CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`22-350
`
`MEDICAL REVIEWg S!
`
`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Sa‘xagliptin (Onglyza'm)
`
`CLINICAL REVIEW
`
`Application Type NDA.
`Submission Number . 22,350
`Submission Cede N000
`
`Letter Date
`Stamp Date
`PDUFA Goal Date
`
`June 30, 2009
`June 30, 2009
`July 30, 2009
`
`RevieWer Name Naomi Lowy, MD
`Review Completion Date May 14, 2009
`
`Established Name Saxagliptin
`(Proposed) Trade Name Onglyza
`Therapeutic Class Dipeptidyl-peptidase IV inhibitor
`Applicant Bristol-Myers Squibb Company
`
`'
`
`Priority Designation
`
`S
`
`Formulation Oral tablet
`
`Dosing Regimen
`
`_
`5 mg daily
`2.5 mg daily (moderate, severe, or
`end-stage renal impairment)
`Indication Treatment of type 2 diabetes
`Intended Population Adults
`
`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (Onglyzam)M
`
`TABLE OF CONTENTS
`
`1
`
`RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ..........................................................................4
`
`1.1
`1.2
`1.3
`1.4
`
`Recommendation on Regulatory Action ..................................................................................................... 4
`Risk Benefit Assessment ...............................................................................................
`....4
`
`Recommendations for Postmarketing Risk Management Activities ..........................
`....6
`Recommendations for other Post Marketing Study Commitments............................................................6
`
`2
`
`INTRODUCTION AND REGULATORY BACKGROUND.........................................................................6
`
`2.1
`2.2
`2.3
`2.4
`2.5
`2.6
`
`Product Information .................................................................................................................................... 6
`....... 8
`Tables of Currently Available Treatments for Proposed Indications.
`
`Availability of Proposed Active Ingredient in the United States ................................................... 10
`
`Important Safety Issues With Consideration to Related Drugs ..................................................... 10
`
`Summary of Presubmission Regulatory Activity Related to Submission ............................... 10
`Other Relevant Background Information ................................................................................................. 13
`
`3
`
`ETHICS AND GOOD CLINICAL PRACTICES ......................................................................................... 14
`
`3.1
`3.2
`3 .3
`
`
`Submission Quality and Integrity ............................................................................................................. 14
`Compliance with Good Clinical Practices........... 14
`Financial Disclosures ................................................................................................................................21
`
`4
`
`SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ......21
`
`4.1
`Chemistry Manufacturing and Controls ...............................................................................21
`4.2
`Clinical Microbiology....................................................................................22
`4.3
`Preclinical Pharmacology/Toxicology.................................
`....22
`
`4.4
`Clinical Pharmacology .................................................................................
`....22
`
`.
`................................................................
`4.4.1 Mechanism of Action...................
`....23
`
`Pharmacodynamics ................................................................
`4.4.2
`....23
`4.4.3
`Pharmacokinetics ................................................................................................................................. 28
`
`
`
`5
`
`SOURCES OF CLINICAL DATA .................................................................................................................33
`
`5.1
`5.2
`5.3
`
`6
`
`6.1
`
`Tables of Clinical Studies ..............'...........................................................................................................34
`Review Strategy.....‘.......................
`.................................40
`
`Discussion of Individual Studies ..........................................................................40
`
`REVIEW OF EFFICACY .........................................................................56
`
`Indication .....................................................................................................................60
`......................................................................................60
`6.1.1 Methods .............
