CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`208082Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross Discipline Team Leader Review
`
`Cross-Discipline Team Leader Review
`
`
`Date
`March 28, 2017
`
`Gerald D. Podskaln , DO, IVIPHS
`From
`m_ Cross-Disci o line Team Leader Review
`NDA/BLA #
`NDA 208082 (Resubmission)
`Su lement#
`
`Teva Phannaceuticals, Ine-
`
`
`
`
`PDUFA Goal Date
`
`A ril 3, 2017
`
`Austedo/Deutetrabenazine
`Proprietary Name /
`
`Established (USAN) names
`Dosa_e forms / Stren_ h
`Pro I osed Indication s
`Recommended:
`
`
`Oral tablets 6mg, 9mg and 12 mg strengths
`M“) Huntington’s disease
`
`1. Introduction
`
`Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder. Its estimated
`prevalence is 5/ 100,000 in the US (Kay C., 2014). The disease causes progressive dementia,
`motor disability including chorea and psychiatric symptoms. Symptoms typically begin
`between ages 30 to 50 years. Disease related disability causes death in 15-20 years after the
`onset of symptoms. Death is most often due to pneumonia but suicide is more frequent among
`patients with HD (Roos, 2014). Although it is possible to detect the genetic abnormality in
`utero, there are no treatments that alter the progression of the disease. Tetrabenazine
`(Xenazine) was approved on August 15, 2008, (NDA 21894) for the treatment of HD
`associated chorea. It is remains the only drug approved for treatment of HD. Tetrabenazine is
`rapidly and extensively metabolized to a—HTBZ and B-HTBZ metabolites, which are active
`and bind reversibly to VMAT2. The u-HTBZ and B-HTBZ metabolites of tetrabenazine are
`inhibitors of VMAT2 in the central nervous system and deplete presynaptic monoamines,
`including dopamine, which reduces chorea in patients with HD. Austedo (deutetrabenazine,
`aka. SD-809) is a deuterated form of tetrabenazine and it follows the same metabolic pathway
`and tetrabenazine. Systemic exposure (AUC) to total (a+B)-HTBZ following deutetrabenazine
`administration is approximately 2-fold greater than with tetrabenazine, which is the rationale
`for administering a lower dose of deutetrabenazine compared to Xenazine.
`
`2. Background
`
`On May 29, 2015, Teva Pharmaceuticals submitted a 505(b)(2) NDA for Austedo
`(deutetrabenazine). The NDA referenced the FDA’s previous finding of efficacy and safety for
`Xenazine (NDA 21894). The primary support for the safety and efficacy of Austedo is
`provided by the clinical trials conducted by the applicant. Deutetrabenazine (dTBZ) was
`determined to be a new molecular entity and the application was reviewed under the Program.
`Deficiencies in product quality and clinical pharmacology and nonclinical portions of the NDA
`
`Page 1 of 24
`
`Reference ID: 40761 18
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`1
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`

`Cross Discipline Team Leader Review
`
`led to the FDA issuing a Complete Response letter on May 27, 2016. The clinical
`pharmacology deficiencies were central to the reason for the FDA’s action. There was
`insufficient information to determine whether the M1 and M4 metabolites of dTBZ were major
`or minor circulating human metabolites. If these metabolites were found to be major
`metabolites in humans, the sponsor would need to show that the M1 and M4 metabolites were
`adequately assessed in the nonclinical studies included in the application.
`
`The FDA’s Controlled Substance Staff (CSS) also requested information to assess whether
`withdrawal of deutetrabenazine (dTBZ) was associated with signs of dependence and rebound.
`Additional clinical information was requested regarding adverse events that led to changes in
`the dose of dTBZ. The additional information requests did not impacted the approvability of
`the application.
`
`Deutetrabenazine was received orphan designation from the Office of Orphan Product
`Development. The original dTBZ NDA (NDA-208082) was filed under a standard review
`clock on August 10, 2015. The applicant’s Class 2 resubmission of the NDA application for
`dTBZ was received on October 3, 2016. This review addresses the applicant’s response to the
`CR issues and the issues that did not impact the approvability of the application for each
`review discipline. The comments (verbatim) from the CR letter are provided at the beginning
`Review discipline and the applicant’s response and my review comments follow.
`
`Table 1: NDA
`Quality Review Team
`Christopher Toscano, PhD
`Lois Freed, PhD
`Kristina Dimova, PhD
`Sreedharan Sabarinath, Ph.D.
