CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`I
`
`APPLICA TION NUMBER:
`
`21-880
`
`PHARMACOLOGY REVIEW(S)
`
`

`

`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`NDA NUMBER:
`
`SERIAL NUMBER:
`
`21—880
`
`001
`
`DATE RECEIVED BY CENTER:
`
`04/07/2005
`
`DRUG NAME:
`
`INDICATION:
`
`SPONSOR:
`
`Revlimid®
`
`Myelodysplastic syndrome (MDS)
`
`Celgene Corporation
`
`86 Morris Avenue, Summit, NJ 07901
`
`DOCUMENTS REVIEWED:
`
`Electronic submission
`
`REVIEW DIVISION:
`
`I
`
`Division of Drug Oncology Products
`
`PHARM/TOX REVIEWER:
`
`M. Anwar Goheer, PhD.
`
`(HFD-150)
`
`Kimberly Benson, Ph.D.
`
`PHARM/TOX SUPERVISOR:
`
`John K. Leighton, Ph.D., D.A.B.T.
`
`ACTING DIVISION DIRECTOR:
`
`Robert Justice, MD, MS.
`
`PROJECT MANAGER:
`
`Carl Huntley, R. Ph., MBA.
`
`Date of review submission to Division File System (DFS):
`
`5 October 2005
`
`

`

`TABLE OF CONTENTS
`
`EXECUTIVE SUMMARY ...................................................................................... 4
`
`2.6
`
`PHARMACOLOGY/TOXICOLOGY REVIEW ............................................ 7
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY ............................................................. 7
`
`2.6.2
`
`PHARMACOLOGY ............................................................................................... 9
`
`2.6.2.2 Primary pharmacodynamics ...................................................................................... 9
`2.6.2.3 Secondary pharmacodynamics ............................................................................... 10
`
`2.6.4 PHARMACOKINETICSITOXICOKINETICS ....................................................... 10
`
`2.6.4.2 Methods of Analysis ................................................................................................... 10
`2.6.4.3 Absorption ..................................................................................................................... 1]
`2.6.4.7 Pharmacokinetic drug interactions 11
`
`2.6.6 TOXICOLOGY ......................................................................'.............................. 1 1
`
`2.6.6.3 Repeat-dose toxicity ................................................................................................... 11
`2.6.6.6 Reproductive and developmental toxicology ............................................................... 12
`
`2.6.3 PHARMACOLOGY ............................................................................................. 13
`
`2.6.2.2 Primary pharmacodynamics .................................................................................... 13
`2.6.2.4 Safety pharmacology .................................................................................................. 13
`
`2.6.4 PHARMACOKINETICS/TOXICOKINETlCS ....................................................... 13
`
`2.6.4.3 Absorption ..................................................................................................................... 13
`2.6.4.5 Metabolism .................................................................................................................... 13
`
`2.6.67 TOXICOLOGY .................................................................................................... 14
`
`2.6.6.2 Single-dose toxicity .................................................................................................... 14
`2.6.6.3 Repeat-dose toxicity ................................................................................................... 14
`6.6.6.4 Genetic toxicology ...................................................................................................... 14
`
`2.6.2
`
`PHARMACOLOGY ............................................................................................. 15
`
`2.6.2.1 Brief summary........................................ 15
`2.6.2.2 Primary pharmacodynamics .................................................................................... 16
`2.6.2.3 Secondary pharmacodynamics ............................................................................... 39
`2.6.2.4 Safety pharmacology.................................................................................................. 41
`
`2.6.3
`
`PHARMACOLOGY TABULATED SUMMARY .................................................. 42
`
`2.6.4
`
`PHARMACOKINETICSITOXICOKINETICS ....................................................... 43
`
`2.6.4.1 Brief summary ............................................................................................................. 43
`2.6.4.2 Methods of Analysis
`............................................................................................... 43
`2.6.4.3 Absorption ..................................................................................................................... 44
`2.6.4.5 Metabolism .................................................................................................................... 53
`2.6.4.6 Excretion....................................................................................................................... 54 .
