CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`209637Orig1s000
`
`NON-CLINICAL REVIEW(S)
`
`
`
`
`
`
`

`

`Tertiary Pharmacology/Toxicology Review
`
`Date: December 1, 2017
`From: Timothy J. McGovern, Ph.D., ODE Associate Director for Pharmacology and
`Toxicology, OND IO
`BLA: 209637
`Agency receipt date: December 5, 2016
`Drug: Ozempic (Semaglutide)
`Sponsor: Novo Nordisk
`
`Indication: Adjunct to diet and exercise to improve glycemic control in adults with type
`2 diabetes mellitus
`
`Reviewing Division: Division of Metabolism and Endocrinology Products
`
`Introductory Comments: The pharmacology/toxicology reviewer and supervisor
`concluded that the nonclinical data support approval of semaglutide for the indication
`listed above.
`
`The established pharmacologic class for semaglutide is glucagon-like peptide-1 (GLP-1)
`receptor agonist. Exenatide (Byetta and Bydureon), dulaglutide (Trulicity), albiglutide
`(Tanzeum), lixisenatide (Adlyxin) and liraglutide (Victoza) are previously approved
`GLP-1 agonists in the US.
`
`Semaglutide is a novel GLP-1 analogue that is engineered to have a low clearance and
`long elimination half-life, achieved by albumin binding that is facilitated by a fatty di-
`acid attached to the peptide backbone. The peptide backbone has also been modified to
`reduce degradation by the DPP-4 enzyme. The maximum recommended clinical dose is a
`1 mg once weekly subcutaneous injection.
`
`An appropriate nonclinical program was conducted by the sponsor to support approval of
`semaglutide. Semaglutide elicited expected pharmacological responses in rats, diabetic
`mice, and minipigs. The primary nonclinical toxicity studies were conducted in mice, rats
`and monkeys; dosing was limited by pharmacologically mediated reductions in food
`intake and body weight. Primary findings included liver necrosis, focal C-cell
`hyperplasia, C-cell nests, and dilated ultimobranchial ducts in mice and ECG
`abnormalities and myocardial vacuolation and degeneration. These findings were
`observed at doses associated with exposures that were 17- to 27-times the anticipated
`clinical exposure.
`
`A standard battery of genetic toxicity studies was conducted and produced no evidence of
`genotoxic potential. Carcinogenicity studies in mice and rats demonstrated a risk for
`tumorigenesis, similar to other GLP-1 agonists, at exposures that were 2-fold (mice) and
`0.4-fold (rats) or greater than the anticipated clinical AUC. The findings included thyroid
`C-cell adenomas and carcinomas. The totality of the available data indicates that rodents
`are more sensitive to the C-cell proliferative effects than nonrodents and presumably
`humans. Although the human relevance of GLP-1 receptor agonist-induced C-cell
`
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`Reference ID: 4189095
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`

`

`tumorigenesis in rodents is unknown, human relevance to drug-induced C-cell tumors
`cannot be discounted and, therefore, a boxed warning and appropriate epidemiological
`monitoring continue to be warranted for GLP-1 agonists.
`
`Reproductive and developmental toxicity studies were conducted in rats, rabbits and
`monkeys. Key findings included reduced growth in rats and monkeys, fetuses with
`visceral and/or skeletal abnormalities at clinically relevant exposures in all species, and
`early pregnancy losses in rabbits and monkeys. The identified developmental findings
`generally occurred in the presence of significant maternal toxicity so the direct
`relationship to drug administration is not clear. Given that they occurred at clinically
`relevant exposures, I agree that they merit discussion in the product label.
`
`Conclusion:
`I agree with the division pharmacology/toxicology conclusion that semaglutide can be
`approved from the pharmacology/toxicology perspective. I have reviewed the proposed
`labeling and agree with the recommendations made by the division regarding the relevant
`nonclinical sections.
`
`Reference ID: 4189095
`
`2
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`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TIMOTHY J MCGOVERN
`12/01/2017
`
`Reference ID: 4189095
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
`
`NDA 209637
`Application number:
`SDN 1
`Supporting document/s:
`12/05/2016
`Applicant’s letter date:
`12/05/2016
`CDER stamp date:
`Semaglutide
`Product:
`Type 2 Diabetes Mellitus
`Indication:
`Novo Nordisk
`Applicant:
`DMEP
`Review Division:
`Federica Basso, Ph.D
`Reviewer:
`Ron Wange, Ph.D
`Supervisor/Team Leader:
`Jean-Marc Guettier, MD
`Division Director:
`Peter Franks
`Project Manager:
`Template Version: September 1, 2010
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 209637 are owned by Novo Nordisk or are data for
`which Novo Nordisk has obtained a written right of reference.
