CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`206321Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`DIVISION OF NEUROLOGY PRODUCTS
`
`CONSULT M E M O R A N D U M
`
`DATE:
`
`June 5, 2014
`
`TO:
`
`Pat Madera, HFD 510, Division of Metabolism and Endocrinology Products
`(DMEP)
`
`THROUGH: Billy Dunn, MD, Acting Director, Division of Neurology Products (DNP)
`
`FROM:
`
`Ronald Farkas, MD, PhD, Clinical Team Leader, DNP
`
`RE:
`
`NDA 206321, Lariglutide injection for obesity: sleep apnea study
`
`
`
`1. Background
`
`Liraglutide is a glucagon-like peptide-1 (GLP-1) agonist currently approved for the
`treatment of type 2 diabetes mellitus (Victoza, NDA 022341). Novo Nordisk submitted
`an NDA in December 2013 for liraglutide for weight management (NDA 206321). The
`Division of Metabolism and Endocrinology Products (DMEP) notes that one of the trials
`supporting this application was a 32-week trial in patients with moderate to severe
`obstructive sleep apnea (OSA).
`
`The sponsor proposes the following text for the INDICATIONS AND USAGE section of
`labeling:
`
`Saxenda is indicated as an adjunct to a reduced calorie diet and increased
`physical activity for chronic weight management in adult patients with an initial
`body mass index (BMI) of
` 30 kg/m2 or greater (obese) (1) or
`
`Reference ID: 3645660
`
`

`

`Ronald Farkas, M.D., Ph.D., HFD-120 Medical Review
`
`Page 2 of 7
`
` 27 kg/m2 or greater (overweight) in the presence of at least one weight
`related comorbidity such as hypertension, dysglycemia (prediabetes and
`type 2 diabetes mellitus), dyslipidemia or obstructive sleep apnea
`[emphasis added]
`
`The sponsor is not proposing a more specific sleep apnea indication than above,
`
`
`
`
`
`DMEP consulted the Division of Neurology Products (DNP) to evaluate the trial,
`including the patient population, study design, and endpoints,
`
`
`
`
`
`2. Liraglutide OSA Study
`
`Title: NN8022-3970, Effect of liraglutide in obese subjects with moderate or severe
`obstructive sleep apnea – a 32 week randomised, double-blind, placebo-controlled,
`parallel group, multi-centre and multinational trial).
`
`The study was conducted at 40 sites in the United States and Canada.
`
`Key Inclusion Criteria:
` BMI ≥30 kg/m2
` Diagnosis of moderate or severe OSA (AHI ≥ 15)
` Unwilling or unable to use CPAP (or other positive airway pressure) treatment
`(≥4 weeks prior to screening)
`
`Key Exclusion Criteria:
` Patients on CPAP
`type 1 or type 2 diabetes
`
` Use of central stimulants, hypnotics, mirtazepine, opioids, trazodone within the
`previous 3 months prior to screening
` Central sleep apnea
`
`Trial duration was 36 weeks, consisting of a 2-week screening period, 4-week dose
`escalation period (0.6 mg starting dose increase by 0.6 mg increments every 7 days
`until target dose of 3.0 mg), 28-week maintenance period, and 2-week follow-up.
`
`Polysomnography (PSG) visits occurred at screening, week 12, and week 32.
`
`Reference ID: 3645660
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Ronald Farkas, M.D., Ph.D., HFD-120 Medical Review
`
`Page 3 of 7
`
`The following PSG endpoints pertinent to OSA were measured:
` AHI score
` AHI severity category (none ≤4.9, mild 5.0−14.9, moderate 15.0−29.9, severe
` ≥30.0 events/hour)
` Lowest blood oxygen saturation (%)
` Percent time with blood oxygen below 80%, 85% and 90%
` Oxygen desaturation index (ODI) ≥4%
` Wake time after sleep onset (WASO) (minutes and %)
` Percent slow wave sleep
` Sleep stage distribution (N1, N2, N3, R)
` Total sleep time
` Respiratory event related arousals (arousals per hour)
` Proportion of supine sleep
` Period limb movement with arousal index (visit 2 only)
` Central apnea percentage (visit 2 only)
` Time in bed
` Heart rate
`
`The following patient-reported outcomes (PRO) pertinent to OSA were measured:
` daytime sleepiness (Epworth Sleepiness Scale),
` health-related quality of life (Short Form 36 [SF-36] Health Survey)
`the impact of daytime sleepiness on multiple everyday activities (Functional
`
`Outcomes of Sleep Questionnaire [FOSQ])
`
`The primary endpoint was change from baseline AHI at week 32.
`
`Secondary endpoints pertinent to OSA included the following:
` Subjects achieving OSA remission defined as AHI <5 events/hour (yes/no) after
`32 weeks of treatment
` Subjects achieving 50% reduction in AHI from baseline after 32 weeks of
`treatment
` Subjects with improved AHI severity category (none ≤4.9, mild 5.0−14.9,
`moderate 15.0−29.9, severe ≥30.0 events/hour) after 32 weeks of treatment
` Change from baseline in polysomnography measures after 32 weeks of
`treatment
`o Lowest blood oxygen saturation (%)
`o Percent time with blood oxygen below 80%, 85% and 90%
`o Oxygen desaturation index (ODI) ≥4% (events/hour)
`o WASO (minutes and %)
`o Slow wave sleep
`o Sleep stage distribution (N1, N2, N3, R)
`o Total sleep time
`o Respiratory event related arousals (RERA) (arousals per hour)
`
`Reference ID: 3645660
`
`

