CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208082Orig1s000
`
`STATISTICAL REVIEW(S)
`
`
`
`
`
`
`
`

`

`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
`
`
`
`
`
`S T A T I S T I C A L R E V I E W A N D E V A L U A T I O N
`
`C L I N I C A L S T U D I E S
`
`NDA Number:
`
`208,082
`
`Drug Name:
`
`Austedo (deutetrabenazine)
`
` Tablet
`
`Indication:
`
`Applicant:
`
`Dates:
`
`
`
`Treatment of Chorea Associated with Huntington's Disease
`
`Teva Pharmaceuticals, Inc.
`
`Receipt Date: May 29, 2015
`
`PDUFA Goal Date: May 29, 2016
`
`Review Priority:
`
`Standard
`
`Biometrics Division:
`
`Division of Biometrics I
`
`Statistical Reviewer:
`
`Xiangmin Zhang, Ph.D.
`
`Concurring Reviewers: Kun Jin, Ph.D., Team Leader
`
`Hsien Ming Hung, Ph.D., Director
`
`Medical Division:
`
`Division of Neurology Products
`
`Clinical Team:
`
`Kenneth Bergmann, M.D., Clinical Reviewer
`
`Gerald Podskalny, D.O., Team Leader
`
`Eric Bastings, M.D., Deputy Director
`
`William Dunn, M.D., Director
`
`Stacy Metz, Pharm.D.
`Project Manager:
`Keywords: analysis of covariance, clinical studies, mixed models, NDA review
`
`Reference ID: 3889120
`
`(b) (4)
`
`

`

`TABLE OF CONTENTS
`
`TABLE OF CONTENTS ............................................................................................................. 2
`LIST OF TABLES ........................................................................................................................ 3
`LIST OF FIGURES ...................................................................................................................... 4
`1 EXECUTIVE SUMMARY .................................................................................................... 5
`2
`INTRODUCTION .................................................................................................................. 5
`2.1 OVERVIEW .......................................................................................................................... 5
`2.2 DATA SOURCES .................................................................................................................. 5
`3 STATISTICAL EVALUATION ........................................................................................... 6
`3.1 DATA AND ANALYSIS QUALITY .......................................................................................... 6
`3.2 EVALUATION OF EFFICACY ................................................................................................. 6
`3.2.1 Study Design and Endpoints ....................................................................................... 6
`3.2.2 Statistical Methodologies ............................................................................................ 7
`3.2.3 Patient Disposition, Demographic and Baseline Characteristics ................................ 8
`3.2.4 Results and Conclusions ........................................................................................... 10
`3.3 EVALUATION OF SAFETY .................................................................................................. 14
`4 FINDINGS IN SPECIAL/SUBGROUP POPULATIONS ............................................... 14
`4.1 GENDER, RACE, AGE, AND GEOGRAPHIC REGION ............................................................ 14
`4.2 OTHER SPECIAL/SUBGROUP POPULATIONS ....................................................................... 17
`5 SUMMARY AND CONCLUSIONS................................................................................... 17
`5.1 STATISTICAL ISSUES ......................................................................................................... 17
`5.2 COLLECTIVE EVIDENCE .................................................................................................... 17
`5.3 CONCLUSIONS AND RECOMMENDATIONS ......................................................................... 17
`
`
`
`
`
`Reference ID: 3889120
`
`2
`
`

`

`LIST OF TABLES
`
`Table 1. Summary of the efficacy study reviewed ..................................................................... 5
`Table 2. Dose levels and tablet numbers by dose for SD-809 treatment .................................. 6
`Table 3. Study SD-809-C-15 patient demographic and baseline characteristics, ITT
`population ....................................................................................................................... 9
`Table 4. Study SD-809-C-15 analyses of efficacy endpoints, mITT population .................... 13
`Table 5. Study SD-809-C-15 analysis of primary endpoint by gender, mITT population ... 14
`Table 6. Study SD-809-C-15 analyses of secondary endpoints by gender, mITT population
`........................................................................................................................................ 15
`Table 7. Study SD-809-C-15 analysis of primary endpoint by age, mITT population ......... 16
`Table 8. Study SD-809-C-15 analyses of secondary endpoints by age, mITT population ... 16
`
`
`
`
`3
`
`Reference ID: 3889120
`
`

