`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`201280Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
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`
`
`

`

`CLINICAL REVIEW
`
`APPLICATION TYPE NDA
`APPLICATION
`0 201280
`NUMBER(S)
`PRIORITY OR
`STANDARD
`
`S
`
`SUBMIT DATE(S) JULY 2, 2010
`RECEIVED DATE(S) JULY 2, 2010
`PDUFA GOAL DATE MAY 2, 2011
`DIVISION / OFFICE DIVISION OF METABOLISM
`AND ENDOCRINOLOGY
`PRODUCTS/OFFICE OF
`NEW DRUGS II
`
`REVIEWER NAME(S) SOMYA VERMA DUNN
`REVIEW COMPLETION
` MARCH 11, 2011
`DATE
`
`ESTABLISHED NAME LINAGLIPTIN
`(PROPOSED) TRADE
`
`NAME
`
`Reference ID: 2917159
`
`

`

`THERAPEUTIC CLASS DIPEPTIDYL-PEPTIDASE
`INHIBITOR
`APPLICANT BOEHRINGER INGELHEIM
`PHARMACEUTICALS, INC.
`
`FORMULATION(S) ORAL TABLET
`DOSING REGIMEN 5 MG DAILY
`INDICATION(S) TREATMENT OF TYPE 2
`DIABETES
`ADULTS
`
`INTENDED
`POPULATION(S)
`
`Template Version: March 6, 2009
`
`Reference ID: 2917159
`
`

`

`Clinical Review
`Somya V. Dunn, M.D.
`NDA 201280
`Linagliptin
`
`Table of Contents
`
`CLINICAL REVIEW ........................................................................................................ 1
`Table of Contents ........................................................................................................ 3
`Table of Tables............................................................................................................ 6
`Table of Figures......................................................................................................... 10
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ....................................... 11
`1.1 Recommendation on Regulatory Action ........................................................... 11
`1.2 Risk Benefit Assessment.................................................................................. 11
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies . 12
`1.4 Recommendations for Postmarket Requirements and Commitments (PMRs and
`PMCs) .............................................................................................................. 12
`2.1 Product Information .......................................................................................... 14
`2.2 Tables of Currently Available Treatments for Proposed Indications ................. 15
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 16
`2.4
`Important Safety Issues With Consideration to Related Drugs......................... 16
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 17
`2.6 Other Relevant Background Information .......................................................... 18
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 19
`3.1 Submission Quality and Integrity ...................................................................... 19
`3.2 Compliance with Good Clinical Practices (GCP) .............................................. 19
`3.3 Financial Disclosures........................................................................................ 21
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 25
`4.1 Chemistry Manufacturing and Controls ............................................................ 26
`4.2 Clinical Microbiology......................................................................................... 26
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 26
`4.4 Clinical Pharmacology...................................................................................... 27
`4.4.1 Mechanism of Action.................................................................................. 29
`4.4.2 Pharmacodynamics.................................................................................... 30
`4.4.3 Pharmacokinetics....................................................................................... 30
`5 SOURCES OF CLINICAL DATA............................................................................ 34
`5.1 Tables of Studies/Clinical Trials ....................................................................... 34
`5.2 Review Strategy ............................................................................................... 39
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 40
`6 REVIEW OF EFFICACY......................................................................................... 40
`Efficacy Summary...................................................................................................... 40
`6.1
`Indication .......................................................................................................... 40
`6.1.1 Methods ..................................................................................................... 40
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`Clinical Review
`Somya V. Dunn, M.D.
