CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208082Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`
`
`

`

`Division of Risk Management (DRISK)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`NDA
`208082
`April 3, 2017
`2015-1301, 2015-1298
`
`Yasmeen Abou-Sayed, PharmD
`Donella Fitzgerald, PharmD
`Jamie Wilkins Parker, PharmD
`
`April 3, 2017
`Evaluation of Need for a REMS
`
`Deutetrabenazine
`Austedo
`Teva
`VMAT2 inhibitor
`Oral tablet as 6 mg, 9 mg, and 12 mg
`6 mg initially, to be titrated up by 6 mg increments weekly up to max
`daily dose of 48 mg
`
`
`Application Type
`Application Number
`PDUFA Goal Date
`OSE RCM #
`
`Reviewer Name(s)
`Team Leader
`Deputy Division Director
`(Acting)
`Review Completion Date
`Subject
`
`Established Name
`Trade Name
`Name of Applicant
`Therapeutic Class
`Formulation(s)
`Dosing Regimen
`
`
`
`Reference ID: 4078877
`
`1
`
`

`

`Table of Contents
`
`EXECUTIVE SUMMARY ......................................................................................................................................................... 3
`1
`Introduction ..................................................................................................................................................................... 3
`2 Background ...................................................................................................................................................................... 3
`2.1
`Product Information ........................................................................................................................................... 3
`2.2
`Regulatory History............................................................................................................................................... 4
`3
`Therapeutic Context and Treatment Options .................................................................................................... 4
`3.1
`Description of the Medical Condition .......................................................................................................... 4
`3.2
`Description of Current Treatment Options ............................................................................................... 5
`4 Benefit Assessment ....................................................................................................................................................... 5
`5 Risk Assessment & Safe-Use Conditions .............................................................................................................. 6
`5.1
`Depression and Suicidality ............................................................................................................................... 7
`5.2
`Drug-Drug Interactions ..................................................................................................................................... 7
`5.3
`QT prolongation .................................................................................................................................................... 9
`5.4
`Expected Postmarket Use ................................................................................................................................. 9
`6 Risk Management Activities Proposed by the Applicant ............................................................................... 9
`7 Discussion of Need for a REMS ............................................................................................................................... 10
`Conclusion & Recommendations ........................................................................................................................... 10
`8
`9 Materials Reviewed ..................................................................................................................................................... 10
`10
`Appendices ................................................................................................................................................................ 11
`10.1 References ............................................................................................................................................................. 11
`
`
`
`Reference ID: 4078877
`
`2
`
`

`

`EXECUTIVE SUMMARY
`This review by the Division of Risk Management (DRISK) evaluates whether a risk evaluation and
`mitigation strategy (REMS) for the new molecular entity Austedo (deutetrabenazine) is necessary to
`ensure the benefits outweigh its risks. Teva Pharmaceuticals, Inc. (Teva) submitted a New Drug
`Application (NDA) 208082 under the 505(b)(2) regulatory pathway for deutetrabenazine with the
`proposed indication for the treatment of chorea associated with Huntington’s Disease (HD). The risks
`associated with deutetrabenazine include depression, suicidality, and drug-drug interactions. The
`applicant did not submit a REMS with this application but did propose routine pharmacovigilance.
`
`DRISK believes that a REMS is not needed to ensure the benefits of deutetrabenazine outweigh its risks.
`In general, healthcare providers who treat HD should be familiar with the heightened risk of depression
`and suicidality, and drug-drug interactions associated with deutetrabenazine, as the RLD, Xenazine (NDA
`021894) was approved with a REMS which addressed these risks. The REMS for Xenazine was released
`on August 25, 2015, because the Agency determined the Communication Plan had been completed and
`the REMS had met its goals.
`
` 1
`
` Introduction
`This review by the Division of Risk Management (DRISK) evaluates whether a risk evaluation and
`mitigation strategy (REMS) for the new molecular entity Austedo (deutetrabenazine) is necessary to
`ensure the benefits outweigh its risks. Teva submitted a New Drug Application (NDA 208082) under the
`505(b)(2) regulatory pathway for deutetrabenazine with the proposed indication for the treatment of
`chorea associated with Huntington’s Disease (HD). This application is under review in the Division of
`Neurology Products (DNP), with reference made to Xenazine (tetrabenazine/NDA 21894). Although
`deutetrabenazine is referencing Xenazine under the 505(b)(2) pathway, it is being reviewed under the
`Program as it is a deuterated form of tetrabenazine, and therefore a New Molecular Entity. The
`applicant did not submit a REMS with this application but proposed to conduct routine
`pharmacovigilance to ensure timely collection, processing, follow-up, analysis, and reporting of all
`adverse events in accordance with pharmacovigilance regulatory requirements.
`
`
` 2
`
` Background
`2.1 PRODUCT INFORMATION
`Deutetrabenazine, a new molecular entity (NME)a, is a vesicular monoamine transporter 2 (VMAT2)
`inhibitor proposed for the treatment of chorea associated with Huntington’s disease. By selectively
`inhibiting VMAT2 in the central nervous system (CNS), deutetrabenazine depletes presynaptic
`monoamines, including dopamine, and decreases chorea in patients with HD. It is structurally related to
`Xenazine (tetrabenazine), which is the only approved therapy for this indication in this class, and is the
`
`a FDAAA factor (F): Whether the drug is a new molecular entity.
`
`Reference ID: 4078877
`
`
`3
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`