`
`2.6.4.7 Pharmacokinetic drug interactions............................................................................... 54
`2.6.4.8 Other Pharmacokinetic Studies .................................................................................... 62
`
`

`

`2.6.4.9 Discussion and Conclusions ................................................................................... 62
`2.6.4.10Tables and figures to include comparative TK summary: ......................................... 63
`
`2.6.5
`
`PHARMACOKINETICS TABULATED SUMMARY ...........................'................. 63
`
`2.6.6 TOXICOLOGY .................................................................................................... 64
`2.6.6.1 Overall toxicology summary..................................................................................... 64
`2.6.6.2 Single-dose toxicity .................................................................................................... 67
`2.6.6.3 Repeat-dose toxicity ................................................................................................... 67
`6.6.6.4 Genetic toxicology ...................................................................................................... 75
`2.6.6.5 Carcinogenicity ............................................................................................................. 75
`2.6.6.6 Reproductive and developmental toxicology ...................................................... 76
`2.6.6.7 Local tolerance........................................................................................................... 127
`2.6.6.8 Special toxicology studies ...................................................................................... 127
`2.6.6.9 Discussion and Conclusions
`................................... 127
`
`2.6.7 TOXICOLOGY TABULATED SUMMARY ........................................................ 128
`
`OVERALL CONCLUSIONS AND RECOMMENDATIONS .......................................... 131
`
`APPENDIX A ................................................................................................................ 132
`
`APPENDIX B .............................................................................................................. 158
`
`ADpears ThIS W0
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`21—880
`
`|.
`
`Recommendations
`
`EXECUTIVE SUMMARY
`
`A. Recommendation on approvability: The non-clinical studies submitted to
`this NDA provide sufficient information to support the use of lenalidomide
`(Revlimid®) in patients with transfusion-dependent anemia due to low- or
`intermediate—1—risk myelodysplastic syndromes (MDS) associated with a
`deletion 5q cytogenetic abnormality with or without additional cytogenetic
`abnormalities.
`
`B. Recommendation for nonclinical studies: Adequate reproductive toxicity
`assessment, specifically embryo—fetal developmental toxicity in two species,
`needs to be conducted.
`
`C. Recommendations on labeling:
`
`A separate review will be conducted.
`
`II.
`
`Summary of nonclinical findings
`
`Lenalidomide (3-(4’aminoisoindoline-1—
`Brief overview of nonclinical findings:
`A.
`one)-1—piperidine—2, 6-dione; CC-5013; lMiD—3 and Revlimid®) is a thalidomide
`analogue.
`It is a racemic mixture of S (-) and R (+) forms. The in vitro and in vivo
`characterization of pharmacological properties of lenalidomide had demonstrated that
`the drug inhibits the secretion of pro-inflammatory cytokines (TNF—a,
`lL—1B, lL-6 and IL-
`12) and increases the secretion of anti—inflammatory cytokine (IL-10) from peripheral
`blood mononuclear cells (PBMC), induces T—cell proliferation (IL-2, lFN—y), inhibits cell
`proliferation (MM, Burkitt’s lymphoma) and inhibits angiogenesis (Knight—R, Semin
`Oncol 2005; 32:24-30 & Dredge et al., Microvasc Res. 2005; 69:56—63). Lenalidomide
`inhibits the expression of cyclooxygenase-2 (COX-2) but did not affect COX—1 in vitro.
`in
`This may translate into adverse effects that need to be fully explored in clinical trials.
`addition to these immune effects, there is evidence that thalidomide and its analogues
`' may act directly on tumor cells, via inducing apoptosis or G1 growth arrest.
`
`The oral administration of lenalidomide at dose levels of 3, 6 and 12 g/m2 produced no
`effects on behavior or general activity in male rats.
`Intravenous administration of the
`drug at doses up to 400 mg/m2 did not produce any significant effect on cardiovascular
`and respiratory systems of the anesthetized dog.
`In vitro, lenalidomide inhibited the
`cloned human potassium channel (hERG) current by 8% only at the highest
`concentration tested (787 pM).
`
`Lenalidomide did not inhibit or induce any of the major cytochrome P450 isozymes in
`vitro and in vivo. indicating limited potential for P450-related drug-drug interactions.
`Distribution of radioactivity in the fetal tissues of pregnant rat was low after oral
`administration but fetal brain showed more activity than maternal brain. The highest
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`21-880
`
`concentrations were found in the kidney (cortex and medulla), liver, spleen and the
`mucosa of the Gl tract of rats.
`
`During traditional toxicity assessment, lenalidomide was administered to rodents (mice,
`rats) and non rodents (monkeys) for 1, 7, and 28 days and 13, 26, and 52 weeks.
