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

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`OFFICE OF BIOSTATISTICS
`
`
`
`S T A T I S T I C A L R E V I E W A N D E VA L UA T I O N
`CLINICAL STUDIES
`
`
`
`NDA/Serial Number:
`203-858/N-000
`Drug Name:
`Lomitapide mesylate capsules
`Indication(s):
`Treatment of homozygous familial hypercholesterolemia
`Applicant:
`Aegerion Pharmaceuticals, Inc.
`Date(s):
`Received 02/29/12; user fee (10 months) 12/29/12
`Review Priority:
`Standard
`
`
`Biometrics Division:
`Division of Biometrics II (HFD-715)
`Statistical Reviewer:
`Cynthia Liu, MA
`Concurring Reviewer(s): Todd Sahlroot, Ph.D., Statistical Team Leader and Deputy
`Director of Biometrics II
`
`Division of Metabolic and Endocrine Products (HFD-510)
`James Smith, M.D., Medical Reviewer
`Eric Colman, M.D., Medical Team Leader and Deputy
`Director of DMEP
`Kati Johnson
`
`NDA review, clinical studies
`
`
`Medical Division:
`Clinical Team:
`
`Project manager:
`
`Keywords:
`
`
`
`Reference ID: 3224348
`
`

`

`Statistical Review and Evaluation of Clinical Trials
`
`
`
`NDA 203-858/N-000
`
`TABLE OF CONTENTS
`
`
`1. EXECUTIVE SUMMARY
`1.1 Conclusions and Recommendations
`1.2 Brief Overview of Clinical Studies
`1.3 Statistical Issues and Findings
`2. INTRODUCTION
`2.1 Overview
`2.2 Data Sources
`3. STATISTICAL EVALUATION
`3.1 Evaluation of Efficacy
`3.1.1 Study Design and Endpoints
`3.1.2 Statistical Methods
`3.1.3 Subject Disposition
`3.1.4 Demographic and Baseline Characteristics
`3.1.5 Efficacy Results and Discussion
`3.2 Evaluation of Safety
`4. FINDINGS IN SPECIAL/SUBGROUP POPULATIONS
`4.1 Gender, Race, and Age
`4.2 Other Special/Subgroup Populations
`5. SUMMARY AND CONCLUSIONS
`5.1 Statistical Issues and Collective Evidence
`5.2 Conclusions and Recommendations
`
`
`
`3
`3
`3
`4
`6
`6
`6
`6
`6
`6
`7
`8
`8
`10
`14
`14
`14
`14
`15
`15
`16
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`1. EXECUTIVE SUMMARY
`1.1 Conclusions and Recommendations
`Data from the pivotal Phase 3 trial have demonstrated that lomitapide was effective in
`reducing LDL-C, total cholesterol (TC), Apo B, triglycerides (TRIG), non-HDL-C, and
`VLDL-C in patients with HoFH after 26 weeks of treatment when used as an adjunct to a
`low-fat diet and other lipid-lowering therapies with or without LDL apheresis. The
`reductions seemed to be maintained through Week 56 for LDL-C, TC, ApoB, and non-HDL-
`C. Lomitapide was also shown to lower HDL-C during the 26-week dose-titration efficacy
`phase. However, the mean HDL-C at Week 56 was returned to its baseline level.
`
`Evaluation of the data after Week 56 may be important for TRIG, VLDL-C, and especially
`HDL-C since the long-term effect of lomitapide on these parameters remains to be seen.
`
`Labeling Comments: The following bullets summarize this reviewer’s comments for the
`sponsor’s proposed labeling in the Clinical Studies section.
`
`
`(cid:131) The sponsor stated the primary efficacy endpoint as “mean” percent change in LDL-C
`from baseline at Week 26. The “mean” should be omitted since it is not an endpoint;
`rather, it is an average of the endpoint values of the treated subjects in the study.
`
` Figure 1 is currently based on the ITT population with LOCF. This reviewer thinks
`that the graph should be based on the completers over time, with Week 26/LOCF
`values alongside.
`
` (cid:131)
`
`
`
`
`
`(cid:131) Table 5 presents the results for Week 26/LOCF (N = 29) and Week 56 (N = 23). It
`may be informative to include Week 26 (N = 23) results also so that there is a direct
`comparison between the 2 time points.
`
`(cid:131) The parameters listed in Table 5 should be clearly identified as the primary, key
`secondary, and other efficacy variables in the text. An asterisk (*) may be used to
`indicate a significant p-value for the primary and key secondary variables since their
`statistical analyses were prioritized.