`

`LIST OF FIGURES
`
`
`Figure 1. Study SD-809-C-15 patient disposition ....................................................................... 8
`Figure 2. Study SD-809-C-15 mean (± standard error) of total maximal chorea score by
`week and treatment .................................................................................................... 10
`Figure 3. Study SD-809-C-15 mean (± standard error) of change from Baseline in total
`maximal chorea score by week and treatment ........................................................ 11
`
`Figure 4. Distribution of Patient Global Impression of Change at Week 12......................... 12
`
`Figure 5. Distribution of Clinical Global Impression of Change at Week 12 ....................... 12
`
`
`
`
`
`
`
`
`
`Reference ID: 3889120
`
`4
`
`

`

`1 EXECUTIVE SUMMARY
`
`This review describes the statistical findings of Austedo as a treatment of chorea associated with
`Huntington’s disease. The review confirmed that Study SD-809-C-15 in the 505(b)(2) new drug
`application provided efficacy evidence that Austedo is efficacious as a treatment of chorea
`associated with Huntington’s disease: Austedo
` tablet is statistically better than
`placebo in terms of change from Baseline to maintenance in total maximal chorea score.
`
` 2
`
` INTRODUCTION
`
`
`2.1 Overview
`
`On May 29, 2015, Teva Pharmaceuticals, Inc. (the sponsor) submitted a 505(b)(2) new drug
`application (NDA) for Austedo (deutetrabenazine or SD-809 under the sponsor’s clinical
`development program) as a treatment of chorea associated with Huntington’s disease (HD). The
`NDA submission lists FDA approved drug Xenazine® (NDA 021,894) as the 505(b)(2)
`reference. The phase 3 study in the NDA application to support the efficacy claim of SD-809 is
`summarized in Table 1. The phase 3 study is reviewed in more details in section 3 of this review.
`
`
`Table 1. Summary of the efficacy study reviewed
`
`Source: Table 1 on page 11 of sponsor’s clinical overview
`
`
`2.2 Data Sources
`
`The electronic submission of this NDA is located at
`\\cdsesub1\evsprod\NDA208082\
`The study report is located at
`\\cdsesub1\evsprod\NDA208082\0003\m5\53-clin-stud-rep\535-rep-effic-safety-
`stud\chorea\5351-stud-rep-contr\
`The datasets are located at
`\\cdsesub1\evsprod\NDA208082\0003\m5\datasets\
`
`
`
`
`
`
`
`
`Reference ID: 3889120
`
`
`
`5
`
`(b) (4)
`
`

`

`3 STATISTICAL EVALUATION
`
`3.1 Data and Analysis Quality
`
`The data quality and analysis quality are adequate. The reviewer was able to perform
`independent review using sponsor’s submitted datasets and confirm sponsors’ analysis results.
`
`3.2 Evaluation of Efficacy
`
`3.2.1 Study Design and Endpoints
`
`Study SD-809—C—15 was a double-blind, placebo-controlled, randomized, 2-arm, parallel—group,
`phase 3, multi-national, multi-center study to evaluate the efficacy, safety and tolerability of SD-
`809 as a treatment of chorea associated with Huntington’s disease. A total of 90 patients were
`planned to be randomized in a 1:1 ratio to placebo and SD-809. Patients were screened in 34
`study centers in the United States and Canada.
`
`The study consisted of a screening period of up to 4 weeks, an 8-week titration period, a 4-week
`maintenance period, and a 1-week washout. The overall treatment period was 12 weeks.
`
`Table 2. Dose levels and tablet numbers by dose for SD—809 treatment
`
`romwauvnose
`
`l
`
`6 111g
`Tablets
`
`6 111g
`1 x 6 1112
`
`Placebo
`l x Placebo tablet
`
`
`
`1 x 12 1119. and l x 91112
`
`
`
`30 mg
`Tablets
`
`-
`
`15 mg
`1 x 9 mg and l x 61112
`
`21mg7
`
`21mg
`
`1 x 131112 and l x 91112
`
`Tablets
`
`Note: SD-SO9 800w strengths include 6. 9. and 12 mg tablets.
`
`Source: Table 2 on page 32 ofprotocol amendment 2
`
`Reference ID: 38891 20
`
`

