fimw m - .ag
`
`
`
`‘T‘,\7 3 UC.CI_CAI‘I_N.L.,“° ‘3
`
`
`
`DATE:
`
`E11091:
`
`24 MAY 2007
`
`3 ‘i: 3‘
`3
`lI.AAI_I_TA_(3*\l>I.];
`C LN I ER DRIV; SUI I E, 300 ROCKVILLE, MD 20850
`
`RE
`
`CORRECTION TO CLINICAL STUDY REPORT ILO522 0104
`
`The following error(s) exist in Report ILO5220lO4:
`
`0
`
`0
`
`I
`
`Page 34, Table 7.4-4 for PK parameter t1/2 (hr) % difference was incorrectly reported
`in this table. The correct value should be 86.4 (instead of 88.3). In addition, the value
`for Ae (° 0 of dose) should be 5“5.61nstead of35.7.
`
`Page 43, Table 7.4—l0 for the PK parameter AUCo..» (ng*hr/ml) % difference was
`incorrectly reported in this table. The correct value should be 9.6 (instead of -9.6)
`based on the formula calculation presented in the footnote of this table.
`
`Page 72 Section 1.3.3 refers to Appendix 11. This appendix is not contained in this
`I
`T .
`
`In addition, the following documents were not provided hy the originator for this study report‘
`
`0 2,
`,, '
`...
`V
`..
`'
`‘
`
`,
`
`'
`
`.,
`
`0
`
`Page 5, Appendix 5a, signatures for DMPK R98—1825
`
`Vanda Pharmaceuticals Inc. - 9605 Medical Center Drive - Suite 300 - Rockville, MD 20850 USA - p 240.599.4500 - f 301. 294.1900
`www.vandapharmaceuticals.com
`
`lofl
`
`CONFIDENTIAL
`
`VNDA_01516679
`
`Vanda Exhibit 2030 - Page 1
`
`

`
`N O V A
`
`I S
`
`Novartis Pharmaceuticals Corporation
`
`East Hanover, New Jersey
`
`Clinical Pharmacology
`
`ILO522
`
`Study No. C|LO522 0104
`
`
`to evaluate the interaction of iloperidone with a cytochrome
`P450 ZD6 prototype substrate (dextromethorphan) in
`healthy subjects
`
`Author:
`
`Choudhury S, Ma P, Sansone A, White M
`
`Document type:
`
`Clinical Pharmacology Study Report
`
`Development phase:
`
`Phase III
`
`First subject dosed:
`
`03-Oct-98
`
`Last subject completed:
`
`13-Apr-99
`
`Document status:
`
`l-"inal
`
`Release date:
`
`14-Oct-O2
`
`Number of pages:
`
`52
`
`P
`Confidential
`
`May not be used, divulged, published or otherwise disclosed
`without the consent of Novartis Pharmaceuticals Corporation
`
`CONFIDENTIAL
`
`VNDA_01516680
`
`Vanda Exhibit 2030 - Page 2
`
`

`
`Novartis
`Report C|LO522 0104
`
`Confidential
`
`Page 2
`|LO522
`
`‘L1
`
`Signatutes
`
`Authors:
`
`Peiming lvla, PhD
`
`Study Biostatistician
`
`Signature
`
`date
`
`Aug: _ __I_eI: PhaJ1mD
`
`Clinical Pharmacology Scientist
`
`signature
`
`date
`
`Approved:
`
`Greg Sedek, MD
`
`Clinical Pharmacology
`Therapeutic Area Head
`
`Andrew Satlin, MD
`
`signature
`
`date
`
`CONFIDENTIAL
`
`VNDA_01516681
`
`Vanda Exhibit 2030 - Page 3
`
`

`
`Novartis
`Report C|LO522 0104
`
`Table of contents
`
`Confidential
`
`Page 3
`ILO522
`
`Signatures ............................................................................................................................ .. 2
`List of tables ........................................................................................................................ .. 5
`
`List of Figures ...................................................................................................................... .. 6
`
`List of appendices ................................................................................................................ .. 7
`List of
`............................................................................................................. .. 8
`
`Study personnel ................................................................................................................. .. 10
`
`Study synopsis .......................................................................................................................... .. 11
`Ethics and Good Clinical Practice .............................................................................................. .. 14
`
`1.
`
`2.
`
`3.
`
`Introduction ....................................................................................................................... .. 14
`
`Study objectives ................................................................................................................ .. 15
`
`Investigational plan............................................................................................................. .. 15
`
`3.1.
`
`3 .2.
`3.3.