`Kenneth Bergmann, MD
`Xiangmin Zhang, PhD
`Alicja Lerner, MD, PhD
`Michael Klein, Ph.D.
`Loretta Holmes, BSN, PharmD
` Chad Morris, PharmD, MPH
`Aline Moukhtara, RN, MPH
`Mathilda Fienkeng, PharmD, RAC
`Sharon W. Williams, MSN, BSN, RN
`Marcia Williams, PhD
`LaShawn Griffiths, MSHS-PH, BSN, RN
`Mathilda Fienkeng, PharmD, RAC
`
`Resubmission Review Team Members
`See Table 2 in the CMC/Device Section
`Nonclinical Reviewer
`Nonclinical Supervisor (Memo)
`Primary Reviewer Office of Clinical Pharmacology
`Team Leader:
`Clinical Reviewer
`Division of Biometrics I
`Medical Officer Controlled Substance Staff
`Director Controlled Substance Staff
`Division of Medication Error Prevention and Analysis (DMEPA)
`
`Regulatory Review Officer
`Team Leader, OPDP
`Regulatory Review Officer Division of Medical Policy Programs (DMPP)
`Team Leader, DMPP
`Associate Director DMPP
`Team Leader OPDP Office of Prescription Drug Promotion (OPDP)
`
`
`
`
`3. CMC/Device
`Table 2: Quality Review Team
`DISCIPLINE
`REVIEWER
`Drug Substance
`Gene Holbert
`Drug Product
`Martha Heimann
`
`BRANCH/DIVISION
`Branch1/DNDAPI/ONDP
`Branch 1/DNDP 1/ONDP
`
`Page 2 of 24
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`Reference ID: 4076118
`
`2
`
`(b) (4)
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`

`Cross Discipline Team Leader Review
`
`Process
`Microbiology
`Facility
`Biopharmaceutics
`Regulatory Business
`Process Manager
`Application Technical Lead
`
`N/A
`N/A
`Wayne Seifert
`N/A
`
`Dahlia Woody
`
`
`
`
`
`
`
`
`
`Branch1/DIA/OPF
`
`Branch 1/DRBPM1/OPRO
`
`Martha Heimann
`
`Branch 1/DNDP 1/ONDP
`
`
`
`Deficiencies in the Complete Response Letter
`
`PRODUCT QUALITY
`. We
`1. The drug substance specification does not include a test for
`acknowledge your commitment dated February 22, 2016, to add a test and acceptance
` as part of
`criterion of not more than
` (ppm)
`the drug substance specification and to amend the NDA with this test, acceptance
`criterion, and method validation report on or before March 22, 2016. However, the test
`method was not submitted until April 14, 2016, and validation data were not provided
`until May 9, 2016. These amendments to the NDA will be reviewed in the next cycle.
`
`2. In your post-approval stability protocol, you indicate that at least one production batch of
`the product in the commercial packaging will be placed on long term stability annually.
`Because the registration stability batches were not manufactured at full commercial scale,
`we request that you update your post-approval stability commitment to include placing
`the first three commercial batches of each strength of the drug product on long-term
`stability through the proposed shelf life, and on accelerated stability for 6 months as per
`ICH Q1A(R2). The data should be tabulated and submitted in the annual report with a
`commitment to withdrawing or discussing any out of specification results in the
`distributed drug product to the Agency.
`
`3. Per 21 CFR 25.15(d), revise your claim for categorical exclusion to include a statement
`that, to the applicant's knowledge, no extraordinary circumstances exist.
`
`
`Resubmission Review
`Gene W. Holbert, Ph.D. in the Division of New Drug API, ONDP reviewed the information
`related to the drug substance. Kasturi Srinivasachar, Ph.D. Acting Branch Chief completed the
`secondary review of the drug substance quality information.
`
`
`The applicant revised the drug substance specification to include a specification for
` content of not more than
`. At the maximum recommended dose of 48 mg/day,
`the daily dose of
` would be
` which is below the threshold of
`toxicological concern of 1.5 μg/day from chronic dosing. Dr. Holbert considered the drug
`substance specification adequate.