`
`
`1.2 Brief Overview of Clinical Studies
`Aegerion Pharmaceuticals, Inc. has submitted an original NDA seeking approval of
`lomitapide mesylate capsules for the treatment of homozygous familial hypercholesterolemia
`(HoFH) when used as an adjunct to a low-fat diet and other lipid-lowering therapies with or
`without LDL apheresis. Lomitapide is a microsomal triglyceride transfer protein (MTP)
`inhibitor. It has received an orphan drug designation for this indication on 10/23/2007. In
`
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`Statistical Review and Evaluation of Clinical Trials
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`this NDA, the sponsor included the results from 24 clinical trials, ranging from Phase 1 to
`Phase 3, that were conducted in healthy subjects, adults with elevated LDL-C and other risk
`factors for CVD (without HoFH), adults with hepatic impairment, adults with end stage renal
`disease on dialysis, and adults with HoFH. The efficacy of lomitapide in patients with HoFH
`would be determined primarily based on the results from a pivotal Phase 3 study
`UP1002/AEGR-733-005 (29 patients) and a supportive Proof-of-Concept Phase 2 study
`UP1001 (6 patients) since the other trials were conducted in different populations.
`
`The pivotal Phase 3 study was a 78-week, open-label, single-arm, dose-escalation (5, 10, 20,
`40, 60 mg/day), multicenter, multinational trial, conducted at 11 sites located in US, Canada,
`South Africa, and Italy. The supportive Phase 2 study was a 16-week, open-label, single-
`arm, dose-escalation (0.03, 0.1, 0.3, 1.0 mg/kg/day), single-center (in US) trial. In the pivotal
`study, subjects were required to continue their concomitant lipid-lowering therapies through
`Week 26 (efficacy phase) and follow a diet with < 20% energy from fat; while in the
`supportive study, subjects were asked to stop all the lipid-lowering therapies prior to the
`Baseline visit but follow a rigorous low-fat diet with < 10% energy from fat.
`
`At the time of the NDA submission, the pivotal trial was still ongoing. Therefore, the
`sponsor’s clinical study report covers only the data and results through Week 56 based on the
`data cut-off date of 04/12/2011.
`
`1.3 Statistical Issues and Findings
`For Study UP1002/AEGR-733-005, a total of 29 subjects were enrolled and treated with
`lomitapide. As of 04/12/2011 the data cut-off date, 6 patients discontinued from the trial
`prior to Week 26; 23 of the 29 enrolled patients completed Week 56; and 18 of the 23
`patients completed the entire 78-week trial. For Study UP1001, all the 6 enrolled subjects
`completed the trial.
`
`As shown in Table 6 in the main body of this review, for the pivotal Phase 3 trial (Study
`UP1002/AEGR-733-005), the mean % decrease in LDL-C from baseline to Week 26 was
`about 40% for the ITT/LOCF population (N = 29) and 50% for the completers (N = 23). In
`addition, a total of 20 patients had a > 15% decrease in LDL-C at Week 26. Although the
`study was not designed as a dose-response trial, it was noted that the mean % reductions in
`LDL-C were increasing as doses were increased over the titration period (see Table 7 in the
`main body of this review). The reduction, however, reached a plateau at Week 18, but was
`sustained around 40-45% between Weeks 36 and 56 with the mean maximum tolerated dose
`(MTD) about 40 mg.
`
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`Note that the sponsor stated that there was a dose-response across patients whose maximum
`tolerated doses were 20, 40, and 60 mg with mean % changes from baseline to Week 26 in
`LDL-C of -33%, -48%, and -55%, respectively, based on the ITT/LOCF population
`(sponsor’s CSR, page 108). This reviewer thinks that the statement is misleading because the
`patient who dropped out at 40 mg had a +17% change from baseline (see Table 8 in the main
`body of this review). In the completer cohort, the mean % changes at Week 26 were
`actually -38% (n = 5), -57% (n = 6), and -55% (n = 10) for the 20, 40, and 60 mg,
`respectively. In other words, the mean % reductions in LDL-C appear to be similar between
`the patients receiving 40 mg and 60 mg at Week 26.
`
`There were statistically significant mean % reductions from baseline in TC, ApoB, and TRIG
`after 26 weeks of treatment with lomitapide (all p ≤ 0.01). Significant mean % changes from
`baseline in non-HDL-C and VLDL-C at Week 26 favoring lomitapide were also observed
`(nominal p < 0.05). As in the case of LDL-C, the reductions in TC, ApoB, and non-HDL-C
`were seen as early as Week 2 and were continuously decreased until Week 18, then slightly
`went back up, but were sustained through Week 56 (see Figures 5 and 7 in the main body of
`this review). The reductions in TRIG and VLDL-C after Week 18 were, however,
`continuously reversed through Week 56.
`
`There was no marked change in Lp(a) after 26 weeks of treatment with lomitapide when
`compared with baseline. There was, however, a beneficial reduction in Lp(a) after 56 weeks
`of treatment.