`NDA 201280
`Linagliptin
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`6.1.2 Demographics............................................................................................ 61
`6.1.3 Subject Disposition..................................................................................... 75
`6.1.4 Analysis of Primary Endpoint(s) ................................................................. 84
`6.1.5 Analysis of Secondary Endpoints(s) ........................................................ 104
`6.1.6 Other Endpoints ....................................................................................... 115
`6.1.7 Subpopulations ........................................................................................ 116
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .. 137
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects............... 137
`6.1.10 Additional Efficacy Issues/Analyses......................................................... 137
`7 REVIEW OF SAFETY........................................................................................... 137
`Safety Summary ...................................................................................................... 137
`7.1 Methods.......................................................................................................... 137
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ....................................... 139
`7.1.2 Categorization of Adverse Events............................................................ 139
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................. 140
`7.2 Adequacy of Safety Assessments .................................................................. 140
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations................................................................................... 140
`7.2.2 Explorations for Dose Response.............................................................. 142
`7.2.3 Special Animal and/or In Vitro Testing ..................................................... 142
`7.2.4 Routine Clinical Testing ........................................................................... 142
`7.2.5 Metabolic, Clearance, and Interaction Workup ........................................ 142
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class 142
`7.3 Major Safety Results ...................................................................................... 142
`7.3.1 Deaths...................................................................................................... 142
`7.3.2 Nonfatal Serious Adverse Events ............................................................ 147
`7.3.3 Dropouts and/or Discontinuations ............................................................ 150
`7.3.4 Significant Adverse Events ...................................................................... 152
`7.3.5 Submission Specific Primary Safety Concerns ........................................ 152
`7.4 Supportive Safety Results .............................................................................. 160
`7.4.1 Common Adverse Events ........................................................................ 160
`7.4.2 Laboratory Findings ................................................................................. 166
`7.4.3 Vital Signs ................................................................................................ 179
`7.4.4 Electrocardiograms (ECGs) ..................................................................... 181
`7.4.5 Special Safety Studies/Clinical Trials....................................................... 182
`7.4.6
`Immunogenicity........................................................................................ 191
`7.6 Other Safety Explorations............................................................................... 191
`7.5.1 Dose Dependency for Adverse Events .................................................... 196
`7.5.2 Time Dependency for Adverse Events..................................................... 196
`7.5.3 Drug-Demographic Interactions ............................................................... 197
`7.5.4 Drug-Disease Interactions........................................................................ 201
`7.5.5 Drug-Drug Interactions............................................................................. 201
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`Clinical Review
`Somya V. Dunn, M.D.
`NDA 201280
`Linagliptin
`
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`7.4 Additional Safety Evaluations ......................................................................... 201
`7.6.1 Human Carcinogenicity............................................................................ 208
`7.6.2 Human Reproduction and Pregnancy Data.............................................. 208
`7.6.3 Pediatrics and Assessment of Effects on Growth .................................... 209
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound.................... 209
`7.7 Additional Submissions / Safety Issues.......................................................... 209
`8 POSTMARKET EXPERIENCE............................................................................. 210
`9 APPENDICES ...................................................................................................... 211
`9.1 Literature Review/References ........................................................................ 211
`9.2 Labeling Recommendations ........................................................................... 211
`9.3 Advisory Committee Meeting.......................................................................... 211
`
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`Reference ID: 2917159
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`Clinical Review
`Somya V. Dunn, M.D.
`NDA 201280
`Linagliptin
`
`
`Table of Tables
`
`
`
`Reference ID: 2917159
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`6
`
`87
`
`92
`
`16
`Table 1 Currently Available Treatments for Type 2 Diabetes
`23
`Table 2 Linagliptin Covered Studies for 21 CFR 54.2.
