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

`

`Tertiary Pharmacology Review
`
`By:
`Paul C. Brown, Ph.D., ODE Associate Director for Pharmacology and
`Toxicology, OND IO
`NDA: 208082
`Submission date: 10/3/2016 Resubmission
`Drug: deutetrabenazine
`Applicant: Teva Pharmaceuticals
`Indication: Treatment of chorea associated with Huntington’s disease
`
`Reviewing Division: Division of Neurology Products
`
`Discussion and conclusion:
`The initial pharm/tox review of this NDA noted that there was insufficient
`information to confirm that the human metabolites, particularly major human
`metabolites, were comparable between tetrabenazine and deutetrabenazine.
`Such a comparison was necessary to understand whether the safety of
`tetrabenazine supported deutetrabenazine. The resubmission has clarified the
`human metabolite profiles sufficiently such that the pharm/tox reviewer and
`supervisor conclude that the nonclinical information provided supports the
`approval of the NDA for the above indication. I agree.
`
`
`Reference ID: 4077805
`
`1
`
`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/
`----------------------------------------------------
`
`PAUL C BROWN
`03/30/2017
`
`Reference ID: 4077805
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`Supporting document:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`
`Applicant:
`Review Division:
`Reviewer:
`Supervisor:
`Division Director:
`Project Manager:
`Disclaimer
`
`208-082
`17, 20, 23, 26
` 1/15/2016; 4/8/2016; 5/9/2016; 10/3/2016
`1/15/2016; 4/8/2016; 5/9/2016; 10/3/2016
`AUSTEDO (SD-809; deutetrabenazine)
`Treatment of chorea associated with
`Huntington’s disease
`Teva Pharmaceuticals, Inc.; La Jolla, CA
`Neurology Products (DNP)
`Christopher D. Toscano, Ph.D., DABT
`Lois M. Freed, Ph.D.
`Billy Dunn, M.D.
`Stacy M. Metz, Pharm. D.
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 208-082 are owned by Teva Pharmaceuticals, Inc. or
`are data for which Teva Pharmaceuticals, Inc. has obtained a written right of reference.
`Any
`information or data necessary
`for approval of NDA 208-082
`that Teva
`Pharmaceuticals, Inc. does not own or have a written right to reference constitutes one
`of the following: (1) published literature, or (2) a prior FDA finding of safety or
`effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or
`information described or referenced below from reviews or publicly available summaries
`of a previously approved application are for descriptive purposes only and are not relied
`upon for approval of NDA 208-082.
`
`Reference ID: 4043245
`
`1
`
`

