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

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`CLINICAL REVIEW
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`2ND REVIEW CYCLE – COMPLETE RESPONSE
`
`Application Type NDA 505(b)(2)
`Application Number 208082
`Priority or Standard Class 2 Resubmission
`
`Submit Date 2016 October 03
`Received Date 2016 October 03
`PDUFA Goal Date 2017 April 03
`Division / Office DNP / ODE1 / OND
`
`Reviewer Name(s) Kenneth Bergmann, MD
`Review Completion Date 2017 February 27
`
`Established Name Deutetrabenazine (SD-809)
`(Proposed) Trade Name Austedo
`Therapeutic Class VMAT2 inhibitor
`Applicant Teva Pharmaceuticals, Inc.
`
`Formulation Oral tablets: 6, 9, and12 mg
`Dosing Regimen Up to 24 mg BID
`Indication Treatment of chorea in
`Intended Population Huntington’s Disease
`
`
`
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`Reference ID: 4071773
`
`

`

`Clinical Review
`Kenneth Bergmann, MD
`NDA 208082
`Austedo (deutetrabenazine)
`
`
`2
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`Table of Contents
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 6
`1.1 Recommendation on Regulatory Action ............................................................. 6
`1.2 Risk Benefit Assessment .................................................................................... 6
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 7
`1.4 Recommendations for Postmarket Requirements and Commitments ................ 7
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 7
`2.1 Product Information ............................................................................................ 7
`2.5 Presubmission Regulatory Activity Related to Class 2 Resubmission ................ 7
`3 ETHICS AND GOOD CLINICAL PRACTICES ......................................................... 9
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ........................................................................................................... 9
`4.4 Clinical Pharmacology ........................................................................................ 9
`5 SOURCES OF CLINICAL DATA............................................................................ 10
`5.1 Tables of Studies/Clinical Trials ....................................................................... 10
`5.2 Review Strategy ............................................................................................... 10
`6 REVIEW OF EFFICACY ......................................................................................... 10
`Efficacy Summary ...................................................................................................... 10
`7 REVIEW OF SAFETY ............................................................................................. 11
`Safety Summary ........................................................................................................ 11
`7.1 Methods ............................................................................................................ 12
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 12
`7.1.2 Categorization of Adverse Events .............................................................. 12
`7.2 Adequacy of Safety Assessments .................................................................... 13
`7.2.1 Overall Exposure at Appropriate Doses/Durations ..................................... 14
`7.3 Major Safety Results ........................................................................................ 18
`7.3.1 Deaths ........................................................................................................ 18
`7.3.2 Serious Adverse Events ............................................................................. 19
`7.3.3 Dropouts and/or Discontinuations .............................................................. 20
`7.3.4 Significant Adverse Events ........................................................................ 22
`7.3.5 Submission Specific Primary Safety Concerns .......................................... 23
`7.4 Supportive Safety Results ................................................................................ 26
`7.4.1 Common Adverse Events .......................................................................... 26
`7.4.2 Laboratory Findings ................................................................................... 28
`7.4.3 Vital Signs .................................................................................................. 28
`7.4.4 Electrocardiograms (ECGs) ....................................................................... 29
`7.6 Additional Safety Evaluations ........................................................................... 29
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound ...................... 29
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`Reference ID: 4071773
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`Clinical Review
`Kenneth Bergmann, MD
`NDA 208082
`Austedo (deutetrabenazine)
`
`9 APPENDICES ........................................................................................................ 32
`9.2 Labeling Recommendations ............................................................................. 32
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`Reference ID: 4071773
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`

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`Clinical Review