`

`The treatment regimen is summarized in Table 2. For each patient assigned the SD-809
`treatment, his/her study mediation started from 6 mg per day and followed the dose level in
`which adequate chorea control had been achieved and the patient was tolerating the treatment
`regimen or until which the maximum permitted dose was reached. If the patient was receiving a
`strong CYP2D6 inhibitor, such as bupropion, fluoxetine, and paroxetine, the maximal total daily
`dose was 36 mg.
`
`The primary efficacy endpoint was change from Baseline to maintenance in total maximal
`chorea (TMC) score. The TMC score is the sum of seven items under the Unified Huntington’s
`Disease Scale (1999 version). Each of the seven items measures the maximal chorea of a body
`part and ranges from 0 to 4, with 0 representing absent chorea and 4 representing
`marked/prolonged chorea. The range of the TMC score is 0 to 28. The Baseline TMC score was
`defined as the mean of the TMC scores at the Screening and at Day 0 visit and the maintenance
`TMC score was defined as the mean of the TMC scores at Week 9 and at Week 12. For the
`calculation of TMC score at each visit, when less than 20% of the items for the TMC score were
`missing, the most recent previous non-missing values of the missing items were used for
`imputation; otherwise, the TMC score of that visit was considered missing. When a patient
`missed a TMC score at the Screening or Day 0 visit, the Baseline TMC score was the available
`TMC score. When a patient missed a TMC score at either Week 9 or Week 12, the maintenance
`TMC score was the available TMC score. When a patient missed both TMC scores at Week 9
`and at Week 12, the maintenance TMC score was the last available post-baseline TMC score.
`
`The secondary efficacy endpoints were
` The proportion of patients who were a treatment success at the end of therapy, based on the
`Patient Global Impression of Change (PGIC). A treatment success was defined as Much
`Improved or Very Much Improved on the PGIC at the Week 12 visit.
` The proportion of patients who were a treatment success at the end of therapy, based on the
`Clinical Global Impression of Change (CGIC). A treatment success was defined as Much
`Improved or Very Much Improved on the CGIC at the Week 12 visit.
` Change from Baseline (Day 0) to Week 12 in the Short From 36 Health Survey (SF-36)
`Physical Functioning score
` Change from Baseline (Day 0) to Week 12 in the Berg Balance Test (BBT) score.
`
`3.2.2 Statistical Methodologies
`
`The primary analysis was performed on the modified intent-to-treat (mITT) population using an
`analysis of covariance (ANCOVA) model with treatment as a factor and Baseline TMC as the
`covariate. The mITT population was defined as all randomized patients who received treatment
`and had at least one post-baseline assessment of the TMC score.
`
`The secondary endpoints of PGIC and CGIC were analyzed on the mITT population using
`Pearson’s chi-square test. The secondary endpoints of SF-36 Physical Functioning score and
`BBT score were analyzed on the mITT population using ANCOVA models with treatment as a
`factor and endpoint specific baseline as the covariate.
`
`
`
`
`7
`
`Reference ID: 3889120
`
`

