CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
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`APPLICATION NUMBER:
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`022567Orig1s000
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`PHARMACOLOGY REVIEW(S)
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`Tertiary Pharmacology/Toxicology Review
`
`From: Paul C. Brown, Ph.D., ODE Associate Director for Pharmacology and
`Toxicology, OND IO
`
`NDA: 22-567
`Agency receipt date: 3/22/2010
`Drug: VIIBRYD (vilazodone hydrochloride)
`Applicant: PGxHealth, LLC
`Indication: treatment of major depressive disorder
`
`Reviewing Division: Division of Psychiatry Products
`
`
`Background:
`The pharm/tox reviewer and team leader concluded that the nonclinical data
`support approval of vilazodone hydrochloride for the indication listed above.
`
`Reproductive and Developmental Toxicity:
`Reproductive and developmental toxicity studies in rats and rabbits revealed no
`evidence of teratogenicity although there was some evidence of reduced fetal
`body weight and delayed ossification in both species. These effects were not
`seen at doses up to 10 times the MRHD in rats or 4 times the MRHD in rabbits.
`The reviewer recommended pregnancy category C.
`
`Carcinogenicity:
`Vilazodone was tested in 2 year rat and mouse carcinogenicity studies. These
`studies were reviewed by the division and the executive carcinogenicity
`assessment committee. The committee concluded that the studies were
`acceptable. There were no drug-related neoplasms in rat. The Committee
`concluded that there was an increased incidence of mammary adenocarcinomas
`and adenoacanthomas (combined) in female mice at the high dose (135 mg/kg)
`and hepatocellular neoplasms (adenomas, carcinomas, and adenomas or
`carcinomas, combined), in male mice at the high dose (135 mg/kg). The division
`has also noted that the mammary adenocarcinomas in female mice appear to be
`increased at the mid dose of 45 mg/kg even though the incidence did not meet
`usual CDER standards for statistical significance for pairwise comparison. The
`reviews also note that vilazodone increased prolactin levels in mice.
`
`Established Pharmacologic Class:
`The pharm/tox reviewer, team leader and supervisor have carefully considered
`the data on the pharmacologic activity of vilazodone. Vilazodone appears to have
`both SSRI and 5-HT1A partial agonist activity.
`
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`Reference ID: 2891807
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`Impurities and metabolites:
`Several genotoxic or potentially genotoxic impurities were identified during review
`of the NDA. This issue is discussed in detail in the team leader memo.
`Specifications for each of these impurities have been limited so humans will be
`exposed to not more than
` μg of each per day at the MRHD of 40 mg.
`
`Two major human metabolites of vilazodone were identified. The nonclinical
`assessment of these is discussed in detail in the team leader memo. Both
`metabolites have been adequately assessed for all toxicity endpoints except it is
`not clear that one metabolite (M17) was adequately assessed for embryofetal
`toxicity because its presence was not confirmed in rats or rabbits. The division is
`recommending that M17 be assessed in an embryofetal study or that data be
`provided demonstrating that M17 was adequately assessed in one of the already
`conducted embryofetal studies. The division is recommending this as a post
`marketing requirement.
`
`Pediatric assessment:
`The division is recommending that the efficacy and safety of vilazodone be
`assessed in pediatric patients with major depressive disorder as part of the
`deferred pediatric requirements. Prior to dosing children less than 13 years of
`age, the division is recommending that the applicant complete a juvenile animal
`study in rats and include evaluation of neurological/behavioral development and
`reproductive development in this study.
`
`
`Conclusions:
`I agree with the division pharm/tox conclusion that this application can be
`approved from a pharm/tox perspective. The proposed post marketing
`requirements are acceptable.
`
` I
`
` have discussed the proposed carcinogenicity labeling with the team leader. The
`proposed wording states that mammary adenocarcinomas in female mice were
`numerically increased at the mid dose in addition to describing the statistically
`significant increase in tumors. This is a true statement and is acceptable.
`Proposed labeling includes wording noting the potential role of elevated prolactin
`in these tumor findings.
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`Other labeling as proposed by the reviewer and team leader is acceptable.
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`Reference ID: 2891807
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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/
`----------------------------------------------------
`
`PAUL C BROWN
`01/14/2011
`
`Reference ID: 2891807
`
`