`35
`Table 3 All Studies in the Linagliptin Clinical Program
`46
`Table 4 Summary of Pivotal Study Medication Eligibility
`62
`Table 5 Demographics in the Four Pivotal Trials—FAS
`64
`Table 6 Baseline Disease Characteristics in the Pivotal Trials—FAS
`65
`Table 7 Demographics—Study 50, Treated Set
`66
`Table 8 Baseline Disease Characteristics —Study 50, FAS
`68
`Table 9 Baseline Demographics—Study 20, Treated Set
`69
`Table 10 Baseline Disease characteristics —Study 20, FAS
`71
`Table 11 Baseline Demographics—Study 35, Treated Set
`72
`Table 12 Baseline Disease Characteristics —Study 35, FAS
`74
`Table 13 Demographic Parameters—Study 40, Treated Set
`75
`Table 14 Baseline Disease Characteristics —Study 40, Treated Set
`76
`Table 15 Disposition of Patients—Pivotal Trials, Screened Set
`77
`Table 16 Discontinuations in the Pivotal Trials—FAS
`78
`Table 17 Disposition of Patients—Study 50, Screened Set
`78
`Table 18 Metformin Intolerance by Stratum—Study 50
`79
`Table 19 Disposition of Randomized Patients—Study 50
`80
`Table 20 Disposition of Randomized Patients—Study 20
`Table 21 Assigned Glimepiride Dose at Scheduled Visits and Dose Adjustments—
`Study 20, FAS
`81
`Table 22 Disposition of Patients—Study 35, Screened Set
`82
`Table 23 Disposition of Randomized Patients—Study 35
`83
`Table 24 Disposition of Patients—Study 40, Screened Set
`84
`Table 25 Main Efficacy Endpoint: Differences Between Adjusted means for HbA1c
`(%) Change from Baseline at Week 24 for Pivotal Studies—FAS
`86
`Table 26 Main Efficacy Endpoint: Differences Between Adjusted means for
`HbA1c (%) Change from Baseline at Week 24 for Pivotal Studies, FAS—OC
`Table 27 Adjusted Means for Change in HbA1c (%) from Baseline to Week 18—
`Study 50, FAS
`Table 28 Adjusted means for HbA1c (%) Change from Baseline Over Time,
`Sensitivity Analysis—OC, Study 50
`Table 29 Adjusted Means for Change in HbA1c (%) from Baseline to Week 52—
`Study 20, FAS—LOCF
`Table 30 Adjusted Means for HbA1c (%) Change from Baseline Over Time in
`Repeated Analysis—Study 20, OC
`Table 31 Adjusted Means for Change in HbA1c (%) from Baseline to Week 18—
`98
`Study 35, FAS
`Table 32 Adjusted means for HbA1c (%) change from baseline at Week 18—Study
`35, OC
`98
`
`93
`
`95
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`97
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`103
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`103
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`Clinical Review
`Somya V. Dunn, M.D.
`NDA 201280
`Linagliptin
`
`Table 33 Descriptive Statistics of HbA1c (%) Over Time by Exposure to
`100
`Linagliptin—Study 40, Treated Set
`Table 34 Adjusted Mean for the Change in HbA1c (%) from Baseline at Week 12—
`FAS, Study 23
`102
`Table 35 Adjusted Mean for Change in HbA1c (%) from Baseline at Week 26—
`Study 23, FAS
`Table 36 Adjusted Mean for Change in HbA1C (%) Week 52 for Patients Who
`Started with Linagliptin—Study 23, FAS
`Table 37 Change from Baseline in FPG (mg/dL) After 24 Weeks in the Pivotal
`105
`Studies—FAS
`Table 38 Patients with HbA1c below 7% after 24 Weeks in the Pivotal Studies, FAS
`
`106
`Table 39 Number of Patients with Use of Rescue Medication in the Pivotal Trials,
`FAS
`108
`Table 40 Change from Baseline in 2hPPG (mg/dL) in Studies 16 & 17, MTT set 109
`Table 41 Adjusted Means for the Change in FPG (mg/dL) from Baseline at Week
`18—FAS, Study 50
`110
`Table 42 Number of Patients with HbA1c <7% at Week 18—Study 50, FAS
