CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`202324Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`MEMORANDUM
`
`
`INLYTA (axitinib)
`
`Date: January 23, 2012
`To:
`File for NDA 202324
`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 Drs. Goheer, Putman
`and Aziz and labeling and secondary memorandum provided by Dr. Palmby. I concur
`with Dr Palmby’s conclusion that INLYTA may be approved and that no additional
`nonclinical studies are needed for the proposed indication.
`
`Reference ID: 3075644
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`01/23/2012
`
`Reference ID: 3075644
`
`

`

`
`
`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number: NDA 202324
`Supporting document/s: 1
`Applicant’s letter date: April 13, 2011
`CDER stamp date: April 14, 2011
`Product:
`INLYTA (axitinib)
`Indication: Advanced renal cell carcinoma (RCC) after
`failure of one prior systemic therapy
`Applicant: Pfizer Inc
`10646 Science Center Drive
`San Diego
`CA 92121
`Review Division: Division of Hematology Oncology Toxicology
`(Division of Oncology Products 1)
`Reviewer: M. Anwar Goheer, Ph.D.
`Alexander H. Putman, Ph.D.
`Robeena Aziz, MPH, Ph.D.
`Acting Supervisor/Team Leader: Todd Palmby, Ph.D.
`Division Director: John Leighton, Ph.D.
`(Robert Justice, M.D., M.S.)
`Project Manager: Lisa Skarupa
`
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and necessary for
`approval of NDA 202-324 are owned by Pfizer or are data for which Pfizer has obtained a
`written right of reference.
`Any information or data necessary for approval of NDA 202-324 that Pfizer does not own or
`have a written right to reference constitutes one of the following: (1) published literature, or (2) a
`prior FDA finding of safety or effectiveness for a listed drug, as described in the drug’s approved
`labeling. Any data or information described or referenced below from a previously approved
`application that Pfizer does not own (or from FDA reviews or summaries of a previously
`approved application) is for descriptive purposes only and is not relied upon for approval of NDA
`202-324.
`
`Reference ID: 3075631
`
`1
`
`

`

`
`
`
`Anwar Goheer, Ph.D.
`
`NDA # 202-324
`
`
`1.1.3 Labeling Review
`
`
`All pertinent information from nonclinical studies conducted with axitinib that is
`included in the package insert can be found in the original Pharmacology/Toxicology
`review for NDA 202324. This labeling review includes calculations of exposure (AUC)
`ratios in animals as compared to humans at the recommended starting dose of 5 mg
`orally twice daily. The following sections of the package insert for axitinib were modified
`from the version proposed by the Applicant with input from the
`Pharmacology/Toxicology team and represent the FDA recommendations:
`
`Under HIGHLIGHTS OF PRESCRIBING INFORMATION:
`------------------------INDICATIONS AND USAGE-------------------------
`INLYTA is a kinase inhibitor indicated for the treatment of advanced renal cell
`carcinoma after failure of one prior systemic therapy. (1)
`---------------------WARNINGS AND PRECAUTIONS--------------------
`•
`INLYTA can cause fetal harm when administered to a pregnant woman based on its
`mechanism of action. Women of childbearing potential should be advised of the
`potential hazard to the fetus and to avoid becoming pregnant while receiving
`INLYTA. (5.12, 8.1)
`
`
`
`Reference ID: 3075631
`
`2
`
`