`

`NDA 22-567 (vilazodone HCl tablets; VIIBRYD™).
`Original submission (3/22/2010).
`
`
`SUPERVISORY PHARMACOLOGY/TOXICOLOGY MEMO TO THE FILE
`
`Linda H. Fossom, Pharmacologist.
`page 1
`
`BACKGROUND:
`
`
`
`NDA 22-567.
`Submissions: N-000, original submission, letter-dated 3/22/2010, received 3/22/2010.
`
`Drug: vilazodone hydrochloride, as 10-, 20-, and 40-mg oral tablets [VIIBRYD™].
`Sponsor: PGxHealth, LLC (original sponsor).
`Indication: treatment of major depressive disorder.
`
`
`Reviewer: Linda H. Fossom, Ph.D., Pharmacologist, Team Leader.
`Division of Psychiatry Products, HFD-130.
`
`
`I.
`
`Vilazodone is a new molecular entity submitted under the current NDA for treatment of
`major depressive disorder. The pharmacology/toxicology studies have been reviewed in
`detail by Violetta Klimek, Ph.D., Pharmacologist (review finalized 12/22/2010). In her
`review, Dr. Klimek has thoroughly and critically evaluated the non-clinical information
`provided in support of this NDA. In general, these studies provided adequate assessment
`of pharmacology, general toxicity (including chronic studies in rats and dogs),
`genotoxicity, carcinogenicity (2-year studies in rats and mice), and reproductive toxicity.
`I agree with Dr. Klimek that vilazodone did not demonstrate any particular concerns
`based on these studies; the findings for genotoxicity, reproductive toxicity, and
`carcinogenicity will be included in labeling.
`
`However, late in the review cycle, it became apparent that 2 major human metabolites,
`one of which had not been identified as circulating in human plasma at the time of NDA
`submission, might not have been adequately assessed for toxicity in animals. We
`contacted the Sponsor to obtain their explanation of this issue (on 12/14/10 and again on
`12/20/10); however, their full response was not available at the time Dr. Klimek’s review
`was finalized. That information is now available and is discussed below.
`
`This memo contains additional comments on 4 issues:
`•
`• The carcinogenicity findings presented in labeling;
`• The control of genotoxic (and potentially genotoxic) impurities;
`• Toxicological assessment of the 2 major circulating human metabolites.
`
`
`
`
`[Of these issues, only the toxicological assessment of one of the major human metabolites
`(M17) needs further study by the Sponsor and this will be required as a post-marketing
`commitment.]
`
`
`Reference ID: 2890371
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`(b) (4)
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`

`

`NDA 22-567 (vilazodone HCl tablets; VIIBRYD™).
`Original submission (3/22/2010).
`
`
`II.
`
`LABELING RELATED TO ESTABLISHED PHARMACOLOGIC CLASS:
`
`Linda H. Fossom, Pharmacologist.
`page 2
`
`
`
`
`
`
`
`
`[It should be noted that the
`Warnings and Precautions Section of labeling already includes serotonin syndrome or
`neuroleptic malignant-like syndrome for vilazodone.]
`
`
`
` However, the Mechanism of Action section will include 5-HT1A partial
`agonist activity, as well as SSRI activity, but will indicate that the role of 5-HT1A partial
`agonism in the antidepressant effect is not as well accepted (or demonstrated) as the role
`of SSRI activity, as recommended by Dr. Rosloff.
`
`
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`Reference ID: 2890371
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

