Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22-350
`
`
`
`
`
`Key study findings:
`0
`Skin lesions were observed at all dose levels, ranging from relatively minimal and self-
`resolving at the low dose to severe and ulcerative requiring surgical amputation of the
`distal tail and moribund sacrifice at the mid and high doses.
`0 Lesion severity and time to lesion emergence was dose and time-dependent. For example,
`lesions erupted earlier with higher doses.
`0 There was no evidence of increased cyanide levels or immunoglobulin deposition in
`tissues at any dose, which appears to discount these mechanisms as causative of the
`lesions.
`
`0 Two females given the high dose became acutely moribund afier 1 or 2 doses, and were
`sacrificed.
`,
`‘
`.
`0 One high dose female became thrombocytopenic. This animal was re-challenged with
`drug after a dosing holiday and thrombocytopenia did not recur.
`- Two animals showed histologically confirmed renal glomerulopathy with associated
`clinical chemistry abnormalities in protein excretion and albumin.
`0 Exposure at lowest dose, 2 mg/kg was 4 to 6 x the clinical exposure at 5 mg, based on
`AUC.
`'
`4
`
`Study no.: DN05063
`Volume #, and page #: eNDA
`Conducting laboratory and location: BMS, One Squibb Drive, New Brunswick, NJ
`Date of study initiation: August 30, 2005
`GLP compliance: No
`QA report: yes ( ) no (x )
`Drug, lot #, and % purity: Batch 4K85994 with free base purity of 93.5%
`Methods .
`.
`'
`
`Intended as a one month dose-ranging study, observations of severe skin lesions altered the study
`design to investigate the nature of the drug-induced toxicities in monkeys. Doses and treatment
`duration are listed in the following table:
`
`.
`Daily Dose
`
`-
`
`.
`Concentration
`
`Number of
`Animals
`
`Dosing
`Duration
`
`Group
`Number
`Saxagliptin
`Volume
`Saxngliptin
`(EMS-477118)
`(mIJkg)
`(EMS-4771 18)
`Weeks
`
`(mg/kg)
`(mg/1111:)
`
`l
`
`2
`3
`
`o
`
`2
`10
`
`1
`
`1
`1
`
`0
`
`2
`10
`
`5M, 5F
`
`3M, 3F
`3M 3F
`
`4 13“
`
`13
`6
`
`;;(:./20b 1 30/20 5M, 5F4 4, 5a 130
`
`
`
`
`
`
`
`
`
`
`
`were necropsied afier 13 weeks of dosing.
`b The high-dose was reduced from 30 mg/kg/day lo 20 mg/kg/day after 3 days of dosing in the males and 2
`days of dosing in the females.
`
`0 A subset of monkeys were necropsied at 4 and 6 weeks. Animal 4102 was necropsied at the end of 13
`weeks (see text for details).
`'
`
`130
`
`

`

`M4)
`
`
`
`Reviewer: Fred Alavi Ph.D. NDA No. 22-350
`
`Doses: 2, 10, 30/20 mg/kg (free base used in the study)
`Species/strain: cynomolgus monkeys from W
`Route, formulation, volume, and infusion rate: oral gavage
`Age: 23 to 38 months old
`Weight: 2.4 to 4.7 kg
`Sampling times:
`' PK data for saxagliptin and active metabolite were collected on Day 1, 28,
`» 84/85 at 0.5, 1, 2, 4, 8 and 24 hrs post dose. Prior to freezing, an aliquot of plasma was
`taken for DPP4 inhibition evaluation. Plasma samples were analyzed at ‘4'
`.
`> J
`C
`3
`
`“(4)
`
`-
`
`Unique study design or methodology: Animals were acclimated for at least 21 days and had ad
`lib access to water. They received daily ration of approximately 12 biscuits each. Cyanide
`and thiocyanate levels were also measured during the first 2 TK time points on Day 1 and
`Day 28. Peripheral blood lymphocyte phenotying was also made in samples collected
`before and on week 2, 3, 4 and 8. The sponsor also investigated serum immunoglobulin
`(1g) levels, antinuclear antibody (ANA) levels and Ig reactivity to red blood cells and
`platelets. Attempts were made to look at skin and kidney samples using electron
`microscopy. Based on histopath findings, paraffin-embedded tail, nose, scrotum, foot,
`skin (face and torso), urinary bladder, kidney, tongue, lung, vagina, testes, skeletal muscle
`intestine (jejunum) were stained for IgG, IgM and IgA deposition by
`immunohistochemistry staining.
`
`Observations and times:
`
`Morta'ligg: daily
`Clinical signs:
`twice daily
`Body weights: weekly
`Food consumption: daily
`Ophthalmoscopy: before and at weeks 4 and 8
`M: before and at weeks 4 and 8
`
`'
`
`Hematology: Blood samples were collected from fasted monkeys twice prior to first dose and at
`week 2, 3, 4, 5, 6, 8, 10 and 13
`Clinical chemistg: The same as above
`Urinalysis: before and at week 4, 6 and 13
`Gross pathology: at the end of each phase (treatment and recovery).
`Organ weights: standard list with greater emphasis on the skin lesions to determine NOAEL.
`Histopathology: Adequate Battery: yes (x )
`Peer review:
`yes (x )
`
`Results
`
`Mortality and clinical signs:
`
`2mg/kg13 month dosing duration)
`Five of the six monkeys developed skin ‘abrasions/ulcerations’ on the tail and-digits during the
`dosing period. Lesions developed within 13 days of dosing. The lesions largely resolved despite
`continued dosing, with only one female harboring minimal lesions at the end of 3 months of
`treatment.
`
`131
`
`