`

`NDA 208-082
`
`Christopher D. Toscano, Ph.D., DABT
`
`Executive Summary
`1
`Introduction
`1.1
` The sponsor of NDA 208-082, Teva Pharmaceuticals, Inc., was provided with a
`Complete Response (CR) letter on May 27, 2016. In the CR letter, the sponsor was
`informed that the “clinical pharmacology studies were not adequate to determine
`whether all major human metabolites of deutetrabenazine have been identified.”
`Specifically, based on
`the
`information provided during
`the development of
`deutetrabenazine (SD-809), metabolites M1 (SD-1021) and M4 (SD-1018) were thought
`to be major human metabolites (MHM). Based on the fact that there was limited
`information on the level of these metabolites circulating in animals dosed with
`deutetrabenazine, the sponsor was informed in the CR letter that “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…” A review of the nonclinical studies provided in the
`initial submission was filed (Toscano CD, Nonclinical Review, February 4, 2016).
` After internal discussions about the clinical pharmacology information provided in the
`NDA resubmission (October 3, 2016), it has been determined that metabolites M1 and
`M4 are not major human metabolites as defined by ICH M3(R2) because they do not
`circulate at levels greater than 10% of the total drug-related exposure (see Clinical
`Pharmacology Review for detailed assessment). Because nonclinical studies of these
`metabolites are no longer needed to support approval of the NDA, the nonclinical
`studies provided in the resubmission to support the safety of metabolite M1 and M4 will
`only be discussed briefly in Section 1.2 of this review. As stated in the February 4, 2016,
`nonclinical review, the nonclinical studies provided in the initial submission are
`adequate to support the approval of NDA 208-082.
`1.2 Discussion of Nonclinical Findings
` In
`the
`resubmission,
`the sponsor provided a series of pharmacology,
`pharmacokinetic, and genetic toxicology studies of metabolites M1 and M4. M1 binding
`to the rat adrenergic α2 receptor and the human adrenergic α2C receptor was
`demonstrated in a series of adequately conducted in vitro high-throughput screens
`(DPR-2016-030, DPR-2016-032, DPR-2016-033); M4 did not demonstrate relevant
`binding in similar studies (DPR-2016-029, DPR-2016-031). The pharmacokinetic
`studies of M1 and M4 after oral dosing of rat, mouse, and rabbit with SD-809 or
`tetrabenazine (TBZ) were performed to determine if exposure to these metabolites had
`been adequate in nonclinical studies previously conducted by the sponsor or those
`described in the Xenazine label (DS-2016-016, DP-2016-037, DP-2016-038, DP-2016-
`054, DP-2016-056, SD-809-NC-062, DP-2016-043, DP-2016-045). Since it has been
`subsequently demonstrated that these metabolites are not MHMs, these studies are not
`required to support the approval of the NDA. There were no findings of concern in the in
`vitro (DP-2016-001, DP-2016-002, DP-2016-003) or in vivo pharmacokinetic studies
`provided in the resubmission and the results of these studies were consistent with what
`was described in the sponsor’s meeting package (July 22, 2016). M4 and M1 were
`negative in an adequately conducted in vitro bacterial reverse mutation assay and an
`
`Reference ID: 4043245
`
`2
`
`

`

`NDA 208-082
`
`Christopher D. Toscano, Ph.D., DABT
`
`adequately conducted in vitro chromosomal aberration study, respectively (DS-2016-
`027, DS-2016-024). Computational toxicology assessment of the mutagenicity of M1
`and M4 was negative (DRK16-0826, DRK16-0834). There were no test article-related
`findings when M1 was tested in a zebrafish developmental toxicity screen (DS-2016-
`038). In summary, there were no test article-related findings of concern in the
`nonclinical studies provided to support the resubmission.
`1.3 Recommendations
`1.3.1 Approvability: The nonclinical studies reviewed under the initial submission are
`adequate to support the approval of NDA 208-082 (see February 4, 2016, review for
`additional details).
`1.3.2 Additional Non Clinical Recommendations: None
`1.3.3
`Labeling: Labeling recommendations can be found in the February 4, 2016,
`nonclinical review.
`2
`Drug Information:
`For detailed drug information, refer to Toscano CD, “Pharmacology/Toxicology NDA
`Review and Evaluation”, NDA 208-082, February 4, 2016.
`3
`Studies Submitted
`3.1
`Studies Reviewed
`Pharmacology:
` DPR-2016-029, VMAT2 and off-target binding SD-1018 (SD-809 M4)
` DPR-2016-030, VMAT2 and off-target binding SD-1021 (SD-809 M1)
` DPR-2016-031, VMAT2 and off-target binding SD-1026 (TBZ M4)
` DPR-2016-032, VMAT2 and off-target binding SD-1027 (TBZ M1)
` DPR-2016-033, binding of SD-1018 (SD-809 M4) and SD-1026 (TBZ M4) to
`adrenergic α2C (human) receptors
`Pharmacokinetics
`Analytical Methods and Validation Reports:
` SD-809-NC-061, Validation of a Method for the Determination of SD-1021
`Metabolite and SD-1018 Metabolites of SD-809 (d6-tetrabenazine) in Rat Plasma
`by LC/MS/MS
` DP-2016-090, An Analytical Method Validation and Stability Study of SD-809
`Metabolite M4 (SD-1018) in Dimethyl sulfoxide Formulations
`Absorption:
` DS-2016-016, A 9-day, twice daily (BID) oral (gavage) pharmacokinetic
`evaluation of M1 (SD-1021 or SD-1027), M4 (SD-1018 or SD-1026), SD-809,
`and SD-808 (tetrabenazine) in Sprague Dawley rats.
` DP-2016-037, Pharmacokinetics of SD-809 in Male and Female CD-1 Mice after
`Single or Repeated Oral Doses
` DP-2016-038, Pharmacokinetics of Tetrabenazine in Male and Female C57/BL6
`Mice after Single or Repeated Oral Doses
`
`Reference ID: 4043245
`
`3
`
`