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`NDA 22-567 (vilazodone HCl tablets; VIIBRYD™).
`Original submission (3/22/2010).
`
`
`III. THE CARCINOGENICITY AND EMBRYO-FETAL TOXICITY
`FINDINGS PRESENTED IN LABELING:
`
`Linda H. Fossom, Pharmacologist.
`page 3
`
`
`Regarding carcinogenicity findings, we have included in labeling only the findings that
`the Executive Carcinogenicity Assessment Committee (E-CAC) found statistically
`significant (based on the statistical analysis provided in the Statistical Review and
`Evaluation, by Mohammad Nagem, Ph.D., 11/9/2010) and biologically relevant, with one
`exception. For mammary tumor findings in female mice, the E-CAC found only the
`incidence of adenocarcinomas and adenoachanthomas combined (but not either tumor
`type alone) to be increased and only at the high dose of 135 mg/kg, based on statistical
`significance in both the trend test and pair-wise comparison with the vehicle control
`group. [Note that the Sponsor had identified significantly increased incidence of
`adenocarcinomas at both the mid dose (of 45 mg/kg) and the high dose.] The statistical
`analysis of these findings is provided below:
`Table 1. Statistical analysis of incidence of mammary tumors (adenocarcinomas and
`adenoacanthomas) in female mice (excerpted and reformatted from the table on
`page 22 of Dr. Nagem’s statistical review, 11/09/2010). An asterisk (*) indicates
`statistical significance.
`TUMORS
`
`P-VALUE
`DOSE, mg/kg
`0 (C) 15 (LD) 45 (MD) 135 (HD) C vs MD1 C vs HD1 Trend2
`3/120
`1/60
`6/60
`7/60
`0.0482
`0.0166
`0.0050*
`3/120
`1/60
`6/60
`8/60*
`0.0482
`0.0069*
`0.0017*
`
`adenocarcinomas
`adenocarcinomas +
`adenonoacanthomas
`1: p ≤ 0.01, indicates statistical significance for pair-wise comparison (for common tumors).
`2: p ≤ 0.005, indicates statistical significance for dose-response by trend test.
`
`Although only total malignant mammary tumors (adenocarcinomas plus
`adenoacanthomas) were statistically significantly increased and only at the high dose, the
`data seem to indicate that adenocarcinomas were increased at both mid and high doses.
`[Note that there was only a single mouse (at high dose) with an adenoacanthoma,
`compared with 6 and 7 mice with adenocarcinomas at the mid dose and high dose,
`respectively.] The incidences for adenocarcinomas alone or combined with
`adenoacanthomas show significant dose-responses (i.e., they are both positive by trend
`test) and the incidences at both mid and high doses are clearly higher than at the low dose
`and for controls, so the significant dose-response for adenocarcinomas depends on the
`findings at the mid dose, as well as the high dose. It would seem more reasonable to
`consider the increased incidence for total malignant mammary tumors (without
`specifying which ones contributed to the statistical significance). The incidence of
`malignant mammary tumors was increased in a dose-related manner (statistically
`significant trend tests for adenocarcarcinomas alone and when combined with
`adenoacanthomas) and this increase was evident at the mid dose (but not statistically
`significant by pair-wise comparison versus control) and at the high dose (statistically
`significant by pair-wise comparison versus control).
`
`
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`Reference ID: 2890371
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`

