CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`205552Orig2s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`MEMORANDUM
`
`
`Imbruvica (ibrutinib)
`
`Date: August 21, 2013
`To: File for NDA 205552
`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 for Imbruvica
`conducted by Drs. Lee, Chiu, Brower and Chang, and secondary memorandum
`and labeling provided by Dr. Saber. I concur with Dr. Saber’s conclusion that
`Imbruvica may be approved and that no additional nonclinical studies are needed
`for the proposed indication.
`
`Reference ID: 3360581
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`08/21/2013
`
`Reference ID: 3360581
`
`

`

`MEMORANDUM
`
`
`Date:
`From:
`
`
`
`August 20, 2013
`Haleh Saber, Ph.D.
`Pharmacology/Toxicology Supervisor
`Division of Hematology Oncology Toxicology (DHOT)
`Office of Hematology and Oncology Products (OHOP)
`Re:
`Approvability for Pharmacology and Toxicology
`
`NDA:
`205552
`Drug:
`IMBRUVICA (ibrutinib) capsules
`Indications: treatment of patients with MCL who have received at least one prior
`therapy and treatment of patients with CLL who have received at least one
`prior therapy
`Pharmacyclics, Inc.
`
`Applicant:
`
`
`Ibrutinib is a small molecule tyrosine kinase inhibitor developed for the treatment of
`mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Ibrutinib
`inhibits Bruton tyrosine kinase (Btk), an enzyme in the B cell receptor (BCR) signaling
`pathway. Btk is involved in B-lymphocyte activation and in the maintenance of some B-
`cell malignancies. Based on an in vitro kinase assay conduced, ibrutinib can also inhibit
`Bmx/Etk, another member of this kinase family, the function of which is not fully
`understood. It can also inhibit EGFR, and some members of the SRC family of kinases
`(e.g. Hck and Yes); however, with up to 10 fold less activity. In xenograft and/ or cell
`culture studies, ibrutinib showed anti-cancer activity against cells derived from B-cell
`malignancies, including MCL and CLL lines. Ibrutinib inhibited the adhesion of MCL
`and CLL cells to fibronectin and vascular cell adhesion molecule-1 (VCAM-1),
`suggesting the potential for ibrutinib to affect the trafficking of B-cells.
`
`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. Ibrutinib-related toxicities in rats and dogs included: GI
`toxicities (e.g. ulceration and inflammation), adverse findings in the lymphoid tissues
`(e.g. depletion, necrosis, and inflammation), and epidermal necrosis and exudate. Other
`findings with unknown association to treatment included muscle degeneration in the
`stomach, effects on bone (e.g. thinning of cortical bone), and pancreatic acinar atrophy/
`reduced zymogen granules.
`
`Transient lymphocytosis reported in patients treated with IMBRUVICA may be due to
`reduced homing of leukocytes as expected based on the pharmacology studies. GI, skin
`and musculoskeletal disorders have been reported in patients and are listed in the label.
`The ongoing studies in patients will provide additional information on the toxicities
`associated with ibrutinib.
`
`
`
`
`Reference ID: 3360258
`
`1
`
`

`

`Ibrutinib was not mutagenic or clastogenic when tested in the battery of genotoxicity
`studies. Several impurities were tested in the bacterial mutagenicity (Ames) assay and/or
`assessed for mutagenicity through SAR (structure- activity relationship) computational
`methods. The impurities were considered negative for mutagenicity. Ibrutinib caused
`fetal malformations in rats when given to pregnant animals during the period of
`organogenesis, at a maternally toxic dose. Pregnancy category D is recommended.
`
`Fertility studies using ibrutinib have not been conducted. The general toxicology studies
`in rats and dogs did not demonstrate adverse findings in male or female reproductive
`organs.
`
`The nonclinical studies needed to support product labeling were reviewed by Drs. Shwu-
`Luan Lee, Brian Chiu, Margaret Brower, and George Chang. The nonclinical findings
`are summarized in the “Executive Summary” of the NDA review and reflected in the
`product label.
`
`Recommendation: I concur with the pharmacology/toxicology reviewers that from a
`nonclinical perspective, IMBRUVICA may be approved and that no additional
`nonclinical studies are needed to support approval of IMBRUVICA for the proposed
`indications.
`
`
`
`Reference ID: 3360258
`
`2
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`08/20/2013
`
`Reference ID: 3360258
`
`

