85
`Figure 15. A-004 – % Change in HDL-C from Baseline Over 12 Weeks....................... 87
`Figure 16. A-004 – % Change in LDL-C from Baseline Over 12 Weeks ....................... 87
`Figure 17. Study Schematic (Post-Baseline)............................................................... 100
`Figure 18. HoFH-pivotal – % Change in LDL-C .......................................................... 115
`Figure 19. HoFH-pivotal – Mean and Median LDL-C Over Time................................. 126
`Figure 20. HoFH-pivotal – Absolute Changes in LDL-C from Baseline Over Time ..... 126
`Figure 21. HoFH-pivotal – Relative Changes in LDL-C from Baseline Over Time ...... 127
`Figure 22. HoFH-pivotal – LDL-C % Change at Week 26 by Maximum Tolerated Dose
`.................................................................................................................................... 128
`Figure 23. HoFH-pivotal – Apheresis Frequency by Subject....................................... 130
`Figure 24. HoFH-pivotal – Mean % Change in LDL-C During Efficacy Period by
`Apheresis .................................................................................................................... 132
`Figure 25. HoFH-pivotal – Subject-level LDL-C Profiles.............................................. 134
`Figure 26. HoFH-pivotal – Correlation of Baseline and Change Measures of LDL-C.. 136
`Figure 27. HoFH-pivotal – Q-Q plot of % Change in LDL-C at Week 26/LOCF .......... 137
`Figure 28. HoFH-pilot – % Change in LDL-C Over Time............................................. 138
`Figure 29. HoFH-pivotal – % Changes in Secondary Lipid Parameters...................... 140
`Figure 30. HoFH-pivotal – % Changes in HDL-C and ApoAI ...................................... 143
`Figure 31. HoFH-pivotal – Association of Changes in LDL-C and HDL-C................... 144
`Figure 32. HoFH-pivotal – LDL-C Through End of Trial (Week 78)............................. 148
`Figure 33. HoFH-pivotal – Mean ALT, AST, % Hepatic Fat Over Time....................... 171
`Figure 34. HoFH-pivotal – Median ALT/AST, Baseline to Week 56 ............................ 172
`Figure 35. HoFH-pivotal – Selected Transaminase Profiles (ALT ≥5x ULN) ............... 173
`Figure 36. HoFH-pilot – Subject AROD85 Transaminase Profile ................................ 176
`Figure 37. HoFH-pilot – Subject DWOL68 Transaminase Profile................................ 176
`Figure 38. HoFH-pilot – Subject SDAG82 Transaminase Profile ................................ 177
`Figure 39. HoFH Phase 3 – % Hepatic Fat Profiles .................................................... 180
`Figure 40. HoFH Population – % Hepatic Fat Profiles ................................................ 181
`Figure 41. HoFH-pivotal – % Hepatic Fat at Baseline vs. Week 26 ............................ 182
`
`Reference ID: 3221657
`
`9
`
`

`

`
`
`
`James P. Smith, MD, MS
`Clinical Review
`
`NDA 203858
`lomitapide mesylate
`
`Figure 42. HoFH-pivotal – Association Between Changes in LDL-C and Hepatic Fat at
`Week 26 ...................................................................................................................... 183
`Figure 43. HoFH-pivotal – Peak ALT vs. Peak Change in Hepatic Fat ....................... 185
`Figure 44. HoFH-pilot - % Hepatic Fat over Time ....................................................... 186
`Figure 45. HoFH-pivotal – Cross-sectional Association Between CK-18 Fragment and %
`Hepatic Fat at Week 56............................................................................................... 190
`Figure 46. HoFH-pivotal – Fat-Soluble Nutrient Trends .............................................. 196
`Figure 47. HoFH-pivotal – Holman Index Over Time................................................... 199
`Figure 48. HoFH-pilot – Fatty Acid Trends .................................................................. 201
`Figure 49. HoFH-pivotal – Body Weight Trend............................................................ 203
`Figure 50. HoFH-pivotal – Baseline Weight vs. Weight Change at Week 26/LOCF.... 204
`Figure 51. HoFH-pivotal – Weight Changes During Efficacy & Safety Phases ........... 205
`Figure 52. HoFH-pilot – Weight Changes Over Time.................................................. 206
`Figure 53. HoFH-pivotal – DLCO Trend...................................................................... 208
`Figure 54. HoFH-pivotal – Vital