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`NDA 22-567 (vilazodone HCl tablets; VIIBRYD™).
`Linda H. Fossom, Pharmacologist.
`page 4
`Original submission (3/22/2010).
`
`It should also be noted that the incidence of acinar hyperplasia was higher at the mid dose
`(11%) and high dose (14%), compared with the low dose (7%) and controls (7.6%) in this
`study; and the incidences of adenocarcinomas at the mid and high doses were above the
`historical range for mammary carcinomas based on the NTP studies in this strain of mice
`[see Dr. Klimek’s review].
`
`Additionally, prolactin was shown to be increased in mice at the high dose of 135 mg/kg
`(but was not assessed at the lower doses of 15 and 45 mg/kg) at week 13 in the
`carcinogenicity study; and at doses of 45 mg/kg (the mid dose used in the carcinogenicity
`study) and 270 mg/kg in a separate 2-week study. The possibility that the increase in
`mammary tumors in mice was due to this increase in prolactin, a mechanism that has
`unclear relevance of humans, is suggested in labeling. The fact that increased prolactin
`was demonstrated at 45 mg/kg adds biological plausibility to a true drug effect on tumors
`at this dose.
`
`The findings for malignant mammary gland tumors in female mice are described in
`labeling (along with the findings for hepatocelluar carcinomas in male mice) as:
`
`
`In mice, the incidence of hepatocellular carcinomas was increased in males at
`16.5 times the MRHD; this finding was not observed at 5.5 times the MRHD.
`The incidence of malignant mammary gland tumors was numerically increased in
`females at 5.5 and 16.5 times the MRHD, with statistical significance at 16.5
`times the MRHD; this finding was not observed at 1.8 times the MRHD. Elevated
`prolactin levels were observed in a 2-week study of vilazodone administered at
`5.5 and 33 times the MRHD. Increases in prolactin levels are known to cause
`mammary tumors in rodents.
`
`
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`Reference ID: 2890371
`
`(b) (4)
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`

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`Linda H. Fossom, Pharmacologist.
`page 5
`
`NDA 22-567 (vilazodone HCl tablets; VIIBRYD™).
`Original submission (3/22/2010).
`
`
`IV. GENOTOXIC IMPURITIES:
`
`During the review of this NDA, 7 genotoxic or potentially genotoxic impurities were
`determined to share a common structural alert: they are all
`. There was
`considerable internal discussion (by Pharmacology/Toxicology and Chemistry
`disciplines) about whether 1) the limit for each genotoxic impurity should be lowered so
`that the daily clinical exposure to each would be no more than
` µg (at the maximum
`recommended human dose of 40 mg) or 2) the limit for the total all 7 genotoxic
`impurities sharing this structural alert should be lowered so that the daily clinical
`exposure to all would be no more than
` µg. We communicated our concerns to the
`Sponsor (10/15/10), as excerpted below:
`
`
`
` …
`
`…
`
`
`In response (11/04/2010), the Sponsor agreed to do the following (as summarized by this
`Reviewer):
`• Regarding impurity
`, they tightened the specification from not more than
`(NMT)
` ppm (i.e., NMT
`, as an unspecified impurity) to NMT
` ppm
`(i.e., NMT
` µg at the maximum recommended human dose of 40 mg [which is
`considered close enough to the
` µg/day limit for human exposure to a
`genotoxic impurity, set according to current policy and Guidances)].
`
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`Reference ID: 2890371
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`(b) (4)
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`NDA 22-567 (vilazodone HCl tablets; VIIBRYD™).
`Original submission (3/22/2010).
`
`• Regarding the other 6
` impurities, they lowered the specifications
` each from NMT
` ppm to NMT
` ppm; and will
`for
` and
`evaluate whether the 4 others (which are currently limited to NMT
` ppm) can
`be further lowered to reduce the overall patient exposure (to be submitted in their
`1st annual report).
`
`Linda H. Fossom, Pharmacologist.
`page 6
`
`
`The Sponsor also noted that the batches used in the 2-year carcinogenicity studies in mice
`and rats were manufactured using Process 1 (not the process currently used for the
`clinical substance/product), which resulted in the formation of
` at levels (i.e., present
`in each batch at amounts between
` ppm [the LOQ] and
` ppm) that are higher than
`the currently-proposed limit of NMT
` ppm, but did not result in the formation of any of
`the other potentially-genotoxic impurities. The presence of
` (which was mutagenic and
`clastogenic when tested directly in in vitro tests) in the batches of vilazodone that were
`used in the carcinogenicity studies at 2.5 (or more) times the limit in the clinical batches
`also might give some small assurance that the findings in the carcinogenicity studies also
`cover this impurity.
`
`Conclusions: The Sponsor’s actions regarding the 7
` impurities are
`considered adequate from a Pharmacology/Toxicology perspective, as described here and
`in Dr. Klimek’s review (and from a Chemistry perspective, see Chemistry review by Pei-
`I Chu, Ph.D., Chemist, 1/03/2010). The specification for each of these impurities has
`been limited so than human will be exposed to not more than
`µg of each per day at
`the MRHD of 40 mg. The Sponsor will attempt to further lower the specifications, to
`reduce the overall patient exposure.
`
`
`
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`Reference ID: 2890371
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`(b) (4)
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`