`

`NDA 208-082
`
`Christopher D. Toscano, Ph.D., DABT
`
` DP-2016-054, Pharmacokinetics of SD-809 and Tetrabenazine in Male and
`Female CD-1 and CF-1 Mice After Single Oral Dose SD-809 or Tetrabenazine
` DP-2016-056, Pharmacokinetics of SD-809 and Tetrabenazine in Female New
`Zealand White Rabbit after Single Oral Dose SD-809 or Tetrabenazine
` SD-809-NC-062, Pharmacokinetics of SD-1021 in rat
` DP-2016-043, In Life Report for DP-2016-054
` DP-2016-045, In Life Report for DP-2016-056
`
`Pharmacokinetic Drug Interactions:
` DP-2016-001, In Vitro Evaluation of SD-1018 (SD-809 Metabolite M4) as an
`Inhibitor of Cytochrome P450 (CYP) Enzymes in Human Liver Microsomes
` DP-2016-002, In Vitro Evaluation of SD-1018 (SD-809 Metabolite M4) as an
`Inducer of Cytochrome P450 Expression in Cultured Human Hepatocytes
` DP-2016-003, In Vitro Evaluation of SD-1018 (SD-809 Metabolite M4) as an
`Inhibitor and a Substrate of Human P-gp, BCRP, OATP1B1, OATP1B3, OAT1,
`OAT3, and OCT2 Transporters
`
`Genetic Toxicology:
` DS-2016-027, SD-1018: Salmonella-E. Coli/Mammalian Microsome Reverse
`Mutation Assay
` DS-2016-024, SD-1021: In Vitro Chromosome Aberration Test in Cultured
`Human Peripheral Blood Lymphocytes
` DRK16-0826, Computational Toxicity Report for Metabolite M4 in SD-809 (TEV-
`50717)
` DRK16-0834, Computational Toxicity Report for Metabolite M1 in SD-809 (TEV-
`50717)
`Developmental Toxicology:
` DS-2016-038, Zebrafish Developmental Toxicity Screen of TEV-48317 and SD-
`1021
`Studies Not Reviewed: None
`3.2
`Previous Reviews Referenced
`3.3
` Toscano CD, “Pharmacology/Toxicology NDA Review and Evaluation,” NDA
`208-082, February 4, 2016.
`
`Reference ID: 4043245
`
`4
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CHRISTOPHER D TOSCANO
`01/18/2017
`
`LOIS M FREED
`01/18/2017
`I concur.
`
`Reference ID: 4043245
`
`