`Single dose administration of lenalidomide up to 6 g/m2 in mice and 12 g/m2 in rats did
`not cause any adverse effects. Daily oral administration of lenalidomide at 6 g/m2 to
`rats for 28 days was associated with moderate to severe tubular nephropathy/nephritis,
`which was attributed to precipitation of the lenalidomide in the kidney. Once daily oral
`administration of lenalidomide to rats at doses of 450, 900 or 1800 mg/mzlday for 26
`weeks was mainly associated with reduced body weight gain (12% ~L) for high dose
`males and reversible pelvic mineralization in the kidney of all treated animals.
`
`Oral administration of lenalidomide to cynomolgus monkeys at dose levels of 12, 24, 48,
`or 72 mg/mzlday for 52 weeks was associated with hemorrhage in multiple organs,
`gastrointestinal tract inflammation and lymphoid and bone marrow atrophy. Dosing at
`48 and 72 mg/m2/day was discontinued after 20 weeks of treatment due to toxicity and
`mortalities. A reversal of the macroscopic and microscopic findings seen in decedent
`and the terminal sacrifice was noted in 7 week treatment-free recovery animals.
`It is
`clear that this species is much more sensitive to lenalidomide than rodents.
`
`Lenalidomide did not induce mutation in the Ames test, chromosome aberrations in
`cultured human peripheral blood lymphocytes, or mutation at the thymidine kinase (tk)
`locus of mouse lymphoma L5178Y cells. Lenalidomide did induce micronuclei in the
`polychromatic erythrocytes of the bone marrow of male rats.
`
`Reproductive studies were conducted
`Reproductive and developmental toxicity:
`with lenalidomide, examining the effects on fertility and early embryo development,
`embryo-fetal development, and pre-and post—natal development. Only the embryo-fetal
`development studies are required for drugs with oncologic indications. These studies
`have not been adequately conducted at this time. The first study, conducted in a rat,
`showed very slight maternal toxicity and no fetal malformations. The rat, however, is
`not an adequate species for the full assessment of lenalidomide's developmental
`effects, given the structural similarity to thalidomide. Historical data indicates that the
`rat is not sensitive to the full range of thalidomide's teratogenic effects.
`'
`
`An additional developmental study was conducted in the rabbit, with a concurrent
`thalidomide dose group. This study had a confounding variable with some rabbits not
`eating prior to the study and all these rabbits had a negative outcome in the study.
`Additionally, the highest dose tested did not meet the standard criteria for sufficient drug
`exposure.
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`21—880
`
`Both lenalidomide and thalidomide have been
`Pharmacologic activity:
`B.
`shown to increase the secretion of anti-inflammatory cytokine lL—1O from LPS-stimulated
`PBMC, stimulates T—cells proliferation and production of lL—2 and IFN—y. Both inhibit the
`secretion of pro-inflammatory cytokines TNF—d,
`lL—1B, and lL-6.
`In addition to these
`immune effects, there is evidence that-thalidomide and its analogues may act directly on
`tumor cells, via inducing apoptosis or 61 growth arrest. Exact mechanisms of action
`however remain unknown.
`
`Inflammation of the
`Nonclinical safety issues relevant to clinical use:
`C.
`gastrointestinal tract and atrophy of the bone marrow, thymus, and lymphoid tissues
`were observed during repeat dose toxicity studies (up to 12 months) in cynomolgus
`monkeys. Embryo-fetal developmental toxicity has not been adequately addressed.
`The structural similarity of lenalidomide to thalidomide, a known human teratogen,
`suggests developmental risk. Lenalidomide also inhibits expression of COX-2 in vitro
`but not COX-1. This finding should be fully explored in clinical trials.
`
`APPEARS TillS WAY
`0N ORlGlNAL
`
`

`

`Reviewer:
`
`Anwar Goheer, PhD.
`
`NDA No.
`
`21—880
`
`2.6
`
`PHARMACOLOGY/TOXICOLOGY REVIEW
`
`2.6.1 INTRODUCTION AND DRUG HISTORY
`
`NDA number:
`Review number:
`
`21-880
`1
`
`Sequence number/date/type of submission: 001 / 12—22-2004 / NDA
`Information to sponsor:
`Yes (X) No ( )
`Sponsor and/or agent:
`Celgene Corporation
`86 Morris Avenue, Summit
`New Jersey 07901.
`
`Manufacturer for drug substance:
`
`/
`
`i
`
`_
`
`Reviewer name:
`
`Division name:
`
`HFD #:
`
`M. Anwar Goheer, Ph.D.