`
`The mean % reduction in HDL-C at Week 26 was statistically significant in the completer
`cohort (-12.3%, nominal p < 0.01), but not in the ITT/LOCF population (-7.0%, nominal p =
`0.07). The decrease in HDL-C after treatment with lomitapide was observed, but was
`reversed after Week 18, and gradually returned to the baseline level at Week 56.
`
`Similar treatment effects on mean % changes from baseline in LDL-C at Week 26/LOCF
`were observed between males and females (-40% vs. -39%), age < 30 years and ≥ 30 years
`(-39% vs. -40%), White and non-White (-40% vs. -35%), US/Canada and other countries
`(-32% vs. -45%), baseline BMI < 30 and ≥ 30 kg/m2 (-40% vs. -37%), and the use (yes or no)
`of apheresis at entry (-34% vs. -49%). There was a negative, but weak, correlation between
`the baseline LDL-C and % change from baseline in LDL-C at Week 26/LOCF in Study
`UP1002/AEGR-733-005.
`
`Results from the supportive Phase 2 trial (Study UP1001) were similar to the results observed
`in the pivotal Phase 3 trial in general.
`
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`Statistical Review and Evaluation of Clinical Trials
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`2. INTRODUCTION
`2.1 Overview
`Aegerion Pharmaceuticals, Inc. has submitted an original NDA seeking approval of
`lomitapide mesylate capsules for the treatment of homozygous familial hypercholesterolemia
`(HoFH) when used as an adjunct to a low-fat diet and other lipid-lowering therapies with or
`without LDL apheresis. Lomitapide is a microsomal triglyceride transfer protein (MTP)
`inhibitor. It has received an orphan drug designation for this indication on 10/23/2007. In
`this NDA, the sponsor included the results from 24 clinical trials, ranging from Phase 1 to
`Phase 3, that were conducted in healthy subjects, adults with elevated LDL-C and other risk
`factors for CVD (without HoFH), adults with hepatic impairment, adults with end stage renal
`disease on dialysis, and adults with HoFH. The efficacy of lomitapide in patients with HoFH
`would be determined primarily based on the results from a pivotal Phase 3 study
`UP1002/AEGR-733-005 (29 patients) and a supportive Proof-of-Concept Phase 2 study
`UP1001 (6 patients) since the other trials were conducted in different populations.
`Therefore, this review focuses on the efficacy evaluation of these two studies.
`
`2.2 Data Sources
`The original clinical study reports and electronic data files are located in the sub-folders of
`EDR \\CDSESUB1\EVSPROD\NDA203858\0000. The sponsor provided datasets with
`SDTM format for individual studies and ADaM format for ISS and ISE. Since datasets with
`SDTM format contained multiple measurements from the same visit window for some
`patients, included data in the US unit for the US sites only, and did not have LOCF flag, this
`reviewer had to use the ISE dataset to extract study-specific data for the purpose of statistical
`analyses. However, there were some slight discrepancies between the results presented in the
`clinical study report (CSR) of the UP1002/AEGR-733-005 trial and the clinical overview
`(ISE). The sponsor stated in the August 1, 2012 submission that the differences were due to
`the baseline date used between the CSR and ISE analyses
`(\\CDSESUB1\EVSPROD\NDA203858\0020). In CSR, the lab assessment Visit 3 date was
`used as the baseline date to calculate subsequent visit windows; while in ISE, the first dose
`date was used as the baseline date. The differences in results for the primary efficacy
`endpoint between the CSR and ISE analyses appeared to be small.
`
`3. STATISTICAL EVALUATION
`3.1 Evaluation of Efficacy
`3.1.1 Study Design and Endpoints
`Protocol UP1002/AEGR-733-005 was a Phase 3, 78-week, open-label, single-arm, dose-
`escalation (5, 10, 20, 40, 60 mg/day), multicenter, multinational trial, conducted at 11 sites
`located in US (2 sites), Canada (2 sites), South Africa (3 sites), and Italy (4 sites). According
`to the sponsor, the dose escalation approach (see the schema below) was designed to achieve
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`Statistical Review and Evaluation of Clinical Trials
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`NDA 203-858/N-000
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`the optimal individualized dose to maximize efficacy and minimize gastrointestinal side
`effects and transaminase elevations. Patients could have their dose titrated to 80 mg if they
`met strict safety and efficacy criteria. There was a 6-week run-in period where subjects were
`instructed to continue their concomitant lipid-lowering therapies (stable dose and regimen
`through Week 26), follow a diet with < 20% energy from fat, and start taking dietary
`supplements of vitamin E and fatty acids provided by the sponsor. After completing 26
`weeks of treatment with lomitapide (Efficacy Phase), patients entered the Safety Phase at
`their established dose defined at Week 26 for an additional 52 weeks. The primary objective
`of this study was to evaluate the efficacy of lomitapide as defined by percent change from
`baseline in LDL-C at an individually-identified maximum tolerated dose after 26 weeks of
`treatment in patients with HoFH. Based on the assumptions of 25% change in LDL-C after
`26 weeks of treatment with a 30% SD and 15% dropout rate, 29 subjects were enrolled to
`obtain at least 90% power for the study. The clinical study report covers only the data and
`results through Week 56 based on the data cut-off date of 04/12/2011.
