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

`

`NDA Number:
`Submission Type:
`Resubmission Date:
`Generic Name:
`Brand Name:
`Dosage form:
`Dosage strength:
`Proposed Indication:
`Applicant:
`Reviewer:
`Team Leader:
`OCP Division:
`OND Division:
`
`Clinical Pharmacology Review
`208082
`Complete Response Resubmission
`Oct 3, 2016
`Deutetrabenazine (SD-809)
`Austedo
`Oral Tablets
`6 mg, 9 mg and 12 mg
`Treatment of Chorea Associated with Huntington’s Disease
`Teva Pharmaceuticals, Inc.
`Hristina Dimova, Ph.D.
`Sreedharan Sabarinath, Ph.D.
`DCP1
`Division of Neurology Products (DNP)
`
`Reference ID: 4060256
`
`1
`
`

`

`1.0 EXECUTIVE SUMMARY
`New Drug Application (NDA) 208082, for SD-809 (deutetrabenazine) for chorea
`associated with Huntington’s Disease (HD), was submitted on 29 May 2015 as a
`505(b)(2) application. Xenazine (NDA 021894) was referenced as the listed drug. This
`NDA submission received a Complete Response (CR) Letter on May 27, 2016 mainly
`due to Clinical Pharmacology and Nonclinical issues listed below1. Please refer to the
`Clinical Pharmacology review in DARRTS (Apr 8, 2016) for further details.
`CLINICAL PHARMACOLOGY
`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.
`NONCLINICAL
`The toxicokinetic analyses of metabolites in the pivotal nonclinical studies of
`deutetrabenazine are limited to quantitation of the primary metabolites of
`deutetrabenazine (i.e., alpha and beta-DHTBZ). If the results of the pending clinical
`pharmacology analyses identify additional major circulating human metabolites, you will
`need to demonstrate that each has been adequately assessed in the appropriate
`nonclinical studies or that plasma exposure to each does not exceed that in humans with
`Xenazine.
`
`The Applicant submitted a Complete Response to NDA 208082 on Oct 3, 2016, which
`included the following sections:
` Updated draft labeling, Update of nonclinical written and tabulated summaries
`(Section 2.6)
` Update of the Summary of Clinical Pharmacology (Section 2.7.2) reflecting
`additional data for SD-809 metabolites
`No new clinical study reports were submitted in this NDA resubmission. 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 to provide definitive human plasma exposure data in this
`resubmission.
`
`1 Complete Response Letter for NDA 208082 dated 05/27/2017
`
`Reference ID: 4060256
`
`2
`
`

`

`1.1 RECOMMENDATION
`The Office of Clinical Pharmacology (OCP)/ Division of Clinical Pharmacology-1 has
`reviewed the Clinical Pharmacology information submitted to NDA 208082 and finds it
`acceptable. The NDA can be approved from a clinical pharmacology perspective.
`
`1.2 SUMMARY OF CLINICAL PHARMACOLOGY FINDINGS
`
`The clinical pharmacology findings are as follows:
` 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 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.
` The Clinical Pharmacology information reviewed during the resubmission is
`adequate to support the approval of NDA 208082.
`
`2.0 NDA RESUBMISSION REVIEW
`2.1 Background
`Deutetrabenazine (SD-809), like tetrabenazine (TBZ), is rapidly converted by carbonyl
`reductase to the active metabolites α-HTBZ and β-HTBZ, which are O-dealkylated by
`CYP450 enzymes, principally CYP2D6 (with minor contribution of CYP1A2), to form 9-
`and 10-desmethyl-α- and β-DHTBZ. Subsequently, they are metabolized to sulfate or
`glucuronide conjugates (See Figure below).
`
`Metabolic Pathway of SD-809 and Tetrabenazine in Humans
`
`Reference ID: 4060256
`
`3
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`Source: Section 2.7.2 Summary of Clinical Pharmacology Studies, Figure 7
`
`The metabolite profiling and identification results of the human [14C]-ADME and mass-
`balance study presented in the original NDA submission were inconclusive to determine
`whether the SD-809 metabolites 2-methylpropanoic acid metabolite of β-HTBZ (M1)
`and monohydroxy tetrabenazine (M4), are major or minor human metabolites.
`
`2.2 Clinical Pharmacology Information Submitted with the Complete
`Response
`No new clinical study reports were submitted in this NDA resubmission. The sponsor has
`validated LC-MS/MS bioanalytical methods for M1 and M4 and analyzed the retained
`clinical plasma samples from the human [14C]-ADME and mass-balance study SD-809-
`C-12 for these metabolites to provide definitive human plasma exposure data.
`The Applicant has also analyzed retained clinical plasma samples from the multiple-dose
`Study AUS-SD-809-CTP-07, Part 2 to provide human exposure of M1 and M4 at steady
`state in order to assess whether these metabolites are adequately represented in
`nonclinical species in the toxicology studies.
`In addition, the sponsor has submitted the results of several nonclinical pharmacology
`studies (off-target binding and genetic toxicology studies of metabolites M1 and M4) and
`the following Analytical Methods and Validation Reports:
` Project Code: VAL194)
` Validation Report DP-2016-068
` Validation Report DP-2016-069
` Project Code: VAL195)
`
`Stability of the analytes M1 and M4 was assumed based on re-analyses of SD-809, α-
`HTBZ, and β-HTBZ in retained plasma samples. According to the Applicant, the stability
`of SD-809 and the HTBZ metabolites can be reasonably expected to reflect stability of
`
`Reference ID: 4060256
`
`4
`
`(b) (4)
`
`(b) (4)
`
`

