CENTER FOR DRUG EVALUATION AND
`
`0 RESEARCH
`
`APPLICATIUN NUMBER.-
`
`22-192
`
`PHARMACOLOGY REVIEW
`
`Vanda Exhibit 2031 - Page 1
`
`VNDA 02700028
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`Vanda Exhibit 2031 - Page 1
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`

`
` ES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`.
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`NDA NUMBER! SERIAL NUMBER:
`
`22-192 / N-0000
`
`DATE RECEIVED BY CENTER:
`
`9/27/2007
`
`PRODU_CT:
`
`Iloperidone
`
`SPONSOR:
`
`DOCUMENTS REVIEWED:
`
`Vanda Pharmaceuticals
`
`REVIEW :IVISIOII 0 syc Iatry Drug Products (ITFD-130)
`
`PHARMII‘OX REVIEWER:
`Sonia Tabacova, Ph.D.
`
`PHARM/TOX SUPERVISOR:
`DIVISION DIRECTOR:
`PROJECT MANAGER:
`
`I
`
`Barry Rosloff, Ph.D.
`Thomas Laughren, M.D.
`Kimberly Updegraff, R.Ph.
`
`Date oi revlew submrssxon to DIVISIOH File Syétem (DFS): 673U7ZOU8
`
`Vanda Exhibit 2031 - Page 2
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`VNDA 02700029
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`

`
` Nfl
`
`EXECULPPVES ....
`
`..........................................._............................... .. 3
`
`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW .......
`
`11
`
`........................................................................ .. 13
`2.6.2 PHARMACOLOGY ..................._......
`' 2.6.2.1
`Brief summary .................................................................................................................... .. 13
`2.6.2.2
`Primary pharmacoclynamics .............................................................................. ..
`15
`2523
`Secondary pharmacodynamics
`26
`2.624 ......................... ..
`28
`2.6.2.5
`Pharmacodynamic drug interactions ...........................
`................................................... 36
`
`
`
`40
`
`44
`
`66
`
`2.6.3 PHARMACOLOGY TABULATED SUMMARY...............................................
`
`.......
`2.6.4 .......
`2.6.4.1
`Brief summary ........................................................................................... .. 44
`2.6.4.2
`Methods ofAnalysis
`........ .. 46
`2.6.4.3
`Absorption .. . . . . . .. . .. . .. . . . . .. .. . . . . .. . . .. .. .. .. . . . . . . .. . . .
`. .. ..
`. 47
`2.6.4.4
`Distribution ... . .... . . . . .... . . .. . . . . . .. ..... ... . .... . . . . .. .. .. . .
`. .. . . .. . .. 51
`2.6.71.5
`Metabolism ......
`54
`2.6.4.6
`Excretion........................................ ..
`62
`2.6.4.7
`Pharmacokinetic drug interactions...
`................................. .. 64
`2.6.4.8
`Other Pharmacokinetic Studies.. .. . .
`.. . . .. . . . . . . .. . . . . . . .. . ... .. . . . .... 64
`2.6.4.9
`Discussion and Conclusions ................................................. ..
`64
`2.1S.4.l0
`Taliles and’figures to include comparative TK summary ............................................... .. 66
`
`
`
`2.6.5 PHARMACOKINETICS TABULATED
`
`..............................
`2.6.6 TOXICOLOGY.............................
`2.6.6.1
`Overall toxicology summary ................................................................. .. 67
`
`2.6.6.2
`Single-dose toxicity ................ ..
`75
`Repeat-dose toxicity . .. ... . . .. .. . . . . .. . . . . .. .. . .
`. . . . . .. 77
`2.6.6.3
`2.6.6.4
` mmWm..................................................................................... H3
`2.6.6.5
`Carcinogenicity...................................................................................................... .............J36
`2.6.6.6
`Reproductive and developmental toxicology.
`............... 167
`2.6.6.7
`Local tolerance .... . ... . . ....... . .. .. . . .. . .. . ... . . . . ... .... . .
`. . ... 213
`2.6.6.8
`Special toxicology studies ........................................................................................ 216
`
`
`
`2.6.6.10
`
`Tables and Figures .......................................................................................................... 217
`
`2.6.7 TOXICOLOGY TABULATED SUMMARY
`
`........
`
`217
`
`
`
`Vanda Exhibit 2031 - Page 3
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`VNDA 02700030
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`

`
`EXECUTIVE SUMMARY
`
`1.
`
`Recommendations
`
`A. Recommendation on approvability: Approvable
`
`B. Recommendation for nonclinical studies: Adequate
`
`C.