`referenced listed drug for this application. Xenazine was approved in 2008 with a REMS to address the
`risk of depression and suicidality, as well as the risk of drug-drug interactions. The REMS consisted of a
`communication plan and timetable for assessments. It was released in August of 2015 after the
`completion of all communication plan activities and assessments demonstrated that the REMS had met
`its goals.
`
`Deutetrabenazine undergoes rapid and extensive hepatic metabolism by carbonyl reductase, and the
`resulting metabolites potently inhibit VMAT2 in the CNS. Cytochrome P450 2D6 (CYP2D6) is the
`principal metabolizer of the active metabolites. The structure of deutetrabenazine, when compared to
`tetrabenazine, allows for a slower rate of metabolism by CYP2D6, which allows for comparable systemic
`exposure with lower doses and lower peak concentrations. This also can lead to a reduction in the
`impact of CYP2D6 impairment, whether from concomitant medication use or genetics, and provide
`increased metabolic stability compared to tetrabenazine, and therefore reduced drug to drug
`interactions.
`
`Deutetrabenazine is proposed as 6mg, 9mg, and 12mg oral tablets and is to be administered as a chronic
`therapy.b The dosing is to be initiated on an outpatient basis at 6 mg daily, and should be titrated up at
`weekly intervals by 6 mg per day to a tolerated dose that reduces chorea. Doses of 12 mg daily and
`higher should be divided in two doses. Doses should be administered with meals, and should be
`swallowed whole. The maximum recommended daily dose is 48 mg (maximum 24 mg in a single dose).
`In poor CYP2D6 metabolizers or for patients taking strong CYP2D6 inhibitors, the maximum daily dose is
`36 mg (maximum 18 mg in a single dose). Deutetrabenazine received orphan drug designation on
`November 5, 2014. It is not currently approved in any jurisdiction.
`
`2.2 REGULATORY HISTORY
`11/05/2014: Orphan-drug designation granted for deutetrabenazine.
`
`05/29/2015: Deutetrabenazine, NDA 208082, submission for the treatment of chorea associated with
`Huntington’s Disease received.
`
`05/27/2016: Complete Response letter sent to the applicant due to clinical pharmacology, non-clinical
`and product quality deficiencies.
`
`10/03/2016: Resubmission of Complete Response received from Applicant.
`
` 3
`
` Therapeutic Context and Treatment Options
`3.1 DESCRIPTION OF THE MEDICAL CONDITION
`
`
`b FDAAA factor (D): The expected or actual duration of treatment with the drug.
`
`Reference ID: 4078877
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`Huntington’s disease (HD) is a rare genetically inherited degenerative disorder of the brain. About
`30,000 people in the US are affected and HD is considered an “orphan disease”.c It is inherited by
`receiving an abnormal gene that can come from either parent. The child of an affected parent has a 50-
`50 chance of inheriting the disease. While the classic sign of the disorder is chorea, involuntary and
`uncontrollable dance-like movements of the face and limbs, the illness is characterized by progressive
`motor, behavioral and psychiatric disturbances, and dementia.d The onset of the illness is generally
`between the ages of 30 and 50, progressing to death within 15 to 20 years.1
`
`Chorea is a hallmark of HD that interferes with daily functioning and can pose a significant risk of injury.
`It can cause gait instability and poor postural control, increasing the risk of serious injury due to falls or
`flailing into objects.2
`
`Suicidal ideation and behavior is more common in patients with HD than in the general population.
`Completed suicides in the HD population have been reported to be as high as 13%, while the general
`population’s suicide rate is below 1%, with suicidal ideation reported in up to 19% of HD patients.3,4
`Dysphagia is also a component of HD, and it can lead to aspiration pneumonia, weight loss, and
`behavioral problems. Because increased involuntary motor activity is driven by central dopamine
`dysregulation, inhibiting vesicular monoamine transporter, type 2 (VMAT2) reduces dopaminergic
`neurotransmission and provides a therapeutic option for controlling chorea in patients with HD.
`
`3.2 DESCRIPTION OF CURRENT TREATMENT OPTIONS
`In some cases, chorea can be managed with nonpharmacological options, such as providing a calm,
`predictable environment, and using assistive devices such as padded reclining chairs and bed padding.
`When pharmacologic therapy is warranted, the only currently approved medication for the treatment of
`chorea in HD is tetrabenazine.
`
`Other pharmacologic options for chorea include neuroleptics, due to the blockade of dopamine
`transmission. Typical neuroleptics used are haloperidol, fluphenazine, and chlorpromazine. Atypical
`neuroleptics which have been used to treat chorea in HD include olanzapine, risperidone, clozapine, and
`aripiprazole. Amantadine can be considered for use in those who cannot tolerate tetrabenazine or the
`neuroleptics mentioned above. Benzodiazepines may be used intermittently when there is transient
`worsening of chorea in stressful situations.5
`
`4 Benefit Assessment
`The clinical development program for deutetrabenazine is composed of two studies, SD-809-C-15 (First-
`HD) which focused on efficacy and safety, and SD-809-C-16 (ARC-HD) which is an on-going unblinded,
`open-label, single-arm long term safety and tolerability study which informed the safety population. The
`
`
`c FDAAA factor (A): The estimated size of the population likely to use the drug involved.
`
`d FDAAA factor (B): The seriousness of the disease or condition that is to be treated with the drug.
`
`Reference ID: 4078877
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`pivotal trial, First-HD, supporting this application consisted of a randomized double-blind, placebo-
`controlled parallel group study which evaluated the use of deutetrabenazine in 90 adult subjects
`(deutetrabenazine group n= 45, placebo group n = 45) with chorea associated with HD. The subjects
`were randomly chosen to be treated with total daily doses of deutetrabenazine ranging from 6 to 48 mg
`over the course of 12 weeks. The primary efficacy endpoint was change in Total Maximal Choreae (TMC)
`score from baseline to maintenance therapy. The deutetrabenazine treatment group had a highly
`statistically significant reduction in TMC (p<0.0001), with subjects achieving a 4.4 unit reduction in TMC
`compared to a 1.9 unit reduction in the placebo group.
`
`Key secondary endpoints included the Patient Global Impression of Change and Clinical Global
`Impression of Change. Global Impression of Change was defined as the proportion of patients who
`perceived themselves as Much Improved or Very Much Improved using a Pearson’s chi-square test. At
`the end of treatment therapy 51.1% of the deutetrabenazine patients compared to 20% of the placebo
`treated group reported Much or Very Much Improved (p = 0.0020). Similar results were seen with the
`Clinical Global Impression of Change reported by site investigators that found 42.2% (19) of the
`deutetrabenazine subjects Much or Very Much Improved compared to 13.3% (6) in the placebo group (p-
`value 0.0022). Other secondary efficacy endpoints were analyzed, however “the clinical team
`determined that they were not statistically significant and held less value due to the unknown metric
`qualities of the outcomes measures and statistical vulnerability due to the multiplicity of analyses
`performed”.
`
`Based upon the results of the deutetrabenazine clinical development program, the Division of Neurology
`Products has concluded that evidence of efficacy of deutetrabenazine as treatment of chorea associated
`with Huntington’s Disease, has been established.f
`
`5 Risk Assessment & Safe-Use Conditions
`The safety analysis for deutetrabenazine includes data from the pivotal efficacy trial, First-HD, and study
`ARC-HD.
`
`A total of 299 subjects have received deutetrabenazine, including 121 subjects with chorea associated
`with HD, and 178 healthy adult volunteers. The most common adverse reactions observed in greater
`than 8% of deutetrabenazine-treated patients were somnolence, diarrhea, dry mouth, and fatigue.
`
`There was one report of death in the deutetrabenazine clinical program. In ARC-HD, one subject died
`due to sudden cardiac death, which was determined to by the investigator to be unlikely related to
`deutetrabenazine, and agreed upon by the clinical reviewer. Serious adverse events to be detailed
`
`
`e Total Maximal Chorea is a subscale of the Unified Huntington disease Rating Scale that was developed by the
`Huntington Study Group as a clinical rating scale to assess four domains of clinical performance and capacity in
`Huntington’s disease: motor function, cognitive function, behavioral abnormalities and functional capacity.
`
`f FDAAA factor (C): The expected benefit of the drug with respect to such disease or condition.
`
`Reference ID: 4078877
`
`
`6
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`

