CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`209091Orig1s000
`
`CLINICAL REVIEW(S)
`
`
`
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`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209091
`QTERN (Saxagliptin and Dapagliflozin)
`
`
`CLINICAL REVIEW
`Application Type New Drug Application (NDA) and Efficacy Supplements (sNDAs)
`Application Number(s) NDA 209091, sNDAs 22350/S-018, and sNDA 200678/S-018
`Priority or Standard Standard
`
`
`Submit Date(s) April 27, 2016
`Received Date(s) April 27, 2016
`PDUFA Goal Date February 27, 2017
`Division/Office Division of Metabolism and Endocrinology Products (DMEP)
`
`
`Reviewer Name(s) Frank Pucino, PharmD, MPH
`Review Completion Date February 21, 2017
`
`
`Established Name Saxagliptin and Dapagliflozin Fixed Combination Drug Product
`(FCDP)
`(Proposed) Trade Name QTERN
`Applicant AstraZeneca
`
`
`Formulation(s) Saxagliptin 5 mg/dapagliflozin 10 mg FCDP tablet
`Dosing Regimen Saxagliptin 5 mg /dapagliflozin 10 mg tablet taken once daily in
`the morning
`Proposed Indication(s) As an adjunct to diet and exercise to improve glycemic control in
`adults with type 2 diabetes mellitus (T2D)
`
`
`Limitations of Use: Should only be used in patients who tolerate
`10 mg dapagliflozin
`Intended Population(s) Patients with T2D
`
`
`Recommendation on
`Approval (pending labeling negotiations)
`Regulatory Action
`Recommended
`Indication(s) (if applicable)
`
`NDA 209091: Adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus who have
`inadequate glycemic control on dapagliflozin or who are already
`treated with dapagliflozin and saxagliptin
`NDA 022350: Adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus
`NDA 200678: Adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus when treatment
`with both saxagliptin and metformin is appropriate
`
`
`
`
`Reference ID: 4058510
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`(b) (4)
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`

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`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209091
`QTERN (Saxagliptin and Dapagliflozin)
`
`
`Table of Contents
`
`Glossary ........................................................................................................................................... 9
`
`1
`
`2
`
`3
`
`4
`
`Executive Summary ............................................................................................................... 13
` Product Introduction ...................................................................................................... 13 1.1.
`
`
` Conclusions on the Substantial Evidence of Effectiveness ............................................ 13 1.2.
`
` Benefit-Risk Assessment ................................................................................................ 15 1.3.
`
`Therapeutic Context .............................................................................................................. 20
` Analysis of Condition ...................................................................................................... 20 2.1.
`
`
` Analysis of Current Treatment Options ......................................................................... 20 2.2.
`
`Regulatory Background ......................................................................................................... 24
` U.S. Regulatory Actions and Marketing History ............................................................. 24 3.1.
`
`Summary of Presubmission/Submission Regulatory Activity ........................................ 25
`3.2.
`
`3.3.
`Foreign Regulatory Actions and Marketing History ....................................................... 30
`
`
`Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`Efficacy and Safety................................................................................................................. 31
` Office of Scientific Investigations (OSI) .......................................................................... 31 4.1.
`
`
` Product Quality .............................................................................................................. 31 4.2.
`
` Clinical Microbiology ...................................................................................................... 32 4.3.
`
` Nonclinical Pharmacology/Toxicology ........................................................................... 32 4.4.
`
` Clinical Pharmacology/Biopharmaceutics ...................................................................... 33 4.5.
`
` Mechanism of Action .............................................................................................. 34 4.5.1.
`
` Pharmacodynamics ................................................................................................. 34 4.5.2.
`
` Pharmacokinetics .................................................................................................... 35 4.5.3.
` Devices and Companion Diagnostic Issues .................................................................... 36 4.6.
`
`
` Consumer Study Reviews ............................................................................................... 36 4.7.
`
`5
`
`Sources of Clinical Data and Review Strategy ....................................................................... 36
` Table of Clinical Studies .................................................................................................. 36 5.1.
`
`
` Review Strategy .............................................................................................................. 40 5.2.