`Any information or data necessary for approval of NDA 209637 that Novo Nordisk 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 reflected in the drug’s approved labeling. Any data or information described or
`referenced below from reviews or publicly available summaries of a previously approved
`application is for descriptive purposes only and is not relied upon for approval of NDA
`209637.
`
`Reference ID: 4134195
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`3
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`4
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`NDA # 209637
`
`Reviewer: Federica Basso, Ph.D
`
`TABLE OF CONTENTS
`
`1
`
`EXECUTIVE SUMMARY.........................................................................................11
`1.1
`INTRODUCTION ...................................................................................................11
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS .....................................................11
`1.3
`RECOMMENDATIONS ...........................................................................................12
`2 DRUG INFORMATION............................................................................................15
`2.1
`DRUG ................................................................................................................15
`2.2
`RELEVANT INDS, NDAS, BLAS AND DMFS..........................................................16
`2.3
`DRUG FORMULATION ..........................................................................................16
`2.4
`COMMENTS ON NOVEL EXCIPIENTS......................................................................17
`2.5
`COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN........................................17
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN.....................................17
`2.7
`REGULATORY BACKGROUND ...............................................................................18
`STUDIES SUBMITTED...........................................................................................18
`3.1
`STUDIES REVIEWED............................................................................................18
`3.2
`STUDIES NOT REVIEWED.....................................................................................22
`3.3
`PREVIOUS REVIEWS REFERENCED.......................................................................22
`PHARMACOLOGY .................................................................................................23
`4.1
`PRIMARY PHARMACOLOGY ..................................................................................23
`4.2
`SECONDARY PHARMACOLOGY .............................................................................31
`4.3
`SAFETY PHARMACOLOGY ....................................................................................31
`PHARMACOKINETICS/ADME/TOXICOKINETICS ...............................................34
`5.1
`PK/ADME .........................................................................................................34
`6 GENERAL TOXICOLOGY......................................................................................44
`6.2
`REPEAT-DOSE TOXICITY .....................................................................................44
`STUDY TITLE: 13 WEEK TOXICITY STUDY IN MICE WITH SUBCUTANEOUS ADMINISTRATION..44
`STUDY TITLE: TOXICITY STUDY BY SUBCUTANEOUS ADMINISTRATION TO CD RATS FOR AT
`LEAST 26 WEEKS FOLLOWED BY A 4-WEEK RECOVERY PERIOD ..........................................53
`STUDY TITLE: TOXICITY STUDY BY SUBCUTANEOUS ADMINISTRATION TO CYNOMOLGUS
`MONKEYS FOR 52 WEEKS FOLLOWED BY A 4 WEEK RECOVERY PERIOD...............................63
`OTHER STUDIES...........................................................................................................76
`STUDY TITLE: COMPARATIVE TOXICITY STUDY BY SUBCUTANEOUS ADMINISTRATION OF FRESH
`OR AGED FORMS OF THE TEST MATERIAL TO SPRAGUE DAWLEY RATS FOR 4 WEEKS (AFTER
`AN INITIAL 2-WEEK DOSE ESCALATION PERIOD) FOLLOWED BY A 2 WEEK RECOVERY PERIOD 76
`STUDY TITLE:
` NNC 0113-0217. COMPARATIVE TOXICITY
`
`STUDY BY SUBCUTANEOUS ADMINISTRATION TO SD RATS FOR 13 WEEKS...........................87
`7 GENETIC TOXICOLOGY........................................................................................97
`7.1
`IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES) .......................97
`
`Reference ID: 4134195
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`NDA # 209637
`
`Reviewer: Federica Basso, Ph.D
`
`IN VITRO ASSAYS IN MAMMALIAN CELLS.............................................................105
`7.2
`IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY) ................108
`7.3
`8 CARCINOGENICITY.............................................................................................113
`STUDY TITLE: CARCINOGENICITY STUDY BY SUBCUTANEOUS ADMINISTRATION TO CD RATS
`FOR 104 WEEKS..........................................................................................................113
`STUDY TITLE: CARCINOGENICITY STUDY BY SUBCUTANEOUS ADMINISTRATION TO CD-1
`MICE FOR 104 WEEKS.................................................................................................128
`OTHER STUDIES ..........................................................................................................137
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY...............................141
`9.1
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT..............................................142
`9.2
`EMBRYONIC FETAL DEVELOPMENT.....................................................................166
`9.3
`PRENATAL AND POSTNATAL DEVELOPMENT........................................................181
`11-WEEK SUBCUTANEOUS TOXICITY STUDY IN JUVENILE RATS FOLLOWED BY A 4-WEEK
`RECOVERY PERIOD .....................................................................................................188
`10