`

`Tertiary Pharmacology Review
`
`By:
`Paul C. Brown, Ph.D., ODE Associate Director for Pharmacology and
`Toxicology, OND IO
`NDA: 208082
`Submission date: 5/29/2015
`Drug: deutetrabenazine
`Applicant: Teva Pharmaceuticals
`Indication: Treatment of chorea associated with Huntington’s disease
`
`Reviewing Division: Division of Neurology Products
`
`Discussion:
`This NDA referred to the Agency’s finding of safety for the approved drug,
`tetrabenazine (Xenazine). A comparison of the human metabolites associated
`with the two drugs is necessary to understand if the safety of tetrabenazine
`supports deutetrabenazine. The primary pharm/tox review and the supervisory
`review discuss the metabolites and note that the clinical pharmacology review is
`unable to confirm that the human metabolites, particularly major human
`metabolites (those that compose greater than 10% of total drug in circulation),
`are comparable between the two drugs. The pharm/tox reviewer and supervisor
`recommend that the human major metabolite profiles be clarified sufficiently such
`that the Agency can determine whether the existing finding of safety for
`tetrabenazine applies to deutetrabenazine.
`
`Conclusions:
`The pharmacology/toxicology reviewer and supervisor conducted a thorough
`evaluation of the nonclinical information submitted in support of this NDA. I agree
`that there needs to be an adequate bridge for the major human metabolites in
`order for the Agency to make a safety decision.
`
`Reference ID: 3936138
`
`1
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`PAUL C BROWN
`05/24/2016
`
`Reference ID: 3936138
`
`

`

`MEMORANDUM
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
` Public Health Service
`
`
` Food and Drug Administration
`
`
`
`
`
`________________________________________________________________________
`
`Division of Neurology Products (HFD-120)
`Center for Drug Evaluation and Research
`
`Date: March 31, 2016
`
`From: Lois M. Freed, Ph.D.
`
`Supervisory Pharmacologist
`
`Subject: NDA 208-082 (SD-809; d6-tetrabenazine; AUSTEDO; Auspex Pharmaceuticals)
`________________________________________________________________________
`
`NDA 208-082 was submitted on May 29, 2015, to support marketing approval of SD-809
`(deutetrabenazine) for treatment of the chorea of Huntington’s disease. The NDA is a
`505(b)(2) submission, with Xenazine (tetrabenazine; NDA 21-894) as the Reference
`Listed Drug (RLD). Clinical development was conducted under IND 112975.
`
`The nonclinical program consists of the following pivotal studies of SD-809:
`• Pharmacology
`• PK/ADME
`• Toxicology
`o 3-month oral toxicity study of SD-809 and tetrabenazine (TBZ) in rat
`o Embryofetal development study of SD-809 and TBZ in rat
`• Genetic toxicology
`o Ames, in vitro mammalian clastogenic assay in human peripheral blood
`lymphocytes, with SD-809 and d6 α- and β-HTBZ
`o In vivo micronucleus assay in mouse, with SD-809
`
`These data were reviewed in detail by Dr. Toscano (cf. Pharmacology/Toxicology NDA
`Review and Evaluation, NDA 208-082, Christopher D. Toscano, Ph.D., February 3,
`2016). Based on that review, Dr. Toscano has concluded that “It is not possible to
`determine if the nonclinical studies…support bridging to the…RLD…” because of the
`inadequacy of the sponsor’s evaluation of the in vivo metabolic profile of SD-809 in
`humans.
`
`The following is a summary of the nonclinical data provided for SD-809 and potential
`review issues; a comprehensive description and discussion of these data are provided in
`Dr. Toscano’s review.
`
`
`
`
`
`Reference ID: 3910569
`
`1
`
`

