CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`208082Orig1s000
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`SUMMARY REVIEW
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`Division Director Summary Review for Regulatory Action
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`_ (electronic stamp)
`Eric Basfings. MD. Deputy Director. DNP.
`
`Subject
`Division Director Summary Review
`NDA/BLA #
`208082
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`Su n ilement #
`
`
`Date of Submission
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`October 3, 2016
`
`Proprietary Name /
`Non-Proprietary Name
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`Austedo/
`Deutetrabenazine (deutetrabenazine)
`
`Dosa_e Form 5 / Stren_th 5
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`Oral tablets I 6 mg, 9 mg, and 12 mg
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`Applicant Proposed
`Indication 5 /Po I ulation 5
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`Treatment of chorea in patients with Huntington’s disease.
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`Recommended Action
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`Approval
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`Recommended
`Indication/Po u ulation 5
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`Treatment of chorea in patients with Huntington’s disease.
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`Material Reviewed/Consulted - Action Packae, includin -:
`Stac Meiz
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`Medical Officer Clinical Review
`
`Ken Bergmann
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`Clinical Pharmacology Review
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`Kristina Dimova; Angela Men; Xiaofeng Wang; Atul
`Bhattaram; Kevin Krudys; Jeffrey Kraft; Christian
`Grimstein
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`Statistical Review
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`Pharmacolo~ Toxicolo~
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`'
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`'
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`; Kun Jin; Hsien Min-
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`Chris Toscano; Lois Freed
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`Chemistry Manufacturing and Controls
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`Wendy Wilson-Lee; Martha Heimann; Gene Holbert;
`Sherita McLamore—Hines; Masih Jaigirdar; Don
`Obenhuber
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`Jin- Li; Okoo Eradin'; An-elica Dorantes
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`QTIIRT
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`OSE PMs
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`Moh Jee Ng; Qianyu Dang; Dinko Rekic; Jiang Liu;
`Michael Li; Norman Stockbridge
`Ermias Zerislasse; Corwin Howard
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`OSE/DEPI
`Cross-Disci-line Team Leader
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`Lockwood Ta lor; Elisa Braver
`Gerald Dave Podskaln
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`OND=0ffice ofNew Drugs
`0PQ=Ofiice of Pharmaceutical Quality
`OPDP=Oifice of Prescription Drug Promotion
`OSI=0flice of Scientific Investigations
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`Reference ID: 4076547
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`CDTL=Cross-Discipline Team Leader
`OSE= Office of Surveillance and Epidemiology
`DEPI= Division of Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DRISK=Division of Risk Management
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`Reference ID: 4076547
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`2
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`1. Benefit-Risk Assessment
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`Reference ID: 4076547
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`3
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`APPEARS THIS WAY ON ORIGINAL
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`Benefit-Risk Summary and Assessment
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`The 505(b)(2) application under review is for deutetrabenazine (Austedo), a deuterated form of tetrabenazine, proposed for the treatment of
`chorea associated with Huntington’s disease. The applicant proposes using tetrabenazine, which is approved for the same indication, as reference
`listed drug. This application relies on the tetrabenazine NDA for some pharmacology/toxicology studies that were not conducted by the applicant,
`including a fertility and early embryonic development study, an embryofetal developmental study, a pre- and post-natal development study, and
`carcinogenicity assessment.
`
`Both deutetrabenazine and tetrabenazine are vesicular monoamine transporter 2 (VMAT2) inhibitors. The mechanism of action of
`deutetrabenazine and tetrabenazine on chorea is believed to be related to their effect as reversible depletors of monoamines (e.g., dopamine,
`serotonin, norepinephrine, and histamine) from nerve terminals.
`
`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. The change from baseline in TMC score was significantly higher (drug-placebo difference of 2.5 points, on a 24-
`point scale) for deutetrabenazine than for placebo (p<0.0001). The meaningfulness of the TMS results was supported by statistically significant
`effects on the Patient Global Impression of Change and the Clinical Global Impression of Change.