`

`M1 and M4 based on the structural similarities of M1 to β-HTBZ and M4 to SD-809 in
`the same samples.
`The Applicant assessed stability/reproducibility of SD-809, α-HTBZ and β-HTBZ
`concentrations in retained plasma samples stored at -80°C from the human [14C]-ADME
`and mass-balance study SD-809-C-12 and from the multiple-dose portion of Study AUS-
`SD-809-CTP-07, Part 2. Audited concentrations for SD-809, α-HTBZ and β-HTBZ
`obtained from reanalysis using the validated LC-MS/MS method were compared to the
`original results listed in their respective clinical study reports (Study SD-809-C-12
`completion date 25 August 2012; Study AUS-SD-809-CTP-07 completion date 22 June
`2012). More than 67% of the re-analyzed samples passed the ISR acceptance criteria for
`SD-809 and for the HTBZ metabolites.
`
`2.3 Metabolite Characterization
`The following changes have been made to the sampling approach, bioanalytical
`methodology and the calculations for the metabolites M1 and M4 with respect to total
`drug-related material from Study SD-809-C-12:
`Plasma samples
`In the original study results submitted to NDA 208082, only 4 plasma samples per
`
`subject (2, 2.5, 6 and 12 hours post-dose) were pooled (per protocol) in a time
`proportional manner, from each of the subjects treated with SD-809 (n = 6) or
`tetrabenazine (n = 6), for radio-chromatographic analysis of metabolites.
`In the new analysis presented in this document, all 11 plasma samples drawn over
`the first 12 hours post-dose were assessed individually 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.
`Reviewer’s Comment: This is acceptable.
`
`
`
`Evaluation of metabolites with respect to total drug related material (TDRM)
`In the original study results submitted to NDA 208082, the plasma pool for each
`
`subject (as described above) was used to estimate the percentage of metabolites
`with respect to total drug-related material in the same pool.
`In the new analysis presented in the NDA 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 infinity (AUCinf) values and were subsequently
`expressed as a percentage of the AUCinf for total drug-related material, which had
`
`
`
`Reference ID: 4060256
`
`5
`
`