`

`
`NDA # 202-324
`
`
`Under FULL PRESCRIBING INFORMATION:
`Recommended Labeling
`5
`WARNINGS AND PRECAUTIONS
`
`Anwar Goheer, Ph.D.
`
`Comments/Justification
`
`
`5.12 Pregnancy
`
`INLYTA can cause fetal harm when
`administered to a pregnant woman based
`on its mechanism of action. There are no
`adequate and well-controlled studies in
`pregnant women using INLYTA. In
`developmental toxicity studies in mice,
`axitinib was teratogenic, embryotoxic and
`fetotoxic at maternal exposures that were
`lower than human exposures at the
`recommended clinical dose.
`Women of childbearing potential should be
`advised to avoid becoming pregnant while
`receiving INLYTA. If this drug is used during
`pregnancy, or if a patient becomes pregnant
`while receiving this drug, the patient should
`be apprised of the potential hazard to the
`fetus [see Use in Specific Populations (8.1)].
`8
`USE IN SPECIFIC POPULATIONS
`
`8.1
`
`Pregnancy
`
`Pregnancy Category D [see Warnings and
`Precautions (5.12)].
`
`There are no adequate and well-controlled
`studies with INLYTA in pregnant women.
`INLYTA can cause fetal harm when
`administered to a pregnant woman based
`on its mechanism of action. Axitinib was
`teratogenic, embryotoxic and fetotoxic in
`mice at exposures lower than human
`exposures at the recommended starting
`dose. If this drug is used during pregnancy,
`or if the patient becomes pregnant while
`receiving this drug, the patient should be
`apprised of the potential hazard to the fetus.
`Oral axitinib administered twice daily to
`female mice prior to mating and through the
`first week of pregnancy caused an increase
`in post-implantation loss at all doses tested
`
`Reference ID: 3075631
`
`3
`
`In the fertility and early embryonic
`development study (#06GR118), the
`AUC0-24 in female mice at 15 mg/kg/dose
`oral axitinib twice daily was 2850
`ng*hr/mL, which is approximately 10
`times the AUC in humans at the
`recommended starting dose of 265
`ng*hr/mL. In the embryo-fetal
`developmental toxicity study
`(#06GR117), female mice receiving 1.5
`mg/kg/dose twice daily had an AUC0-24 of
`142 ng*hr/mL, which is approximately 0.5
`times the human AUC of 265 ng*hr/mL.
`Mice in this study had an AUC0-24 of 39.5
`ng*hr/mL at a dose of 0.5 mg/kg/dose
`twice daily, which is approximately 0.15
`times the human AUC of 265 ng*hr/mL.
`
`

`

`
`NDA # 202-324
`
`
`(≥ 15 mg/kg/dose, approximately 10 times
`the systemic exposure (AUC) in patients at
`the recommended starting dose). In an
`embryo-fetal developmental toxicity study,
`pregnant mice received oral doses of 0.15,
`0.5 and 1.5 mg/kg/dose axitinib twice daily
`during the period of organogenesis.
`Embryo-fetal toxicities observed in the
`absence of maternal toxicity included
`malformation (cleft palate) at 1.5 mg/kg/dose
`(approximately 0.5 times the AUC in patients
`at the recommended starting dose) and
`variation in skeletal ossification at ≥ 0.5
`mg/kg/dose (approximately 0.15 times the
`AUC in patients at the recommended
`starting dose).
`
`8.3 Nursing Mothers
`It is not known whether axitinib is excreted
`in human milk. Because many drugs are
`excreted in human milk and because of the
`potential for serious adverse reactions in
`nursing infants from INLYTA, a decision
`should be made whether to discontinue
`nursing or to discontinue the drug, taking
`into account the importance of the drug to
`the mother.
`
`8.4
`
`Pediatric Use
`
`The safety and efficacy of INLYTA in
`pediatric patients have not been studied.
`Toxicities in bone and teeth were observed
`in immature mice and dogs administered
`oral axitinib twice daily for 1 month or longer.
`Effects in bone consisted of thickened
`growth plates in mice and dogs at ≥15
`mg/kg/dose (approximately 6 and 15 times,
`respectively, the systemic exposure (AUC)
`in patients at the recommended starting
`dose). Abnormalities in growing incisor
`teeth (including dental caries, malocclusions
`and broken and/or missing teeth) were
`observed in mice administered oral axitinib
`twice daily at ≥ 5 mg/kg/dose (approximately
`1.5 times the AUC in patients at the
`
`Reference ID: 3075631
`
`4
`
`Anwar Goheer, Ph.D.
`
`
`
`In the 28-day repeat-dose toxicology
`study in mice (#6750-
`145) the mean AUC0-24 at the dose of 15
`mg/kg/dose oral axitinib twice daily was
`1600 ng*hr/mL, which is approximately 6
`times the AUC in humans at the
`recommended starting dose of 265
`ng*hr/mL. In the 28-day repeat-dose
`toxicology study in dogs (#6750-
`143) the mean AUC0-24 at the dose of 15
`mg/kg/dose twice daily was 4150
`ng*hr/mL, which is approximately 15
`times the AUC in humans at the
`recommended starting dose of 265
`ng*hr/mL. In the 28-day repeat-dose
`toxicology study in mice (#6750-145) the
`mean AUC0-24 at the dose of 5
`mg/kg/dose twice daily was 370
`ng*hr/mL, which is approximately 1.5
`
`