`further include events of depression and suicidality, drug-drug interactions and discussion of potential
`QT prolongation.g
`
`5.1 DEPRESSION AND SUICIDALITY
`Depression is more common in the HD population than the general population. A majority of subjects in
`First-HD (74%) had a history of depression, with 57.7% of subjects using an antidepressant medication at
`baseline. Approximately 15% of the study population had a lifetime history of suicidal ideation.
`Depression in First-HD was evaluated through use of the Hospital Anxiety and Depression Scale-
`Depression Subscale (HADS-D)h, and suicidality was evaluated through use of the Columbia Suicide
`Severity Rating Scale (C-SSRS).i There was no evidence of an increase in the incidence of depression
`over time in either the deutetrabenazine or placebo group based on the HADS-D scores. The same
`outcome was seen in ARC-HD, where depression incidence did not increase in treatment subjects
`through week 80. However, the clinical reviewer notes in his review that the adverse event data sets
`showed five patients with previous histories of depression that reported increased symptoms, including
`one who reported suicidal ideation.
`
`5.2 DRUG-DRUG INTERACTIONS
`The safety data from both deutetrabenazine studies (First-HD, ARC-HD) indicates a similar incidence of
`adverse events in subjects who were using a concomitant strong CYP2D6 inhibitor compared with those
`who were not. A total of 8 subjects in the First-HD deutetrabenazine treatment group were using a
`strong CYP2D6 inhibitor at baseline. Among those 8 subjects, all reported AE’s were of mild to
`moderate severity, and none of the subjects experienced a serious adverse event. The following table
`illustrates the incidence of AE’s in subjects using a strong CYP2D6 inhibitor versus those who are not:
`
`
`
`g FDAAA factor (E): The seriousness of any known or potential adverse events that may be related to the drug and
`the background incidence of such events in the population likely to use the drug.
`
`h The Hospital Anxiety and Depression Scale is one of the most widely used instruments to assess and monitor the
`severity of symptoms of anxiety and depression. The depression subscale separates that aspect from the anxiety
`portion.
`
`i The Columbia Suicide Severity Rating Scale is a suicidal ideation rating scale created to evaluate suicidality in
`subject ages 12 and up. It identifies behaviors which may be indicative of an individual’s intent to commit suicide.
`
`Reference ID: 4078877
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`
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`