`

`been previously quantified from samples throughout the same 216-hour post-dose
`time course (Study Report SD-809-C-12, Listing 16.2.6.2).
`Reviewer’s Comments: According to SD-809-C-12 study report (see below),
`elimination half-life for the total plasma radioactivity could only be calculated in 1
`subject. Therefore, according to this report, the AUCinf for total plasma radioactivity
`could not be adequately estimated for 5 out of the 6 subjects.
`
`From Original NDA 208082 Submission, Clinical Study Report SD-809-C-12 Amendment
`01 (
`113049) Version 2.0 (06 March 2015), Page 66 of 287:
`Pharmacokinetic parameter estimates for whole blood and plasma total radioactivity are
`presented in Data Listings 16.2.6.1 and 16.2.6.2, and summarized in Tables 14.2.8.1 and
`14.2.8.2, respectively. Following oral administration of 25 mg [14C]-SD-809,
`concentrations of total radioactivity in plasma were detected at 0.67 h (i.e., 40 min) after
`dosing in all subjects. Maximum concentrations occurred between 0.67 and 6.00 h post-
`dose in individual subjects; thereafter, concentrations declined in a biphasic manner.
`Maximal concentrations for each subject ranged from 90.7 to 148.5 ng equivalents/mL in
`plasma. Radioactivity in plasma was less than 2 x background for the majority of subjects
`by 96 h and was below the limit of detection by 144 h post-dose for all subjects. An
`elimination half-life could only be calculated in 1 subject and is therefore not included in
`Table 7. The geometric mean MRT for total radioactivity was 22.9 h.
`
`
`Reference ID: 4060256
`
`6
`
`(b) (4)
`
`

`

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`
`
`TEIPABDIAZDE - 25 :9 [11C] >teczabena:ine
`Nova: Izeatnen: definition: SD-EDB - 25 mg [14C] -SD-EI39
`a=R.-q cf xchcsainn ..C'.5’JDD. Estimt: res-D:c:d but not. :nsluicd m awry 53cc:
`L‘=Per‘.cd use: for regression analysu < 1—fcld tne calmlatei I—halz'. Est xepcrted bu: not included in mammary stats
`mam: calculazed
`PROGRAM ERIE: I{:\ » “13045“. -‘.IE'IS\PRODCCZIOH\LIS_PI1
`
`3131332013 13:52
`
`Source: Clinical Study Report SD—809-C-I2 Amendment 01 ( ”(0113049) Version 2.0
`(06 March 2015)
`
`This issue was discussed with the sponsor at the End of Review (Type A Meeting) on
`Sept 20, 2016. The clinical pharmacology team recommended calculating the percentage
`of total drug-related material based on AUC¢t (for total plasma radioactivity and for
`Ml/M4) instead of the AUCM.
`
`The discussion at the Type A meeting focused mainly on Ml since (according to the
`nonclinical reviewer) M4 was adequately bridged to Xenazine.
`
`Applicant’s justification for using AUCM instead of AUCM:
`
`The Applicant focused on presenting M1 and M4 with respect to total drug related
`material (TDRM) using AUC04,o as AUCM clearly underestimates overall exposure to
`TDRM but not to these metabolites (2.7.2 Summary of Clinical Pharmacology Studies,
`page 63).
`
`Reviewer’s Comments: I agree with the sponsor that AUCQt seem to underestimate the
`total radioactivity but not so much that the systemic exposure to M1/M4 due to the
`differences in bioanalytical methods for metabolites and for TDRM: the lowest value
`reported for TDRM was 7.9 ng eq/mL at 96 h post-dose (Report SD-809-C-12), while for
`M1 the lowest value reported was 0.22 ng/mL (also at 96 h post-dose). The extrapolated
`areas under the curve (AUCymap) were <2% for M1 and M4 for all subjects.
`Extrapolation was <25% for 5 of the 6 subjects for TDRM due to the slower terminal
`decline of total drug-related material than for M1 and M4.
`
`Reference ID: 4060256
`
`

`

`However, according to the sponsor (Table 1 below), elimination rate constant can be
`reliably estimated for 4 out of 6 subjects in the mass-balance study.
`
`Source: NDA 208082, Sequence No. 0024, 1.6.2 Meeting Background Materials (July 22,
`2016)
`In the Type A Meeting Briefing document, the sponsor had accepted AUCinf for 5 of the
`6 subjects. One subject was excluded due to AUC%extrap >45%.
`In light of FDA’s comments, the sponsor revisited the criteria for accepting elimination
`rate constants in the original mass balance study report and believes that r2 > 0.75 and
`%AUCextrap less than 25% are the most relevant to the current analysis of total drug-
`related material.
`Upon this re-evaluation, the sponsor considers 4 out of the 6 subjects in the mass-balance
`study as acceptable, as their r2 for elimination rate constants were greater than 0.75, and
`AUCextrap values ranged from 8.4% to 16.3% (See Table 1 above). In a single subject
`(S005; See Table 1 above), the r2 for elimination rate constant was less than 0.75; this
`AUCinf could be considered not evaluable.
`The sponsor further argues that, based on AUCinf, assessment of the systemic exposures
`to M1 and M4 at steady state indicate that, across the dose range (7.5 mg to 22.5 mg
`BID), M1 corresponds to on average 6.5% (range across 3 doses: 4.5% to 8.8%) and M4
`
`Reference ID: 4060256
`
`8
`
`

