Clinical Review
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`Baseline Alc
`
`Although shown to be effective across baseline Alc subgroups, saxagliptin 5 mg was shown in
`most studies to produce numerically greater reductions from baseline for those with higher
`baseline Ale. The treatment-by-subgroup interaction p-value was <O.1 for in 3 of the 6 studies.
`As seen in Figure 6.6 below, the trend of greater reduction in Alc in subjects with higher
`baseline Al 0 values was not seen in Study CV181038. The Sponsor did not present this analysis
`for Study CV181039, however noted that a statistically significant interaction was not generated
`because a similar pattern of greater reduction in Alc was seen in the active-control group.
`
`Figure 6.6. Plot of Adjusted Mean Change from Baseline in Ale and 95% Confidence
`Intervals at Week 24 for Saxagliptin 5 mg Groups in Each Protocol, by Baseline Alc
`Subgroups
`
`gmmg?"
`:
`I:
`5
`
`i
`
`Adj Mean Change from Basetine
`with 95% Cl
`_
`.
`
`3
`
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`cvmvoitaasenne A10 <m§fi§°MG
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`Basellne A“: >- BSL
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`mills
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`MW
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`IS
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`.
`saws
`
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`16
`CVlM-ON. Baseline MC z 5%
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`EMMA“: >- 0%
`< 95
`wills
`Baseline A10 >- 95‘
`saws
`
`:
`
`.
`
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`
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`
`.
`
`-
`
`.
`
`'
`
`‘
`
`..
`
`
`-u
`
`Source: Summary ofClinical Eflicacy, Figure 3. 3A
`
`Race
`
`In the Core Phase 3 studies, the majority of subjects enrolled were white. P-values for treatment—
`by-race interactiOns were <O.1, however the Sponsor asserts that this is due to variability in Alc
`responses in the placebo or active-control treatment groups. The point estimate of the adjusted
`change from baseline in Alc for the saxagliptin 5 mg group was fairly consistent for race
`subgroups across studies, and the 95% CI crossed zero only for nonwhite subjects in CV1810lh
`(n=13, right panel in Figure 6.7 below).
`
`The treatment-by-race subgroup interaction p-value was <0.l in the trials with treatment-naive
`subjects (CV18101 1, CV181038, and CV181039). It is unclear why this was seen. Overall,
`however, it appears that no conclusions regarding the effect of race in saxagliptin treatment can
`be made.
`
`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`Reviewer comment: According to Ms. Mele’s analysis of HbAlc treatment effect by race,
`although Asians were a minority of enrolled subjects (highest enrollment was 15% in Study
`CV181039), two studies (CV181011 and CV181039) produced significant interactions.
`Given this, the clinical implications for the treatment of Asians, including PK exposure,
`and safety, should be considered.
`
`Figure 6.7. Plot of Adjusted Mean Change from Baseline in Ale and 95% Confidence
`Intervals at Week 24 for Saxagliptin 5 mg Groups in Each Protocol, by Race Subgroups
`Difference from control
`Adi Mean Change fmm Baseline
`(Sam-Pia) with 95% Cl
`WWI 95% Ci
`
`-
`
`-
`
`-
`
`-
`
`’
`
`-
`
`-
`
`cvwwn. Racezwm: W's
`Race Nemvnl m cm
`cvwwaa. Racewme
`x: Ms
`
`Rice: mm mm
`. momma: mm
`emu-ma. Raee:wme
`,fl?‘31i"6
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`Race: Asian
`fi’fiomc
`m m sea“;
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`%ng119
`
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`
`Source: Summary ofClinical Efi‘icacy, Figure 3.33
`
`Baseline Creatinine Clearance
`
`The interaction p-values were >0.l in both monotherapy trials and <0.1 in 2 of the 3 add-on
`combination trials. This may be explained by a greater dose-response separation in subjects in
`the subgroups with baseline creatinine clearance S80 mL/min in the add-on combination studies.