`Kenneth Bergmann, MD
`NDA 208082
`Austedo (deutetrabenazine)
`
`
`Table of Tables
`Table 1 Clinical Studies (source: Complete Response Safety Update, page 16) .......... 10
`Table 2 Duration of Exposure to SD-809 in combined Studies C-15 and C-16 in the first
`cycle review ................................................................................................... 14
`Table 3 Study C-16 Patients remaining in the study by visit week ................................ 15
`Table 4 Study C-16 Tally of important Treatment Emergent Adverse Events ............... 18
`Table 5 Study C-16 Serious Adverse Events ................................................................ 19
`Table 6 Study C-16 Drop-outs and discontinuations (CR Safety Update, p 26) ............ 21
`Table 7 Study C-16 Adverse events leading to discontinuation .................................... 21
`Table 8 Study C-16 Adverse events leading to dose reduction ..................................... 22
`Table 9 Study C-15 Sponsor's summary of psychiatric adverse events (Response to
`information request, 1.11.4, Table 2, p 8) ...................................................... 24
`Table 10 Study C-16 Sponsor's summary of psychiatric adverse events (Response to
`information request, 1.11.4, Table 3, p 9) ...................................................... 25
`Table 11 Study C-16 Moderate and severe AEs by SOC .............................................. 26
`Table 12 Study C-16 Nervous system disorders SOC AEs ........................................... 26
`Table 13 Study C-16 Psychiatric SOC AEs ................................................................... 27
`Table 14 Study C-16 Most frequent relevant AEs by Preferred Term occurring in the
`Rollover and Switch cohorts. ......................................................................... 28
`Table 15 Study C-16 TMS score before and after SD-809 washout at study end
`(Sponsor’s CR safety update, Table 2, p 5) ................................................... 30
`Table 16 Study C-15 Vital signs before and after SD-809 washout at study end .......... 31
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`Reference ID: 4071773
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`Clinical Review
`Kenneth Bergmann, MD
`NDA 208082
`Austedo (deutetrabenazine)
`
`
`Table of Figures
`Figure 1 Study C-16 Number of visits at a given daily dose of SD-809 ......................... 16
`Figure 2 Study C-16 Maintenance dose (mg/d) by N (Sponsor’s ADEX dataset) .......... 16
`Figure 3 Study C-16 Total daily dose of SD-809 by patient by week ............................ 17
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`Clinical Review
`Kenneth Bergmann, MD
`NDA 208082
`Austedo (deutetrabenazine)
`
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`SD-809 or deutetrabenazine is the deuterated form of tetrabenazine, an orphan status
`designated drug approved for the treatment of chorea due to Huntington’s disease (HD).
`While SD-809 has been designated a new molecular entity (NME), it is also a 505(b)(2)
`application using tetrabenazine (Xenazine, NDA 21894) as the Reference Listed Drug
`(RLD).
`
`This is the second review cycle for this drug. The NDA submission was issued a
`Complete Response Letter (CRL) because the clinical pharmacology studies were not
`adequate to determine whether all major human metabolites of SD-809 had been
`identified. That information was needed to assess whether the bridge to the RLD was
`scientifically justified.
`
`The clinical trials submitted in support of approval were fully reviewed in the first review
`cycle. The results of a single positive pivotal study (First-HD) were judged by the
`reviewer to be of sufficient quality to support a claim of effectiveness for the treatment of
`chorea in HD. In the clinical development program no new, novel, previously
`undescribed, or more frequent events occurred in the SD-809 safety population when
`compared to that of the RLD. While approvable on the basis of clinical efficacy and
`safety, the full risk of SD-809 could not be assessed because of the unanswered
`questions related to drug metabolites. Review of the safety update from an on-going
`open label safety study in HD provided in this Class 2 resubmission does not change
`the initial assessment of clinical risk and the risk-to-benefit balance for this drug remains
`favorable.
`
`With resolution of the clinical pharmacology questions regarding metabolites and the
`bridge to the RLD, my clinical assessment of the safety and efficacy of SD-809 is in
`support of its approval.
`
`The first cycle clinical review, relevant parts of which are summarized in the clinical
`sections below, is available in DARRTS:
`
`http://darrts.fda.gov:9602/darrts/ViewDocument?documentId=090140af803e9849
`
`1.2 Risk Benefit Assessment
`
`SD-809 represents an additional oral therapeutic option for treating the chorea of HD
`patients. The clinical safety profile of SD-809 is acceptable given the severity of this
`disorder and the demonstrated benefit. The identified clinical safety concerns, shared by
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`Clinical Review
`Kenneth Bergmann, MD
`NDA 208082
`Austedo (deutetrabenazine)
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`the reference listed drug (RLD) for this 505(b)(2) application, can be adequately
`addressed through appropriate product labeling (including a boxed warning about
`depression and suicidality) and the Medication Guide.