`
`6
`
`Review of Relevant Individual Trials Used to Support Efficacy ............................................. 41
`
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`
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`Reference ID: 4058510
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`2
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`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209091
`QTERN (Saxagliptin and Dapagliflozin)
`
`
`
` Trial CV181168 ............................................................................................................... 41 6.1.
`
` Study Design............................................................................................................ 41 6.1.1.
`
` Study Results ........................................................................................................... 52 6.1.2.
`
`Integrated Review of Effectiveness ....................................................................................... 63
` Assessment of Efficacy Across Trials .............................................................................. 63 7.1.
`
`
` Primary Endpoints ................................................................................................... 63 7.1.1.
`
` Secondary and Other Endpoints ............................................................................. 63 7.1.2.
`
` Subpopulations ....................................................................................................... 64 7.1.3.
`
` Dose and Dose-Response........................................................................................ 64 7.1.4.
`
` Onset, Duration, and Durability of Efficacy Effects ................................................ 64 7.1.5.
`
` Additional Efficacy Considerations ................................................................................. 64 7.2.
`
` Considerations on Benefit in the Postmarket Setting ............................................ 64 7.2.1.
`
` Other Relevant Benefits .......................................................................................... 65 7.2.2.
`Integrated Assessment of Effectiveness ........................................................................ 65
`
`7.3.
`
`
`Review of Safety .................................................................................................................... 66
`8.1.
`Safety Review Approach ................................................................................................ 66
`
`
` Review of the Safety Database ...................................................................................... 67 8.2.
`
` Overall Exposure ..................................................................................................... 67 8.2.1.
`
` Relevant characteristics of the safety population: ................................................. 68 8.2.2.
`
` Adequacy of the safety database: .......................................................................... 70 8.2.3.
`
` Adequacy of Applicant’s Clinical Safety Assessments .................................................... 70 8.3.
`
` Issues Regarding Data Integrity and Submission Quality ....................................... 70 8.3.1.
`
` Categorization of Adverse Events ........................................................................... 71 8.3.2.
`
` Routine Clinical Tests .............................................................................................. 72 8.3.3.
`Safety Results ................................................................................................................. 73
`
` Deaths ..................................................................................................................... 74 8.4.1.
`
` Serious Adverse Events ........................................................................................... 75 8.4.2.
`
` Dropouts and/or Discontinuations Due to Adverse Effects ................................... 78 8.4.3.
`
` Significant Adverse Events ...................................................................................... 79 8.4.4.
`
` Treatment Emergent Adverse Events and Adverse Reactions ............................... 80 8.4.5.
`
`8.4.
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`3
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`7
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`8
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`Reference ID: 4058510
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`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209091
`QTERN (Saxagliptin and Dapagliflozin)
`
`
` Laboratory Findings ................................................................................................ 81 8.4.6.
`
`
` Vital Signs ................................................................................................................ 91 8.4.1.
`
` Electrocardiograms (ECGs) ...................................................................................... 92 8.4.2.
`
` QT ............................................................................................................................ 93 8.4.3.
`
` Immunogenicity ...................................................................................................... 93 8.4.4.
`
` Analysis of Submission-Specific Safety Issues ................................................................ 93 8.5.
`
` Malignancies ........................................................................................................... 94 8.5.1.
`
` Cardiovascular Events ............................................................................................. 96 8.5.2.
`
` Confirmed Adjudicated Hepatic Events .................................................................. 98 8.5.3.
`
` Decreased Lymphocyte and Platelet Counts ........................................................ 100 8.5.4.
`
` Fractures ............................................................................................................... 101 8.5.5.
`
` Genital Infections .................................................................................................. 102 8.5.6.
`
` Urinary Tract Infections ........................................................................................ 103 8.5.7.
`
` Infections .............................................................................................................. 104 8.5.8.
`
` Hypoglycemia ........................................................................................................ 104 8.5.9.
`8.5.10.
`Pancreatitis .................................................................................................... 105
`
`8.5.11.
`Renal Failure/Impairment ............................................................................. 106
`
`8.5.12.
`Severe Cutaneous Adverse Reactions ........................................................... 107
`
`8.5.13.
`Severe Hypersensitivity Reactions................................................................. 107
`
`8.5.14.