`

`NDA # 202-324
`
`recommended starting dose). Other
`toxicities of potential concern to pediatric
`patients have not been evaluated in juvenile
`animals.
`
`
`
`
`11
`
`DESCRIPTION
`
`INLYTA (axitinib) is a kinase inhibitor.
`Axitinib has the chemical name N-methyl-
`2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-
`6-ylsulfanyl]-benzamide. The molecular
`formula is C22H18N4OS and the molecular
`weight is 386.47 Daltons. The chemical
`structure is:
`
`
`
`
`
`Axitinib is a white to light-yellow powder with
`a pKa of 4.8. The solubility of axitinib in
`aqueous media over the range pH 1.1 to pH
`7.8 is in excess of 0.2 μg/mL. The partition
`coefficient (n-octanol/water) is 3.5.
`INLYTA is supplied as red, film-coated
`tablets containing either 1 mg or 5 mg of
`axitinib together with microcrystalline
`cellulose, lactose monohydrate,
`croscarmellose sodium, magnesium
`stearate, and Opadry II red 32K15441 as
`inactive ingredients. The Opadry II red
`32K15441 film coating contains lactose
`monohydrate, HPMC 2910/Hypromellose
`15cP, titanium dioxide, triacetin (glycerol
`triacetate), and red iron oxide.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`Reference ID: 3075631
`
`5
`
`Anwar Goheer, Ph.D.
`times the AUC in humans at the
`recommended starting dose of 265
`ng*hr/mL.
`
`
`
`
`
`

`

`NDA # 202-324
`
`
`
`
`
`Anwar Goheer, Ph.D.
`
`12.1 Mechanism of Action
`Axitinib has been shown to inhibit receptor
`tyrosine kinases including vascular
`endothelial growth factor receptors
`(VEGFR)-1, VEGFR-2, and VEGFR-3 at
`therapeutic plasma concentrations. These
`receptors are implicated in pathologic
`angiogenesis, tumor growth, and cancer
`progression. VEGF-mediated endothelial
`cell proliferation and survival were inhibited
`by axitinib in vitro and in mouse models.
`Axitinib was shown to inhibit tumor growth
`and phosphorylation of VEGFR-2 in tumor
`xenograft mouse models.
`
`Reference ID: 3075631
`
`6
`
`

`

`NDA # 202-324
`
`
`
`
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis,
`Impairment of Fertility
`
`Carcinogenicity studies have not been
`conducted with axitinib.
`
`Axitinib was not mutagenic in an in vitro
`bacterial reverse mutation (Ames) assay
`and was not clastogenic in the in vitro
`human lymphocyte chromosome aberration
`assay. Axitinib was genotoxic in the in vivo
`mouse bone marrow micronucleus assay.
`
`INLYTA has the potential to impair
`reproductive function and fertility in humans.
`In repeat-dose toxicology studies, findings in
`the male reproductive tract were observed in
`the testes/epididymis (decreased organ
`weight, atrophy or degeneration, decreased
`numbers of germinal cells, hypospermia or
`abnormal sperm forms, reduced sperm
`density and count) at ≥15 mg/kg/dose
`administered orally twice daily in mice
`(approximately 7 times the systemic
`exposure (AUC) in patients at the
`recommended starting dose) and ≥ 1.5
`mg/kg/dose administered orally twice daily in
`dogs (approximately 0.1 times the AUC in
`patients at the recommended starting dose).
`Findings in the female reproductive tract in
`mice and dogs included signs of delayed
`sexual maturity, reduced or absent corpora
`lutea, decreased uterine weights and uterine
`atrophy at ≥ 5 mg/kg/dose (approximately
`1.5 or 0.3 times the AUC in patients at the
`recommended starting dose compared to
`mice and dogs, respectively).
`In a fertility study in mice, axitinib did not
`affect mating or fertility rate when
`administered orally twice daily to males at
`any dose tested up to 50 mg/kg/dose
`following at least 70 days of administration
`
`Anwar Goheer, Ph.D.
`Axitinib was reported as genotoxic in the
`in vivo mouse bone marrow
`micronucleus assay rather than
`clastogenic, because results indicated an
`aneugenic mechanism lead to the
`increase in micronucleated
`polychromatic erythrocytes.
`
`In the 26-week repeat-dose toxicology
`study in mice (#6750-148) and dogs
`(#6750-150), effects on the testes and
`epididymis were observed in males at
`≥15 mg/kg/dose and ≥1.5 mg/kg/dose,
`respectively, oral axitinib twice daily.
`The AUC0-24 in males at 15 mg/kg/dose
`twice daily was 1885 ng*hr/mL in mice
`and at 1.5 mg/kg/dose twice daily was
`12.3 ng*hr/mL in dogs, which is
`approximately 7 and 0.1 times,
`respectively, the AUC in humans at the
`recommended starting dose of 265
`ng*hr/mL.
`
`Findings in the female reproductive tract
`were observed at ≥5 mg/kg/dose twice
`daily in mice and dogs. In the 26-week
`repeat-dose toxicology study in mice
`(#6750-148), the AUC0-24 was 457.04
`ng*hr/mL in females at 5 mg/kg/dose
`twice daily, which is approximately 1.5
`times the AUC in humans (265 ng*hr/mL)
`at the recommended starting dose. In
`the 28-day repeat dose toxicology study
`in dogs (#6750-143), the AUC0-24 was 70
`ng*hr/mL in females at 5 mg/kg/dose
`twice daily, which is approximately 0.3
`times the AUC in humans (265 ng*hr/mL)
`at the recommended starting dose.
`
`In the fertility and early embryonic
`development study in mice (#06GR118),
`the AUC0-24 in males at 50 mg/kg/dose
`twice daily, the highest dose tested, was
`15200 ng*hr/mL, which is approximately
`57 times the AUC (265 ng*hr/mL) in
`humans at the recommended starting
`
`Reference ID: 3075631
`
`7
`
`

