CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203341Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`MEMORANDUM
`
`
`Bosulif (bosutinib)
`
`Date: August 15, 2012
`To: File for NDA 203341
`From: John K. Leighton, PhD, DABT
`
`Acting Director, Division of Hematology Oncology Toxicology
`
`Office of Hematology and Oncology Products
`
`
` I
`
` have examined pharmacology/toxicology supporting review of Dr. Luan Lee and
`labeling and secondary memorandum provided by Dr. Saber. I concur with Dr.
`Saber’s conclusion that Bosulif may be approved and that no additional
`nonclinical studies are needed for the proposed indication.
`
`Reference ID: 3174668
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOHN K LEIGHTON
`08/15/2012
`
`Reference ID: 3174668
`
`

`

`MEMORANDUM
`
`
`Date:
`From:
`
`
`
`Re:
`
`NDA:
`Drug:
`Indication:
`
`August 9, 2012
`Haleh Saber, Ph.D.
`Pharmacology/Toxicology Supervisor
`Division of Hematology Oncology Toxicology (DHOT)
`Office of Hematology Oncology Products (OHOP)
`Approvability for Pharmacology and Toxicology
`203341
`BOSULIF® (bosutinib) tablets for oral administration
`indicated for the treatment of chronic, accelerated, or blast phase Ph+
`chronic myelogenous leukemia (CML) in adult patients with resistance, or
`intolerance to prior therapy
`Applicant: Wyeth Pharmaceuticals, Inc.
`
`
`Bosutinib is a small molecule tyrosine kinase inhibitor (TKI) developed for the treatment
`of CML. Bosutinib inhibits the Bcr-Abl kinase and the Src-family kinases, including Src,
`Lyn, and HCK as demonstrated in vitro by Invitrogen Z-Lyte assay. Bosutinib inhibited
`several mutant forms of Bcr-Abl; however, it did not inhibit the T315I mutant in vitro as
`demonstrated by IC50s greater than 100-fold for T315I-Abl compared to those for Src
`and c-Abl. In in vitro studies, bosutinib inhibited proliferation of CML cell lines.
`Bosutinib treatment reduced the size of CML tumors growing in nude mice and inhibited
`growth of murine myeloid tumors expressing several imatinib-resistant forms of Bcr-Abl;
`very low or minimal inhibition was seen for cells containing the T315I mutation in the
`panel of mutants examined. The pharmacologic class assigned to bosutinib is “kinase
`inhibitor” consistent with other drugs of the same class, such as imatinib, dasatinib, and
`nilotinib.
`
`Pharmacology, safety pharmacology, pharmacokinetic/ADME (absorption, distribution,
`metabolism and excretion), and toxicology studies were conducted in in vitro systems
`and/or in animal species. Animal toxicology studies were conducted in appropriate
`species, using the administration route and dosing regimens that adequately addressed
`safety concerns in humans. In general, the toxicity profile was similar in rodent and
`nonrodent species. The main drug-related toxicities in toxicology studies were in the GI
`tract and the hematologic system. GI toxicities included hemorrhage and erosion and was
`considered the cause of deaths in animals. Hematologic toxicities may be secondary to
`the GI bleeding and the resulting inflammation; effects included increases in white blood
`cells and differentials, changes in red blood cell parameters, and increased platelet
`counts. Adverse findings in the liver (e.g. increased ALT and AST) were reported in
`patients; however, hepatobiliary toxicity was of low incidence in animals and was mainly
`seen upon histopathology examination with no correlating changes in clinical chemistry
`parameters. In a safety pharmacology study, bosutinib inhibited the hERG channel
`current at an IC50 value of 0.3 μM and may be hence considered a moderate potency
`blocker. In a safety pharmacology study in dogs, transient increases in blood pressure
`and a secondary reduction in heart rate were observed for 2 minutes after IV infusion of
`
`
`
`Reference ID: 3172580
`
`1
`
`