`
`Study design .......................................................................................................... ..15
`
`Study population .................................................................................................... .. lo
`Treatments ............................................................................................................. .. 17
`
`3.3.1.
`
`3.3.2.
`
`lnvestigational drug ................................................................................ .. 17
`
`Blinding ................................................................................................. .. 17
`
`3.3 .3. ............................................................................ .. 17
`
`3.3 4.
`
`3 .3 .5.
`
`Concomitanttherapy...
`
`17
`
`Treatment compliance............................................................................ .. 18
`
`3 .4.
`
`Study schedule and assessmelits ............................................................................. .. 18
`
`3.4.1.
`
`Study conditions and restrictions ............................................................ .. 18
`
`$4.”. Bad ____________________________________________ _. 19
`
`3.4.3.
`3.4.4.
`
`Safety assessments ................................................................................ .. 19
`Pharniacokinetic assessments................................................................. .. 19
`
`4. Deviations from investigational plan .................................................................................... .
`
`. 20
`
`4 1
`
`1310101101 amendments
`
`20
`
`4.2.
`
`Other®Vm ............................................................................... .
`
`. 20
`
`5. Data management and quality oontrol.................................................................................. ..21
`
`5.1.
`
`Clinical data collection, database management and quality control............................ ..21
`
`Bioanalytical data management and quality control .................................................. ..2l
`5.2.
`. !,,: 5.4;;-5.-e
`e!-—e --1-es ............................................................................... ..77
`
`6.1.
`
`6.2.
`
`General statistical considerations ............................................................................. .
`
`. 22
`
`Analysis of background and demographic data ....................................................... ..22
`
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`
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`
`Vanda Exhibit 2030 - Page 4
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`

`
`Novartis
`Report C|LO522 0104
`
`Confidential
`
`Page 4
`ILO522
`
`6.3.
`
`Safety and
`6.3.1.
`
`. 22
`........................................................................... .
`Adverse events...................................................................................... .22
`
`6.3.2.
`
`6.3.3.
`
`6.3 .4.
`6.3 .5.
`
`Clinical laboratory variables ................................................................... .
`
`. 22
`
`Vital signs .............................................................................................. ..22
`
`Elcctrocardiographic evaluation.............................................................. ..22
`Statistical methods ................................................................................. .
`. ‘>3
`
`6.4.
`
`Phaimacokinetic evaluations ................................................................................... .
`
`. 23
`
`6.4.1.
`
`6.4.2.
`
`Phamiacokinetic variables...................................................................... .. 23
`
`Statistical methods ................................................................................. .
`
`. 24
`
`7. Results ............................................................................................................................... .26
`
`7. l .
`
`7.2.
`
`Subject disposition ................................................................................................. .
`
`. 26
`
`Background and demographic results ..................................................................... .
`
`. 26
`
`7.2.1.
`
`7.2.2.
`
`7.2.3.
`
`7.2.4.
`
`Relevant medical history and current medical conditions .......................... .
`
`. 26
`
`Medications at screening ancfbaseline .................................................... .
`
`. 26
`
`Demographic data ................................................................................. ..27
`
`Genotyping............................................................................................ .. 27
`
`7.3.
`
`Safety and tolerability results .................................................................................. ..27
`7.3 . 1.
`Serious aelverseevents .......................................................................... . . 27
`
`7.3.2.
`
`7.3.3.
`
`Adverse events...................................................................................... . .27
`
`Concomitant medications due to adverse events ..................................... .
`
`. 28
`
`7.3.4.
`
`Clinical laboratory findings ..................................................................... .
`
`. 28
`
`7 3 5
`
`Vitatsigs
`
`28
`
`7.3.6. E c findings .................................................................
`Phannacokinetic results .......................................................................................... .29
`
`7.4.
`
`7 .4. 1 .
`
`7.4.2.
`7.43.
`
`Assay perfomiance................................................................................ .
`
`. 29
`
`Phaimacokinetic profiles and variables ................................................... .. 33
`Statistical results .................................................................................... . . 45
`
`8. Discussion ......................................................................................................................... .
`
`. 48
`
`9. Conclusions ....................................................................................................................... .. 50
`
`10. Reference list ..................................................................................................................... .. 5 l
`
`11. Post-text Tables................................................................................................................. .. 52
`
`1.2
`
`CONFIDENTIAL
`
`VNDA_01516683
`
`Vanda Exhibit 2030 - Page 5
`
`

`
`Novartis
`Report C|LO522 0104
`
`Confidential
`
`Page 5
`ILO522
`
`1.3
`
`List of tables
`
`Table 3.1-1,
`
`Table 7.3- 1.