`

`on average 3.4% (range across 3 doses: 1.7% to 5.5%) of total drug-related material,
`indicating that systemic exposures to M1 and M4 are below 10%.
`Reviewer’s Comments: The metabolite/ TDRM ratio described above was calculated
`using results from different studies, different formulations and single vs. multiple dosing:
`the metabolite M1/M4 plasma steady state values are from Study AUS-SD-809-CTP-07,
`Part 2, while the total radioactivity (single dose) values are from the mass-balance study
`SD-809-C-12. Assessing metabolite/ TDRM ratio using results from different studies,
`different formulations and single vs. multiple dosing may not be appropriate for the
`reasons discussed below.
`The sponsor claims that using AUCinf of total drug-related material from SD-809-C-12 as
`a surrogate for AUCtau of total drug-related material at steady state in AUS-SD-809-
`CTP-07, is justified based on two assumptions:
`First, the pharmacokinetics of parent and metabolites should be dose and time
`independent.
`Reviewer’s Comment: While linearity was demonstrated for the primary metabolites α-
`HTBZ and β-HTBZ, this cannot be confirmed for all metabolites that comprise the
`remaining total drug-related material. Therefore, the single-dose AUCinf for total drug-
`related material cannot be assumed to reliably predict the corresponding AUCtau at steady
`state.
`The second assumption is that subjects in the single-dose human [14C]-ADME and mass-
`balance study are representative of those in Study AUS-SD-809-CTP-0.
`Reviewer’s Comments: The second assumption is not justified due to the high
`variability in the metabolism of SD-809.
`In addition, two different formulations were used in these 2 studies.
`Therefore, assessing metabolite/ TDRM ratio using results from different studies,
`different formulations and single vs. multiple dosing may not be appropriate.
`
`Notes:
`The steady state M1/M4 human exposure information was requested by the Agency (Late-
`Cycle Meeting Minutes, March 21, 2016) in order to assess whether these metabolites
`are adequately represented in nonclinical species in the toxicology studies. M1/M4
`plasma steady state values were not meant to be used to calculate metabolite/TDRM ratio
`as no data for TDRM is available from study AUS-SD-809-CTP-07.
`While the steady-state exposures to M4 after SD-809 administration are less compared to
`the M4 exposures after tetrabenazine, exposures to M1 after SD-809 administration are
`about 5x higher than those after tetrabenazine (2.8x higher after extrapolating to
`equipotent dose).
`
`Plasma Metabolites of SD-809 and Tetrabenazine: AUC0-24 Values for M1 and M4
`at Steady State from AUS-SD-809-CTP-07, Part 2
`
`Reference ID: 4060256
`
`9
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`