`

`bosutinib. The effect of a single dose of bosutinib at 500 mg was investigated in 70
`healthy subjects. No significant changes in the QTc were observed. However, QTc
`prolongation was reported in patients treated with bosutinib. See the label for additional
`information.
`
`Bosutinib was not mutagenic or clastogenic when tested in the battery of genotoxicity
`studies. A unique human metabolite, metabolite M2, was tested to assess its genotoxicity
`potential. M2 was not genotoxic in the studies conducted, the Ames test and the
`chromosomal aberration assay in human peripheral blood lymphocytes. A 2-year
`carcinogenicity study was conducted in Sprague-Dawley rats. The study was negative
`for drug-induced neoplasms.
`
`In embryofetal developmental (EFD) studies in rats and rabbits, bosutinib was
`administered orally to pregnant animals. There was no maternal toxicity or adverse
`embryo-fetal developmental toxicity in rats treated with bosutinib up to 10 mg/kg/day. It
`appears that this study did not expose pregnant rats to enough bosutinib to fully evaluate
`adverse outcomes. The inadequacy of dosing in rats is supported by the following
`observations: lack of maternal toxicities in the rat EFD study, presence of bosutinib-
`derived radioactivity in the fetus in a distribution study indicating that bosutinib and/or its
`metabolites can cross the placenta, and the embryonic toxicities observed in the fertility
`and early embryonic developmental study when female rats were dosed with 30
`mg/kg/day of bosutinib.
`
`Adverse embryofetal effects were evident in rabbits. At the maternally-toxic dose of 30
`mg/kg/day of bosutinib in rabbits, there were fetal anomalies (fused sternebrae, and
`various visceral observations), and an approximate 6% decrease in fetal body weight.
`Due to the adverse embryofetal findings, a pregnancy Category D has been assigned to
`bosutinib.
`
`In a fertility and early embryonic developmental study conducted in rats, drug-treated
`males were mated with untreated females, or untreated males were mated with drug-
`treated females. When males treated with bosutinib were mated with females, the
`number of pregnancies was reduced. When treated female rats were mated with
`untreated males, the number of pregnancies was unaffected but there were increased
`embryonic resorptions, decreased implantations, and reduced number of viable embryos.
`
`In a distribution study, lactating rats were administered a single oral dose of radioactive
`bosutinib. Significant amount of radioactivity was detected in the milk of lactating rats.
`In addition, the level of radioactivity in suckling offspring was significant (8-fold the
`radioactivity in the plasma of lactating rats). The presence of radioactivity in the
` plasma of suckling offspring has been added to Section 8.3 of the label,
`Nursing Mothers.
`
`The nonclinical studies were reviewed by Dr. Shwu-Luan Lee. The nonclinical findings
`are summarized in the “Executive Summary” of the NDA review and reflected in the
`
`
`
`
`
`Reference ID: 3172580
`
`2
`
`(b) (4)
`
`(b) (4)
`
`

`

`product label. The carcinogenicity study was reviewed by Dr. Shawna Weiss and
`archived separately. For product labeling, see the approved label.
`
`Recommendation: I concur with Dr. Lee that from a nonclinical perspective, BOSULIF
`may be approved for the proposed indication. No additional nonclinical studies are
`needed to support approval of BOSULIF for the proposed indication.
`
`
`
`Reference ID: 3172580
`
`3
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`HALEH SABER
`08/09/2012
`
`Reference ID: 3172580
`
`

`

`NDA # 203341
`
`
`
`
`
`
`
`Reviewer: Shawna L. Weis, PhD
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Reviewer:
`
`
`ECAC Meeting Date:
`NDA #:
`
`
`Drug Code:
`
`
`CAS#:
`
`
`Division(s):
`
`
`
`
`
`
`
`
`
`
`CARCINOGENICITY ASSESSMENT COMMITTEE (CAC/CAC-EC) REPORT
`AND
`FDA-CDER RODENT CARCINOGENICITY DATABASE FACTSHEET
`
`
`Shawna L. Weis, PhD
`26 June 2012
`203341
`SKI-606, WAY-173606
`
`
`380843-75-4
`
`
`Division of Hematology and Oncology Toxicology in
`support of the Division of Hematology Products
`
`Bosutinib ®
`Pfizer Global Research and Development
`Until Week 36: Wyeth, Chazy, NY
`Thereafter:
`
`
`
`
`
`
`
`Drug Names:
`
`Applicant:
`
`
`Conducting Laboratory:
`
`
`
`
`Carcinogenicity Final
`Study Report Date:
`
`Therapeutic Category/MOA:
`Indicated for the treatment of chronic , accelerated, or blast phase Ph+ chronic myelogenous
`leukemia (CML) in adult patients with resistance, or intolerance to prior therapy via Inhibition of
`Src family kinase and Abl protein tyrosine kinase
`Pharmacological Classification: Kinase inhibitor
`Mutagenicity/Genotoxicity: No. Bosutinib was negative in Ames, and in vitro chromosome
`aberration both with and without S9 activation, as well as in the in vivo micronucleus assays in
`rats.
`
`
`
`
`
`
`24 May 2012
`
`Reference ID: 3164961
`
`(b) (4)
`
`

`

`NDA # 203341
`
`Reviewer: Shawna L. Weis, PhD
`
`The following were the conclusions of the Executive Carcinogenicity Assessment
`Committee on 17 July 2012:
`
`6' The Committee agreed that the study was acceptable, but noted that moving an
`ongoing carcinogenicity study is undesirable and rendered historical control data
`difficult to interpret due to numerous differences between the two sites.
`
`.0
`.0 The Committee concurred that the study was negative for drug-induced neoplasms.
`
`RAT CARCINOGENICITY STUDY: Standard two-year bioassay
`
`Rat study duration (weeks):
`
`91-100 weeks with early termination due to mortality
`
`Study starting date:
`
`16 July 2009
`
`Study ending date:
`
`23 March 2010
`
`Rat strain:
`
`Route:
`
`Comments:
`
`Sprague-Dawley CD‘D
`
`Oral gavage Dosing
`
`None
`
`Number of rats used: 360Isex (Main Study) + 9Isex TK
`
`Table 1: Study Design
`
`Toxicology
`
`Dose
`
`# l Sex
`
`Toxicokinetic
`
`Dose
`
`# I Sex
`
`(“mg/kgMay)
`G'°“ps
`(mglkglday)
`emu"
`W‘- 6°"”6°F ———
`
`
`
`
`
`
`
` 2. 5 60 M 13 7.5 9 M
`
`“--
`
`
`
`Group 1 = water
`
`§Groups 2, 3 = vehicle (0.5% CMC, 2.0% TWEEN
`80, 0.06% acetic acid and water)
`
`Basis for doses selected:
`
`Reference ID: 3164961
`
`