`
`
`
`
`
`Protocol UP1001 was a Phase 2, 16-week, open-label, single-arm, dose-escalation (0.03, 0.1,
`0.3, 1.0 mg/kg/day), single-center (in US) trial. In contrast to Study UP1002/AEGR-733-
`005, subjects in this trial were required to stop all lipid-lowering therapies including
`apheresis within 4 weeks prior to the Baseline visit and throughout the trial. In addition,
`subjects were asked to follow a rigorous low-fat diet with < 10% energy from fat and were
`provided a standard multivitamin supplying 100% of the current dietary reference intake
`(DRI) for all essential vitamins and minerals. The primary objective of this study was to
`evaluate the safety and tolerability of 4 doses of lomitapide. Evaluation of the efficacy (lipid
`panel) was secondary.
`
`3.1.2 Statistical Methods
`For Study UP1002/AEGR-733-005, the primary efficacy endpoint was percent change from
`baseline in LDL-C at Week 26 and was analyzed using paired t-test by the sponsor. This
`reviewer also analyzed the data using Wilcoxon signed-rank test which can accommodate
`small sample sizes and non-normality. The proportions of LDL-C responders defined as
`greater than 15%, 25%, and 50% decreases from baseline to Week 26/LOCF were
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`Statistical Review and Evaluation of Clinical Trials
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`summarized. There were 3 key secondary efficacy variables: total cholesterol (TC), Apo B,
`and triglycerides (TRIG). They were prioritized sequentially by the sponsor and analyzed
`using the same test to preserve the Type 1 error rate at α = 0.05. Other lipid variables such as
`non-HDL-C, VLDL-C, Lp(a), and HDL-C were also analyzed in a similar fashion, but
`without multiplicity adjustment. The baseline value was calculated as the average of
`Week -2 and Week 0 values. The ITT population consisting of subjects who had received at
`least one dose of lomitapide, and had a baseline and a post-baseline LDL-value was the
`primary population for efficacy analyses. Missing data at Week 26 were imputed using the
`LOCF method. Analyses based on the completers at Week 26 as well as at Week 56 were
`also performed to evaluate the impact of dropouts on efficacy.
`
`For Study UP1001, there was no formal statistical analysis plan developed. Although safety
`and tolerability were the primary interest of this study, percent change from baseline in LDL-
`C at Week 16 was the primary efficacy endpoint. For the ease of discussion, efficacy
`evaluation for this supportive study was performed similarly to the pivotal study.
`
`3.1.3 Subject Disposition
`For Study UP1002/AEGR-733-005, a total of 29 subjects were enrolled and treated with
`lomitapide. As of 04/12/2011 the data cut-off date, 6 patients discontinued from the trial
`prior to Week 26; 23 of the 29 enrolled patients completed Week 56; and 18 of the 23
`patients completed the entire 78-week trial. Among the 6 dropouts (21%), 3 (10%)
`discontinued due to withdrawn consent, 2 (7%) due to adverse event, and 1 (3%) due to non-
`compliance or lack of cooperation. Their final titrated doses were 5 mg (n = 2), 10 mg (n =
`2), 20 mg (n = 1), and 40 mg (n = 1). For Study UP1001, all the 6 enrolled subjects
`completed the trial.
`
`3.1.4 Demographic and Baseline Characteristics
`There were no geriatric (≥ 65 years) patients enrolled in these 2 studies. Most patients were
`White. Males and females were approximately equally distributed. Half of the population in
`each study had BMI < 25 kg/m2. As shown in Table 1, the mean baseline LDL-C in Study
`UP1001 (614.2 mg/dL) was much higher than that in Study UP1002/AEGR-733-005 (337.0
`mg/dL), as were the mean baseline values of TC, ApoB, and triglycerides. As explained by
`the sponsor, the high elevation in baseline lipids in Study UP1001 was due to the requirement
`of no lipid-lowering therapies within 4 weeks of the study entry; while in Study
`UP1002/AEGR-733-005, subjects were required to be on a stable regimen of their standard
`of care therapies during the run-in period. The majority of subjects in Study UP1002/AEGR-
`755-005 received their maximum tolerated doses of statins with or without ezetimibe at
`baseline.
