CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`208082Orig1s000
`
`
`OFFICE DIRECTOR MEMO
`
`
`
`

`

`Office of Drug Evaluation-l: Decisional Memo
`
`April 3, 2017
`
`Ellis F. Unger, MD, Director
`
`Office of Drug Evaluation-l, Office of New Drugs,
`CDER
`
`Subject:
`NDA #:
`
`Applicant Name:
`
`Date of Submission:
`
`PDUFA Goal Date:
`Proprietary Name:
`
`Office Director Decisional Memo
`208082
`
`Teva Pharmaceuticals, Inc.
`
`October 3, 2016
`
`April 3, 2017
`Austedo
`
`Eric Bastings
`
`EStabliShed (USAN) Name:
`
`Deutetrabenazine (SD-809)
`
`Dosage Formsl Strengths:
`
`Oral tablets: 6 mg, 9 mg, and 12 mg
`
`Indication:
`
`Action:
`
`Treatment of chorea in patients with Huntington’s
`disease.
`
`Approval
`
`Material Reviewed/Consulted - Action Packaoe, includino:
`Pro'ect Manaer M
`Medical Officer Clinical Review
`
`Clinical Pharmacology Review
`
`Kristina Dimova; Angela Men; Xiaofeng Wang; Atul
`Bhattaram; Kevin Krud s; Jeffre Kraft; Christian Grimstein
`
`Statistical Review
`
`XIanomIn Zhano; Kun Jin; Hsien Mino Huno
`
`Pharmacolo- Toxicolo o
`
`Chris Toscano; Lois Freed; Paul Brown
`
`.
`.
`Office Of Pharmaceutical Quality
`
`Wendy Wilson-Lee; Martha Heimann; Gene Holbert; Sherita
`McLamore-Hines; Masih Jaio irdar; Don Obenhuber
`
`Jing Li; Okpo Eradiri; Angelica Dorantes
`Office Of New Drug Quality Assessment
`BI0oharmaceutIcs Revrew
`
`Controlled Substance Staff
`Alicja Lerner; Michael Klein
`Office of Scientific Investio ation
`Antoine El Hao e; Susan Thom oson; Kassa A alew
`
`OSE, Division of Medication Error
`Prevention and Anal sis
`
`Deborah Myers; Danielle Harris
`
`OSE, Division of Risk Manaoement
`
`Jasmine Kumar; Jamie Wilkins Parker
`
`QT Interdisciplinary Review Team
`
`Moh Jee Ng; Qianyu Dang; Dinko Rekic; Jiang Liu; Michael
`
`OSE Pro'ect Manaoers
`
`OSE Division of E oidemio|0o
`
`Cross-Disci o line Team Leader
`
`Ermias Zerislasse; Corwin Howard
`
`Lockwood Ta or; Elisa Braver
`Gerald Dave Podskaln
`
`Deputy Director, Division of Neurology
`Products
`
`Director, Division of Neurol o o Products
`
`OSE = Office of Surveillance and Epidemiology
`
`Reference ID: 4079060
`
`NDA 208082, Office Director Memo, page 1
`
`

