Clinical Review
`
`Naomi Lowy, M.D.
`' NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`Results for Broad SMQ MACE
`
`As shown earlier, the SMQ MACE endpoint is a broad endpoint so the event rate for SMQ
`MACE was notably greater than the rate observed for Custom MACE. In comparing SMQ
`MACE events from the ST period (Table 7.69 below) to Custom MACE events, it is important to
`note that a disproportionately large number of subjects represented in the SMQ MACE analysis
`had a PT of “blood creatine phosphokinase increased”. Fifiy of the 58 first SMQ MACE events
`for the saxagliptin group and 14 ,of the 25 SMQ MACE events for the comparator group were
`creatine phosphokinase (CPK) increases. Of note, CPK was measured routinely in all patients at
`select clinic visits. Therefore this PT alone, which may easily not represent an important
`cardiovascular event, comprised a significant number of events in the broad SMQ analysis. This
`was also true for the ST+LT period where additional events of increased CPK were observed;
`again the majority of first Broad SMQ MACE events for the saxagliptin group and about half of
`the events for comparator were recorded as increased CPK.
`
`Table 7.69. SMQ MACE: Observed Preferred Terms
`
`
`
`ST Treatment Period
`
`S stem Or_an Class %
`
`Preferred Term (%)
`
`Total Subjects with an Event
`Cardiac Disorders
`
`Acute Myocardial Infarction
`
`Cardiac Failure
`
`Cardiogenic Shock
`
`Myocardial Infarction
`
`General Disorders and Administration Site Conditions
`Sudden Cardiac Death
`.
`
`Investigations
`Blood Creatine Phosphokinase Increased
`
`Electrocardiogram ST Segment Abnormal
`Blood Creatine Phosphokinase MB
`Increased
`
`Nervous System Disorders
`Cerebrovascular Accident
`
`Carotid Artery Stenosis
`Cerebrovascular Disorder
`
`Hemorrhagic Stroke
`
`14 (1.5)
`14 (1.5)
`
`0
`
`0
`
`17 (1.3)
`16 (1.3)
`
`1 (<01)
`
`0
`
`1 (<0.1)
`1 (<0.1)
`
`Transient Ischemic Attack
`
`'
`
`.
`
`Vascular Disorders
`Infarction
`Source: Applicant '3 "Response to Lelterfiom the FDA, 11-Jan—2009", Table 2.1
`
`227
`
`Saxa 2.5 m_
`
`Saxa 5 m
`
`Saxa 10 m_
`
`All Saxa
`
`Com arator
`
`N=937
`
`16 (1.7)
`
`N=1269
`
`18 (1.4)
`
`N=1000
`
`19 (1.9)
`1 (0.1)
`
`N=3356
`
`58 (1.7)
`1 (<01)
`
`.
`
`N=1251
`
`25 (2.0)
`5 (0.4)
`
`1 (<0-1)
`
`1 (<0.1)
`
`1 (<0.1)
`
`3 (0.2)
`
`1 (<0.1)
`1 (<0.1)
`
`14 (1.1)
`14 (1.1)
`
`-
`
`_
`
`16 (1.6)
`15 (1.5)-
`
`0
`
`1 (0.1)
`
`2 (0.2)
`0
`
`1 (0.1)
`0
`
`1 (0.1)
`
`0
`
`1 (0.1)
`1 (0.1)
`
`52 (1.5)
`50 (1.5)
`
`1 (0.1)
`
`1 (0.1)
`
`4 (0.1)
`2 (<0.1)
`
`1 (<0.1)
`0
`
`1 (<0.1)
`
`1 (<0.1)
`
`2 (<0.1)
`2 (<0.1)
`
`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)—_—________________—___—_
`
`228
`
`

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`
`

`

`Clinical Review
`
`Naomi LoWy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`As for the Custom MACE endpoint, no dose response was seen for the SMQ MACE endpoint
`(Table 7.71 below) where again a higher percentage of events is seen for comparators than for
`any dose of saxagliptin overall and for most of the studies individually.
`
`Table 7.71. Incidence of SMQ MACE b Dose of Saxa li tin and b Stud
`
`Saxa 2.5 mg
`n/N (%)
`
`Saxa 5 mg
`n/N (%)
`
`Pooled
`CV181008
`CV181011
`CV181013
`CV181014
`CV181038
`CV181039
`CV181040
`CV181041
`
`16/937 (1.7)
`1/55 (1.8)
`0/102 (0)
`5/195 (2.6)
`5/192 (2.6)
`2/145 (1.4)
`NA
`3/24: (1 2.)
`
`18/1269 (1.4)
`3/47 (6.4)
`2/106 (1.9)
`5/186 (2.7)
`1/191 (0.5)
`1/146 (0.7)
`0/320
`6/253 (2.4)
`0/20
`
`Saxa 10 mg
`n/N (%)
`
`19/1000 (1.9)
`0/63 (0)
`1/98 (1.0)
`NA
`5/181 (2.8)
`NA
`13/658 (2.0)
`NA
`
`All Saxa
`n/N (%)
`
`58/3356 (1.7)
`9/315 (2.9)
`3/306 (1.0)
`10/381 (2.6)
`11/564 (2.0)
`3/291 (1.0)
`13/978 (1.3)
`9/5010(1.8)
`
`'
`
`Comparator
`n/N (%)
`
`25/1251 (2.0)
`1/108 (0.9)
`2/95 (2.1)
`3/184 (1.6)
`3/179 (1.7)
`1/74 (1.4)
`6/328 (1.8)
`8/267 (3.0)
`1/16 6.3
`
`ST + LT Treatment Period 120 Da Safe U- date Database
`
`‘
`
`
`
`
`
`
`
`
`
`
`
` Saxa 10 mgSaxa 5 mgSaxa 2.5 mg_omparator_n/N%)n/N (%) n/N (%) All Saxan/N (%) n/N(%)
`
` ST Treatment Period _,
`
`
`
`
`
`
`
`
`
`30/1000
`
`Pooled
`CV181008
`CV181011
`CV181013
`CV181014
`CV181038
`CV181039
`CV181040
`CV181041
`
`28/397 (3.0)
`1/55 (1.8)
`0/102 (0)
`9/195 (4.6)
`6/192 (3.1)
`3/145 (2.1)
`NA
`9/248 (3.6)
`NA
`
`37/1269 (2.9)
`3/47 (6.4)
`4/106 (3.8)
`10/186 (5.4)
`6/191 (3.1)
`1/146 (0.7)
`2/320 (0.6)
`11/253 (4.3)
`
`(3.0)
`0/63 (0)
`2/98 (2.0)
`NA
`9/181 (5.0)
`NA
`19/658 (2.9)
`~ NA
`
`100/3356 (3 .0)
`9/315 (2.9)
`6/306 (2.0)
`19/381 (5.0)
`21/564 (3.7)
`4/291 (1.4)
`21/978 (2.1 )
`20/501 (4.0)
`0/20 (0
`
`41/1251 (3.3)
`1/108 (0.9)
`4.95 (4.2)
`4/184 (2.2)
`6/179 (3.4)
`2/74 (2.7)
`11/328 (3.4)
`12/267 (4.5)
`1/16 (6.3)
`
`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)W
`
`The results for SMQ MACE, for both ST and ST+LT, show essentially no treatment difference
`withestimates of 0.85 to 0.96. The upper bounds for the 95% confidence intervals are less than
`or equal to 1.52 for all analyses so this data satisfies the 1.8 boundary but not the 1.3 boundary
`set by the guidance.