`

`Pharmacology
`
`SD-809 is a deuterated form of the RLD (TBZ), with substitution of two d-methoxy
`(-OCD3) groups in place of the two methoxy (-OCH3) groups of TBZ. SD-809, like TBZ,
`is an inhibitor of the vesicular monoamine transporter, type 2 (VMAT2). Binding
`affinities for VMAT2 were similar for the deuterated and non-deuterated active
`metabolites (α- and β-HTBZ) (sponsor’s table below), as were binding affinities to a
`panel of other receptors/binding sites.
`
`
`
`
`
`Safety Pharmacology
`
`The sponsor assessed CNS safety pharmacology in the pivotal 3-month oral toxicity
`study in Sprague-Dawley rat but only in males (6/group, Week 12), which was justified
`by the higher plasma exposures and more severe clinical signs in males. An in vitro
`hERG assay indicated IC50’s of >10 µM for the active metabolites of SD-809 and TBZ
`(identified in Table 1 above). In vivo cardiovascular or respiratory safety pharmacology
`studies were not conducted.
`
`PK/ADME
`
`PK/ADME studies of SD-809 and TBZ were conducted in CD-1 mouse and rat (Sprague-
`Dawley [non-pregnant and pregnant], Lister Hooded), as well as in vitro metabolism
`studies in rat and human liver preparations (S9, microsomes, or hepatocytes).
`
`In general, the PK/ADME of SD-809 was similar to that of TBZ. The major, active,
`metabolites quantified were d6 α- and β-dihydrotetrabenazine (d6 α- and β-HTBZ) In
`Sprague-Dawley rat, acute oral doses (2.5 and 15 mg/kg) of SD-809 resulted in up to 2.4-
`fold higher plasma AUCs for parent and metabolites, d6 α- and β-HTBZ, compared to
`TBZ and metabolites, α- and β-HTBZ, at the same doses. The pattern of tissue
`distribution, including brain penetration, in Lister Hooded or Sprague-Dawley rats, was
`also similar following acute oral doses of radiolabeled SD-809 and TBZ.
`
`In vivo metabolism studies were not conducted in animals. The sponsor stated that “None
`are planned as human exposure to the metabolites of the listed tetrabenazine will be used
`to qualify the SD-809 metabolites” (Pharmacokinetics Written Summary, pg. 8 of 25).
`However, the OCBP team has concluded that because of deficiencies in the evaluation of
`the in vivo metabolic profile in humans, it is unclear, based on the available data, whether
`
`
`
`Reference ID: 3910569
`
`2
`
`

`

`or not all major circulating metabolites of SD-809 in humans have been identified. The
`primary deficiencies are as follows:
`
`
`•
`
`Inconsistent values obtained for metabolite M1 (2-methylpropanoic acid
`metabolite of β-HTBZ), using semi-quantitative methods, resulting in an inability
`to determine whether or not M1 is a major metabolite in humans. It was not
`identified as a major human metabolite of TBZ, either by the sponsor or in TBZ
`labeling.
`• The inability of the sponsor to demonstrate, using semi-quantitative methods, that
`a known (based on TBZ labeling) major human metabolite of TBZ, 9-O-
`desmethyl-β-HTBZ, is a major human metabolite of SD-809 or TBZ. This
`deficiency increases the overall concern regarding the adequacy of these methods,
`as noted for M1.
`• Lack of information on an unidentified peak on the radiochromatograms of
`pooled plasma samples, which appears “much higher” with SD-809 compared to
`TBZ.
`
`
`Without an adequate understanding of the in vivo metabolic profile in humans, it is not
`possible to determine if all major circulating metabolites have been adequately evaluated
`in the appropriate nonclinical studies.
`
`The available data do suggest that M4 (monohydroxy TBZ) is a major human metabolite
`of SD-809 and TBZ; however, M4 is not identified as such in labeling for TBZ.
`
`General Toxicology and Reproductive and Development Toxicology
`
`The only pivotal studies of SD-809 conducted by the sponsor were a 3-month oral
`toxicity study and an embryofetal development study in Sprague-Dawley rat. In the 3-
`month study, SD-809 was administered at doses of 0, 2.5, 5, and 15 mg/kg BID; TBZ
`was administered at a single dose level (15 mg/kg BID). In the embryofetal development
`study, SD-809 was administered at doses of 0, 2.5, 5, and 15 mg/kg BID on gestation
`days 6-17; TBZ was administered at a single dose level (15 mg/kg BID) during the same
`period. Based on his review of the data, Dr. Toscano concluded that SD-809 exhibited no
`unique toxicities, based on direct comparison to TBZ.
`
`Genetic Toxicology
`
`SD-809 and metabolites, d6 α- and β-HTBZ, were negative when tested in separate in
`vitro (Ames, chromosomal aberration assay in human peripheral blood lymphocytes)
`assays. SD-809 and TBZ (0, 20, 40, 80 mg/kg QD x 3 for both) were negative in an in
`vivo mouse micronucleus assay.
`
`Conclusions and Recommendations
`
`The sponsor was informed multiple times during clinical development (cf. Memorandum
`of Meeting Minutes, PIND 112975, 12/9/2011; Memorandum of Meeting Minutes, End of
`
`
`
`Reference ID: 3910569
`
`3
`
`