`110
`Table 43 Number of Patients with Rescue Therapy, Study 50, FAS
`111
`Table 44 Change from Baseline in FPG (mg/dL) after 52 Weeks—Study 20, FAS 112
`Table 45 Change from Baseline in FPG (mg/dL)—Study 35, FAS
`112
`Table 46 Number of Patients with HbA1c <7% at Week 52—Study 20, NCF FAS 113
`Table 47 Number of Patients with Rescue Therapy—Study 20, FAS
`114
`Table 48 Adjustment Means for the Change from Baseline in 2hPPG at Week 52—
`Study 20, MTT52 set
`114
`Table 49 Change from baseline in body weight [kg] after 52 weeks in the active
`controlled trial—Study 20, FAS
`115
`Table 50 Baseline Disease Characteristics – Study 43, FAS
`118
`Table 51 Demographic data—Study 43, Treated Set
`119
`Table 52 Disposition of Randomized Patients—Study 43
`120
`Table 53 Adjusted Means for Change in HbA1c (%) from Baseline at Week 12—
`121
`Study 43, FAS
`Table 54 Key Demographics in the Pivotal Studies by Renal Impairment (MDRD)—
`FAS
`122
`Table 55 Key Baseline Characteristics in the Pivotal Studies by Renal Impairment
`(MDRD)—FAS
`123
`Table 56 Key Demographics in the Pivotal Studies by Age—FAS
`124
`Table 57 Key Baseline Characteristics in the Pivotal Studies by Age—FAS
`125
`Table 58 Key Demographics in the Pivotal Studies by Gender—FAS
`126
`Table 59 Key Baseline Characteristics in the Pivotal Studies by Gender—FAS 126
`Table 60 Key Demographics in the Pivotal Studies, Hispanic/Latino Ethnicity
`Group—FAS
`Table 61 Baseline Characteristics in the Pivotal Studies in the Hispanic/Latino
`Ethnicity Group—FAS
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`Clinical Review
`Somya V. Dunn, M.D.
`NDA 201280
`Linagliptin
`
`129
`Table 62 Key Demographics in the Pivotal Studies by Race—FAS
`129
`Table 63 Key Baseline Characteristics in the Pivotal Studies by Race—FAS
`130
`Table 64 Key Baseline Characteristics in the Pivotal Studies by BMI—FAS
`Table 65 Disposition of the Patients in the Pivotal Studies by Subgroup—FAS 131
`Table 66 Unadjusted Mean Change from Baseline in HbA1c (%) by Subgroups—
`Study 20, FAS
`135
`Table 67 Adjusted Mean HbA1c (%) Change from Baseline at Week 52 by Baseline
`HbA1c (4 categories)—Study 20, FAS
`136
`Table 68 Adjusted Mean HbA1c (%) Change from Baseline at Week 52 by Gender
`at Baseline—Study 20, FAS
`136
`Table 69 SAF-2 and Study 20 Study Grouping—Doses and Patients
`138
`Table 70 SAF-3 Study Grouping—Doses and Patients
`139
`Table 71 Total Exposure to Linagliptin 5 mg in all T2DM Patients
`140
`Table 72 Exposure to Linagliptin in SAF-2 and Study 20
`141
`Table 73 Estimates of Death Incidences per 1000 Patient Years Exposure, All
`143
`Patients Treated with Linagliptin
`Table 74 Patients with AEs Leading to Death by Treatment, Primary System Organ
`Class and Preferred Term, Treated Set
`144
`Table 75 Frequency [N (%)] of Patients with SAEs by Treatment, SOC—SAF-2, TS
`
`148
`Table 76 Frequency [N (%)] of Patients with SAEs by Treatment, SOC—Study 20,
`TS
`149
`Table 77 Frequency [N (%)] of Patients with AEs Leading to Discontinuation by
`Treatment, SOC—SAF-2 TS
`150
`Table 78 Frequency [N (%)] of Patients with AEs Leading to Discontinuation by
`Treatment, SOC—Study 20, TS
`151
`Table 79 Frequency [N (%)] of Patients with Hypoglycemic AEs by Preferred
`153
`Terms—SAF-2, TS
`Table 80 Frequency of Patients with Investigator Defined Hypoglycemia by Phase
`III Studies in SAF-2, TS
`154
`Table 81 Frequency of Patients with AEs of Special Interest Based on Narrow
`155
`SMQs—SAF-2, TS