`
`H.
`
`Summary of nonclinical findings
`
`A. Brief overview of nonclinical findings
`Pharmacology: Iloperidone has high affinity for serotonin 5-HT2A, adrenergic (ll,
`adrenergic (12, .D2, D3, and 5-HTlA receptors in humans, and acts as an antagonist at
`selected dopaminergic, serotonergic, and noradrenergic receptor subtypes. Affinity was
`highest for 5-HT2 and adrenergic 0.] receptors, and lower for dopamine D2, which is a
`profile of an atypical antipsychotic. Iloperidone metabolites P88 and P89 have a profile
`similar to that of iloperidone in receptor-binding studies, with potential to exert CNS
`effects mediated by dopaminergic, serotonergic, and noradrenergic antagonism. P95
`exhibits a similar affinity to iloperidone for human 5-HT2A and adrenergic receptor
` mmmmmm,m,mm»
` .P%bb$Hkdym$mC wm,m
`shown by whole—body autoradiography,
`it apparently does not cross the blood-brain
`barrier. The high affinities of iloperidone and its metabolites for 411- adrenergic receptors
`m wwmmfi$u%m&%mmm P%,P%,md
`no
`I
`Illl
`.‘_.‘
`|‘.‘u
`cg.
`.
`-5-
`_ n.
`--gu
`
`In vitro evaluation of iloperidone effects in isolated dog Purkinje fibers and in
`mammalian cells expressing the cloned hERG showed that iloperidone has the capacity to
`prolong action potential duration and to block hERG currents;
`this indicates that
`iloperidone has the capacity to prolong QTc interval. Iloperidone metabolite PS8, but not
`P95, also exhibited this potential. In hemodynamic evaluations conducted in rats and
`dogs, iloperidone was found to dose-dependently decrease blood pressure and to induce
`transient increases in heart rate; however, cardiac output and ECG par_ameters_ were not
`affected. Neither iloperidone nor its metabolite P95 was associated with any adverse
`respiratory effects as evaluated in rats.
`’
`Pharmacokinetics:
`Iloperidone was rapidly absorbed in all animal species tested
`following oral and iv. administrations, but its bioavailability was very low due to a
` -pass effect. Oral bioavailability was <T% in rat, 5% in mouse, I9% in
`both rabbit and
`og, an
`a
`x'
`ey
`0 i
`u a
`.
`e absorption profiles of
`metabolites P88 and P95 were similar to the parent compound; their absorption was
`rapid after either oral or i.v. administration. At equal oral doses, bioavailability of P95
`P%3 (5%) in mice-
`levels genfl dose-
` (Cmax and AUC)
`proportionally in -the tested animal species, except for the rat in which exposure increased
`over—proportiona1ly possibly due to inhibitory activity of iloperidone to CYP enzymes.
`
`Vanda Exhibit 2031 - Page 4
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`VNDA 02700031
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`Gender differences in exposure were present in the rat, the mean AUC in female rats
`being significantly greater than that in males.
`‘
`Distribution of iloperidone and its metabolites after oral administration was rapid; the
`highest drug concentrations were observed in the liver, kidney, gastrointestinal system,
`and secretory glandular tissues; placental transfer was limited; and drug concentration in
`the brain was very low. P95 metabolite did not pass the Blood-brain barrier in the rat
`(whole-body autoradiography). Afier oral administration to lactating rats, iloperidone was
`excreted in milk; Cmax was attained 4 hours post dosing when iloperidone concentration
`
`
`
`metabolites in humans (P95 and P88) are found in the species used in toxicology studies.
`However, in rodents, P95 and P88 are only minor circulating metabolites, in contrast to
`'
`P
`mmms.P 88ini=oelentsanddogsislower
`gg‘
`IQI‘
`I
`' II II.l
`_u'_,_
`
`
`thanthatof
`.
`,
`,
`,_ .
`.
`_
`‘
`-=-
`-=e
`-19:1-
`
`compound. For P95, the differences between humans and animals are even greater than
`for P88. Results of pharmacology and pharmacokinetic studies that have bearing on the
`potential toxicological characteristics of metabolite P95, include the following:
`- While P95 is the predominant circulating metabolite of iloperidone in humans,
`comprising 25% to 54% of its total metabolism, in rodents it represents only 3.9%
`to 5.7% of the total measurable exposure to iloperidone and its metabolites.