`

`1. Benefit-Risk Assessment
`Benefit-Risk Summary and Assessment
`
`Deutetrabenazine will be approved for the treatment of chorea associated with Huntington’s disease. The
`drug is a deuterated form of tetrabenazine, which was approved for the same indication in 2008. Both drugs
`are vesicular monoamine transporter 2 (VMAT2) inhibitors, and the activity of both drugs is related to their
`metabolites, (cid:68)- and (cid:69)-dihydrotetrabenazine. Deuteration affects the metabolism and pharmacokinetics of the
`drug, such that for equivalent doses, exposure to the active metabolites of deutetrabenazine is approximately
`twice that of tetrabenazine, and the half-life is longer. This is a 505(b)(2) NDA that relies on tetrabenazine for
`its pharmacology/toxicology studies, including a fertility and early embryonic development study, an
`embryofetal developmental study, a pre- and post-natal development study, and assessment of
`carcinogenicity. Deutetrabenazine’s effectiveness in Huntington’s disease was demonstrated in a new
`controlled trial.
`
`The efficacy of deutetrabenazine was established in a 12-week placebo-controlled study that used a well-
`accepted measure of chorea, the total maximal chorea (TMC) score, as the 1° endpoint. The change from
`baseline in TMC score was significantly higher (a drug-placebo difference of 2.5 points on a 24-point scale)
`for deutetrabenazine than for placebo (p<0.0001). These results were supported by statistically significant
`effects on 2° outcome measures: the Patient Global Impression of Change and the Clinical Global Impression
`of Change. Deutetrabenazine’s only known advantage over tetrabenazine is the need for less frequent
`dosing (BID instead of TID) at the higher end of the dosing range. No doubt there will be individuals who,
`having had an inadequate response to tetrabenazine, will switch to deutetrabenazine in search of better
`efficacy. There is no basis for believing that the two products differ with respect to efficacy; moreover, an
`attempt to show superiority of deutetrabenazine to tetrabenazine would seem futile.
`
`The deutetrabenazine safety database was closely examined with consideration of tetrabenazine’s known
`adverse effects. These include sedation and somnolence, akathisia, depression, and suicidality.
`Notwithstanding the recognized limitations of cross-study comparisons, the frequencies of these events
`appear similar for the two drugs. Huntington’s Disease (HD) is an orphan disease, and the safety database
`was therefore small. Given the size of the database and lack of a head-to-head study, it is impossible to
`reach any definitive conclusions regarding comparative safety, but there are no obvious new safety concerns.
`A QT prolongation signal is known and labeled for tetrabenazine. The TQT study conducted by the applicant
`did not reach sufficiently high deutetrabenazine exposures to rule out QT prolongation at supratherapeutic
`concentrations that would likely occur in patients who are CYP2D6 poor metabolizers, as well as patients
`taking CYP2D6 inhibitors. As was the case for tetrabenazine, this will be addressed in labeling. The
`possibility that deuteration leads to specific safety issues seems remote. Presumably, if such toxicity exists at
`all, its manifestations would be rare and would not have been detected in a development program of this size.
`
`The benefit-risk calculus is straightforward here: the potential benefit for patients is a reduction in symptoms;
`the potential harms are manifested as symptoms. Aside from the risk of suicide, the risks seem reversible.
`Thus, individual patients can make their own decisions with respect to initiating and, if desired, discontinuing
`the drug.
`
`NDA 208082, Office Director Memo, page 2
`
`Reference ID: 4079060
`
`

`

`Dimension
`
`Analysis of
`Condition
`
`Evidence and Uncertainties
`Huntington's disease (HD) is an autosomal
`dominant neurodegenerative disorder. HD
`has an estimated prevalence of 5/100,000 in
`the US. HD is an orphan disease.
`
`The affected gene codes for a cytosine-
`adenine-guanine (CAG) repeat expansion
`that produces abnormal Huntingtin protein.
`Patients with a CAG repeat length (cid:116) 37
`become symptomatic. The length of the
`CAG repeat influences the severity of the
`disease and the age of onset (longer is
`worse).
`
`The disease is characterized by progressive
`dementia, motor impairment, and psychiatric
`symptoms, beginning most often between 30
`and 50 years of age. Death usually occurs
`within 20 years of symptom onset.
`Tetrabenazine is the only drug approved for the
`treatment of HD, specifically, for the treatment of
`chorea associated with HD. Tetrabenazine may
`cause side effects, including sedation, worsening
`depression, suicidality and drug-induced
`Parkinsonism.
`
`Antidepressants and antipsychotics are used to
`treat the psychiatric and behavioral aspects of HD.
`Benefit was established in a mostly US,
`multicenter, randomized, double-blind,
`placebo-controlled study in 90 patients
`(Study C-15). The study used a well-
`accepted measure of chorea as the 1°
`outcome measure: the Total Maximal Chorea
`(TMC) score.
`
`There was a statistically significant difference
`between deutetrabenazine and placebo for
`the primary endpoint (difference in score
`change from baseline of -2.5, p<0.0001).
`This effect size was similar to that seen with
`tetrabenazine.
`
`Current
`Treatment
`Options
`
`Benefit
`
`Conclusions and Reasons
`
`HD is a serious and profoundly
`disabling disorder. HD essentially
`represents a death sentence.
`
`There is currently no treatment that is
`known to delay the progression of the
`disease.
`
`Tetrabenazine is the only available
`treatment for patients with HD. The
`drug has no effect on the progression of
`the disease, but is indicated to reduce
`chorea.
`
`There is substantial evidence for the
`efficacy of deutetrabenazine. The
`treatment effect appears similar to that
`of tetrabenazine, which is approved for
`the treatment of chorea in HD patients.
`
`The meaningfulness of the benefit of
`deutetrabenazine to patients was supported
`by statistically significant improvements on 2°
`endpoints: the Patient Global Impression of
`Change and the Clinical Global Impression of
`Change, compared with placebo.
`NDA 208082, Office Director Memo, page 3
`
`Reference ID: 4079060
`
`