`

`In order to handle the multiplicity of secondary endpoints, the secondary endpoints were to be
`tested sequentially in the following order: PGIC, CGIC, SF-36 Physical Functioning score, and
`BBT score. Each test was conducted at the two-sided significance level α = 0.05.
`
`3.2.3 Patient Disposition, Demographic and Baseline Characteristics
`
`
`Figure 1. Study SD-809-C-15 patient disposition
`
`
`
`Source: Figure 1 on page 56 of sponsor’s clinical study report
`
`
`The patient disposition is presented in Figure 1. A total of 123 patients were screened, of which
`90 (73.2%) randomized. Among the 90 randomized patients, 45 (50.0%) were randomized to the
`placebo group and 45 (50.0%) to the SD-809 group. A total of 87 patients completed the study:
`43 in the placebo group and 44 in the SD-809 group. One patient in the placebo group and one
`patient in the SD-809 group dropped out due to adverse event. One patient in the placebo group
`dropped out due to physician decision.
`
`
`
`
`8
`
`Reference ID: 3889120
`
`

`

`Table 3. Study SD-809-C-15 patient demographic and baseline characteristics, ITT
`population
`
`
`
`Source: Tables 8 on page 60 of sponsor’s clinical study report
`
`
`The patient demographic characteristics of the intent-to-treat (ITT) population, defined as all
`patients randomized and treated, are summarized in Table 3. The ITT population of Study SD-
`809-C15 happened to be the same as the mITT population. The treatment groups did not appear
`similar in terms of age, gender, race, or mean TMC score at Baseline. The ITT population was
`mainly White patients and had an average age of approximately 54 years. There were noticeably
`more males than females in the placebo group but more females than males in the SD-809 group.
`A chi-squared test performed independently by the reviewer did not imply that the gender and
`treatment group assignment are dependent.
`
`
`
`9
`
`Reference ID: 3889120
`
`

`

`3.2.4 Results and Conclusions
`
`
`Figure 2. Study SD-809-C-15 mean (± standard error) of total maximal chorea score
`by week and treatment
`
`
`
`Source: Figure 3 on page 75 of sponsor’s clinical study report
`
`
`Figure 2 illustrates the means of TMC score by week and treatment for the ITT population (or
`equivalently, the mITT population). The means of TMC score at Baseline did not appear similar
`for the two treatment groups. There appeared some placebo effect because the means of TMC
`score of the placebo group decreased from Baseline during the treatment period. After the
`washout period, the mean TMC scores at Week 13 of both treatment groups appeared to return to
`the Baseline levels.
`
`
`
`
`10
`
`Reference ID: 3889120
`
`

`

`Figure 3. Study SD-809-C-15 mean (± standard error) of change from Baseline in total
`maximal chorea score by week and treatment
`
`
`
`Source: reviewer
`
`
`Figure 3 illustrates the means of change from Baseline in TMC score by week and treatment for
`the ITT population (or equivalently, the mITT population). The figure shows that the SD-809
`treatment group had consistent improvements of TMC score over the treatment period until
`Week 12. Although the placebo treatment group also had improvements of TMC score over the
`treatment period, the improvements in the SD-809 group was on average greater than the ones in
`the placebo group after Week 4 until the washout period.
`
`
`
`
`11
`
`Reference ID: 3889120
`
`

`

`Figure 4. Distribution of Patient Global Impression of Change at Week 12
`
`-3: Very Much Worse; -2: Much Worse; -1: Minimally Worse; 0: Not Change;
` 1: Minimally Improved; 2: Much Improved; 3: Very Much Improved.
`
`Source: reviewer
`
`
`
`Figure 5. Distribution of Clinical Global Impression of Change at Week 12
`
`-3: Very Much Worse; -2: Much Worse; -1: Minimally Worse; 0: Not Change;
` 1: Minimally Improved; 2: Much Improved; 3: Very Much Improved.
`
`Source: reviewer
`
`
`
`
`
`Reference ID: 3889120
`
`
`
`
`
`12
`
`