`The saxagliptin 5 mg group had a greater adjusted mean reduction in Alc at Week 24 than the
`2.5 mg groups in the add-on combination studies. However, the change from baseline Alc in the
`control group was similar between the subgroups. As seen in Figure 6.8 below, the control-
`corrected adjusted mean Alc reduction and the adjusted mean Alc reduction was consistently
`greater for saxagliptin 5 mg in the subgroup with creatinine clearance <80 mL/min. The Sponsor
`hypothesizes that reduced renal clearance of insulin (saxagliptin1ncreases post-prandial insulin
`secretion) may contribute to these findings.
`
`103
`
`

`

`Clinical Review
`
`Naomi Lowy, MD.
`NDA 22,350 (Submission 000)
`Saxagliptin (Onglyzam)
`
`Figure 6.8. Alc Changes from Baseline in Subgroups Based on Creatinine Clearance in
`Monotherapy and Add-0n Therapy Studies
`Difference from control
`(Sam-Control) with 95% C1
`:
`: .
`I
`:
`: 1*0—1
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`_
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`with 95% C!
`
`chat-011. Creamme clearance :- an mumn
`sax: 5 ms
`Piaowo
`curring Cleme> so mvrm
`sansm;
`Puma
`011814133. Cm Clearance <- 80 mm
`Sam 5 MG MM
`PM
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`91303170
`(311814113. €123:th (lemme :- 811 murmn
`5385156
`Pla+TZD
`Oahu")! Clem 2 8‘11 mVlflh
`Sam 5 MG
`Pla+ TZD
`CHM-1149. Creatmne clearance <- 811 mmnn
`Sax: 5 MG
`Pla+GLY
`OEZUHIM CW9 > 5” "11711111
`Sin S ’15
`1313+ GLY
`011151-0111. Cmaznme cxearanoe z-OD mmrm
`Sara 5 MG
`1113+ MET
`033111111)! (3mg, GD mvmn
`Sara 5m
`
`P13 41- ME?
`
`u
`u
`o
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`an
`m
`11.1
`o
`on
`-w
`«as
`an
`an
`
`$5 Benet canto: 55w
`
`Source: Summary ofClinical Eflicacy, Figure 3. 3D
`
`Other subgroups
`Several subgroups, including gender, had interaction p--values <0.11n only one trial; each of
`these trials involved treatment--na'1've subjects.
`
`For age and baseline BMI, there were no analyses with an interaction p-value <0.1. Regarding
`age, it is important to note that the percentage of subjects >75 years old in the Core Phase 3
`studies was low (1.4%). Interpretation of this specific subgroup analysis is therefore limited.
`
`Overall, subgroup analyses did not reveal any unexpected conclusions. Greater reductions in
`Alc associated with higher baseline Alc is typically seen with other drugs used for the treatment
`of diabetes.
`
`6. 1 .8 Analysis of Clinical Information Relevant to Dosing Recommendations
`
`In Phase 1 and 2 studies, saxagliptin 5 mg was associated with greater inhibition of plasma DPP4
`activity at the trough of the dosing interval compared to 2.5 mg. In the Phase 2b study, the 5 mg
`dose also resultedin maximal reductionsin Ale and fasting serum glucose (Section 4.4). The
`Phase 3 studies confirmed the effects of saxagliptin 5 mg on Alc. A major strength of the
`
`104
`
`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`-—————_————_________—______
`
`Sponsor’s clinical development program was the incorporation of multiple doses in the Phase 3
`studies, allowing for a more thorough evaluation of the dose chosen from Phase 2.
`
`In the Phase 3 studies, saxagliptin 10 mg did not result in incremental benefit, and in fact, was
`associated with certain adverse effects not observed with the 5 mg dose (Section 7).
`'
`
`The benefit of 5 mg versus 2.5 mg was adequately demonstrated in the primary efficacy
`endpoint:
`-
`0 With the exception of the monotherapy studies, subjects in the saxagliptin 5 mg groups
`demonstrated greater decreases from baseline in Alc at 24 weeks versus the 2.5 mg
`groups. In both monotherapy studies, subjects in the 2.5 mg and 5 mg groups
`demonstrated similar Al c reductions.