`
`As demonstrated by clinical trials performed in support of this application, SD-809
`appears to provide benefits similar to the other available therapy for chorea,
`tetrabenazine, and represents a worthy additional oral treatment option for persons with
`Huntington’s disease.
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation
`Strategies
`
`None
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`None
`
`2 Introduction and Regulatory Background
`
`2.1 Product Information
`
`SD-809 (deutetrabenazine) is a vesicular monoamine transporter 2 (VMAT2) inhibitor.
`Under the proposed proprietary name Austedo, approval is being sought for the
`treatment of chorea associated with Huntington’s disease (HD).
`
`The drug product is a tablet with 6, 9, or 12 mg of deutetrabenazine. The maximum
`proposed dose is 48 mg /d given orally in two divided doses with food. In persons who
`are poor metabolizers of CYP 2D6 or persons receiving concomitant medication that
`strongly inhibits CYP 2D6, the maximum proposed dose is 36 mg/d in two divided
`doses.
`
`2.5 Presubmission Regulatory Activity Related to Class 2 Resubmission
`Type A Post-Action Meeting - September 20, 2016
`Following issuance of the Complete Response Letter on May 27, 2016, the sponsor
`requested further discussion on the development of SD-809. The discussion centered
`upon new data from bioanalytical characterization of M1 and M4 that purportedly
`demonstrated that M1 and M4 are minor metabolites, and to reach agreement with FDA
`that the bioanalytical results presented for M1 and M4 identifying them as minor
`complete the characterization of the metabolites of SD-809 in humans.
`
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`Reference ID: 4071773
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`Clinical Review
`Kenneth Bergmann, MD
`NDA 208082
`Austedo (deutetrabenazine)
`
`The sponsor discussed their plan and the Agency reiterated that this will be a review
`issue and recommended that the sponsor submit all supporting information/justification
`in the NDA resubmission.
`
`The sponsor also had questions regarding the re-submission requests from the
`Controlled Substance Staff (CSS). The Complete Response Letter contained the
`following:
`
`“The data provided in the application suggest a possible rebound effect following withdrawal of
`deutetrabenazine. You need to conduct a systematic evaluation of clinical dependence. We
`recommend that you evaluate clinical dependence in patients as they complete Study ARC-HD
`(SD-809-C-16). We suggest you evaluate patients for signs and symptoms of clinical dependence
`for two weeks after discontinuing deutetrabenazine. In patients who chose to discontinue
`treatment with deutetrabenazine early, you should extend the follow up period after discontinuing
`deutetrabenazine to 3 weeks.
`
`You should administer the following scales to evaluate patients for signs of rebound:
`• Hospital Anxiety and Depression Scale (HADS)
`• Columbia Suicide Severity Rating Scale (C-SSRS)
`• Epworth Sleepiness Scale (ESS)
`• Montreal Cognitive Assessment (MoCA)
`• Total Maximal Chorea Score (TMC)
`• Unified Huntington Disease Rating Scale, including behavioral and cognitive scores
`• Unified Parkinson’s Disease Rating Scale Speech/Dysarthria
`• Barnes Akathisia Rating Scale (BARS)
`• Berg Balance Test Score (BBT)
`
`
`We recommend you submit for FDA review your planned analyses for abuse potential and
`rebound.”
`
`CSS was not present at the meeting and responded in writing on November 2, 2016. In
`the meeting, the sponsor responded to the CRL that the comments from CSS relating to
`the assessment of possible rebound effect and clinical dependence were not an
`approvability issue. The sponsor indicated that because this assessment relies on
`completion of Study SD-809-C-16, which continues through marketing authorization in
`the US, it cannot be addressed as part of this complete response submission. The
`sponsor also reiterated that there was nothing in the side effect profile of the drug to
`suggest withdrawal or drug-seeking behavior.
`
`CSS noted that “CSS agrees with the Sponsor that the drug is indeed not likely to have
`increased abuse potential” however, CSS on review of SD-809-C-15 (First HD) thought
`that the drug “appeared to produce rebound in ~20% of patients during the first week of
`withdrawal and tolerance that started week 9 during the treatment.” Because this had not
`been evaluated in the development program in a systematic fashion with “appropriate
`tools and timing for the assessment of withdrawal symptoms …CSS repeats the request for the
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`Clinical Review
`Kenneth Bergmann, MD
`NDA 208082
`Austedo (deutetrabenazine)
`
`evaluation of dependence, withdrawal and rebound and that you provide approximate dates of
`the final analysis of the study. The Sponsor should provide the requested data as soon as the
`study # ARC-HD (SD-809-C-16) is finished and analyzed; at this point it will be considered a
`Post-Marketing Commitment (PMC).”