`— Although P95 did not appear to cross the blood-brain barrier as assessed in the
`whole-body autoradiography study in rats, in general toxicity studies in rodents
`and dogs with direct oral administration of P95, it induced CNS clinical signs
`similar to those induced by iloperidone, which suggests that the blood-brain
`barrier is not impenetrable to P95.
`P95 is rapidlyd min in mice, 40 min
`inSmagw- a half-life of
`23-26 hours for P95 in humans. _
`
`-
`
`In vitro metabolic studies showed that iloperidone has stronger inhibitory activity to
`CYP2D6 and CYP3A4/3A5 compared with either PS8 or P95; neither iloperidone nor its
`metabolites had potential to induce cytochrome P450 enzymes.
`Excretion profiles of iloperidone, P85 and P99 were similar. They are mainly eliminated
`through the feces,
`in contrast
`to humans in which urinary excretion is the major
`elimination pathway.
`Toxicology: Repeat-dose studies of general toxicity and corresponding toxicokinetic
`parameters were conducted with iloperidone in mice,
`rats,
`rabbits, and dogs.
`Additionally, toxicology studies were performed in rats and mice with the predominant
`'
`,
`,
`r c arac erize i s safety and
`inviewoftlrelower
`'
`i
`ioeione
`P
`
`"
`
`'
`
`administration in animal species vs. humans.
`General toxicology: Among all the repeat-dose general toxicology studies on iloperidone
`-“.ae‘a~e.
`.6‘
`e
`-‘
`i‘:‘
`‘ "““ “‘i“‘i‘
`
`to safety rat study and th<.L12-month dog study%
`with iloperidone, and the 6-month rat study conducted with P95 metabolite. These studies
`are the subject of the present review.
`.
`_
`'
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`Vanda Exhibit 2031 - Page 5
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`VNDA 02700032
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`iloperidone 6-month oral administration to rats (Sprague-Dawley) at doses of 0,
`I2, 24, and 48 mg/kg/fl induced dose-related clinical signs indicative of C'NS7lepression
`(ptosis, decreased motor activity, relaxation of the scrotum, anus, vaginal opening) and
`decrease of mean body weight at all dose levels; hematological changes (lower total
`.
` mummLD,MfimmHBmmbwa satMD
`m@);%%— mgmmmkmmmam
`doses and in MD and HD males. Prolactin was not determined. Increased incidence and
`severity of vacuolization of glandular epithelium in the mammary glands of males and
`&mmww%wwmw®mgoups, m&mfl%m
`
`bone marrw sections i
`op. rng the 5-week ecovery period, an incomplete
`reversibility was seen for decreased body weight, hematology and mammary glandular
`epithelium changes. The MTD was 12m
`(18-22% vs. control) at the next higher dose tested (24 m%gd was not
`reached in this study, as the lowest tested dose (12 mg/kg/d) induced a decrease in body
`and organ weights, hematological and clinical chemistry changes, and histopathology
`changes in the mammary glands of males and females. This dose is about 5 times the
`human dose at MRHD (24 mg/day) on an mg/m2 basis.
`Iloperidone l-year oral administration to beagle dogs at 6, 12, and 24 mg/kg/d ,
`induced drug-related clinical signs at all dosages (decreased spontaneous activity,
`tremors, bizarre behaviors, labored breathing, ptosis, slow response times and/or lack of
` mw reflex); firm and high-dose induced ataxia, loss of righting and toe pinch
`reflex (in single
`Bfily weight decreases of 7.3% and $276 vs.
`control were registered over
`the treatment period at LD and HI),
`respectively.
`Hematology and clinical chemistry changes were induced dose-dependently at MD and
`I=ED,he., ‘ ‘“'-“ ~‘- e‘-'‘‘--‘ 2-:
`- “”i‘ii
`as
`.0
`"" In
`malesandfemales;lower ‘e
`-e
`- =='
`'
`
`
`alanin aminotransferase in HD males. No abnrmalities were found in any dose group on
`ECG and auditory examination. Higher mean absolute and relative liver weights and
`hepatocellularh ,I‘1.IIl
`‘
`I;
`III oo'.n Q
`n- ‘n!!!..
`' '
`
`were found in males in the HDgrou
`MTD was 6 mg/kg/d in view of severe clinical signs and emaciation induced at and
`above the next higher dose of 12 mg/kg/d. NOAEL was not reached in this study as the
`lowest tested dose (6 mg/kg/d) induced decreased body weight and neurological clinical
`signs. This dose is 8 times the human dose at MRHD (24 mg/day) on an mg/m2 basis.