`

`
`
`
`
`
`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 205552
`
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`
`Applicant:
`Review Division:
`
`Reviewer:
`
`Supervisor/Team Leader:
`Division Director:
`
`Project Manager:
`
`N-000
`May 31, 2013
`April 30, 2013
`Ibrutinib (Imbruvica)
`Mantle cell lymphoma (MCL) and chronic
`lymphocytic leukemia (CLL), with at least one
`prior therapy
`Pharmacyclics, Inc.
`Division of Hematology and Oncology
`Toxicology (DHOT), for
`Division of Hematology Products (DHP)
`Shwu-Luan Lee, Ph.D., Haw-Jyh (Brian) Chiu,
`Ph.D., George Ching-Jey Chang, Ph.D.,
`Margaret E. Brower, Ph.D.
`Haleh Saber, Ph.D.
`John Leighton, Ph.D., DABT (DHOT)
`Ann Farrell, MD (DHP)
`CAPT Diane Hanner
`
`
`Disclaimer
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 205552 are owned by Pharmacyclics or are data for
`which Pharmacyclics has obtained a written right of reference.
`Any information or data necessary for approval of NDA 205552 that Pharmacyclics 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 [name of applicant] does
`
`Reference ID: 3360071
`
`1
`
`

`

`
`
`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 205552.
`
`Reference ID: 3360071
`
`2
`
`

`

`NDA # 205552
`
`
`
`
`Reviewer: Lee, Brower, Chiu, Chang
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 7
`1.1 RECOMMENDATIONS............................................................................................ 7
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 7
`2 DRUG INFORMATION .......................................................................................... 10
`
`3 STUDIES SUBMITTED.......................................................................................... 13
`
`4 PHARMACOLOGY................................................................................................ 17
`4.1
`PRIMARY PHARMACOLOGY................................................................................. 17
`4.2
`SECONDARY PHARMACOLOGY............................................................................ 31
`4.3
`SAFETY PHARMACOLOGY................................................................................... 32
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 41
`5.1
`PK/ADME........................................................................................................ 41
`5.2
`TOXICOKINETICS ............................................................................................... 47
`6 GENERAL TOXICOLOGY..................................................................................... 47
`6.1
`SINGLE-DOSE TOXICITY..................................................................................... 47
`6.2 REPEAT-DOSE TOXICITY.................................................................................... 48
`7 GENETIC TOXICOLOGY ...................................................................................... 77
`7.1
`IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES)....................... 77
`7.2
`IN VITRO ASSAYS IN MAMMALIAN CELLS.............................................................. 81
`7.3
`IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY).................. 95
`8 CARCINOGENICITY ........................................................................................... 120
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY .............................. 120
`9.1
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT............................................. 120
`9.2
`EMBRYONIC FETAL DEVELOPMENT ................................................................... 120
`9.3
`PRENATAL AND POSTNATAL DEVELOPMENT....................................................... 132
`10
`SPECIAL TOXICOLOGY STUDIES................................................................. 132
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION ......................................... 132
`
`APPENDIX/ATTACHMENTS........................................................................... 133
`
`12
`
`
`Reference ID: 3360071
`
`3
`
`