`
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`
`
`Characteristic
`Age (years):
`
`
`
`
`Table 1 – Demographic and Baseline Characteristics – ITT Population
`
` UP1002/AEGR-733-005
`UP1001
`
`
`(N = 29)
`(N = 6)
`Mean ± SD
`30.7 ± 10.6
`25.0 ± 9.2
`
`Median
`
`30
`21.0
`Range
`
`18.0 – 55.0
`17.0 – 39.0
`
`
`Sex:
`
`
`Race:
`
`16 (55.2)
`13 (44.8)
`
`25 (86.2)
`2 (6.9)
`1 (3.4)
`1 (3.4)
`
`7 (24.1)
`5 (17.2)
`6 (20.7)
`11 (37.9)
`
`25.9 ± 5.5
`23.9
`19.3 – 41.3
`
`337.0 ± 113.8
`357.1
`152.4 – 565.0
`
`430.4 ± 135.3
`459.5
`191.4 – 721.6
`
`260.1 ± 80.1
`262.0
`124.0 – 431.5
`
`102.7 ± 47.8
`92.1
`31.9 – 253.0
`
`18 (62.1)
`11 (37.9)
`
`27 (93.1)
`2 (6.9)
`
`22 (75.9)
`7 (24.1)
`
`3 (50.0)
`3 (50.0)
`
`3 (50.0)
`1 (16.7)
`0
`2 (33.3)
`
`6 (100.0)
`0
`0
`0
`
`24.9 ± 4.0
`24.8
`18.5 – 30.2
`
`614.2 ± 105.8
`622.5
`480 – 789
`
`850.5 ± 194.8
`796.5
`684.0 – 1212.0
`
`310.0 ± 51.6
`309.0
`240.0 – 387.0
`
`282.8 ± 187.7
`259.0
`82.0 – 605.0
`
`NA
`NA
`
`NA
`NA
`
`NA
`NA
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Male (%)
`Female (%)
`
`
`
`
`
`
`
`
`
`
`White (%)
`
`Asian (%)
`Black or African American (%)
`Other (%)
`
`
`
`Country:
`
`
`
`
`
`BMI (kg/m2):
`
`
`
`USA (%)
`Canada (%)
`Italy (%)
`South Africa (%)
`
`Mean ± SD
`Median
`Range
`
`
`LDL-C (mg/dL): Mean ± SD
`
`Median
`
`Range
`
`Mean ± SD
`Median
`Range
`
`Mean ± SD
`Median
`Range
`
`Mean ± SD
`Median
`Range
`
`Yes (%)
`No (%)
`
`
`TC (mg/dL):
`
`
`
`
`ApoB (mg/dL):
`
`
`
`
`TRIG (mg/dL):
`
`
`
`
`Use of Apheresis: Yes (%)
`
`
`No (%)
`
`Use of Statins:
`
`
`
`Use of Ezetimibe: Yes (%)
`
`
`No (%)
`
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`3.1.5 Efficacy Results and Discussion
`Unless otherwise stated, all the tables and graphs presented in this report were generated by
`this reviewer.
`
`Primary Efficacy Endpoint. In Study UP1002\AEGR-733-005, after treatment with
`lomitapide, mean LDL-C in patients with HoFH was significantly reduced from 337.0 mg/dL
`at baseline to 191.3 mg/dL at Week 26 (Table 2). The mean % change from baseline in
`LDL-C at Week 26 in this pivotal trial was -40% based on the ITT/LOCF population (p <
`0.0001) and the median % change was -50%. In Study UP1001, mean LDL-C was also
`significantly reduced from 614.2 mg/dL at baseline to 303.0 mg/dL at Week 16. The mean
`and median % changes from baseline in LDL-C at Week 16 in this supportive trial were -
`51% and -52%, respectively (p < 0.0001).
`
`
`UP1001 (16-week)
`614.2 ± 105.8 (6)
`622.5
`480.0, 789.0
`303.0 ± 81.3 (6)
`303.5
`201.0, 403.0
`-50.9 ± 9.3 (6)
`(-60.7, -41.2)
`-52.3
`-62.4, -33.8
`< 0.0001
`0.0313
`
`Table 2 – Statistical Results for LDL-C (mg/dL)
`UP1002/AEGR-733-005 (26-week)
`ITT/LOCF population
`Baseline
`Mean ± SD (N)
`337.0 ± 113.8 (29)
`Median
`357.1
`Min, Max
`152.4, 565.0
`Endpoint Mean ± SD (N)
`191.3 ± 106.6 (29)
`Median
`169.4
`Min, Max
`28.0, 442.8
`% Change Mean ± SD (N)
`-39.6 ± 32.0 (29)
`95% CI
`(-51.8, -27.4)
`Median
`-49.6
`Min, Max
`-92.6, 20.5
`Paired t-test p-value
`< 0.0001
`Signed-rank test p-value
`< 0.0001
`Results were generated using the study-specific data extracted from the ISE ADaM dataset.