`Volume Depletion .......................................................................................... 107
`
`
` Myopathy/Rhabdomyolysis ........................................................................... 108 8.5.15.
`8.5.16.
`Other Adverse Events Associated with DPP-4 Inhibitors and SGLT-2 Inhibitors
`
`111
`
`Specific Safety Studies/Clinical Trials ........................................................................... 111
`8.6.
`
`
` Additional Safety Explorations ..................................................................................... 111 8.7.
`
` Human Carcinogenicity or Tumor Development .................................................. 111 8.7.1.
`
` Human Reproduction and Pregnancy ................................................................... 111 8.7.2.
`
` Pediatrics and Assessment of Effects on Growth .................................................. 112 8.7.3.
`
` Overdose, Drug Abuse Potential, Withdrawal, and Rebound .............................. 112 8.7.4.
`Safety in the Postmarket Setting.................................................................................. 113
`
` Safety Concerns Identified Through Postmarket Experience ............................... 113 8.8.1.
`
`8.8.
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`Reference ID: 4058510
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`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209091
`QTERN (Saxagliptin and Dapagliflozin)
`
`
` Expectations on Safety in the Postmarket Setting ............................................... 113 8.8.2.
`
` Additional Safety Issues From Other Disciplines.......................................................... 114 8.9.
`
`Integrated Assessment of Safety .............................................................................. 114
`8.10.
`
`
`9 Advisory Committee Meeting and Other External Consultations ....................................... 115
`
`10 Labeling Recommendations ................................................................................................ 115
`10.1.
`Prescribing Information ............................................................................................ 115
`
`10.2.
`Patient Labeling ........................................................................................................ 116
`
`Non-Prescription Labeling ........................................................................................ 116
`10.3.
`
`
`11 Risk Evaluation and Mitigation Strategies (REMS) .............................................................. 117
`11.1.
`Safety Issue(s) that Warrant Consideration of a REMS ............................................ 117
`
`11.2.
`Conditions of Use to Address Safety Issue(s) ........................................................... 117
`
`11.3.
`Recommendations on REMS .................................................................................... 117
`
`
`12 Postmarketing Requirements and Commitments ............................................................... 117
`
`13 Appendices .......................................................................................................................... 118
`13.1.
`References ................................................................................................................ 118
`
`13.2.
`Antihyperglycemic Products Approved in the United States ................................... 128
`
`13.3.
`Financial Disclosure .................................................................................................. 176
`
`13.4.
`Schedule of Trial Procedures .................................................................................... 180
`
`13.5.
`SGLT2 Inhibitor & DPP-4 Inhibitor Adverse Events of Special Interest
`
`(System/Custom MedDRA Queries) ....................................................................................... 192
`13.6.
`Thrombocytopenia ................................................................................................... 214
`
`
` Marked CK Elevations ............................................................................................... 215 13.7.
`Expedited Safety Reports - Rhabdomyolysis Associated with Saxagliptin or
`13.8.
`
`Dapagliflozin: .......................................................................................................................... 229