`
`
`Demographics ........................................................................60
`6.1.2
`
`
`Patient Disposition .......................................................................................74
`6.1.3
`
`6.1.4
`Analysis of Primary Endpoint(s) ............................................................................78
`
`
`.......................................... 87
`6.1.5
`Analysis of Secondary Endpoints(s)
`
`
`Other Endpoints ..................................................................................... 100
`6.1.6
`
`Subpopulations ............................................................................................................ 100
`6.1.7
`
`Analysis of Clinical Information Relevant to Dosing Recommendations ................... 104
`6.1.8
`Discussion of Persistence of Efficacy and/or Tolerance Effects ............................... 106
`6.1.9
`6.1.10
`Additional Efficacy Issues/Analyses ............................................................................................. 106
`
`
`
`7
`
`REVIEW OF SAFETY .................................................................................................................................. 106
`
`7.1
`
`Methods ..................................................................................................................................;............... 108
`Clinical Studies Used to Evaluate Safety ......................................................................... 108
`
`Adequacy of Data ........................................................................................................ 110
`Pooling Data Across Studies to Estimate and Compare Incidence .................................................... 110
`
`7.1.1
`7.1.2
`7.1.3
`
`2
`
`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)M
`
`7.3
`
`
`
`7.2
`Adequacy of Safety Assessments ........................................................................................................... 112
`7.2.1
`Overall Exposure at Appropriate Doses/Durations and Demographics of Target Populations.......... 112
`7.2.2
`Explorations for Dose Response ........................................................................................................ 113
`7.2.3
`Special Animal and/or In Vitro Testing ............................................................. 1 15
`
`7.2.4
`Routine Clinical Testing ......................................................................................... 1 15
`7.2.5 Metabolic, Clearance, and Interaction Workup .................................................................. 115
`
`...... 115
`7.2.6
`Evaluation for Potential Adverse Events for Similar Drugs in Drug Class
`
`Major Safety Results ..................................................................................................
`.
`...... 116
`Deaths .......................................................................................... 116
`7.3.1
`
`
`Nonfatal Serious Adverse Events .................................. 122
`7.3.2
`
`Dropouts and/or Discontinuations ....................
`............................... 138
`7.3.3
`
`Significant Adverse Events ..................................................................................................... 157
`7.3.4
`
`Submission Specific Primary Safety Concerns....................................... 157
`7.3.5
`
`Supportive Safety Results.................................................................234
`7.4
`
`....................................................234
`Common Adverse Events .
`7.4.1
`7.4.2 Laboratory Findings ...............................................................................................248
`7.4.2
`Vital Signs ............................................................................289
`Electrocardiograms (ECGs) ................................292
`7.4.3
`
`Special Safety Studies.................................................................................293
`7.4.4
`
`Immunogenicity .............................................................................................293
`7.4.5
`
`7.5
`Other Safety Explorations .............................................293
`
`
`Dose Dependency for Adverse Events .......................................
`
`
`Time Dependency for Adverse Events ...............................................................................293
`7.5.1
`
`Drug—Demographic Interactions ......................................
`7.5.2
`
`Drug-Disease Interactions ..............................
`7.5.3
`
`Drug-Drug Interactions ................
`7.5.4
`
`Additional Safety Explorations .............
`
`Human Carcinogenicity ..................................
`
`Human Reproduction and Pregnancy Data .................................................298
`
`Pediatrics and Effect on Growth ....................................................................................................299
`
`Overdose, Drug Abuse Potential, Withdrawal and Rebound ......................299
`Additional Submissions ..........................................................................................................................299
`
`7.6
`
`7.6.1
`7.6.2
`7.6.3
`7.6.4
`7.7
`
`8
`
`9
`
`POSTMARKETING EXPERIENCE............................................................................................................299
`
`APPENDICES ........................................................................................................................300
`
`
`.............................................................300
`Literature Review/References
`
`Labeling Recommendations ..............................................
`....305
`Advisory Committee Meeting ................................................................................................................305
`
`9.1
`9.2
`9.3
`
`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`.
`
`1
`
`Recommendations/Risk Benefit Assessment
`
`Saxagliptin (ONGLYZATM) is an orally-active, reversible dipeptidyl peptidase 4 (DPP4)
`inhibitor that has been developed as an adjunct to diet and exercise to improve glycemic control
`in adults with type 2 diabetes. The Sponsor is seeking three indications: as monotherapy, in
`combination therapy with metformin, a sulfonyurea (SU), or a thiazolidinedione (TZD), when
`the single agent alone does not provide adequate glycemic control, and as initial combination
`with metformin, when treatment with dual saxagliptin and metformin is appropriate. The
`proposed usual clinical dose is 5 mg once daily, with a recommended dose of 2.5 mg once daily
`in subjects with moderate or severe renal impairment, and end-stage renal disease requiring
`hemodialysis.