`

`
`NDA # 202-324
`
`
`(approximately 57 times the AUC in patients
`at the recommended starting dose). In
`female mice, reduced fertility and embryonic
`viability were observed at all doses tested (≥
`15 mg/kg/dose administered orally twice
`daily) following at least 15 days of treatment
`with axitinib (approximately 10 times the
`AUC in patients at the recommended
`starting dose).
`
`
`Anwar Goheer, Ph.D.
`dose. The AUC0-24 in females at 15
`mg/kg/dose twice daily in this study was
`2850 ng*hr/mL, which is approximately
`10 times the AUC (265 ng*hr/mL) in
`humans at the recommended starting
`dose.
`
`
`Reference ID: 3075631
`
`8
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`M A GOHEER
`01/23/2012
`
`TODD R PALMBY
`01/23/2012
`
`Reference ID: 3075631
`
`

`

`MEMORANDUM
`
`
`Date:
`From:
`
`January 6, 2012
`Todd R. Palmby, Ph.D.
`Acting Supervisory Pharmacologist
`Division of Hematology, Oncology Toxicology
`
`To:
`File for NDA 202324 axitinib
`
`Re:
`Approvability for Pharmacology and Toxicology
`Indication: Treatment of patients with advanced renal cell carcinoma after
`failure of one prior systemic therapy
`
`
`Non-clinical pharmacology and toxicology studies to support axitinib NDA 202324
`for the treatment of renal cell carcinoma after failure of one prior systemic
`therapy were reviewed by Anwar Goheer, Ph.D, Alexander H. Putman, Ph.D.,
`and Robeena Aziz, MPH, Ph.D. Information included studies conducted with
`orally administered axitinib investigating the drug’s pharmacology, toxicokinetics
`and ADME, safety pharmacology, general toxicology (mouse and dog), and
`genetic toxicity (in vivo and in vitro). Reproductive and developmental toxicology
`studies were conducted in mice to assess the effects of axitinib on fertility and
`embryo-fetal development. The studies cited in the review consist primarily of
`original research studies conducted by the applicant.
`
`Pharmacology studies submitted to the NDA support that axitinib is a kinase
`inhibitor which binds to and inhibits the activity of multiple receptor tyrosine
`kinases including vascular endothelial growth factor receptor (VEGFR)-1,
`VEGFR-2 and VEGFR-3.
`
`The most common adverse reactions observed with axitinib in patients (≥ 20%
`according to Highlights section of the label) were diarrhea, hypertension, fatigue,
`decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia
`(hand-foot) syndrome, weight decrease, vomiting, asthenia, and constipation.
`Safety pharmacology studies conducted with axitinib in mice, rats and dogs
`identified the potential for increased systolic blood pressure and decreased heart
`rate. In repeat-dose studies, toxicities in bone and teeth, spleen and thymus (in
`mice), and elevated cholesterol and triglycerides (in dogs) were not observed
`clinically, but may be relevant to patient risk under certain circumstances.
`Toxicities were observed throughout the gastrointestinal tract in mice and dogs.
`
`Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay
`and was not clastogenic in the in vitro human lymphocyte chromosome
`aberration assay. However, axitinib was genotoxic in the in vivo mouse bone
`marrow micronucleus assay. Kinetochore staining results from the in vivo
`micronucleus assay indicated that the increases in micronucleated polychromatic
`erythrocytes were due to an aneugenic mechanism.
`
`
`Reference ID: 3068538
`
`