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`Linda H. Fossom, Pharmacologist.
`page 7
`
`NDA 22-567 (vilazodone HCl tablets; VIIBRYD™).
`Original submission (3/22/2010).
`
`
`V. MAJOR HUMAN METABOLITE(S):
`
`The non-clinical sections of the original NDA submission provided no indication that
`there were any metabolites circulating in humans that were not also circulating in animal
`species. In fact, the Cross-Species Metabolite Comparison summary table (Table 3 in the
`Non-clinical Overview section of this NDA), showing the presence (or by implication
`absence) of 15 metabolites in the urine, feces, or plasma of humans, rats, and dogs,
`indicated that only metabolite M10 was present in human plasma and that metabolite was
`also present in plasma of rat and dog. It should be noted that metabolite M10, which had
`been early recognized as a significant metabolite circulating in humans, had also been
`quantified in plasma of animals in the toxicity studies. However, in the table referred to
`above, metabolite M17 was indicated to be present in urine of humans, rats, and dogs, but
`not in plasma of any of these species [with a footnote that “In nonclinical species, only
`metabolites present as ≥ 3.0% of dose or ≥ 5.0% of sample radioactivity are listed, where
`information is available.”].
`Figure 1. Structures of vilazodone and major human metabolites M10 and M17
`(structures excerpted from the Sponsor’s Figure 7, on page 52 of the Non-clinical
`Overview section).
`
`
`
`
`
`
`Although the report for the mass-balance study (PGX-08-P1-07) was provided with the
`original submission of this NDA, the quantitative metabolite data for humans was
`submitted late in the review cycle (08/31/2010) and indicated that 2 metabolites, namely
`M17 in addition to M10, were each present in plasma at greater than 10% of total drug-
`related species (see Clinical Pharmacology review by Bei Yu, Ph.D., 12/08/2010). The
`data provided in that submission are summarized in the table below and indicate that M10
`and M17 each represented more than 10% of total circulating vilazodone (M16)-related
`species after a single 20-mg dose to healthy male subjects. The amount of M10
`represented more the 10% of total radioactivity at 5-8 hr (~12%), and 10-24 hr (~14%).
`
`
`Reference ID: 2890371
`
`

`

`NDA 22-567 (vilazodone HCl tablets; VIIBRYD™).
`Linda H. Fossom, Pharmacologist.
`page 8
`Original submission (3/22/2010).
`
`The amount of M17 represented more the 10% of total radioactivity at 0.5-4 hr (~11%),
`5-8 hr (~18%), and 10-24 hr (~22%), as shown in the table below.
`
`Table 2. Human plasma exposure to vilazodone (M16) and major human
`metabolites M10 and M17 in healthy males administered 20 mg (radiolabeled)
`vilazodone in the mass-balance study (PGX-08-P1-07). [Relevant sections were
`excerpted directly from Table 2 of the study report, page 15; high-lighting added.]
`
`…
`
`
`
`When this new information came to our attention, we contacted the Sponsor (12/14/10),
`asking them to address the safety and toxicity of both metabolites M10 and M17, as
`assessed in non-clinical studies, and referring them to the ICH Guidance: M3(R2)
`Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing
`Authorization for Pharmaceuticals (2010); and the CDER Guidance: Safety Testing of
`Drug Metabolites (2008).
`
`In response to the Sponsor’s reply (12/20/2010 email) and to clarify our concerns, we
`immediately contacted the Sponsor for a second time (12/20/10):
`
`
`“We appreciate your (12/20/10) response addressing the presence of M17 as a
`metabolite in the plasma of vilazodone-treated dogs. We agree that you should
`submit your response to the NDA and that you should correct Table 3 (Cross
`Species Comparison) to reflect the presence of M17 in plasma of dogs and
`humans.
`
`However, qualification of major human metabolites requires studies other than
`those that assess chronic toxicity, as in the 52-week study in dogs that you cite.
`
`Specifically, the potentials for reproductive (embryo-fetal) toxicity, genotoxicity,
`and carcinogenicity need to be addressed. We have the following questions:
`
`
`• Regarding embryo-fetal toxicity, were M10 and M17 detected and
`quantified in plasma of rats or rabbits and, if so, at what levels? This
`would determine whether the embryo-toxicity studies for vilazodone in
`rats and rabbits would also assess the embryo-fetal toxicity of the
`metabolites.
`• Regarding genotoxicity, does either M10 or M17 have structural alerts?
`• Regarding carcinogenicity, were M10 and M17 detected and quantified in
`plasma of rats or mice and, if so, at what levels? This would determine
`
`
`Reference ID: 2890371
`
`