`

`
`
`Reviewer: Shawna L. Weis, PhD
`
`NDA # 203341
`
`The high dose selection was based on the results of the 6-month rat toxicology study.
`Decreased body weight, food consumption and survival were observed at doses of 100 / 70
`mg/kg/day. Animals tolerated 30 mg/kg/day bosutinib in that study.
`Prior FDA dose concurrence:
`Yes. Dose selection was per CAC recommendation (16 June 2009).
`Rat Carcinogenicity:
`No. There were no tumors or combinations of tumors that met the criteria for statistical
`significance in this study. As indicated in the Table 2 and Table 3 below (Males and Females,
`respectively), there were tumors that met criteria for acceptance by either trend or pairwise
`comparison; however, none met both criteria. Moreover, when the high dose groups were
`excluded from the analysis due to early mortality, the positive trends were no longer statistically
`significant.
`
`Reference ID: 3164961
`
`

`

`NDA # 203341
`
`Reviewer: Shawna L. Weis, PhD
`
`Table 2: Rat tumor findings: Males
`
`Site
`
`Tumor
`
`Pairwise (treated vs
`control)
`.
`.
`,
`,
`Excluding
`Including
`Low
`Mid
`High
`High
`High
`
`
`Common or
`Uncommon
`
`Incidence
`in
`controls
`
`schwannomas
`
`Pituitary
`(pars
`distalis)
`
`Thyroid
`
`Skin
`
`Adenoma
`
`0.0271
`
`0.0979
`
`Adenoma and
`Carcinoma
`
`Follicular cell
`carcinoma
`
`Fibroma
`
`Fibroma and
`fibrosarcoma
`
`Malignant
`
`0.6961
`
`0.0338
`
`0.2074
`
`0.7843
`
`0.0596
`
`0.2899
`
`1.0000
`
`0.3735
`
`0.1133
`
`0.0094
`
`0.4028
`
`1.0000
`
`0.0194
`
`0.7927
`
`0.9516
`
`0.3333
`
`0.3182
`
`0.0696
`
`Site
`
`Tumor
`
`Table 3: Tumor findings (females)
`
`
`
`
`Pain/vise (treated vs
`Common or
`Incidence
`
`Uncommon
`in
`control)
`
`
`_
`_
`controls
`
`
`Mld
`High
`
`Low
`
`Adrenal
`glands
`
`Skin
`
`Pheochromocytoma
`(benign)
`
`Fibroma
`
`Keratocanthoma and
`
`squamous cell
`tumors
`
`
`
`0.0289
`
`0.6768
`
`0.0381
`
`0.6768
`
`0.3204
`
`0.0963
`
`Pituitary
`(pars
`distalis)
`
`Adenomas and
`carcinomas
`
`Common
`
`72.5%
`
`0.1377
`
`0.1459
`
`0.0398
`
`0.1685
`
`Rat Study Comments
`
`0 Mid-Study Relocation and Applicability of Historical Controls: This study originated
`at the Wyeth facility in Chazy, NY and was relocated during Week 36 to
`W"
`
`Reference ID: 3164961
`
`

`

`NDA # 203341
`
`
`
`
`Reviewer: Shawna L. Weis, PhD
`
` Dose Modifications and Early Termination: Dose reductions, suspensions, and
`terminations were implemented during the dosing phase for males and females in the
`high dose group, as described below:
`o Males: During Week 78, Group 9 Male doses were reduced from 25 to 15
`mg/kg/day; however due to ongoing mortality, dosing was suspended during
`week 79, and the group was terminated during week 86. All remaining male
`groups were terminated during week 91.
`o Females: Dosing was suspended for High Dose females during week 92. All
`females were terminated during Weeks 97-100. Preterminal cessation of dosing
`may have impacted the assessment of non-neoplastic findings in High Dose
`animals due to potential for recovery.
`
`
`
`
`
`TABLE OF CONTENTS
`
`NON NEOPLASTIC ........................................................................................................ 30
`
`Reference ID: 3164961
`
`Appears This Way On Original
`
`