`

`Reviewer: Fred AlaviI Ph.D.
`
`NDA No. 22-350
`
`10mg/kg (6 weeks dosing duration)
`Four of six monkeys developed abrasions/ulcerations on the tail, digits, and scrotum within 13
`days of dosing. While some lesions resolved, there remained ulcerative, inflamed lesions of the
`tail and multifocal scabs of the skin/subcutis in some animals at the end of 6 weeks treatment.
`
`30/20m
`ose reduction at da 2/3 then 4 & 6 weeks at 20m /k
`Two females (#8 4202 & 4205) were sacrificed afier the first or secOnd dose afier becoming
`acutely moribund (ataxia, collapse). Skin lesions were not observed in these two acutely ill
`females. The dose was reduced in remaining animals to 20mg/kg for an additional 4 or 6 weeks
`duration.
`
`Severe ulcerative lesions were identified in 7 of 8 monkeys as early as day 6. Surgical amputation
`of the tail was required in one male and female; the female was found dead the following
`morning. An additional male was sacrificed moribund on day 39. Edema was feature of the skin
`lesions.
`
`Body weights: No drug-related change in BW
`Food consumption: No drug-related change in food intake
`Ophthalmoscopy: No drug-related change
`
`EKG and arterial oxygenation:
`There was no drug-related change in cardiovascular parameters. One monkey had inverted QRS
`before treatment and at week 4. This appeared to be a pre-existing condition and not a drug-
`related finding.
`
`Hematology: The decrease in RBC parameters may have been due to some form of hemorrhage
`from vascular damage and skin lesions due to the fact that reticulocyte levels were increased and
`albumin levels were increased.
`Increase in WBC parameters and albumin to globulin ratio is
`consistent with inflammation and inflammatory cell infiltration in the damaged tissue identified
`microscopically.
`'
`
`Hematological changes relative to pre-dose levels at 2 mg/kg
`0 Decrease in RBC, Hgb, HC, decrease in platelets
`increase in neutrophils
`o Compensatory 2.4x increase in reticulocyte on Days 35 to 56,
`0 Presence of reactive lymphocytes (typical of lymphoid activation) on Day 35; and,
`
`Hematological changes at 10 mg/kg
`0 Decreased in RBC, Hgb, HCt and decrease in platelet count
`0
`Increase in reticulocytes and WBC (predominantly due to increased neutrophil count)
`and monocytes (1.8 to 2.9x) and increase in lymphocytes (1.4x),
`
`Hematological changes at 30/20 mg/kg,
`0 Decrease in RBC, hemoglobin, Hot and decreased in platelet
`-
`Increase in reticulocyte, Neutrophils, monocytes
`0 Presence of reactive lymphocytes
`O
`Additionally I (4102) developed severe thrombocytopenia (-77 to -94%) at 2weeks
`leading to temporary halt in treatment until platelet counts recovered. This animal was re—
`challenged with drug without recurrence of the thrombocytopenia.
`
`132
`
`