`
`Table 7.4- 1.
`
`TableJ.4-2.
`
`Table 7.4-3.
`
`Table 7.4-4.
`
`Table 7.4-5.
`
`Table 7.4-6.
`
`Table 7.4-7,
`
`Table 7.4.-8.
`
`Table 7.4-9.
`
`Table7A-LO.
`
`Treatment Design .................................................................................. .. 16
`
`Adverse Events ..................................................................................... .
`
`. 27
`
`Summary of within-study assay validation in plasma ................................ . .29
`
`in4,uine ................................... .. 30
`
`Summary of within-study assay validation in serum ................................. .
`
`. 32
`
`Mean (CV%) ilopeiidone phaimacokinetic parameters in extensive and
`poor CYPZD6 metabolizers following a 3 mg single oral dose of
`ileperielene ............................................................................................ .. 34
`
`Mean (CW o) P88—8991 phaimacokinetic parameters in extensive and
`poor CYPZD6 metabolizers following a 3 mg single oral dose of
`iloperidone ............................................................................................ . . 3 5
`
`Mean (CV%) P95-12113 pharmacokinetic parameters in extensive and
`poor CYPZDIS metabolizers following a 3 mg single oral dose of
`flopendone ............................................................................................ .
`
`. 37
`
`Mean (CV%) ilopeiidone pharmacokinetic parameters following a 3 mg
`single oral dose of ilopeiidone administered alone and in combination
`with an 80 mg single oral dose of dextromethorphan HBr ....................... .. 38
`
`Mean (CV%) P8 8-8991 phannacokinetic parameters following a 3 mg
`single oral dose of iloperidone administered alone and in combination
`with an 80 mg single oral dose of dextromethorphan HBr ....................... ..40
`
`Mean (CV%) P95-12113 pllarmacokiiletic paraineters following a 3
`mg single oral dose of iloperidone administered alone and in
`combination with an 80 mg single oral dose of dextromethorphan HBr .... . .41
`
` V° .
`=-eA.--.-e==--1:. :9
`an 80 mg single oral dose of dextromethorphan HBr administration
`
`alone and in combination with a 3 mg single oral dose of iloperidone ....... .
`
`. 43
`
`Table7,4-1 1.
`
`Mean (CV%) dextroiphan pliaimacokinetic pa1‘a111eters following a11 80
`mgsi_nglerl
`f
`x m
`h HBr mini
`'
`
`Table 7.4-12.
`
`Table 74-13.
`
`Table 74-14.
`
`
`
`Mean (CV%) of ratios of metabolite to parent diug following
`ilopeiidone and dextromethorphan administration ................................... .
`
`. 45
`
`Least— squares mean ratio of PK parameters from ANOVA of poor vs.
`........................................................................... .
`
`. 46
`
`Least— squares mean ratio of PK parameters (AUC0_8, Al;C0_[, Cmax,
`CLR, CLT/F, and Aeoi) from ANOVA of iloperidone +
`dextromethorphan vs. iloperidone alone _________________________________________________ _
`
`. 47
`
`CONFIDENTIAL
`
`VNDA_01516684
`
`Vanda Exhibit 2030 - Page 6
`
`

`
`Novartis
`Report C|LO522 0104
`
`Confidential
`
`Page 6
`ILO522
`
`TableJ.4-15 mm— wc%, AIJCH, Cnm,
`
`and CI:pDFH’rem ANO3vQ& of VS.
`dextromethorphan alone ........................................................................ ..48
`
`Table 11.1-1.
`
`Evaluation study schedule ...................................................................... .. 52
`
`L4
`
`LisLofFigLu:es
`
`Figure 7.4-].
`
`Figure 7.4-2.
`
`Figure 7.4-3.
`
`Figure 7.4-4.
`
`Mean plots of iloperidone in extensive and poor CYPZD6 metabolizers
`following a 3 111g single oral dose of iloperidone ...................................... .. 34
`
`Mean plots of metabolite P88- 8991 in extensive and poor CYP2D6
`metabolizers following a 3 mg single oral dose ofilopendone ___________________ _ 375
`
`Mean plots of metabolite P95-12113 in extensive and poor CYPZD6
`metabolizers following a 3 mg single oral dose of iloperidone .................. .. 36
`
`Mean plots of iloperidone following a 3 mg single oral dose of
`iloperidonc administered alone and in combination with an 80 mg single
`
`oral dose of dextromethorphan HBr ....................................................... .
`
`. 38
`
`Figure 7.4-5.