`"
`'
`
`The interpretation of the SMQ MACE results compared to the Custom MACE results are
`complicated by the inclusion of the events defined by increased CPK in the SMQ endpoint. As
`noted earlier, the primary difference between the two endpoints is the inclusion of these events.
`Because more events of increased CPK occurred in the-saxagliptin group than the comparator
`group (ST+LT: 2.1% versus 1.4%, respectively), the inclusion of these events shifts the estimate
`to the right (Custom MACE point estimate of 0.5—)SMQ point estimate of 0.96).
`
`Table 7.72. Overall Results for SMQ MACE
`
`Comparator
`N=1251
`
`
`
`1289
`
`25 (2.0%)
`41 (3.2%)
`
`
`54
`32
`
`
`
`
`
`Patient-years
`
`=335
`
`
`
`
`
`
`ST+LT
`3753
`
`Events (%)
`
`ST
`58 (1.8%)
`100 (3.1%)
`ST+LT
`Events/ 1000 pt-years
`ST »
`ST+LT
`
`46
`28
`
`
`
`
`
`
`
`Stud —stratified Estimate of Treatment Difference‘ 95% C
`Odds Ratio — Exact method _
`
`ST
`’
`0.90 (0.55, 1.52)
`
`
`
`ST+LT
`0.96 (0.65, 1.42)
`
`Incidence Rate Ratio
`
`
`ST»
`
`0.85 (0.52, 1.42)
`
`ST+LT
`
`0.89 (0.61, 1.31)
`
`
`
`Risk Difference ’
`
`
`ST
`-0.2% (-1.1%, +0.7%)
`
`
`
`ST+LT
`-0.1% (-1.3%, +1 .0%)
`1- Odds ratios under 1 and risk differences less than 0 favor saxagliptin.
`Source: Joint Clinical and Statistical Briefing Documentfor Endocrinologic and Metabolic Drugs Advisory
`Committee meeting, NDA 22,350
`
`232
`
`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`The forest plot for SMQ MACE (Figure 7.3 below) shows the contribution of each study to the
`overall estimate of risk and that no single study shows significant increased or decreased risk of
`MACE events due to saxagliptin. The Kaplan-Meier curve also provides further support for no
`treatment difference.
`
`Figure 7.3. Forest Plot of SMQ MACE Odds Ratio Results — ST+LT
`
`Study
`CV181—008
`CV181-01 1
`CV181—013
`CV181—014
`CV181-038
`CV1 81 -039
`CV181-040
`CV181-O41
`
`Overall
`
`9/315 (2.9%) 1/108 (09%)
`6/306 (2%) 4/95 (4.2%)
`19/381 (5%) 4/184 (2.2%)
`21/564 (3.7%) 6/179 (3.4%)
`4/291 (1.4%) 2/74 (2.7%)
`21/978 (2.1%) 11/328 (3.4%)
`20/501 (4%) 12/267 (4.5%)
`0/20 (0%) 1/16 (6.3%)
`
`OR
`
`
`.
`3.1
`0.5 <—-——;—
`2.4
`j—«————
`1.1
`——-_‘-I—
`0.5 <—-——§—— -
`0.6
`———I—;—
`0.9
`————-;——
`
`f
`'
`0.3
`
`1
`
`—I—
`r—r—fil—l—‘—l—l_"‘l—l
`02
`1.01.3 1.8
`4.0
`6.0
`10.0
`0.5
`20.0 '
`
`Better
`
`Worse
`
`Source: Joint Clinical and Statistical Briefing Documentfor Endocrinologic and Metabolic Drugs Advise/y
`Committee meeting, NDA 22,350
`
`233
`
`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`Figure 7.4. Kaplan-Meier Plot of SMQ MACE Results - ST+LT
`
`0.95
`
`e \o
`
`
`
`ProportionWithoutanEvent
`
`Treatment:
`
`Saxagliptin
`- - - Comparator
`
`P co0:
`
`0.8
`
`0
`
`13
`
`26
`
`39
`
`52
`
`65
`
`78
`
`91
`
`104 117
`
`130
`
`143
`
`156
`
`Time to First SMQ MACE (weeks)
`
`Source: Joint Clinical and Statistical Briefing Documentfor Endocrinologic and Metabolic Drugs Advisory
`Committee meeting, NDA 22, 350
`
`Conclusions regarding MACE events:
`0 The MACE results produced by FDA and the Sponsor met the Guidance criterion of an
`upper bound on the 95% CI of the odds ratio of the less than 1.8.
`o The Custom MACE results showed upper bounds for the CI less than 1.3, regardless of
`analytical approach.
`
`The results of the advisory committee meeting are discussed in detail in Section 9.
`
`7.4
`
`Supportive Safety Results
`
`7.4.1 Common Adverse Events
`
`Pooled Monotherapy Studies
`Table 7.73 Summarizes the most common AEs (22%) by PT during the ST period for the Pooled
`Monotherapy Analysis. Hypoglycemic events are excluded from this analysis and have been
`discussed separately in Section 7.3.5. Overall, the proportion of subjects with AEs during the ST
`
`234
`
`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`.
`
`'
`
`
`
`period was higher in all saxagliptin treatment groups (64.4%, 65.65%, and 76.5% in the
`saxagliptin 2.5, 5, and 10 mg groups, respectively) compared to placebo (59.8%). The most
`frequent AEs across all treatment groups were URI and headache.