`Iloperidone metabolite P95 six-month administration to rats (Wistar) at oral doses
`of 50 and 500 mg/kg/day (yielding P95 plasma exposures of about 2 to 3x and 150 to
`400x, respectively, the human P95 plasma exposure at iloperidone MRHD of 24 mg/d),
`induced dose—dependent CNS clinical signs at both dose levels throughout the entire
`treatment period, similar to those induced by iloperidone (ptosis, decreased motor
`activity, relaxation of the scrotum, anus, vaginal opening) that are attributable to
`pharmacological effect. Body weight and weight gain decreases were induced at 1-H)
`oniy. There were no drug-reiated wmmm chemistry
` plasma leveis), or urine anaiysis. ogic
`reproductive system changes were induced in both genders. In females, dose—dependent
`cycle prolongation occurred at both LD and HD, consistent with the finding of vaginal
`
`Vanda Exhibit 2031 - Page 6
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`VNDA 02700033
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`epithelium mucilication and decreased uterine weight in the treated groups. In males,
`atrophy of testicular seminiferous tubule epithelium (in 2 animals) and an increased
`incidence of mixed cell inflammation of prostate gland with associated degenerative
`changes were found at HD.
`In both genders,
`increased cellular proliferation in the
` mw gland (ah/Tlar hyperplasia, increased secretion and dilatation of mammary
`ducts) occurred with dose-related severity at LD and HD, non-reversible after the
`recovery period. Drug—related proliferative histopathology changes, demonstrable by
`routine histology and/or immunohistochemical method (BrdU labeling) were induced in
`me adrenals in
`, thyroid in females, and pancreas in
`
`
`
`
`-
`:A- --rear
`both
`-
`:
`,
`--.4.----.-L 5.-e as - _-_’-=-
`organs (ovary, uterus,
`testes, prostate). Statistically significant, treatment—related increase in cell proliferation
`(increased proportion of cells in S phase of the cell cycle, as assessed by BrdU labeling)
`was found in
`gland (duetandalveoli) inbeth
`genders (LDM, I-IDJM, HDF), and the , HDF).
`Most of these histopathology deviations (with the exception of the adrenal, testicular and
`secondary sex organ pathology in males) were induced in a dose-dependent manner at
`both tested dose levels. An NOAEL was not reached in either male or femal
`pathomorphological proliferative changes in multiple organs/tissues were present at the
`lowest tested dose of 50 mg/kg/day, corresponding to plasma exposure (AUC 0-24)
`approximately 2 to 3x the human P95 plasma exposure at MRI-ID of 24 mg
`iloperidone/day.
`Genetic toxicology: Iloperidone was clastogenic in one in vitro test (chromosomal
`alftenaion assay in Chinese Hamster Ovary (CHO) cells). ITis likely that the positive
`results obtained in the chromosomal aberration assay in vitro are of little biological
`relevance, having in mind the negative results obtained in the in vivo micronucleus
`assays in rat hepatoeytes and mouse bone marrow. Iloperidone metabolite P95 was
`‘
`-- ‘ ‘ . ,achromosomal
`
`aberration test
`in CHO cells, and a bone marrow micronucleus test
`in rats. For
`
`iloperidone genotoxic and potentially genotoxic impurities ".1..-
`
`theacceptancecriteriaaresetatthelevelef.e— each,sethatthe
`ommH®® :-~e.gdw.
`Carcinogenicity: Two—year carcinogenicity studies of iloperidone were conducted in mice '
`and rats of both genders.
`Iloperidone administration tc -~—‘,D-l (ICR) ‘BR mice ‘at oral doses of L5, 5, and L0
`mg/kg/d (causing an increased mortality in males at HD and in females at all dose levels),
`did not exert carcinogenic effect
`in males. In females,
`the incidence of malignant
`mammary tumors was significantly increased above the concurrent and historical control
`range in the low dose group only. On an mg/m2 basis, there is no safety margin between
`the low dose employed in the study (2.5 mg/kg/day) and the maximal recommended dose
`in humans (24 mg/day). However, mammary tumor incidences were not increased in the
`mid— and high—dose groups, although the duration of treatment was the same in the mid—
`dose and low dose groups. It is not clear why similar increases in mammary tumor
`J1 seen at the higher doses employed in this study. Drugs which elevate
` y cause mammary tumors in rodents.