`

`NDA 22-567 (vilazodone HCl tablets; VIIBRYD™).
`Linda H. Fossom, Pharmacologist.
`page 9
`Original submission (3/22/2010).
`
`whether the carcinogenicity studies for vilazodone in rats and mice would
`also assess the carcinogenicity of the metabolites.
`
`”
`
`
`The Sponsor (12/22/10 email; 12/29/10 official submission) provided their response,
`which I have summarized and reviewed below.
`
`The Sponsor had provided (12/20/2010 email) the following table summarizing the
`plasma exposures to vilazodone (M16) and major metabolites M10 and M17 in humans,
`based on the human mass-balance study at a single 20-mg dose in healthy males.
`
`
`
`The Sponsor calculated the projected exposures to M10 and M17 at steady-state at the
`MRHD of 40 mg, based on the AUC for 40 mg of vilazodone at steady-state of 1645
`ng•h/mL (based on study PGX-08-P1-06) and the metabolite/parent AUC ratios from the
`mass-balance study (see table, above); the estimated AUC for M10 was 534 ng•h/mL per
`day and for M17 was 829 ng•h/mL per day at steady-state.
`
`Both M10 and M17 have been adequately assessed for general toxicity in dogs: The
`Sponsor had also provided (12/20/2010) data on systemic exposure to both M10 and M17
`in dogs. They had calculated (estimated) steady-state exposures for M10 and M17 and
`determined that: 1) human AUC exposure to M10 at the MRHD of 40 mg was 6.3% of
`that for dogs at the NOAEL (mid dose) of 10 mg/kg in the 52-week toxicity study and 2)
`human exposure to M17 at the MRHD of 40 mg was ~26% of that for dogs at the
`NOAEL (mid dose) of 10 mg/kg in the 52-week toxicity study. Thus, the NOAEL of 10
`mg/kg in the 52-week study in dogs provided human safety margins of 16-fold for M10
`and 4-fold for M17.
`
`
`
`Reference ID: 2890371
`
`