`SPECIAL TOXICOLOGY STUDIES..................................................................198
`
`MECHANISTIC STUDIES TO EXPLORE EFFECTS ON EMBRYO-FETAL
`DEVELOPMENT IN RATS...........................................................................................198
`BACKGROUND .............................................................................................................198
`EMBRYOFETAL NUTRITION IN RODENTS VERSUS PRIMATES..............................................200
`MECHANISTIC STUDIES KEY FINDINGS............................................................................201
`CONCLUSION...............................................................................................................201
`TIME DEPENDENCY OF EMBRYONIC EFFECTS..................................................................202
`PRESENCE OF FUNCTIONAL GLP-1 RECEPTORS IN YOLK SAC AND EMBRYO......................221
`DISTRIBUTION OF SEMAGLUTIDE TO THE INVERTED YOLK SAC PLACENTA ..........................225
`FUNCTIONAL EFFECTS OF SEMAGLUTIDE ON INVERTED YOLK SAC PINOCYTOSIS ................228
`11
`INTEGRATED SUMMARY AND SAFETY EVALUATION................................230
`SAFETY PHARMACOLOGY.............................................................................................230
`GENERAL TOXICITY ......................................................................................................231
`GENOTOXICITY ............................................................................................................232
`CARCINOGENICITY.......................................................................................................232
`DART ........................................................................................................................233
`LOCAL TOLERANCE ......................................................................................................235
`12
`APPENDIX/ATTACHMENTS ............................................................................236
`
`Reference ID: 4134195
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`NDA # 209637
`
`Reviewer: Federica Basso, Ph.D
`
`Table of Tables
`
`Table 1. Composition of semaglutide 1.34 mg/ml solution for injection (Applicant’s table)
`........................................................................................................................................17
`Table 2. Effect of semaglutide on AgRP, NPY, CART, and POMC mRNA in the arcuate
`nucleus (Applicant’s figure).............................................................................................29
`Table 3. VivoTag750-semaglutide signal in the brain (Applicant’s table) .......................31
`Table 4. Irwin test in the rat (Applicant’s table)...............................................................32
`Table 5. Pharmacokinetic parameters for male rats following single SC dose
`(Applicant’s table) ...........................................................................................................33
`Table 6. Effect on renal function in rats at 0-8h (Applicant’s table) ................................33
`Table 7. Effect on renal function in male SD rats at 8-24h (Applicant’s table) ...............34
`Table 8. Interspecies comparison of dose-normalized (1 mg/kg) pharmacokinetics for
`repeated subcutaneous administration of semaglutide (Applicant’s table).....................35
`Table 9. In vitro plasma protein binding (Applicant’s table) ............................................36
`Table 10. Tissue:plasma radioactivity concentration ratio in pigmented rats (Applicant’s
`table)...............................................................................................................................37
`Table 11. Tissue:plasma radioactivity concentration ratio in male Wistar rats (Applicant’s
`table)...............................................................................................................................38
`Table 12. Tissue:plasma radioactivity concentration ratio in pregnant albino rats
`(Applicant’s table) ...........................................................................................................39
`Table 13. Tissue : plasma radioactivity concentration ratio in fetal tissues from pregnant
`female albino rats (Applicant’s table)..............................................................................40
`Table 14. Overview of plasma metabolite profiling data (Applicant’s table) ...................41
`Table 15. [3H]Oct-semaglutide: Metabolite profiling of rat plasma after single and
`repeated doses (Applicant’s table) .................................................................................41
`Table 16. [3H]Oct-semaglutide: Metabolite profile of urine, feces and bile in the rat
`(Applicant’s table) ...........................................................................................................42
`Table 17. [3H]Oct-semaglutide: Metabolite profile of urine, feces and bile in the monkey
`(Applicant’s table) ...........................................................................................................42
`Table 18. Excretion of [3H]Oct-semaglutide in intact rat following a single SC dose
`(Applicant’s table) ...........................................................................................................43
`Table 19. Excretion of [3H]Oct-semaglutide following a single SC dose to the bile
`cannulated rat (Applicant’s table) ...................................................................................43
`Table 20. Excretion of [3H]Oct-semaglutide in male cynomolgus monkey (Applicant’s
`table)...............................................................................................................................43
`Table 21. Secretion of [3H]Oct-semaglutide in lactating rats (Applicant’s table).............44
`Table 22. Clinical signs (Applicant’s table) .....................................................................45