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`Reference ID: 4058510
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`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209091
`QTERN (Saxagliptin and Dapagliflozin)
`
`
`Table of Tables
`
`
`Table 1: Approved Therapeutic Options for the Management of Type 2 Diabetes Mellitus ....... 23
`Table 2: Summary of Presubmission/Submission Regulatory History for NDA 209091 ............... 27
`Table 3: Listing of Clinical Trials Relevant to this NDA .................................................................. 37
`Table 4: Criteria for Initiation of Antihyperglycemic Rescue Therapy .......................................... 48
`Table 5: Subject Disposition (Randomized Population)* .............................................................. 53
`Table 6: Relevant Protocol Deviations (Randomized Population)* .............................................. 54
`Table 7: Demographics (Randomized Population)* ..................................................................... 55
`Table 8: Baseline Clinical Characteristics (Randomized Population)* .......................................... 56
`Table 9: Commonly Used (>10%) Concomitant Medications by Therapeutic Class ..................... 57
`Table 10: Analysis of Mean Change in HbA1c from Baseline to Week 24 .................................... 59
`Table 11: Analysis Secondary Endpoints (Change from Baseline to Week 24) ............................ 60
`Table 12: Agency Analysis of Mean Change in HbA1c from Baseline to Week 24 ─ Trials
`CV181168, CV181169, and MB102129 (Data after Rescue/Discontinuation Included) .............. 63
`Table 13: Integrated Safety Population, Size and Duration of Exposure (ST+LT Pool) ................. 68
`Table 14: Demographics and Clinical Characteristics (Safety Population)* ................................. 68
`Table 15: Summary of Adverse Events (Integrated ST and ST+LT Safety Pools) .......................... 73
`Table 16: Summary of Serious Adverse Events by System Organ Class ....................................... 76
`Table 17: Summary of Discontinuations Due to Adverse Events (Integrated ST and ST+LT Safety
`Pools)............................................................................................................................................. 78
`Table 18: Summary of Common TEAEs (Integrated ST and ST+LT Safety Pools).......................... 80
`Table 19: Summary of Marked Laboratory Abnormalities (ST+LT Safety Pool) ........................... 81
`Table 20: Mean Changes from Baseline in Hemoglobin and Hematocrit (ST+LT Safety Pool) ..... 83
`Table 21: Mean Changes from Baseline in Serum Creatine Kinase (ST+LT Safety Pool) .............. 85
`Table 22: Mean Changes from Baseline in Serum Creatinine and eGFR (ST+LT Safety Pool) ...... 86
`Table 23: Mean Changes from Baseline to End-of-Study in Fasting Lipid Parameters ─ Trials
`CV181168, CV181169, MB102129 (ST and ST+LT Safety Pools) ................................................... 88
`Table 24: Subjects with Elevated Liver Laboratory Tests (ST and ST+LT Safety Pools) ................ 90
`Table 25: Mean Changes from Baseline to End-of-Study in Vital Signs ........................................ 92
`Table 26: Summary of Malignancies and Premalignant Conditions (ST and ST+LT Safety Pools) 96
`Table 27: Summary of Adjudicated Cardiovascular Events (ST and ST+LT Safety Pools) ............. 97
`Table 28: Summary of Genital Infections (ST and ST+LT Safety Pools) ...................................... 103
`Table 29: Summary of Urinary Tract Infections (ST and ST+LT Safety Pools) ............................. 104
`Table 30: Summary of Hypoglycemic Events (ST and ST+LT Safety Pools)* ............................... 105
`Table 31: Renal Impairment/Failure ........................................................................................... 106
`Table 32: Summary of Potential Volume Depletion-Related Adverse Events ............................ 107
`Table 33: Demographics and Clinical Characteristics of Subjects with CK Elevations ................ 109
`Table 34: Summary Table of Approved Antihyperglycemic Products ........................................ 128
`Table 35: Schedule of Trial Procedures for the Short-Term Treatment Period ......................... 180