`
`
`Page 3 of 24
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`
`3
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`

`

`Cross Discipline Team Leader Review
`
`The sponsor used headspace gas chromatography for the analytical method to test for
`mu) content. Dr. Holbert reviewed the method validation for the determination of
`M“) content. The list of the assay specifications is included in his review. He considered the
`analytical method adequate and validated for the intended use.
`
`(b) (4)
`
`(D) (4)
`
`The sponsor also revised the claim for categorical exclusion from environmental assessment to
`include a statement that to the applicant’s knowledge, no extraordinary circumstances exist.
`
`Facilities
`
`All facilities proposed for manufacture and testing of deutetrabenazine and
`Austedo (deutetrabenazine) tablets are currently acceptable.
`
`OPQ’s Assessment and Recommendation
`From a quality perspective, approval of NDA 208082 is recommended. The applicant has
`adequately addressed the outstanding deficiencies from the original review.
`
`4. Nonclinical Pharmacology/Toxicology
`
`Deficiencies in the Complete Response Letter
`The toxicolrinetic analyses ofmetabolites in the pivotal nonclinical studies ofdeutetrabenazine
`are limited to quantitation ofthe primary metabolites ofdeutetrabenazine (i. e., alpha and
`beta- DHTBZ). If the results ofthe pending clinicalpharmacologv analyses identifi/ additional
`major circulating human metabolites, you will need to demonstrate that each has been
`adequately assessed in the appropriate nonclinical studies or thatplasma exposure to each
`does not exceed that in humans with Xenazine.
`
`Resubmission Review
`
`Dr. Christopher Toscano was the nonclinical reviewer for the original NDA and this
`resubmission for dTBZ. Drs. Toscano and Freed concluded the nonclinical studies included in
`
`the NDA were adequate to support approval. The need for additional nonclinical studies was
`dependent on whether or not the M1 or M4 metabolites were determined to be a major
`circulating metabolite as defined in ICH M3 0(2) (i.e., > 10% of total drug-related exposure).
`The Office of Clinical Pharmacology (OCP) determined the concentrations of M1 and M4 do
`not exceed the 10% of the total drug related material; therefore, the M1 and M4 metabolites
`are not major human metabolites of deutetrabenazine.
`
`The resubmission included several additional study reports for completed pharmacology,
`pharmacokinetic, pharmacokinetic drug interaction and genetic toxicology studies of the M1
`and M4 metabolites. This included several high—throughput screens to evaluate M1 and M4
`binding to the rat adrenergic a2 receptor and the human adrenergic a2C receptor. Dr.
`Toscano’s review findings for theses study reports are summarized below.
`
`0 M1 binding to the rat adrenergic (x2 receptor and the human adrenergic a2C receptor
`was demonstrated but M4 did not demonstrate relevant binding in similar studies.
`
`Page 4 of 24
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`Cross Discipline Team Leader Review
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`• M4 and M1 were negative in an adequately conducted in vitro bacterial reverse
`mutation assay.
`• M4 and M1 were negative in an adequately conducted in vitro chromosomal aberration
`study.
`• Computational toxicology assessment of the mutagenicity of M1 and M4 was negative.
`• There were no test article-related findings for M1 in a zebrafish developmental toxicity
`screen.
`
`
`Pharmacology/Toxicology Assessment and Recommendation
`The nonclinical studies reviewed under the initial submission are adequate to support the
`approval of NDA 208082 (see February 4, 2016, review for additional details).
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`Deficiencies in the Complete Response Letter
`Your clinical pharmacology studies were not adequate to determine whether all major human
`metabolites of deutetrabenazine have been identified. This information is needed to assess
`whether the bridge to the listed drug on which you are relying (Xenazine) is scientifically
`justified to address the toxicity of all major metabolites of deutetrabenazine.
`
`Please note that the method you proposed in your April 8, 2016, amendment to this NDA to
`assess potential major metabolites is acceptable, on face, and pending demonstration of
`suitable stability.
`
`Resubmission Review
`At the end of the NDA review, the Office of Clinical Pharmacology (OCP) concluded both the
`M1 and M4 metabolites exceeded 10% of the total plasma sample radioactivity in the single
`dose, mass balance recovery, and metabolite profiling and identification study (SD-809-C-12).
`However, the original analysis of the study information used the percentage of the total plasma
`sample radioactivity to quantify the levels of M1 and M4. OCP considered this to be a semi-
`quantitative method that should be confirmed using LC/MS with validated reference standards
`to quantify the amounts of M1 and M4 in humans.