`Table 23. Body weight gain (Applicant’s table)...............................................................46
`Table 24. Food consumption (Applicant’s table) ............................................................46
`Table 25. Histopathology findings, mice, 13-week (Applicant’s table)............................51
`Table 26. Toxicokinetic parameters, mice, Day 1 and week 13 (Applicant’s table)........52
`Table 27. Clinical signs (Applicant’s table) .....................................................................54
`Table 28. Body weight, rat (Applicant’s table) ................................................................55
`Table 29. Feed consumption (Applicant’s table) ............................................................56
`Table 30. Hematology, percent difference from control (Applicant’s table) ....................57
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`Reference ID: 4134195
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`NDA # 209637
`
`Reviewer: Federica Basso, Ph.D
`
`Table 31. Clinical chemistry, percent difference from control (Applicant’s table) ...........58
`Table 32. Urinalysis, percent change vs. control (Applicant’s table) ..............................59
`Table 33. Macroscopic findings (Applicant’s table) ........................................................59
`Table 34. Organ weight, females, percent change from control.....................................60
`Table 35. Histopathological findings, dosing period (Applicant’s table)..........................61
`Table 36. Histopathological findings, recovery period (Applicant’s table) ......................61
`Table 37. Toxicokinetic parameters (Applicant’s table) ..................................................62
`Table 38. Clinical signs (Applicant’s table) .....................................................................65
`Table 39. Body weight, monkeys (Applicant’s table) ......................................................65
`Table 40. Hematology, monkey, week 52 (Applicant’s table).........................................66
`Table 41.Clinical chemistry, monkeys (Applicant’s table)...............................................67
`Table 42. Serum calcitonin levels-male monkeys (Applicant’s table).............................68
`Table 43. Serum calcitonin levels-female monkeys (Applicant’s table)..........................68
`Table 44. Urinalysis, female monkeys, week 51 (Applicant’s table)...............................69
`Table 45. Gross pathology, monkeys (Applicant’s table) ...............................................69
`Table 46. Organ weights, monkey, 52 week (Applicant’s table).....................................70
`Table 47. Summary of histopathology findings (Applicant’s table) .................................71
`Table 48. Toxicokinetic parameters (Applicant’s table) ..................................................73
`Table 49. Body weight change, percent change from control (Applicant’s table)...........78
`Table 50. Hematology, percent change vs. control (Applicant’s table)...........................81
`Table 51. Hematology, recovery, percent change vs. control (Applicant’s table)...........81
`Table 52. Clinical chemistry, percent change vs. control (Applicant’s table)..................82
`Table 53. Clinical chemistry, recovery, percent change vs. control (Applicant’s table) ..83
`Table 54. Urinalysis, percent change vs. control (Applicant’s table) ..............................83
`Table 55.Urinalysis, recovery, percent change vs. control (Applicant’s table) ...............84
`Table 56. Organ weight, percent change vs. control (Applicant’s table) ........................84
`Table 57. Summary of histopathology findings (Applicant’s table) .................................85
`Table 58. Estimated toxicokinetic parameters on Day 15 and Week 6 (Applicant’s table)
`........................................................................................................................................86
`Table 59. Body weight ....................................................................................................89
`Table 60. Hematology, percent change vs. control (Applicant’s table)...........................91
`Table 61. Clinical chemistry, percent change vs. control (Applicant’s table)..................92
`Table 62. Urinalysis, percent change vs. control (Applicant’s table) ..............................93
`Table 63. Organ weights, percent change vs. control (Applicant’s table).......................94
`Table 64. Toxicokinetic parameters,
` NNC0113-0217
`(Applicant’s table) ...........................................................................................................96
`Table 65. Antidrug antibody (Applicant’s table) ..............................................................96
`Table 66. Summary of mutagenicity data (Applicant’s table) .......................................100
`Table 67. Historical negative controls (Applicant’s table) .............................................104
`Table 68. Historical positive controls (Applicant’s table) ..............................................105
`Table 69. Chromosome aberrations assay, Experiment 1 (Applicant’s table)..............107
`Table 70. Chromosome aberrations assay, Experiment 2 (Applicant’s table)..............107
`Table 71. Historical vehicle control ranges – Male donors (Applicant’s table) .............108
`Table 72. Clinical signs (Applicant’s table) ...................................................................110
`Table 73. Body weight gain, percent change (Applicant’s table)..................................111
`Table 74. Micronucleus assay, 24h sample time (Applicant’s table) ............................112
`
`Reference ID: 4134195
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`(b) (4)
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`NDA # 209637
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`Reviewer: Federica Basso, Ph.D
`