`

`
`
`Reviewer: Fred Alavi Ph.D. NDA No. 22-350
`
`Hematolo ' ical chan - e in c nomol . us monke 5 relative to retest values
`m
`
`
`
`
`
`
`
`1-5 to 2-5x
`
`
`
`
`
`Clinical chemistry:
`0 There were decreases in albumin and albumin/globulin ratio and increases in globulin,
`total protein and fibrinogen at saxagliptin doses 2 2 mg/kg
`=
`In contrast to other MD and HD animals, a MD female monkeys (#3203) and a HD male
`monkey (#4103) with kidney lesions (glomerulopathy) had decreased levels of total
`protein and albumin
`
`0
`
`
`m
`
`
`
`
`
`--—-—
`-———
`
`
`
`
`
`
`
`
`
`
`Cyanide levels:
`There were no detectable levels of cyanide in the whole blood of any monkey. Serum thiocyanate
`were detected only in the HD monkeys (1.1 to 2.7 ug/mL) but were within the background levels
`noted in humans (nonsmokers: 2.9 and smokers 7.1 ug/mL). The skin lesions were therefore not
`related to liberation of cyanide from saxagliptin.
`
`Peripheral—Blood Lymphocfle Phenotyping and Immunology Assessment:
`0 There were no drug-related changes in lymphocyte subsets.
`0 Total IgG and IgM levels in drug-treated monkeys were significantly increased compared
`to individual pre-study levels and controls
`0 There were no detectable antinuclear antibodies (ANAs).
`0 Overall findings do not support a significant immune-mediated mechanism for skin
`lesions in monkeys.
`
`133
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22-350
`
`saxagliptin: One—Month Oral Toxicity Study in Monkeys
`Summary of Absolute Number of Lymphocytes (10e‘3 lpL)
`for Male Monkeys at Prestudy
`
`N Mean (SD)
`5
`3.66 (1.45)
`3
`3.52 (0.73)
`3
`2.38 (0.72)
`5
`3.78 (1.38)
`
`Group
`Control
`2 mg/kg
`EMS-477118
`EMS—477118 10 mg/kg
`EMS—477118 30/20 mg/kg
`
`Parameter
`CD2+CD20-
`
`CD20+002—
`
`CD4+CD8-
`
`cna+cn4—
`
`Control
`2 mg/kg
`EMS—477118
`EMS-477118 10 mg/kg
`EMS—477118 30/20 mg/kg
`
`5
`3
`3
`5
`
`0.63 (0.45)
`0.61 (0.17)
`0.68 (0.25)
`0.67 (0.26)
`
`Control
`2 mg/kg
`EMS-477118
`EMS-477118 10 mg/kg
`BMS~477118 30/20 mg/kg
`
`1.80 (0.55)
`5
`1.43 (0.27)
`3
`3 1.08 (0.33)
`5 1.67 (0.67)
`
`2.43 (1.19)
`5
`Control
`2.59 (0.39)
`3
`2 mg/kg
`EMS—477118
`1.65 (0.30)
`3
`EMS—477118 10 mg/kg
`2.67 (0.66)
`5
`EMS-477118 30/20 mg/kg
`Female Monkeys at Prestudy
`
`Saxagliptin: one—Month Oral Toxicity Study in Monkeys
`Summary of Absolute Number of Lymphocytes (10e"3 /)1L)
`for Male Monkeys at Day 22
`
`Parameter
`CD2+CD20-
`
`CDZO+CD2—
`
`CD4+CD8—
`
`cos+cn4-
`
`Group
`Control
`2 mg/kg-
`EMS—477118
`EMS-477118 10 mg/kg
`EMS-477118 30/20 mg/kg
`
`N Mean (SD)
`5
`3.47 (0.87)
`3
`2.83 (0.63)
`3 2.80 (1.04)
`5
`2 89 (1.54)
`
`Control
`2 mg/kg
`EMS—477118
`EMS-477118 10 mg/kg
`EMS—477118 30/20 mg/kg
`
`5
`3
`3
`5
`
`0.70 (0.23)
`0.54 (0.24)
`0.91 (0.13)
`0.74 (0.20)
`
`Control
`2 mg/kg
`EMS—477118
`EMS—47711310 mg/kg
`EMS—477118 30/20 mg/kg
`
`1.74 (0.39)
`5
`1.14 (0.11)
`3
`1.19 (0.40)
`3
`5 1.41 (0.73)
`
`5
`Control
`3
`2 mg/kg
`EMS-477118
`3
`EMS—477118 10 mg/kg
`5
`EMS—477118 30/20 mg/kg
`Female Monkeys at Day 21
`
`2 22 (0.56)
`1.97 (0.70)
`1.86 (0.56)
`1 83 (0.80)
`
`Parameter
`
`Group
`
`N Mean (SD)
`
`Parameter
`
`Group
`
`N Mean (SD)
`
`CD2+CD20—
`
`CD20+CD2-
`
`Control
`2 mg/kg
`EMS—477118
`EMS-477118 10 mg/kg
`EMS-477118 30/20 mg/kg
`
`Control
`2 mg/kg
`EMS—477118
`EMS—477118 10 lug/kg
`EMS-477118 30/20 mg/kg
`
`5
`3
`3
`5
`
`5
`3
`3
`5
`
`2.89 (0.88)
`3.49 (0.56)
`2.45 (0.75)
`1.92 (0.57)
`
`0.65 (0.25)
`0.62 (0.14)
`0.57 (0.28)
`0.53 (0.14)
`
`CD2+CD20—
`
`CD20+CD2-
`
`CD4+CD8—
`
`Control
`2 mg/kg
`EMS—477118
`EMS-477118 10 mg/kg
`Control
`2 mg/kg
`EMS-477118
`EMS—477118 10 mg/kg
`
`3.89 (0.93)
`5
`3.40 (0.99)
`3
`3 06 (0.66)
`3
`5 0.76 (0.27)
`3
`0.60 (0.23)
`3
`0.51 (0.40)
`
`Control
`2 mg/kg
`EMS-477118
`EMS-477118 10 mg/kg
`
`Control
`2 mg/kg
`EMS—477118
`EMS-477118 10 mg/kg
`
`5 2.01 (0.74)
`3
`1.51 (0.17)
`3
`1.79 (0.48)
`
`5 2.01 (0.25)
`3
`2.17 (0.35)
`3 1.52 (0.05)
`
`CD4+CDB—
`
`CD8+CD4—
`
`‘
`
`CD8+CD4—
`
`1.52 (0.63)
`5
`Control
`1.65 (0.31)
`3
`2 mg/kg
`EMS-477118
`1.27 (0.58)
`3
`EMS—477118 10 mg/kg
`0.89 (0.32)
`5
`EMS—477118 30/20 mg/kg
`1.59 (0.28)
`5
`Control.
`No significant differences from the vehicle control
`2.19 (0.77)
`3
`2 mg/kg
`EMS—477118
`group were observed, based on the Dunnett
`1.67 (0.50)
`3
`EMS—477118 10 mg/kg
`
`
`
`1-36 (0.26)5EMS—477118 30/20 mg/kg multiple—comparison t—test procedure (1:20.05) .W
`
`134
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22-350
`
`0nc~ to Three-Month Oral Toxicity Study In Monkeys
`Amrhmem 3:
`lndlvldual And-Nuclear Antibody (ANA) Reactivity
`
`
`
`1
`EMS-477118
`(Urns/ks)
`
`ZKZEZZZZ
`
`sum Day
`Dayn
`Dny34
`
`Ratio'ANA” Ralio'ANA"
`
`
`1101
`0.24
`-
`0.26
`-
`
`1102
`0.25
`—
`0.29
`.
`
`1103
`0.29
`-
`0.25
`-
`
`-
`
`
`210l
`2
`025
`-
`.
`0.38
`-
`
`EMS-477113
`2102
`0.33
`—
`0.48
`-
`
`(2 mE’kS)
`
`
`
`.
`3
`
`
`BMS~477118
`3l02
`0.24
`-
`0.64
`
`(10 Ina/ks)
`
`-
`
`4101
`
`0.22
`4
`4102‘
`NA
`NA
`
`0.30
`EMS-477118
`4103
`NA
`NA
`
`NA
`NA
`(30/20 tug/kg)
`4104
`4105
`
`
`EZEZZ
`
`' Calwlated as the mean sample 0D divided by the refinance control OD
`" Reactivity considered:
`negative (~) ifratio is less than 0.7
`positive (+) iflatiu is gram than orequal to 1.0
`borderline (+l-)ifmlio is greater than or equal to 0.7 and loss than 1.0
`
`‘ Evaluated serum sample collected on Day 42.
`NA - Not available.
`
`Immunohistochemistry:
`,
`0 Except for presence of IgG and IgM, in the glomerulus or tubular epithelium of 2
`monkeys (1 MD, lHD) with glomerulopathy, there was no immunoglobulin deposition in
`any of the other tissues evaluated.
`Similar to immunoassessment data, the absence of immunoglobulin deposition suggests
`that skin lesions were unlikely to be an autoimmune or complement-mediated mechanism.
`
`0
`
`135
`
`
`
`