`

`NDA 22-567 (vilazodone HCl tablets; VIIBRYD™).
`Linda H. Fossom, Pharmacologist.
`page 10
`Original submission (3/22/2010).
`
`Regarding metabolite M10, the Sponsor provided (12/29/10 submission) their evidence
`that M10 was present at adequate levels in plasma of rats and rabbits: the AUC in rats at
`the high dose of 75 mg/kg in the 26-week study was 3-5 times the estimated AUC at
`steady-state in humans at the MRHD of 40 mg [in the rat embryo-fetal toxicity study,
`although the mid dose of 40 mg/kg was the NOEL for embryo-fetal toxicity, only
`decreased fetal weights and delayed skeletal ossification were seen at the high dose of
`200 mg/kg; there was no increases in malformations] and the AUC in rabbits at the high
`dose of 50 mg/kg in the embryo-fetal study was 22 times that in humans at the MRHD.
`This confirmed our previous conclusion that the toxicity of M10 has been adequately
`assessed for general toxicity, reproductive (specifically embryo-fetal) toxicity, and
`carcinogenicity in the studies conducted with vilazodone. [The Sponsor also found no
`structural alerts for genotoxicity or carcinogenicity, based on Derek and Multicase
`analyses.]
`
`However, metabolite M17 was only present in plasma of dogs and mice (and not
`demonstrated in the plasma of rats or rabbits), so the reproductive toxicity of this
`metabolite cannot be considered to have been adequately assessed. Regarding
`genotoxicity/carcinogenicity, it should be noted that this metabolite did not have any
`structural alerts for genotoxicity or carcinogenicity (based on Derek and Multicase
`analyses, as stated by the Sponsor). Additionally, M17 appears to have been detectable in
`plasma of mice (at 1-2% of total radioactivity after an intravenous dose of 1 mg/kg;
`however, M17 was only identified by retention time, not by identification and specific
`analysis). Thus, the mouse carcinogenicity study for vilazodone might also provide some
`assessment of the carcinogenicity of M17. Finally, although not mentioned by the
`Sponsor, no preneoplastic changes were noted by the pathologist for the 52-week dog
`study. [It should be noted that fibroepithelial hyperplasia in mammary gland was found in
`several drug-treated female dogs, but not in controls. However, the study pathologist did
`not comment on this finding; and it is not standard nomenclature for dogs, whereas for
`cats it is recognized as a benign, hormone-responsive proliferation. Consequently, this
`finding seems unlikely to indicate an additional concern for carcinogenicity with M17. It
`should also be noted that mammary gland tumors in mice, that are presumed to be
`prolactin-dependent, are included in the labeling for vilazodone.]
`
`The Sponsor also noted that metabolite M17 was generated “robustly” by hepatocytes
`from rabbits (mice, monkeys, and humans), citing study GPP-007-NCD-PKM-2002-034;
`however, it should also be noted that in that study, M17 was only identified by retention
`time in rabbits (and monkeys).
`
`
`Conclusions regarding the toxicological assessment of major human metabolites
`M10 and M17: Metabolite M10, which is present at significant levels in plasma of rats,
`dogs, and rabbits, is considered to have been adequately assessed for toxicity (general,
`embryo-fetal, and carcinogenicity) in the animal studies with vilazodone.
`
`Metabolite M17, which is present in plasma of dogs and (probably) mice, is considered to
`have been adequately assessed for general toxicity (in dogs) and for
`
`
`Reference ID: 2890371
`
`