`Table 75. Micronucleus assay, 48h sample time (Applicant’s table) ............................112
`Table 76. Toxicokinetics (Applicant’s table) .................................................................112
`Table 77. Group distribution of mortality (Applicant’s table) .........................................117
`Table 78. Factors contributory to death (Applicant’s table) ..........................................117
`Table 79. Clinical signs (Applicant’s table) ...................................................................117
`Table 80. Body weight ..................................................................................................117
`Table 81. Clinical chemistry-percent change vs. control (Applicant’s table).................119
`Table 82. Summary of macroscopic findings (Applicant’s table) ..................................120
`Table 83. Summary of neoplastic findings in the thyroid glands ..................................121
`Table 84. Summary of neoplastic findings in the deep cervical LN (Applicant’s table) 121
`Table 95. Summary of hyperplastic findings in the thyroid glands (Applicant’s table)..123
`Table 96. Summary of non-neoplastic changes in the Brunner’s glands (Applicant’s
`table).............................................................................................................................124
`Table 97. Summary of non-neoplastic changes in the stomach (Applicant’s table) .....125
`Table 98. Summary of non-neoplastic changes in the lungs (Applicant’s table) ..........126
`Table 99. Summary of non-neoplastic changes in the adrenal glands (Applicant’s table)
`......................................................................................................................................126
`Table 100. Summary of TK parameters in the rat (Applicant’s table)...........................127
`Table 101. Group distribution of mortality (Applicant’s table) .......................................129
`Table 102. Clinical signs (Applicant’s table) .................................................................131
`Table 103. Body weight, percent change vs. controls (Applicant’s table) ....................132
`Table 104. Food consumption-percent change vs. control (Applicant’s table) .............133
`Table 105. Macroscopic findings in the thyroid gland (Applicant’s table) .....................134
`Table 106. Macroscopic findings in the gall bladder (Applicant’s table) .......................134
`Table 107. Neoplastic findings in the mouse thyroid gland ..........................................135
`Table 108. Summary of findings of ectopic thyroid tumors or metastatic findings
`(Applicant’s table) .........................................................................................................135
`Table 110. Non neoplastic findings in the thyroid and duodenum (Applicant’s table) ..136
`Table 111. Summary of toxicokinetic parameters (Applicant’s table)...........................137
`Table 113. Plasma calcitonin in rats at week 6 (Applicant’s table)...............................141
`Table 114. Percentage of histological sections with diffuse C-cell hyperplasia
`(Applicant’s table) .........................................................................................................141
`Table 115. Number of animals with focal C-cell hyperplasia (Applicant’s table) ..........141
`Table 116. Pregnancy Performance (Applicant’s table) ...............................................144
`Table 117. Group incidence of major fetal abnormalities (Applicant’s table)................145
`Table 118. Incidence of minor abnormalities and variants (Applicant’s table)..............146
`Table 119. Incidence of skeletal ossification parameters (Applicant’s table) ...............148
`Table 120. Toxicokinetic parameters, GD 6 and GD16 (Applicant’s table) ..................149
`Table 121. Maternal and fetal toxicokinetic parameters (Applicant’s table) .................151
`Table 122. Litter data, group mean values on GD 20 (Applicant’s table) .....................152
`Table 123. Placental, litter and fetal weights, group mean values on GD 20 (Applicant’s
`table).............................................................................................................................153
`Table 124. Fetal examinations-major abnormalities (Applicant’s table) .......................154
`Table 125. Fetal examinations-skeletal and visceral abnormalities (Applicant’s table)154
`Table 126. Fetal examinations-minor skeletal abnormalities/variants (Applicant’s table)
`......................................................................................................................................155
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`NDA # 209637
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`Reviewer: Federica Basso, Ph.D
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`Table 127. Fetal examinations-minor visceral abnormalities (Applicant’s table) ..........156
`Table 128. Body weights (Applicant’s table).................................................................159
`Table 129. Toxicokinetic parameters on GD6 and GD17 (Applicant’s table) ...............163
`Table 130. Estrous cycles (Applicant’s table)...............................................................164
`Table 131. Historical control data for Crl:CD (SD) female rats approximately 11 to 13
`weeks old at pairing (Applicant’s table) ........................................................................164
`Table 132. Litter data - group mean values on GD20 (Applicant’s table).....................165
`Table 133. Placental, litter and fetal weights - group mean values (g) GD 20 (Applicant’s
`table).............................................................................................................................165
`Table 134. Offspring data (Applicant’s table) ...............................................................166
`Table 135. Toxicokinetic parameters, female rabbits, GD6 and GD19 (Applicant’s table).