`
`Reviewer’s comment: This is further discussed below in the review of safety, Section
`7.6.4.
`
`3 Ethics and Good Clinical Practices
`Submission quality and integrity, compliance with Good Clinical Practices and financial
`disclosures were previously reviewed and deemed acceptable. No new studies in this
`indication or investigators were added in the interim.
`
`4 Significant Efficacy/Safety Issues Related to Other Review
`Disciplines
`
`4.4 Clinical Pharmacology
`
`The major reason of non-approval was due to residual review questions about the
`metabolites of deuterated tetrabenazine. In the CR letter, FDA indicated that the
`original analyses of the human [14C]-ADME and mass-balance study SD-809-C-12 was
`not adequate to determine whether SD-809 metabolites M1 and M4 were major or
`minor.
`
`The sponsor validated liquid chromatography with tandem mass spectrometry (LC-
`MS/MS) bioanalytical methods for M1 and M4 metabolites and analyzed the retained
`clinical plasma samples from the mass-balance study SD-809-C-12 for these
`metabolites.
`
`Based on the reanalysis, M4 was determined to be a minor metabolite (about 6% of
`total drug related material (TDRM). The mean ratio of M1 as a percentage of TDRM
`was about 10%. Therefore, M1 is not a major human metabolite as defined by ICH
`M3(R2) as it does not circulate at levels greater than 10% of the total drug-related
`exposure.
`
`This information reviewed during this resubmission was deemed adequate by the
`Clinical Pharmacology reviewer to support the approval of NDA 208082.
`
`As a result no additional nonclinical pharmacological toxicology studies are needed.
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`Reference ID: 4071773
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`Clinical Review
`Kenneth Bergmann, MD
`NDA 208082
`Austedo (deutetrabenazine)
`
`5 Sources of Clinical Data
`
`5.1 Tables of Studies/Clinical Trials
`Table 1 Clinical Studies (source: Complete Response Safety Update, page 16)
`
`
`
`5.2 Review Strategy
`The designs of the cited trials are described in the first cycle review.
`
`This clinical review looks at updated safety information on SD-809 for the period
`beginning on the closing date for the first review cycle 120 day Safety Update (March
`31, 2015) and extending until the cut-off date for this complete response (March 31,
`2016) . Because the First-HD trial had been completed, only open label data from the
`extension trial C-16 is new for this second cycle.
`
`The sponsor reports that an additional 379 patients have been treated in development
`programs for indications of tardive dyskinesia and Tourette’s syndrome. While these
`are populations very different from the HD population, some safety data from these
`programs is also reviewed.
`
`6 Review of Efficacy
`Efficacy Summary
`No new efficacy data is submitted in this Complete Response.
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`Clinical Review
`Kenneth Bergmann, MD
`NDA 208082
`Austedo (deutetrabenazine)
`
`
`The efficacy of SD-809 was demonstrated in the First-HD study (n=90), a randomized
`trial in which SD-809 was compared to placebo. Over an 8 week period, HD patients
`were given increasing doses of medication based upon control of their involuntary
`movement, up to a maximum of 48 mg/d given in two split doses. They were then
`observed on this stable dose for 4 weeks. Throughout this period, the severity of the
`movement disorder was blindly rated using the Total Maximal Chorea Score, a part of a
`standardized rating scale for HD. In addition, participants and their physicians were
`independently asked to rate how they felt they were doing overall. Over half the
`patients reached 48 mg/d. At the end of the study, the SD-809 group had reduced their
`chorea on average 2.5 points more than the placebo treated group, a statistically
`significant difference. In addition, 51% of the SD-809 group felt they were either “Much
`Improved” or “Very Much Improved” compared with only 20% of the placebo group. The
`patients’ investigators thought 42 % of SD-809 patients and 13% of the placebo patients
`were so improved. These results were also statistically significant.