`
`Mean plots of P88-8991 following a 3 mg single oral dose of
`iloperidone administered alone and in oombination with an 80 mg single
`
`oral dose of dextromethorphan HBr ....................................................... .
`
`. 39
`
`Figure 74-6
`
`M n l
`
`fP95-l2ll3 f ll
`
`
`
`Figure 7.4-7.
`
`Mean plots of dextromethorpllall following all 80 mg single oral dose of
`dextromethorphan HBr administration alone and in combination with a 3
`
`5|" _-_
`
`mg single oral dose of iloperidone .......................................................... . .42
`‘v“" i i ‘ ii“i'i'I"I’ ‘ i"'i ‘u’ H "6 "Ear 6" ‘
`
`dextromethorphan HBr administration alone and in combination with a 3
`mg single oral dose of ilopendone .......................................................... . .44
`
`1.5
`
`CONFIDENTIAL
`
`VNDA_01516685
`
`Vanda Exhibit 2030 - Page 7
`
`

`
`Novartis
`Report C|LO522 0104
`
`Confidential
`
`Page 7
`|LO522
`
`L6
`
`Listofappendices
`
`Appendix 1. Study information
`
`Protocol and protocol amendments
`
`Information for subjects and sample consent form
`
` bm
`
`Appendix 2. Study center information
`
`Independent Ethics Committee or Institutional Review Board
`
`Information on investigators
`
`Laboratory quality assurance (QA) procedures
`
`Appendix 3. Safety and pharmacodynamic tables, figures and listings
`
`Appendix 4. Pharmacokinetic tables, figures and listings
`
`Appendix 5. Bioanalytical data report
`All‘ll.I
`I-ll-l.l‘l.l0ll-II-ll‘ ll-lI.l|l-II .|- .|0
`
`
`
`E
`
`f
`
`.
`
`. 1.‘;
`
`Appendix 7. Publications
`
`not applicable
`
`1.7
`
`CONFIDENTIAL
`
`VNDA_01516686
`
`Vanda Exhibit 2030 - Page 8
`
`

`
`Novartis
`Report C|LO522 0104
`
`Confidential
`
`Page 8
`|LO522
`
`‘L8
`
`Listofabbreyiatians
`
`AE
`
`AHA
`
`ALT
`
`AST
`AUC
`
`AV
`
`b_1_d.
`
`BP
`
`BPM
`
`BUN
`
`CLT/F
`
`CPK
`
`CRF
`
`CRO
`
`CS&E
`
`CYl°42Dé
`
`CYP3A4
`
`DEX
`
`adverse event
`
`American Heart Association
`
`alanine aminotransterase
`
`aspartate aminotransferase
`area under the concentration time curve
`
`atrioyentricular
`
`bis in cfiem / twice a day
`
`blood pressure
`
`beats per minute
`
`blood urea nitrogen
`
`creatine phosphokinase
`
`case report / record form
`
`Contract Research Organization
`
`Clinical Safety and Epidemiology
`
`cytochrome¥450 2196
`
`cytochrome P450 3A4
`
`dextromethorphan
`
`ECG '
`
`ED5o
`
`EM
`
`FDA
`
`GCP
`
`Y-GT
`
`HbsAg
`
`HCV
`
`HIV
`HR
`
`IEC
`
`ILO
`
`IN D
`
`effective dose (the dose at which 50% of the maximum effect is reached)
`
`extensive cytochrome P450 ZD6 metabolizer
`
`Food and Drug Administration
`
`good clinical practice
`
` p®m
`
`hepatitis B surlace antigen
`
`hepatitis C Virus
`
`human immunodeficiency virus
`heart rate
`
`Indepgidcnt E1 iics Qloinmittee
`
`iloperidone
`
`lnvestigational New Dmg application
`
`CONFIDENTIAL
`
`VNDA_01516687
`
`Vanda Exhibit 2030 - Page 9
`
`

`
`Novartis
`Report C|LO522 0104
`
`Confidential
`
`Page 9
`ILO522
`
`ITD
`
`i.V.
`
`LDH
`
`mm Hg
`
`NC S
`N OAEL
`
`NTEL
`
`q.d.
`
`pH
`
`PD
`
`PK
`
`PM
`
`BR
`
`p.o.