`

`Figure 4 and Figure 5 illustrate the distributions of PGIC and CGIC by treatment at Week 12,
`without imputation for the two patients in the placebo group that did not have the Week 12 PGIC
`or CGIC. Both figures show that, compared to patients in the placebo group, more patients in the
`SD-809 group were in the categories of Much Improved or Very Much Improved at Week 12.
`
`
`Table 4. Study SD-809-C-15 analyses of efficacy endpoints, mITT population
`
`
`
`Source: efficacy table on page 7 of sponsor’s clinical study report
`
`
`The analysis results of the primary endpoint are presented in Table 4. SD-809 was statistically
`significantly better than placebo (p-value < 0.0001) in terms of change from Baseline to
`maintenance in TMC score, with a least square SD-809-placebo difference of -2.49 points (95%
`CI = (-3.69, -1.29)). The analysis using a mixed effect model repeated measures (MMRM)
`confirmed that SD-809 was statistically better than placebo. The low dropout rates (2.2% and
`4.4% for the SD-809 group and placebo group, respectively) and the MMRM results implied that
`the primary analysis results were reasonably robust.
`
`The analysis results of the secondary endpoints are also presented in Table 4. Following the pre-
`specified step-wise testing procedure, SD-809 were statistically significantly better than placebo
`
`
`
`13
`
`Reference ID: 3889120
`
`

`

`in terms of PGIC, CGIC, and SF-36 Physical Functioning score (p-values = 0.0020, 0.0022, and
`0.0308, respectively). The analyses of the secondary endpoints of PGIC, CGIC and BBT used
`the last available observations when the Week 12 measurement was not available. More
`specifically, the last available observations were carried forward for two patients in the placebo
`group because those patients did not have Week 12 measurements. The analysis of SF-36
`physical functioning score did not use any imputation for missing Week 12 measurements. The
`reviewer independently performed ANCOVA analyses on PGIC, CGIC and BBT without using
`imputation and on SF-36 physical functioning score carrying the last available observations for
`patients missing Week 12 measurements. The alternate approaches for dealing with missing data
`did not indicate different statistical conclusions for these secondary endpoints.
`
`3.3 Evaluation of Safety
`
`Please refer to Dr. Kenneth Bergmann’s clinical review for a detailed evaluation of safety.
`
` 4
`
` FINDINGS IN SPECIAL/SUBGROUP POPULATIONS
`
`
`Overall, there is no compelling evidence from the subgroup analyses in Section 4.1 that a specific
`gender, race, age, or geographic region subgroup benefits differently from SD-809.
`
`4.1 Gender, Race, Age, and Geographic Region
`
`Gender
`
`
`Table 5. Study SD-809-C-15 analysis of primary endpoint by gender, mITT population
`
`Gender
`
`Change from
`Baseline to maintenance
`in TMC score
`
`Placebo
`
`SD-809
`
`Female
`
`Male
`
`N
`Means (SD)a
`N
`Means (SD)a
`mITT: modified intent-to-treat; N: number of mITT patients; SD: standard deviation; TMC: total maximal chorea.
`a Obtained from all observations in the gender specific mITT population at maintenance, with the last observation carried forward
`method for missing data.
`
`17
`-2.65 (2.685)
`28
`-1.59 (2.621)
`
`23
`-4.91 (2.453)
`22
`-3.80 (3.362)
`
`Source: reviewer
`
`
`
`
`
`Reference ID: 3889120
`
`14
`
`

`

`Table 6. Study SD-809-C-15 analyses of secondary endpoints by gender, mITT population
`
`Gender
`
`CGIC or PGIC at Week 12
`
`Placebo
`
`SD-809
`
`Female
`
`Male
`
`N
`PGIC Treatment Success n (%)a
`CGIC Treatment Success n (%)a
`N
`PGIC Treatment Success n (%)a
`CGIC Treatment Success n (%)a
`CGIC: Clinical Global Impression of Change; mITT: modified intent-to-treat; N: number of mITT patients; PGIC: Patient Global
`Impression of Change.
`a Obtained based on all observations in the gender specific mITT population at Week 12, with the last observation carried forward
`method for missing data.
`
`17
`4 (23.5)
`4 (23.5)
`28
`5 (17.9)
`2 ( 7.1)
`
`23
`14 (60.9)
`9 (39.1)
`22
`9 (40.9)
`10 (45.5)
`
`Source: reviewer
`
`
`For both gender groups, SD-809 appeared superior to placebo in terms of mean change from
`Baseline to maintenance in TMC score, PGIC success number and percentage at Week 12, and
`CGIC success number and percentage at Week 12.
`
`Race
`
`As shown in Table 3, the majority (83 out of 90 patients) of the mITT population was White.
`There were only five and two patients in the Black population and multiple race population,
`respectively. The numbers are so small that the analysis of Black patients and multiple race
`patients would not provide conclusive results on these populations. Therefore, the reviewer did
`not perform subgroup analysis by race.
`
`
`
`
`
`
`
`15
`
`Reference ID: 3889120
`
`