`

`BID Dose
`
`Metabolite
`
`Extrapolated to Equipotent Dosea
`Observed Data
`AUC0-24
`Cmax
`Cmax
`AUC0-24
`b
`TBZ
`SD-809
`TBZ
`SD-809
`SD-809
`TBZ
`SD-809
`TBZ
`50 mg
`24 mg
`50 mg
`24 mg
`22.5 mg
`25 mg
`22.5 mg
`25 mg
`M1
`11.5
`531
`190
`28.6
`26.8
`5.74
`498
`95
`M4
`109
`274
`981
`25.4
`23.8
`54.3
`257
`491
`a Equipotent Dose=Observed AUC/Cmax for M1/M4* (24 mg/22.5 mg for SD-809) or (50 mg/25 mg for TBZ)
`b AUCτ•2=AUC0-24
`Abbreviations: AUC0-24, area under the concentration-time curve from time 0 to 24 hours; AUCτ, area under the
`concentration-time curve over the dosing interval; BID, twice daily; Cmax, maximum concentration AUC=ng•h/mL,
`Cmax=ng/mL
`To compare their exposures at the maximum recommended daily dose for each treatment, steady-state
`areas under the concentration-time curve from time 0 to 24 hours post-dose (AUC0-24) were normalized to
`24 mg BID SD-809 from the 22.5 mg treatment group or 50 mg BID for tetrabenazine.
`
`Source: NDA 208082, 2.7.2 Summary of Clinical Pharmacology Studies, Table 16
`
`The results from the single-dose mass-balance study show the same trend for M1
`exposures.
`
`2.4 Results of the Evaluation of M1 and M4 with Respect to Total Drug
`Related Material (TDRM)
`The systemic exposures to M1 and M4, expressed as a % of TDRM using AUC0-∞ for
`both metabolites and TDRM, are shown below. (Note: The applicant has included subject
`S005 in the analysis even though initially considered excluding this subject).
`Applicant’s Analysis Using AUCinf
`AUC0-∞
`SD-809 Individual Exposure (AUC0-∞) Parameters and TDRM for M1 and M4 in
`Subjects S001 through S006 (Cohort 1)
`( h•ng/mL)
`S001
`S002
`S003
`S004
`
`S005
`
`S006
`
`Mean (SD)
`
`M1
`
`M4
`
`346
`
`185
`
`322
`
`158
`
`447
`
`294
`
`TDRM
`
`3750
`
`3220
`
`4370
`
`223
`
`194
`
`NCa
`
`457
`
`213
`
`326
`
`243
`
`353 (87.4)
`
`214 (48)
`
`5290
`
`4450
`
`4220 (781)
`
`Metabolite
`
`M1
`
`M4
`
`SD-809: Percentage of TDRM Ratio in Subjects S001 through S006 (Cohort 1) b
`
`S001
`
`9.2
`
`4.9
`
`S002
`
`10.0
`
`4.9
`
`S003
`
`10.2
`
`6.7
`
`S004
`
`NCa
`
`NCa
`
`S005
`
`S006
`
`Mean (SD)
`
`8.6
`
`4.0
`
`7.3
`
`5.5
`
`9.1 (1.2)
`
`5.2 (1.0)
`
`Data calculated from following equation: AUC0-∞ of M1 or M4/AUC0-∞ of total plasma sample radioactivity
`a NC = not used for group mean of AUC0-∞ total radioactivity, as %AUCextrap ~45%.
`
`Reference ID: 4060256
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`

`b 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-∞, area under the concentration-time curve from time 0 extrapolated to infinity; DPM,
`disintegrations per minute; NC, Not calculated; SD, standard deviation; TDRM, total drug-related material
`
`Reviewer’s Comments: The applicant used the following criteria for calculating the PK
`parameters for M1 and M4 (Report DP-2016-065, Section 3.4. Pharmacokinetic
`Analysis):
`For calculating pharmacokinetic parameters, a BLQ value at time 0, at a sampling time
`before the first quantifiable plasma concentration, or at a sampling time between 2
`quantifiable concentrations was treated as zero. All other BLQ values were treated as
`missing.
`However, the same criteria were not applied to calculating the PK parameters for TDRM.
`For example, for Subject 006, the BLQ value at 96 h was excluded (instead of setting to
`0).
`
`Source: Clinical Study Report SD-809-C-12 Amendment 01
`06 March 2015
`
`113049) Version 2.0
`
`The reviewer re-analyzed the PK parameters for M1, M4 and TDRM for all subjects
`using non-compartmental analysis (NCA); the results of this analysis are presented
`below. Of note, for subjects 002, 004 and 005, the slope (and therefore AUC0-∞ of
`TDRM) could not be reliably estimated. An example is shown below.
`
`Reference ID: 4060256
`
`11
`
`(b) (4)
`
`