`

`NDA No. 22-350
`Reviewer: Fred Alavi Ph.D.
`
`Individual immunoglobulin levels in male and female monkeys:
`One— to Three-Month Oral Toxicity Study in Monkeys
`Attachment 4512 Indlvldnnl Serum Immunoglobnlin Levels in Male: (mg/41L)
`
`
`
`Stu Day
`
`
`
`
`1
`
`BMs4771 18
`
`(0 mglke)
`
`
`
`
`
`1232
`230
`1148
`225
`65
`
`
`
`Sthev
`103
`41
`41
`41
`4
`
`
`
`2101
`
`
`2102 V
`
`2103
`Mean 1
`1229
`
`111
`
`
`3101
`
`
`
`3102 Q/
`1256
`167
`
`1103
`
`2
`HMS—477118
`gsz/kg)
`
`3
`EMS-477118
`
`
`
`
`
`
`62
`2
`
`2'20“
`36
`
`"1082
`59
`
`
`
`242
`39
`
`226
`11
`
`72
`41
`
`1359
`115
`
`258
`48
`
`83
`51
`
`1554
`302
`
`268
`70
`
`W
`
`87
`64
`
`,,
`
`1461
`210
`
`262
`68
`
`1522
`130
`
`248
`42
`
`67
`7
`
`
`
`97*
`16
`
`
`
`1888‘
`500
`
`253
`70
`
`71
`4
`
`'1§54*
`425
`
`244
`55
`
`D
`'
`
`*****
`
`"
`
`111‘“
`
`,190"
`
`76
`
`.1
`72
`6
`
`l
`.J54
`21
`
`4
`4102'
`
`EMS-477118
`4103
`(3020111348)
`4104
`4105
`Mean
`Sthev
`
`1219
`138
`
`249
`61
`
`71
`26
`
`1513
`83
`
`303
`83
`
`92*
`29
`
`1968‘
`542
`
`286
`73
`
`64
`21
`
`V W
`1789‘
`718
`
`'271’
`75
`
`
`
`
`Bold value: indicates that the Day mean was significantly different from the Preatudy mean (p<0.05)2 Arithmetic means are presented.
`‘ Indicates significant difference from vehicle control (p<0.05). Comparisons were based on least squares adjusted mean Erom ANOCOV model.
`' Evaluated using serum collected on Day 42.
`NA = Not applicable.
`
`One- to Three-Month Oral Toxlclty Study In Monkeys
`Attachment 4111 Individual Serum Immunoglobulin Levels in Female: (mg/11L)
`
`Grou -
`
`LG
`
`1
`
`LG
`
`Study Day
`
`1_M
`
`Day 34
`1;‘
`
`1G
`
`I
`EMS-4771 18
`(0 mg/kg)
`
`2
`BMSA77118
`2 m ;
`;
`
`3
`EMS-4771 18
`10 m :
`'.
`
`4
`EMS-4771 1 8
`(3OIZO mg/kg)
`
`Animal No.
`1201
`1202
`1203
`1204
`1205
`Mean
`Sthev
`
`2201
`2202
`2203
`Mean
`Sthev
`
`3201
`3202
`3203
`Mean
`Sthev
`
`4201
`4202
`4203
`4204
`4205
`Mean
`Sthev
`
`Prestudy
`I-A
`
`Day 13
`1A
`
`Day 42
`1; A
`
`1;G
`
`I
`
`1498
`17s
`
`240
`75
`
`100
`7
`
`1293
`113
`
`216
`75
`
`1245
`153
`
`177
`20
`
`92
`31
`
`1346*
`77
`
`190
`22
`
`87
`8
`
`95
`22
`
`1267
`119
`
`1356*
`112
`
`1600*
`432
`
`206
`58
`
`140*
`35
`
`1826*
`539
`
`1475
`325
`
`235
`84
`
`"107
`24
`
`
`
`1 -
`
`»_
`
`-
`
`
`
`1264
`157
`
`261 ’
`84
`
`l
`
`314*
`73
`
`1 86
`23
`
`83
`13
`
`2
`
`044*
`700
`
`201
`12
`
`111*
`8
`
`263
`88
`
`191
`16
`
`187
`3
`
`95
`9
`
`90
`9
`
`107
`18
`
`
`
`“T297
`204
`
`266 .___ 93
`80
`25
`
`1562*
`157
`
`213
`25
`
`111*
`9
`
`NA
`NA
`
`NA
`NA
`
`NA
`NA
`
`NA
`NA
`
`3.1
`NA
`NA
`
`NA
`NA
`
`136
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22-350
`
`Saxagliptin: One-Month Oral Toxicity Study in Monkeys
`Summary of Absolute Number of Lymphocytes (10e‘3 /uL)
`for Male Monkeys at Prestudy
`
`Saxagliptin: One—Month oral Toxicity Study in Monkeys
`Summary of Absolute Number of Lymphocytes
`(10e‘3 /pL)
`for Male Monkeys at Day 22
`
`Parameter
`CD2+CD20-
`
`CD20+CD2~
`
`CD4+CD8—
`
`CDB+CD4~
`
`Group
`Control
`2 mg/kg
`EMS—477118
`EMS—477118 10 mg/kg
`EMS—477118 30/20 mg/kg
`
`N Mean (SD)
`5 3.66 (1.45)
`3
`3.52 (0.73)
`3
`2.38 (0.72)
`5
`3.78 (1.38)
`
`Control
`2 mg/kg
`EMS—477118
`EMS—477110 10 mg/kg
`EMS—477118 30/20 lug/kg
`
`5 0.63 (0.45)
`3
`0.61 (0.17)
`3
`0.68 (0.25)
`5
`0.67 (0.26)
`
`1.80 (0.55)
`5
`Control
`1.43 (0.27)
`3
`2 mg/kg
`EMS—477118
`1.08 (0.33)
`3
`EMS—477118 10 mg/kg
`1.67 (0.67)
`5
`EMS—477118 30/20 lug/kg
`2.43 (1.19)
`5
`Control
`2.58 (0.39)
`3
`2 mg/kg
`EMS—477118
`1.65 (0.30)
`3
`EMS—477118 10 mg/kg
`2.67 (0.66)
`5
`EMS—477118 30/20 tug/kg
`Female Monkeys at Prestudy
`
`Parameter
`CD2+CD20—
`
`CD20+CD2—
`'
`
`CD4+CDB-
`
`CD8+CD4—
`
`Group
`Control
`2 mg/kg
`EMS—477118
`EMS—477118 10 lug/kg
`EMS-477118 30/20 mg/kg
`
`N Mean (SD)
`5
`3.47 (0.87)
`3
`2.83 (0.63)
`3
`2.80 (1 04)
`5
`2 89 (1.54)
`
`Control
`2 mg/kg
`EMS—477118
`EMS-477118 10 Eng/kg
`EMS—477118 30/20 mg/kg
`
`5
`3
`3
`5
`
`5
`Control
`3
`2 mg/kg
`EMS-477113
`3
`EMS-477118 10 mg/kg
`5
`EMS-477118 30/20 mg/kg
`5
`Control
`3
`2 rug/kg
`EMS-477113
`3
`EMS-477118 10 mg/kg
`5
`EMS—477118 30/20 rug/kg
`Female Monkeys at Day 21
`
`0.70 (0.23)
`0.54 (0.24)
`0.91 (0.13)
`0.74 (0.20)
`
`1.74 (0.39)
`1.14 (0.11)
`1.19 (0.40)
`1.41 (0.73)
`2.22 (0.56)
`1.97 (0.70)
`1 86 (0.56)
`1.83 (0.80)
`
`Parameter
`
`Group
`
`N Mean (SD)
`
`Parameter
`
`Group
`
`N Mean (SD)
`
`CD2+CD20—
`
`CD20+CD2—
`
`Control
`2 mg/kg
`EMS—477118
`EMS—477118 10 mg/kg
`EMS—477118 30/20 rug/kg
`
`5 2.89 (0.88)
`3 3.49 (0.56)
`3 2.45 (0.75)
`5
`1.92 (0 57)
`
`Control
`2 mg/kg
`EMS—477118
`EMS-477118 10 mg/kg
`EMS-477118 30/20 lug/kg
`
`5 0.65 (0.25)
`3
`0.62 (0.14)
`3
`0.57 (0.28)
`5
`0.53 (0.14)
`
`CD2+CD20-
`
`CDZO+CD2—
`
`C04+CD8—
`
`Control
`2 mg/kg
`EMS—477118
`Bus—477118 10 mg/kg
`Control
`2 rug/kg
`EMS-477118
`EMS—477118 10 mg/kg
`
`5
`3
`3
`5
`3
`3
`
`3-89 10-93)
`3.40 (0.99)
`3.06 (0.66)
`0.76 (0 27)
`0.60 (0 23)
`0.51 (0 4D)
`
`Control
`2 mg/kg
`EMS—477118
`EMS-477118 10 rug/kg
`
`5
`3
`3
`
`2.01 (0 74)
`1.51 (0 l7)
`1.79 (0 48)
`
`CD4+CD8—
`
`-
`
`CD8+CD4—
`
`CD8+CD4—
`
`1.52 (0.63)
`5
`Control
`1.65 (0.31)
`3
`2 mg/kg
`EMS—477113
`5 2.01 (0.25)
`Control
`1.27 (0.58)
`3
`EMS—477118 10 mg/kg
`3
`2.17 (0.85)
`2 mg/kg
`EMS—477118
`0.89 (0.32)
`5
`EMS—477118 30/20 mg/kg
`3
`1.52 (0.05)
`EMS—477118 10 mg/kg
`'
`1.59 (0.28)
`5
`Control
`No significant differences from the vehicle control
`2.19 (0.77)
`3
`2 mg/kg
`EMS—477118
`group were observed, based on the Dunnett
`1.67 (0.50)
`3
`EMS—477118 10 mg/kg
`
`
`
`1.36 (0.26)5EMS—477118 30/20 rug/kg multiple—comparison t—test procedure (1320.05) .
`
`Platelet Reactive immunoglobulin
`
`0.400
`
`- 0.350
`
`
`
`
`0.300 ~
`0.2.50
`
`0.200 ~
`
`0.150 ~
`
`
`35
`
`3'0
`
`25
`- 20
`
`15
`
`1°
`5
`
`0100
`0.050
`
`0.000
`
`—
`1101 1102 1103- 1104 1105 1201 12:02 1203 1204 1205 4101 4-102 4103 4104 4105 4201 4203
`
`* 0
`
`.
`-0D ‘71? meeme +MPV
`
`Evaluation of Platelet—Associated Ig at Day 29/30
`at Day 2913.0.
`Observed increases
`in PA—lg correlates with increased mean platelet volume
`Thromboc'ytopenic monkey, 41.02 (denoted with a star), had the greatest amount of PA—Ig, PA—Ig is
`expxessed as optical density Values on 1e 11 ‘y‘ axis; mean platelet volume indices are on Hie right ‘y’ axis.
`
`137
`
`