`Table 82 Incidence of Pancreatic-Related Adverse Events—SAF-2 (minus study
`37), Randomized Patients
`156
`Table 83 Cases of Pancreatitis in All Patients Treated with Linagliptin
`157
`Table 84 Frequency [N (%)] of Patients with Hypoglycemic AEs by Preferred
`Terms, Study 20--TS
`Table 85 Frequency of Patients with AEs of Special Interest Based on Narrow
`SMQs—Study 20, TS
`Table 86 Frequency of Patients with AEs in more than 1% of Patients by
`Treatment, Sorted by SOC—SAF-2, TS
`Table 87 Incidence of Musculoskeletal Conditions—SAF-2 (minus study 37)
`Table 88 AEs Possibly Associated with Linagliptin Based on SAF-2 by
`Background Medication—SAF-2, TS
`
`158
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`Clinical Review
`Somya V. Dunn, M.D.
`NDA 201280
`Linagliptin
`
`Table 89 AEs Reported in ≥2% of Patients Treated with Linaglitin and at Least 2-
`Fold Greater than with Placebo in Placebo-Controlled Clinical Studies of
`Linagliptin Monotherapy or Combination Therapy
`Table 90 Frequency of Patients with AEs in more than 5% of Patients by
`166
`Treatment, Sorted by SOC—Study 20, TS
`Table 91 Mean and Median Changes from Baseline to Week 24 by Treatment—TS,
`SAF-3
`168
`Table 92 Normal to High Values ≥0.5% Higher in Linagliptin Group Versus
`170
`Placebo—SAF-2
`170
`Table 93 Incidence of Elevated Amylase in SAF-2 (minus study 37)
`173
`Table 94 Potential Hy's Law Case—SAF-2
`174
`Table 95 Frequency of Patients with Grade 2 LFTs—SAF-2
`175
`Table 96 Laboratory Abnormality Incidences—Study 20, TS
`175
`Table 97 Incidence of Elevated Amylase—Study 20
`178
`Table 98 Frequency of Patients with Grade 2 LFTs—Study 20
`Table 99 Mean Changes in Systolic and Diastolic Blood Pressure from Baseline
`over Time for the SAF-3 (pivotal trials) - TS
`179
`Table 100 Mean Changes in Systolic and Diastolic Blood Pressure from Baseline
`Over Time for Study 20 - TS
`180
`Table 101 SOCs with Higher Frequency (≥2.5% in Moderate Renal Impairment) in
`Linagliptin Treated Patients—SAF-2, TS
`182
`Table 102 Frequency of Patients [N(%)] with Shifts in Renal Impairment—SAF−2,
`TS
`185
`Table 103 Frequency of Patients SAE by Treatment, SOC and PT—Study 43, TS
`
`186
`Table 104 Frequency of patients with AEs Leading to Treatment Discontinuation
`by Treatment, SOC and PT—Study 43, TS
`188
`Table 105 Frequency of Patients with AEs Occurring More Than 2.0% in Either
`189
`Treatment Group on the Preferred Term Level—Study 43, TS
`Table 106 Frequency of Patients with AEs by Use of Rescue Medication in More
`than 1% by Treatment Group on the Preferred Term Level, Sorted by
`192
`Table 107 Frequency of Patients with AEs by Use of Rescue Medication in More
`than 1% by Treatment Group on the Preferred Term Level, Sorted by
`193
`Table 108 Summary of Adverse Events by Treated Group—Study 40, TS
`195
`Table 109 Adverse Events Summary for 52 weeks—Study 20, TS
`196
`Table 110 Incidence of AEs by Demographic—SAF-2, TS
`198
`Table 111 Incidence of AEs by Demographic—Study 20, TS
`200
`Table 112 Studies Included in the CV Meta-analysis
`202
`Table 113 Demographics of CV Study Cohort
`203
`Table 114 Baseline T2DM Characteristics for CV Study Cohort
`204
`Table 115 CV Risk at Baseline in the CV Study Cohort Displayed by Treatment 205
`Table 116 CV Meta-analysis Framingham Risk by Study
`206
`Table 117 Summary of MACE Event by Study and Treatment
`207
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`Clinical Review
`Somya V. Dunn, M.D.