`
`Division of Oncology Drug Products
`
`HFD—150
`
`Review completion date:
`
`September 27, 2005
`
`Drug:
`
`Trade name:
`Generic name:
`Code name:
`Chemical name:
`
`REVLIMID®
`Lenalidomide
`CC-5013, CDC—501, lMiD 3
`3—(4’-amino—1,3-dihydro-1—oxo-2H—isoindol—2-
`yl)-2,6-piperidinedione,
`3-(4’—amino-1—oxo—1 ,3-dihydro—2H—isoindol—2-
`yl) piperidine-2,6—dione.
`191732—72-6
`C13H13N303/ 259.25
`-
`
`CAS registry number:
`Molecular formula/molecular weight:
`Structure:
`
`0 0
`
`HN
`
`Niko
`
`NH2.
`
`..
`DMF Numbers: '
`Relevant _lNDs/NDAs/DMFs:
`“a
`lND numbers: 60,100,
`Immunomodulator/ anti—angiogenesis
`
`Drug class:
`
`

`

`Reviewer:
`
`Anwar Goheer, PhD.
`
`NDA No.
`
`21-880
`
`Indication:
`
`Transfusion-dependent anemia due to low— or intermediate-1-risk
`myelodysplastic syndromes (MDS) associated with a deletion 5q
`cytogenetic abnormality with or without additional cytogenetic
`abnormalities.
`Clinical formulation:
`Composition of lenalidomide capsules
`
`
`
`10 mg
`5 mg
`
`Capsule
`Capsule
`
` Ingredient
`Quality
`
`Theoretical Weight per
`
`Standard
`Function
`
`
`Capsule (mg)
`Lcnalidomidcfl
`
`
`
`
`
`Lactose Anhydrousb
`
`Microcn-‘smlline Cellulose
`
`._'—
`
`C‘rosczu‘mcllose Sodium
`
`
`Magnesium Stearate
`.=
`
` _—
`400.0
`Total Fill Weight
`
`
`
`
`White Capsule Shells (Size 2)
`
`Imprinted with Black Ink°
`
`
`
`
`
`
`
`
`In-housc
`--
`
`Pale Yellow Body'Bluc Green
`
`I (‘upsulc
`Cap Capsule Shells (Size 0)
`
`
`Imprinted with Black Ink‘
`
`:
`
`"/
`The capsule shells are supplied by
`gelatin in the capsule shells isprovided in PA.
`
`lnfommtion pertaining to the components and source of
`
`(Excerpted from the sponsor’s submission)
`
`Route of administration:
`
`Oral
`
`“Lenalidomide (10 mg daily) is. indicated for the treatment of
`Proposed use:
`patients with transfusion-dependent anemia due to low- or intermediate-1-risk
`myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality
`with or without additional cytogenetic abnormalities.”
`
`Disclaimer: Tabular and graphical information are constructed by the reviewer unless
`cited otherwise.
`'
`
`Data reliance : Except as specifically identified below, all data and information
`discussed below and necessary for approval of NDA 21—880 are owned by Celgene
`Corporation or are data for which Celgene has obtained a written right of reference.
`Any information or data necessary for approval of NDA 21-880 that Celgene 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
`
`

`

`Reviewer:
`
`Anwar Goheer, PhD.
`
`NDA No-
`
`21—880
`
`described in the drug’s approved labeling. Any data or information described or
`referenced below from a previously approved application that Celgene 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 21-880.
`
`APPEARS T’rllS WAY
`0N ORlGlNAL
`
`Studies reviewed within this submission:
`
`2.6.2 PHARMACOLOGY
`
`2.6.2.2
`
`Primary pharmacodynamics
`
`Mechanism of action:
`
`1.
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`9°.“
`
`9.
`
`10.
`
`11.
`
`12.
`
`Amino- Substituted thalidomide analogs: Potent inhibitors of TNF—a production.
`Inhibition of TNF-a production by PBMC and elevation of lL—2 and 'MlP-3a
`production by T cells by CC—4047, CC—5013, and C-11006 in vitro.
`Inhibition of tumor necrosis factor alpha (TNF-a) production by 004047, CC-
`5013, and CC—11006 from human and rat whole blood stimulated with
`Iipopolysaccharide.
`Elevation of lL—2 production by CC-4047, CC—5013, and CC-11006 from human
`and rat whole blood stimulated with Concanavalin A.
`Cytokine profiling for five classes of lMiDs in primary human PBMCs and CD4+ T
`lymphocytes.