`

`
`
`Reviewer: Fred Alavi Ph.D. NDA No. 22-350 '
`
`
`
`Urinalysis: Only notable change was an increase in urinary protein in 1 MD female (1083 mg/dl)
`and 1 HD male (128 mg/dl) with glomerulopathy.
`
`Organ weights:
`A drug-related increase in spleen weight was noted at 2 mg/kg (21 to 83%), 10 mg/kg
`(107% due to 1 female at week 4) and 30/20 mg/kg (25 to 31%). The significance of
`slightly higher kidney weight in the HD females is uncertain. The increase in spleen
`weight was correlated to lymphoid hyperplasia
`
`Gross pathology:
`There were no macroscopic drug related finding at 2 mg/kg
`Macroscopic findings at 10 mg/kg (MD) included tail skin, focal or multifocal erosion and
`scabs on distal part ofthe tail, scrotal skin (focal erosion), skin erosion of the face
`(multifocal erosion), in the nose (multifocal erosion). These lesions were not seen in all
`MD animals but rather I or more and occasionally the same animal with more sites. The
`female monkey with glomerulopathy has subcutaneous edema (ascites) and hydrothorax
`secondary to urinary protein loss.
`Macroscopic findings1n the HD animals were similar to MD animals except that tail
`lesion appeared necrotic in at least to males
`One HD male (4103, sacrificed on Day 39) had scrotal edema that was associated with
`ulceration/inflammation determined microscopically.
`
`Histopathology:
`In general histopathology findings noted at 2 mg/kg occurred in more animals at higher doses
`with increased severity and occasionally recruited new target organs
`
`2 mg/kg
`Minimal to mild subacute to chronic inflammation and or mononuclear cell infiltration in
`the glandular organs (pituitary, parathyroid, mandibular, mammary, reproductive organs
`including testes, epididymides, seminal vesicles, prostate) and brain (choroid plexus),
`peripheral nerve (sciatic), liver, kidney and urinary bladder
`Minimal subacute vasculitis1n the skeletal muscle, minimal to slight lmphoid
`hyperplasia1n the spleen and bone marrow.
`
`10 mg/kg,
`Minimal to moderate subacute, chronic, and/or chronic-active inflammation and/or
`mononuclear-cell infiltration in glandular organs [pituitary, parathyroid, mandibular
`salivary gland, pancreas and mammary gland, skin (abdominal, dorsal, tail, and/or
`scrotum, nose), reproductive organs, including testes, epididymides, seminal vesicles,
`prostate, vagina, and uterus], brain (choroid plexus only), peripheral nerve (sciatic nerve),
`liver (3 of 3 females), kidneys, esophagus, tongue and urinary bladder
`Minimal to moderate subacute vasculitis1n the glandular organs (thyroid gland), skin
`(dorsal, face, and nose), skeletal muscle, diaphragm, urinary bladder, lung and intestine, I
`vagina and cervix.
`
`138
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22—350
`
`There was also slight to marked interface inflammation and/or mononuclear-cell
`infiltration in the skin (abdominal, dorsal, tail, and face), vagina, and tongue, urinary
`bladder,
`
`Minimal to moderate ulceration and/or erosion in the skin, including tail, nose, face, and
`scrotum correlating with erosions, scabs, and/or the misshapen nostril (due to a healed
`ulcer)
`Minimal to mild lymphoid hyperplasiain the spleen and bone marrow
`Mild multifocal glomerulopathy of the kidneys with secondary pulmonary artery thrombus
`formation, subcutaneous and organ edema, ascites, and hydrothorax due to urinary protein
`loss in lfemale.
`
`30/20 mg/kg
`Minimal to moderate subacute, chronic, and/or chronic-active inflammation and/or
`mononuclear-cell infiltrations in the glandular organs [pituitary, parathyroid gland; skin
`(tail, scrotum, and/or foot), testes, epididymides, and prostate; liver, kidneys, and urinary
`bladder
`
`Minimal to mild subacute vasculitis in the skin, including tail, foot; lung, testes and with
`fibrinoid necrosis of pulmonary arteries and foot microvasculature
`Moderate interface inflammation in the skin, including tail and/or scrotum
`Mild to marked ulceration with or without hemorrhage in the skin, tail, foot and scrotum
`Moderate to marked coagulative necrosis in the tail correlating with the hard and/or dark
`distal tails observed clinically (including 2 amputated tails)
`Minimal to slight lymphoid hyperplasia in the spleen
`Slight multifocal glomerulopathy of the kidneys with secondary thrombus formation of
`pulmonary arteries and small vessels in small intestine (jejunum) and foot due to Urinary
`protein loss in 1 male
`
`139
`
`