`

`NDA # 203341
`
`Reviewer: Shawna L. Weis, PhD
`
`Study title: BOSUTINIB: TWO YEAR ORAL (GAVAGE)
`
`Study no.:
`
`10-2185 (SPONSOR #09_0837)
`
`Study report location:
`
`(W)
`
`Conducting laboratory and location:
`
`Until Week 36: Wyeth, Chazy, NY
`
`Thereafter:
`
`"M"
`
`Date of study initiation:
`
`16 July 2009
`
`GLP compliance:
`
`QA statement:
`
`Yes
`
`Yes
`
`Drug, lot #, and % purity:
`
`SKI—606 Monohydrate (WAY—173606)
`Batch #MR090034, purity: 97.3%
`
`CAC concurrence:
`
`Yes
`
`Key Study Findings
`
`0 Daily oral (gavage) administration of bosutinib decreased survival, body weight and food
`consumption in males and females at the highest dose level of 25/15 mglkglday for
`males and 15 mglkglday for females.
`
`. There were no increases in tumor incidences related to bosutinib administration. A
`
`complete tabulation of tumors observed in this study is provided in Table 12, whereas a
`tabulation of those observed in animals that survived to scheduled termination is
`
`provided in Table 13.
`
`o The systemic exposures achieved at the high dose level of 25 mglkglday in the male and 15
`mglkglday in the female, represent an approximately 1.4-2.9-fold multiple (AUC024) of the
`therapeutic exposure achieved at a dose of 500 mglday.
`
`0 However, as the high dose of 25l15 or 15 mglkglday in males and females, respectively,
`exceeded the MTD for 2 years of repeated—dosing, exposure at the tolerable dose level of 7.5 or 5
`mglkglday in males and females, respectively, represents an exposure multiple of 0.25-0.52X of
`those achieved clinically at the 500 mglday dose level.
`
`0
`
`This study was relocated during week 36 of the dosing phase. Animals were transferred by truck
`from the Sponsor site in Chazy, NY to
`M". An analysis of the number of
`deaths during the weeks preceding and following the move indicates that, although variable, the
`treatment groups were comparable to control groups in overall mortality rates, and in the
`percentage of decedents that were found to have tumors at termination or death.
`.
`
`Non-Neoplastic Findings.
`
`The target organs in this study were the GI tract (stomach, small and large intestine).
`Summaries of the treatment-related, non-neoplastic findings are provided in Sponsor Text
`Tables 10-12, below. Other histopathological changes attributed to bositinib administration were
`observed in the kidneys of males and females, lymphatic vessel, lymph nodes, and exocrine
`pancreas. These findings were considered non-adverse by the Sponsor’s pathologist.
`
`Reference ID: 3164961
`
`

`

`NDA # 203341
`
`Reviewer: Shawna L. Weis, PhD
`
`e1'ke1'atosis sli_
`
`Incidence of test article related non-neoplastic findings in the forestomach of
`Text Table 10:
`rats dosed with bosutinib for 11: to 2 was
`———
`—II-IIIIIIImI
`—IIIIImmIIIII
`mm
`Illllfllflllllfl
`"“ IIIIIIIIIIII
`l13'pe1'plasia'hype1"ke1atosisHUIIIIIIIIIIIII
`IIIIIIIIIIIIIII
`IIIIIIIIIIIIII
`IIIIIIIIIIIIIII
`I'IIIIIIIIIIII
`
`Inflammation/edema/hemor1'hage
`
`VV: water control. V': vehicle control
`
`Reference ID: 31 64961
`
`

`

`NDA # 203341
`
`Reviewer: Shawna L. Weis, PhD
`
`Incidence of hyaline change in the stomach and small intestine of rats dosed with
`Text Table 11:
`bosutinib for up to 2 years
`———
`—II-IIInImmmnlm
`—mmmmmmammmmm
`—llnnII-nnllnnn
`““WIIIIIIIHIIW
`Duodenum: colla e_n de . osition
`—IIIIIIIIIIIIIIIEI
`mnIIIIIIIflflfln
`—IIIIIIIIIIIIIIII
`—nnnIIa-nnnlaII
`#examined
`58
`59
`59
`58
`57
`57
`59
`58
`
`—IIIIIIIIIIII
`—nnnnInnnnnn
`IIIIIIIHIIIII
`—nnnnnflnnnnnn
`_n
`# examined
`57
`
`59
`
`Ileum: colla _en de n osition
`
`Total Incidencen
`w: water control. v: vehicle control
`
`Incidence of erosions/ulceration/necrosis and mucosal congestion/hemorrhage in
`Text Table 12:
`the small and [an _e intestine of rats dosed with bosutinib for u: to 2 vears
`
`
`
`—III-IIIIniInInInI
`—-Immmmmmmmmm
`I—IIIIIIIIIII
`—IInnnnInnnnn
`—IIIIIIIIIIII
`—nnnnllnnnnnnll
`*Incidence represents the total number of animals with the finding in one or more regions of the small
`and/or large intestine.
`W: water control. v: vehicle control
`
`Reference ID: 31 64961
`
`

`

`NDA # 203341
`
`
`
`
`
`Reviewer: Shawna L. Weis, PhD
`
`Adequacy of Carcinogenicity Study
`Design of this rat carcinogenicity study was based upon feedback from the CAC. The study
`was conducted in accordance with the protocol and provided sufficient histopathological
`assessment of the designated organs and tissues to evaluate both the non-neoplastic and
`neoplastic effects of bosutinib at all dose levels including effects in control animals.
`The MTD was achieved in this study. Decreases in food consumption, absolute body weight
`and body weight gain, relative to pooled vehicle control groups was observed for both males
`and females in the high dose groups. Moreover, a positive dose-related trend (p < 0.001) in
`male mortality (see Sponsor Text Table 3.3-1 was observed in treated groups versus pooled
`vehicle control groups that was not positive when the high dose group was excluded. No such
`trend was evident for females.
`
`Appropriateness of Test Models
`The animal model (Sprague-Dawley rat) is commonly used in carcinogenicity studies to assess
`human tumor risk, and the oral route of administration reflects the intended clinical route.
`
`Evaluation of Tumor Findings
`
`
`Reference ID: 3164961
`
`