`
`The study was judged by this reviewer to be of sufficient robustness and quality to
`support a claim of effectiveness for the treatment of chorea in HD.
`
`7 Review of Safety
`Safety Summary
`First Cycle Safety Summary (from the primary clinical review, DARRTS 5/24/2016)
`
`
`At the time of the 120 day Safety update, the safety population across the development
`program for SD-809 encompassed 229 persons who received at least one dose of
`medication.
`
`There were no deaths reported in HD studies. Two deaths had occurred in the tardive
`dyskinesia development program; neither appeared to be drug related.
`
`There were 624 instances of AEs. Of these, 19 were labelled as SAEs occurring in 13
`patients. In the randomized and blinded Study C-15, 221 TEAEs occurred in 57 of 90
`randomized patients: 111 events in 27 SD-809 patients and 108 events in 30 Placebo
`patients. Three patients with depression and suicidality were plausibly drug related
`serious adverse events. The rest appeared unrelated and common to neurologically
`ill patients. The most common adverse events occurring in SD-809 patients at a rate
`greater than placebo include: somnolence (11%), dry mouth (9%), fatigue (9%),
`insomnia (7%), anxiety (4%), back pain and constipation.
`
`Events that were related to drop out in Phase 3 trials in addition to the SAEs noted
`above include 5 patients with depression, with or without suicidal ideation, and
`akathisia.
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`Clinical Review
`Kenneth Bergmann, MD
`NDA 208082
`Austedo (deutetrabenazine)
`
`
`Dose reductions occurred in 17 patients in Phase 3 trials for somnolence (9), dizziness
`or imbalance (3), worsening depression (3) and akathisia (2).
`Adverse events of special interest including suicidality and depression, akathisia,
`Parkinsonism, dysphagia, sedation and somnolence, and abuse potential including
`withdrawal and rebound were addressed at length in the first cycle review.
`
`Second Cycle Safety Summary
`
`No new or novel adverse drug effects were noted in the additional open label safety
`data for SD-809. No adverse drug effect increased over time with longer expose to SD-
`809. Following review of the clinical data, there was nothing to suggest that tolerance
`develops to the clinical efficacy of SD-809 or that withdrawal occurs on treatment
`cessation.
`
`The balance between therapeutic benefit and the risk from taking SD-809 remains
`acceptable.
`
`7.1 Methods
`
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety
`
`The additional safety data from the long term open label study C-16 are evaluated in
`this review. No new patients have been added to this study since the original NDA
`application.
`
`At each visit during the open label study the safety evaluation included vital signs,
`clinical laboratory (chemistry, hematology and urine analysis), pregnancy test and the
`C-SSRS. An electrocardiogram was performed at weeks 4, and 8 and the end of
`treatment. A physical examination (including neurological examination) was to be
`performed at the end of treatment, which has not occurred for most patients enrolled in
`this study.
`
`The sponsor also responded to requests to re-tabulate particular adverse events as
`described in Section 7.2, below.
`
`7.1.2 Categorization of Adverse Events
`
`As described in the first cycle review, the adverse events were collected and
`characterized in accordance with accepted ICH and FDA guidelines. The sponsor did
`this in an acceptable fashion. Adverse events were coded using MedDRA version 16.1
`in C-15 and C-16 but other versions of MedDRA were used in the Phase 1 studies.
`
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`Reference ID: 4071773
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`Clinical Review
`Kenneth Bergmann, MD
`NDA 208082
`Austedo (deutetrabenazine)
`
`In the sponsor’s safety update for this second cycle review, adverse event experience
`was presented in comparison to the first cycle AE data, as requested by the review
`team in the pre-submission meeting with the sponsor.
`
`It is evident that the adverse event experience observed over this longer period is very
`much the same as described in the first cycle review. For the sake of clarity, the first
`cycle open label and second cycle open label adverse event data are combined for this
`safety review. Any pertinent changes are pointed out by the reviewer.
`
`7.2 Adequacy of Safety Assessments
`
`In the Complete Response Letter, the sponsor was asked to assemble the sections
`describing discontinuations due to adverse events, serious adverse events, and
`frequently reported adverse events, incorporate new safety data as follows:
`
`
`• Provide updated exposure information for the clinical studies/trials (e.g., number
`of subjects, person time).