`

`
`
`Reviewer: Fred Alavi Ph.D. NDA No. 22-350
`
`A summary of drug—related microscopic findings are presented in the table below.
`
`Summary of Drug-related Microscopic Lesions in Affected Organ Systems
`
`
`
`
`30/20 mg/kg/day (HD)
`2 mg/kg/day (LD)
`10 mg/kg/day (MD)
`
`D16 (1F); D39 (1M)
`Dosing Duration
`13 wks (3M 3F)
`D29 (1F)
`
`
`
`6 wks (3M, 2F)
`4 wks (2F, 2M)
`
`
`6 wks (1M); 13 wks (1M)
`
`(acute deaths excluded)
`
` _——_-I-__
`
`
`Inflammation and/or Mononuclear—cel] infiltrates
`
`
`
`+Severity: LD= minimal; MD=minimal to moderate; HD minimal to moderate
`Ulcers and/or Emsions
`
`Total __—-n-
`Skin“
`MSeven'ty: MD= slight to moderate; HD = mild to marked
`
`
`
`
`
`
`——-——_—
`“Severity: LD= minimal to slight; MD=slight to mild; HD =minimal to slight
`
`
`
`
`
`
`
`————_——
`
`
`
`———_——-—
`
`
`
`
`
`- indicates absence of finding in group
`Wm: pituitary gland, parathyroid gland, thyroid gland, salivary gland, pancreas, and/or mammary gland
`
`Skin: routine (dorsal), tail, nose, distal appendages (hand/foot), scrotum, and/or face
`
`Reproductive Organs: testes, epididymides, seminal vesicles, prostate, vagina, and/or uterus
`
`Solid Organs: liver, kidneys, brain (choroid plexus), peripheral nerve (sciatic, cauda equina), urinary bladder, tongue,
`
`skeletal muscle, diaphragm, lung, intestine, and/or esophagus
`
`140
`
`