`
`1.1 Recommendation on Regulatory Action
`
`According to my review of the clinical data, I recommend approval of saxagliptin as an adjunct
`to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (although
`the Sponsor requested individual indications for various treatment settings, the Division has
`streamlined the indications for anti-diabetic drugs). The Sponsor has demonstrated modest
`efficacy along with an acceptable safety profile. However, the following recommendations also
`apply:
`0 A dose reduction to 2.5 mg when saxagliptin is used with CYP3A4/5 inhibitors, such as
`ketoconazole. C
`_
`.
`7
`7
`J
`0 As of the completion of this Review, recommendations regarding the use of saxagliptin in
`women of childbearing potential have not been finalized. This issue arose out of a pre-
`clinical study done to support the fixed dose combination of saxagliptin and metformin in
`which certain fetal abnormalities were seen (discussed in Section 4.3). Final decisions
`regarding this issue will be addressed in a pharmacology/toxicology memorandum and
`the Cross Discipline Team Leader (CDTL) memorandum.
`
`1.2 Risk Benefit Assessment
`
`Although there are a number of available medical therapies available for type 2 diabetes mellitus
`(Section 2.2), the progressive nature of the disease demands new therapies that can safely and
`effectively be used either alone or added on to the current armamentarium of drugs. Given that
`the Sponsor has demonstrated efficacy in monotherapy and combination therapy settings,
`saxagliptin can play a useful role in type 2 diabetes treatment.
`
`The Sponsor conducted six Phase 3 studies (referred to as‘“Core Phase 3 studies” in this Review)
`that were randomized, double—blind, and placebo-controlled (two monotherapy studies, three
`add-on combination studies to metformin, sulfonylurea, and a thiazolidinedione, and one initial
`combination with metformin study). In the Phase 3 program, the Sponsor chose to study 3 doses
`
`4
`
`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)M
`
`of saxagliptin (2.5, 5, and 10 mg), which allowed for a more comprehensive safety and efficacy
`evaluation.
`
`The Sponsor has demonstrated modest efficacy with saxagliptin, demonstrated with the
`following reductions in HbAlc relative to placebo: 0.52-0.56% as monotherapy, 0.72-0.83%
`when used as add-on to metformin, 0.6-0.7% when used as add-on to sulfonylurea, and 0.4-0.6%’
`when used as add-on to thiazolidinedione. Saxagliptin was also studied as initial combination
`therapy with metformin, and this combination reduced HbAlc 0.5% relative to metforrnin alone.
`With this modest efficacy, saxagliptin offers the benefit of an oral formulation, convenient once—
`daily dosing independent of food intake, weight neutrality, low risk for hypoglycemia, and
`further HbAlc lowering in diabetic patients who are already receiving maximum doses of other
`antihyperglycemic therapies.
`
`The Sponsor has also demonstrated a favorable safety profile of saxagliptin. This is basedon an
`exposure database of 3422 subjects exposed to saxagliptin in Phase 2 and 3 studies, including
`1269 subjects exposed to the proposed clinical dose of saxagliptin (5 mg). This exposure also
`reflects 1937 subjects exposed to saxagliptin for 252 weeks. Although non-clinical data for
`saxagliptin were concerning for necrotic skin lesions in monkeys at concentrations X-fold higher
`than clinical exposures with the 5 mg daily dose, this was not observed in the clinical program,
`which tested doses up to 100 mg in 44 subjects for 6 weeks and up to 400 mg in 6 subjects for 2
`weeks. Additional safety concerns that arose in the clinical program included saxagliptin—related
`decreases in lymphocyte and platelet counts (see Section 7). These safety issues, which do not
`appear to have clinical relevance, have been adequately addressed by the Sponsor, and do not
`appear to outweigh the demonstrated benefit of saxagliptin.
`
`Although I agree with the Sponsor’s proposed clinical dose of 5 mg daily as well as the
`recommended dose of 2.5 mg daily in subjects with moderate, severe, and end-stage renal
`disease, the Sponsor has not adequately addressed dose adjustment concerning certain drug-drug
`interactions (see Section 4.4). Saxagliptin is predominantly metabolized in the liver by
`CYP3A4/5. In the Clinical Pharmacology review of this drug, the effect of strong CYP3A
`inhibitors and inducers on saxagliptin concentrations emerged as an important issue. Drug—drug
`interaction (DDI) studies identified a more than 2-fold increase in AUC of saxagliptin in the
`presence of ketoconazole. In one in viva DDI study, the combination resulted in a majority of
`subjects experiencing a decline in lymphocyte count accompanied by pyrexia and chills. Given
`these findings, a dose reduction to 2.5 mg is recommended when patients are prescribed
`concomitant CYP3A4/5 inhibitors.