`

`NDA # 203341
`
`Reviewer: Shawna L. Weis, PhD
`
`Methods
`
`
`Doses (active moiety):
`
`Males:0 , 0, 0, 2.5, 7.5, 25/153 mg/kg/day
`
`Frequency of dosing:
`
`Dose volume:
`
`Route of administration:
`
`FormulationNehicle:
`
`Basis of dose selection
`
`Species/Strain:
`
`Females: 0, 0, 0, 1.5, 5, 15 mglkg/day
`
`Daily
`
`10 mng
`
`Daily oral gavage (10 mng)
`
`0.5% methylcellulose (4000 cps) (WM, 2.0%
`
`polysorbate 80, NF (w/v), 0.06% glacial acetic acid,
`NF (WM and distilled water
`
`MTD from chronic study
`
`CD0 (Sprague-Dawley derived) [Crl:CD0 (SD) IGS
`BR]
`
`Number/Seleroup:
`
`60/sexlgroup
`
`Age
`
`Animal Housing
`
`~ 7 weeks (Males: 234-289 9; Females: 161-205 g)
`
`1-2 rats/cage in plastic solid bottom cages
`
`Paradigm for dietary restriction
`
`None
`
`Dual control employed
`
`Interim sacrifice
`
`Satellite groups
`
`Yes, 3 control groups: Group 1 = water; Groups 2—3
`= Vehicle
`
`No
`
`TK animals (9/sex in Groups 11-16 + 3/sex in
`Vehicle control Group 10)
`
`Deviation from study protocol
`
`None that significantly impact study interpretation.
`
`Special Features
`
`Study relocated during Week 36
`
`adose reduction for males occurred during week 78; termination of group week 79d
`
`Observations and Results
`
`Clinical signs:
`
`Body weight:
`
`Food consumption
`
`Ophthalmoscopy
`
`Hematology
`
`Clinical chemistry
`
`Urinalysis:
`
`Daily beginning Day -8
`
`Twice pretest, then once weekly through week 13, then
`every 4 weeks thereafter
`
`pretest, then once weekly through week 13, then every 4
`weeks thereafter
`
`Not conducted
`
`Not conducted
`
`Not conducted
`
`Not conducted
`
`Reference ID: 3164961
`
`

`

`NDA # 203341
`
`Gross pathology
`
`Organ weights
`Histopathology:
`
`Toxicokinetics
`
`
`
`
`
`Reviewer: Shawna L. Weis, PhD
`
`Complete macroscopic examinations included the following
`parameters: examination of the external surface and all
`orifices; the external surfaces of the brain and spinal cord;
`the organs and tissues of the cranial, thoracic, abdominal
`and pelvic cavities and neck; and the remainder of the
`carcass for the presence of macroscopic morphologic
`abnormalities.
`Not conducted
`A complete histopathological assessment was performed
`on a comprehensive list of tissues collected from all main
`study animals. All collected tissues were microscopically
`examined.
`Day 182, 6 timepoints/group, 3 animals/timepoint.
`Control groups: 1 timepoint/group; 3 animals/timepoint.
`Samples were collected into tubes containing the
`anticoagulant, dipotassium-EDTA. Samples were collected
`from the jugular vein under CO2/O2 anesthesia. Terminal
`samples were collected from the caudal vena cava or
`abdominal aorta.
`
`Survival:
`There were a large number of preterm deaths on this study, the majority of which were
`attributable to tumors of the pituitary and mammary glands; however, within a sex, there were
`no significant differences between the groups in the number tumors observed (see Sponsor
`Text Table 3.3-2). Kaplan-Meier Survival Curves are provided for Males and Females, in
`Figure 1 and Figure 2, respectively.
`
`
`
`Reference ID: 3164961
`
`
`
`

`

`NDA # 203341
`
`Reviewer: Shawna L. Weis, PhD
`
`Figure 1: Kaplan-Meier Survival Function for Males
`
`—_ Groupi.wnel
`Guangzmd
`“_"—"—"— 5700935011101
`'''''''''''' GroupS 25mgrlg
`Glenn 75mgy‘kg
`Groups 24min
`
` 1oo
`
`
`
`‘5Survival
`
`1Swan!
`
`Group! Wlov
`—————— GroupiConlrol
`"—"—"—"— GroupJComol
`————————————— Groupl 15109ka
`GIoquSmgin
`Groups 15mg“)
`
`Reference ID: 31 64961
`
`