`

`
`
`Reviewer' Fred Alavi Ph D. NDA N 22-350
`
`Detailed Histopathology findings in monkeys at interim 4 week and 6 week and at the end of the
`study termination in monkeys treated with 0, 2, 10 and 30/20 mg/kg of saxagliptin (groups 1, 2, 3
`and 4, respectively).
`
`NUMBER OF ANIMALS wz-m MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX
`Necropsy status: Interim/Schemled Necropsy (K1), Except Deaths
`4 flee): Interim Necropsy
`
`NUMBER or Alumna WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SBX
`Nscrnpsy Status: Interim/Scheduled Necropsy (KI), Except Deaths
`4 “sex Interim Necropsy
`
`
`
`m,
`3
`-
`-
`-
`—
`-
`-
`—
`-
`-
`-
`-
`—
`-
`-
`-
`-
`_
`-
`-
`-
`—
`-
`-
`-
`-
`-
`-
`-
`_
`_
`-
`..
`-
`_
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`—
`—
`
`-
`-
`-
`-
`_
`_
`-
`-
`-
`~
`—
`-
`—
`
`I
`2
`2
`-
`I
`1
`-
`—
`1
`1
`-
`-
`-
`-
`2
`2
`2
`1
`-
`-
`—
`-
`I
`1
`2
`2
`-
`-
`-
`-
`_
`_
`_
`-
`_
`-
`-
`2
`1
`-
`-
`1
`1
`2
`2
`-
`-
`2
`2
`-
`—
`—
`—
`-
`-
`2
`1
`I
`I
`-
`2
`1
`1
`i
`-
`-
`—
`-
`—
`
`
`
`
`I
`2
`2
`I
`—
`-
`—
`-
`1
`1
`-
`—
`-
`-
`2
`2
`2
`_
`-
`-
`-
`-
`2
`2
`2
`-
`—
`-
`i
`1
`_
`_
`-
`-
`1
`l
`-
`2
`I
`-
`-
`l
`1
`2
`1
`1
`l
`2
`1
`-
`—
`—
`—
`I
`1
`2
`-
`Z
`1
`l
`2
`1
`-
`t
`l
`1
`_
`-
`_
`
`was
`3
`1
`l
`-
`-
`-
`-
`-
`-
`1
`l
`1
`1
`i
`l
`1
`-
`1
`1
`I
`1
`1
`l
`1
`-
`-
`-
`-
`_
`1
`1
`1
`1
`_
`-
`-
`1
`—
`—
`-
`1
`1
`1
`l
`—
`-—
`I
`-
`-
`—
`1
`I
`-
`—
`1
`l
`-
`—
`—
`1
`1
`_
`-
`_
`l
`—
`1
`1
`1
`
`.
`
`4
`2
`2
`2
`-
`-‘
`-
`'
`‘
`"
`-
`-
`'
`’
`2
`2
`2
`2
`-
`-
`-
`—
`-
`-
`2
`1
`-
`-
`'
`_
`_
`..
`_
`-
`1
`-
`1
`2
`"
`1
`1
`1
`]
`2
`1
`1
`i
`2
`1
`x
`1
`
`-
`1
`1
`2
`-
`2
`2
`'
`2
`1
`1
`-
`1
`'
`-
`_
`-
`_
`
`I
`2
`2
`-
`-
`-
`2
`2
`2
`2
`-
`-
`-
`—
`2
`2
`2
`_
`-
`—
`-
`—
`2
`2
`2
`1
`1
`1
`-
`_
`_
`.
`..
`-
`1
`1
`-
`2
`1
`—
`~
`1
`1
`2
`2
`-
`-
`2
`2
`-
`—
`-
`-
`-
`—
`2
`l
`I
`-
`1
`f
`-
`i
`i
`1
`—
`—
`-
`
`_ m
`Dose Group
`Nu. Animals per Dose Group
`KIDNEYS
`Nd. Examined
`NM)
`- Mineralization
`Grade 1
`- Giant can: muitlnucieated
`Grade 1
`- Infiltration: nononucieir Cell
`Grade 1
`
`BONE, RIB
`
`Dose Group
`No. Animals per base Group
`Imam HANDS
`No. Examined
`»
`"AD
`ADRTA
`No. qunined
`NRD
`BONE MARROW, RIB
`No. Examined
`NAB
`BONE MARROW; 5WD. Examined
`NAD
`No. Exsminrd
`NM)
`BONE, 51mm
`No. Examinsd
`
`NAD
`Na. Examined
`BRAIN
`NA!)
`- Infiltration: nononuciear cell
`Grade I
`Na. Examinad
`menu
`NM?
`- Giant c211: mutinuciented
`Grade 1
`
`
`
`- Inflammation: subacute
`
`CERVYX
`
`EYES
`
`Grads 1
`"no minim!
`NAD
`Nc- Examined
`C010"
`"AD
`' Inflammation: “55'5““
`Grade 2
`- Giant coll: multlnuclaatad
`Grade 1
`No. Exanunmo
`DIAPHRAGM
`"AD
`- Infiltration: nononuciesr cell
`Grade 1
`1110mm
`No. Examined
`"AD
`EPIDIDYMIDBS
`No. Examined
`"An
`— Infiltration: mononuclesr c211
`Grade 1
`tsomcus
`No. examined
`MD
`— Infiltration: nononuclear col)
`Grade 1
`No. mullinfld
`W
`- Infiltratinn: nonolluciedr cell
`Grade 1
`summon
`No. Examined
`"*9
`HEART
`No. Examined
`““3
`- Infiltration: mononuclear cell
`on“? 1
`11mm
`No. Examined
`"AD
`“m “mag:
`nan - Noan abnormal discovered
`temsles: Ssxagliptln (o lug/kg)
`Group
`1, fitntrai. males: Suxuqliptirfinw Isa/k9);
`Group
`3,
`o nose, males: Saxaglipt
`(1
`nag/kg): Imues: saxaguptin uu lug/kg)
`Group
`4, High Dose, males: Saxagllptin (20 rug/kg); funnies: Saxagliptin (20 lag/kg)
`
`2
`2
`
`2
`1
`1
`1
`
`1
`1
`
`2
`1
`1
`1
`2
`1
`1
`1
`
`1
`1
`
`
`
`- Inflammation: subacute
`
`- Clmruiopathy
`MCRIMAL GLANDS
`
`LIVER
`
`Grade 2
`Grade 3
`No. Examined
`HAD
`No. Examined
`Mp
`- Leukocytnsis: sinusoid!
`Grade I
`
`- Innmmation: subacuta
`
`Grade 2
`- Infiltratiun: mononuciaar can
`Grade 1
`No. Examined
`NM)
`- Histiocytnsis: alvroinr space
`Grads 1
`- Infiltration: monanucloar can
`Grade 1
`_ Inlisnmtion: subacutr
`
`nuns
`
`Grade g
`Grade 4
`
`_ “nub“: "acute
`_ Inflammation: chronic
`
`Grade I
`Grade 3
`mounnmzrs mamas. Examined
`NAD
`
`— Histincytes
`Grade 2
`- Infiltration: monenuclur call
`Grams 1
`my mun
`No. Examined
`NAD
`- Infiltration: mononucisar cell
`Grade I
`MANDXB. 1mm mm: No. Examined
`NAD
`- are blood sens: sinuses
`6““ Z
`Grade I
`
`- Inflammation: acute
`
`- Histlozytosls: sinus
`6““ 2
`mummsnmwuw GLNDNo. Examined
`NAD
`- Infiltration: mononuclear cell.
`Grade 1
`Grade 2
`.
`am.
`:1
`M E" 3,,
`Ln
`Grade 4
`Brad: 2
`r us
`No. Ruined
`HAD
`
`:
`
`_
`
`Histiocytosis
`NOSE
`
`Hrsm. LYMPH NOD:
`
`Grade 2
`
`141
`
`- Inflammation: vascular
`- Erosion
`MAD - Nothing abnormal discovered
`females: Smgliptin m rug/kg)
`Group
`1, Control, males: Ssxagliptin (0 lug/kg):
`Group 3, Mid Dose, muss: Saxagllptin ()0 mg/kg); remiss: saxagupun no lug/kg)
`Group
`4, High nose, miles: Ssxaqliptin (20 mg/kg);
`remains: Saxagnptin (20 lug/kg)
`
`