`
`There were 2 sites (Nos. 31 and 32, two patients each, all completers) showing larger mean
`% changes from baseline in LDL-C at Week 26 with very small standard deviations (-61% ±
`2.5% and -52% ± 0.7%) when compared to the other sites in the study. When the 2 sites
`were excluded from the primary efficacy analysis, similar results were observed (-37% ±
`34%, N = 25, p < 0.0001).
`
`For the completer cohort in Study UP1002/AEGR-733-005 (N = 23), similar significant
`findings were also observed (mean % change at Week 26 = -50%, p < 0.0001). The
`following Figure 1 depicts that the mean % reductions from baseline in LDL-C were 9%,
`15%, 27%, 44%, and 53% by Week 2, 6, 10, 14, and 18, respectively, where the
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`
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`corresponding mean doses were 5, 10, 18, 33, and 40 mg, implying that the reductions in
`LDL-C were increasing as the doses were increased during the titration period. Then the
`mean % reduction was reduced to 50% by Week 26 with a mean dose of 45 mg, and further
`reduced to around 40%-45% between Weeks 36 and 56 with mean doses around 40 mg. At
`Week 26, the mean % reductions in LDL-C associated with the 5, 10, 20, 40, and 60 mg
`doses were 51% (n = 1), NA (n = 0), 38% (n = 5), 57% (n = 6), and 55% (n = 10),
`respectively. One patient received 80 mg at Week 26 and experienced a 29% reduction in
`LDL-C. In Study UP1001, the mean % reductions from baseline in LDL-C were small and
`insignificant during the 1st half of the study, which was probably due to the small doses used
`(2 mg at Week 4 and 7 mg at Week 8). By Week 12, the mean dose was increased to 20 mg
`and the mean % reduction was 25%. At the end of the 16-week study, 51% mean reduction
`in LDL-C was observed and it was associated with a higher mean dose of 67 mg.
`
`
`
`
`Figure 2
`Study UP1001: LDL-C (mg/dL)
`Completers (N = 6)
`
`-3.74
`
`7.14
`
`-24.71
`*
`
`4
`
`12
`8
`Nominal Visit Week
`
`-50.94
`*
`16
`
`
`
`0
`
`-10
`
`-20
`
`-30
`
`-40
`
`-50
`
`-60
`
`Mean % Change from Baseline in LDL-C
`
`Figure 1
`
`
`
`
`
`Study UP1002/AEGR-733-005: LDL-C (mg/dL)
`Completers (N = 23)
`
`-8.94
`
`-15.03
`*
`
`-26 59
`*
`
`-43.68
`*
`
`-40.82
`*
`
`-42.87
`*
`
`-39.59
`*
`
`-43.96
`*
`
`-49 -50.2
`*
`*
`-53.19
`*
`36
`26
`22
`18
`Nominal Visit Week
`
`2
`
`6
`
`10
`
`14
`
`46
`
`56
`
`26/LOCF
`(N
` 29)
`
`0
`
`-10
`
`-20
`
`-30
`
`-40
`
`-50
`
`-60
`
`Mean % Change from Baseline in LDL-C
`
`
`
` Significant at p < 0.05
`
`* = Significant at p < 0.05
`
`
`Slightly more than 2/3 of the 29 patients in the pivotal trial and all of the 6 enrolled patients
`in the supportive trial had greater than 15% of decrease in LDL-C from baseline at the end of
`the efficacy phase (Table 3). From Figures 3 and 4 below, one can easily obtain the % of
`subjects achieving a given level of response for any definition of responders. There were 4
`patients (14%) in Study UP1002/AEGR-733-005 with an increased LDL-C from baseline
`after 26 weeks of treatment with lomitapide.
`
`
`
`
`
`
`Table 3 – Responders for LDL-C (mg/dL)
`UP1002/AEGR-733-005
`Yes
`Yes
`No
`6/6 (100%)
`> 15% reduction from baseline to Week 26/LOCF 20/29 (69%) 9/29 (31%)
`> 25% reduction from baseline to Week 26/LOCF 19/29 (66%) 10/29 (34%) 6/6 (100%)
`> 50% reduction from baseline to Week 26/LOCF 14/29 (48%) 15/29 (52%) 5/6 (83%)
`
`UP1001
`
`No
`
`0
`0
`1/6 (17%)
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`NDA 203-858/N-000
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`
`
`Figure 4
`Study UP1001: LDL-C (mg/dL)
`Cumulative Distribution Function (N = 6)
`
`-70
`
`-60
`
`-20
`-30
`-40
`-50
`% Change from Baseline at Week 16
`
`-10
`
`0
`
`
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`% of Subjects in ITT Population
`
`
`
`
`
`Statistical Review and Evaluation of Clinical Trials
`
`Figure 3
`
`
`
`Study UP1002/AEGR-733-005: LDL-C (mg/dL)
`Cumulative Distribution Function (N = 29)
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`% of Subjects in ITT Population
`
`0
`-100 -90
`
`10
`0
`-10
`-20
`-30
`-40
`-50
`-60
`-70
`-80
`% Change from Baseline at Week 26/ LOCF
`
`20
`
`30
`
`
`Key Secondary Efficacy Endpoints. As Table 4 shows, lomitapide significantly reduced
`total cholesterol (TC), ApoB, and triglycerides (TRIG) in patients with HoFH after 26 weeks
`of treatment in Study UP1002/AEGR-733-005 and after 16 weeks of treatment in Study
`UP1001 (all p < 0.05).