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`The safety profile of deutetrabenazine is acceptable. There were no unique toxicities identified for deutetrabenazine, as compared with
`tetrabenazine. A close examination of the deutetrabenazine safety database was conducted for the safety issues known for tetrabenazine. These
`issues include sedation and somnolence, akathisia, depression, and suicidality. Notwithstanding the usual limitations of cross-study comparisons,
`the frequency of these events appears no higher for deutetrabenazine than for tetrabenazine. Absent a head to head comparative study, it is
`impossible to make any definitive conclusions about the comparative safety profile between tetrabenazine and deutetrabenazine, but there are no
`new safety concerns identified. A QT prolongation signal is known and labeled for tetrabenazine. The TQT study conducted by the applicant did
`not use sufficiently high concentrations of deutetrabenazine to rule out QT prolongation at supratherapeutic or therapeutic concentrations. As for
`tetrabenazine, this can be addressed by labeling.
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`Tetrabenazine is already marketed for the same indication as that proposed for deutetrabenazine, and deutetrabenazine does offer as only clear
`advantage over tetrabenazine that, at high end of the dosing range, tetrabenazine must be taken two to three times a day, while deutetrabenazine
`may be taken just twice a day.
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`Reference ID: 4076547
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`4
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`Evidence and Uncertainties
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`Conclusions and Reasons
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`Huntington’s disease (HD) is an autosomal dominant
`neurodegenerative disorder. HD has an estimated prevalence of
`5/ 100,000 in the US.
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`HD is a serious and profoundly disabling
`disorder. There is currently no treatment that
`can delay the progression of the disease.
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`Tetrabenazine is the only available
`symptomatic treatment of chorea in HD
`patients.
`
`Efficacy of deutetrabenazine appears similar to
`that of tetrabenazine, which is approved for the
`treatment of chorea in 1-D patients.
`
`The affected gene codes for a trinucleotide (CAG) repeat
`expansion producing abnormal Huntingtin protein (Huntingtin).
`Patients with a CAG repeat length of 37 CAG repeats or more
`become symptomatic. The length of the CAG repeat also
`influences the age of onset. Long repeat sequence lengths are
`associated with an onset of symptoms at a younger age.
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`
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`The disease is characterized by progressive dementia, motor
`impairment and psychiatric symptoms, beginning most ofien
`between ages 30 to 50 years. Death usually occurs within 20
`years of symptoms onset.
`A less common 'uvenile form of HD does also exist.
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`Tetrabenazine (Xenazine) 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.
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`Antidepressants, and antipsychotics are used to treat the
`s chiatiic and behavioral as u ects of 1-D.
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`Benefit was established in a double-blind, placebo-controlled
`clinical study in 90 patients (Study C-15). The study used a well-
`accepted measure of chorea as primary outcome measure: the
`Total Maximal Chorea (TMC) score.
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`There was a highly significant difference between
`deutetrabenazine and placebo for the primary endpoint
`(difference in score change from baseline of -2.49, p<0.0001).
`This effect size is similar to that seen with tetrabenazine.
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`Evidence and Uncertainties
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`Conclusions and Reasons
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`Deutetrabenazine has a safety profile similar to that of
`tetrabenazine.
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`Deutetrabenazine has a safety profile
`similar to that of tetrabenazine.
`
`0 The meaningfulness of the benefit of deutetrabenazine to patients
`was supported by statistically significant improvements on the
`Patient Global Impression of Change and the Clinical Global
`Impression of Change, compared with placebo.
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`depression in patients with HD.
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`As for tetrabenazine, the risks associated with deutetrabenazine
`can be managed by labeling.
`o Routine pharmacovigilance is recommended.