`

`Dimension
`
`Evidence and Uncertainties
`Deutetrabenazine has a safety profile similar to that
`of tetrabenazine.
`
`Adverse effects include sedation/somnolence,
`depression and suicidality, parkinsonism, akathisia,
`restlessness, and cognitive decline. It may be
`difficult to differentiate between adverse reactions
`and progression of the underlying disease, which
`could be problematic for prescribers and patients.
`The labeling recommends periodic reassessment
`of the need for the drug, and withdrawal, if
`necessary, to determine whether symptoms are
`drug-related or a manifestation of the underlying
`disease.
`As is the case for tetrabenazine, the risks
`associated with deutetrabenazine can be
`managed by labeling.
`
`Routine pharmacovigilance is recommended.
`
`Risk
`
`Risk
`Management
`
`Conclusions and Reasons
`
`The potential harms of the drug are, by
`and large, reversible and manageable,
`with the exception of suicide.
`
`Labeling will include a Boxed Warning
`for increased risk for suicidality and
`depression in patients with HD, as per
`the labeling for tetrabenazine. There
`will also be a Medication Guide to
`highlight the need for vigilance for the
`emergence of depression, suicidal
`thoughts, and suicidal actions.
`
`2. Background
`
`Huntington’s disease (HD) is a genetic neurodegenerative disorder characterized by
`progressive dementia, motor impairment, and psychiatric symptoms. Patients with the adult
`form of the disease typically become symptomatic between 30 and 50 years of age, with death
`ensuing 15 to 20 years after symptom onset. The Huntingtin gene is located on the short arm
`of chromosome 4, and inheritance is autosomal dominant. The gene mutation codes for a
`cytosine-adenine-guanine (CAG) triplet repeat that produces abnormal huntingtin protein.
`Patients with a CAG repeat length of 37 or more become symptomatic. Despite discovery of
`the genetic basis of the disease some 24 years ago, no treatment is known to affect its
`inexorable progression. Prevalence is estimated at 5/100,000 in the US. HD was the subject
`of a public patient-focused drug development meeting at FDA on September 22, 2015.
`Patients made it clear that although tetrabenazine can be helpful, they are hoping for the
`availability of a drug that will prevent progression of the disease.
`
`Tetrabenazine is the only approved treatment for HD. Initially approved in 2008, the drug is
`indicated for the treatment of chorea associated with Huntington’s disease, but does not affect
`disease progression. Deutetrabenazine is a deuterated form of tetrabenazine that is proposed
`for the same indication: treatment of chorea associated with Huntington’s disease.
`
`Tetrabenazine and deutetrabenazine are vesicular monoamine transporter 2 (VMAT2)
`inhibitors. Their anti-chorea effects are believed to be mediated by decreased uptake of
`monoamines into synaptic vesicles with depletion of monoamine stores (e.g., dopamine,
`serotonin, norepinephrine, and histamine).
`
`The NDA is a 505(b)(2) submission, with tetrabenazine (NDA 21894) as the Reference Listed
`Drug (RLD). Clinical development was conducted under IND 112975. This application relies
`NDA 208082, Office Director Memo, page 4
`
`Reference ID: 4079060
`
`