`

`NDA # 203341
`
`Reviewer: Shawna L. Weis, PhD
`
`Disposition:
`
`Tables 4 and 5 summarize the disposition of all males and females, respectively. Although
`timing of unscheduled deaths may have differed between groups, here were no appreciable
`differences between the groups in the overall number of unscheduled deaths (i.e. aggregate of
`humane and moribund sacrifices), suggesting that factors other than bosutinib toxicity were
`responsible for some preterm deaths.
`It is unclear whether the number of preterm deaths
`observed in Groups 1-3 (water and vehicle controls), exceed historical controls for the Wyeth
`and Huntingdon facilities.
`
`Table 4 Disposition (Males)
`
`Dose (mg/kglday)
`
`Scheduled
`Euthanasia
`
`Found Dead
`
`Unscheduled
`
`—\
`
`a:
`
`—L
`
`NN01
`
`N
`
`25/15
`
`Mortality
`
`l:—i
`
`Cause of Death
`
`A
`
`II—|.
`
`Accidental —2°
`
`Undetermined
`
`—i
`
`A
`
`water
`
`"vehicle (0.5% methylcellulose (4000 cps) (w/v), 2.0% polysorbate 80, NF (w/v), 0.06% glacial
`acetic acid, NF (WM and distilled water)
`
`1‘Humane + Moribund euthanasia
`
`Table 5 Disposition (Females)
`
`—WWWWW_
`
`
`
`Scheduled
`Euthanasia
`
`20
`
`20
`
`17
`
`——
`—_—_—--I-
`Unscheduled
`
`Cause of Death
`
`—- n—un
`—-
`----
`water
`
`--
`
`"vehicle (0.5% methylcellulose (4000 cps) (w/v), 2.0% polysorbate 80, NF (w/v), 0.06% glacial
`
`Reference ID: 3164961
`
`

`

`NDA # 203341
`
`Reviewer: Shawna L. Weis, PhD
`
`
`
`acetic acid, NF (WM and distilled water)
`
`"Humane + Moribund euthanasia
`
`Effect of Study Relocation on Primary Endpoints:
`
`Relocation of this study occurred during week 36 of the dosing phase. Animals were
`transported by truck from the Sponsor site in Chazy, NY to the
`
`“m.
`
`Morality rates were highly variable between groups, however, the percentage decedents in
`treatment groups was generally comparable to those of concurrent control groups (both water
`and vehicle). Moreover, among the preterm decedents that succumbed in the interval before
`and immediately following the move, there was no relationship between dose level and tumor
`status at death or termination (Table 6).
`
`Table 6: Move Impact on Mortality
`
`
`
`Date of Death
`
`239
`
`258
`
`260
`
`266
`
`268
`
`270
`
`Animal
`
`Number
`
`720
`
`141
`
`470
`
`566
`
`83
`
`38
`
`
`
`
`
`Disposition
`
`AD
`
`FD
`
`FD
`
`AD
`
`HE
`
`AD
`
`
`
`Tumor
`
`N
`
`N
`
`N
`
`N
`
`Y
`
`N
`
`
`
`AD: accidental death; FD: found dead; HE: humane euthanasia
`
`Treatment group
`
`9
`
`2
`
`5
`
`7
`
`1
`
`1
`
`In addition, in the week immediately following the move, the group mean body weight loss in
`treatment groups were comparable to those of controls over the interval immediately following
`the move (Table 7). Animals in treated and control groups lost between 1.0-1.7% of body
`weight following the move, compared to Week 36 baseline measurement. Similarly, over the 4-
`week period preceding and following the move, there was no net decrement in body weight gain
`across treatment groups (Table 7).
`
`Table 7: Move Impact on Animal Body Weights
`
`
`Group
`Dose (mglkglday)
`
`tallVHI INN u:c
`
`-m8
`
`48.6
`
`33
`
`onw7‘V
`
`36 - before
`
`854.
`
`A
`
`E_oN
`
`Male
`
`Female
`
`%A
`
`wN
`
`%A*
`
`000)
`
`36 - before
`
`858
`--
`mm
`mm
`473.7
`471.4
`--
`
`
`
` A
`
`ontoF"V
`
`m3O)
`
`Eo A
`L a;.
`851.8
`
`NN
`
`‘1 0)
`
`Reference ID: 3164961
`
`

`

`NDA # 203341
`
`Reviewer: Shawna L. Weis, PhD
`
`36 - after
`469.1
`466.3
`460.8
`477.6
`*
`467.5
`*
`456.0
`*
`
`
`"/oA
`-1 .0
`-1 .1
`-1 .1
`-1 .0
`*
`-1 .0
`*
`-1 .0
`*
`
`
`37
`472.1
`468.7
`464.5
`481 .6
`*
`473.1
`*
`459.4
`*
`
`
`
`
`
`
`
`
`
`
`3.1 * 3.2 * 2.62.81.62.6%A* *
`
`
`
`
`
`
`
`
`
`
`
`* = Overall % gain relative to baseline measurement on Week 33
`
`Clinical Signs
`
`Clinical signs:
`
`Clinical signs exhibiting an apparent treatment-relationship, as evaluated by increased
`incidence in treated males and/or females relative to concurrent controls, include: red pigment
`around eyes, oral/nasal salivation, alopecia, hunched posture, thin appearance, pale
`appearance, ptosis, swollen limbs, anogenital staining, decreased food consumption, and
`decreased fecal volume.
`
`Treatment Distribution of Tumors:
`
`The frequency of tumors was generally greater in females than males irrespective dose,
`however within genders, there was no dose—related increase in the frequency of tumors
`observed. When the frequency of tumors is evaluated by mode of disposition (found dead,
`unscheduled euthanasia or terminal sacrifice), no increase in the percentage of tumors was
`observed with dose. Indeed, among early decedents, there was a decrease in the frequency of
`tumors observed at the highest dose level (particularly in males), which suggests that animals at
`the high dose levels succumbed prior to tumor formation (see Figure 1 and Figure 2, Kaplan-
`Meier plots).
`
`Table 8: Distribution of Tumors (total) by Treatment Group
`
`Males
`
`_—__ 9
`o.............,,
`0 ———
`N (# animals with Masses
`24 u 22
`17 u 15
`% mass incidence per
`40%
`30%
`37%
`28%
`25%
`25%
`group
`(24/60)
`(18/60)
`(22/60)
`(17/60)
`(15/60)
`(15/60)
`
`FEMALE
`
`_‘--i 8
`o..........,...,
`0 "mi- 15
`N (# animals with Masses
`43
`45
`41 u 20
`% mass incidence per
`72%
`75%
`68%
`67%
`33%
`group
`(43/60)
`(45/60)
`(41/60)
`(40/60)
`(20/60)
`
`72%
`(43/60)
`
`Table 9: Percentage of Tumors by Mode of Disposition
`
`Disposition (Male)
`
`——‘-—_—
`
`Reference ID: 3164961
`
`
`
`
`
`
`
`