`
`The clinical reviewer’s analysis of the data concluded that the overall summary of adverse events was
`similar in subjects who were using a strong CYP2D6 inhibitor versus those who were not using a strong
`CYP2D6 inhibitor at baseline.
`
`
`
` A
`
` total of 16 subjects in ARC-HD were using a strong CYP2D6 inhibitor at baseline, versus 64
`deutetrabenazine treatment subjects not using a strong CYP2D6 inhibitor at baseline. There were
`no notable differences in the overall adverse event profile in subjects who were versus those
`who were not using a strong CYP2D6 inhibitor at baseline. The AE’s of interest reported are as follows:
`
`Adverse Event
`
`Injury (including falls)
`Somnolence
`Depression
`Suicidal Ideation
`
`
`With the exception of 1 adverse event of severe intensity (1 subject experienced worsening chorea and
`withdrew from the study), all adverse events in the subjects in ARC-HD who were using a strong CYP2D6
`inhibitor at baseline were of mild or moderate severity. Because 1 subject did experience a serious
`adverse event likely caused by a drug-drug interaction, DNP in the last review cycle, agreed upon a cap
`of 36 mg/day (18 mg bid) for individuals concomitantly taking a strong CYP2D6 inhibitor.
`
`
`Yes (n=16)
`2
`3
`2
`0
`
`Baseline use of strong CYP2D6 inhibitor
`No (n=64)
`9
`5
`1
`1
`
`
`
`Reference ID: 4078877
`
`
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`