`Anti- Inflammatory effects of CC~4047, CC-5013 and CC-11006 on G-CSF, lL-10,
`and COX-2 Expression by LPS—stimulated PBMC.
`Effect of the lMiD CC-5013 on Akt phosphorylation in the *Jurkat T cell line.
`Effect of the PDE4 Inhibitors CC—10004, CC—10082 (cilomilast), CC—11050 and
`CC—14064 (roflumilast), and the lMlD CC-5013 on lL-6 production by human, rat,
`mouse, and monkey whole blood stimulated with LPS in vitro.
`lmmunomodulatory drugs (lMiDsTM) inhibit expresSion of cyclooxygenase—2 from
`TNF—a, lL-1l5 and LPS stimulated human PBMC in a partially lL-10- dependent
`manner.
`
`lmmunomodulatory analogs of thalidomide inhibit growth of Hs Sultan cells and
`angiogenesis in vivo.
`Thalidomide and its analogues inhibit lipopolysaccharide-mediated induction of
`cyclooxygenase—Z.
`Anti-proliferative activity and mechanism of action of thalidomide, CC-4047, CC—
`5013 and CC-11006 in chromosome 5 deleted cells N-amalwa and KG-1 and
`control cell lines MUTZ—5 and UT—7 in vitro.
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`21-880
`
`13.
`
`14.
`
`15.
`
`16.
`17.
`
`18.
`
`19.
`
`Effects of lMiDs on proliferation of breast cancer, NSCLC, CML and NHL cell
`lines in vitro.
`
`Anti- proliferative activity of CC-4047, CC—5013, CC—5079, and CC-10004 against
`the non-Hodgkin’s B lymphoma cell line Farage in vitro.
`Effect of CC—10004 and CC-5013 on proliferation of the mouse CLL line LNC,
`alone and in combination with vincristine.
`'
`Inhibition of endothelial cell migration by thalidomide, 00-4047, and CC-5013.
`Effect of CC-5013 on HlF—1 alpha expression and VEGF production in PC-3
`cells.
`
`Lenalidomide inhibits angiogenesis in vitro and reduces lung metastasis of
`mouse melanoma cells in an animal model.
`Novel thalidomide analogues display anti—angiogenic activity independently of
`immunomodulatory effects.
`
`2.6.2.3
`
`Secondary pharmacodynamics
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Addition of immunomodulatory drugs CC-5013 or CC-4047 to Rituximab
`enhances anti-tumor activity in a severe combined immunodeficiency (SCID)
`mouse lymphoma model.
`Use of lmiD3, a thalidomide analog, as an adjunct to therapy for experimental
`tuberculous meningitis.
`Thalidomide and its analogs overcome drug resistance of human multiple
`myeloma cells to conventional therapy.
`lMiDs augment fetal hemoglobin synthesis and can be used for the treatment of
`hemoglobin disorders like sickle cellanemia and B-thalassemia.
`Thalidomide and thalidomide analogue drug costimulate virus- specific CD8+ T
`cells in vitro.
`
`See previous reviews for details; a brief
`2.6.2.4 Safety Pharmacology
`summary of these studies is presented in this section.
`
`2.6.4 PHARMACOKINETICSITOXICOKINETICS,
`
`2.6.4.2
`
`Methods of Analysis
`
`1.
`
`2.
`
`Validation for the determination of CC-5013 in rat plasma (Heparin anticoagulant)
`using
`_
`“J
`for sample preparation and liquid chromatography
`with mass spectrometric detection.
`Validation of an analytical procedure for the determination of the enantiomers of
`CC-5013 in rat plasma (Heparin) using solid phase extraction and liquid
`chromatography with 5-—
`. mass spectrometric detection.
`
`lO
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`21-880
`
`3.
`
`4.
`
`5.
`
`Validation of an analytical procedure for the determination of CC—5013 in rabbit
`plasma (Heparin) using
`_ I
`i and liquid chromatography with
`—— mass spectrometric detection.
`Validation for the determination of CC-5013 in dog plasma (Heparin
`anticoagulant) using
`/ or sample preparation and liquid
`chromatography with mass spectrometric detection.
`.
`Validation for the determination of CC—5013 in primate plasma (Heparin
`anticoagulant) using
`_ V
`"for sample preparation and liquid
`chromatography with mass spectrometric detection.
`
`2.6.4.3
`
`Absorption
`
`1.
`
`2.
`
`[14C] CC-5013: A study of absorption and excretion following oral and
`intravenous administration to the rat.