`NDA 201280
`Linagliptin
`
`Table of Figures
`
`14
`28
`29
`32
`33
`33
`42
`43
`49
`53
`53
`59
`89
`90
`91
`91
`94
`96
`
`Figure 1 Molecular Structure of Linagliptin
`Figure 2 Adjusted mean (SE) for HbA1c change from Baseline, Study 1218.6
`Figure 3 Linagliptin Mechanism of Action
`Figure 4 Steady-state AUC values of linagliptin after multiple 5 mg doses
`Figure 5 Drug Effect on Linagliptin
`Figure 6 Linagliptin Effect on Other Drugs
`Figure 7 Study Design for Studies 15, 16 and 17
`Figure 8 Study Design—Study 18
`Figure 9 Study Design—Study 50
`Figure 10 Study Design—Study 20
`Figure 11 Study Design—Study 35
`Figure 12 Study Design—Study 23
`Figure 13 Mean HbA1c (%) and SE Over Time—Study 15, FAS
`Figure 14 Mean HbA1c (%) and SE Over Time—Study 16, FAS
`Figure 15 Mean HbA1c (%) and SE Over Time—Study 17, FAS
`Figure 16 Mean HbA1c (%) and SE Over Time—Study 18, FAS
`Figure 17 Mean HbA1c (%) and SE Over Time—Study 50, FAS
`Figure 18 Adjusted Mean HbA1c (SE) Over Time, Study 20—FAS
`Figure 19 Adjusted HbA1c Mean Change from Baseline Over Time—Study 35,
`99
`FAS
`Figure 20 Mean Change From Baseline in HbA1c over time in the Pivotal Studies
`and the Extension Study 40
`101
`Figure 21 Forest Plot of HbA1c results for Pivotal Studies Subgroups
`133
`Figure 22 Incidence of Selected AE Across Time and Dose—Phase 2 and Phase 3
`Trials
`162
`Figure 23 Amylase Over Time in SAF-2
`171
`Figure 24 Uric Acid Over Time—SAF-2
`171
`Figure 25 CK Over Time—SAF-2
`172
`Figure 26 Amylase Over Time, Study 20
`176
`Figure 27 CK Over Time—Study 20
`176
`Figure 28 Mean Serum Creatinine Over Time—Study 20, TS
`178
`Figure 29 Forest Plot of Relative Risk by Study Based on CMH Analysis
`208
`
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`Clinical Review
`Somya V. Dunn, M.D.
`NDA 201280
`Linagliptin
`
`1 Recommendations/Risk Benefit Assessment
`Linagliptin is an orally-active dipeptidyl peptidase (DPP-4) inhibitor. The applicant seeks
`the indication for linagliptin as an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus (T2DM). The proposed dose is 5 mg oral
`dose once daily. There is no proposed dosage adjustment for renal impairment.
`
`1.1 Recommendation on Regulatory Action
`
`According to my review of the clinical data, I recommend approval for linagliptin as an
`adjunct to diet and exercise to improve glycemic control in adults with T2DM. The
`applicant has demonstrated efficacy along with an acceptable safety profile.