`

`Source: Clinical Study Report SD-809-C-12 Amendment 01
`06 March 2015
`
`113049) Version 2.0
`
`Reviewer’s Analysis Using AUCinf
`AUC0-∞
`SD-809 Individual Exposure (AUC0-∞) Parameters and TDRM for M1 and M4 in
`Subjects S001 through S006 (Cohort 1)
` (h•ng/mL)
`S001
`S002
`S003
`S004
`
`S005
`
`S006
`
`M1
`
`M4
`
`346
`
`185
`
`322
`
`158
`
`447
`
`294
`
`TDRM
`
`3744
`
`3221
`
`4379
`
`223
`
`194
`
`NCa
`
`457
`
`213
`
`326
`
`243
`
`4553
`
`4511
`
`Mean (SD)
`(SD)
`353
`
`214
`
`4082
`
`Metabolite
`
`M1
`
`M4
`
`SD-809: Percentage of TDRM Ratio in Subjects S001 through S006 (Cohort 1)
`
`S001
`
`9.2
`
`4.9
`
`S002
`
`10.0
`
`4.9
`
`S003
`
`10.2
`
`6.7
`
`S004
`
`NCa
`
`NCa
`
`S005
`
`10.0
`
`4.7
`
`S006
`
`Mean (SD)
`
`8.0
`
`5.9
`
`9.5
`
`5.4
`
`Source: Reviewer’s analysis
`
`Reference ID: 4060256
`
`12
`
`(b) (4)
`
`

`

`The systemic exposures to M1 and M4, expressed as a % of TDRM using AUC0-t for
`M1/M4 metabolites and TDRM, are presented below:
`
`AUC0-t
` (h•ng/mL)
`
`SD-809 Individual Exposure (AUC0-t) Parameters and TDRM for M1 and M4 in
`Subjects S001 through S006 (Cohort 1)
`
`S001
`
`S002
`
`S003
`
`S004
`
`S005
`
`S006
`
`M1
`
`M4
`
`339
`
`181
`
`319
`
`156
`
`440
`
`292
`
`217
`
`191
`
`448
`
`209
`
`319
`
`238
`
`Mean
`(SD)
`347 (86.5)
`
`211 (48.2)
`
`TDRM
`
`3310
`
`2700
`
`4000
`
`1980
`
`3980
`
`3760
`
`3290 (809)
`
`SD-809: Percentage of TDRM Ratio in Subjects S001 through S006 (Cohort 1) a
`
`Metabolite
`
`M1
`
`S001
`
`10.2
`
`S002
`
`11.8
`
`S003
`
`11.0
`
`S004
`
`11.0
`
`S005
`
`11.3
`
`S006
`
`8.5
`
`Mean
`(SD)
`10.6 (1.2)
`
`6.3
`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: Reviewer’s analysis
`
`6.6 (1.7)
`
`2.5 Discussion of the Results of the Evaluation of M1 and M4 with
`Respect to TDRM
`The applicant has validated sensitive assays for M1 and M4 and reanalyzed M1 and M4
`in retained clinical samples of subject treated with SD-809 as requested in the Complete
`Response Letter (May 27, 2016).
`The sponsor has re-evaluated the criteria for acceptance of 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. The
`sponsor has used the following criteria (see Table 1): r2 > 0.75 and %AUCextrap less than
`25% and ratio of the duration of time used to derive the regression constant/half-life >1.
`Reviewer’s Comments: The sponsor did not provide a convincing justification for using
`these acceptance criteria. In addition, the sponsor acknowledges that the elimination rate
`constant of TDRM cannot be reliably estimated from 2 of the 6 subjects (using the above
`criteria). in fact, the elimination rate constant of TDRM could not be reliably estimated
`for 3 of the 6 subjects. It is arguable whether or not excluding half of the subjects dosed
`with SD-809 in the mass balance study from the estimation of the metabolite/ TDRM ratio
`is appropriate.
`
`Reference ID: 4060256
`
`13
`
`