`

`
`
`NDA # 203341
`
`Reviewer: Shawna L. Weis, PhD
`
`Dose (mg/kglday)
`
`0
`
`0
`
`0
`
`2.5
`
`7.5
`
`25/1 5
`
`525%)
`_ 525%)
`_————— 22552%>
`_ 555555%>
`5552525%5
`Ts
`9/21 (43%)
`7/15(50%)
`
`9/26(35%)
`
`Disposition (Female)
`
`Dose (mg/kglday)
`
`0/1
`
`1l1 (100%)
`
`4/8 (50%)
`
`7/12 (58%)
`
`8/12 (67%)
`
`-— 8
`— 55
`_ 1/2(50%)
`5l12(42%)
`
`7/11(%)
`
`8/29 (28%)
`
`6/17 (35%)
`
`21/32 (66%)
`
`22/31(71%)
`
`20l27 (74% 20l30 (67%)
`
`TS
`
`18/20 (90%)
`
`
`
`14l16 (87% 16/20 (80% 14l19 (74%)V
`
`V V
`
`FD = Found Dead; UE = Unscheduled Euthanasia (i.e. moribund euthanasia + humane euthanasia); TS =
`Terminal Sacrifice
`
`Body Weights
`
`Mean body weight: Statistically significant differences in mean body weights were observed in
`Group 6 animals versus controls, which began during week 6 in males and week 53 in females.
`There was no decrease in absolute baseline adjusted body weight during the dosing interval for
`either sex.
`
`Figure 3: Group Mean Male Body Weights
`
` Mean Body Weights
`
`Fiaure 1
`
`(alums)
`
`
`—o—omup1 . a 0 lug 'kpfiy (was. ('onhol)
`
`
`—I— Group 2 ~ 0 0 mg 'kgy'day Il'ehicle (outmf)
`
`
`2 0.0 mg'kg (13v (Vehicle Comm!)
`
`'
`. 2.5 mph; 6:"
`
`+Gxoup7 2 7.5 mg‘kg'day
`(k ‘dnv
`525.0110
`mg E2
`_
`
`Study Relocation
`
`
`PREl DOS I
`3
`5
`7
`9
`ll
`13
`21
`29
`368
`37
`45
`53
`61
`69
`77
`85
`\"eel:
`
`
`
`
`IIOO
`
`1000
`
`900
`
`800
`
`700
`
`600
`
`500
`
`400
`
`300
`
`200
`
`
`
`
`
`Bml)\Vuiglll(mum)
`
`Reference ID: 3164961
`
`

`

`NDA # 203341
`
`Reviewer: Shawna L. Weis, PhD
`
`Figure 4: Group Mean Female Body Weights
`
`
`
`Mean Body Weights
`(grams)
`
`Females
`
`, 0.0 mg'kgidly «Wane: Common
`— 0 0 mgkg‘flny ("elude Control)
`- o 0 mg 11mm (Vehicle Control)
`— I t mzrkzmny
`- 5 0 mszfllny
`. l 5.0 mg’kgmhy
`
`Body
`
`“ciglllimmsi
`
`PRE 1 D051
`
`3
`
`5
`
`7
`
`9
`
`11
`
`IS
`
`21
`
`36:
`
`29
`\Veol;
`
`37
`
`45
`
`53
`
`61
`
`69
`
`77
`
`85
`
`93
`
`Feed Consumption
`
`A statistically significant reduction in food consumption was observed for male and female
`animals in the highest dose groups.
`
`Figure 5: Male Group Mean Food Consumption
`
`Group Mean Food Consumption (Males)
`
`Weeks
`
`—o—Grotp 1 (Wder)
`+Groq) 2 (Vehicle)
`+6”? 3 (Vehicle)
`+6pr 5 (2—5 M9)
`4—er 7 (7-5 mike)
`+Group 9 (25(15mglkg)
`
`12 3 4 5 6 7 8 9101112131822263)3438424650545862667074788286m§4
`
`Reference ID: 3164961
`
`