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`AS tetrabenazine, deutetrabenazine
`should include a Boxed Warning for
`increased TiSk for suicidality and
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`2. Background
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`
`Huntington’s disease is an autosomal dominant inherited neurodegenerative disorder
`characterized by progressive dementia, motor impairment and psychiatric symptoms. The
`505(b)(2) application under review is for deutetrabenazine (Austedo), a deuterated form of
`tetrabenazine, proposed for the treatment of chorea associated with Huntington’s disease.
`
`The applicant proposes using Xenazine (tetrabenazine), which is approved for the treatment of
`chorea associated with Huntington’s disease, as reference listed drug. This application relies
`on the Xenazine NDA for some pharmacology/toxicology studies that were not conducted by
`the applicant, including fertility and early embryonic development study, an embryofetal
`developmental study, a pre- and postnatal development study, and carcinogenicity studies.
`
`Both deutetrabenazine and tetrabenazine are vesicular monoamine transporter 2 (VMAT2)
`inhibitors. The mechanism of action of deutetrabenazine and tetrabenazine on chorea is
`believed to be related to their effect as reversible depletors of monoamines (e.g., dopamine,
`serotonin, norepinephrine, and histamine) from nerve terminals.
`
`The submission under review is a response to a Complete Response letter that was issued on
`May 27, 2016. The primary reason for the action was that clinical pharmacology studies were
`not adequate to determine whether all major human metabolites of deutetrabenazine have been
`identified. This information is needed to determine whether the bridge to the listed drug on
`which the applicant is relying (Xenazine) is scientifically justified to address the toxicity of all
`major metabolites of deutetrabenazine.
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`In addition, a few product quality issues remained to be addressed, including the need for a test
`for
`, a change of the post-approval stability commitment to include
`placing the first 3 commercial batches of each strength of the drug product on long-term
`stability through the proposed shelf life and on accelerated stability for 6 months, and the need
`for a revision of the the claim for categorical exclusion to include a statement that, to the
`applicant's knowledge, no extraordinary circumstances exist.
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` I
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` refer the reader to my first cycle Division Director Summary Review for a detailed
`discussion of the application, and of the issues that led to a Complete Response action.
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`3. Product Quality
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` I
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` concur with the conclusions reached by the chemistry reviewer 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. Stability
`testing supports an expiry of 32 months. There are no outstanding product quality issues.
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`Reference ID: 4076547
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`7
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`(b) (4)
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`4. Nonclinical Pharmacology/Toxicology
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` I
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` concur with the conclusions reached by the pharmacology/toxicology reviewer that there are
`no outstanding pharm/tox issues that preclude approval.
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`In the first cycle, because it was unclear whether all major circulating metabolites of
`deutetrabenazine in humans had been identified, it was not possible to determine whether
`bridging to the nonclinical studies conducted with tetrabenazine was appropriate for this
`505(b)(2) application, i.e., whether all major circulating metabolites of deutetrabenazine had
`been adequately evaluated in nonclinical studies.
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`As discussed below, circulating metabolites of deutetrabenazine in humans have now been
`adequately characterized, and no new major metabolite was identified. Therefore, all major
`circulating metabolites of deutetrabenazine have indeed been adequately evaluated in
`nonclinical studies.
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`5. Clinical Pharmacology
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`Deutetrabenazine is a selectively deuterated form of tetrabenazine in which the two O-linked
`methyl groups (CH3) of the tetrabenazine molecule have been replaced by two
`trideuteromethyl groups (CD3).
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` I
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` refer the reader to my first cycle Division Director Summary Review for a discussion of the
`pharmacokinetics of deutetrabenazine.
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`As this 505(b)(2) application relies, in part, on FDA’s prior finding of safety and efficacy for
`Xenazine (tetrabenazine), an adequate PK bridge has to be provided to the Xenazine NDA. In
`particular, it is critical to know how the metabolites levels compare for both drugs, and
`whether there is any major metabolite unique to deutetrabenazine.
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`Deficiencies in clinical pharmacology studies led to the Complete Response action in the first
`review cycle of deutetrabenazine, as the applicant had not adequately characterized the in vivo
`metabolic profile of deutetrabenazine in humans. There was a concern that the level of the M1
`and M4 metabolites may exceed a threshold of 10% of the total drug-related material, and
`therefore be considered major metabolites.