`
`
`
`
`Table 7.73. Most Common AEs (Incidence 22%)--Summary by PT During Short-term Treatment
`
`Period for Pooled Monotheram
`
`
`
`Saxa 10 mg
`Placebo
`All Saxa
`Saxa 2.5 mg
`Saxa 5 mg
`
`
`=98
`N=169
`N=597
`N=247
`N=252
`Preferred Term
`
`
`
`
`Upper Resp. Tract Infection
`17 (10.1)
`53 (8.9)
`21 (8.5)
`21 (8.3)
`11 (11.2)
`
`Headache
`9 (5.3)
`34 (5.7)
`9 (3.6)
`14 (5.6)
`11 (11.2)
`Nasopharyngitis
`8 (4.7)
`29 (4.9)
`12 (4.9)
`11 (4.4)
`6 (6.1)
`Urinary Tract Infection
`6 (3.6)
`28 (4.7)
`12 (4.9)
`12 (4.8)
`4 (4.1)
`Sinusitis
`3 (1.8)
`25 (4.2)
`11 (4.5)
`8 (3.2)
`6 (6.1)
`Diarrhea
`4 (2.4)
`22 (3.7)
`11 (4.5)
`5 (2.0)
`6 (6.1)
`Pain in Extremity
`5 (3.0)
`21 (3.5)
`10 (4.0)
`8 (3.2)
`3 (3.1)
`Arthralgia
`3 (1.8)
`19 (3.2)
`5 (2.0)
`9 (3.6)
`5 (5.1)
`Cough
`4 (2.4)
`16 (2.7)
`9 (3.6)
`5 (2.0)
`2 (2.0)
`Peripheral edema
`5 (3.0)
`16 (2.7)
`9 (3.6)
`5 (2.0)
`2 (2.0)
`Musculoskeletal Pain
`1 (0.6)
`16 (2.7)
`6 (2.4)
`6 (2.4)
`4 (4.1)
`Rash
`l (0.6)
`15 (2.5)
`7 (2.8)
`5 (2.0)
`3 (3.1)
`Influenza
`l (0.6)
`14 (2.3)
`4 (1.6)
`5 (2.0)
`5 (5.1)
`Nausea
`2 (1.2)
`14 (2.3)
`5 (2.0)
`7 (2.8)
`2 (2.0)
`Hypertension
`5 (3.0)
`13 (2.2)
`5 (2.0)
`6 (2.4)
`2 (2.0)
`Dizziness
`8 (4.7)
`13 (2.2)
`3 (1.2)
`9 (3.6)
`1 (1.0)
`Vomiting
`1 (0.6)
`13 (2.2)
`5 (2.0)
`7-(2.8)
`1 (1.0)
`Back pain
`8 (4.7)
`12 (2.0)
`3 (1.2)
`9 (3.6)
`0
`Insomnia
`4 (2.4)
`12 (2.0)
`5 (2.0)
`6 (2.4)
`1 (1.0)
`Depression
`2 (1.2)
`12 (2.0)
`4 (1.6)
`5 (2.0)
`3 (3.1)
`Pharyngitis
`4 (2.4)
`10 (1.7)
`5 (2.0)
`4 (1.6)
`1 (1.0)
`Bronchitis
`0
`10 (1.7)
`7 (2.8)
`2 (0.8)
`1 (1.0)
`Dyspepsia
`0
`10 (1.7)
`8 (3.2)
`l (0.4)
`1 (1.0)
`Fatigue
`1 (0.6)
`10 (1.7)
`3 (1.2)
`5 (2.0)
`2 (2.0)
`Sinus Congestion
`2 (1.2)
`10 (1.7)
`3 (1.2)
`5 (2.0)
`2 (2.0)
`Contusion
`1 (0.6)
`9 (1.5)
`7 (2.8)
`1 (0.4)
`1 (1.0)
`Muscle Spasms
`3 (1.8)
`8 (1.3)
`3 (1.2)
`2 (0.8)
`3 (3.1)
`Myalgia
`2 (1.2)
`7 (1.2)
`5 (2.0)
`1 (0.4)
`1 (1.0)
`Constipation
`5 (3.0)
`7 (1.2)
`3 (1.2)
`4 (1.6)
`0
`Gastritis
`0
`7 (1.2)
`2 (0.8)
`2 (0.8)
`3 (3.1)
`Toothache
`1 (0.6)
`7 (1.2)
`5 (2.0)
`2 (0.8)
`0
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`‘
`
`"
`
`235
`
`

`

`Clinical Review
`
`Naomi Lowy, MD.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`Preferred Term
`
`M
`
`ry by PT During Short-term Treatment
`
`
`
`Table 7.73. Most Common AEs (Incidence 22%)—-Summa
`
`Period. for Pooled Monothera .
`
`
`Saxa 5 mg
`Saxa 10 mg
`Saxa 2.5 mg
`All Saxa
`Placebo
`
`
`N=252
`N=98
`N=247
`N=597
`N=l69
`
`
`
`
`
`
`Paraesthesia
`
`2 (0.8)
`1 (1.0)
`4 (1.6)
`'4 (2.4)
`7 (1.2)
`
`
`1 (0.4)
`2 (2.0)
`4 (1.6)
`0
`7 (1.2)
`Sciatica
`1 (0.4)
`3 (3.1)
`3 (1.2)
`-
`Pyrexia
`0
`7 (1.2)
`
`1 (0.4)
`0
`6 (2.4)
`Contact Dermatitis
`0
`7 (1.2)
`2 (0.8
`2 (2.0)
`2 (0.8)
`Pain
`2 (1.2)
`6 (1.0)
`
`3 (1.2)
`2 (2.0)
`1 (0.4)
`Pharyngolaryngeal Pain
`. 5 (3.0)
`6 (1.0)
`3 (1.2)
`2 (2.0)
`1 (0.4)
`Hematuria
`1 (0.6)
`6 (1.0)
`
`l (0.4)
`2 (2.0)
`2 (0.8)
`Blood Pressure Increased
`0
`5 (0.8)
`
`2 (0.8)
`2 (2.0)
`1 (0.4)
`GERD
`0
`5 (0.8)
`
`0
`0
`5 (2.0)
`_
`Eczema
`2 (1.2)
`5 (0.8)
`
`0
`3 (3.1)
`1 (0.4)
`Gastroenteritis Viral
`0
`4 (0.7)
`
`O
`2 (2.0)
`2 (0.8)
`Lower Resp. Tract Infection
`0
`4 (0.7)
`2 (0.8)
`2 (2.0)
`0
`Burning Sensation
`l (0.6)
`4 (0.7)
`
`2 (0.8)
`2 (2.0)
`0
`Anxiety
`0
`4 (0.7)
`
`
`
`1 (0.4)
`2 (2.0)
`1 (0.4)
`Ear pain
`0
`4 (0.7)
`0
`2 (2.0)
`1 (0.4)
`Palpitations
`1 (0.6)
`3 (0.5)
`
`
`Rash Papular
`0
`
`Carpal Tunnel Syndrome
`0
`
`Pneumonia
`0
`
`.