`.
`-
`Reviewer comment: In Study CV181038, the decreases from baseline in Alc at 24 weeks
`for the 2.5 mg and 5 mg groups were -0.71% and -0.66%, respectively. As mentioned
`earlier in this Review, this study had the smallest number of subjects per dose group and
`therefore was more prone to confounding factors or chance findings. This one exception to
`the otherwise demonstrated benefit of 5 mg over 2.5 mg should be viewed with this study
`limitation.
`
`When analyzing secondary endpoints, the benefit of 5 mg versus 2.5 mg was also generally
`demonstrated.
`
`0
`
`In all studies, the saxagliptin 5 mg group had a greater reduction in postprandial glucose
`AUC versus the 2.5 mg group, although differences in the monotherapy trials were
`modest.
`'
`.
`V
`
`o The proportion of subjects who achieved a glycemic response of A1c<7% was higher in
`the saxagliptin 5 mg groups versus the 2.5 mg groups in one of the monotherapy studies
`and the add-on combination study to metformin. Minimal differences were observed in
`the other monotherapy study and the 2 add-on combination studies.
`In the add-on combination studies only, the saxagliptin 5 mg group had greater decreases
`from baseline in FPG than the saxagliptin 2.5 mg groups, although differences were
`modest for the add-on to sulfonylurea trial and the 2.5 mg and 5 mg groups reduced FPG
`to a similar extent in the monotherapy trials.
`
`0
`
`As discussed in Section 4.4, while the 5 mg per day dose appears to be the optimal dose in most
`subjects, those with moderate or severe renal insufficiency are recommended a dose adjustment
`to 2.5 mg.
`'
`
`Finally, the Sponsor examined subgroups to determine if there was a particular group of subjects
`in which the greater efficacy of the 5 mg dose versus the 2.5 mg dose was observed. This was
`seen in the subjects with creatinine clearance 580 ml/min in the add-on studies, with an
`approximately 2—fold difference in the reduction from baseline Alc at the 5 mg dose compared to -
`2.5 mg. This was previously discussed in Section 6.1.7.
`
`105
`
`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTMW
`
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects
`
`Each Core Phase 3 study included an extension phase of at least 12 months to allow for
`additional safety and efficacy data. These periods were ongoing at the time of NDA submission,
`and therefore only interim results were submitted. Subjects remained in the treatment group to
`which they were assigned in the ST period, although some required'rescue in addition to their
`randomized treatment.
`
`Despite these long-term extensions, the Phase 3 studies were not designed to specifically look at
`persistence of drug effect beyond Week 24. LOCF methodology is used in the Sponsor’s
`analyses, and this is problematic, particularly if subjects were rescued early in the study. There
`are limitations to the utility of such analyses. Sample sizes by the end of the evaluated periods
`are low. For example, in Study CV181038, approximately 10 subjects each remained in the
`treatment groups. Such low sample sizes limit a meaningful interpretation and extrapolation to a
`wider population.
`
`6. 1 . 1 0 Additional Efficacy Issues/Analyses
`
`7 Review of Safety
`
`Safety Summary
`
`In general, saxagliptin appears to have a favorable safety profile. The safety database from the
`Phase 2b/3 program is based on exposure of 3422 subjects. Of these, 2642 subjects were
`exposed to study drug for 224 weeks and 1080 subjects were exposed for 252 weeks.
`
`Issues that will be discussed in this section of the Review include:
`
`Deaths and Major Adverse Cardiovascular Events (MACE): There were no increased deaths
`in saxagliptinetreated subjects. As discussed in depth in this Section, although the saxagliptin
`clinical development program did not prospectively plan an evaluation of MACE, a retrospective
`and comprehensive analysis did not reveal an increased frequency of MACE events among
`saxagliptin—treated subjects. This was also the subject of an Advisory Committee meeting,
`discussed at length in Section 9.3.