`

`Phase 2, IND 112975, 12/26/2012) and review of the NDA (cf. email communication,
`October 15, 2015; Mid-Cycle Communication, NDA 208082, 12/2/2015; Late-Cycle
`Meeting Background Package, NDA 208082, 2/19/2016) of the importance of providing
`an adequate comparison of the in vivo metabolic profile of SD-809 with that of the RLD.
`However, the OCBP team has concluded that the sponsor has not adequately
`characterized the in vivo metabolic profile of SD-809 in humans. Without this
`information, the adequacy of the nonclinical data cannot be determined. The need for
`additional nonclinical data will depend on the new human mass balance data being
`collected by the sponsor (cf. Memorandum of Teleconference Minutes, March 23, 2016).
`This issue should be addressed prior to approval.
`
`
`
`
`
`Reference ID: 3910569
`
`4
`
`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/
`----------------------------------------------------
`
`LOIS M FREED
`03/31/2016
`
`Reference ID: 3910569
`
`

`

` DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`
`Applicant:
`Review Division:
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`
`208-082
`3
`5/29/2015
`5/29/2015
`Austedo (SD-809; deutetrabenazine)
`Treatment of chorea associated with
`Huntington’s disease
`Teva Pharmaceuticals; La Jolla, CA
`Neurology Products (DNP)
`Christopher D. Toscano, Ph.D., DABT
`Lois M. Freed, Ph.D.
`Billy Dunn, M.D.
`Stacy Metz, Pharm.D.
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 208-082 are owned by Teva Pharmaceuticals, Inc. or
`are data for which Teva Pharmaceuticals, Inc. has obtained a written right of reference.
`Any information or data necessary for approval of NDA 208-082
`that Teva
`Pharmaceuticals, Inc. does not own or have a written right to reference constitutes one
`of the following: (1) published literature, or (2) a prior FDA finding of safety or
`effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or
`information described or referenced below from reviews or publicly available summaries
`of a previously approved application are for descriptive purposes only and are not relied
`upon for approval of NDA 208-082.
`
`Reference ID: 3881963
`
`1
`
`

`

`1
`
`TABLE OF CONTENTS
`EXECUTIVE SUMMARY...........................................................................................3
`1.1
`INTRODUCTION .....................................................................................................3
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS .......................................................3
`1.3
`RECOMMENDATIONS .............................................................................................3
`2 DRUG INFORMATION............................................................................................10
`2.1
`DRUG ................................................................................................................10
`2.2
`RELEVANT INDS, NDAS, BLAS AND DMFS..........................................................11
`2.3
`DRUG FORMULATION ..........................................................................................11
`2.4
`COMMENTS ON NOVEL EXCIPIENTS......................................................................11
`2.5
`COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN........................................12
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN.....................................15
`2.7
`REGULATORY BACKGROUND ...............................................................................15
`STUDIES SUBMITTED...........................................................................................16
`PHARMACOLOGY .................................................................................................21
`4.1
`PRIMARY PHARMACOLOGY ..................................................................................21
`4.2
`SECONDARY PHARMACOLOGY .............................................................................21
`4.3
`SAFETY PHARMACOLOGY ....................................................................................22
`PHARMACOKINETICS/ADME/TOXICOKINETICS ...............................................23
`5.1
`PK/ADME .........................................................................................................23
`6 GENERAL TOXICOLOGY......................................................................................29
`6.1
`SINGLE-DOSE TOXICITY ......................................................................................29
`6.2
`REPEAT-DOSE TOXICITY .....................................................................................33
`7 GENETIC TOXICOLOGY........................................................................................48
`7.1
`IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES) .......................48
`7.2
`IN VITRO ASSAYS IN MAMMALIAN CELLS...............................................................55
`7.3
`IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY) ..................64
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY.................................67
`9.2
`EMBRYONIC FETAL DEVELOPMENT.......................................................................67
`11
`INTEGRATED SUMMARY AND SAFETY EVALUATION..................................76
`
`3
`4
`
`5
`
`Reference ID: 3881963
`
`2
`
`