`Table 36: Schedule of Trial Procedures for the Long-Term Treatment Period .......................... 189
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`Reference ID: 4058510
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`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209091
`QTERN (Saxagliptin and Dapagliflozin)
`
`Table 37: Summary of Myopathy/Rhabdomyolysis MedDRA Preferred Terms(ST+LT Safety Pool)
`..................................................................................................................................................... 228
`Table 38: Summary of Expedited Safety Reports of Rhabdomyolysis (Saxagliptin and
`Dapagliflozin; February 2017) ..................................................................................................... 229
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`Reference ID: 4058510
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`Clinical Review
`
`Frank Pucino, PharmD, MPH
`NDA 209091
`
`QTERN (Saxagliptin and Dapagliflozin)
`
`Table of Figures
`
`Figure 1: Study Design of Trial CV181168 ..................................................................................... 42
`
`Figure 2: Longitudinal Adjusted Mean Changes in HbA1c (Baseline to Week 52)* ..................... 61
`Figure 3: Graphical Patient Profile of Subject M31021gm;
`W" ........................................... 214
`Figure 4: Graphical Profile of Subject CV181168
`— Marked Creatine Kinase ............... 216
`
`Figure 5: Graphical Profile of Subject CV181168
`
`— Marked Creatine Kinase ............... 217
`
`Figure 6: Graphical Profile of Subject CV181168
`
`Marked Creatine Kinase ................. 218
`
`Figure 7: Graphical Profile of Subject CV181168
`
`Marked Creatine Kinase ................. 219
`
`Figure 8: Graphical Profile of Subject CV181169
`
`— Marked Creatine Kinase ............... 220
`
`Figure 9: Graphical Profile of Subject CV181169
`Figure 10: Graphical Profile of Subject CV181168-
`Figure 11: Graphical Profile of Subject M8102129-
`Figure 12: Graphical Profile of Subject M8102129—
`
`Marked Creatine Kinase ................. 221
`(m6) — Marked Creatine Kinase ............... 222
`om— Marked Creatine Kinase ............. 223
`— Marked Creatine Kinase ............. 224
`
`Figure 13: Graphical Profile of Subject M3102129-
`Figure 14: Graphical Profile of Subject CV181168-
`Figure 15: Graphical Profile of Subject M3102129-
`
`— Marked Creatine Kinase ............. 225
`(hm — Marked Creatine Kinase ............... 226
`m6) — Marked Creatine Kinase ............. 227
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`Reference ID: 4058510
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`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209091
`QTERN (Saxagliptin and Dapagliflozin)
`
`
`Glossary
`
`
`AC
`
`ACEI
`
`ADA
`
`AE
`AEOSI
`ALT
`
`ARB
`
`AST
`
`AUC
`
`B-cell
`
`BE
`
`BMI
`
`BMS
`
`BPCA
`
`BRF
`
`CABG
`
`CDC
`
`CDER
`
`CDTL
`
`CFR
`
`CHF
`
`CK
`
`Cmax
`
`CMC
`
`CMQ
`
`COSTART
`CRF
`
`CRL
`
`CRO
`
`CRT
`
`CSR
`
`CSS
`
`CT
`
`CV
`
`CVOT
`
`CYP3A4/5
`DBP
`
`
`
`
`
`Reference ID: 4058510
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`Advisory Committee
`Angiotensin Converting Enzyme Inhibitor
`American Diabetes Association
`Adverse Event
`Adverse Event of Special Interest
`Alanine Aminotransferase
`Angiotensin Receptor Blocker
`Aspartate Aminotransferase
`Area-Under-the-Curve
`Beta-Cell
`Bioequivalence
`Body Mass Index
`Bristol-Myers Squibb
`Best Pharmaceuticals for Children Act
`Benefit Risk Framework
`Coronary Artery Bypass Grafting
`Center for Disease Control and Prevention
`Center for Drug Evaluation and Research
`Cross-Discipline Team Leader
`Code of Federal Regulations
`Congestive Heart Failure
`Creatine Kinase
`Maximum Plasma Concentration
`Chemistry, Manufacturing, and Controls
`Custom MedDRA Query
`Coding Symbols for Thesaurus of Adverse Reaction Terms
`Case Report Form
`Complete Response Letter
`Contract Research Organization
`Clinical Review Template
`Clinical Study Report
`Controlled Substance Staff
`Computerized Tomography
`Cardiovascular
`Cardiovascular Outcomes Trial
`Cytochrome P450 3A4/5
`Diastolic Blood Pressure
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`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209091
`QTERN (Saxagliptin and Dapagliflozin)
`
`
`DCCT
`
`DMC
`
`DMF
`DPP-4