`
`Serious Adverse Events: There were no concerning signals of specific serious adverse events
`among saxagliptin-treated subjects.
`
`106
`
`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (Onglyzam)
`
`-
`
`0
`
`Common adverse events: Overall, common adverse events were higher in saxagliptin—treated
`subjects versus placebo. The following common AEs were more frequent in saxagliptin groups
`compared to placebo:
`o
`In monotherapy studies: urinary tract infection, sinusitis, influenza, vomiting, nausea,
`diarrhea, arthralgia, musculoskeletal pain, and rash. The 5 mg group had the highest
`frequency of vomiting and nausea.
`In the add-on combination study with metformin: URI, abdominal pain, arthralgia,
`pharyngolaryngeal pain, and blood CK increased.
`In the add-en combination study with sulfonylurea: gastroenteritis, abdominal pain,
`headache, and hypertension.
`.
`In the add-on combination with TZD: URI, sinusitis, arthralgia, musculoskeletal pain,
`headache, anemia, peripheral edema, and blood CK increased.
`In the initial combination with metformin study: For the saxagliptin 5 mg +‘metformin
`group, these included nasopharyngitis, URI, bronchitis, dyspepsia, headache, back pain,
`arthralgia, and hypertension.
`
`o
`
`0
`
`Of note, none of these adverse events (except arthralgia) occurred consistently more frequently
`with saxagliptin than comparator across the phase 3 studies.
`
`Of the most common AEs occurring more frequently with saxagliptin than comparator, the
`following appeared to exhibit a possible dose-dependency:
`
`0
`0
`0
`
`0
`
`In the monotherapy studies: influenza and arthralgia.
`In the add—on combination study with SU: hypertension.
`In the add-on combination study with TZD: URI, musculoskeletal pain, and anemia
`appeared to be dose-related.
`Initial combination with metformin: dyspepsia and hypertension.
`
`Although hypertension is an adverse event that appears to have a possible relationship to
`saxagliptin dose in the add-on to SU and initial combination with metformin studies, the
`objective blood pressure data do not support an adverse effect of saxagliptin on blood pressure.
`
`Hypoglycemia: The frequency of reported hypoglycemia was higher in the monotherapy studies
`and particularly in the add-on combination study to glyburide (CV181040). The frequency of
`confirmed hypoglycemic episodes was higher in saxagliptin-treated subjects Only in Study
`CV181040 (1.6% versus 0.7% in placebo subjects).
`
`Decreased lymphocyte counts: Decreases in lymphocyte count were seen in all studies,
`particularly in the saxagliptin 10 mg groups. However, an increase in infectious associated with
`T-cel] dysfunction among saxagliptin-treated subjects was not found.
`
`Thrombocytopenia: Although small decreases were observed in all dose groups, subjects in the
`10 mg dose group had the largest mean decrease in percent change from baseline in platelets.
`
`107
`
`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`Overall, these changes were of unclear clinical significance and were not associated with an
`increased rate of bleeding.
`
`Skin findings: Higher frequencies of rash-related AEs were seen in saxagliptin-treated subjects
`versus comparator groups in all analyses, and the highest rates were seen in the 10 mg groups.
`However, pre-defined events intended to capture AEs related to non-clinical findings Were rare.
`
`Peripheral edema: With the exception of the add-on combination to TZD study (CV181013),
`there were generally low rates of reported localized edema. In Study CV181013, whose placebo
`group had a higher frequency of localized edema AEs compared to placebo groups in other
`studies, the frequency of localized edema AEs was highest in the 5 mg group (7.0% vs2.5% in
`placebo group). None of the events resulted in study drug discontinuation.
`
`. Aside from the lymphocyte and platelet abnormalities mentioned above, there were no other
`significant saxagliptin—related laboratory findings. In addition, there were no clinically
`significant changes in vital signs or EKGs observed in the safety monitoring program.