`
`• Present new safety data from the studies/clinical trials for the proposed indication
`using the same format as the original NDA submission.
`
`• Provide case report forms and narrative summaries for each patient who died
`during a clinical trial or who did not complete a trial because of an adverse event.
`In addition, provide narrative summaries for serious adverse events.
`
`• Present tabulations of the new safety data combined with the original NDA data.
`Include tables that compare frequencies of adverse events in the original NDA
`with the re-tabulated frequencies described in the bullet above.
`
`• For indications other than the proposed indication, provide separate tables for the
`frequencies of adverse events occurring in clinical trials.
`
`
`
`• Review the characterization of certain adverse events and present a re-tabulation
`of the reasons for premature trial discontinuation by incorporating the drop-outs
`from completed trials. Review all Psychiatry system-organ-class (SOC) adverse
`events in Study C-15 and Study C-16 for accuracy of the Preferred Term coding
`of the verbatim report of the adverse event. Provide a separate analysis for each
`study of all Psychiatry SOC events that led to an adverse event, a dose
`reduction, or a dose interruption regardless of whether the event was considered
`related to drug or not.
`
`Reviewer’s comment: while the sponsor fulfilled these requests, the findings were
`verified by the reviewer using the sponsor’s own SDTM and ADaM datasets and, where
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`Reference ID: 4071773
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`Clinical Review
`Kenneth Bergmann, MD
`NDA 208082
`Austedo (deutetrabenazine)
`
`in agreement, the reviewer’s tabulations are used. Any discrepancies between the
`sponsor’s and reviewer’s tabulations are noted.
`
`7.2.1 Overall Exposure at Appropriate Doses/Durations
`
`As submitted at the time of the first review cycle’s 120 Day Safety Update, there were
`229 persons who received at least one dose of SD-809. At the time of this
`submission, no additional patients received SD-809 in the HD development program.
`However, with continuation of the open label study C-16, there has been longer
`exposure to SD-809.
`
`An additional 379 subjects have been exposed to SD-809 in 1 completed and 2 ongoing
`studies in patients with Tardive Dyskinesia and an additional 23 persons have been
`exposed to SD-809 in the completed study in subjects with Tourette’s syndrome.
`
`Exposure was calculated through the sponsor’s cutoff date of March 31, 2016. First-HD
`had 45 patients who received drug in the active arm and an equal number received
`placebo. Of the 90 patients in First-HD, 82 rolled over into Study C-16 (ARC–Rollover).
`An additional 37 patients were switched from tetrabenazine to SD-809 (ARC-Switch),
`for a total of 119 patients in the open label long-term extension study.
`
`In the first cycle the Phase 3 duration of exposure was described by this table derived
`from the sponsor’s ADEX datasets (the double blind and open label populations were
`combined to derive this table):
`
`Table 2 Duration of Exposure to SD-809 in combined Studies C-15 and C-16 in the
`first cycle review
`Phase 3 Safety Population (N=121) - Duration of Exposure
`≤ 3
`≤ 6
`≤ 9
`≤ 12
`>12
`months
`months
`months
`months
`months
`
`Epoch
`
`N
`
`5
`
`29
`
`45
`
`27
`
`15
`
`
`At the time of the data cut-off for this second cycle review of safety, 99 HD patients had
`had at least 1 year’s exposure to SD-809. The average duration of treatment was 71
`weeks and the longest duration of treatment for any HD patient is 75 weeks.
`
`As of the data lock date for this submission, 90 of 119 participants remain in Study C-
`16. The sponsor’s updated ADEX dataset in this submission shows that the number of
`patients in the ongoing C-16 open label study present at each visit is as follows:
`
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`Clinical Review
`Kenneth Bergmann, MD
`NDA 208082
`Austedo (deutetrabenazine)
`
`Table 3 Study C-16 Patients remaining in the study by visit week
`
`Visit Week N reported
`
`1
`2
`4
`8
`15
`28
`41
`54
`67
`80
`93
`106
`
`119
`118
`118
`116
`114
`109
`103
`99
`94
`59
`29
`8
`
`
`While the dose tested in First-HD was 48 mg/day (24 mg BID) or 36 mg/day (18 mg
`BID) if receiving a concomitant medication that was a CYP2D6 inhibitor, patients were
`titrated to best clinical response in the open label study at doses up to 72 mg/d. The
`first cycle review revealed 28 patients had been treated above 48 mg/d in Study C-16.