`

`NDA 22-567 (vilazodone HCl tablets; VIIBRYD™).
`Linda H. Fossom, Pharmacologist.
`page 11
`Original submission (3/22/2010).
`
`genotoxicity/carcinogenicity, based on the absence of structural alerts and also supported
`by the carcinogenicity study in mice and the 52-week study in dogs. However, since M17
`was not demonstrated to be present in plasma of either rats or rabbits, the original
`embryo-fetal toxicity studies with vilazodone did not adequately assess the toxicity of
`M17. Nonetheless, M17 is present in plasma of dogs and there were no indications of
`treatment-related histopathology in sex organs of female (or male) dogs in the 52-week
`study up to the high dose of 40 mg/kg (as assessed by Dr. Klimek in her review and
`verified by this Reviewer). Although the AUC for M17 at this dose in dogs was not
`calculated, it would be expected to be ~16 times that for humans at the MRHD (estimated
`from the safety margin of 4 afforded by the 10 mg/kg dose in dogs, as provided in the
`Sponsor’s 12/20/2010 email submission, see above).
`
`The Sponsor will need to assess the reproductive toxicity of metabolite M17 in an
`embryo-fetal study. However, this will be allowed as a post-marketing requirement,
`rather than being required for approval, based on lack of effects on sex organs in dogs in
`the 52-week study (at estimated steady-state systemic exposures ~16 times those
`estimated for humans at the MRHD of 40 mg) and the lack of other specific concerns,
`such as structural alerts for genotoxicity.
`
`Based on the formation of M17 by hepatocytes from rabbits, it is possible that M17 may
`be present at adequate amounts in plasma of rabbits treated with vilazodone (i.e., at
`exposures equal to or greater than those in humans at the MRHD). If this is demonstrated
`for the doses of vilazodone that were used in the original embryo-fetal study, that study
`would be considered to have adequately assessed M17. Otherwise, a study administering
`M17 directly to rats or rabbits, using a route that will produce adequate systemic
`exposure, will be needed.
`
`The following wording was sent to the Sponsor (1/4/2011) to explain the PMR that will
`be required (the Sponsor agreed to this PMR on 1/4/11):
`
`
`Because the major human metabolite M17 was not demonstrated to be present in
`plasma of either rats or rabbits, the embryo-fetal reproductive toxicity studies with
`vilazodone did not adequately assess the toxicity of M17. Consequently, you will
`need to commit to assessing the reproductive toxicity of metabolite M17 in an
`embryo-fetal study.
`
`However, because M17 was formed by hepatocytes isolated from rabbits, it is
`possible that M17 is present in plasma of rabbits treated with vilazodone. If the
`systemic exposure to M17 at the doses of vilazodone that were used in the
`original embryo-fetal study is demonstrated to be equal to or greater than the
`exposure in humans at the MRHD, the original rabbit study would be considered
`to have adequately assessed the embryo-fetal toxicity for M17.
`
`Otherwise, an embryo-fetal study in either rats or rabbits where M17 is
`administered by a route that will produce systemic exposure equal to or greater
`than the exposure in humans at the MRHD will be required.
`
`
`Reference ID: 2890371
`
`

`

`Linda H. Fossom, Pharmacologist.
`page 12
`
`NDA 22-567 (vilazodone HCl tablets; VIIBRYD™).
`Original submission (3/22/2010).
`
`
`
`VI. OVERALL CONCLUSIONS:
`
`There are no pharmacology/toxicology issues that would prevent the approval of this
`NDA.
`
`Some labeling is still being negotiated, however, the wording for the carcinogenicity
`findings of malignant mammary tumors in female mice has been agreed upon.
`Additionally, the genotoxic impurities have been adequately limited in the drug
`substance/product.
`
`Regarding the 2 major human metabolites: 1) M10, which is present at significant levels
`in plasma of rats, dogs, and rabbits, is considered to have been adequately assessed for
`toxicity (general, embryo-fetal, and carcinogenicity) in the animal studies with
`vilazodone; and 2) M17, which is present at significant levels in plasma of dogs and
`(possibly) mice, is considered to have been adequately assessed for general toxicity (in
`dogs) and for genotoxicity/carcinogenicity, based on the absence of structural alerts and
`possibly supported by the carcinogenicity study in mice. However, since M17 was not
`demonstrated to be present in plasma of either rats or rabbits, the original embryo-fetal
`toxicity studies with vilazodone did not adequately assess the toxicity of M17.
`Consequently, the Sponsor will need to assess the reproductive toxicity of M17 in an
`embryo-fetal study. However, this will be allowed as a post-marketing requirement,
`rather than being required for approval; and the Sponsor has agreed to this PMR.
`
`Additionally, to support use of vilazodone in children under 13 years of age (the deferred
`pediatric studies under PREA), the Sponsor will need to conduct a study to assess the
`safety/toxicity of vilazodone in juvenile rats. This study must include evaluation of
`neurological/behavioral development and reproductive development. The Sponsor has
`agreed to this PMR.
`
`
`VII. RECOMMENDATIONS:
`
`From a Pharmacology/Toxicology perspective, because the Sponsor has agreed to
`conduct a reproductive (embryo-fetal) toxicity assessment for the major human
`metabolite M17 as a post-marketing requirement, there are no issues that would prevent
`the approval of this NDA, assuming that labeling issues can be negotiated.
`
`
`Linda H. Fossom, Ph.D., Pharmacologist, Team Leader {see appended electronic
`signature page}
`
`
`Reference ID: 2890371
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`-----------------------------------