`
`_
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Source: Summary ofClinical Safety, Table 2.1.1.1A
`Abbreviations: GERD=Gastroesophageal Reflux Disease
`
`_
`
`Table 7.74 presents the most common and more frequent AEs in the monotherapy studies.
`Events were included in this table if the frequency of ABS was 22% in either the All Saxa or
`placebo group and there was an absolute difference of more than 1% in either direction between
`any saxagliptin group and the placebo group. The following AEs were more frequent (_>_1%
`difference) in the all saxagliptin group compared to placebo: urinary tract infection, sinusitis,
`influenza, vomiting, nausea, diarrhea, arthralgia, musculoskeletal pain, and rash. Focusing on
`specific dose groups, the saxagliptin 10 mg group had the highest frequency of upper respiratory
`tract infection, sinusitis, influenza, diarrhea, arthralgia, musculoskeletal pain, and headache,
`when compared with any other group (saxagliptin or placebo). The group receiving saxagliptin 5
`mg, the proposed dose, had the highest frequency of vomiting and nausea compared with any
`group. The following AEs were also more frequent (>1% difference) in the saxagliptin 5 mg
`group compared to placebo: urinary tract infection, sinusitis, influenza, vomiting, nausea,
`arthralgia, musculoskeletal pain, and rash.
`'
`
`236
`
`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`Groug or Placebo Durn ST Period for Monothera h Po ulations
`Placebo—controlled Studies
`
`mg
`
` Table 7.74. Most Common AEs (22%) and More Frequent (>1 %) with Any Saxagliptin
`
`77
`
`
`Pooled Monothera-
`,
`
`
`
`
`Saxa 10
`Saxa 2.5
`Saxa 5
`
`mg
`
`
`
`,
`All Saxa
`Placebo
`mg
`
`
`N=252 umber and % of sub'ects N=247
`
`N=l 69
`
`N=98
`N=597
`Infections and Infestations
`
`
`
`
`Upper resp. tract infection
`21 (8.5)
`21 (8.3)
`11 (11.2)
`53 (8.9)
`17 (10.1)
`Urinary tract infection
`12 (4.9)
`12 (4.8)
`4 (4.1)
`28 (4.7)
`6 (3.6)
`
`Sinusitis
`11 (4.5)
`8 (3.2)
`6 (6.1)
`25 (4.2)
`3 (1.8)
`Influenza
`4 (1.6)
`5 (2.0)
`5 (5.1)
`14 (2.3)
`1 (0.6)
`
`Pharyngitis
`5 (2.0)
`4 (1.0)
`1 (1.0)
`10 (1.7)
`4 (2.4)
`
`Gastrointestinal Disorders
`
`
`7 (2.8)
`5 (2.0)
`Vomiting
`7 (2.8)
`5 (2.0)
`Nausea
`5 (2.0)
`11 (4.5)
`Diarrhea
`4 (1 .6)
`3 (1.2)
`Constipation
`Musculoskeletal and Connective Tissue Disorders
`
`
`
`
`
`
`
`Arthralgia
`Back pain
`Pain in extremity
`Musculoskeletal pain
`Nervous System Disorders
`Headache
`Dizziness
`Paraesthesia
`Vascular Disorders
`
`‘
`
`5 (2.0)
`3 (1.2)
`10 (4.0)
`6 (2.4)
`
`9 (3.6)
`3 (1.2)
`4 (1.6)
`
`9 (3.6)
`9 (3.6)
`8 (3.2)
`6 (2.4)
`.
`14 (5.6)
`9 (3.6)
`2 (0.8)
`
`1 (1.0)
`2 (2.0)
`6 (6.1)
`0 (0.0)
`
`5 (5.1)
`0 (0.0)
`3 (3.1)
`4 (4.1)
`
`11 (11.2)
`1 (1.0)
`1 (1.0)
`
`‘ 13 (2.2)
`14 (2.3)
`22 (3.7)
`7 (1.2)
`
`19 (3.2)
`12 (2.0)
`21 (3.5)
`16 (2.7)
`
`34 (5.7)
`13 (2.2)
`7 (1.2)
`
`'
`
`1 (0.6)
`2 (1.2)
`4 (2.4)
`5 (3.0)
`
`3 (1.8)
`8 (4.7)
`5 (3.0)
`1 (0.6)
`
`9 (5.3)
`8 (4.7)
`4 (2.4)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Hypertension
`Investigations
`Blood Creatine Phosphokinase
`2 (0'8)
`Increased
`Skin and Subcutaneous Tissue Disorders
`
`5 (2.0)
`
`6 (2.4)
`
`2 (2.0)
`
`13 (2.2)
`
`5 (3.0)
`
`V
`
`2 (0-8)
`
`1 (1-0)
`
`,
`
`5 (0.8)
`
`3 (1.8)
`
`Rash
`
`1 (0.6)
`
`15 (2.5)
`3 (3.1)
`5 (2.0)
`7 (2.8)
`Respiratory, Thoracic, and Mediastinal Disorders
`4 (2.4)
`9 (3.6)
`5 (2.0)
`2 (2.0)
`16 (2.7)
`Cough
`5 (3.0)
`1 (0.4)
`3 (1.2)
`2 (2.0) _
`6 (1.0)
`I
`Pharyngolaryngeal Pain
`
`
`Source: Summaty ofClinical Safety, Table 2.1.1.1B
`
`
`
`237
`
`

`

`Clinical Review
`Naomi Lowy, MD.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`The following AEs appeared to have a possible dose-dependency: influenza, arthralgia, and
`headache.
`'
`
`Add-on Combination Studies
`
`Table 7.75 presents the common AEs for the 3 add-on combination studies. Table 7.76 presents
`only the most common and frequent AEs versus placebo.
`
`Add-on to Metformin: The overall frequency of ABS during the ST period (excluding rescue)
`was 78.1%, 69.6%, 71.8%, and 64.8% in the saxagliptin 2.5 mg, 5 mg, 10 mg, and placebo
`groups, respectively. The most frequently reported AEs in saxagliptin-treated subjects were:
`nasopharyngitis, headache, diarrhea, URI, influenza, and UTI.
`
`Add-on to SU: The overall frequency of ABS during the ST period was 71.4%, 70.4%, and
`74.2% in the saxagliptin 2.5 mg, 5 mg, and placebo groups, respectively. The most frequently
`reported AEs in saxagliptin-treated subjects were: UTI, headache, nasopharyngitis, URI, back
`pain, and hypertension.