`
`At the time of this submission, 119 patients had had1086 open label visits. At 283
`(26%) of those visits, patients were taking more than 48 mg total daily dose (from the
`sponsor’s ADEX dataset):
`
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`Reference ID: 4071773
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`Clinical Review
`Kenneth Bergmann, MD
`NDA 208082
`Austedo (deutetrabenazine)
`
`
`Figure 1 Study C-16 Number of visits at a given daily dose of SD-809
`
`
`Of the 119 patients, 37 (31%) had their maintenance total daily dose above 48 mg/d. In
`this open label study the mean maintenance dose was 45 mg/d ± 16 mg/d SD (range 6
`to 72 mg/d). Median dose was 42 mg /d with quartiles at 36 and 54 mg/d:
`
`Figure 2 Study C-16 Maintenance dose (mg/d) by N (Sponsor’s ADEX dataset)
`
`
`
`
`
`Reference ID: 4071773
`
`16
`
`
`
`

`

`Clinical Review
`Kenneth Bergmann, MD
`NDA 208082
`Austedo (deutetrabenazine)
`
`Given the protocol-driven titration to best clinical response, it is interesting to note how
`long that took across the patient population. (Visits for this study took place at 1, 2, 4, 8,
`15, 28, 41, 54, 676, 80, 93, and 106 weeks). Patients began at Week 0 with the dose
`they took in C-15 if they had been on active drug (up to 48 mg), or were titrated up from
`0 mg, or were converted overnight from tetrabenazine (switch cohort).
`
`As is evident from the total daily dose (Y axis) curves of each of the 119 patients, most
`patients were stabilized on their treatment dose by the Week 15 Visit (X axis) with
`lesser variation after that. This is consistent with the onset of drug effect of other
`catecholamine and indoleamine modulators of the central nervous system such as
`antipsychotic agents and antidepressants.
`
`
`Figure 3 Study C-16 Total daily dose of SD-809 by patient by week
`
`
`At the time of the data lock for this submission, 29 patients enrolled in Study C-16 have
`left the trial. The sponsor notes that “all of the early withdrawals due to adverse events
`occurred following at least 100 days of study participation.” The graphic representation
`of the titration of SD-809 in Study C-16 suggests that adverse events coincide with the
`onset of full drug effect after 15 weeks (105 days). This may explain why certain
`adverse drug effects begin to occur or occur more frequently in this study when
`compared to the C-15 placebo-controlled double-blind trial that lasted only 12 weeks (of
`which 8 were a titration phase).
`
`
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`Reference ID: 4071773
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`17
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`

`

`Clinical Review
`Kenneth Bergmann, MD
`NDA 208082
`Austedo (deutetrabenazine)
`
`7.3 Major Safety Results
`
`Study C-16 TEAEs
`
`Second Cycle
`
`Total
`
`The population of Studies C-15 and C-16 is described in the first cycle review. This
`clinical review addresses the newly submitted treatment emergent events but presents
`the safety experience of Study C-16 as a whole:
`
`Table 4 Study C-16 Tally of important Treatment Emergent Adverse Events
`First
`Cycle
`19
`26
`0
`14
`14
`4
`
`SAE
`Severe AE
`AE leading to death
`AE resulting in dose reduction
`AE resulting in dose interruption
`AE leading to withdrawal
`
`13
`24
`1
`44
`6
`5
`
`32
`50
`1
`58
`20
`9
`
`
`Reviewer’s Comment: It should be noted that the sponsor’s Table 8 that summarizes
`TEAEs on page 30 of the Complete Response Safety update is entirely incorrect. The
`numbers in my table above are taken from the ADAE dataset. Checking this against my
`first cycle review, submitted CRFs, and narratives suggest that the SDTM and ADaM
`datasets are accurate.
`
`7.3.1 Deaths
`
`In the first cycle review, no deaths had occurred in the HD development program.
`There had been two deaths in the TD development program, both (appropriately)
`judged to have been unrelated to study drug.
`
`There