`

`Axitinib may impair reproductive function and fertility in males and females. In
`repeat-dose toxicology studies in mice and dogs, findings in the male
`reproductive tract were observed in the testes/epididymis at exposures
`approximately equivalent to and lower than patient exposure, respectively.
`Findings in the female reproductive tract in mice and dogs included signs of
`delayed sexual maturity, reduced or absent corpora lutea, decreased uterine
`weights and uterine atrophy at exposures approximately equivalent to exposure
`in patients.
`
`In a fertility study in mice, axitinib did not affect mating or fertility rate when
`administered to males at any dose tested. Reduced fertility and embryonic
`viability were observed in female mice at all doses tested. Doses in this study
`resulted in systemic exposures greater than exposures in patients.
`
`Axitinib is embryotoxic, fetotoxic, and teratogenic to mice, at exposures lower
`than human exposures at the recommended human starting dose. During a
`fertility and early embryonic development study, axitinib administered to female
`mice prior to mating and through the first week of pregnancy caused an increase
`in post-implantation loss. In an embryo-fetal developmental toxicity study,
`pregnant mice received oral axitinib twice daily during the period of
`organogenesis. Embryo-fetal toxicities observed in the absence of maternal
`toxicity included malformations (cleft palate) and variations in skeletal ossification
`(interfrontal ossification sites, incomplete ossification of the supraoccipitals). A
`no effect level for adverse embryo-fetal effects was not identified in this study.
`The potential benefit of axitinib in pregnant women in this patient population may
`outweigh the potential risk to the developing fetus. Therefore, Pregnancy
`Category D is recommended for the use of axitinib in this patient population.
`
`Recommendations: I concur with Drs. Goheer’s, Putman’s and Aziz’s
`conclusion that pharmacology and toxicology data support the approval of NDA
`202324 for axitinib. There are no outstanding nonclinical issues that would
`preclude the approval of axitinib for the proposed indication.
`
`Reference ID: 3068538
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TODD R PALMBY
`01/06/2012
`
`Reference ID: 3068538
`
`

`

`
`
`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number: NDA 202324
`Supporting document/s: 1
`Applicant’s letter date: April 13, 2011
`CDER stamp date: April 14, 2011
`Product:
`INLYTA (axitinib)
`Indication: Advanced renal cell carcinoma (RCC) after
`failure of one prior systemic therapy
`Applicant: Pfizer Inc
`10646 Science Center Drive
`San Diego
`CA 92121
`Review Division: Division of Hematology Oncology Toxicology
`(Division of Oncology Products 1)
`Reviewer: M. Anwar Goheer, Ph.D.
`Alexander H. Putman, Ph.D.
`Robeena Aziz, MPH, Ph.D.
`Acting Supervisor/Team Leader: Todd Palmby, Ph.D.
`Division Director: John Leighton, Ph.D.
`(Robert Justice, M.D., M.S.)
`Project Manager: Lisa Skarupa
`
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 202-324 are owned by Pfizer or are data for which Pfizer
`has obtained a written right of reference.
`Any information or data necessary for approval of NDA 202-324 that Pfizer does not
`own or have a written right to reference constitutes one of the following: (1) published
`literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug, as
`described in the drug’s approved labeling. Any data or information described or
`referenced below from a previously approved application that Pfizer does not own (or
`from FDA reviews or summaries of a previously approved application) is for descriptive
`purposes only and is not relied upon for approval of NDA 202-324.
`
`Reference ID: 3068534
`
`1
`
`