`
`The division and the applicant’s representatives discussed the plan to address the uncertainty
`of the status of the M1 and M4 metabolites as major or minor during the End of Review
`meeting (9/20/2016).
`
`The applicant analyzed the retained samples from healthy subjects from the mass-balance
`study (SD-809-C-12) to provide human plasma exposure data for M1 and M4 from dTBZ and
`tetrabenazine (TBZ) to determine their status are a major or minor circulating metabolites in
`humans1.
`
`
`1 A major metabolite is typically determined to be > 10% of the parent molecule. Because SD-809 and
`tetrabenazine are rapidly metabolized to α-HTBZ plus β-HTBZ, the combined total amount of these two
`metabolites is used in place of the parent for the determination of major metabolites.
`
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`Cross Discipline Team Leader Review
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`
`The sponsor used validated liquid chromatography with tandem mass spectrometry (LC-
`MS/MS) to measure the deuterated (DP-2016-068) and non-deuterated (Validation Report DP-
`2016-069) α-HTBZ and β-HTBZ) metabolites. The sponsor submitted the methods validation
`reports (LC-MS/MS) for the M1 (2-methylpropanoic acid-β HTBZ) and M4 (monohydroxy
`SD-809) assays. Dr. Dimova noted that the method validation was reviewed with the original
`NDA and in OCP’s opinion, the analytical methods and their respective validation methods are
`acceptable.
`
`The sponsor updated the methods used to characterize the M1 and M4 metabolites compared
`to the total drug related material from Study SD-809-C-12. The sponsor’s analysis included
`all 11 plasma samples drawn over the first 12 hours post-dose which were assessed for each
`subject. In addition, the remaining plasma samples in the 216-hour study period were included
`in the analysis, for a total of 23 samples per subject, allowing for evaluation over the full
`plasma time course of total drug-related material which Dr. Dimova found to be acceptable.
`
`The sponsor analyzed retained plasma samples from the multiple-dose Study AUS-SD-809-
`CTP-07, Part 2. The objective was to provide human exposure for M1 and M4 at steady state.
`
`The feasibility of using retained plasma samples from studies SD-809-C-12 and AUS-SD-809-
`CTP-07 depended on the sponsor showing that the samples were stable after being stored at
`-80˚C since the completion of the original PK analysis in 2012. The sponsor compared the
`original results for the concentration of SD-809, α-HTBZ and β-HTBZ from the respective PK
`studies to the reanalyzed samples placed on storage using the validated LC-MS/MS assays to
`demonstrate the stability of the stored samples. The sponsor justification for using SD-809, α-
`HTBZ and β-HTBZ as an indicator of stability for M1 and M4 is based on the structural
`similarity shared between the compounds. The samples were reanalyzed as planned and 67%
`of the samples met the predefined acceptance criteria.
`
`The sponsor re-evaluated the acceptance criteria for the elimination rate constants (from the
`original SD-809-C-12 report) and %AUCextrap to determine which subjects were suitable for
`calculation of the percentage of total drug-related material for M1 and M4. The details of the
`sponsor’s acceptance criteria are described in Dr. Dimova’s review.
`
`Dr. Dimova had the following comments regarding the sponsor’s approach of comparing M1
`and M4 to TDRM:
`
`
`• The sponsor did not provide a convincing justification for the acceptance criteria
`• The elimination rate constant of TDRM could not be reliably estimated for 3 of the 6
`subjects
`• She questioned whether excluding half of the subjects dosed with SD-809 in the mass
`balance study from the estimation of the metabolite/ TDRM ratio was appropriate
`
`
`The reanalysis of the PK samples was presented in the applicant’s resubmission. The plasma
`concentrations for M1 and M4, obtained using validated bioanalytical methods were used to
`calculate their respective area under the concentration-time curve from time 0 extrapolated to
`
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`Cross Discipline Team Leader Review
`
`infinity (AUCinf). These values were expressed as a percentage of the AUCinf for total drug-
`related material (TDRM). The clinical pharmacology team recommended calculating the
`percentage of TDRM based on AUC0-t (for total plasma radioactivity and for M1/M4) instead
`of the AUCinf. Dr. Dimova cautioned, “Assessing metabolite/ TDRM ratio using results from
`different studies, different formulations and single vs. multiple dosing may not be
`appropriate.”