`
`The Clinical Pharmacology review determined no need for higher doses of saxagliptin when
`taken with CYP3A4/5 inducers.
`’
`
`Limitations of the saxagliptin clinical development program include low enrollment of blacks
`and the elderly. Therefore despite subgroup analyses which did not identify major differences
`between subgroups, interpretation of these results is limited.
`
`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (Onglyzam)M
`
`' 1.3 Recommendations for Postmarketing Risk Management Activities
`
`As discussed later in this Review, cardiovascular safety was the subject of an Endocrinologic and
`Metabolic Advisory Committee (EMDAC) meeting held on April 1, 2009. With the
`implementation of the committee’s recommendations, and as per the Food and Drug
`Administration Amendments Act of 2007 (FDAAA), the Division will require a post-marketing
`cardiovascular safety trial, particularly in a higher risk population. See Sections 7 and 9.3 for
`details regarding the advisory committee.
`
`The timelines for the cardiovascular postmarketing requirement are still under discussion but the
`final dates will be included in the Approval letter.
`
`1.4 Recommendations for other Post Marketing Study Commitments
`
`Saxagliptin has been studied in subjects 218 years old. Under the Pediatric Research Equity Act
`(PREA), saxagliptin must be studied in the pediatric population unless there are reasons to waive
`this requirement. The Sponsor requested a waiver for pediatric studies in children less than 10
`years of age, and this waiver has been granted because there are too few children with the disease
`to study. FDA has previously granted a waiver for pediatric studies in children less than 10 years
`of age for another DPP4 inhibitor. The Division agrees with the Sponsor’s proposal to study
`subjects 10 years of age up to but excluding 18 years with type 2 diabetes mellitus. The
`Sponsor proposes to conduct a multicenter, randomized, double-blind, placebo-controlled study
`to evaluate the efficacy, safety, tolerability, and pharmacokinetics of saxagliptin monotherapy in
`pediatric patients with type 2 diabetes. This would include a 16-week, randomized, double-blind
`phase, followed by a 36-week extension phase of continued double-blind treatment (for group
`randomized to saxagliptin) or a cross-over to double-blind metformin (for group randomized to
`placebo). The Sponsor also proposes a pre-randomizati'on pharrnacokinetic sub-study. The
`details of pediatric testing will be finalized when complete protocols are submitted. The
`sponsor’s pediatric plans were discussed with the Pediatric Review Committee, which agreed
`with the cut points for the waiver and deferral and the overall general approach to assessing
`efficacy and safety of saxagliptin in children.
`
`2
`
`Introduction and Regulatory Background
`
`2.1
`
`Product Information
`
`Product Description
`
`Saxagliptin, (1S,3S,5S)-2-[(ZS)-2—Amino-2-(3-hydroxytricyclo[3.3 .1 .13,7]dec-1-yl)acetyl]—2-
`azabicyclo[3.l.0]hexane-3-carbonitrile, monohydrate, is an orally active, selective, reversible
`inhibitor of dipeptidyl peptidase IV (DPP4) intended to improve glycemic control for patients
`with type 2 diabetes mellitus in adults.
`
`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`Established Name
`
`'
`
`.
`
`Saxagliptin (also identified as EMS-477118)
`
`Proposed Trade Name
`
`The proposed trade name for saxagliptin is Onglyza®. The Division of Medication Error
`Prevention and Analysis found this proposed name acceptable'
`
`Chemical Class
`
`Saxagliptin is a New Molecular Entity (NME).
`
`Pharmacologic Class
`
`Saxagliptin, a selective, reversible, and competitive dipeptidyl peptidase 4 (DPP4) inhibitor,
`belongs to a newer class of oral anti-diabetic agents termed “incretin enhancers”.
`
`Saxagliptin is the fourth DPP-IV inhibitorto undergo FDA review as a New Drug Application
`(NDA). This includes one that is currently under review in the Division.