`

`However, 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 but not so much the systemic exposure to
`M1/M4 due to differences in bioanalytical ranges applied to metabolites and to TDRM),
`M4 is clearly a minor metabolite (mean 6.6% of TDRM) and M1 is about 10% (mean
`10.6% of TDRM).
`In addition, the nonclinical studies provided to support the resubmission (pharmacology,
`pharmacokinetic, and genetic toxicology studies of metabolites M1 and M4) do not show
`any findings of concern. Therefore, we believe the concerns raised during the original
`NDA review about M1/M4 are addressed in this resubmission.
`
`Reference ID: 4060256
`
`14
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`Appendix
`Updates to the Biopharmaceutic Studies and Associated Analytical
`Methods
`Liquid chromatography with tandem mass spectrometry (LC-MS/MS) bioanalytical
`methods for M1 (2-methylpropanoic acid-β HTBZ) and M4 (monohydroxy SD-809) have
`been validated and used for the analysis of retained clinical plasma samples from studies
`SD-809-C-12 and AUS-SD-809-CTP-07, Part 2 for these metabolites.
`Note: Separate validated LC-MS/MS methods were used to measure plasma
`concentrations of SD-809, its deuterated α-HTBZ and β-HTBZ metabolites (SD-809-
`CLN-12) and ODM (SD-809-CLN-051) and tetrabenazine, its nondeuterated α-HTBZ
`and β-HTBZ metabolites (SD-809-CLN-11) and ODM metabolites (SD-809-CLN-50) in
`all clinical studies. The results from these analyses and the validation reports were
`discussed in the original NDA submission (see Clinical Pharmacology review Apr 8,
`2016).
`Summary of Method Validation for M1 and M4 Metabolites of SD-809 and
`Tetrabenazine by LC-MS/MS in Human Plasma Containing Lithium Heparin as
`Anticoagulant
`Document Control
`Number: Report
`Type
`
`Precisiona (%CV)
`
`Intra
`
`Inter
`
`Accuracyb over
`Assay Range (%)
`Intra
`Inter
`
`Stability
`
`Analyte
`
`Standard
`Curve
`Range
`(ng/mL)
`0.2 to 200
`
`DP-2016-069:
`method validation
`report
`
`DP-2016-068:
`method validation
`report
`
`Nondeuterated M1
`(SD-1027)
`
`Nondeuterated M4
`(SD-1026)
`
`Deuterated M1
`(SD-1021)
`
`Deuterated M4
`(SD-1018)
`
`1.0 to 8.9 2.3 to 7.7 -5.8 to
`9.0
`
`1.2 to 6.7 2.1 to 4.5 -4.7 to
`5.3
`
`0.2 to 200
`
`0.9 to 5.1 1.9 to 4.9 -3.3 to
`5.7
`
`1.5 to 7.7 2.2 to 5.1 -2.7 to
`6.5
`
`Room temperature: 25
`h Freeze/thaw: 5 cycles
` Long-term stability:
`145 days @ -80oC
`
`Room temperature: 24
`h Freeze/thaw: 5 cycles
` Long-term stability:
`145 days @ -80oC
`
`-2.7 to
`1.3
`
`-3.3 to
`2.8
`
`-2.7 to
`3.2
`
`-2.0 to
`4.3
`
`DP-2016-127: fit
`for purpose method
`validation report
`
`Nondeuterated M1
`(SD-1027)
`
`0.2 to 200 1.0 to 9.1 3.8 to 6.6 0.0 to 3.7 -3.5 to
`2.7
`
`DP-2016-126: fit
`for purpose method
`validation report
`
`Deuterated M1
`(SD-1021)
`
`0.2 to 200 1.7 to 6.9
`
`2.3 to
`10.4
`
`-3.7 to
`4.5
`
`-5.3 to -
`0.5
`
`Room temperate: 24 h
`Long term stability: 449
`days @ -80°C
`
`Room temperate: 24 h
`Long term stability: 449
`days @ -80°C
`
`a Precision: (SD/Mean Measured Concentration) x 100
`b Accuracy: [(Mean Measured Concentration – Nominal Concentration) x 100]/ Nominal Concentration
`Abbreviations: CV, coefficient of variation; HTBZ, dihydrotetrabenazine; SD, standard deviation.
`
`The validated methods used to quantify deuterated and non-deuterated M1 and M4
`metabolites in human plasma demonstrated stability of all analytes for at least 140 days in
`samples stored at -80ºC. Prior to availability of the validated methods, qualified (fit for
`purpose) methods for deuterated and non-deuterated M1 in human plasma demonstrated
`
`Reference ID: 4060256
`
`15
`
`

