CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 202207Orig1s000 PHARMACOLOGY REVIEW(S) --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- PAUL C BROWN 07/26/2012 Reference ID: 3164980 NDA #: 202-207 Reviewer: Olayinka A. Dina, DVM, Ph.D. TABLE OF CONTENTS 1 EXECUTIVE SUMMARY ......................................................................................... 8 1.1 INTRODUCTION .................................................................................................... 8 1.2 BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 8 1.3 RECOMMENDATIONS .......................................................................................... 10 2 DRUG INFORMATION .......................................................................................... 14 2.1 DRUG ............................................................................................................... 14 2.2 RELEVANT INDS, NDAS, BLAS AND DMFS......................................................... 17 2.3 DRUG FORMULATION ......................................................................................... 17 2.4 COMMENTS ON NOVEL EXCIPIENTS..................................................................... 22 2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 22 2.6 PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 23 2.7 REGULATORY BACKGROUND .............................................................................. 23 3 STUDIES SUBMITTED.......................................................................................... 23 3.1 STUDIES REVIEWED........................................................................................... 23 3.2 STUDIES NOT REVIEWED ................................................................................... 25 3.3 PREVIOUS REVIEWS REFERENCED...................................................................... 25 4 PHARMACOLOGY................................................................................................ 25 4.1 PRIMARY PHARMACOLOGY ................................................................................. 25 4.2 SECONDARY PHARMACOLOGY ............................................................................ 40 4.3 SAFETY PHARMACOLOGY................................................................................... 40 5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 47 5.1 PK/ADME........................................................................................................ 47 5.2 TOXICOKINETICS ............................................................................................... 54 6 GENERAL TOXICOLOGY..................................................................................... 54 6.1 SINGLE-DOSE TOXICITY ..................................................................................... 58 6.2 REPEAT-DOSE TOXICITY .................................................................................... 77 7 GENETIC TOXICOLOGY ...................................................................................... 97 7.1 IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES)....................... 97 7.2 IN VITRO ASSAYS IN MAMMALIAN CELLS............................................................ 102 7.3 IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY)................ 107 7.4 OTHER GENETIC TOXICITY STUDIES.................................................................. 111 8 CARCINOGENICITY.......................................................................................... 111 9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY .............................. 111 10 SPECIAL TOXICOLOGY STUDIES................................................................. 112 10.1 LOCAL TOLERANCE STUDIES ............................................................................ 112 10.2 ANTIGENICITY.................................................................................................. 119 2 Reference ID: 3151224 NDA #: 202-207 Reviewer: Olayinka A. Dina, DVM, Ph.D. 11 INTEGRATED SUMMARY AND SAFETY EVALUATION............................... 124 12 APPENDIX/ATTACHMENTS........................................................................... 128 12. 1 REFERENCES .................................................................................................... 128 3 Reference ID: 3151224 NDA #: 202-207 Reviewer: Olayinka A. Dina, DVM, Ph.D. Table of Tables Table 1: Tilmanocept / Technetium Tc 99m Tilmanocept CAS Number........................ 14 Table 2: Tilmanocept / Technetium Tc 99m Tilmanocept Generic Name...................... 14 Table 3: Chemical Name of Tilmanocept / Technetium Tc 99m Tilmanocept ............... 15 Table 4: Drug substance and product ........................................................................... 17 Table 5: Formulation of DTPA-Mannosyl-Dextran 1, 2, 3 ................................................. 18 Table 6: Composition of Technetium Tc 99m Tilmanocept Injection 1, 2 ........................ 18 Table 7: Components and Composition of Buffered Saline 1, 2...................................... 19 Table 8: Drug formulations ............................................................................................ 20 Table 9: List of Nonclinical studies and Drug formulations used ................................... 21 Table 10: Specified Impurities in DTPA-Mannosyl-Dextran (drug substance)1 ............. 22 Table 11: Dosage regimen for Technetium Tc 99m Tilmanocept Injection 1, 2 ............... 23 Table 12: Summary Data from Concentration-Dependent Binding of Technetium Tc 99m Tilmanocept to Multisite MBR in Vitro at 0-40C 1 ........................................................... 34 Table 13: DTPA-Mannosyl-Dextran Dose multiples (Study No. 1146-102) ................... 41 Table 14: Summary of Methods/Observations (Study No. 1146-102) ........................... 41 Table 15: Thromboxane B2 and histamine data (Study No. 1146-102) ........................ 42 Table 16: Study design - (b) (4) 1576-04774 1, 2 ................................................... 44 Table 17: DTPA-Mannosyl-Dextran Dose multiples (Study No. 1156-04774) ............... 44 Table 18: Summary of Methods/Observations (Study No. 1576-04774) ....................... 44 Table 19: Summary of changes in QT interval in dogs (study 1156-04774).................. 46 Table 20: Summary of cardiovascular changes in dogs (Study 1156-04774) ............... 46 Table 21: Determination of NOAEL in Study 1156-04774............................................. 47 Table 22: Overview of Pharmacokinetic Studies1, 2 ....................................................... 48 Table 23: Study Design (Study No. (b) (4) 608002).......................................................... 50 Table 24: Tissues and Organs collected after euthanasia............................................. 51 Table 25: 1Percentages injected dose (%ID±SD) of Technetium Tc 99m Tilmanocept in tissues of rabbit at 0.25, 1 and 3 h after a single SC injection of 5 μg/animal ............... 53 Table 26: Overview of Toxicology Studies 1, 2 ............................................................... 55 Table 27: Study groups and dose levels (Study No. 1146-100) .................................... 59 Table 28: DTPA-Mannosyl-Dextran Dose multiples ( (b) (4) 1146-100) .............. 59 Table 29: Summary of Methods/Observations (Study No. 1146-100) ........................... 60 Table 30: Determination of NOAEL in Study No. 1146-100 .......................................... 61 Table 31: Study Errata – Study No. 1576-06049........................................................... 63 Table 32: Study Design and Dose groups (Study No. 1576-06049).............................. 64 Table 33: DTPA-Mannosyl-Dextran Dose multiples (Study No. 1576-06049) ............... 64 Table 34: Summary of Methods/Observations (Study No. 1576-06049) ....................... 64 Table 35: 1Summary of clinical chemistry findings on SD15 (Study No. 1576-06049) .. 65 Table 36: Determination of NOAEL in Study No. 1576-06049 ...................................... 67 Table 37: Study Design and Dose groups (Study No. 1146-101).................................. 68 Table 38: DTPA-Mannosyl-Dextran Dose multiples (Study No.1146-101).................... 69 Table 39: Summary of Methods/Observations (Study No. 1146-101) ........................... 69 Table 40: 1Summary of hematology and serum chemistry findings on SD15................ 70 Table 41: Determination of NOAEL in Study No. 1146-101 .......................................... 71 Table 42: Study Design and Dose groups (Study No.1576-04582)............................... 73 4 Reference ID: 3151224 NDA #: 202-207 Reviewer: Olayinka A. Dina, DVM, Ph.D. Table 84: Summary of findings in Dermal Draize Test ................................................ 118 Table 85: Determination of NOAEL in Study No. (b) (4) 1576-06069................. 119 Table 86: Study No. (b) (4) 1576-04583.......................................................................