`
`
`
`
`Study
`
`UP1002
`/AEGR-
`733-005
`
`Table 4 – Statistical Results for % Change from Baseline for Key Secondary Efficacy Endpoints
`ITT/LOCF
`TC (mg/dL)
`ApoB (mg/dL)
`TRIG (mg/dL)
`Ln TRIG
`Population
`(mg/dL)
`Mean ± SD (N)
`-35.7 ± 29.4 (29)
`-39.3 ± 30.3 (29)
`-28.2 ± 57.6 (29)
`-0.60 ± 0.75 (29)
`95% CI
`(-46.9, -24.5)
`(-50.8, -27.8)
`(-50.1, -6.3)
`(-0.88, -0.31)
`Median
`-40.0
`-46.2
`-44.5
`-0.59
`Min, Max
`-81.4, 24.2
`-90.4, 19.0
`-87.4, 169.4
`-2.07, 0.99
`Paired t-test p
`< 0.0001
`< 0.0001
`0.0136
`0.0002
`Signed-rank test p
`< 0.0001
`< 0.0001
`0.0023
`< 0.0001
`UP1001 Mean ± SD (N)
`-58.4 ± 8.6 (6)
`-55.6 ± 13.5 (6)
`-65.2 ± 13.3 (6)
`-1.12 ± 0.39 (6)
`95% CI
`(-67.4, -49.3)
`(-69.7, -41.4)
`(-79.1, -51.3)
`(-1.53, -0.71)
`Median
`-56.7
`-57.0
`-68.2
`-1.15
`Min, Max
`-68.7, -50.3
`-70.0, -36.8
`-82.1, -43.9
`-1.72, -0.58
`Paired t-test p
`< 0.0001
`0.0002
`< 0.0001
`0.0009
`Signed-rank test p
`0.0313
`0.0313
`0.0313
`0.0313
`Results were generated using the study-specific data extracted from the ISE ADaM dataset.
`Note: The raw TRIG data in Study UP1002/AEGR-733-005 were not normally distributed.
`Ln TRIG = Log-transformed triglycerides
`
`The response patterns of TC, ApoB, and TRIG over time in both studies (Figures 5 and 6)
`were similar to that of the primary efficacy variable, LDL-C (Figures 1 and 2). That is, in the
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`pivotal study, the reductions were seen as early as Week 2 and were continuously decreased
`
`until Week 18, then slightly went back up, but were sustained through Week 56 (except for
`
`TRIG of which reduction at Week 56 was smaller). In the supportive study, the reductions
`were continuous until the end of the trial.
`
`Figure 5
`
`Figure 6
`
`Study UP1002/AEGR—733—005: Secondary Variables
`C
`I
`(N = B)
`+1131“ +WHII-l +135“
`
`sud-V “1°01: 3““de “"3ka
`Cowleuls (N — 6)
`+ 70m + Anal-Ml) + “KN-W)
`
`
`I
`a
`E
`g
`fl
`5
`5
`:Q
`E
`8
`Z
`
` E
`
`In
`o
`
`E
`E
`a!
`40
`E
`i -20
`E a”
`U 40
`.\'
`I:
`60
`8
`2'
`40
`>10
`
`1
`4
`
`1
`1
`12
`a
`Noni-alVifl't‘Veek
`
`1
`10
`
`Other Efficacy Endpoints. As Table 5 shows, lomitapide also significantly reduced non-
`
`HDL—C and VLDL-C in patients with HoFH afier 26 weeks of treatment in Study
`
`UP1002/AEGR—733-005 and after 16 weeks of treatment in Study UP1001 (nominal p <
`
`0.05). The reductions in Lp(a) and I-IDL-C at the end of the efficacy phase in both studies
`
`were observed, but not statistically significant.