`

`NDA # 202-324
`
`
`
`Anwar Goheer, Ph.D.
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 4
`1.1
`INTRODUCTION.................................................................................................... 4
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 4
`1.3 RECOMMENDATIONS............................................................................................ 6
`2 DRUG INFORMATION ............................................................................................ 6
`2.1 DRUG................................................................................................................. 6
`2.2 RELEVANT IND/S, NDA/S, AND DMF/S ................................................................. 7
`2.3 DRUG FORMULATION ........................................................................................... 7
`2.4 COMMENTS ON NOVEL EXCIPIENTS....................................................................... 7
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ......................................... 7
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ...................................... 8
`2.7 REGULATORY BACKGROUND ................................................................................ 8
`3 STUDIES SUBMITTED............................................................................................ 8
`3.1
`STUDIES REVIEWED............................................................................................. 8
`STUDIES NOT REVIEWED ................................................................................... 11
`3.2
`3.3
`PREVIOUS REVIEWS REFERENCED...................................................................... 14
`4 PHARMACOLOGY................................................................................................ 15
`4.1
`PRIMARY PHARMACOLOGY................................................................................. 15
`4.2
`SECONDARY PHARMACOLOGY............................................................................ 45
`SAFETY PHARMACOLOGY................................................................................... 48
`4.3
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 64
`
`6 GENERAL TOXICOLOGY..................................................................................... 65
`6.1
`SINGLE-DOSE TOXICITY..................................................................................... 65
`6.2 REPEAT-DOSE TOXICITY.................................................................................... 67
`7 GENETIC TOXICOLOGY ...................................................................................... 85
`7.1
`IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES)....................... 85
`IN VITRO ASSAYS IN MAMMALIAN CELLS.............................................................. 85
`7.2
`7.3
`IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY).................. 85
`8 CARCINOGENICITY: ............................................................................................ 86
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ................................ 86
`9.1
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT............................................... 86
`9.2
`EMBRYONIC FETAL DEVELOPMENT ..................................................................... 92
`10
`SPECIAL TOXICOLOGY STUDIES................................................................. 102
`
`11
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION............................... 109
`
`Reference ID: 3068534
`
`2
`
`

`

`NDA # 202-324
`
`
`
`Anwar Goheer, Ph.D.
`
`APPENDIX/ATTACHMENTS........................................................................... 115
`
`12
`
`
`Reference ID: 3068534
`
`3
`
`

`

`NDA # 202-324
`
`
`
`Anwar Goheer, Ph.D.
`
`1
`
`Executive Summary
`
`1.1
`
`Introduction
`
`NDA 202324 was submitted to the U.S. Food and Drug Administration as a full New
`Drug Application (NDA) for axitinib for the indication of the treatment of patients with
`advanced renal cell carcinoma (RCC). Axitinib is a new molecular entity kinase
`inhibitor, which inhibits multiple kinases including vascular endothelial growth factor
`receptor (VEGFR)-1, VEGFR-2, and VEGFR-3. The proposed clinical starting dose of 5
`mg is administered orally as a tablet twice daily. Nonclinical pharmacology,
`pharmacokinetic and toxicology studies have been submitted to support the approval of
`axitinib for the proposed indication.
`
`1.2 Brief Discussion of Nonclinical Findings
`
`
`
`Nonclinical primary pharmacology studies evaluated the ability of axitinib to inhibit the
`activity and function of Vascular Endothelial Growth Factor Receptors (VEGFRs), in
`vitro and in vivo, thereby inhibiting angiogenesis and tumor progression in experimental
`cancer models in mice. Utilizing biochemical and cell-based assays, axitinib was shown
`to inhibit receptor tyrosine kinases including VEGFR-1, VEGFR-2, and VEGFR-3 at
`therapeutic plasma concentrations. Additional in vitro studies demonstrated that axitinib
`was able to inhibit VEGF-stimulated endothelial cell survival, vascular tube formation,
`adhesion, migration, and induce endothelial cell apoptosis. Axitinib-induced alterations
`in endothelial cell function were demonstrated in vivo. Specifically, axitinib was shown
`to decrease vascular permeability and density in tumor xenografts in mice. Axitinib was
`shown to inhibit the phosphorylation of VEGFR-2 and PDGFR-β in tumor xenografts
`and produce tumor growth inhibition in experimental models of cancer in mice. Based
`on primary pharmacology data submitted with this NDA and on other FDA approved
`products which inhibit tyrosine kinases, the Established Pharmacologic Class of “kinase
`inhibitor” was determined to be both clinically meaningful and scientifically valid for
`axitinib.
`
`In safety pharmacology studies, axitinib administered orally to mice and rats did not
`demonstrate signs of neurotoxicity or adverse effects on the respiratory system. Axitinib
`increased gastric emptying (stomach) in rats. There were no significant effects of
`axitinib on the hERG channel in vitro or on cardiac function (e.g., PR, QRS, QT, QTcB,
`QTcF) in dogs. Cardiovascular effects of axitinib may include increased systolic blood
`pressure and a concomitant decrease in heart rate, as demonstrated in mice, rats and
`dogs. Hypertension was observed in clinical trials conducted with axitinib.
`
`Toxicities in bone and teeth were observed in immature mice and in dogs administered
`oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened
`growth plates in mice and dogs at ≥15 mg/kg/dose. Abnormalities in growing incisor
`teeth (including dental caries and broken and/or missing teeth) were observed in mice
`
`Reference ID: 3068534
`
`4
`
`