`

`NDA # 203341
`
`Reviewer: Shawna L. Weis, PhD
`
`Figure 6: Female Group Mean Food Consumption
`
`Group Mean Food Consumption (Female)
`
`,‘_‘,
`. _ 774
`“.2 ;, 4’s"
`
`VA"-
`
`.v
`
`_._Gmup1(waer)
`—I— Group 2 (Velicle)
`+ Gimp 3 (Velicle)
`—x— Gimp 4 (1.25 mglkg)
`—I— Group 6 (5 mglkg)
`—o— Group 8 (15 mglkg)
`
`Weeks
`
`-
`
`5.00
`
`Study Relocation
`
`O
`O
`Q
`Q
`0
`3° .59 59 «S? 99° <59 ¢9° {19°49 (89 .99 Q53) 6190 «99° 459° #90 ¢§®¢9
`
`Ophthalmology:
`
`There were no treatment-related effects on ophthalmological endpoints in this study.
`
`Hematology:
`
`Hematology was not conducted
`
`Overall, the predominant cause of death for all dose groups was pituitary and mammary tumors;
`however, there were no differences between treatment groups in the assigned causes of death
`among animals that died or were euthanized for humane reasons prior to scheduled
`termination.
`
`
`Table 10: Probable Cause of Death Among Preterm Decedents (All Groups):
`
`FEMALES
`MALES
`
`
`
`Dose (mglkglday)
`
`# Examined
`
`
`Brain Tumor
`
`Pituitary Tumor
`
`
`Mammary Gland Tumor
`
`Undetermined
`
`
`Lymphoreticular Tumor
`
`Skin Tumor
`
`Reference ID: 3164961
`
`

`

`NDA # 203341
`
`Reviewer: Shawna L. Weis, PhD
`
`Adrenal Tumor
`
`Pancreatic Tumor
`
`Ovarian Tumor
`
`Uterine Tumor
`
`Intestinal Tumor
`
`Vascular Tumor
`
`
`
`
`
`
`
`Nerve Sheath Tumor (Schwannoma)
`
`Severe Skin Lesions/Pododermatitis
`
`
`
`nannannnnnnnalannmamA
`
`nanmnannaaaaaaaaaaaaaonanmnaanaamaaaaaaaaaaA
`IIIIIIIHIIHIIHHIIIHIIIaanaannannannnaalnaanaoIaaaaaaaannnaaanlmm:oIaaaaaaaaaaaaaaanaaanaoHflflflflflflflflflflflflflfllfllflflflfl°
`ananaanaanaaaaaaanaanaounannnannannnaaaamm:o
`HflflflflflflflflflflflflflflfllfllflflflI-Eflflflflflflflflllflflllflflflflfl°
`
`Severe Nephropathy /Renal Injury
`
`Urogenital Infection
`
`Liver Necrosis
`
`Gastrointestinal Lesions
`
`
`
`
`
`
`
`
`(ArteritisIPeriarteritis)
`
`Accidental (Gavage Related)
`
`Reference ID: 3164961
`
`

`

`NDA # 203341
`
`
`
`
`
`Reviewer: Shawna L. Weis, PhD
`
`Reference ID: 3164961
`
`Appears This Way On Original
`
`

`

`NDA # 203341
`
`Reviewer: Shawna L. Weis, PhD
`
`Gross Pathology
`
`There were few gross findings associated with bosutinib treatment. Most treatment-related
`gross observations (Table 11) occurred in the organs of the GI tract, but were not considered a
`cause of death in the animals, as reflected in Table 10 above.
`
`Table 11: Gross Necropsy Observations (all animals)
`
`MALES
`
`Dose (mg/kglday) nnnfi- 25/15
`ddnndeennned mammals:
`Cecum
`
`
`
`FEMALES
`
`lfifllfl
`IWI
`
`con
`
`Df5°°'°’e°' nnnflll-lflllnflfl
`CD:S‘e"de°'
`nun-IEIIIIIIIIIIII
`Distended
`IIIIl-flflflnfll
`DN°:"'9 “Ii-I-m
`Distended
`nnnflnilflfllfllfll
`Abnormal Contents nnnnn-flinnin
`Mass
`"Hanan-i...-
`Extremity
`
`uo enum
`
`SW°"e"
`General Comments
`
`nunnflflnnnnnn
`
`Gut Lymph Tissue
`
`nun-“Innuma
`
`mm III-I-IEIIIIIIIIII
`ea
`
`Ei'eidei
`
`eum
`
`nnnnn-IIIIIIIIIIII
`nnnnnilnnnllnn
`nnnnnnII-IIIIIIII
`
`Hanan-nun
`II
`Aimnninieniiidnen flflflflII-Iilfl
`II
`III-I-Iilll
`
`H
`
`Jejunum
`
`nunIIII-nn
`dinindnnnidndne unnnII-nn
`
`II
`II
`
`
`
`Reference ID: 3164961
`
`

`

`NDA # 203341
`
`Reviewer: Shawna L. Weis, PhD
`
`Diverticulum
`Kidneys
`
`I.— *
`
`*
`
`* nun 0
`
`1
`
`0
`
`Dilated Pelvis “an
`El
`Discolored nun
`Mesenteric LN
`
`Discolored
`Enlarged
`““5
`
`“n
`II