`The structure of deutetrabenazine, when compared to tetrabenazine, allows for a slower rate of
`metabolism by CYP2D6. This reduces the impact of CYP2D6 inhibition, whether from concomitant
`medication use or genetics, and therefore reduced drug to drug interactions.
`
`With tetrabenazine, patients who require doses greater than 50 mg per day should be genotyped for
`CYP2D6 – with poor metabolizers capped at a maximum single dose of 25 mg and max daily dose of 50
`mg. The REMS approved for tetrabenazine in 2008 required the sponsor, Valeant Pharmaceuticals, to
`inform healthcare professionals (HCPs) about the need to slowly titrate the dose, perform CYP2D6
`testing on patients requiring doses over 50 mg daily, and to cap the daily dose in poor metabolizers to
`50 mg daily. Based on the 6-year assessment report submitted November 13, 2014, in which survey
`results indicated respondents were aware of the risks associated with dosing and CYP2D6 inhibitors, the
`REMS was released on August 25, 2015.6
`
`
`5.3 QT PROLONGATION
`A Thorough QT (TQT) Prolongation study was performed in healthy volunteers using a single-dose
`deutetrabenazine of 12 mg and 24 mg. This led to maximum, time-matched, placebo-adjusted, average
`increases from baseline QTcF interval of 2.8 ms and 4.5 ms, respectively. The sponsor and the Agency
`agree this is not a significant effect on QT prolongation and therefore has no clinical impact. The FDA
`Interdisciplinary Review Team (IRT) that analyzed the data believes the study is limited based on the
`challenge dose selected, and does not account for higher daily doses which are in the therapeutic range,
`nor does it account for situations where CYP2D6 metabolism may be impaired. Therefore, the opinion
`of the IRT review team, as well as the clinical reviewer, is that the language which exists in the current
`Xenazine label should be retained: “Effects at higher exposures to either XENAZINE or its metabolites
`have not been evaluated.”
`
`5.4 EXPECTED POSTMARKET USE
`Deutetrabenazine is likely to be prescribed by neurologists and movement disorder specialists, who are
`familiar with the management of Huntington’s Disease. Prescribers should be familiar with the potential
`risks associated with deutetrabenazine as they are similar, to those of the RLD, Xenazine, which was
`subject to a REMS which has been released due to completion of the communication plan and
`assessments which demonstrated it had met its goals. It is expected that the drug will be used in both
`an in-patient and out-patient setting. Patients with early stage Huntington’s disease marked by low
`cognitive and physical impairment are likely to self-medicate, taking the tablets by mouth as directed by
`their healthcare provider. Advanced disease progression leads to behavioral, cognitive and physical
`impairment that will likely necessitate dispensation and/or administration of deutetrabenazine under
`the supervision of a caregiver, and ongoing management by a neurologist and/or movement disorder
`specialist.
`
`6 Risk Management Activities Proposed by the Applicant
`
`Reference ID: 4078877
`
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`9
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`