`

`NDA # 202-324
`
`
`
`Anwar Goheer, Ph.D.
`
`administered oral axitinib twice daily for 26-weeks at ≥5 mg/kg/dose. These toxicities
`are consistent with the activity of axitinib for inhibiting VEGFR, and should be
`considered when axitinib is administered to pediatric patients.
`
`Other toxicities observed in mice and dogs administered axitinib included effects on the
`gastrointestinal tract with microscopic findings of inflammation, hyperplasia, necrosis,
`erosion and ulcers. These findings correlate to the gastrointestinal perforations
`observed clinically. In addition, elevated cholesterol and triglyceride levels in dogs
`suggest axitinib may have effects on lipid metabolism. In mice, lymphoid depletion was
`present in the spleen and thymus, but there were no significant correlating
`hematological findings.
`
`The overall exposure (Cmax and AUC) after repeated dosing in mice and dogs did not
`show significant and consistent accumulation. The increase in AUC value was slightly
`greater than dose proportional. This may suggest nonlinear toxicokinetics due to a
`combination of potential inhibition or saturation of elimination pathways.
`In repeat-dose toxicology studies, findings in the male reproductive tract were observed
`in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased
`numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm
`density and count) at ≥15 mg/kg/dose twice daily in mice and ≥1.5 mg/kg/dose twice
`daily in dogs. These doses correlate to systemic exposures (AUC) approximately 7 and
`0.1 times, respectively, that in patients at the recommended starting dose in humans.
`Findings in the female reproductive tract in mice and dogs included signs of delayed
`sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine
`atrophy at ≥5 mg/kg/day. This dose correlates to a systemic exposure (AUC)
`approximately 1.5 or 0.3 times, respectively, the exposure in patients at the
`recommended starting dose.
`
`In a fertility study in mice, axitinib did not affect mating or fertility rate when administered
`to males at any dose tested up to 50 mg/kg/dose (approximately 57 times the AUC in
`patients at the recommended starting dose) following at least 70 days of administration.
`Reduced fertility and embryonic viability were observed in female mice at all doses
`tested (≥15 mg/kg/dose) following at least 15 days of treatment with axitinib. This dose
`correlates to a systemic exposure (AUC) approximately 10 times that in patients at the
`recommended starting dose. Data from repeat-dose toxicology studies and this fertility
`study indicate axitinib has the potential to impair reproductive function and fertility in
`humans.
`
`In reproduction and developmental toxicity studies, axitinib was teratogenic,
`embryotoxic and fetotoxic at maternal exposures that were lower than human
`exposures at the recommended starting dose. During a fertility and early embryonic
`development study, axitinib administered to female mice prior to mating and through the
`first week of pregnancy caused an increase in post-implantation loss. In an embryo-
`fetal developmental toxicity study, pregnant mice received oral axitinib twice daily during
`the period of organogenesis. Embryo-fetal toxicities observed in the absence of
`maternal toxicity included malformations