`eCRF
`
`ECG
`
`eCTD
`
`eGFR
`
`EOS
`
`ETD
`
`FCDP
`
`FDA
`
`FDAAA
`FDASIA
`FPG
`
`FT4
`
`GCP
`
`GM
`
`GRMP
`HbA1c
`HDL-C
`HLGT
`
`HLT
`
`HPF
`
`ICH
`
`IND
`
`iPSP
`
`ISE
`
`ISS
`
`ITT
`
`IVR
`
`LDL-C
`
`LTSS
`
`MDRD
`MedDRA
`mITT
`
`MTT
`
`MRHD
`NCI-CTCAE
`NDA
`
`NGSP
`
`
`Diabetes Control and Complication Trial
`Data Monitoring Committee
`Drug Master File
`Dipeptidyl Peptidase-4
`Electronic Case Report Form
`Electrocardiogram
`Electronic Common Technical Document
`Estimated Glomerular Filtration Rate
`End-of-Study
`Early Treatment Discontinuation
`Fixed Combination Drug Product
`Food and Drug Administration
`Food and Drug Administration Amendments Act of 2007
`Food and Drug Administration Safety and Innovation Act
`Fasting Plasma Glucose
`Free Thyroxine
`Good Clinical Practice
`Geometric Mean
`Good Review Management Practice
`Hemoglobin A1c (Glycosylated Hemoglobin)
`High-Density Lipoprotein Cholesterol
`High Level Group Term
`High Level Term
`High-Power Field
`International Conference on Harmonization
`Investigational New Drug
`Initial Pediatric Study Plan
`Integrated Summary of Effectiveness
`Integrated Summary of Safety
`Intent-to-treat
`Interactive Voice Response
`Low-Density Lipoprotein Cholesterol
`Long-term Stability Study
`Modification in Diet and Renal Disease
`Medical Dictionary for Regulatory Activities
`Modified Intent-To-Treat
`Meal Tolerance Test
`Maximum Recommended Human Dose
`National Cancer Institute-Common Terminology Criteria for Adverse Event
`New Drug Application
`National Glycohemoglobin Standardization Program
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`Reference ID: 4058510
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`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209091
`QTERN (Saxagliptin and Dapagliflozin)
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`NME
`NSAID
`NYHA
`OCS
`
`OPQ
`
`OSE
`
`OSI
`
`PBRER
`PCTA
`
`PD
`
`PI
`
`PIND
`
`PK
`
`PLLR
`
`PMC
`
`PMR
`
`PPG
`
`PPI
`
`PREA
`
`PSUR
`
`PT
`
`P-Y
`
`REMS
`SA
`
`SAE
`
`SAP
`
`SAVOR
`
`New Molecular entity
`Nonsteroidal Anti-Inflammatory Drugs
`New York Heart Association
`Office of Computational Science
`Office of Pharmaceutical Quality
`Office of Surveillance and Epidemiology
`Office of Scientific Investigation
`Periodic Benefit-Risk Evaluation Report
`Percutaneous Transluminal Coronary Angioplasty
`Pharmacodynamics
`Prescribing Information
`Pre-Investigational New Drug
`Pharmacokinetics
`Pregnancy and Lactation Labeling Rule
`Postmarketing Commitment
`Postmarketing Requirement
`Postprandial Glucose
`Patient Package Insert
`Pediatric Research Equity Act
`Periodic Safety Update Report
`Preferred Term
`Patient-Year
`Risk Evaluation and Mitigation Strategy
`Sickle Cell Trait
`Serious Adverse Event
`Statistical Analysis Plan
`Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes
`Mellitus
`Systolic Blood Pressure
`Serum Creatinine
`Study Endpoints and Labeling Development
`Special Government Employee
`Sodium-Glucose Cotransporter 2
`System MedDRA Query
`Supplemental New Drug Application
`System Organ Class
`Elimination Half-Life
`Type 1 Diabetes Mellitus
`Type 2 Diabetes Mellitus
`Triglycerides
`Treatment-Emergent Adverse Event
`
`
`SBP
`
`Scr
`SEALD
`SGE
`
`SGLT-2
`SMQ
`
`sNDA
`
`SOC
`
`T1/2
`
`T1D
`
`T2D
`
`TG
`
`TEAE
`
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`Reference ID: 4058510
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`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209091
`QTERN (Saxagliptin and Dapagliflozin)
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`TIA
`Tmax
`
`Total-C
`TSH
`
`UGT
`
`ULN
`
`US
`
`UKPDS
`WHO
`
`WOCBP
`XR
`
`
`Transient Ischemic Attack
`Time to Maximum Concentration
`Total Cholesterol
`Thyroid-Stimulating Hormone
`Uridine 5'-diphospho-glucuronosyltransferase
`Upper Limit of Normal
`United States
`United Kingdom Prospective Diabetes Study
`World Health Organization
`Women of Childbearing Potential
`Extended-release
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`Reference ID: 4058510
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`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209091
`QTERN (Saxagliptin and Dapagliflozin)
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` 1
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` Executive Summary
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`1.1.