`Iloperidone administration to ~«~-=-- 3D(SD)BR rats at oral doses of 4, 8, and 16 mg/kg/d
`for 24 months (inducing a dose-related, significant decrease in mean body weights of
`
`b(4)
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`Vanda Exhibit 2031 - Page 7
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`VNDA 02700034
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`over 10% in all treated groups), did not exert carcinogenic effect in male rats. In females,
`the combined incidences for pancreatic islet cell adenomas and islet cell carcinomas were
`increased at HD (2, 2, 0, 3, and 7 for the two controls, LD, MD and HD, respectively).
`The incidence value at HD was within historical control range for this species and strain;
`the dose—response trend analysis showed a p-value ofTH)051 that approachecfbut did not
`reach the level of statistical significance required for common tumors (alpha=0.003).
`Having in mind that the incidences of pancreatic islet cell tumors in this study were
`within the reported historical control range for this species and strain and that there was
`mema fimmm,
`
`elo mental toxici was assessed in a Fertility (Segment 1) study in
`;andinaPi=e—and
`"'
`" ' ,
`
`'
`
`Segment I rat fertilifl study: Iloperidone oral administration at doses of O, 4, 12,
`36 mg/kg/day to Sprague'Dawley male and female rats
`for a period starting 10 weeks
`prior to mating (males) or 2 weeks prior to mating (females) and continuing mmug
`mating, gestation and lactation,
`resulted in the following drug-related effects:
`'
`pharmacological clinical signs at all doses, significant decreases in body weight of both
`males and females at MD and HD, female estrous cycle disturbances (all doses, dose-
`dependently) and reduction in male reproductive organs’ weight
`(prostate weight
`decreased in all dosed groups; testis and epididymis weights decreased at HD), lower
`fertility indices (72% and 88% at HD and MD, respectively, vs. 100% in control), lower
`pregnancy rates at MD and HD groups (86%, and 60%, respectively, vs. 100% in
`control), reduction of corpora lutea count at HD in comparison to control; increased
`m neonatalldeaths at
`M33andI-EB.ArtI-H3,
`'
`"o raes
`(dilatation of lateral and third brain ventricles, dilatation of heart ventricles) were
`increased, but no external malformations were observed in the treated groups. There were
`1219' ::I.:.' e: :9:--2-;
`.--e--.
`e ' -nee‘-.-e.
`-
`efthe
`
`
`" 0:, In." I,.
`.1:
`-.--9'
`I -I --
`a.-.7
`and behavioral evaluations because of the low pregnancy rate and neonatal deaths).
`Reproductive performance of F1 generation was apparently not affected. The NOAEL
`was 4 mg/kg/day (1.6 times the human dose at MRHD (24 2 basis).
`Although this dose induced estrous cycle disturbances and a decrease in prostate weight,
`it did not affect parental fertility or the prenatal and postnatal survival, development and
`reproductive capacity of the progeny.
`Segment II Prenatal developmental toxicity studies in rats:
`Iloperidone administration to pregnant Wistar rats at oral doses of 0, 4, 16, and 64
`mg/kg/day during the period of major organogenesis (Gestation Days 7 through 18)
`induced developmental toxicity (expressed as embryofetal lethality, retarded intrauterine
`development and minor skeletal abnormalities) at oral doses above 16 mg/kg/day. Signs
`of maternal toxicity (reduced weight and weight gain, reduced placental weight) were
`premtfit and above T6 mg/kg/day. The NOAEL for developmental toxicity was 16
`mg/kg/day (6 times the human dose at MRHD of 24 mg/day on an mg/m2 basis).
`
`Vanda Exhibit 2031 - Page 8
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`VNDA 02700035
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`The predominant circulating iloperidone metabolite in humans (fifi) administered to
`pregnant rats at oral doses ofZ0, 80 and 200 mg/kg/day (Gestation Days 7 through T7),
`produced dose-dependent maternal pharmacological effect (signs of sedation) at all dose
`levels, but no maternal toxicity. Maternal plasma exposure (AUC) at the high dose was
` mm.mnmpbmmkUCfi P%MmflmpflWt
`
`not induce embryo/fetal mortality or congenital malformations but produced a dose-
`dependent increase in the incidence of retarded skeletal ossification vs. the concurrent
`connmatafltesteddoseleve1s,mngmgfi=om8%(LD)teM%(l=H9).Thesevalues,
`IQ.‘ ‘
`." .1: I‘: g.