`

`stability for at least 449 days in samples stored at -80ºC (DP-2016-126 and DP-2016-
`127). The “qualified methods” were not validated.
`In all validation reports, the following analyte ID numbers were used:
`
` Project Code: VAL194)
`Validation Report DP-2016-068
`The objective of this study was to validate a method for analysis of SD-1021 (d6-M1)
`metabolite and SD-1018 (d6-M4) metabolite of SD-809 (d6-tetrabenazine) in human
`plasma containing lithium heparin (LiH) as anticoagulant.
`
`
`
`The method was fully validated to investigate method selectivity*, accuracy & precision
`(including sensitivity at LLOQ), recovery, linearity, dilution, the effect of haemolysis and
`lipaemia on quantitation, matrix factor and matrix effects, ruggedness (e.g. system and
`analyst) and stability (i.e. freeze/thaw, benchtop, processed stability, reinjection, stock
`solutions**, long term** and whole blood).
`*OTC drugs: No interference with the analyte or IS was observed when tested with
`acetaminophen, amoxicillin, aspirin, caffeine, chlorpheniramine maleate, lidocaine,
`naproxen, desipramine, ibuprofen, RR(-)-pseudoephedrine, salicylic acid, theobromine,
`theophylline, tetracycline and xanthine.
`
`Reference ID: 4060256
`
`16
`
`(b) (4)
`
`

`

`**Long term stability in plasma and stock solution stability (145 days) was reported as an
`addendum (Sept 14, 2016) to the validation report.
`Validation Results
`
`Reviewer’s Comment: The validation results are acceptable.
`
`Reference ID: 4060256
`
`17
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

` Project Code: VAL195)
`Validation Report DP-2016-069 (
`The objective of this study was to fully validate a method for the determination of SD-
`1027 (d0-M1) metabolite and SD-1026 (d0-M4) metabolite of tetrabenazine in human
`plasma containing lithium heparin (LiH) as anticoagulant.
`
`The method was fully validated to investigate method selectivity, accuracy & precision
`(including sensitivity at LLOQ), recovery, linearity, dilution, the effect of haemolysis and
`lipaemia on quantitation, matrix factor and matrix effects, ruggedness (e.g. system and
`analyst) and stability (i.e. freeze/thaw, benchtop, processed stability, reinjection, stock
`solutions, long term and whole blood).
`Validation Results
`
`
`
`Reference ID: 4060256
`
`18
`
`(b) (4)
`
`

`

`
`
`
`
`Reviewer’s Comment: The validation results are acceptable.
`
`Reference ID: 4060256
`
`19
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`HRISTINA DIMOVA
`02/23/2017
`
`SREEDHARAN N SABARINATH
`02/23/2017
`
`Reference ID: 4060256
`
`

`

`
`
`PRODUCT (Generic Name):
`PRODUCT (Brand Name):
`
`NDA:
`
`
`
`DOSAGE FORM:
`
`
`DOSAGE STRENGTHS:
`
`INDICATION:
`
`
`
`
`
`
`
` Deutetrabenazine (SD-809)
` Austedo
` 208082
` Tablets
` 6 mg, 9 mg and 12 mg
`Treatment of chorea associated with
`Huntington’s disease (HD)
`NDA TYPE Standard
`
`SUBMISSION DATE:
`
`
` May 29, 2015
`SPONSOR:
`
`
`
`
` Teva Pharmaceuticals, Inc
`PRIMARY REVIEWER:
`
`
` Hristina Dimova, Ph.D.
`TEAM LEADER:
`
`
`
` Angela Men, M.D, Ph.D.
`PHARMACOMETRICS REVIEWER: Xiaofeng Wang, Ph.D.
`PHARMACOMETRICS TEAM LEADER: Kevin Krudys, Ph.D.
`GENOMICS REVIEWERS: Jeffrey Kraft, Ph.D.
` Christian Grimstein, Ph.D.
`OCPB DIVISION:
`
`
`
` DCP-I
`OND DIVISION:
`
`
`
` HFD-120
`
`
`
`Clinical Pharmacology/Biopharmaceutics Review
`
`
`
`
`
`Reference ID: 3914812
`
`1
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`
`
`TABLE OF CONTENTS
`
`TABLE OF CONTENTS ............................................................................................................................... 2
`EXECUTIVE SUMMARY ................................................................................................................ 4
`1.0
`1.1
`RECOMMENDATION .............