`
`Applicant’s Proposed Indication
`
`The Sponsor proposes saxagliptin as an adjunct to diet and exercise to improve glycemic control
`in patients with type 2 diabetes mellitus:
`0 As monotherapy
`o
`In combination with metformin, a thiazolidinedione (TZD), or a sulfonylurea (SU) when
`the single agent alone, with diet and exercise, does not provide adequate glycemic
`control; and
`0 As initial combination therapy with metformin, when treatment with dual saxagliptin and
`metformin therapy is appropriate.
`
`Applicant’s Proposed Dosing Regimen
`
`The proposed clinical dose is 5 mg once daily. In subjects with moderate or severe renal
`impairment, and end-stage renal disease requiring hemodialysis, the proposed dose is 2.5 mg
`once daily.
`
`Saxagliptin is a CYP3A4/5 substrate, and the effect of strong CYP3A inhibitors and inducers on
`saxagliptin concentrations was analyzed by Clinical Pharmacology. A dosage reduction to 2.5
`mg is recommended when patients will be prescribed CYP3A4/5 inhibitors, such as
`ketoconazole. The Sponsor’s proposed label does not recommend a dose adjustment while
`taking concomitant CYP3A4/5 inhibitors. On the other hand, the use of CYP3A4/5 inducers
`with saxagliptin does not require a dosage increase of saxagliptin.
`
`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`
`Saxagliptin (Onglyza'm) ,W
`
`Anglicant’s Proposed Age Grougs
`
`Adults (218 years of age).
`
`_ 2.2 Tables of Currently Available Treatments for Proposed Indications
`
`

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`

`

`Clinical Review
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`MM
`
`_ 2.3 Availability of Proposed Active Ingredient in the United States
`
`Saxagliptin is a new molecular entity and has not yet been marketed in the Unites States.
`
`2.4
`
`Important Safety Issues With Consideration to Related Drugs
`
`Several DPP-IV inhibitors in development, including saxagliptin, produce dose~ and duration-
`dependent necrotic skin lesions in Cynomolgus monkeys. The FDA therefore has required that
`each DPP-IV inhibitor undergo testing in a three-month monkey toxicity study.
`
`Vildagliptin, another DPP-IV inhibitor in development, has been associated with liver test
`elevations.
`
`Finally, there have been postmarketing reports of serious allergic and hypersensitivity reactions
`in patients treated with sitagliptin (Januviam). These include anaphylaxis, angioedema, and
`exfoliative skin conditions including Stevens-Johnson syndrome.
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`
`End of Phase 2 meeting (July 27, 2005)
`FDA: One Phase 3 monotherapy clinical trial should be sufficient. Two have been presented in
`the meeting briefing document: CV181011 and CV1 8103 8. Study CV181038 should be
`adequate, because it includes the 1 mg dose and the titration extension. The titration—to goal
`design for the extension study mimics real world practice.
`‘
`
`Reviewer comments: The Sponsor performed two monotherapy studies (CV181011 and
`CV181038), for which results of both are included in the NDA. Rather than incorporating
`dose titration into an extension portion of one monotherapy study, the Sponsor
`incorporated dose titration of saxagliptin into the short-term (ST) and long-term (LT)
`periods of CV181038 (see below for an explanation of the ST and LT period). No other
`Phase 3 study incorporated dose titration. The 1 mg dose was not used in the Phase 2b/3
`program. Doses of saxagliptin were restricted to 2.5, 5, and 10 mg.
`‘
`
`FDA: For patients requiring rescue, the last value before rescue therapy should be used in the
`statistical analyses.
`
`Reviewer comments: The primary efficacy endpoint of each Core Phase 3 Study was the
`change in HbAlc from baseline to Week 24 for saxagliptin compared with placebo or active
`comparator. If a subject was rescued, the last pre-rescue post-baseline measurement prior
`to Week 24 was used. If no Week 24 assessment was available, Last Observation Carried
`Forward (LOCF) methodology was used.
`
`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`
`Pre-NDA meeting 1 November 14, 2007:
`FDA: The Division acknowledged that although there are several secondary variables based on
`efficacy, some are Considered exploratory and may not be appropriate in labeling.