`
`Table 5 — Statistical Results for % Change from Baseline for Other Efficacy Endpoints
`
`Population
`
`(mg/dL)
`
`(mg/dL)
`
`UP1002 Mean i SD (N)
`
`-39.2 i 31.1 (29)
`
`-27.9 i 58.4 (29)
`
`-10.6 i 33.9 (29)
`
`-7.0 i 19.7 (29)
`
`95% CI
`733-005 Median
`
`(-51.1, -27.4)
`-47.7
`
`(-50.1. -5.7)
`-45.1
`
`(-23.5. +2.3)
`-l3.4
`
`(-l4.5, +0.6)
`-5.6
`
`
`
`Min, Max
`
`-89.7, 25.9
`
`-87.5, 175.0
`
`-62.9. 88.1
`
`-48.5. 28.3
`
`Paired t-test p
`
`Signed-rank test p
`
`< 0.0001
`
`< 0.0001
`
`0.0155
`
`0.0021
`
`0.1034
`
`0.0324
`
`0.0683
`
`0.0751
`
`Mean 5: SD (N)
`
`-60.1 :I: 8.9 (6)
`
`-78.7 i 23.1 (6)
`
`-1o.5 :I: 20.5 (6)
`
`-2.2 i 18.0 (6)
`
`95% CI
`
`Median
`
`(-69.4, -50.8)
`
`(403.0. -54.5)
`
`(32.0. +11.0)
`
`(-21.1, +16.7)
`
`-58.7
`
`-88.8
`
`-16.1
`
`-9.9
`
`Min Max
`
`-70.5, -52.1
`
`-93.3, -33.3
`
`-36.1, 18.8
`
`-18.5. 30.0
`
`Paired t-test p
`
`< 0.0001
`
`Signed-rank test p
`
`0.0313
`
`0.0004
`
`0.0313
`
`0.2632
`
`0.2188
`
`0.7742
`
`0.5625
`
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`Statistical Review and Evaluation of Clinical Trials
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`NDA 203-858/N—000
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`
`
`Results were generated using the study-specific data extracted from the [SE ADaM dataset.
`
`Note: The raw VLDL-C data in both studies were not normally distributed.
`
`Note: The raw Lp(a) data in Study UPIOOZ/AEGR—733-005 were not normally distributed.
`
`In the pivotal study, the response patterns of non-HDL-C and VLDL-C over time were
`
`similar to that of LDL-C and TRIG, respectively. As exhibited in Figure 7, the reductions in
`
`HDL—C from baseline were continued through Week 18, and then were gradually reversed to
`
`the baseline level at Week 56. In contrast to the pivotal study, mean HDL—C in the
`
`supportive study was increased from Week 4 to Week 12, and then decreased back to the
`
`baseline level at Week 16 (Figure 8).
`
`Figure 7
`
`Figure 8
`
`Study UPIOOZIAEGR—733—005: on." Variables
`WW=B)
`+ M + m4: + ma) + II“:
`mm
`mm
`(—qu
`my
`
`
`S‘m'Y “32:1: 0‘3: g'fi‘bks
`_
`—0— man. + VLDL-c —I— up)
`—0— "DH:
`m,
`m)
`(mm
`t-I'Il-l
`
`
`
`
`
`Mun'/oChangefromBaseline
`
`3a5
`
`
`
`sssssssseassss
`sssss‘
`Mean'/uChangefromBasellne
`
`
`
`3.2 Evaluation of Safety
`
`In consultation with the reviewing medical officer, there were no aspects of safety that
`
`required review by a statistician. See Dr. James Smith’s report for safety evaluation.
`
`4. FINDINGS IN SPECIAL/SUBGROUP POPULATIONS
`
`4.1 Gender, Race, and Age
`
`In the pivotal study, mean % decreases from baseline in LDL—C at Week 26/LOCF were
`
`similar between males and females (-40% vs. -39%), between age < 30 years and Z 30 years
`
`(-39% vs. -40%), and between White and non-White (-40% vs. -3 5%).
`
`4.2 Other Special/Subgroup Populations
`
`In the pivotal study, mean % decreases from baseline in LDL-C at Week 26m0CF were
`
`similar between US/Canada and other countries (-32% vs. -45%), between baseline BMI <
`30 and 2 30 kg/m2 (-40% vs. -3 7%), and between the use (yes or no) of apheresis at entry
`
`(-34% vs. —49%).
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`Statistical Review and Evaluation of Clinical Trials
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`NDA 203-858/N-000
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`
`As seen in Figure 9, there was a negative, but weak, correlation between the baseline LDL-C
`(x-axis) and % change from baseline in LDL-C at Week 26/LOCF (y-axis) in Study
`UP1002/AEGR-733-005.
`
`
` Figure 9
`
`
`
`
`
`
`
`
`
` Figure 10
`
`
`
`
`
`
`5. SUMMARY AND CONCLUSIONS
`5.1 Statistical Issues and Collective Evidence
`As shown in Table 6, for the pivotal Phase 3 trial (Study UP1002/AEGR-733-005), the mean
`% decrease in LDL-C from baseline to Week 26 was about 40% for the ITT/LOCF
`population (N = 29) and 50% for the completers (N = 23). In addition, a total of 20 patients
`had a > 15% decrease in LDL-C at Week 26. Although the study was not designed as a
`dose-response trial, it was noted that the mean % reductions in LDL-C were increasing as
`doses were increased over the ti