`

`Executive Summary
`1
`Introduction:
`1.1
` Austedo (SD-809) is a deuterated form of tetrabenazine (TBZ), a drug substance
`approved under the trade name Xenazine (NDA 21-894) for the treatment of chorea
`associated with Huntington’s disease. By deuterating TBZ, the sponsor plans to take
`advantage of the kinetic isotope effect (KIE) of deuterium to alter the metabolism of TBZ
`and increase exposure to the active metabolites, α- and β-dihydrotetrabenazine. The
`sponsor has requested approval of Austedo under 505(b)(2), with Xenazine serving as
`the reference listed drug (RLD).
`1.2 Brief Discussion of Nonclinical Findings
` The pivotal toxicology studies conducted to support the approval of SD-809 consist
`of a 3-month oral toxicity study and an embryofetal development (EFD) study in rat, with
`TBZ as a comparator, and a complete genetic toxicology battery. Overall, there were no
`adverse findings unique to SD-809, relative to TBZ. It is important to note that there is
`uncertainty regarding the adequacy of the available information on the human
`metabolism of SD-809; therefore, it is unclear if all major human metabolites of SD-809
`have been adequately tested. The sponsor has provided adequate nonclinical
`information to support the proposed specifications for the known impurities in SD-809.
`1.3 Recommendations
`1.3.1 Approvability
` It is not possible to determine if the nonclinical studies submitted in the application
`support bridging to the available nonclinical information for the RLD without a
`determination of the status of SD-809 metabolites as major or minor, as defined by ICH
`M3(R2), by the Clinical Pharmacology review team. If it is determined that the
`metabolite profile for SD-809 is similar to the RLD and that there are no new MHMs of
`SD-809, then the current nonclinical package would support the approval of the NDA.
`However, if the available information on human metabolism of SD-809 is not adequate
`to determine the status of the metabolites in humans or if it is determined that there are
`MHMs of SD-809 that are not MHMs of TBZ, then the sponsor would need to
`demonstrate that the level of each MHM was qualified in nonclinical studies in order to
`support the level of exposure in humans.
`1.3.2 Additional Non Clinical Recommendations
`If the Clinical Pharmacology review team determines that there is a marked
`
`difference in the profile of MHMs between SD-809 and the RLD, the sponsor will
`need to provide additional nonclinical information to support the safety of these
`metabolites. For example, quantification of the level of each metabolite of
`concern at steady state in the 3-month repeat dose pivotal study and EFD
`studies would be necessary. If any of the SD-809 specific MHMs are found not to
`be covered in the pivotal studies conducted in rat or if there are MHMs of SD-809
`that are not described in the labeling of the RLD, additional nonclinical studies
`may be required to demonstrate the safety of the metabolite(s), including a
`
`3
`
`Reference ID: 3881963
`
`