`
`RBC
`SAE
`
`SGOT
`
`SGPT
`
`tmax
`
`ti,/_,
`
`TBD
`
`V2/F
`
`WBC
`
`WHO
`
`lntemational Therapy Dictionary
`
`intravenous(ly)
`
`lactate dehydrogenase
`
`millimeters of mercury
`
`not
`no-observable adverse effect level
`
`no—toxic—elfect level
`
`once a day
`
`negative log hydrogen ion concentration
`
`pharmacodynamics
`
`pharmacokinetics
`
`poor cytochrome P450 2D6 metabolizers
`
`p11LseJ:aIe
`
`peros / by11routl17”0rally
`
`red blood cells (erythrocytes)
`serious adverse event
`
`serum glutamic oxaloacetic transaminase (same as AST)
`
`serum glutamic pyruvic transaminase (same as ALT)
`
`time to reach Cmax
`
`elimination half- life
`
`tobedetennrned
`
`V0lLl111C of distribution (corrected for absolute bioavailability)
`
`white blood cells (leukocytes)
`
`World Health Organization
`
`CONFIDENTIAL
`
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`
`Vanda Exhibit 2030 - Page 10
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`

`
`Novartis
`
`Report ClLO522 0104
`
`Confidential
`
`Page 10
`|LO522
`
`‘L9Studype1:sonnel
`
`1.9.1.1 Key Novartis personnel
`Clinical Pharmacology Study Leader
`Clinical Pharmacology Physician
`Clinical Pharmacokineticist
`
`Study Biostatistician
`Bioanalyst
`Medical Data Manager
`
`1.9.1.2
`
`External personnel
`
`Clinical Laboratory
`
`Marilyn White, MPH
`Greg Sgjek, MD
`Somesh Choudhury, PhD
`Peiming Ma, PhD
`Michael Hayes, PhD
`Kristina Miscik
`
`' , MD
`PPE) Pharmaco, lnc.
`706 Ben White Blvd.
`
`Austin, Texas 78704
`
`Charles Ryan, PhD
`PPD Pharmaco
`
`Z06 Ben White Bud.
`
`Austin, Texas 78704
`
`CONFIDENTIAL
`
`VN DA_0151 6689
`
`Vanda Exhibit 2030 - Page 11
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`

`
`Novartis
`Report C|LO522 0104
`
`Confidential
`
`Page 11
`|LO522
`
`2
`
`Studysvneie-sis
`
`Title of study: An open-label study to characterize the pharmacokinetics of iloperidone in poor and
`extensive 2D6 metabolizers and to evaluate the interaction of iloperidone with a cytochrome P450 2D6-
`prototype substrate (dextrornethorphan) in healthy subjects
`
`lnvestigator(s):
`
`Thomas Hunt, MD, PPD Pharmaco, Inc.
`
`706A Ben White Blvd. Austin, Texas 78704
`
`Publication(s): None
`
`Study period: first subject dosed 03-Oct-98
`
`last subject completed 13-Apr-99
`
` To E the
`extensive CYP2D6 metabolizers
`
`JSUOTWVS.
`
`To assess the pharmacokinetic interactions of iloperidone and dextromethorphan in subjects genotyped
`as extensive CYP2D6 metabolizers
`
`This was a two—cohort, randomized, open—|abe|, three—period crossover study. Healthy subjects identified
`by genotyping as extensive CYP2D6 metabolizers were enrolled in Cohort 1 and healthy subjects
`identified by genotyping as poor CYP2D6 metabolizers were enrolled in Cohort 2.
`
`1 participated in a screening period, a baseline period (repeated prior to each
`Subjects in Cohort
`treatment period), three treatment periods, and a study completion evaluation. In Period 1, all subjects
`received a single dose of 3 mg iloperidone. In Periods 2 and 3 subjects received 80 mg dextromethorphan
`and 3 mg iloperidone + 80 mg dextromethorphan in a sequence determined by a randomization scheme.
`lloperldone plasma samples were collected for 72‘hours after administration of iloperidone and Iloperldone
`+ dextromethorphan. Dextromethorphan serum samples were collected for 24 hours after administration
`of dextromethorphan alone and 72 hours after administration of iloperidone + dextromethorphan. Subjects
`were discharged from the unit after the last PK sample was drawn in each period. All subjects in Cohort
`1m¢a7day .
`
`Subjects In Cohort 2 parficlpated In a screenlng period, a basellne period, one treatment period, and a
`study completion evaluation. Subjects received a single 3 mg dose of iloperidone. Plasma samples were
`collected for 72 hours after dosing. Subjects were discharged from the study after the last PK sample
`was drawn.
`
`Number of subjects: Nineteen (19) subjects were identified by genotyping as extensive CYP2D6
`metabolizers (EM). Eight (8) subjects were identified by genotyping as poor CYP2D6 metabolizers (PM).
`Twenty seven subjects were entered (19 EM and 8 PM). Twenty six subjects completed (18 EM and 8
`PM). One (1) subject dropped out due to an adverse event.