`

`on the RLD for various pharmacology-toxicology studies, including a fertility and early
`embryonic development study, a pre- and postnatal development study, and assessment of
`carcinogenic potential. There was, however, a new randomized placebo-controlled
`effectiveness study to demonstrate efficacy of deutetrabenazine in HD.
`
`Deutetrabenazine has not been approved in any country, and has orphan drug designation.
`
`The clinical pharmacology studies in the original submission were not adequate to determine
`whether all of deutetrabenazine’s major human metabolites had been identified. Specifically,
`there was concern that levels of the M1 and M4 metabolites exceeded the regulatory threshold
`of 10% of total drug-related material. We are now satisfied, however, that these metabolites do
`not exceed the 10% threshold, such that all relevant metabolites have been characterized and
`adequately studied.
`
`3. Product Quality
`
`I concur with the conclusions reached by the Office of Pharmaceutical Quality regarding the
`acceptability of the manufacturing of the drug product and drug substance. The deficiencies
`identified in the first cycle have been resolved. Manufacturing site inspections were
`acceptable, and there are no outstanding product quality issues. Sufficient data have been
`presented to support a 32-month expiry.
`
`4. Nonclinical Pharmacology/Toxicology
`
`I concur with the conclusions reached by the pharmacology/toxicology reviewer: the original
`pharm/tox issues that precluded approval have been resolved. The original submission lacked
`sufficient information to confirm that the major human metabolites were comparable between
`tetrabenazine and deutetrabenazine. This comparison was necessary to determine whether
`the safety of tetrabenazine supported that of deutetrabenazine. The resubmission sufficiently
`clarified the human metabolite profiles; no new major metabolites (>10% of drug-related
`materials) have been identified, such that reliance on the tetrabenazine data is appropriate.
`
`5. Clinical Pharmacology
`
`Deutetrabenazine is a deuterated form of tetrabenazine in which the two O-linked methyl
`groups of the tetrabenazine molecule have been replaced by two trideuteromethyl groups.
`
`NDA 208082, Office Director Memo, page 5
`
`Reference ID: 4079060
`
`

`

`Figure 1: Structure of Deutetrabenazine
`
`Pharmacokinetics of deutetrabenazine (and of tetrabenazine): Refer to the original review.
`
`Bridging of deutetrabenazine to tetrabenazine: Bridging is a critical issue that is well covered by
`the reviews of clinical pharmacology, biopharmaceutics, the CDTL, and the Deputy Division
`Director.
`
`This 505(b)(2) application relies, in part, on FDA’s prior finding of safety and efficacy for
`tetrabenazine. Thus, an adequate PK bridge has to be provided to the tetrabenazine NDA. In
`particular, it is critical to know how levels of metabolites compare for the two drugs, and
`whether there are major metabolites unique to deutetrabenazine.
`
`In the first review cycle, there was concern whether the in vivo metabolic profile of
`deutetrabenazine had been adequately characterized; specifically, whether levels of the M1
`and M4 metabolites exceeded 10% of total drug-related material, which would have
`categorized them as major metabolites.
`
`The reviewers have determined that M4 levels are about 6% of total drug-related exposure, and
`M1 levels are approximately 10%. Thus, reliance on the tetrabenazine data to support the
`deutetrabenazine 505(b)(2) application is scientifically supported and justified, and there are no
`outstanding clinical pharmacology issues that preclude approval.
`
`6. Clinical Microbiology
`
`Not applicable.
`
`7. Clinical/Statistical-Efficacy
`
`Considering the similarities between tetrabenazine and deutetrabenazine, the division agreed
`to rely on a single efficacy study for deutetrabenazine.
`
`NDA 208082, Office Director Memo, page 6
`
`Reference ID: 4079060
`
`

`

`The clinical study is well described in the original reviews of Drs. Bergmann, Zhang, Podskalny,
`and Bastings, and summarized in my original memo of May 26, 2016.
`
`The review team had considered placing a figure in labeling showing the cumulative distribution
`of responses in the study, similar to the figure shown in tetrabenazine labeling. I believe,
`however, it would be more clear to show a histogram of the distribution of responses. Figure 2
`shows the distribution in the change in total maximal chorea score from baseline to
`maintenance, and a version of this figure will be provided in Section 14 of labeling.
`
`Figure 2: Distribution of the Change in Total Maximal Chorea Scores
`
`8.
`
`Safety
`
`Please refer to my original Office Director Summary Review for a discussion of the safety of
`deutetrabenazine. The applicant included a safety update with this new submission, but there
`are no new issues. Deutetrabenazine appears to have a safety profile similar to that of
`tetrabenazine, with no unique issues identified.
`
`NDA 208082, Office Director Memo, page 7
`
`Reference ID: 4079060
`
`