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`Product Introduction
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`QTERN (saxagliptin and dapagliflozin) is a new fixed combination drug product (FCDP) submitted
`for marketing approval by the AstraZeneca Pharmaceuticals LP (referred to as the Applicant
`throughout the remainder of this review) as a New Drug Application (NDA 209091) in
`accordance with Section 505(b)(1) of the Federal Food, Drug and Cosmetic Act1 and Section 314
`of Title 21 CFR 314.50.2
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`The components of QTERN (i.e., saxagliptin and dapagliflozin) are approved antihyperglycemic
`agents with an indication as an adjunct to diet and exercise to improve glycemic control in
`adults with T2D. Saxagliptin is a competitive dipeptidyl peptidase-4 (DPP-4) inhibitor that slows
`the inactivation of the incretin hormones, thereby increasing their concentrations in the blood
`and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner
`in patients with type 2 diabetes mellitus (T2D).3 Dapagliflozin is a sodium glucose cotransporter
`2 (SGLT-2) inhibitor that reduces reabsorption of filtered glucose and lowers the renal threshold
`for glucose, thereby increasing urinary glucose excretion.4
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`Both saxagliptin and dapagliflozin are approved antihyperglycemic agents with an indication as
`an adjunct to diet and exercise to improve glycemic control in adults with T2D. The proposed
`indication for QTERN is as an adjunct to diet and exercise to improve glycemic control in adults
`with T2D
` QTERN is not
`indicated for the treatment of type 1 diabetes mellitus (T1D) or diabetic ketoacidosis (DKA), and
`should only be used in patients who tolerate 10 mg dapagliflozin.
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`QTERN will be available as a film-coated tablet for once daily oral administration, and will contain
`5 mg of saxagliptin and 10 mg of dapagliflozin.
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`1.2.
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`Conclusions on the Substantial Evidence of Effectiveness
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`I recommend an approval action for this NDA, pending agreement on proposed labeling. In
`accordance with 21 CFR 314.126(a)(b),5 I believe that the Applicant has provided sufficient
`evidence of effectiveness to support approval of this FCDP with an amended indication (i.e.,
`T2D patients who tolerate, but have inadequate glycemic control, with dapagliflozin 10 mg/day
`or who are already on both therapies).
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`Reference ID: 4058510
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`13
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`(b) (4)
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`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 209091
`QTERN (Saxagliptin and Dapagliflozin)
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`To support the proposed indication, the Applicant has provided clinical data from Trial
`CV181168, a 24-week (with a 28-week long-term [LT] extension), randomized, double-blind,
`placebo-controlled, parallel-group Phase 3 clinical trial designed to evaluate the efficacy and
`safety of stepwise (sequential) addition of saxagliptin to dapagliflozin and metformin compared
`with the addition of placebo to dapagliflozin and metformin in subjects with T2D who had
`inadequate glycemic control on maximum tolerated doses of dapagliflozin (i.e., 10 mg/day) and
`metformin (≥1500 mg/day). Based on the Agency analysis of the primary efficacy endpoint (i.e.,
`mean change in HbA1c from baseline to week 24), the saxagliptin triple therapy arm resulted in
`a modest but statistically significant HbA1c reduction compared to the placebo dual therapy
`arm (-0.3%; 95% confidence interval [CI], -0.2% to -0.5%). The Applicant intends to include only
`this trial in Section 14 of product labeling.
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`Efficacy and safety data from two additional Phase 3 trials (i.e., CV181169 and MB102129) were
`also submitted to support the pivotal efficacy trial. Trial CV181169 was a 24-week randomized,
`double-blind, active-controlled, parallel-group trial that compared the addition of saxagliptin 5
`mg/day plus dapagliflozin 10 mg/day (dual therapy) versus placebo plus saxagliptin 5 mg/day
`and versus placebo plus dapagliflozin 10 mg/day, when administered concomitantly to
`metformin in adults with T2D who had inadequate glycemic control on a stable dose of
`metformin monotherapy. The Applicant asserts that this supportive trial fulfils the
`requirements of 21 CFR 300.50.6 However, only the highest dose (i.e., 10 mg) of the two
`approved dapagliflozin doses (i.e., 5 and 10 mg) was studied. Trial MB102129 was a 24-week
`(with a 28-week LT extension) that evaluated the efficacy and safety of the se