`......................................................................................................................................170
`Table 136. Cesarean section data (Applicant’s table) ..................................................171
`Table 137. Fetal examination (Applicant’s table)..........................................................172
`Table 138. Gestational body weight, monkey (Applicant’s table) .................................175
`Table 139. Toxicokinetic parameters, gestational monkey (Applicant’s table) .............176
`Table 140. Summary of fetal malformations, monkeys (Applicant’s table)...................179
`Table 141. Summary of external findings (Applicant’s table) .......................................181
`Table 142. Histopathology findings (Applicant’s table).................................................181
`Table 143. Gestational body weight (Applicant’s table)................................................183
`Table 144. Maternal body weight during lactation (Applicant’s table) ..........................183
`Table 145. Toxicokinetic parameters on GD 16, 18, 20, 50, and 140 (Applicant’s table)
`......................................................................................................................................184
`Table 146. Infant body weight after birth (Applicant’s table).........................................186
`Table 147. Clinical pathology (Applicant’s table)..........................................................194
`Table 148. Urinalysis, percent change vs. control (Applicant’s table) ..........................195
`Table 149. Histopathology (Applicant’s table) ..............................................................196
`Table 150. Toxicokinetic parameters at week 5 and 11 (Applicant’s table)..................197
`Table 151. Summary of fetal findings in rats (Applicant’s table)...................................198
`Table 152. Summary of fetal findings in rabbits (Applicant’s table)..............................199
`Table 153. Summary of fetal findings in monkeys (Applicant’s table) ..........................199
`Table 154. Litter data (Applicant’s table) ......................................................................205
`Table 155. Plasma concentration (Applicant’s table) ...................................................205
`Table 156. Growth and development of cultured embryos, subgroup A (Applicant’s
`table).............................................................................................................................206
`Table 157. Summary of observations in cultured embryos, subgroup A (Applicant’s
`table).............................................................................................................................207
`Table 158. Growth and development at GD 11, subgroup B (Applicant’s table) ..........207
`Table 159. Growth and development at GD 13, subgroup C (Applicant’s table)..........208
`Table 160. Growth and development at GD 15, subgroup D (Applicant’s table)..........208
`Table 161. Summary of observations on GD 11, subgroup B (Applicant’s table) ........209
`Table 162. Summary of observations on GD 13, subgroup C (Applicant’s table) ........210
`Table 163. Summary of observations on GD 15, subgroup D (Applicant’s table) ........211
`Table 164. Growth and development (Applicant’s table)..............................................212
`Table 165. Summary of observations (Applicant’s table) .............................................213
`Table 166. Clinical signs (Applicant’s table) .................................................................217
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`Reference ID: 4134195
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`NDA # 209637
`
`Reviewer: Federica Basso, Ph.D
`
`Table 167. NNC 0113-0236 plasma concentration (Applicant’s table).........................219
`Table 168. Litter data (Applicant’s table) ......................................................................219
`Table 169. Fetal malformations (Applicant’s table) ......................................................220
`Table 170. GLP-1R expression in embryonic tissue and yolk sac (Study # 212301,
`Applicant’s table) .........................................................................................