`
`1.2 Risk Benefit Assessment
`
`The applicant has demonstrated safety and efficacy in both monotherapy and a variety
`of combination therapy settings. They seek approval for only one dose of linagliptin, 5
`mg. This was the only dose tested in all phase III studies with the exception of one
`treatment arm in one study where a dose of 10 mg was also tested (study 1218.23, see
`Table 3 in section 5.1 Tables of Studies/Clinical Trials). There were a total of 9 phase III
`studies, four of which had a 24 week treatment period. One of these studies had data
`from 52 weeks of treatment with linagliptin (study 1218.20). Therefore, the data
`available for the 5 mg dose are sufficient to allow for a comprehensive review of this
`dose.
`
`Linagliptin offers an oral, once daily therapy for T2DM that has a low risk of
`hypoglycemia (when not taken with a sulfonylurea). This can be used for patients either
`on other antidiabetic medications or in monotherapy. Efficacy has been demonstrated in
`two phase III monotherapy studies. It has also been demonstrated in separate phase III
`studies in combination with pioglitazone, metformin and a sulfonylurea. Overall, efficacy
`in lowering HbA1c ranges from 0.4-0.7% (placebo-subtracted) at 24 weeks. The
`applicant was also able to meet their predetermined non-inferiority margin in a large
`phase III, 52-week study against the active control glimepiride, although it was clear that
`glimepiride offered better glycemic control.
`
`The safety assessment for linagliptin was also adequate and revealed a safe profile for
`patients with T2DM. A total of 4338 patients had exposure to 5 mg linagliptin, 3430 of
`these patients were treated for at least 24 weeks and at the time of NDA filing, 2390 had
`been treated for at least 52 weeks. Nonclinical data did not reveal skin lesions seen in
`other drugs of this class. Overall, animal toxicity findings were only at doses that were at
`high exposure multiples, indicating that human risk was minimal.
`
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`Reference ID: 2917159
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`Clinical Review
`Somya V. Dunn, M.D.
`NDA 201280
`Linagliptin
`
`Safety issues that have arisen in this class include pancreatitis, serious allergic and
`hypersensitivity reactions, and more recently worsening renal function. Pancreatitis was
`reported in a higher number of patients treated with linagliptin than placebo or other
`treatments (8 patients versus 0). In view of the large denominator, the imbalance of
`overall randomization (2.3:1) and the very small number of events of pancreatitis, the
`precise incidence rate of pancreatitis associated with linagliptin treatment is uncertain.
`Aside from this issue, at this time, the data provided in this application show minimal
`concern for the other class concerns mentioned.
`
`Linagliptin is predominantly excreted unchanged in the feces, with renal excretion being
`a minor pathway of elimination. Pharmacokinetic studies and the clinical pharmacologist
`review of these studies conclude that dosage adjustment is not necessary in patients
`with renal impairment. The number of patients with moderate and severe renal disease
`is small in the clinical program. However, the applicant submitted 12 week data from a
`dedicated study in subjects with moderate to severe renal impairment and has one
`additional study ongoing in this population. The results from these studies will shed
`further insight on the adverse event profile in these patients.
`
`There were few patients of African-American origin in the linagliptin clinical program.
`However, at this time, pharmacokinetic/pharmacodynamic studies do not indicate that
`these patients should have a different safety or efficacy profile than other racial groups
`that were exposed to linagliptin.
`
`The required cardiovascular meta-analysis was performed. This meta-analysis revealed
`that linagliptin is not associated with higher risk of predefined cardiovascular events.
`
`Overall, linagliptin can offer benefit of glycemic control to patients with T2DM and has
`an acceptable safety profile.
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies
`
`Linagliptin, and other drugs of this class, have been found to have higher incidence of
`pancreatitis. The applicant will be expected to submit 15 day expedited reports with
`narratives for all post marketing cases of pancreatitis regardless if they are classified as
`serious or unexpected.
`
`1.4 Recommendations for Postmarket Requirements and Commitments (PMRs
`and PMCs)
`
`The applicant will be required to conduct a dedicated study to assess for
`i.