`

`NDA # 205552
`
`
`
`
`Reviewer: Lee, Brower, Chiu, Chang
`
`Table of Tables
`
`Table 1- Clinical formulation......................................................................................... 11
`Table 2- Summary of impurities/degradants in drug substance and drug product ....... 12
`Table 3- IC50 values of PCI-32765 vs. selected kinases ............................................... 18
`Table 4- Growth inhibition of B cell lymphoma derived cell lines by PCI-32765 ........... 25
`Table 5- Inhibition of radioligand binding to receptors by PCI-32765 (10 μM).............. 31
`Table 6- Mean percent inhibition at PCI-32765 concentrations tested ......................... 35
`Table 7- Mean percent inhibition at PCI-45227 concentrations.................................... 36
`Table 8- Protein binding ............................................................................................... 42
`Table 9- Summary of in vitro metabolites in humans and laboratory animals .............. 46
`Table 10- Observations and Results: 4-week study in rats .......................................... 49
`Table 11- Histological Findings: 4-week study in rats................................................... 50
`Table 12- Toxicokinetics: 4-week study in rats............................................................. 50
`Table 13- Body weight changes: 13-week study in rats .............................................. 53
`Table 14- Hematology parameters: 13-week study in rats ........................................... 54
`Table 15- Clinical chemistry parameters: 13-week study in rats ................................... 55
`Table 16- Histopathological findings: 13-week study in rats......................................... 56
`Table 17- Summary of toxicokinetic parameters in rats: PCI-32765 (ibrutinib) and
`metabolite PCI-45227.................................................................................................... 60
`Table 18- Observations and Results: 4-week study in dogs......................................... 63
`Table 19- Toxicokinetic parameters: 4-week study in dogs.......................................... 64
`Table 20- Study design of the 13-week study in dogs.................................................. 65
`Table 21- Cumulative weight changes (weight gains) in the 13-week study in dogs.... 66
`Table 22- Hematology parameters................................................................................ 68
`Table 23- Clinical chemistry parameters ....................................................................... 71
`Table 24- Histopathology ............................................................................................. 74
`Table 25- Toxicokinetics parameters of PCI-32765 and PCI-45227: 13-week study in
`dogs .............................................................................................................................. 75
`Table 26- Summary of results from definitive mutagenicity assays (Experiments B2 and
`B3) with PCI-32765 (Study No. 06-027-Sal-X-MU). ...................................................... 80
`Table 27- Summary of results from in vitro mammalian chromosomal aberration assay
`(Assay 2) with PCI-32765 [Lot No. SCR-182-77
`. (Study No. 07-038-CHO-
`X-MU)............................................................................................................................ 85
`Table 28- Summary of results from in vitro mammalian chromosomal aberration assay
`(Assay 3) with PCI-32765 [Lot No. SCR-182-77
`. (Study No. 07-038-CHO-
`X-MU)............................................................................................................................ 86
`Table 29- Summary of results from in vitro mammalian chromosomal aberration assay
`(Assay 4) with PCI-32765 (Lot No. 082032). (Study No. 07-038-CHO-X-MU). ............ 87
`Table 30- Historical control data: chromosome aberration in CHO cells ...................... 89
`Table 31- Preliminary toxicity assay............................................................................. 92
`Table 32- Group means of mitotic index and cytogenetic analysis............................... 92
`Table 33- Summary of study design in Study No. 07-037-M-PO-MU........................... 96
`Table 34- Summary of bone marrow micronucleus analysis following a single oral
`concentration of PCI-32765 in ICR mice in Study No. 07-037-M-PO-MU. .................... 98
`Table 35- Summary of toxicokinetic data in Study No. 07-037-M-PO-MU.................... 98
`
`Reference ID: 3360071
`
`4
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`Reviewer: Lee, Brower, Chiu, Chang
`
`NDA # 205552
`
` in the absence of S9
`Table 36- Summary of results from Ames Assay with
`activation (Study No. 11-113-Sal-X-MU). .................................................................... 102
`Table 37- Summary of results from Ames Assay with
` in the presence of S9
`activation (Study No. 11-113-Sal-X-MU). .................................................................... 104
`Table 38- Summary of results from Ames Assay (Experiment B3) with
` (Lot
`No. 758-47-2) in the absence of S9 activation (Study No. 11-098-Sal-Mu)................. 109
`Table 39- Summary of results from Ames Assay (Experiment B3) with
` (Lot
`No. 758-47-2) in the presence of S9 activation (Study No. 11-098-Sal-Mu)................ 111
`Table 40- Summary of results from Ames Assay (Experiment B4) with
` (Lot
`No. 758-47-2) in the presence of S9 activation (Study No. 11-098-Sal-Mu)................ 113
`Table 41- Summary of results from Ames Assay (Experiment B5) with
` (Lot
`No. RM758-188-1) in the presence of S9 activation (Study No. 11-098-Sal-Mu). ....... 114
`Table 42- Summary of results from Ames Assay (Experiment B6) with
` (Lot
`No. RM758-188-1) in the presence of S9 activation (Study No. 11-098-Sal-Mu). ....... 115
`Table 43- Group mean body weight change in dams:................................................ 123
`Table 44- Toxicokinetic parameters ........................................................................... 124
`Table 45- Terminal and necroscopic evaluations, Dams............................................ 125
`Table 46- Offspring: external, visceral and skeletal variations ................................... 126
`Table 47-Summary of study result: embryo-fetal development study in rabbits
`(concentration range finding study) ............................................................................. 130
`
`
`Reference ID: 3360071
`
`5
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA # 205552
`
`
`
`
`Reviewer: Lee, Brower, Chiu, Chang
`
`Table of Figures
`
`Figure 1- Structure of ibrutinib (PCI-32765) ................................................................. 10
`Figure 2- Inhibition of B and T Cell Activation by PCI-32765........................................ 19
`Figure 3- Active-site occupancy of Btk by PCI-32765 in whole blood correlates with
`Inhibition of B cell activation .......................................................................................... 20
`Figure 4- Inhibition of growth and occupancy of Btk in ABC DLBCL cell lines ............. 21
`Figure 5- Inhibition of BCR-stimulated MCL cell line adhesion by ibrutinib .................. 22
`Figure 6- Inhibition of BCR-signaling, adhesion and migration in CLL cells ................. 23
`Figure 7- Tumor growth in SCID female mice bearing OCl-Ly10 administered vehicle or
`ibrutinib.......................................................................................................................... 27
`Figure 8- DOHH2 Tumor volume – time profiles in mice dosed with PCI-32765.......... 28
`Figure 9- DOHH2 Tumor volume – time profiles in mice dosed once daily (QD) or twice
`daily (BID) with PCI-32765 by oral gavage.................................................................... 28
`Figure 10- DLCL2 tumor volume – time profiles in mice dosed twice daily (BID) with.. 29
`Figure 11- hCD19+ Mino mantle cell counts in tissues ................................................ 30
`Figure 12- Reduction in peripheral CLL cells by ibrutinib treatment ............................. 31
`Figure 13- Concentration-response relationship and mean percent inhibition of hERG
`potassium current.......................................................................................................... 35
`Figure 14- Concentration-response relationship and mean percent inhibition of hERG
`potassium current following treatment of PCI-45227.................................................... 37
`Figure 15- Radiotelemetry data – Heart Rate............................................................... 39
`Figure 16- Radiotelemetry data – Heart Rate............................................................... 39
`Figure 17- Radiotelemetry data – QTcV Interval .......................................................... 40
`
`
`Reference ID: 3360071
`
`6
`
`