`
`Limitations of the safety evaluation include low enrollment of non-white subjects and elderly
`subjects. In addition, the Phase 3 program had very limited enrollment of subjects with renal
`impairment. No subjects had severe renal impairment at baseline. However, an ongoing
`dedicated renal study will provide data on the safety and efficacy of saxagliptin in subjects with
`type 2 diabetes mellitus with moderate, severe, or end—stage renal disease. Additional
`information in renally impaired patients will be obtained in the longer-term cardiovascular safety
`trial that will be required as a condition of approval.
`
`7.1 Methods
`
`7.1.1 Clinical Studies Used to Evaluate Safety
`
`The Sponsor presented all safety data for Treated Subjects, defined as subjects who received at
`least one dose of study drug (saxagliptin, placebo, glyburide, metformin, or a TZD). Section 5.1
`summarized all clinical studies in the development program. Table 7.1 summarizes the studies
`used in the saxagliptin safety database.
`
`108
`
`

`

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`
`

`

`Clinical Review
`' Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`
`Saxagliptin (OnglyzaTM) .W
`
`7.1 .2Adequacy of Data
`
`All AEs were coded and grouped into Preferred Terms (PTs) by System Organ Class (SOC)
`using the Medical Dictionary for Regulatory Activities (MedDRA). MedDRA version 10.1 was
`used for the Core Phase 3 studies. Narratives for deaths, serious adverse events, and
`discontinuations were reviewed. Overall, terms appeared to be coded appropriately. Exceptions
`identified by this Reviewer were as follows:
`0
`Subject CV181038-87-811 (placebo group) was coded as having “coronary artery
`disease” on Day 84. However, the narrative provided described this subject as having
`had an “extensive AW STEMI”. The Sponsor was questioned regarding this and clarified
`that they reported an SAE “extensive anterior wall ST elevation myocardial infarction”
`only after database lock. Indeed, the Sponsor did later identify this subject as having had
`a MACE event.
`
`The Sponsor was asked to provide narratives for subjects with potential cardiac PTs that may
`have been classified under other SOCs. This process identified 2 subjects who had no AB in the
`cardiac SOC, but had cardiac procedures. The Sponsor recognized that these events should have
`been coded differently:
`0
`Subject CV181040-l49-862, a subject in the saxagliptin 2.5 mg group, was coded as
`having “chest pain” in the General Disorders SOC. However, the Sponsor confirmed that
`he had an acute stent placement.
`0 Subject CV181014-183-1096, a subject in the placebo group, was coded as having “pain
`in extremity”. However, the Sponsor confirmed that he hadan angioplasty that appeared
`to have been done as a response to the workup for the index event.
`
`7.1.3 Pooling Data Across Studies to Estimate and Compare Incidence
`
`The focus ofthe Sponsor’s safety evaluation was the 24-week double-blind treatment period of
`the 6 core Phase 3 studies. Four populations (termed Population l-Population 4), summarized in
`Table 7.2 below, were created to summarize the safety of saxagliptin. Although there is utility in
`using a' pooled safety population, particularly when monitoring for rare events, in this Review I
`frequently present the safety of the individual studies rather than using pooled data. This is done
`to assess for potential differences in the safety profile of the varying study populations.
`Population 3 (Table 7.2) contains pooled safety data for the 2 monotherapy studies and the 3
`add-on combination studies. A major limitation of this population is the pooling of dissimilar
`subjects with dissimilar background therapies. Population 4 is independently presented from the
`pooled safety population as this study had an active metforrnin comparator arm without a
`placebo arm. Therefore, it did not fit the pooling strategy for used for Population 3.
`
`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (Onglyzam)
`
`Placebo
`
`
`
`
`
`
`
`
`
`
`
`Treatment Grou n s
`
`
`
`Table 7.2. Summa
`of P0 ulations for Safe Evaluation
`
`
`Population 1: Pooled Monotherapy Safety
`At least one dose of double-blind treatment
`
`
`Includes studies: CV1.81011 and 038
`
` Treatment Grou o s
`
`
`
`
`
`saxagliptin 2.5
`saxagliptin 5 mg
`.
`.
`
`
`(includes PM
`mg (includes
`525352231133?