`
`Reviewer comment: In the proposed labeling, the Sponsor has included claims of
`
`K
`
`>
`
`PM)
`
`FDA: The Division expressed concern that the Sponsor planned to submit a lot of data in the 4
`month update report (SUR), particularly for the add—on to sulfonylurea (SU) and
`thiazolidinedione (TZD) studies. The projected one-year exposures to saxagliptin for these
`studies at the time ofNDA filing appeared low and would then double at the 4 month update.
`The Division requested sample sizes of at least 200 saxagliptin-treated subjects at 50 weeks at
`the time ofNDA filing for the monotherapy and for the each ofthe combination therapy settings.
`Based on these concerns, on December 7, 2007, the Sponsor submitted a revised proposal for
`saxagliptin patient exposures at the time ofNDA submission and at the time of the safety update.
`The revised proposal is summarized here:
`
` 224 Weeks
`
`Overall
`
`
`
`
`Mono (011, Combo
`038, 039,
`Metformin
`041
`014, 039
`
`Combo SU
`(040)
`
`
`
`Combo TZD
`(013)
`
`
`
`
`
`
`N at NDA
`
`
`
`316
`459
`1029
`813
`2617
`N at 4 Month
`316
`459
`1029
`813
`2617
`
`
`SUR
`
`
`=0
`A=0
`A=0
`A=0
`A=0
`
`250 Weeks
`
`N at NDA
`
`
`
`1338
`335
`527
`306’
`17ob
`N at 4 Month
`2180
`652
`853
`410
`265
`
`
`
`SUR
`A=842
`A=3 1 7
`A=326
`A=104
`A=95
`
`
`
`
`aversus 185 in plan proposed at pre-NDA meeting on November 14, 2007
`bversus 150 in plan proposed at pre-NDA meeting on November 14, 2007
`
`The Division agreed to the revised proposal. Exposures as submitted in the NDA and the SUR
`are presented. in Table 2.2 below. These met and exceeded the numbers proposed by the
`Sponsor.
`
`11
`
`

`

`Clinical Review
`Naomi Lowy, MD.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)M
`
`Table 2.2. Extent of Ex 1 osure for ST + LT Periods: All Phase 2/3 Studies 120-Da Safe U 1 date
`
`N= Number of Treated Subjects
`
`Mean in Weeks (SD)
`Sub'ect-Years
`
`Pooled Monotherapy
`(CV181011, CV181038)
`
`2.5 m
`N=247
`
`5 m_
`N=252
`
`N=98
`
`All Saxa
`N=597
`
`Control
`N=169
`
`59.2 (35.34)
`280.02
`
`63.5 (37.00)
`306.46
`
`84.4 (45.48)
`158.57
`
`65.1 (38.81)
`745.06
`
`64.6 (39.32)
`209.37
`
`
`
`Add-on Combination
`
`N=192
`
`N=191
`
`+ Met
`
`(CV181014)
`+ SU
`
`(CV181040)
`
`+TZD
`
`(CV181013)
`
`91.7 (42.08)
`337.35
`
`87.9 (44.17)
`321.79
`
`N=248
`
`N=253
`
`63.0 (20.71)
`299.52
`
`63.6 (20.98)
`308.45
`
`N=195
`
`N=186
`
`58.7 (21.73)
`219.39
`
`54.6 (24.61)
`194.46
`
`N=181
`
`N=564
`
`N=179
`
`95.2 (40.42)
`330.38
`
`91.5 (42.31)
`989.52
`
`75.9 (43.73)
`260.39
`
`N=501
`
`N=267
`
`63.3 (20.83)
`607.97
`
`60.0 (22.38)
`307.06
`
`N=381
`
`N=184
`
`56.7 (23.25)
`413.86
`
`52.4 (24.67)
`307.06
`
`Initial Combination
`+ Met
`
`(CV1 81 03 9)
`
`Source: 120-Day Safety Update, Table 2.1.1B
`
`N=320
`
`N=323
`
`N=978
`
`N=328
`
`50.1 (19.83)
`307.51
`
`51.0 (20.29)
`315.88
`
`49.3 (20.32)
`924.01
`
`48.0 (21.72)
`301.47
`
`N=335
`
`(monotherapy)
`
`46.8 (20.63)
`300.62
`
`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (Onglyza‘m)
`
`FDA: The Division requested that the Sponsor use 2 methods to define Hy’s Law—one
`definition should require alkaline phosphatase <2x ULN; the second definition should not have
`an alkaline phosphatase requirement. The Division also requested that the Sponsor provide, in
`easily accessible format, the actual liver test values for patients with ALT or AST > 3x ULN and
`actual serum creatinine for patients with outlier values for serum creatinine.