`

`chronic study in a single species (up to 6 months in rodent and 9 months in
`nonrodent), reproductive and development studies (e.g., EFD and pre- and
`postnatal development), and a carcinogenicity assessment.
`
`Reference ID: 3881963
`
`4
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`Sponsor Proposed
`
`Reviewer Recommended
`
`No change recommended
`
`No change recommended
`
`Labeling
`1.3.3
`Labeling
`Section
`Highlights
`of
`Prescribing
`Information
`
`5
`Warnings
`and
`Precautions
`
` Indications and Usage
`AUSTEDO
`is
`a
`vesicular
`monoamine transporter 2 (VMAT2)
`inhibitor indicated for the treatment
`of
`chorea
`associated
`with
`Huntington’s disease. (1)
` Use in Specific Populations
` Pregnancy: Based on animal
`data,
` may cause
`fetal harm. (8.1)
`5.12
`Binding to Melanin-
`Containing Tissues
`Since deutetrabenazine or its
`metabolites bind to melanin-
`containing tissues, it could
`accumulate in these tissues over
`time. This raises the possibility that
` may cause
`toxicity in these tissues after
`extended use. Neither
`ophthalmologic nor microscopic
`examination of the eye has been
`conducted in the chronic toxicity
`studies in a pigmented species
`such as dogs. Ophthalmologic
`monitoring in humans was
`inadequate to exclude the
`possibility of injury occurring after
`long-term exposure.
`The clinical relevance of
`deutetrabenazine’s binding to
`melanin-containing tissues is
`unknown. Although there are no
`specific recommendations for
`periodic ophthalmologic monitoring,
`prescribers should be aware of the
`possibility of long-term
`ophthalmologic effects [see Clinical
`Pharmacology (12.2)].
`
`Reference ID: 3881963
`
`5
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`8.1
`
`8.1
`Pregnancy
`Pregnancy Risk Summary
`
`8.1
`
`Pregnancy
`
`Risk Summary
`
`(I!) (4)
`
`(b) (4)
`
`(b) (4)
`
`There are no adequate and well-
`controlled studies in pregnant
`women. AUSTEDO should be used
`
`during pregnancy only if the potential
`benefit justifies the potential risk to
`the fetus.
`
`Animal Data
`
`A dose-dependent increase in the
`incidence of 7th cervical rib occurred
`
`in fetuses of pregnant rats given oral
`doses of 5, 10, or 30 mg/kg/day BID
`deutetrabenazine or 30 mg/kg/day
`BID tetrabenazine throughout the
`period of organogenesis. The lowest
`dose of deutetrabenazine was similar
`
`to the maximum recommended
`
`human dose [MRHD] of 48 mg/day
`AUSTEDO on a mg/m2 basis.
`Deutetrabenazine has not been
`
`assessed in embryo-fetal
`development studies in pregnant
`rabbits. Tetrabenazine had no effects
`
`on embryo—fetal development when
`administered to pregnant rabbits
`during the period of organogenesis at
`oral doses up to 60 mg/kglday (or 12
`times the MRHD on a mg/m2 basis).
`Because neither rat nor rabbit dosed
`
`with tetrabenazine produce 9-
`desmethyl-beta-DHTBZ, a major
`human metabolite, these studies may
`not have adequately addressed the
`potential effects of tetrabenazine on
`embryo-fetal development in humans.
`
`Deutetrabenazine has not been
`
`assessed in a pre-and postnatal
`developmental study. When
`tetrabenazine was administered to
`
`
`
`female rats (doses of 5, 15, and 30
`mg/kg/day) from the beginning of
`organogenesis through the lactation
`period, an increase in stillbirths and
`
`
`Animal Data
`
`
`
`Reference ID: 3881963
`
`

`

`offspring postnatal mortality was
`observed at 15 and 30 mg/kg/day,
`and delayed pup maturation was
`observed at all doses. The no-effect
`dose for stillbirths and postnatal
`mortality was 0.5 times the MRHD of
`tetrabenazine on a mg/m2 basis.
`Labor and Delivery
`The effect of AUSTEDO on labor and
`delivery in humans is unknown.
`
`8.3
`
`Females and Males of
`Reproductive Potential
`
`Infertility
`AUSTEDO has not been assessed
`on impairment of fertility. In a study
`conducted with tetrabenazine, no
`effects on mating and fertility indices
`or sperm parameters (motility