`

`NDA # 205552
`
`
`1
`
`Executive Summary
`
`
`
`Reviewer: Lee, Brower, Chiu, Chang
`
`1.1 Recommendations
`There are no pharmacology/toxicology issues which preclude approval of Imbruvica for
`the proposed indication.
`
`1.1.1 Approvability
`
`Recommending approval
`
`1.1.2 Additional Non Clinical Recommendations
`
`No additional non-clinical studies are required for the proposed indications.
`
`1.1.3 Labeling
`
`Recommendations on labeling have been provided within team meetings and
`communicated to the Applicant. See the approved label.
`
`1.2 Brief Discussion of Nonclinical Findings
`
`Ibrutinib (PCI-32765) is an irreversible inhibitor of Bruton’s tyrosine kinase (Btk); it binds
`covalently to a cysteine in the active site of Btk. The IC50 of ibrutinib was 0.46 nM in the
`in vitro kinase assay. Ibrutinib may also inhibit Bmx/Etk, another member of this
`tyrosine kinase family as indicated by the IC50 of 0.76 nM and B lymphocyte kinase,
`BLK (IC50= 0.52 nM). The following kinases were inhibited by ibrutinib with IC50s up to 4
`nM: CSK, FGR, Brk, and HCK. Ibrutinib showed anticancer activity against B cell tumor
`cells in cell culture or xenograft studies. The tumor cells tested included mantle cell
`lymphoma (e.g. MINO), chronic lymphocytic leukemia (TCL1-192, a line of murine
`leukemia cells), non-Hodgkin lymphoma/follicular lymphoma (e.g. DOHH2), and diffuse
`large B-cell lymphoma (e.g. OCI-LY10) cell lines.
`
`Ibrutinib inhibited the adhesion of mantle cell lymphoma (MCL) and chronic lymphocytic
`leukemia (CLL) cell lines as well as the normal B cells to fibronectin and vascular cell
`adhesion molecule-1 (VCAM-1). Therefore, ibrutinib may affect the trafficking and
`localization of leukocytes; this effect may explain lymphocytosis reported in patients
`treated with ibrutinib.
`
`Ibrutinib inhibited hERG channel currents with an IC50 value of approximately 1 μM and
`may be considered a low-potency blocker. In a single-dose safety pharmacology study in
`Beagle dogs, an oral ibrutinib dose up to 150 mg/kg did not induce QT interval
`prolongation; increases in the RR interval were observed. Dose-dependent RR interval
`prolongation and decreased heart rate was reported in dogs in the 13-week toxicology
`
`Reference ID: 3360071
`
`7
`
`