`
`Dr. Dimova conducted an independent analysis of the exposure to the M1 and M4 metabolites
`relative to the TDRM using AUCinf (Table 3) and AUC0-t. (Table 4).
`
`Table 3: FDA Clinical Pharmacology Reviewer’s Analysis Using AUCinf
`AUC0-∞
`SD-809 Individual Exposure (AUC0-∞) Parameters and TDRM for
` (h•ng/mL)
`M1 and M4 in Subjects S001 through S006 (Cohort 1)
`S001
`S002
`S003
`S004
`S005
`S006 Mean (SD)
`(SD)
`
`M1
`
`M4
`
`346
`
`185
`
`322
`
`158
`
`447
`
`294
`
`TDRM
`
`3744
`
`3221
`
`4379
`
`223
`
`194
`
`NCa
`
`457
`
`213
`
`326
`
`243
`
`353
`
`214
`
`4553
`
`4511
`
`4082
`
`
`Metabolite
`
`M1
`M4
`
`S003
`10.2
`6.7
`
`SD-809: Percentage of TDRM Ratio in Subjects S001 through S006
`(Cohort 1)
`S001
`S002
`9.2
`10.0
`4.9
`4.9
`
`S004
`NCa
`NCa
`
`S005
`10.0
`4.7
`
`S006 Mean (SD)
`8.0
`9.5
`5.9
`5.4
`
`Source: FDA Clinical Pharmacology Review
`
`Table 4: Clinical Pharmacology Reviewer’s Analysis of Exposure to the M1 and M4
`Metabolites Using AUC0-t.
`AUC0-t
`SD-809 Individual Exposure (AUC0-t) Parameters and TDRM for
` (h•ng/mL)
`M1 and M4 in Subjects S001 through S006 (Cohort 1)
`S001
`S002
`S003
`S004
`S005
`S006 Mean
`(SD)
`
`M1
`
`M4
`
`339
`
`181
`
`319
`
`156
`
`440
`
`292
`
`217
`
`191
`
`448
`
`209
`
`319
`
`238
`
`347 (86.5)
`
`211 (48.2)
`
`TDRM
`
`3310
`
`2700
`
`4000
`
`1980
`
`3980
`
`3760
`
`3290 (809)
`
`
`Metabolite
`
`SD-809: Percentage of TDRM Ratio in Subjects S001 through S006
`(Cohort 1) a
`
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`Cross Discipline Team Leader Review
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`S001
`
`S002
`
`S003
`
`S004
`
`S005
`
`S006 Mean
`(SD)
`8.5
`10.6 (1.2)
`11.3
`11.0
`11.0
`11.8
`10.2
`M1
`6.3
`6.6 (1.7)
`5.3
`9.7
`7.3
`5.8
`5.5
`M4
`Data calculated from following equation: AUC0-t of M1 or M4/AUC0-t of total plasma sample radioactivity
`a ng equiv were calculated from each plasma sample: ng eq/mL= ((DPM/sample- background dpm)/mL)•% efficiency)) /
`specific activity for each individual’s SD-809 dose (dpm/mg). The ng eq/mL, or total radioactivity, represents the TDRM in
`each sample.
`Abbreviations: AUC0-t, area under the plasma concentration-time curve from time 0 to the time of the last measurable
`concentration; DPM, disintegrations per minute; NC, Not calculated; SD, standard deviation; TDRM, total drug-related
`material
`Source: FDA Clinical Pharmacology Review
`
`Dr. Dimova opined that even in the case when the percentage of systemic exposures to M1 and
`M4 are expressed as a % of TDRM using AUC0-t for M1/M4 metabolites and TDRM (a
`method which underestimates the total radioactivity, it does not impact the systemic exposure
`to M1/M4 as much due to differences in bioanalytical ranges applied to metabolites and to the
`TDRM. The results indicate that M4 is clearly a minor metabolite (mean 6.6% of the TDRM)
`and M1 is about 10% (mean 10.6% of TDRM).
`
`Clinical Pharmacology Assessment and Recommendation
`• Based on the reanalysis of M1 and M4 metabolites in retained clinical samples of subjects
`treated with SD-809, M4 was determined to be a minor metabolite (about 6% of the
`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.
`• The Clinical Pharmacology information reviewed during the resubmission is adequate to
`support the approval of NDA 208082.
`
`
`
`6. Clinical Microbiology
`The resubmission did not include new microbiology information.