`
`Reviewer comments: The Sponsor did this.
`
`FDA: The Division requested that when reporting the most common adverse events (AEs), the
`Sponsor should use a cut-offvalue of22% instead ofthe proposed “\ ) cut point.
`
`b
`
`‘4}
`
`Reviewer comment: The Sponsor reported all common AEs using a cut-off value of 22%.
`
`2.6 Other Relevant Background Information
`
`The Incretin Effect
`
`The incretin effect is defined by a significantly greater insulin stimulatory effect evoked afier an
`oral glucose load than that evoked from an intravenous infusion when plasma glucose
`concentrations are matched.‘ The majority of this phenomenon is thought to primarily be due to
`oral glucose stimulating the release of glucose-dependent insulinotropic peptide (GIP) and
`glucagon like peptide-1 (GLP~1), both termed incretins. Patients with type 2 diabetes have a
`significant reduction of this effect. GLP-l concentrations are reduced in patients with type 2
`diabetes in response to a meal, and GIP concentrations are either normal or increased.
`
`GIP and GLP—1
`
`Within minutes after food ingestion, GIP is secreted from the K—cells located in the proximal
`region of the jejunum. Although it stimulates insulin release in response to hyperglycemia, GIP
`does not inhibit glucagon secretion and has no effect on gastric emptying. GLP-1 is stored in the
`L—cells of the ileum and colon. It is also released with food ingestion. Its effects on postprandial
`glucose concentration arise from the following mechanisms: enhancing insulin secretion,
`suppressing postprandial glucagon secretion in a glucose-dependent manner, and slowing the rate
`of gastric emptying. Patients with type 2 diabetes have an impaired insulin response to GIP but a
`preserved insulin response to GLP-l. Therefore, GLP-l has been the focus of incretin
`therapeutics in type 2 diabetes.
`
`DPP-IV
`
`In plasma, both GIP and GLP-1 undergo proteolytic cleavage by DPP-IV, a serine protease
`distributed throughout the body and located on the cell surfaces of multiple organs, including
`kidneys, liver, and intestine.‘1 It is also expressed on a subset of CD4+ and CD8+ T cells. DPP-
`IV activity is extremely fast so that the half-lives of GIP and GLP-1 are approximately 7.3
`minutes and 1-2 minutes, respectively. The rationale for DPP-IV inhibitor therapy is to block the
`
`

`

`Clinical Review
`
`Naomi Lowy, M.D.
`NDA 22,350 (Submission 000)
`Saxagliptin (OnglyzaTM)
`
`action of DPP-IV with a molecule that competes for the binding site on the DPP-IV enzyme.
`This approach prolongs the circulating time of active endogenous GLP-l by preventing its
`cleavage.
`
`3 Ethics and Good Clinical Practices
`
`3.1 Submission Quality and Integrity
`
`The Sponsor’s application was adequately organized. With minor exceptions, information was
`easily retrievable. Minor information requests to the Sponsor generally received prompt and
`adequate attention. Narratives for all Serious Adverse Events could not initially be located;
`however, the Sponsor promptly and thoroughly identified the locations, which were dispersed
`throughout the initial submission.
`
`Inspections of the Sponsor and certain clinical sites were completed. The studies appear to have
`been conducted adequately, and the data generated by the clinical sited may be used in support of
`the respective indication.
`
`3.2 Compliance with Good Clinical Practices
`
`The clinical studies were conducted in accordance with ethical standards. Two issues arose
`which could have potentially affected data quality:
`1)
`In studies CV181038 (monotherapy), CV181039 (initial combination with metformin),
`and CV181040 (add—on combination to sulfonylurea), glucose in excess of the intended
`75 g dose was ingested in a number of oral glucose tolerance tests (OGTTs). Data from
`these procedures, which affected a total of 382 subjects, were excluded from OGTT-
`related parameters (including AUCs of insulin, glucagon, and glucose). This error
`primarily impacted the, efficacy results in Study CV181038 by further reducing the
`sample size in this