`
`Add-on to TZD: The overall frequency of ABS during the ST period was 61.5%, 74.2%, and
`66.3% in the 2.5 mg, 5 mg, and placebo groups. The most frequently reported AEs in
`saxagliptin-treated subjects were: URI, peripheral edema, UTI,‘ headache, and hypertension.
`
`Table 7.75. Most Common AEs (Incidence 22%)—-Summary PT During ST
`Period for h Add-on Combination Stuies
`
`Add-on to Metformin CV181014
`
`u o 0 er
`
`Placebo +
`Met
`
`14 (7.8)
`13 (7.3)
`20 (11.2)
`9 (5.0)
`13 (7.3)
`8 (4.5)
`5 (2.8)
`12(6.7)
`6 (3.4)
`6 (3.4)
`5 (2.8)
`6 (3.4)
`7(3.9)
`10 (5.6)
`
`All Saxa
`
`49 (8.7)
`45 (8.0)
`' 40 (7.1)
`37 (6.6)
`34 (6.0)
`29 (5.1)
`25 (4.4)
`24 (4.3)
`20 (3.5)
`19 (3.4)
`19 (3.4)
`19 (3.2)
`17(3.0)
`17 (3.0)
`
`,
`
`Nasopharyngitis
`Headache
`Diarrhea
`URI
`Influenza
`UTI
`Arthralgia
`Back pain
`Hypertension
`Cough
`Vomiting
`Dyspepsia
`Nausea
`Pain in extremity
`Abdominal pain
`
`Saxa 2.5 mg +
`Met
`
`Saxa 5 mg +
`Met
`
`Saxa 10 mg
`+ Met
`
`18 (9.4)
`18 (9.4)
`19 (9.9)
`13 (6.8)
`12 (6.3)
`10 (5.2)
`8 (4.2)
`. 11(5.7)
`11 (5.7)
`10 (5.2)
`9 (4.7)
`4 (2.1)
`6(3.1)
`5 (2.6)
`
`13 (6.8)
`11 (5.8)
`22 (5.8)
`9 (4.7)
`12 (6.3)
`10 (5.2)
`8 (4.2)
`5(2.6)
`4 (2.1)
`6 (3.1)
`6 (3.1)
`10 (5.2)
`. 4(2.1)
`4 (2.1)
`
`19 (9.9)
`16 (8.8)
`10 (5.5)
`15 (8.3)
`10 (5.5)
`9 (5.0)
`9 (5.0)
`8(4.4)
`5 (2.8)
`3 (1.7)
`4 (2.2)
`4 (2.2)
`7(3.9)
`8 (4.4)
`
`

`

`
`
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`
`

`

`Clinical Review
`
`Naomi Lowy, MD.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`7.4.1.2.l.2 Add-0n Combination Studies
`
`7.4.1.2.1.2.1 Hematology
`
`Add-on to Metformin
`
`Table 7. 85 summarizes the changes from baseline to Week 24 for hematology parameters for
`Study CV181014. Lymphocytes and platelets have previously been addressed1n Section 7. For
`all parameters, there were no clinically significant changes over time.
`
`Table 7.85. Change from Baseline to Week 24 According to Hematology Parameter and Treatment
`Gron for Stud CV181014
`
`000320.12
`
`Basophils (103 c/uL)
`
`Eosinophils (103 c/uL)
`
`Hemoglobin (g/dL)
`
`Hematocrit (%)
`
`Monocytes (103 c/uL)
`
`Neutrophils (103 c/uL)
`
`00310.03
`
`0 (-0.1, 0)
`0224.007
`
`-0.20
`
`-0.31d:0.21
`
`0 (—0.7, 0.1
`0.01:l:0.02
`
`0 0, 0)
`
`0.02:l:O.10
`
`-0.02i0.01
`
`0.0 0, 0
`
`-0.02:l:0.02
`
`0 (-0.1, 0)
`-0.24d:0.06
`
`-0.02:!:0.01
`
`-0.25:I:0.07
`
`-0.12;-t0.07
`
`—0.30 -0.4, -0.1
`-0.32:l:0.21
`
`-0.15 -0.4, -0.1
`-0.36:|:0.22
`
`0 (-07, 0.1)
`
`0.01:!:0.02
`
`0 (0, 0
`
`0.22i0.15
`
`0.00i0.01
`
`0 (0, 0)
`
`0.181010
`
`~0.20:|:0.26
`
`0.01:}:0.01
`
`0.10 (—0.2, 0.2
`Source: Clinical Stud Reort, CV181014 A I endix 7. 5
`
`010(-.,010.5)
`
`0.,10(0 0.4)
`
`Add--on to Sulfon'ylurea
`Table 7.86 summarizes the changes from baseline to Week 24 for hematology parameters for
`Study CV181014. Lymphocytes and platelets have previously been addressed in Section 7. For
`all parameters, there were no clinically significant changes over time.
`
`Table 7.86. Change from Baseline to Week 24 According to Hematology Parameter and
`
`Treatment Grou for Stud CV181040
`
`Basophils (103 c/uL)
`
`-0.01i0.002
`
`0:1:0.002
`
`

`

`Clinical Review
`
`Naomi Lowy, MD.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`
`0 (-0.01, 0.002)
`0 (0.004, 0.003)
`-0.03d:0.012
`—0.02£:0.016
`
`
`
`
`0 (-0.006, 0.003)
`-0.02:l:0.011
`
`
`
`
`
`Eosinophils (103 c/uL)
`
`-0.01 (-0.042, 0.003)
`0 (-0.056, 0.008)
`-0.02 (-0.051, -0.003)
`
`
`
`-0.0110.063
`-0.1 li0.056
`0:1:0.057
`Hemoglobin (g/dL)
`
`
`0 (-0.13, 0.117)
`-0.10 (-0.223, -0.002)
`0 (-0.117, 0.109)
`'
`
`
`
`
`—0.4i0.1 8
`-0.20:|:0.19
`Hematocrit (%)
`
`
`
`
`
`-0.3 (-0.6, 0.15
`-0.4 (—0.73, -0.04)
`
`. Monocytes (103 c/uL)
`-0.02¢0.011
`0.0130011
`0.01i0.013
`
`
`
`0.01 (0.04, 0.003)
`0.01 (0.009, 0.032)
`0.01 (0.012, 0.038)
`
`
`
`
`
`
`'
`Neutrophils (103 c/uL)
`0.000.072
`0.09i0.091
`0.02:0089
`
`
` 0.02 -0.201, 0.082)
`
`Source: Clinical Study Re 1 art, CV181040, A I . endix 7.‘ 5
`
`
`
`0.02 (-0.091, 0.268
`
`-0.04 (-O.154, 0.197)
`
`Add-on to TZD
`
`Table 7.87 summarizes the changes from baseline to Week 24 for hematology parameters for
`Study CV181013. Lymphocytes and platelets have previously been addressed in Section 7. For
`all arameters, there were no clinical]
`si -
`ificant chan ' es over time.