`7. Clinical/Statistical- Efficacy
`The resubmission did not include new clinical efficacy information. Study SD-809-C-15 was a
`double blind placebo controlled efficacy study. The completed study report was submitted in
`with the NDA and the results supported the effectiveness for the treatment of chorea in
`patients with Huntington’s disease. The complete review of Study SD-809-C-15 can be found
`in Dr. Bergmann’s review (archived in DARRTS 5/24/2016) and my review (archived in
`DARRTS 5/24/2016) of the NDA.
`8. Safety
`Request for Additional Information Included in the Complete Response Letter
`
`We have the following comments/recommendations that are not approvability issues:
`
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`
`When submitting the safety update, include narratives for patients who dropped out of Study
`C-16 for any reason and provide ADaM datasets in the same format as submitted with the
`120-Day Safety Update.
`
`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.
`
`Resubmission Clinical Safety Review
`
`Table 5:Clinical Studies Contributing Safety information to the Resubmission Update for
`Huntington Disease.
`
`
`
`Source: Adapted From TEVA Table
`
`EXPOSURE
`
`Study C-15 was the sole study supporting efficacy for the dTBZ NDA along with referencing
`the FDA’s previous finding of safety. Dr. Kenneth Bergmann, MD and Dr. Xiangmin Zhang,
`PhD (FDA statistical reviewer) and this reviewer, completed the efficacy assessment of this
`application. Study SD-809-C-16 Alternatives for Reducing Chorea in Huntington Disease
`(ARC-HD) was an open-label, long-term safety study of SD-809 (aka dTBZ=
`deutetrabenazine) in patients with chorea associated with HD. The study was ongoing with
`119 patients enrolled by the 120 day update cutoff date for submission to the NDA. No new
`patients were enrolled in Study C16 since the 120 day update. There were study 37 sites in the
`
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`Cross Discipline Team Leader Review
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`US, Canada, and Australia with no other ongoing studies of patients treated with SD-809 for
`HD.
`
`The study population was divided into two-cohorts:
`• Rollover Cohort (N=82) had successfully completed study SD-809- C-15 (First-HD),
`including a 1-week washout.
`• Switch Cohort (N=37) switched overnight from stable dosing (≥8 weeks) with
`Xenazine to SD-809. The Switch analysis is completed but patients could elect to
`continue open label treatment.
`
`≥80
`Weeks
`
`≥93
`Weeks
`
`--
`
`66
`33
`99
`
`--
`
`34
`25
`59
`
`--
`
`17
`12
`29
`
`81
`35
`119
`
`79
`35
`114
`
`75
`34
`109
`
`
`The cutoff date for the resubmission safety update was March 31, 2016. There were no new
`patients enrolled in Study SD-809-C-16 after the 120 day safety update for the NDA. The
`increase in the mean days of exposure was 82.4 days (405.1 increased to 487.5).
`
`Table 6: Patient Exposure by Duration (days) in Study SD-809-C-16
`Study
`Any SD-809
`≥8
`≥15
`≥28
`≥54
`exposure
`Weeks
`Weeks
`Weeks
`Weeks
`Phase 3 (Subjects with chorea associated with Huntington’s disease)
`First-HD
`45
`45
`--
`--
`ARC-HD (Complete Response)a
`ARC-Rollover
`82
`ARC-Switch
`37
`Total HD subject
`121
`exposureb
`Source: Complete Response Safety Update Table 14.1.5.3, Safety Update ISS Table 3.2; AUS-SD-809-CTP-06,
`AUS-SD-809-CTP-07, SD-809-C-08, SD-809-C-11, SD-809-C-12, SD-809-C-21.
`a Exposure calculated through 31 March 2016.
`b For subjects who received SD-809 in both First-HD and ARC-Rollover (N=43), exposure is calculated as the
`combined total across the 2 studies; these subjects are counted only once in the total number of subjects exposed.
`HD=Huntington’s disease.
`Source: Adapted From TEVA Table
`
`
`By the resubmission cutoff date, 5 patients were treated with 72 mg/day and 2 patients were
`treated with 66 mg daily dose at Week 93 which is above the maximum dose studied in the
`placebo controlled efficacy and safety study.