`
`Criteria for inclusion: Healthy male and female subjects genotyped as extensive or poor metabolizers
`between the ages of 18 and 45
`
`I
`
`-
`
`I.-vI-
`
`n- so .1 rrrgcapsu1es,BatclT#‘FO‘l—T02‘r98
`
`Benylin® Adult Formula (Dextromethorphan): 15mg/5ml, Lot # 24558L, Manufacturer: ParkeDavis
`
`CONFIDENTIAL
`
`VNDA_01516690
`
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`Report C|LO522 0104
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`Page 12
`|LO522
`
`Duration of treatment: Cohort 1: 3 periods with 2 single doses of 3 mg iloperidone and 2 single doses
`of 80mg dextromethorphan given
`
`Cohort 2: one period with a single 3 mg iloperidone dose given
`
`Criteria for evaluation:
`
`Safety and tolerability: Medical history, physical examination, vital signs, ECG, laboratory evaluations
`=: g...
`.5
`.-.._ =3,‘
`_
`._V
`_.= _=V-
`- -V-.
`..=.
`=
`.3
`7
`7
`7
`
`Pharmacokinetics: Plasma and urine concentratlons of lloperfione and its metabolites P888991 and
`P95-12113. Serum concentrations of dextromethorphan and its metabolite dextrorphan.
`
`Statistical methods: An analysis of variance (ANOVA) model based on a parallel group design was
`used to compare iloperidone, P88—8991, and P95—12113 PK profiles between Cohort 2 and Cohort 1 (first
`period). The model was fitted to the log—transformed PK parameters.
`
`mANDwmdmmmdmaa2m§mmd%gnw%mmmmmmm
`dextrorphan PK profiles from Periods 2 and 3. The model was fitted to the log—transformed PK
`parameters. An ANOVA model based on a randomized block design was used to compare iloperidone,
`P88—8991, and P95—12113 PK profiles from all three periods.
`
`Results:
`
`Safety and tolerability:
`
`Adverse events (AEs) were reported by 20 of 27 subjects. The most common adverse events suspected
`to be related to the study medications were dizziness,
`rhinitis, tachycardia, headache, nausea, and
`vomiting. The frequency of AEs in the Cohort 2 (PM) was not significantly different than the frequency in
`Cohort 1
`(EM). However, the number of AEs per subject was higher in Cohort 1
`(EM) than in Cohort 2
`(PM). There were less AEs reported when iloperidone and dextromethorphan were given in combination
`(n=14) versus iloperidone given alone (n=39) in Cohort 1. One subject (03) withdrew after the first dose
`due to a primary adverse event of anxiety.
`Pharmacokinetics:
`
`Extensive vs. Poor CYP2D6 Metabolizers
`
`Though the mean CW of iloperidone in extensive metabolizers (2.79 ng/mL) was only slightly higher than
`in poor metabolizers (2.26 ng/mL), the exposure to iloperidone as measured by AUC0_,X. was 57% more in
`poor metabolizers (46.3 ng*hr/mL) than in extensive metabolizers (29.4 ng*hr/mL). The elimination half-
`life in poor metabollzers was prolonged by 88%. fince the apparent volume of distributlon ofTloperldone
`was similar in both populations, this prolongation of the half-life of iloperidone in poor metabolizers was
`due to a 43% decrease in the apparent clearance of iloperidone. The amount of unchanged iloperidone
`excreted in urine was negligible (O.45% and 0.70% of the administered dose in extensive and poor
`
`The mean CW of P88-8991, one of the metabolltes which IS formed via reductlon of lloperidone, was
`"-. -- W14%mmz.fimTmmaEmW
`AUC0_x of P88—8991 also increased by 95% in poor metabolizers (mean of 96.4 vs. 49.4 ng*hr/mL). The
`terminal elimination half—life was prolonged to 37.5 hr in poor metabolizers in comparison to 25.5 hr in
`extensive metabolizers. Although the amount of drug excreted in urine as metabolite P88—8991 was
`increased from 4.2% of administered dose in extensive metabolizers to 8.0% in poor metabolizers, the
`renal clearance remained similar between extensive (46.5 mL/min) and poor (51.3 mL/min) metabolizers.