`
`Table 7.87. Change from Baseline to Week 24 According to Hematology Parameter and
`Treatment Gr_nu for Stud CV181013
`Saxa 2.5 m + TZD
`
`Saxa 5 m + TZD
`
`Placebo + TZD
`
`
`
`
`00040002
`
`0 (0.002, 0.005)
`
`0.0140011
`0 (-0.036, 0.009)
`0500.21
`
`
`0 (0.004, 0.001)
`0 (0.003, 0.004)
`
`
`Eosinophils (103 c/uL)
`
`0.0040014
`0.0000011
`
`001 (0.032, 0.023)
`0 (0.022, 0.021)
`
`
`
`
`
` Hematocrit (%)
`0100.17
`0.51020
`
`
`
`
`0.87, 0.04)
`.
`0.4 (0.95, 0.14)
`
`
`
`-0.15:l:0.065
`-0.19i0.066
`Hemoglobin (g/dL)
`
`
`
`0.10 (-0.318, 0.057)
`0.15 (0.281, 0.024)
`0.10 (0.296, 0.078)
`
`
`
`
`
`
`
`
`Monocytes (103 c/uL)
`-0.02:t0.009
`-0.01:t0.012
`-0.030:l:0.0'11
`
`
`
`—0.01 (-0.034, 0.001)
`0 (-0.028, 0.018
`-0.048, -0.003)
`
`
`
`
`-0.0l:l:0.089
`0.04:b0.103
`-0.07i0.105
`Neutrophils (103 c/uL)
`
`0.11 (—0.l82, 0.169)
`-0.04 (-0.278, 0.136)
`
`
`
`
`
`Source: Clinical Stud Relort, CV181013, A I endz'x 7.6
`
`
`
`Basophils (103 c/uL)
`
`0.0010002
`
`0.00:1:0.001
`
`
`-0.6 (-0.98, 0.29)
`
`-0.19i0.055
`
`-0.01 (-0.166, 0.242)
`'
`
`7.4.1..2.1.2.2 Chemistry
`
`Add-0n to Metformin
`
`259
`
`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`—————._—_.—_—_—__.._.________________._____
`Saxagliptin (OnglyzaTM)
`
`Table 7.88 summarizes the changes from baseline to Week 24 for chemistry parameters for
`Study CV181013. Liver function tests and CPK have previously been addressed in Section 7.
`For all parameters, there were no clinically significant changes over time.
`
`
`
`Table 7.88. Change from Baseline to Week 24 According to Chemistry Parameter and Treatment
`
`Grout for Stud CV181014 _
`
`
`
`
`
`
`Saxa 2.5 mg + Met
`N=192
`
`Saxa 5 mg + Met
`N=l91
`
`Saxa 10 mg + Met Placebo + Met
`
`N=18l
`N=l79
`
`
`0.7i0.3
`1.0i0.2
`l.l:l:0.2
`Sodium (mEq/L)
`
`
`1.0 (-03, 1.1)
`1.0 (0.8, 1.7)
`'
`‘
`
`
`
`
` Potassium (mEq/L)
`
` Chloride (mEq/L)
` BUN (mg/d1)
` Creatinine (mg/dL)
`
` Alkaline phosphatase,
`
`(u/L)
`
`
`
`Add-onto Sulfonlyurea
`Table 7.89 summarizes the changes from baseline to Week 24 for chemistry parameters for
`Study CV181013. Liver function tests and CPK have previously been addressed in Section 7.
`For all parameters, there were no clinically significant changes over time.
`
`Table 7.89. Change from Baseline to Week 24 According to Chemistry Parameter and Treatment
`Groun for Stud CV181040
`77
`
`0 (-0.14, 0.67) ,
`
`Sodium (mEq/L)
`
`Potassium (mEq/L)
`,
`.
`Chloride (mEq/L)
`
`0025:0027
`0 (-0.035, 0.073)
`0.33:0.21
`
`-0.04fl:0.026v
`0 (—0.087, 0.017 .
`
`_
`
`_
`
`260
`
`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`BUN (mg/d1)
`
`0.3:!:0.29
`
`Creatinine (mg/dL)
`
`Alkaline phosphatase (u/L)
`
`Total Bilirubin (mg/dL)
`
`.
`
`’
`
`.
`.
`-3.19&:l.19
`-4.0 (-6.22, -1.54)
`
`003220.014
`
`0 (-0059, -0004
`
`
`
`0.1:l:0.25
`'
`0 (-0.44, 0.55)
`0.09i0.013
`0.02 0.061, 0.113)
`-4.7:|:1.18
`-30 (—6.98, -2.33)
`
`-0.03:l:0.013
`
`0 (0052, 0
`
`0i0.28
`0 (-0.58, 0.54)
`0.07i0.016
`0 (0.042, 0.105)
`- -2.8-J:l .43
`-30 05.59, 0.07)
`
`0.01:0.014
`
`0 (-0.037, 0.02
`
`Add-on to TZD
`
`Table 7.90 summarizes the changes from baseline to Week 24 for chemistry parameters for
`Study CV181013. Liver function tests and CPK have- previously been addressed in Section 7.
`For all parameters, there were no clinically significant changes over time.