`

`
`
`Reviewer: Lee, Brower, Chiu, Chang
`
`NDA # 205552
`
`study during Weeks 1 and 12. The effect occurred at 1 hour post-dose. One of the major
`metabolites of PCI-32765, PCI-45227, inhibited hERG channel currents with an IC50 value
`of 9.6 μM, i.e. ten fold less potency for blocking the Ikr current compared to the parent drug.
`QTc prolongation was not reported in patients treated with ibrutinib.
`
`The ADME studies were not reviewed; however, based on the summary information
`provided by the Applicant, orally administered ibrutinib was absorbed fairly rapidly (tmax
`of ~ 5 min-2.5 hr in rats and 0.5-4 hr in dogs), with variable oral bioavailability (~7% to
`23%) in animal species. Ibrutinib was highly bound to plasma proteins in all species
`tested (96-99%): mouse, rat, rabbit, dog, and human plasma. Following an oral dose of
`14C-ibrutinib in Long Evans male rats, radioactivity was high in the following tissues and
`organs: small intestine, esophagus, liver, urinary bladder, and kidney. Ibrutinib-derived
`radioactivity was not detectable in tissues of the central nervous system with the
`exception of the olfactory lobe, indicating a limited ability of ibrutinib and/or its
`metabolites to cross the blood-brain barrier in rats. The distribution in the milk of
`lactating rats was not investigated. There was no clear difference in the distribution of
`radioactivity in the pigmented tissues when compared to the non-pigmented tissues, in
`treated rats. A total of 41 metabolites were identified in the in vitro or in vivo studies.
`The main circulating metabolites in rat plasma were M15, M5 and M37 (PCI-45227).
`Following oral doses of 14C ibrutinib in rats, up to 47% of the radioactivity was excreted
`in bile, with M21 (a sulfate conjugate of M35) as the main metabolite. While very low
`radioactivity was found in urine (<2% of the dose), the main metabolites in feces were
`M34, M35 and M17 (approximately 8-16% of the dose). In human liver microsomes,
`ibrutinib was predominantly metabolized by CYP3A4/5. The primary route of elimination
`of ibrutinib was via feces (hepatobiliary) in animals. Accumulations of ibrutinib and one
`of its major metabolites, PCI-45227 (M37), occurred following repeated oral doses of
`ibrutinib in both rats and dogs.
`
`The general toxicology studies in rats and dogs identified GI tract, lymphoid tissues, bone
`and skin as the main target of toxicities. The major findings are as follows:
`
` •
`
` Gastro-intestinal tract:
`The most prominent effect of ibrutinib in rats and dogs was dose-dependent GI
`toxicities. The toxicities were observed following multiple oral administrations of the
`drug, and were considered the cause of mortalities in the rat (acute inflammation and
`ulceration of the small intestines) and the dog (enterocolitis). GI histopathology findings
`included atrophy of squamous epithelium with progression to ulceration in the
`nonglandular stomach, acute inflammation and ulceration of the intestinal tract, as well
`as muscle degeneration in the stomach.
`• Hematopoietic/lymphoid system:
`Findings included increased white blood cells and differentials (which may be due to
`ulceration/necrosis and inflammation reported in various tissues or may be due to
`reduced homing of B cells); lesions in lymphoid tissues; lymphoid depletion;
`inflammation, necrosis, and atrophy in lymph nodes, spleen, as well as thymus.
`Immunophenotyping incorporated into the 13-week study in rats indicated lower
`absolute B cells and increased T- and natural killer cells in peripheral blood.
`
`Reference ID: 3360071
`
`8
`
`