`
`DISPOSITION
`
`Table 7: Summary of Subject Disposition in SD-809-C-16 (ARC-HD) (Safety
`Population)
`
`
`
`
`Number of subjects in safety population
`
`Rollover cohort
`(N=82)
`n (%)
`82 (100.0)
`
`Switch cohort
`(N=37)
`n (%)
`37 (100.0)
`
`Total
`(N=119)
`n (%)
`119 (100.0)
`
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`Cross Discipline Team Leader Review
`
`24 (29.3)
`
`5 (13.5)
`
`29 (24.4)
`
`11 (13.4)
`7 (8.5)
`1 (1.2)
`1 (1.2)
`1 (1.2)
`0 (0.0)
`0 (0.0)
`
`1 (1.2)
`2 (2.4)
`
`1 (2.7)
`0 (0.0)
`1 (2.7)
`0 (0.0)
`0 (0.0)
`1 (2.7)
`1 (2.7)
`
`0 (0.0)
`1 (2.7)
`
`12 (0.8)
`7 (5.9)
`2 (1.7)
`1 (0.8)
`1 (0.8)
`1 (0.8)
`1 (0.8)
`
`1 (0.8)
`3 (2.5)
`
`Number of subjects who withdrew from study early
`Primary reason for withdrawal
`Adverse event
`Subject withdrawal
`Investigator judgment
`Lost to follow-up
`Noncompliance with study drug dosing
`Major violation or deviation of study protocol
`The need to take medication, which may interfere
`with study measurements
`Death
`Other
`Source :TEVA Complete Response Safety Update
`Disposition summarized through visit cut-off date of 31 March 2016. The Safety Population includes all
`subjects who were administered SD-809. Percentages are calculated based on the number of subjects in each
`cohort or overall, as appropriate
`Source: Adapted From TEVA Table
`
`One hundred thirty six patients were screened and 17 were excluded because they failed to
`meet study entry criteria leaving 119 in the safety population. Adverse event was the most
`common reason for discontinuing from Study C16 but overall, only about 1% discontinued
`because of an adverse event (Table 7).
`
`ADVERSE EVENTS
`
`Deaths
`One patient from the Rollover cohort died due to sudden cardiac death in while enrolled in
`Study 016. Since the CR action, Teva submitted a second NDA for the treatment of tardive
`dyskinesia to the Division of Psychiatry products. The applicant included narratives for 5
`patient deaths from the clinical development program for tardive dyskinesia (TD) in the
`resubmission safety update. Three patients in TD Study SD-809-C-20 and another two
`patients in TD StudySD-809-C-23 died. In Study SD-809-C-20, one patient died from septic
`shock following gastric perforation discovered on autopsy (25 days after stopping SD-809),
`another patient died following to a brainstem infarct visualized on CT scan and the third
`patient had a complex cardiac history and suffered sudden cardiac death. None of the deaths
`seemed related to SD-809. In StudySD-809-C-23, one patient died during sleep and the other
`was reported to have died from a cardiopulmonary arrest but few details were included in the
`case narrative.
`
`Table 8: Nonfatal Serious Adverse Events SD-809-C-16 (ARC-HD)
`USUBJID
`AEDECOD
`AEOUT
`SD809C15-007-3047
`Penile cancer Recovered/Resolved
`SD809C15-024-3121
`Chest discomfort Recovered/Resolved
`
`DOSE AE (mg)
`54
`36
`
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`Recovered/Resolved
`
`Recovered/Resolved
`
`Depression
`suicidal
`Mental status
`changes
`Suicide attempt Recovered/Resolved
`Appendicitis Recovered/Resolved
`Hip fracture Recovered/Resolved
`Lumbar spinal
`Recovered/Resolved
`stenosis
`Recovered/Resolved
`Spondylolisthesis
`Infection
`Deep vein
`thrombosis
`Pulmonary
`embolism
`Upper limb
`fracture
`Dehydration Recovered/Resolved
`Suicide attempt Recovered/Resolved
`Pneumonia
`Recovered/Resolved
`Cellulitis
`Recovered/Resolved
`staphylococcal
`Recovered/Resolved With Sequelae
`Intestinal