`
`Table 7.90. Change from Baseline to Week 24 According to Chemistry Parameter and
`Treatment Grou for Stud CV181013
`
`
`
`Placebo + TZD
`Saxa 2.5 m_ + TZD
`Saxa 5 m + TZD
`
`
`
`Sodium (mEq/L)
`0.7:t0.18
`0.4:t0.21
`1.0 (0.37, 1.08)
`0 (0.03, 0.85)
`1.0 (0.39, 1.16)
`
`
`
`
`‘
`
`
`Potassium (mEq/L)
`
`
`
`
`
`-0.03:l:0.033
`
`0:1:0.034
`
`-0.06:I:0.034
`
`0.83:0.19
`
`0 (-0.095, 0.034)
`
`0 (-0.066, 0.069)
`
`-1.10 {-0.127, 0.01)
`
`Chloride (mEq/L)
`
`0.8:b0.23
`
`0.6i0.28
`
`0.6i0.26
`
`1.0 (0.13, 1.17)
`1.0 (0.08, 1.19)
`1.0 (0.36, 1.27)
`
`0.2:i:1.29
`
`BUN (mg/d1)
`
`0.8 (-0.37, 0.76)
`
`
`0.01:l:0.009
`
`
`0.01d:0.011
`0.02:1:0.013
`
`
`Creatinine (mg/dL)
`
`
`0 (0.011, 0.032)
`0 (-0.002, 0.031)
`0 (-0.011, 0.042)
`
`
`
` Alkaline phosphatase (u/L)
`-6.2il.52
`
`
`
`-6.0 (-10.4, -4.54)
`.1.0 (-591, -0.6)
`~5.0 (-9.25, -3.23)
`
`
` Total Bilirubin (mg/dL)
`-0.04:t0.012
`-0.05i0.016
`-0.04i0.016
`
`
`
`0079, -0.015)
`—0.07, -0.086)
`
`
`
`
`0 (-0.061, -0.012)
`
`7.4.1 .2.1 .2.2 Urinalysis
`
`See Section 7.42.33 for marked abnormalities in urinalysis.
`
`261
`
`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`
`Saxagliptin (OnglyzaTM) 'W
`
`7.4.1.2.1.3
`
`Initial Combination with Metformin Study
`
`'
`
`7.4.1.2.].3.l Hematology
`
`Table 7.91 summarizes the changes from baseline to Week 24 for hematology parameters for
`Study CV181039. Lymphocytes and platelets have previously been addressed in Section 7. For
`all parameters, there were no clinically significant changes over time.
`
`Table 7.91. Change from Baseline to Week 24 According to Hematology Parameter and Treatment Group
`for Stud CV181039
`W
`
`Saxa 2.5 m_ + Met
`
`Saxa 5 m_ + Met
`
`Saxa 10 m_ + Met
`
`Placebo + Met
`
`
`
`
`
`
`Basophils
`(103 c/uL) '
`
`Eosinophils
`(103 c/uL)
`
`
`0i0.002
`0:0.002
`0i0.002
`010.002
`
`0 (0, 0.006)
`0 (0.001, 0.007)
`0 (0.001, 0.007)
`
`
`0.0110016
`0.01 -0.019, 0.043
`
`0.022t0.011
`0.01 -0.001, 0.041
`
`-0.01i0.009
`0 —0.029, 0.007
`
`0.03:t0.014
`0.02 0.004, 0.058)
`
`Hemoglobin
`(g/dL)
`
`-0.49d:0.064
`-0.50 (-0.621, -0.368
`
`
`Hematocrit (%)
`-1.2:|:1.21
`'
`-1.3 (-1.67, -0.83)
`
`Monocytes
`
`(103 c/uL)
`0.02:1:0011
`
`0.03 0.001, 0.043
`
`
`
`-0.14i0.060
`-0.41:t0.'056
`-0.49i0.051
`-0.20 (-0.262, -0.023)
`-O.40 (-0.519, -0.298)
`-.0.50 (-O.586, -0.386
`
`—0.4:l:0.18
`-1.2:l:0.17
`~0.8d:0.20
`-0.3 (-0.71, 0.01)
`-1.2 (91.48, -0.83)
`
`
`
`
`
`
`0033:0009
`0.03zt0.010
`0.02i0.010
`
`0.02 0.016, 0.052
`
`
`0293:0086
`0.10i0.076
`0253:0092
`0.26:t0.083
`
`
`
`
`0.42 (0.118, 0.457)
`0.20 (-0.048, 0.251)
`0.30 (0.068, 0.43)
`0.22 (0.092, 0.421)
`Source: Clinical Study Report, CV181039, Appendix 7.5
`
`
`Neutrophils
`(103 c/uL)
`
`
`
`7.4.1 .2.1 .32 Chemistry
`
`Table 7.92 summarizes the changes from baseline to Week 24 for chemistry parameters for
`- Study CV181039. Liver function tests and CPK have previously been addressed in Section 7.
`For all arameters, there were no .clinicall
`si 1
`ificant chan es over time.
`
`
`
`Table 7.92. Change from Baseline to Week 24 According to Chemistry Parameter and Treatment
`Grouu for Stud CV181039M
`
`Metformin
`Saxa 10 mg
`Saxa 10 mg + Met
`Saxa 5 mg + Met
`N=328
`,
`N=335
`N=323
`'N=263
`
`
`
`
`262
`
`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`Sodium (mEq/L)
`
`1.5i0.22
`
`162120.19
`
`0.5212022
`
`0.83:0.20
`
`2.0(1.06,1.91)
`
`2.0(1.23,1.99).
`
`0.5 (0.05, 0.91)
`
`1.0(0.37,1.15)
`
`0.09i0.033
`
`0.09:1:0.026
`
`02t0.030
`
`0.10i0.027
`
`-
`
`0.10 (0.02, 0.151
`
`0.10 (0.042, 0.146)
`
`0 (-0.063, 0.056)
`
`0.10 (0.04, 0.151)
`
`1.3i0.22
`
`1.5i0. 1 9
`
`1.1i0.22
`
`0.8i0.21
`
`1.0 (0.87, 1.76)
`
`2.0 (1.08, 1.84)
`
`1.0 (0.69, 1.55)
`
`1.0 (0.4, 1.24)
`
`BUN (mg/d1)
`
`.
`
`0740.30
`
`1.0 (0.07, 1.24
`
`
`
`
`
`Potassium
`(mEq/L)
`
`Chloride
`
`(mEq/L)
`
`Creatinine
`
`(mg/dL)
`
`.
`Alkaline
`
`phosphatase
`(u/L)
`
`
`
`0.02:l:0.007
`
`-
`
`002320.009
`
`0.03:1:0.007
`
`0013:0007
`
`0 (0.004, 0.031)
`
`-0.002, 0.033)
`
`0 0.013, 0.039)
`
`0 (—0.01 1, 0.028)
`
`-17.8:l:1.26
`15.0 (-20.26, -
`15.3)
`
`-16.4:1:1.31
`
`-
`
`-14.0 -18.97, —13.8)
`'
`
`-9.8:|:1.30
`-10.0 (—12.37, -
`7.25)
`
`-14.1il.12
`-13.0 (-16,28, -
`11.88)
`
`Total Bilirubin
`
`(mg/dL)
`
`-0.06:|:0.014
`
`'
`
`-0.09:l:0.014
`-0.10 (-0.119, -
`.