`

`
`
`Reviewer: Lee, Brower, Chiu, Chang
`
`NDA # 205552
`
`• Skin
`In rats, epidermal necrosis, surface exudate, dermal abscess, and acute and
`subacute inflammation were observed at the end of a 4-week treatment; squamous
`atrophy of epithelium was noted at the end of the 13-week study. There were no
`remarkable findings in the skin of dogs.
`• Liver
`Hepatotoxicity was evident in rats in the 4-week study, as shown by increased ALTAST
`and hepatic necrosis. Liver toxicities were not observed in the 13-week study in rats or
`in studies in dogs.
`• Bone
`Minimal to mild decreases in cortical and trabecular bones were found in rats treated for
`13 weeks.
`• Other target organs:
`Acinar atrophy and decrease in zymogen granules in pancreas was observed in rats.
`Bilateral corneal dystrophy/degeneration (opacity of the cornea) was found in dogs
`treated with ibrutinib for 4 weeks and in one dog in the 13-week study. The association
`of these findings to the ibrutinib treatment is unclear.
`
`
`
`
`Ibrutinib was not mutagenic in bacterial Ames test or clastogenic in a chromosome
`aberration test in Chinese Hamster Ovary cells (CHO). Ibrutinib did not increase
`micronucleus formation in mice after oral doses up to 2000 mg/kg. The mutagenicity of
`impurities was assessed through Ames test or by 2 computational SAR analyses (DEREK
`Nexus and MultiCase). The impurities tested were not mutagenic.
`
`Reproductive and developmental toxicities of ibrutinib were investigated in rats and rabbits.
`Ibrutinib was administered orally to pregnant rats during the period of organogenesis at
`doses of 10, 40 and 80 mg/kg/day. Increased post-implantation loss and increased
`resorption occurred at the high dose of 80 mg/kg. Fetal toxicities (visceral malformations and
`variations, and skeletal variations) were observed at the high dose of 80 mg/kg. Reduced
`fetal weight was seen at ibrutinib doses at 40 mg/kg and 80 mg/kg. The dose of 80 mg/kg
`resulted in maternal toxicities. The dose of 80 mg/kg/day in animals resulted in exposures
`(total AUC) approximately 14 times the AUC in patients with MCL (ibrutinib dose of 560
`mg/day) and 20 times the AUC in patients with CLL (ibrutinib dose of 420 mg/day). The
`exposure at 40 mg/kg/day was approximately 6 times the AUC in patients with MCL and 8
`times the AUC in patients with CLL.
`
`In a non-GLP study conducted in rabbits, ibrutinib was administered orally to pregnant
`animals during the period of organogenesis at doses of 10, 30, and 100 mg/kg/day. At the
`ibrutinib dose of 100 mg/kg, which is greater than the maternally-toxic dose (≥30
`mg/kg/day), there were embryo-fetal toxicities. Findings included increases in resorption
`and implantation loss, decreases in viable fetuses and fetal body weights, as well as
`spontaneous abortions.
`
`
`
`Reference ID: 3360071
`
`9
`
`

`

`
`
`Reviewer: Lee, Brower, Chiu, Chang
`
`NDA # 205552
`
`Ibrutinib did not cause adverse findings in male or female reproductive organs in
`general toxicology studies. Testicular seminiferous tubule degeneration was found in
`one dog that was treated with 220 mg/kg of ibrutinib and sacrificed early due to poor
`conditions. This finding was possibly an indirect effect of ibrutinib due to the poor
`condition of the animal.
`
`2
`
`Drug Information
`
`2.1 Drug
`
`2.1.1 CAS Registry Number
`
` 936563-96-12.1.2
`
`Generic Name
`
`Ibrutinib
`
`2.1.3 Code Name
`
`PCI-32765-00
`
`2.1.4 Chemical Name
`
`R enantiomer of 1-[3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-
`d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one (free base)
`
`2.1.5 Molecular Formula/Molecular Weight
`
`C25H24N6O2/440.5 g/mol
`
`2.1.6 Structure
`
`Figure 1- Structure of ibrutinib (PCI-32765)
`
`
`
`10
`
`Reference ID: 3360071
`
`