`obstruction
`Not Recovered/Not Resolved
`Weight decreased
`Pneumonia Recovered/Resolved
`Fall
`Recovered/Resolved
`Laceration
`Recovered/Resolved
`
`Recovered/Resolved
`Recovered/Resolved
`Recovered/Resolved
`
`Recovered/Resolved
`
`SD809C15-028-3583
`
`SD809C15-029-3181
`
`SD809C15-031-3621
`SD809C15-031-3624
`SD809C15-031-3627
`SD809C15-045-3641
`
`SD809C15-052-3323
`SD809C15-052-3324
`
`SD809C15-083-3373
`
`SD809C15-341-3841
`SD809C15-342-3863
`SD809C16-007-7023
`
`SD809C16-020-7880
`
`SD809C16-083-7323
`SD809C16-083-7329
`
`SD809C16-093-7841
`SD809C16-093-7842
`
`36
`
`42
`
`48
`
`24
`
`48
`48
`12
`36
`
`60
`48
`
`12
`
`66
`60
`24
`
`42
`
`48
`36
`
`24
`42
`
`Cross Discipline Team Leader Review
`
`SD809C15-027-3161
`
`
`Major depression
`Suicidal ideation
`Anxiety
`
`Recovered/Resolved With Sequelae
`Recovered/Resolved
`Recovered/Resolved With Sequelae
`
`SD809C15-028-3582
`
`Dehydration
`Encephalopathy
`Lethargy
`
`Recovered/Resolved
`Recovered/Resolved
`Recovered/Resolved
`
`Dehydration Recovered/Resolved
`Pyelonephritis
`Recovered/Resolved
`acute
`Failure to thrive Not Recovered/Not Resolved
`
`SD809C16-342-7822
`Source: Reviewer
`
`Twenty two patients experienced a serious adverse event 5 of these patients were on daily
`doses that exceeded the maximum recommended dose of 48 mg and another 5 were taking 48
`mg daily when they experienced a serious adverse event. Pneumonia and suicide attempt were
`the most commonly reported serious adverse events (2 patients each) with all of the remaining
`adverse events reported in a single patient.
`
`
`72
`
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`Cross Discipline Team Leader Review
`
`Adverse Events Leading to Dose Change of Discontinuation of Study SD-809
`Treatment with dTBZ was interrupted or the dose was reduced in 21 patients. Twelve patients
`had adverse events that caused them to ultimately, discontinued dTBZ; however, some of these
`patients had their dose reduced or temporarily withheld before stopping the drug. The most
`common adverse events leading to discontinuation were depression (6%), akathisia (5%),
`somnolence (5%), suicidal ideation (4%), with anxiety, fatigue dysphagia and parkinsonism
`reported in 3%. The combined the incidence of patients reporting the terms somnolence,
`fatigue, lethargy and fatigue is 12%. The full list of adverse events leading dose change or
`withdrawal of SD-809 is included in Dr. Bergmann’s review.
`USUBJID
`TRT01A
`AEDECOD
`AEOUT
`
`DOSEAEO
`N
`54
`
`SD809C15-
`007-3047
`SD809C15-
`024-3121
`SD809C15-
`027-3161
`SD809C15-
`027-3161
`SD809C15-
`027-3161
`SD809C15-
`028-3582
`SD809C15-
`028-3582
`SD809C15-
`028-3582
`SD809C15-
`028-3583
`SD809C15-
`029-3181
`SD809C15-
`031-3621
`SD809C15-
`031-3624
`SD809C15-
`031-3627
`SD809C15-
`045-3641
`SD809C15-
`045-3641
`SD809C15-
`052-3323
`SD809C15-
`052-3324
`SD809C15-
`052-3324
`SD809C15-
`083-3373
`SD809C15-
`341-3841
`SD809C15-
`342-3863
`
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`C-15 SD-809 ER
`ROLLOVER
`
`Penile cancer
`
`RECOVERED/RESOLVED
`
`Chest discomfort RECOVERED/RESOLVED
`
`Major depression RECOVERED/RESOLVED
`WITH SEQUELAE
`RECOVERED/RESOLVED
`
`Suicidal ideation
`
`Anxiety
`
`Dehydration
`
`RECOVERED/RESOLVED
`WITH SEQUELAE
`RECOVERED/RESOLVED
`
`Encephalopathy
`
`RECOVERED/RESOLVED
`
`Lethargy
`
`RECOVERED/RESOLVED
`
`Depression
`suicidal
`Mental status
`changes
`Suicide attempt
`
`RECOVERED/RESOLVED
`
`RECOVERED/RESOLVED
`
`RECOVERED/RESOLVED
`
`Appendicitis
`
`RECOVER