`
`-0.03:t0.016
`
`-0.06:l:0.012
`—0.10(-0.085, -
`0.036)
`
`-0.09, ~0.037)
`Source: Clinical Study Report, CV181040, Appendix 7. 7
`
`0 (—0.062, 0.001)
`
`
`
`
`Week 24 Value--Number (%) of
`Sub'ects
`
`
`
`Saxa 2.5 mg
`N=247
`
`Saxa 5 mg
`N=252
`
`Saxa 10 mg
`N=98
`
`All Saxa
`N=597
`
`>ULN
`ZLLN to SULN
`<LLN
`Baseline value (g/dL)
`0 (0)
`4 (66.7)
`2 (33.3)
`<LLN
`
`2 (0.9)
`222 (95.7)
`8 (3.4)
`ZLLN to SULN
`2 (50.0)
`2 (50.0)
`0 (0)
`>ULN
`
`0 (0)
`3 (42.9)
`4 (57.1)
`<LLN
`
`5 (2.1)
`227 (96.2)
`4 (1.7)
`ZLLN to SULN
`0 (0)
`4 (100.0)
`0 (0)
`>ULN
`
`0 (0)
`2 (40.0)
`3 (60.0)
`<LLN
`
`
`2 (2.3)
`85 (96.6)
`1 (1.1)
`ZLLN to SULN
`3 (75.0)
`1 (25.0)
`0 (O)
`>ULN
`
`0(0)
`9 (50.0)
`9 (50.0)
`<LLN
`
`9 (1.6)
`534 (96.0)
`13 (2.3)
`ZLLN to SULN
`
`5 (41.7)
`7 (58.3)
`0 (0)
`>ULN
`
`0 (0)
`4 (50.0)
`4 (50.0)
`<LLN
`Placebo
`
`7 (4.6)
`142 (92.8)
`4 (2.6)
`ELLN to SULN
`N=169
`
`
`
`
`0 (0) 1 (33.3)>ULN 2 (66.7)
`
`-
`
`.
`
`263
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`Clinical Review
`
`7
`Naomi Lowy, MD.
`NDA 22,350 (Submission 000)
`——___——__..________________________
`Saxagliptin (OnglyzaTM)
`
`Saxa 2.5 mg
`N=247
`
`Saxa 5 mg
`N=252
`
`Saxa 10 mg
`N=98
`
`All Saxa
`N=597
`
`Placebo
`N=169
`
`Baseline value (g/dL)
`<LLN
`ZLLN to SULN
`>ULN
`<LLN
`ZLLN to SULN
`>ULN
`
`<LLN
`ZLLN to SULN
`>ULN
`<LLN
`ZLLN to SULN
`>ULN
`<LLN
`ZLLN to SULN
`>ULN
`
`<LLN
`1 (25.0)
`11 (4.7)
`0 (0)
`5610
`4 (1.7)
`0 (0)
`1 (50.0)
`2 (2.3)
`o (0)
`7 (46.7)
`17 (3.1)
`o (0)
`5 (71.4)
`4 (2.7)
`
`ZLLN to SULN
`3 (75.0)
`217 (92.7)
`3 (75.0)
`4 (44.4)
`212 (91.4)
`2 (33.3)
`1 (50.0)
`84 (95.5)
`2 (28.6)
`s (53.3)
`513 (92.6)
`7 (41.2)
`2 (28.6)
`
`>ULN
`
`6 (2.6)
`1 (25.0)
`0 (0)
`16 (6.9)
`4 (66.7)
`0 (0)
`2 (2.3)
`5 (71.4)
`0 (0)
`24 (4.3)
`10 (58.8)
`0 (0)
`9 (6.0)
`
`136 (91.3) 0 (0)
`
`
`
`Baseline value (g/dL)
`<LLN
`ZLLN to SULN
`>ULN
`
`Saxa 2.5 mg
`N=247
`
`Saxa 5 mg
`N=252
`
`Saxa 10 mg
`=98
`
`All Saxa
`N=597
`
`Placebo
`N=169
`
`Saxa 2.5 mg
`N=247
`
`Saxa 5 mg
`N=252
`
`Saxa 10 mg
`N=98
`
`All Saxa
`N=597
`
`<LLN
`ELLN to SULN
`>ULN
`<LLN
`ZLLN to SULN
`>ULN
`<LLN
`ZLLN to SULN
`>ULN
`<LLN
`ZLLN to SULN
`>ULN
`<LLN
`BLLN to SULN
`>ULN
`
`Baseline value (g/dL)
`
`$100
`>100 - 5600
`>600
`£100
`>100 - £600
`>600
`$100
`>100 - $600
`>600
`$100
`>100 - $600
`>600
`
`264
`
`3 (30.0)
`4 (1.8)
`0 (0)
`4 (50.0)
`4 (1.7)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`7 (38.9)
`8 (1.4)
`0 (0)
`0 (0)
`5 (3.3)
`0 0
`
`$100
`
`0 (0)
`0 (0)
`0(0)
`0 (0)
`0 (0)
`0 (0)
`' 0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`
`'
`
`7 (70.0)
`218 (97.3)
`4 (50.0)
`4 (50.0)
`222 (94.9)
`4 (80.0)
`0 (0)
`91 (95.8)
`1 (50.0)
`11 (61.1)
`531 (96.0)
`9 (60.0)
`5 (100.0)
`145 (94.8)
`4 66.7
`
`>100 - S600
`
`0(0)
`240 (100.0)
`1 (100.0)
`0(0)
`246 (100.0)
`0 (0)
`0 (0)
`94 (100.0)
`0 (0)
`0 (0)
`580 (100.0)
`1 (100.0)
`
`0(0)
`2 (0.9)
`4 (50.0)
`0 (0)
`8 (3.4)
`1 (20.0)
`0 (0)
`4 (4.2)
`1 (50.0)
`0(0)
`14 (2.5)
`6 (40.0)
`0 (0)
`3 (2.0)
`2 33.3
`
`>600
`
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0(0)
`
`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`
`
`0(0)
`0 (0)
`0 (0)
`5100
`Placebo
`0(0) .
`164 (100.0)
`'
`0 (0)
`>100 - £600,
`N=169
`
`
`.
`>600
`
`Source: Response to FDA Question Received on 18-March-2009
`
`7.4.1.2.1.3.3 Chemistry
`
`Table 7.94 summarizes shifis from baseline to Week 24 for pertinent chemistry parameters for
`the pooled monotherapy group. No unusual shifts were observed.
`
`Table 7.94. Shift from Baseline to Week 24 (LOCF) for Chemistry Parameters
`
`. Week 24 Value-—Number (%) of
`Sub'ects
`
`Sodium
`
`<LLN'
`Baseline value (ngL)
`>ULN
`
`Saxa 2