`

`Age
`
`
`Table 7. Study SD-809-C-15 analysis of primary endpoint by age, mITT population
`
`Age
`
`Change from
`Baseline to maintenance
`in TMC score
`
`Placebo
`
`SD-809
`
`< 65 years N
`Means (SD)a
`≥ 65 years N
`Means (SD)a
`mITT: modified intent-to-treat; N: number of mITT patients; SD: standard deviation; TMC: total maximal chorea.
`a Obtained from all observations in the age group specific mITT population at maintenance, with the last observation carried
`forward method for missing data.
`
`35
`-2.17 (2.810)
`10
`-1.35 (2.082)
`
`38
`-4.22 (2.844)
`7
`-5.14 (3.637)
`
`Source: reviewer
`
`
`
`Table 8. Study SD-809-C-15 analyses of secondary endpoints by age, mITT population
`
`Age
`
`CGIC or PGIC at Week 12
`
`Placebo
`
`SD-809
`
`< 65 years N
`PGIC Treatment Success n (%)a
`CGIC Treatment Success n (%)a
`≥ 65 years N
`PGIC Treatment Success n (%)a
`CGIC Treatment Success n (%)a
`CGIC: Clinical Global Impression of Change; mITT: modified intent-to-treat; N: number of mITT patients; PGIC: Patient Global
`Impression of Change.
`a Obtained based on all observations in the age group specific mITT population at Week 12, with the last observation carried
`forward method for missing data.
`
`35
`7 (20.0)
`6 (17.1)
`10
`2 (20.0)
`0 ( 0.0)
`
`38
`20 (52.6)
`16 (42.1)
`7
`3 (42.9)
`3 (42.9)
`
`Source: reviewer
`
`
`For both age groups, SD-809 appeared superior to placebo in terms of mean change from
`Baseline to maintenance in TMC score, PGIC success number and percentage at Week 12, and
`CGIC success number and percentage at Week 12.
`
`Geographic Region
`
`Study SD-809 was conducted mainly in the United States. A total of 7 out of the 90 patients in
`the mITT population were from the three Canadian study centers. Therefore, the reviewer did not
`conduct subgroup analysis by region.
`
`
`
`
`16
`
`Reference ID: 3889120
`
`

`

`4.2 Other Special/Subgroup Populations
`
`No other subgroups were analyzed.
`
` 5
`
` SUMMARY AND CONCLUSIONS
`
`
`5.1 Statistical Issues
`
`No statistical issues were identified.
`
`5.2 Collective Evidence
`
`Study SD-809-C-15 provided efficacy evidence that Austedo is efficacious as a treatment of
`chorea associated with Huntington’s disease: Austedo
` tablet is statistically
`better than placebo in terms of change from Baseline to maintenance in total maximal chorea
`score.
`
`5.3 Conclusions and Recommendations
`
`Based on the statistical evidences from Study SD-809-C-15, the reviewer concluded that
`Austedo
` tablet is superior to placebo in treating chorea associated with
`Huntington’s disease.
`
`
`
`
`17
`
`Reference ID: 3889120
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`XIANGMIN ZHANG
`02/18/2016
`
`KUN JIN
`02/19/2016
`I concur with the review.
`
`HSIEN MING J HUNG
`02/19/2016
`
`Reference ID: 3889120
`
`