`
`
`
`95-07’-' -;ii"
`;O"";ii‘O"IV;
`'0" ;o 0*’
`;"u'
`-'
`was decreased significantly (by 87%) in poor metabolizer (4.5 vs 0.67 ng/mL). This decrease in Cm was
`also reflected in AUCOW, which was decreased by 80%. The elimination half—life was prolonged from 23 hr
`in extensive metabolizers to 30.6 hr in poor metabolizers. The amount of drug excreted in urine as
`
`CONFIDENTIAL
`
`VNDA_01516691
`
`Vanda Exhibit 2030 - Page 13
`
`

`
`Novartis
`Report C|LO522 0104
`
`Confidential
`
`Page 13
`|LO522
`
`metabolite P95—12113 was also significantly less (76%) in poor metabolizers. In spite of smaller amount
`of metabolite being excreted in urine,
`the renal clearance of P95—1 2113 remained similar in both
`population (66.4 mL/min in extensive metabolizers vs 75.0 mL/min in poor metabolizers).
`
`Effect of Dextromethorphan on iloperidone pharmacokinetics
`
`time profiles for iloperidone, following administration of iloperidone
`The mean plasma concentration vs.
`alone and in
`combination with dextromethorphan, were superimposable. The mean maximum
`
`.=:-. -eatthesamemeelian'
`-a--
`_
`.-=- =----= =-.-
`parameters of iloperidone were similar between both treatments. The differences in Cnax, AUCo_...,
`CLT/F, and V2/F between the two treatments were less than 4.0%.
`
`t«,.,
`
`The mean plasma concentration vs. time profiles of P88—8991 following administration of iloperidone alone
`and in combination with dextromethorphan were essentially identical. The maximum concentration of the
`..
`c
`...
`-
`...
`-.
`.
`.- .
`..
`.-
`..-
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`.--.- -.
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`.==
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`-=- 7.0%.
`
`time profiles of P95—12113 following administration of iloperidone
`The mean plasma concentration vs.
`alone and in combination with dextromethorphan were also indistinguishable. The formation and
`clearance of the metabolite were similar between treatments. The differences in Cm AUCo_.,, Ae, and
`CLR between the two treatments were less than 6%, and the difference in ty, was about 13.0%.
`
`Effect of iloperidone on Dextromethorphan’s pharmacokinetics
`
`Dextromethorphan was absorbed quickly with a similar median tm, of 2 hrs following both treatments of
`dextromethorphan alone and in combination with iloperidone. There was a 24% increase in the mean Cmax
`value of dextromethorphan (7.0 vs. 8.68 ng/mL), however there was only a 9.6% increase in AUC0..,,
`following combination treatment. The differences in t%, CLT/F, and V,/F were less than 10%.
`
`The metabolitemm of dextmmefhmzphan was fmmecl quickly
`and at the same rate with a median tma, of 2 hrs following both treatments. dextromethorphan alone and in
`combination with iloperidone. The differences in Cm (1049 vs. 996 ng/mL) and AUC0_.,, (5776 vs. 5833
`ng*hr/mL) between the treatments were less than 5%. However, concomitant administration of
`iloperidone increased the elimination half-life of dextrorphan by 58% (4.55 vs. 7.17 hr).
`
`CO|‘IC|l.lSiO|1S:
`
`significantly increased (AUCOW by 57% and 95%,
`Exposure to iloperidone and P88-8991 was
`respectively), while exposure to P95-12113 was significantly decreased (AUC0_.., by 80%)
`in poor
`CYPZD6 metabolizers compared to extensive CYPZD6 metabolizers.
`
`Poor and extensive CYP2D6 metabolizers tolerated the drug similarly and there were no safety concerns
`in either population.
`
`be too small
`
`to be of clinical
`
`substrates is unlikely.
`
`'
`
`'
`
`I
`
`‘
`
`
`
`V‘ done and other- CXPZD6.
`
`iloperidone and dextromethorphan were tolerated when given together or alone, with no clinically
`significant findings in the safety assessments.
`
`Date of the report:
`
`
`
`
`CONFIDENTIAL
`
`VNDA_01516692
`
`Vanda Exhibit 2030 - Page 14
`
`

`
`Novartis
`Report C|LO522 0104
`
`Confidential
`
`Page 14
`|LO522
`
`3
`
`Ethics and Good Glinical Practice
`
`This study was performed in accordance with standard operating procedures of the sponsor
`Novartis, operating at the time of the study. These were designed to ensure adherence to GCP and
`ensure the protection of the subjects, as required by the following directives in operation at the time:
`
`1. Declaration of Helsinki, concerning medical research in humans (‘Recommendations Guiding
`Physicians in Biomedical Research Involving Human Patients‘, Helsinlfi T964, amendedTol<yo
`1975, Venice 1983, Hong Kong 1989, Somerset West, 1996).
`
`2. Directive 91/507/EEC: The Rules Goveming Medicinal Products in the European Community.