`

`9.
`
`Advisory Committee Meeting
`
`The NDA was not presented to the Peripheral and Central Nervous System Drugs Advisory
`Committee. This is a 505(b)(2) application without novel or controversial safety or efficacy
`issues.
`
`10. Pediatrics
`
`Deutetrabenazine is an orphan drug, and therefore, no pediatric obligations exist.
`
`11. Other Relevant Regulatory Issues
`
`Controlled Substances Staff (CSS): Tetrabenazine is not a scheduled drug. Although the
`issue was not a reason for the Complete Response action in the first cycle review, the CSS
`reviewer noted that neither abuse potential nor dependence were evaluated in the
`preclinical/clinical studies, and suggested evaluation of withdrawal and rebound symptoms at
`the end of study SD-809-C-15 ARC HD, which is ongoing.
`
`Subsequent to our Complete Response action, the applicant was not able to conduct this
`assessment because the study is still ongoing; however, they noted the following:
`
`“During the clinical development of SD-809, abrupt discontinuation did not produce
`adverse events. This observation suggests that SD-809 does not produce a withdrawal
`syndrome. A search for events relating to drug abuse, drug dependence and drug
`withdrawal, as well as euphoric mood, was conducted using standardized MedDRA
`query (SMQ) terms; no such adverse events were found in Studies SD-809-C-15 and
`SD-809-C-16 (Complete Response Safety Update, Section 8.6). The studies in the SD-
`809 clinical development program did not reveal any tendency for drug-seeking
`behavior. Moreover, Xenazine® (tetrabenazine) is neither a controlled substance nor
`has abuse been reported from the postmarketing experience.”
`
`CSS continues to have concerns (the applicant did not submit any new data). CSS stresses
`that the deutetrabenazine appeared to produce rebound in ~20% of patients during the first
`week of withdrawal, as well as tolerance that began on Week 9 of treatment. Their original
`review drew attention to a number of scales that showed worsening during washout.
`
`The clinical review team and Dr. Bastings remain unimpressed by the nature of the adverse
`events reported. Dr. Bastings also notes that tetrabenazine is not known to have such effects,
`and he believes there is no need for further assessment of withdrawal or rebound for
`deutetrabenazine.
`
`I agree with the Division on this issue. I cannot find explicit data in the original CSS review to
`support the concept that some 20% of patients experienced symptoms of rebound. Moreover,
`because patients were not blinded to washout (i.e., they knew they were discontinuing their
`
`NDA 208082, Office Director Memo, page 8
`
`Reference ID: 4079060
`
`

`

`study drug), I believe the data obtained during the washout period must be interpreted with
`caution.
`
`The applicant still plans to assess adverse events after drug withdrawal in the ongoing study. (I
`think that if it were important to gain more certainty about withdrawal and/or rebound, we would
`suggest a randomized [double-blind] withdrawal phase.) But I, like Dr. Bastings, take
`reassurance from the fact that these issues have not been reported for tetrabenazine, despite
`almost a decade of marketing experience, and see no reason to request a formal post-
`marketing commitment.
`
`12.
`
`Labeling
`
`Labeling has been negotiated with the applicant. Originally, we were considering a cumulative
`distribution plot for the 1° endpoint, similar to the figure in the tetrabenazine labeling. But I
`believe that a histogram showing the range of responses in patients randomized to
`deutetrabenazine and placebo will be more comprehensible and helpful, and such a figure will
`be placed in Section 14.
`
`13. Postmarketing
`
`I agree with Dr. Bastings and see no reason for a REMS or for any postmarketing requirements
`or commitments.
`
`NDA 208082, Office Director Memo, page 9
`
`Reference ID: 4079060
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`ELLIS F UNGER
`04/03/2017
`
`Reference ID: 4079060
`
`(
`
`
`
`