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`The metabolic profile of deutetrabenazine has now been adequately characterized, and no
`metabolite exceeds the 10% threshold of the total drug-related material, i.e., there are no new
`major metabolites. The results of the new analyses indicate that M4 levels are about 6% of
`total drug-related exposure, while the levels of M1 are about 10%. Therefore, reliance on
`tetrabenazine to support the deutetrabenazine 505(b)(2) application is scientifically supported,
`and acceptable.
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`Reference ID: 4076547
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`8
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`I concur with the conclusions reached by the clinical pharmacology/biopharmaceutics reviewer
`that there are no outstanding clinical pharmacology issues that preclude approval.
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`6. Clinical Microbiology
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`Not applicable.
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`7. Clinical/Statistical-Efficacy
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`Considering the similarities in the PK profile of tetrabenazine and deutetrabenazine, the
`division accepted to rely on a single efficacy study for deutetrabenazine. I refer the reader to
`my first cycle Division Director Summary Review for a discussion of the efficacy study
`conducted by the applicant, Study C-15. The study met its objectives, and establishes the
`efficacy of deutetrabenazine for the treatment of chorea in patients with Huntington’s disease.
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`8. Safety
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` I
`
` refer the reader to my first cycle Division Director Summary Review for a discussion of the
`safety of deutetrabenazine. The applicant included a safety update in this new submission.
`Deutetrabenazine has a safety profile similar to that of tetrabenazine. There are no safety
`issues unique to deutetrabenazine, compared with tetrabenazine.
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`9. Advisory Committee Meeting
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`No advisory committee meeting was held for this 505(b)(2) application.
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`10.
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`Pediatrics
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`As the product has orphan exclusivity, PREA was not triggered by this application.
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`11.
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`Other Relevant Regulatory Issues
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`
`Controlled Substances Staff (CSS)
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`In the first cycle review, the CSS reviewer noted that there were no preclinical or clinical
`studies designed to evaluate abuse potential and dependence of deutetrabenazine, and the
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`Reference ID: 4076547
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`9
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`reviewer recommended evaluation of clinical dependence at the end of a trial lasting at least 4
`weeks, e.g., an ongoing open-label safety study. That request, however, was not a reason for
`the Complete Response action, considering the reliance on tetrabenazine as a reference listed
`drug, which should be largely be adequate to address the potential for abuse and dependence of
`deutetrabenazine.
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`The applicant was not able to conduct the assessment suggested by the CSS reviewer in their
`ongoing open-label safety study, but notes that in efficacy study C-15, abrupt discontinuation
`did not produce adverse events. The applicant also noted that studies in the SD-809 clinical
`development program did not reveal any tendency for drug-seeking behavior, and that
`tetrabenazine is neither a controlled substance nor has abuse been reported from the
`postmarketing experience. In addition, the clinical review team assessed whether there was any
`indication of rebound in Study C-15 after the study drug was discontinued at the end of the
`trial, and concluded that there was not.
`
` I
`
` agree with the review team that there is no evidence for a pattern of drug withdrawal or
`rebound for deutetrabenazine. Also, considering the bridge to tetrabenazine and the fact that
`tetrabenazine is not known to have such issues, I believe that there is no need for further
`assessment of withdrawal or rebound for deutetrabenazine.
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`12.
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`Labeling
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`Agreement was reached on labeling with the applicant.
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`13.
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`Postmarketing
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`As for Xenazine, no Postmarketing Risk Evaluation and Mitigation Strategy should be
`necessary for this product.
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` do not recommend any postmarketing requirement or commitment.
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`
` I
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`Reference ID: 4076547
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`10
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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/
`----------------------------------------------------
`
`ERIC P BASTINGS
`03/29/2017
`
`Reference ID: 4076547
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`