`All
`
`
`
`
`
`
`dosing arm from
`2.5/5 titration arm
`0t included)
`saxagliptin
`
`
`
`
`
`
`from 038)
`03 8)
`n
`'
`
`
`
`
`Population 2: Pooled Monotherapy Long-term Safety
`At least 24 weeks of double-blind treatment
`
`Includes studies: CV18101] and 038
`
`
`Treatment Grou s
`
`
`
`
`
`saxagliptin 5 mg
`
`
`
`saxagliptin 10 mg
`All
`saxagliptin 2.5
`(includes PM
`
`
`(OL arm in 011
`
`
`dosing arm from
`mg
`
`saxagliptin
`not included)
`
`
`03 8)
`
`
`
`Population 3: Pooled Safety
`
`At least one dose of double—blind treatment
`
`
`Includes studies: CV18101], 038, 013, 040, and 014
`
`
`Treatment Grou l s
`
`
`
`
`
`saxagliptin 2.5
`saxagliptin 5 mg
`
`
`saxagliptin 10 mg
`
`mg (Includes 2.5
`*
`(includes PM
`All
`.
`(0L arm in 011
`
`
`
`
`
`to 5 t1trat10n arm
`dosmg arm from
`saxagliptln
`.
`
`
`
`
`from 038)
`038)
`not included)
`
`
`
`‘ Population 4: CV181039 Safety
`At least one dose of double-blind treatment
`
`
`
`Includes studies: CV181039
`
`saxagliptin 10 mg
`saxaghptln 5 mg
`saxagliptin 10 mg
`All
`Placebo +
`+ metformin
`+ metformm
`+ placebo
`saxagliptin
`metformin
`Source: Integrated Summary ofSafety, Table 1.1.1
`The following data were not pooled for safety analyses (except for exposure and deaths):
`0 Data from subjectsin Study CV181008: this study was of shorter duration (12 weeks)
`and therefore exposure was not comparable to the Core Phase 3 studies.
`0 Data from subjects1n Study CV181041 (12-week mechanism of action study). this study
`was of shorter duration, employed difference baseline Alc criteria, and was of small
`sample size.
`I Data from subjects in Study CV181039: this was discussed above.
`
`
`
`
`
`
`
`111
`
`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`- Data from subjects receiving open-label 10 mg saxagliptin in Study CV181011: there was
`no control group and Ale criteria for inclusion at baseline were higher in this cohort (10-
`12%) than. in the other placebo-controlled studies.
`
`7.2 Adequacy of Safety Assessments
`
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target
`Populations
`,
`'
`
`Guidelines and recommendations regarding study drug design and exposure can be found in both
`International Conference on Harmonization (ICH) guidelines and the FDA Draft Guidance on-
`Diabetes.
`
`The Draft Guidance from February 2008, which provides recommendations for the development
`of drugs and therapeutic biologics regulated within the Center for Drug Evaluation and Research
`at FDA for the treatment and prevention of diabetes mellitus, refers to 6 month, placebo-
`controlled phase 3 studies as well as an extension phase of 6—12 months.1 The Guidance also
`recommends that phase 3 trial data for drugs developed for type 2 diabetes be available for at
`least 2,500 subjects exposed to the investigational product with at least 1,300 to 1,500 of these
`subjects exposed to the product for 1 year or more and at least 300-500 subjects exposed to the
`product for 18 months or more. The Table below summarizes these exposures, and confirms that
`the Sponsor met these recommendations.
`'
`
`able 7.3. Number of Subjects Exposed to Saxagliptin in ST + LT
`I' eriods for Phase 2/3 Studies
`
`
`
`
`
`
`
`
`
`N 224 Weeks
`
`N 252 Weeks
`
`2642 ‘
`
`1080
`
`2655
`
`1937
`
`Limitations of the safety assessments, including limited enrollment cf certain populations, was
`previously discussed above under Section 7, Safety Summary.
`
`
`
`1 FDA Guidance for Industry (Drafi Guidance), Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for
`Treatment and Prevention, February 2008.