`IIII
`.nI‘
`n
`u-_
`-_
`<1
`5- . ;n5
`
`ent II_Prenaa_l eve entltxi stud _in_rits:
`Se
`Iloperidone administration at oral (gavage) doses ‘of 0, 4, 10 and 25 mg/kg/day to
`‘ pregnant rabbits from gestationda Q1115) and
`decreased maternal body weight at the HD and dose-dependent dru -related clinic 1
`'
`(sedation) at all dose levels. Maternal food intake was reduced at MD and HD. The high
`dose induced increase in embryo/fetal
`intrauterine lethality and a decrease in fetal
`viability at term. No embryo/fetal toxicity or teratogenicity were observed at LD and
`MD. Based on these results, the NOAEL for embryo/fetal toxicity is 10 mg/kg/day (8x
`the human dose at MRHD of 24 mg/day on an mg/m2 basis).
`Segment III Prenatal and postnatal developmental toggicity -study in rats
`Iloperidone oral administration to pregnant CD rats from gestation day 17 through
` posmatal day 217 at doses of 4, T6 and 48736 mg/kg/day, caused matema]
`toxicitym mortality at HD and dose-
`dependent decrease in maternal body weight at HD, MD and LD), significantly prolonged
`.
`gestation and parturition, high perinatal- and postnatal mortality (stillbirths and neonatal
`
`deaths)inFlgeneratien' atHDandMD,andsememerease'in '
`
`‘
`
`was impaired at MD and HD, as demonstrated by the reduced pup weight at birth and
`weight gain through weaning. However, there was no apparent adverse effect on F1
`16
`I
`.
`1
`1.
`1
`I
`.
`I
`.
`1
`1
`.
`.
`of
`
`the administered dose levels. The NOAELwa (L5 times the human dose at
`MRHD of 24 mg/day on an mg/m2 basis).
`B. Pharmacologic activity
`The pharmacological profile of iloperidone is consistent with that of an atypical
`antipsychotic with a reduced potential for extrapyramidal side effects and therapeutic
`potential with regard to positive, negative, and social withdrawal symptoms of
`schizophrenia. Iloperidone has the potential to induce hypotensive effects and to prolong
`QTc interval duration
`
`C. Nonclinical safety ISSUCS relevant to clinical use
`
`— The high affinity for 0L1- adrenergic receptors in peripheral vascular tissues,
`mmm
` .
`Iloperidone prolongs action potential duration and block hERG currents in vitro;
`indicating a capacity to prolong QTc interval.
`In vivo,
`iloperidone dose-
`
`—
`
`Vanda Exhibit 2031 - Page 9
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`VNDA 02700036
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`
`dependently decreases blood pressure and induces transient increases in heart rate
`in rats and dogs; however, ECG parameters were not affected.
`the
`Iloperidone has the potential
`to inhibit CYP2D6 and CYP3A4/5 at
`recommended therapeutic dose in humans (12 mg BID); its metabolites P88 and
`
`and of iloperidone P95 metabolite to rats (6 months) induced general toxicity in
`all tested species. An NOAEL was not reached in either of these studies. The
`mwmm@$& ,wm5
`times
`on an mglm2 basis) induced a
`decrease in body and organ weights, hematological and clinical chemistry
`changes, and histopathology changes in the mammary glands of males and
`females. The lowest tested dose
`8 times the human dose at MRHD on an mg/m2 basis body
`weight and neurological clinical signs. The lowest tested dose of P95 in the 6-
`month rat study (50 mg/kg/day, corresponding to plasma exposure (AUC 0-24)
`approximately 2 to 3x the human exposure at MRHD) induced proliferative
`pathomorphological changes in multiple organs/tissues,
`i.e., endocrine glands
`(pituitary, thyroid, and pancreas), mammary gland (both genders) and ovary.
`Iloperidone was clastogenic in one in vitro test (chromosomal aberration assay in
`Chinese Hamster Ovary (CHO) cells) but was not clastogenic in the in vivo
`m’c onuc eus assays in rat hepatocytes and mouse bone marrow. The positive
`results wm afiterraion assay in CHO cells in vitro are of
`little biological relevance, having in mind the negative results obtained in vivo.
`Iloperidone
`genotoxic
`and potentially genotoxic
`impurities ._———.\
`
`
`pp sot
`ug/day.
`
`(female) administered oral doses of 2.5, 5 and 11) mglkglday for 2 years the
`incidence of malignant mammary tumors was significantly increased above the
`concurrent and historical control range in the low dose group only. On an mg/m2
`basis, there is no safety margin between the low dose employed in the study (2.5
`mg/kg/day) and the maximal
`recommended dose in humans (24 mg/day).