`[14C] CC—5013: A study of absorption, excretion and metabolism following oral
`and intravenous administration to the cynomolgus monkey.
`
`2.6.4.4
`
`Distribution
`
`1.
`
`[14C] CC-5013: Quantitative whole-body autoradiography following a single oral
`administration (150 mg/kg) to the rat.
`
`2.6.4.7
`
`Pharmacokinetic drug interactions
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`N93
`
`CC- 5013: Effect on cytochrome P450 and related parameters in the male and
`female Sprague Dawley rat following oral (gavage) administration at 0, 75, 150
`and 300 mg/ kg/ day for 26 weeks.
`'
`CC— 5013: Effect on cytochrome P450 and related parameters in the male and
`female cynomolgus monkey following oral (gavage) administration at 0, 1 and 2
`mg/ kg/ day for 52 weeks.
`identification of the cytochrome P450 enzymes responsible for the in-vitro
`metabolism of (14C)—CC-5013 in human liver microsomes.
`Identification of human P450 isozymes involved in the metabolism of CC-1088
`and CC-5013.
`
`Effects of CC—1088 and CC-5013 on selected cytochrome P450 activities in
`human liver microsomes:_Prediction of drug interactions.
`Metabolism of (14C)—CC—5013 in isolated human hepatocytes.
`Comparison of chemical degradation pathways of Ienalidomide and thalidomide.
`
`2.6.6 TOXICOLOGY
`
`2.6.6.3
`
`Repeat-dose toxicity
`
`1-.
`2.
`
`CC— 5013: 7- day oral (gavage) administration range—finding study in the mouse.
`CC- 5013: 7 day oral (gavage) range-finding toxicity study in the rat.
`
`ll
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`21-880
`
`3.
`4.
`5.
`
`CC— 5013: 28 day oral (gavage administration) toxicity study in the rat.
`CC— 5013: 13 week oral (gavage administration) toxicity study in the rat.
`CC— 5013: 26 week oral (gavage) administration toxicity study in the rat with a 4
`week treatment— free period.
`
`2.6.6.6
`
`Reproductive and developmental toxicology
`
`Fertility and early embryonic development
`
`1.
`
`CC- 5013: Oral (gavage) study of fertility and early embryonic development in the
`rat (Segment 1).
`
`Embryofetal development
`
`1.
`
`.wzv
`
`4.
`
`5.
`
`CC- 5013: Oral (gavage) range-finding study of embryo-foetal development in the
`rat.
`'
`
`CC- 5013: Oral (gavage) study of embryo—foetal development in the rat.
`Preliminary study of CC- 5013 embryo-foetal development (Segment ll) in the
`non—pregnant New Zealand white rabbit.
`CC— 5013: Oral (gavage) range—finding study of embryo-foetal development in the
`rabbit.
`_
`CC— 5013: Oral (gavage) study of embryo-foetal development in the rabbit.
`
`Prenatal and postnatal development
`
`1.
`
`CC— 5013: Oral (gavage) study of pre—and postnatal development in the rat.
`
`MREEXRS nits writ
`Etta deleted.
`
`12
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`21-880
`
`See Appendix A for studies reviewed by Dr.
`Studies Previously Reviewed:
`Anwar Goheer on 4/27/2000, 6/2/2000, & 2/14/2001 and Appendix B for
`studies reviewed by Dr. Anthony Proakis on 6/06/01, 10/29/02, 12/23/02,
`& 3/31/05,
`.
`
`2.6.3 PHARMACOLOGY
`
`2.6.2.2
`
`Primary pharmacodynamics
`
`Mechanism of action:
`
`1.
`2.
`
`3.
`
`Amino-substituted thalidomide analogs: Potent inhibitors of TNF-a production.
`Differential cytokine modulation and T cell activation by two distinct classes of
`thalidomide analogues that are potent inhibitors of TNF-a.
`Thalidomide and its analogs overcome drug resistance of human multiple
`myeloma cells to conventional therapy.
`
`2.6.2.4
`
`Safety pharmacology
`
`Neurological effects:
`
`1.
`
`CC-5013: Effects on general activity and behaviour in the rat following oral
`administration.
`
`Cardiovascular effects:
`
`1.
`2.
`
`Effects of CC—5013 on cloned hERG channels expressed in mammalian cells.
`CC— 5013: Cardiovascular and respiratory effects in the anaesthetised dog
`following intravenous administration.