`The Applicant did not propose any risk management activities for deutetrabenazine beyond routine
`pharmacovigilance and labeling.
`
`7 Discussion of Need for a REMS
`The Clinical Reviewer recommends approval of deutetrabenazine on the basis of the efficacy and safety
`information currently available.
`
`DRISK believes a REMS is not necessary for deutetrabenazine at this time. Per the clinical reviewer,
`while no direct comparison was studied between deutetrabenazine and tetrabenazine, the safety
`concerns which initially warranted a REMS for tetrabenazine are of less concern with deutetrabenazine.
`With regards to depression and suicidality, and increased drug-drug interactions based on the CYP2D6
`pathway, deutetrabenazine overall has a similar profile when compared to tetrabenazine, but with
`fewer events in the deutetrabenazine development program. Deutetrabenazine does not show a
`clinically significant increase in depression and suicidality when compared to placebo, and it is not
`possible to know if the events of depression (n=27) and suicidality (n=6) seen in ARC-HD are an
`increased risk from deutetrabenazine, given the background rate of affective disorder in HD.7 With
`regards to CYP2D6 interactions, the metabolic profile of deutetrabenazine reduces the rate at which the
`drug is metabolized by CYP2D6, when compared to tetrabenazine. The reduced rate of metabolism
`reduces the likelihood drug toxicity due to drug interactions or in patients who are poor CYP2D6
`metabolizers. While Xenazine (tetrabenazine) was approved with a REMS in 2008 to address these two
`risks and due to completion of communication plan activities, the REMS was subsequently released in
`2015. Therefore, DRISK believes the product labeling can sufficiently convey the risks associated with
`deutetrabenazine, via a boxed warning for depression and suicidality and a warning for drug-drug
`interactions, as well as a medication guide. No new, novel, or previously undescribed adverse drug
`reactions have been described that would warrant a REMS at this time, and the prescribing population
`for deutetrabenazine is likely to be the same as that of Xenazine.
`
`8 Conclusion & Recommendations
`Based on the available data, DRISK believes a REMS is not necessary to ensure the benefits of
`deutetrabenazine outweigh the risks. In general, healthcare providers who treat Huntington’s disease
`are familiar with the heightened risk of depression and suicidality that initially prompted a REMS with
`Xenazine and are aware of the importance of patient monitoring during titration and continued therapy
`to detect treatment-emergent depression and suicidal behavior or ideation, given the high background
`incidence of affective disorders in the HD population. The Division of Neurology Products should notify
`DRISK if new safety information becomes available that changes the benefit-risk profile; this
`recommendation can then be reevaluated.
`
`9 Materials Reviewed
`The following is a list of materials informing this review:
`
`Reference ID: 4078877
`
`
`10
`
`