`However, mammary tumor incidences were not increased in the mid— and high-
`dose groups, although the duration of treatment was the same. It is not clear why
`similar increases in mammary tumor incidences were not seen at higher doses.
`In view ofthe proliferative effects seen with iloperidone metabolite P95 in the 6-
`month rat study, the Division required a 2-year carcinogenicity study with P95 in
`he rat which is ongoing (CAC meeting of March 25, 2008).
`lloperidone induces decreased fertility, prolonged gestation, increased prenatal
`and mmmd growth of the progeny upon oral
` wmmmmmmmammmm o
`mating (males) or 2 weeks prior to mating (females) and continuing through
`
`13(4)
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`gestation, parturition and lactation. The NOAEL is 4 mg/kg/day (1.6 times the
`huvlose at MRHD (24 mg/day) on an mg/m2 basis).
`Iloperidone oral administration to pregnant rats and rabbits during the period of
`major organogenesis induces developmental
`toxicity (embryofetal
`lethality in
`
`'
`
`'
`
`'
`
`'
`
`m$em8a%mmfim
`toxicity is 16 mg/kg/day in rats and 10 mg/kg/day in rabbits (6- and 8 times,
`respectively, the human dose at MRI-ID of 24 mg/day on an mg/m2 basis).
`
`.-. 2..
`---—e-
`
`--
`..
`-
`-
`
`
`gestation and parturition, incresdincdence o sillirths, neonatal mortality, d
`retarded growth of progeny up to weaning, but did not affect neurobehavioral and
`"reproductive development of the survivingpu 's.'The'
`_
`(L6
`times the human dose at MRHD (24 mg/day) on anmg/m2’ basis). ''
`
`
`
`'
`
`APPEARS THIS WAY ON ORIGINFL
`
`l0
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`2. 6 PHARMA COLOGY/TOXICOLOGY RE VIEW
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY
`
`NDA number: 22-192
`Review number:
`1
`
`Sequence number/date/type of submission: N-0000
`Information to sponsor: No (x)
`Sponsor and7or agent: Vanda Rharmaceuticals
`Manufacturer for drug substance: Vanda Pharmaceuticals
`
`Reviewer name: Sonia Tabacova
`
`IH?‘l}#- B0
`Revievv completion date:
`
`June 2008
`
`Drug:
`
`Trade name: None provided
`Generic name: Iloperidone
`Code name: ILO522 (Novartis); ILO522—NXA (Novartis); VYV-683 (Vanda)
`C nafiie: J -[4-[3-FL (?$—Fiuor0benzo[a7isoxaz0l—3—yl)-I -
` ahanone V
`Chemical Abstract Service_(CAS) Number: 133454-47-4
`Mole file number:
`
` m weight: C24H27N2O4F F4265 ‘
`Structure:
`
`04333
`
`Relevant INDs/NDAs/DMFS: IND 36827
`
`Drug class: Antipsychotic
`Intended clinical population: Adults with schizophrenia
`Clinical formulation: Tablets
`Route of administration: oral
`
`Disclaimer: Tabular and graphical information is from sponsor’s submission unless
`stated otherwise.
`
`11
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`Studies reviewed Wifllill this‘ submission: All submitted studies, except for the non-
`pivotal floperidone repeat—dose general toxicology studies
`
`Studies go_t reviewed within this submission: Non-pivotal
`1.]
`1.
`
`iloperidone repeat-dose
`
`INPPBNRSTFIIS WAY ON ORIGINAL
`
`12
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`2.6.2 GGY
`
`2.6.2.1 Brief summary
` mMmw has an 1%vi ro and7or ex ‘vivo binding profile consistent with an atypical
`affinity for human dopamine (D), serotonergic (5-HT), ot-
`noradrenergic, and sigma receptors, and no affinity for glycine-binding site, N-methy1—D
`aspartate (Nl\/IDA) receptor channel, or muscarinic receptors. Affinity of iloperidone was
`fbundtebehighestferhumm15-HTl74\,5-HT2A,D2,D3,adrenergica1anda2
` b%rkrm,D5,mdema h$m
`agonist activity at any receptors evaluated (rat or human), but was found to have
`significant in vitro and in vivo antagonist activity at rat and human dopaminergic,
`serotomggam m%#ewmfi%mdmfiw
`functionalassa activities on 5-
`HT2 receptors and weak effects on D2 receptors as shown in an ex vivo study in rats. The
`high 5—HT2/D2 receptor binding ratio of iloperidone suggests that this compound has the A
`potential to act as an atypical antipsychotic agent with a relatively low potential to
`produce extrapyramidal side effects. Preferential affinity for (11 over I12 receptors
`suggests a potential for iloperidone to cause orthostatic hypotension.