`
`2.6.4 PHARMACOKINETICSITOXICOKINETICS
`
`2.6.4.3
`
`Absorption
`
`1.
`
`2.
`3
`
`CC- 5013: A study to determine the oral bioavailability in the rat, dog and
`monkey.
`.
`CC- 5013: In vitro binding to plasma proteins in rat, rabbit, monkey and human.
`00-1088, CC—4047, CC-5013 and CC~7025: Comparative absorption by the
`Caco-2 cell line.
`
`2.6.4.5
`
`Metabolism
`
`1.
`
`Metabolism of (14C)—CC-5013 in isolated human hepatocytes.
`
`l3
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`21-880
`
`2.6.6 TOXICOLOGY
`
`2.6.6.2
`
`Single-dose toxicity
`
`1.
`
`2.
`
`3.
`
`4.
`
`CC— 5013: Single dose oral toxicity study in the mouse (approximation of the
`minimum lethal dose level).
`CC- 5013: Single dose intravenous toxicity study in the mouse (approximation of
`the minimum lethal dose level).
`CC— 5013: Single dose oral toxicity study in the rat (approximation of the
`minimum lethal dose level).
`CC— 5013: Single dose intravenous toxicity study in the rat (approximation of the
`minimum lethal dose level).
`
`2.6.6.3
`
`Repeat-dose toxicity
`
`.U‘F‘P’Nr"
`
`6.
`7.
`
`CC—5013: 7 day oral (gavage) range— inding toxicity study in the rat.
`CC-5013: 28 day oral (gavage administration) toxicity study in the rat.
`CC—5013: 13 week oral (gavage administration) toxicity study in the rat.
`CC-5013: 28 day oral (gavage administration) toxicity study in the monkey.
`CC-4047 & CC-5013: 28 day oral (gavage administration) toxicity study in the
`monkey.
`CC-5013: 13 week oral (gavage administration) toxicity study in the monkey.
`CC—5013: 52 week oral (gavage) administration toxicity study in the monkey with
`a 7 week treatment free period.
`
`6.6.6.4
`
`Genetic toxicology
`
`1.
`
`2.
`
`3.
`
`4.
`
`CC-5013: Reverse mutation in four histidine—requiring strains of Salmonella
`typhimurium and two tryptophan-requiring strains of Escherichia coli.
`CC-50-13: Mutation at the thymidine kinase (tk) locus of mouse lymphoma l5178y
`cells (MLA) using the microtitrer fluctuation technique.-
`CC—5013: Induction of chromosome aberrations in cultured human peripheral
`blood lymphocytes.
`CC-5013: lnduction of micronuclei in the bone marrow of treated rats.
`
`2.6.6.6
`
`Reproductive and developmental toxicology
`
`1
`
`Developmental and reproductive toxicity screening study for effects on embryo-
`fetal development in rabbits.
`
`14
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`21-880
`
`2.6.2 PHARMACOLOGY
`
`2.6.2.1
`
`Brief summary
`
`Structural analogues of thalidomide have been synthesized and'examined for inhibition
`of TNF-a production. The tested compounds can be classified into two classes. One
`class of compounds (selective cytokine inhibitory drugs, SelCleTM) are
`phosphodiesterase 4 inhibitors, inhibit TNF—a production, increase lL-10 production (in
`LPS-induced PBMC), and have little effect on T cell activation. The second class of
`compounds (immunomodulatory drugs, lMiDsTM), similar tothalidomide, are not
`phosphodiesterase 4 inhibitors, markedly stimulate T cell proliferation, and lL-2 and
`lFN-y production.
`In addition to these immune effects, there is evidence that
`thalidomide and its analogues act directly on tumor cells, via inducing apoptosis or G1»
`growth arrest.
`
`Lenalidomide (CC-5013) is a thalidomide analogue.
`R (+) forms.
`
`It is a racemic mixture of S (-) and
`
`0 o
`
`‘
`
`S
`
`NH2
`Lenalidomide
`
`O O
`
`n
`
`0
`Thalidomide
`
`Angiogenesis, the formation of new bloodavesselsby pre- existing endothelial cells
`(EC), depends mainly on proper activation, proliferation, adhesion, migration and
`maturation of EC (Griffioen & Molema, Pharmacol Rev 2000; 52:237—268). Therefore,
`inhibition of EC growth, adhesion and migration, and growth factor expression are
`putative anti—angiogenic targets. A series of preclinical studies had been performed to
`support the clinical evaluationof CC:5013in_.can,c,er patients.