`

`1. Teva. Risk Management Plan for deutetrabenazine, October 3, 2016.
`
`2. Teva. Proposed Prescribing Information for deutetrabenazine, October 3, 2016.
`
`3. Teva. Clinical Overview for deutetrabenazine, October 3, 2016.
`
`4. Teva. Summary of Clinical Safety for deutetrabenazine, October 3, 2016.
`
`5. Teva. Complete Response Safety Update for deutetrabenazine, October 3, 2016.
`
`6. Teva. Proposed Label for deutetrabenazine, October 3, 2016.
`
`7. Valeant. Label for Xenazine, June 3, 2015.
`
`8. Bergmann, K. DNP. Clinical Review for deutetrabenazine NDA 208082, May 24, 2016.
`
`9.
`
` Late-Cycle Meeting Minutes for deutetrabenazine, March 21, 2016.
`
`10. Kumar, J. DRISK. REMS Modification Review for Xenazine, August 25, 2015.
`
`11. Bastings, E. DNP. Division Director Review for deutetrabenazine NDA 208082, May 27, 2016.
`
`10 Appendices
`10.1 REFERENCES
`
`1 Bergmann, K. Division of Neurology Products. Clinical Review for Deutetrabenazine NDA 208082, May 24, 2016.
`
`2 Burgunder J-M, Guttman M, Perlman S, Goodman N, van Kammen DP, Goodman L. An international survey-based
`algorithm for the pharmacological treatment of chorea in Huntington’s disease. Version 1. PloS Currents
`Huntington’s Disease. 2011 Aug 30;3:RRN1260.
`
`3 Cummings J. Behavioral and psychiatric symptoms associated with Huntington disease. In: Weiner WJ, Lang AE,
`editors. Behavioral Neurology of Movement Disorders. Raven Press; New York: 1995. pp. 179–186.
`
`4 Farrer LA. Suicide and attempted suicide in Huntington disease: implications for preclinical testing of persons at
`risk. American Journal of Medical Genetics. 1986;24:305–311.
`
`5 Suchowersky O. Huntington Disease: Management. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA.
`(Accessed on March 31, 2017.)
`
`6 Kumar, J. DRISK. REMS Modification Review for Xenazine, August 25, 2015.
`
`7 Bergmann, K. Division of Neurology Products. Clinical Review for Deutetrabenazine NDA 208082, May 24, 2016.
`
`Reference ID: 4078877
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`
`11
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`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`YASMEEN I ABOU-SAYED
`04/03/2017
`
`JAMIE C WILKINS PARKER
`04/03/2017
`
`Reference ID: 4078877
`
`

`

`
`
`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`DEFERRAL OF RISK EVALUATION AND MITIGATION STRATEGY (REMS)
`REVIEW
`
`
`
`Date:
`
`Reviewer:
`
`May 2, 2016
`
`Jasminder Kumar, Pharm.D.
`Risk Management Analyst
`Division of Risk Management (DRISK)
`
`Team Leader:
`
`Jamie Wilkins Parker, Pharm.D.
`
`Division Director:
`
`Cynthia LaCivita, Pharm.D.
`
`Subject:
`
`Defer comment on DRISK evaluation of the need for a
`REMS for deutetrabenazine
`
`Drug Name:
`
`Austedo (deutetrabenazine)
`
`Therapeutic class and
`Dosage Form:
`
`vesicular monoamine transporter 2 (VMAT2) inhibitor, oral
`tablets
`
`Application
`Type/Number:
`
`NDA 208082
`
`Applicant/sponsor:
`
`Teva Pharmaceuticals, Inc.
`
`2015-1301
`
`OSE RCM #
`
`
`
`
`
`
`
`
`
`
`
`
`*** This document contains proprietary and confidential information that should not be
`released to the public. ***
`
`Reference ID: 3925567
`
` 1
`
`

`

`
`
`This memo is to defer the Division of Risk Management’s (DRISK) review of the need
`for a risk evaluation and mitigation strategy (REMS) for Austedo (deutetrabenazine),
`NDA 208082.
`
`A 505(b)(2) application for deutetrabenazine was received by the Division of Neurology
`Prodcuts (DNP) Teva Pharmaceuticals, Inc. on May 29, 2015, with the proposed
`indication for the treatment of chorea associated with Huntington’s disease. The
`submission did not include a REMS, but did include a risk management plan consisting
`of routine and enhanced pharmacovigilance.
`
`The Supervisory Pharmacologist has made the following recommendation for regulatory
`action based on the submission:
`
`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… 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.1
`
`
`In addition, the Pharmacology/Toxicology reviewer stated the following:
`
`Based on the available information provided by the sponsor for circulating
`metabolites in humans dosed with SD-809, there is concern regarding the
`variability in reported levels of SD-809 metabolites and that the level of
`circulating metabolites may have been underestimated…If the Clinical
`Pharmacology review team finds that the currently available human data on SD-
`809-related metabolites are inadequate, then, due to the lack of nonclinical data
`on circulating metabolites, it will not be possible to make a determination if the
`sponsor has successfully bridged to the nonclinical data available for the RLD, a
`critical element for the approval of Austedo under 505(b)(2).2
`
`Therefore, an evaluation of the need for REMS for deutetrabenazine will be undertaken
`by DRISK after the Applicant addresses the deficiencies identified by the Supervisory
`Pharmacologist and the Pharmacology