`
`3. US 21 Code of Federal Regulations dealing with clinical studies, parts 50 and 56, concerning
`Informed Patient Consent and IRB approval.
`
`4
`
`1.
`
`Introduction
`
`Schizophrenia is a severe mental illness that affects an estimated 1% of the world’s population.
`Patients suffer from productive symptoms (e.g., hallucinations and delusions) and deficit symptoms
`--7
`‘i
`
`”Ii;4"| ’Ir'|;i’
`
`I ’‘I'
`
`III
`
`‘E "‘Ii’Iv"
`
`I’
`
`I’v'I
`
`chlorpromazine, haloperidol) has been demonstrated to be etfective in treating productive symptoms,
`although this antagonism is also associated with extrapyramidal side effects, tardive dyskinesia, and
`elevations in prolaclin levels.
`
`‘II ‘IIII‘IIIa|‘3II'.I‘
`I I
`III *1“ a I“ 4
`I
`‘-IV‘
`"I
`to one of a combined antagonism of serotonin DHT2 and dopamine D2 receptors. The discovery of
`
`new pharmacological agents, Wl11Ch exhibit a more balanced, mixed D2/SHTZ antagomsm, has
`resulted in a new generation of improved therapeutic agents (e. g., risperidone) that are effective not
`only against productive symptoms but also deficit and cognitive symptoms of schizophrenia. These
`all!
`IOI
`I‘lIII la ‘ ‘III! ‘I
`I‘ II
`I
`A‘
`I
`‘ I‘
`I ‘xlal
`I III
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`III
`
`e---. --.e : ee:- ' e
`
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`
`
`
`
`
`lloperidone is a mixed 1;/51-1'1’; antagonist with preferential afiinity for 51-1'1'2A receptors in humans
`classifying it as a novel antipsychotic. lloperidone shares some phaimacologic characteristics with
`clozapine, iispeiidone, olanzapine, and ziprasidone. Ilopeiidone also exhibits an afinity for human
`e==.-.---- B: receptors and for rat serotonin SHEL. receptors, properties thatm%o
`‘iiii"l
`l’='i‘Ii‘ 3iV“‘;“ I
`l'=
`i" ““
`5 “‘I'ii‘I“l‘
`5"i_‘ has béefl
`
`emons a e to bfid with high affinity to sites tlfit clfily resemble 5HT6 sero
`dopamine D, receptor is primarily present in the nucleus accumbens with very low levels in the
`caudate and putaineii. Taken together, these binding cliaracteiistics indicate that ilopeiidone may
`result in enhanced control of psychotic symptoms with relatively little additional liability for inducing
`-4.‘. «III:
`IIOOII
`
`flopendone is extensively metabolized in the liver and is primarily eliminated via renal excretion. In
`
`vitra human liver microsome studies and in viva human ADME data indicate that ilopeiidone
`undergoes metabolism via at least three metabolic pathways: reduction, hydroxylation (mediated by
`
`CONFIDENTIAL
`
`VNDA_01516693
`
`Vanda Exhibit 2030 - Page 15
`
`

`
`Novartis
`Report C|LO522 0104
`
`Confidential
`
`Page 15
`ILO522
`
`_ I A‘ .
`
`.-
`
`9
`
`!..'.9I n-4,.-.9 9
`
`-. 9,. .u,q-._
`CYP2D6), and e-.n:_,-
`
`
`=--==-- mpHsmaw%mewdu%d ,wMchh%anAEC%90°ogre%a
`than that of the parent compound. The P89-9124 metabolite, resulting from 0-demethylation via
`CYP3A4, was only a minor component in plasma Data from the human ADMP, study indicate that
`the CYP2D6 pathway may play a more important role than originally thought. In this study the major
`urinary components were P88-8991 and P95-12113, a metabolite formed along the CYP2D6
`pathway. Since CYP2D6 is known to be polymorphic, with approximately 7- lO% of the Caucasian
`population categorized as poor metabolizers of this isozyme, this study was conducted to evaluate
`whether or not there are differences in the elimination of iloperidone in subjects genotyped as
`extensive or poor metabolizers of CYP2D6. However, since iloperidone undergoes metabolism via
`at least three metabolic pathways and the combination of P88—8991 and P95—121l3 in urine still
`only accounted for approximately 7- 12% of the administered dose, differences arising due to
`CYP2D6 polymorphism were not expected to have a. significant a.fi“ect on total clearance of
`iloperi done.
`
`In addition,
`
`the potential
`
`for drug-drug interactions will be explored in this study by using
`
`substrate. The metabolism of
`a CYP2D6 prototype
`dextromethorphan hydrobroni