`-
`
`112
`
`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`————__——__~_________—___
`
`7.2.2 Explorations for Dose Response
`
`In the Phase 1-3 clinical development program, a total of 4042 subjects (3018.7 subject-years)
`were exposed to saxagliptin, including 620 in clinical pharmacology studies, 315 in the Phase 2b
`clinical study, 20 in a Phase 3 MOA study, and 3087 in the 6 Core Phase 3 studies. The extent of
`exposure for the ST + LT periods of the phase 2/3 studies (from lZO—day safety update) have
`been presented by individual study in Table 2.2 in Section 2.5. Table 7.4 and 7.5 below present
`the exposures by close for the ST + LT Periods for the phase 2/3 studies, both from the initial
`submission and the safety update.
`
`113
`
`

`

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`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`
`
`
`Table 7.5. Ex 1 osure in ST + LT Periods from the 120-Da Safe U date: Phase 2/3 Studies
`
`
`Saxa 2.5mg
`Saxa 5mg
`Saxa 10mg
`All Saxa
`Control
`
`Weeks
`N=937
`N=1269
`N=1066
`N=3422
`N=1251
`
`
`
`
`
`945 (76%)
`
`
`689 (55%)
`
`N (%) 224
`
`N (%) 252
`
`773 (83%)
`
`622 (66%)
`
`1046 (82%)
`
`772 (61%)
`
`836 (78%)
`
`543 (51%)
`
`2655 (78%)
`
`1937 (57%)
`
`Mean (SD)
`Median
`
`64.0 (35)
`65.1
`
`60.1 (33)
`63
`
`58.5 (36)
`52.6
`
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`0.1,‘1443
`0.1,141.6
`Ran_e
`Source: A I licant’s 120-day Sa e Uldate, A I endix 1.4.5
`
`
`
`
`
`
`
`58.5 (36)
`62.3
`
`0.1, 157.1
`
`53.9 (33)
`60
`
`0.1, 141.1
`
`
`
`
`
`
`
`Demographic data has already been presented in Section 6.1.2.
`
`7.2.3 Special Animal and/or In Vitro Testing
`
`Refer to Dr. Fred Alavi’s review for details.
`
`7.2.4 Routine Clinical Testing
`
`Laboratory tests, vital signs, and EKGs were performed at acceptable time points during the
`studies. This Reviewer did not identify missing key measurements.
`
`7.2.5 Metabolic, Clearance, and Interaction Workup
`
`The Sponsor’s testing of saxagliptin’s metabolism, clearance, and potential for interaction has
`already been discussed in Section 4.4.
`‘
`
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class
`
`The Sponsor adequately monitored for adverse events that have been associated with other DPP-
`4 inhibitors, including infections, skin-related AEs, hypersensitivity, and liver test abnormalities.
`The Phase 3 program incorporated pre~defmed analyses related to these potential events.
`
`The development program was not prospectively designed to monitor for Major Adverse
`Cardiovascular Events (MACE), although the Sponsor adequately responded to Division
`requests for analysis of such events. This is further discussed in this Section under
`Cardiovascular Safety as well as in Section 9.3
`
`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`7.3 Major Safety Results
`
`7.3.1Deaths
`
`In the Phase 2-3 studies, a total of 16 deaths were reported during the ST and LT periods as of
`the data cutoff for LT interim CSRs. These include 2 subjects (0.2%) in the 2.5 mg saxagliptin
`group, 2 subjects (0.2%) in the 5 mg group, 3 subjects (0.3%) in the 10 mg group, 5 subjects
`(05%) in the placebo group, and 4 subjects (1.2%) in the metformin monotherapy group. As
`expected for this patient population, most of the deaths were due to cardiovascular causes. Of the
`7 deaths in saxagliptin-treated subjects, 2 occurred during ST and 5 during LT. There were no
`deaths among subjects who received a 20 mg or 40 mg dose, although exposure to these doses
`was of short duration. Short narratives for the deaths follow the table below.