`
`Lenalidomide inhibited TNF—a, lL-1B, lL-6 and lL-12 in LPS—stimulated PBMC (Muller et
`al., Bioorg Med Chem lett 1999; 921625-1630).
`It enhanced lFN-y and lL-2 production in
`anti-CD3 stimulated CD4+ T cells (Schafer et al., J Pharmacol Exp Ther 2003;
`305:1222-1232). Lenalidomide increased fetal hemoglobin in human CD34+ progenitor
`cells.
`It inhibited the expression of COX—2, but not COX-1 protein in LPS—, TNF—d, and
`lL-1B stimulated PBMC. Neutralizing antibody to lL-10 but not lL—1B or TNF—o partially
`reversed the inhibitory effect of CC-5013v on COX—2 expression. These results suggest
`that the anti—tumor effects of lenalidomide may be due to in part to elevation of lL-10
`production and its subsequent inhibition of COX-2 expression. Lenalidomide inhibited
`the growth of Namalwa, cells (ahuman. B celliymphoma cellline with a deletion of one
`chromosome 5) but less effective in inhibiting growth of KG-1 cells (human'myeloblastic
`cell line, also with a deletion of one chromosome 5) and other cell lines without
`'
`chromOsome 5 deletions. Patients with an isolated interstitial deletion of chromosome
`5q31 may benefit from this immunomodUlatory / antiangiogenic drug.
`
`15
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`21-880
`
`2.6.2.2
`
`Primary pharmacodynamics
`
`Mechanism of action:
`
`1.
`
`Amino-substituted thalidomide analogs: Potent inhibitors of TNF- a
`production. Muller et al., Bioorg Med Chem Lett 1999; 9:1625-1630. See
`Appendix A for details.
`
`TNF-or inhibition in LPS stimulated human PBMC and whole blood
`b thalidomide analo-ues.
`
`
`
`
`
`
`480
`100
`74
`00-5013
`
`
`
`
`
`
`Compound
`TNF—or Whole blood
`TNF—or Inhibit (%).
`
`Name
`At 100 MM
`ICSO(nM)
`TNF-CX IC50 (nM)
`
`004047
`95
`13
`25
`
`
`CC—4047
`99
`3.9
`14
`
`
`93
`73
`
`
`
`00—4047
`
`85
`
`2.
`
`Inhibition of TNF-a production by PBMC and elevation of lL-2 and MlP-3a
`production by T cells by CC-4047, CC-5013, and C-11006 in vitro. Study
`Number: 5043— 152- 5119- 172.
`
`Final_lC5o and EC50 values
`
`cc-4047
`cc-so13
`CC-11006
`
`
`
`
`HUT’R‘i‘ch’FCXCdg/gay
`0.013
`0.100
`0.050
`muff—2213:“ if“
`0.010
`0.150
`0.11
`
`
`I
`”JifgaTE‘Z';a???
`0.069
`1 .2
`12
`
`‘
`1
`Human T cell 3-day
`0.0075
`Q15
`15
`lL—2 EC50 (11M)
`(Excerpted from the sponsor’s submission)
`
`’
`
`1
`
`l6
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`21-880
`
`3.
`
`Inhibition of tumor necrosis factor alpha (TNF-a) production by CC-4047,
`CC-5013, and CC-11006 from human and rat whole blood stimulated with
`lipopolysaccharide. Study Number: 5196— 175.
`
`Blood samples from three individual human donors and three rats were used to
`compare the ability of lMiDs to inhibit TNF-a production by LPS. TNF—a production was
`inhibited in human blood as shown below.
`
`
`
`Compound Human Whole Blood Rat Whole Blood
`
`
`TNF—a IC50 (pM)
`TNF-a IC50 (HM)
`
`
`
` cc—4047 0.14 .12
`CC-5013
`13
`>100
`
`
`CC-l 1006 | 73. 0-53
`
`
`
`(Excerpted from the sponsor’s submission)
`
`leo for lenalidomide (CC-5013) in rat whole blood could not be calculated.
`
`4.
`
`Elevation of lL-2 production by CC-4047, CC-5013, and CC-11006 from
`human and rat whole blood stimulated with Concanavalin A. Study Number:
`5197— 189- 5226— 016.
`
`Blood samples from three individual human donors and three rats were used to
`compare the ability of lMiDs to elevate IL—2 production. Human and rat heparinized
`whole blood was plated on 96 well flat-bottom tissue culture plates. After 1 hour of
`incubat