`increased cardiovascular risk in high risk patients. This is in line with all oral antidiabetic
`drugs under development or review at this time per FDA Guidance for Industry Diabetes
`Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type
`2 Diabetes The primary objective of this trial will be to establish that the upper bound of
`
`Reference ID: 2917159
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`Clinical Review
`Somya V. Dunn, M.D.
`NDA 201280
`Linagliptin
`
`the 2-sided 95% confidence interval for the estimated risk ratio comparing the incidence
`of major adverse cardiovascular events observed with linagliptin to that observed in the
`control group is less than 1.3. Secondary objectives must include an assessment of the
`long-term effects of linagliptin on pancreatitis and renal safety. For cases of pancreatitis,
`serum amylase and/or lipase concentrations with accompanying normal ranges and any
`imaging study reports should be included in the narratives. At this time, the applicant
`does have a protocol submitted under the Investigational New Drug application for this
`study and it is currently under review.
`Secondary objectives in this long term study must include an assessment of the long-
`term effects of linagliptin on immunological reactions, hypersensitivity reactions,
`neoplasms, serious hypoglycemia, pancreatitis, and renal safety. For hypersensitivity
`reactions, especially angioedema, reports should include detailed information on
`concomitant use of an angiotensin-converting enzyme inhibitor or an angiotensin-
`receptor blocker. For cases of pancreatitis, serum amylase and/or lipase concentrations
`with accompanying normal ranges and any imaging study reports should be included in
`the narratives.
`
` Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all
`ii.
`applications for new active ingredients are required to contain an assessment of the
`safety and effectiveness of the product for the claimed indication(s) in pediatric patients
`unless this requirement is waived, deferred, or inapplicable.
`
`Our agency has decided to waive the pediatric study requirement for ages 0 to 9 years
`because are too few children in this age range with T2DM to practically enable an
`adequate study for safety and efficacy. In addition we accepted the deferral of studies in
`patients 10 to
` because linagliptin had not been proven safe and effective in adults at
`the time of the request. Once approved, we will require that the applicant complete two
`clinical trials in pediatrics. One will be a 12-week, randomized, double-blind, placebo-
`controlled, parallel dose-finding study evaluating at least 2 dose levels (e.g. 1 mg and 5
`mg) of linagliptin monotherapy compared to placebo. The other study will be a
`randomized, double-blind, 12-week efficacy and safety study comparing linagliptin
`monotherapy, metformin, and placebo in a 2:1:1 ratio, followed by a 40 week extension
`(52 weeks total) during which the patients previously treated with placebo will be
`randomized to treatment with linagliptin or metformin in a 2:1 ratio for the remaining 40
`weeks of the study. The applicant must either add an arm to this study, or conduct a
`third trial, with patients that were inadequately controlled on metformin (on maximum
`allowed doses) that has linagliptin treatment as an add treatment to metformin.
`
`At this time, a requirement for a study in moderate and severe renal impairment
`iii.
`as a PMR is under discussion. There were very few of these patients (56 moderate
`impairment, 2 severe impairment) in the clinical program at the time of NDA submission.
`The 12 week data from a dedicated study in moderate and severe renal impairment,
`1218.43—133 patients, was available at the Four Month Safety Update. The study is
`ongoing. There is another study in this population, 1218.64—240 patients that is
`
`Reference ID: 2917159
`
`13
`
`(b)
`(4)
`
`

`

`Clinical Review
`Somya V. Dunn, M.D.
`NDA 201280
`Linagliptin
`
`ongoing. Once completed, both will provide one year of data. In total, this number of
`patients and exposure time are acceptable in this population to evaluate safety and
`efficacy. Therefore, there is not a need to request specific patient exposure
`requirements in this population for the dedicated cardiovascular study as has been the
`case for other DPP-4 inhibitors (i.e. saxaglipt