`

`Reviewer: Fred Alavi Ph.D.
`NDA No. 22-350
`
`W OF ANIHAU HI'A'H MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX
`Necropsy Status:
`Interim/Scheduled Necropsy (K1). Except Deaths
`4 Meek Interim Necropny
`
`Dose Group
`No. Animus per Dose Group
`
`1
`2
`
`
`
`
`
`
`
`
`Il
`
`1
`1
`1
`1
`
`_
`2
`i
`
`2
`2
`2
`2
`-
`-
`2
`-
`1
`l
`-
`-
`1
`i
`2
`2
`2
`I
`1
`l
`
`THIRD“) GLAND
`
`- Depletion: colloid
`
`" Erosion
`
`289
`
`
`
`- "netball
`
`Grade 5
`
`- Inflamnatian: vascular
`Grade 1
`Grade 2
`
`‘ lluwullnge
`Grade 4
`- Inflammation: chronic-activeGrade A
`- Granule»: foreign bodyGrade 2
`— ulcer
`Grade 1
`Grade 3
`Grads 4
`Grade 5
`— Necrosis: coagulntiva Grade 4
` MAD - Nothing abnormal. discovered
`females: quliptin (D m Ikg)
`Group 1, Control, males! Saanliptin (o lug/k9)!
`Group
`3, Mid Dose, nuey: Saxagiiptin (10 rag/kg); females: Smugliptln u Ila/kg)
`Group
`4. High Doze, maies: Saxagiiptin (20 lug/kg):
`females: Suagilptin (20 Lug/kg)
`
`142
`
`
`
` I'll.b””HIII
`
`
`
`
`Human OF ANIMAL? WITH MICROSCOPIC FINDIM‘vS BY ORGAN/GROUP/SEX
`Nncropsy Status: Interim/Schwinn Necropsy (K1), Excapt Deaths
`
`
`
`4 Week Interim Necropsy
`SPA!
`Females
`
`Doss Group
`1
`1
`Z
`1
`No. Animal: par Dos: Group
`TESTBS
`Na. ExaminedMD
`
`— Infiltration: mnnnuclear call
`Grade 1
`- Atrophy: aeminitarau: tubuleGrade 1
`THYHUS
`Na. Examined
`NAD
`No. Examined
`NAD
`Gradu 2
`No. banned
`MGUB
`NAD
`- Degeneration: skeletal muscle
`cell
`(Slide 1
`- Infiltration: mononucloar can
`crane i
`Gracia 2
`HA. Examined
`TRACHZA
`NAD
`No. mamined
`URINARY BMwER
`NAD
`- Infiltration: mnnnnuciear can
`Grade 1
`UTERUS
`No. ExaminedNM)
`VAGINA
`- Intimtionx :ubacute Grade 1
`Grade 2
`
`HAD - Nothing abnormal discovered
`Group
`1, Control, males: Smgliptin (a lbs/kg): remains: Sungliptin (0 lug/kg)
`Group
`3, Mid Dose. males- suagiiptin (m tug/k9); funnies: Smgiiptin (10 lug/kg)
`Group
`4, High Don, males: Snugliptin (20 lug/kg):
`females: Saxaglipfln (20 rug/kg)
`
`m
`m- men ———
`- Erosion
`conl‘d.
`Grade 2
`
`OVAIuES
`No. ExaminedNAD
`- Hinnralization
`Grade 2
`FANCIE“
`ND. RammedMAD
`PARATHYRDID CLANDS Nu. ExaminedNAD
`- Cyst: multiiocuuted
`and: 3
`PERIPHER. NERVEHS)
`NO. 3(3)“anHAD
`no. Exlmlned
`NM)
`lb. namined
`PROSTATE GLAND
`NA!)
`- Infiltration: woman-nuclear cell
`Grade 1
`Grads 2
`
`PITUITARY GLAND
`
`2
`2
`
`2
`1
`)
`-
`1
`
`SKIN/SUBCMIS
`
`i
`-
`1
`
`I
`1
`
`-
`-
`
`Dose Group
`No. Animus per Dose Group
`SHINAL VEICLES
`No. ExaminedNAB
`No. BannedNAD
`- Infiltration: mononuclear cell
`Gradu l
`Grade 2
`— Eden:
`Grade 4
`SFINAL CORD, CERVICJIO. ExaminedNAB
`- Axunai spnurom
`Grade 1
`SPINAL CORD. LINEAR No. ExaminedNM!
`2
`SPLE'KN
`Rn. Examined
`1
`NAD
`~ Hyperplasia:
`lymphoid
`-
`1
`Grade 1
`-
`i
`
`- Any1oid
`2
`-
`Grade 1
`i
`-
`Grade 2
`i
`-
`
`STOMMJH
`No. Examined
`2
`2
`MD
`1
`-
`— Inflammation: subacute
`2
`Grade 1
`-
`1
`Grade 2
`1
`Grade 3
`Grade 1
`Grade 2
`Nu. ExaminedNAD
`TAIL
`- Inflammation: sublcuta
`Grade 2
`Grade 4
`
`

`

`Reviewer: Fred Alavi Ph.D.
`
`NDA No. 22-350
`
`NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS B! ORGAN/GROUP/SEX
`Necropsy Status: Interim/Scheduled. Necropsy (K2)
`6 week Interim Necropsy
`
`
`Sex
`
`
`Dose Group
`No. Animals per Dose Group
`
`
`No . ExaminedMD
`KIDNEYS
`
`
` Mineralization
`Grade 2
`
` Inflammation: chronic
`
`Grade 2
`
`Giant cell: multinucleatedGrade 1
`
`
`
`Infiltration: mononuclear cell
`Grade 1
`'-
`
`Grade 2
`
`Fibroplasia/tibrosie
`Grade 1
`
`
`
` LACRIMAL GLANDS No . Examined“AD
`
`
`
`LIVER No. Examined
`
`
`
`- Vacuolation: hepatocyteGrade 2
`
` - Inflammation: subacute Grade 1
`Grade 3
`
`- Infiltration: mononuclear cell
`Grade 1
`
`
` LUNG No. maminedNM)
`
`
` Mteritis
`Grade 3
`
` Histiocytosis: alveolar space
`Grade 1
`
`
`Inflammation: subacute
`Grade 3
`
`Inflammation : chronic Grade 1
`
`
`M.QUADR1CEPS E‘EMORISNO . Examined
`
`
`- Infiltration: mononuclear cell
`Grade 1
`
`
`- Inflammation: vascular
`3_
`Grade 1
`1
`
`
`Grade 2
`2
`
`Grade 3
`-
`ND. ExaminedMD
`- Inflammation: subacute
`
`MAMMARY GLAND
`
`Grade 2
`— Infiltration: mononuclear cell
`Grade 1
`MANDIB. LYHPH NODB NO. Examined
`HAD
`
`- Histiocytosis: sinus
`
`Grade 2
`
`1
`1
`
`3
`3
`
`l
`1
`
`2
`l
`1
`1
`
`
`
`NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX
`Necropsy status: Interim/Scheduled Necropsy (K2)
`
`6 Week Interim
`Necropsy
`
`
`sex
`Dose Group
`No. Animals per Dose Group
`ADRENAL GLANDS
`No. ExaminedNAD
`No. Examined
`NAD
`No. ExaminedNAD
`BONE mason, STERNUMNO. Examined
`MAD
`
`AORTA
`
`BONE MARROW. RIB
`
`— Hyperplasia:
`
`BONE, RIB
`
`some, 51mm:
`
`BRAIN
`
`lymphoid
`
`Grade 1
`Grade 2
`Na. Examined
`HAD
`
`No. Examined
`HAD
`No. Examined
`HAD
`
`— Mineralization
`
`Grade 1
`— Infiltration: mononuclear cell
`Grade 1
`Grade 2
`
`CECUM
`
`No. Examined
`“AD
`
`— Inflammation: subacute
`
`Grade 1
`
`— Inflammation: vascular
`
`1
`-
`1
`3
`3
`
`3
`3
`3
`1
`-
`-
`2
`2
`-
`
`3
`2
`1
`1
`-
`-
`
`
`
`CERVIX
`
`Grade 2
`No. ExaminedNAD
`- Inflammation: vascular
`
`COLON
`
`Grade 2
`No. Examined
`3
`HAD
`1
`
`- Parasite
`1
`- Inflammation: vascular Grade 2
`1
`- Giant cell: multinucleated
`1
`Grade 1
`-
`Gra