`

`NDA # 205552
`
`Reviewer: Lee, Brower, Chiu, Chang
`
`POI-32765 is an R—enantiomeric chiral compound.
`
`2.1.7 Pharmacologic class
`
`Kinase inhibitor
`
`Mechanism of action: Bruton's tyrosine kinase inhibitor
`
`2.2 Relevant IND/s, NDA/s, and DMF/s
`
`IND 102688; DMF W"
`
`2.3 Clinical Formulation
`
`2.3.1 Drug Formulation
`
`Table 1- Clinical formulation
`
`(Table from the Applicant, eCTD Module 3, Sction 3.2.P.1)
`Component
`Quality Reference
`Function
`
`Ibrutinib
`
`In house specification
`
`Active
`pharmaceutical agent
`
`Microcrystalline cellulose
`Croscarmellose sodium
`Sodium lauryl sulfate
`Magnesium .stearateh
`Size 0, white, opaque, hard gelatin
`capsule with black “ibr 140 mg"
`Print °
`
`NF. Ph. Eur, JP
`NF, Ph. Eur, JP
`NR Ph. Eur” JP
`NF, Ph. Eur, JP
`In house specification
`
`Quantityx’Unit Dose
`(mg/capsule)
`140 '
`
`00(4)
`
`Capsule shell
`
`1 capsule
`
`Total
`330.0
`mm mm—
`M‘" with a corresponding adjustment to the microcrystalline cellulose quantity.
`b
`(b) (4)
`
`‘ Capsules are composed of gelatin, NF. Ph. Eur. and titanium dioxide, USPtPhEurI'JP; the capsule shells are
`printed with
`“’m’printing inks (see Table 2 and Table 3 for ink
`compositions).
`
`2.3.2 Comments on Novel Excipients
`
`None. All excipients are USP or NF grade.
`
`mglcapsule is
`Reviewer’s note: the amount of microcrystalline cellulose, i.e.,
`within the range of FDA approved drug for this excipient in hard gelatin capsule (up to
`“mmg/capsule).
`
`(II) (4)
`
`Reference ID: 3360071
`
`1 1
`
`

`

`NDA # 205552
`
`2.3.3 Comments on Impurities/Degradants of Concern
`
`
`
`Reviewer: Lee, Brower, Chiu, Chang
`
`There are five impurities in the drug substance at levels higher than the qualification
`threshold described in ICH Q3A. Among them,
` and
` were also
`degradants found in the drug product (DP). However, the contents in the DP were
`below qualification threshold. All impurities above the qualification threshold of ICH
`Q3A were assessed for genotoxicity. Genotoxicity assessment was also done for
`impurities
` and
` which were below qualification threshold. The table
`below is the summary of safety assessment conducted for the impurities of concern:
`
`
`Table 2- Summary of impurities/degradants in drug substance and drug product
`Impurity
`Description
`Specification (NMT % w/w)
`Comment
`(ID #)
`
`Actual DS Impurity -
`Synthesis impurity
`
`
`
`Actual DS Impurity Synthesis
`Impurity Degradation product
`
`Actual DS impurity - Synthesis
`impurity
`
`
`Actual DS Impurity Synthesis
`impurity
` Degradation
`product
`
`Actual DS Impurity Degradation
`product
`(ibrutinib dimer)
`
`Potential DS Impurity* Carryover
`impurity from starting material
`
`Potential DS Impurity* Synthesis
`impurity
` Degradation
`product
`DS: drug substance; DP: drug product
`
`Reviewer’s note:
`The proposed specification limits (% w/w) of impurities
`acceptable, according to ICH guidance S9.
`
`Reference ID: 3360071
`
`12
`
`• Derek and MultiCase
`were conducted. The
`impurity is considered
`negative for
`mutagenicity
`
`• Qualified in a general
`toxicity study
`• Ames negative
`
`• Qualified in a general
`toxicity study
`• Ames negative;
`• A general toxicity: study
`with this impurity is
`ongoing
`• Derek and MultiCase:
`were conducted. The
`impurity is considered
`negative for
`mutagenicity
`• A general toxicity: study
`with this impurity is
`ongoing
`• Derek and MultiCase:
`were conducted. The
`impurity is considered
`negative for
`mutagenicity
`• Below qualification
`threshold
`• Ames negative
`• Below qualification
`threshold
`• Ames negative
`
` and
`
` are
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)