`Behavioral assays conducted in mice,
`rats and monkeys compared the in vivo
`pharmacological activities of iloperidone with both typical
`(thioridazine and/or
`haloperidol) and atypical (clozapine) antipsychotic agents. The results indicated that
` as potential for atypical antipsychotic action with reduced capacity for
`inducing extrapyramidal (EPS) symptoms, potential anxiolytic properties at doses similar
`to its antipsychotic properties and a potential to increase social interaction. Overall, the in
`vivo
`irnimted properties conslstent with an
`
`The major metabolites of iloperidone in humans are P88, P89 and P95. It is important to
`note that P88 and P89 cross the blood-brain barrier, while P95 does not do so detectahlga
`Therefore, P95 is less likely to exert pharmacological effects on the central nervous
`system and was primarily evaluated for the potential
`to exert peripheral effects.
`Pharmacodynamic studies have been performed with P88, P89 and P95 metabolites
`directly and their receptor-binding profiles were separately characterized. P89 was found
`to binfi with high affinity to D2 and 5—HT2 receptors, whereas P88 was approximately
`36_—fi)ld and W- er at these sites, respectively. Both P88 and P89 also exhibited
`affinity for 5-HTlA receptors and oL2- noradrenergic receptors. P95 exhibited similar
`affinity for the human 5—HT2A receptor compared with iloperidone, and also exhibited
`higher or we tested as compared
`with
`D1, DZS, DZL, and
`D3 receptor subtypes compared with iloperidone. Neither iloperidone nor P95 showed
`appreciable affinity for histamine H1 receptors.
`TmmmmmaflmwmoflksMP95wdP%
`bmad-spectmmmceptoraffinityforhumamratandguineapigreeeptorsusing
`radiolabeled ligand-binding techniques. The results showed that the P88 metabolite had
`moderate to strong affinity at the adrenergic on,
`(1213, one, dopamine D1, D2, D3, D4,
`
`13
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`
`histamine Hi, 5-HT113, and 5-HT2c sites. It had relatively weak affinity at the adrenergic
`(1213, 5-HT1A, and 5-I:ITs sites.
`In comparison,
`the P95 metabolite showed weak to
`moderate affinity at the adrenergic cu, a2A, a213, a.2c, dopamine D1, D3, D4, and 5-HT6
`sites. Compared with the receptor profile of iloperidone,
`these metabolites were
` mmWmm%akmammwmfimmmm aseparatesmdy,
`
`both compounds exhibit dopamine receptor antagonist properties. Additional behavioral
`a$%$ P%mdP%mm%,mB,mdmmkew_
`
`
`
`in contrast to the parent compound, nither
`profile similar to iloperidone. However,
`metabolite appeared to possess anxiolytic activity, as measured in behavioral assays.
`
`In a series of safety pharmacology studies, the cardiovascular safety of iloperidone was
`evaluated in vitro and in vivo in rats and dogs. In dog Purkinje fibers paced atstimulation
`frequencies of 0.5 and 1 Hz, iloperidone and P88 at a concentration of 0.1 uM and above
`induced a prolongation in action potential duration. The highest concentration of 10 uM
`induced amd 3 Hz,
`indicating a
` %mmpmure
`to P95 at concentration of 0.01, 0.1,
`1 and 10 p.M induced a prolongation in action
`
`
`toprolong’tl=ieQ5l'.41ntewal' atfieeplasma
`concentrations of 0.1 uM and above, while P95 has the potential to prolong the QT
`interval at free plasma concentrations of over 10 uM. This extent of exposure to P95 is
`unlikely, as administration of iloperidone doses of 24 mg given once-a-day in human
`patients yielded maximal P95 steady-state plasma levels of 55.5 ng/mL, or 0.13 uM. In
`vitro effects of iloperidone and its metabolites P95 and P88 in comparison with
`risperidone and ziprasidone on the cardiac ion channel hERG showed that all test articles
`produced rapid, reversible blockade of hERG currents. The block potency rank order was
`iloperidone > ziprasidone 3 P88 > risperidone > P95. These data suggest that P95 is
`unlikely to contribute to the QT prolongation potential of iloperidone.
`
`In vivo, iloperidone was found to have hypotensive and vasodilatory effects similar to
`mmed m$mdmem%mmmd
`
`preferential affinity for 111- over (12 adrenergic receptors in vit