`
`116
`
`

`

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`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`Brief Narratives of Deaths
`
`Deaths during ST
`
`Saxagliptin—treated subjects
`Subject CV181038-85-572, a 47 year old white male with a history of splenectomy secondary to
`trauma was in the saxagliptin 2.5 mg group, died on Day 54 with a recent history of upper
`respiratory symptoms 5 days prior. He had not received Pneumovax. On Day 54, the subject
`awoke with fever and chills and presented to the emergency room (ER) with abdominal pain,
`hypotension, and bradycardia. He was treated for sepsis, but his clinical condition deteriorated
`and he died despite cardiopulmonary resuscitation. Post-mortem results from blood cultures
`obtained in the ER demonstrated Streptococcus pneumoniae. The investigator characterized the
`death as unrelated to study medication.
`
`Subject CV181013-74-386, a 66 year old white female in the saxagliptin 2.5 mg group, died in
`an automobile accident on Day 102. She encountered slippery road conditions, and the car lost
`control and spun onto oncoming traffic. She died from trauma. The investigator characterized
`the event leading to death as not likely related to study medication.
`
`-
`Placebo-treated subjects
`Subject CV181014—171-1341, a 35 year old white male in the placebo group, died of
`cardiogenic shock on Day 157. He had a history of hypertension and hypertriglyceridemia.
`The investigator characterized the death as unrelated to study medication.
`
`Subject CV1810040-68-1424, a 58 year old Asian male in the placebo group, died of sudden
`cardiac death on Day 112. He had a medical history of coronary artery disease and
`cerebrovascular disease. The investigator characterized the death as unlikely related to study
`medication.
`
`Metformin-treated subjects
`Subject CV181039—60-1617, a 65 year old white male in the metformin group, was found dead
`in his home on Day 144 (death due to cardiac failure). He had a medical history of
`hypertension and myocardial infarction. The investigator characterized the death as unrelated to
`study medication.
`
`Subject CV181039-140-1597, a 60 year old white male in the metformin group, died of an acute
`myocardial infarction on Day 6. He had a history of hypertension and myocardial infarction.
`The investigator characterized the death as unrelated to study medication.
`
`Subject CV181039-14l-1059, a 62 year old white male in the metformin group, had a
`cerebrovascular accident on Day 130 and underwent drainage for an intracerebral hematoma.
`He died on Day 135. The investigator characterized the death as unrelated to study medication.
`
`Deaths during LT
`
`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`Saxagliptin-treated subjects
`Subject CV181014—171-778, a 48 year old white male in the saxagliptin 10 mg group, had a
`history of smoking, was diagnosed with a Grade 3 pulmonary neoplasm on Day 431. He had
`presented with weight loss, dysphagia, right eyelid ptosis, and leukocytosis. He was hospitalized
`on Day 449 for a bronchoscopy. However, on the same day, he experienced a pulmonary
`embolism and died. This occurred prior to rescue and 14 days after study medication was
`discontinued. The investigator characterized the event leading to death as unrelated to study
`medication.
`
`Subject CV181039-148-943, a 57 year old white male in the saxagliptin 10 mg group, had a
`medical history of hypertension, coronary artery disease, previous myocardial infarction, stable
`angina, obesity, hypercholesterolemia, hypertriglyceridemia, and mixed dyslipidemia.
`According to the subject’s relative, on Day 294, the subject died suddenly. The investigator
`characterized the event leading to death as unrelated to study medication.
`
`Subject CV181039-232-2798, a 55 year old Asian male in the saxagliptin 10 mg+metformin
`group, died of “sudden death” on Day 254. He had a medical history of poorly controlled
`hypertension and overweight. He was noted to have a right bundle branch block on Days 101
`and 180. On the day of his death, the subject reported feeling unwell and fell to the ground.
`There was no medical observation of the death or medical intervention performed. The ‘
`investigator characterized the event leading to death as possibly related to study medication.
`
`Subject CV181040-100—l810, a 68 year old male in the saxagliptin 5 mg group, died on Day 214
`of