`

`Ronald Farkas, M.D., Ph.D., HFD-120 Medical Review
`
`o Proportion of supine sleep
`
`Efficacy Findings
`
`Page 4 of 7
`
`A total of 359 patients were randomized, with 72% male, and 80% between the
`ages of 40 and 65 years. The majority, 67%, had severe sleep apnea, and the
`mean baseline AHI was 49 events/hour, which the sponsor notes as “highly
`severe.”
`
`Withdrawals from the study were higher in the liraglutide vs. placebo group, 26%
`vs. 21%, respectively, and were related to adverse effects.
`
`From a baseline AHI of 49 in each group, at week 32 the drug arm decreased by
`12 events/hour and the placebo group by 6 events/hour (sponsor-reported p-
`value of 0.015; LOCF imputation). Results for females were numerically similar to
`males, but not statistically significant (p = 0.24). Sensitivity analyses were either
`positive (e.g. “completers” p-value 0.03) or close to positive (e.g. multiple
`imputation p = 0.054)
`
`Secondary endpoints showed the following:
`– OSA remission (AHI <5 event/hours) 5.4% drug vs. 1.2% placebo
`(reported p = 0.07)
`– 50% reduction in AHI: 32% drug vs. 22% placebo (reported p = 0.05)
`– Subjects with improved OSA severity category: the sponsor represents a
`number of analyses, including the below figure showing final (not change)
`in OSA severity in patients with severe baseline OSA.
`
`Reference ID: 3645660
`
`

`

`Ronald Farkas, M.D., Ph.D., HFD-120 Medical Review
`
`Page 5 of 7
`
`No statistically significant differences between liraglutide and placebo were
`observed for any of the parameters related to blood oxygen saturation.
`
`No statistically significant differences between liraglutide and placebo were
`observed for any of the parameters related to sleep or sleep architecture.
`
`Fasting body weight decreased 5.7% with liraglutide and 1.6% with placebo
`(reported p <0.0001).
`
`Findings on the Epworth Sleepiness Scale and most domains of the two other
`PROs were not statistically significant.
`
`The sponsor’s efficacy conclusions regarding OSA endpoints are as follows:
`Primary endpoint:
`– From a mean baseline AHI of approximately 49 events/hour in
`both treatment groups, the mean changes in AHI were −12.2
`events/hour with liraglutide 3.0 mg and −6.1 events/hour with
`placebo after 32 weeks of treatment. The ETD was statistically
`significant in favor of liraglutide 3.0 mg (−6.10 events/hour,
`p=0.0150).
`Secondary endpoints:
`
`Reference ID: 3645660
`
`

`

`Ronald Farkas, M.D., Ph.D., HFD-120 Medical Review
`
`Page 6 of 7
`
`– No statistically significant differences between groups were
`observed after 32 weeks of treatment for the secondary
`endpoints related to OSA.
`– Numerical improvement in favor of liraglutide 3.0 mg was
`observed for 14 out of 15 sleep related endpoints
`
`3. Discussion and Conclusions
`
`Elevated BMI is a strong risk factor for OSA, and weight loss is associated with
`improvement in OSA, with the degree of improvement correlated to the degree of weight
`loss. OSA severity can be classified by AHI, but, as the sponsor notes in the study
`report, the correlation between any specific improvement in AHI and clinically relevant
`benefit remains poorly established. For example, while OSA may resolve after weight
`loss in patients with mild OSA, clinical benefits in terms of improved psychomotor
`performance and decreased risk of cardiac and metabolic adverse events can be
`difficult to measure, while in patients with more severe OSA, weight loss usually does
`not result in resolution of OSA or substantially decrease the need for other OSA
`treatments like continuous positive airway pressure (CPAP).
`
`This study of liraglutide in obese patients with OSA was generally well-designed and
`conducted, with appropriate efficacy endpoints for characterizing a number of different
`aspects of OSA severity. However, the study also had important limitations in both
`design and findings that impacts interpretability:
`
` The study enrolled a relatively narrow population with moderate or severe OSA
`who were unable or unwilling to use CPAP. The specific size of change in
`endpoints like AHI, the primary endpoint, is affected by baseline values, and thus
`appears to be of limited usefulness for communicating effects of the drug in
`patients with less severe OSA. While some patients with OSA are intolerant to
`CPAP, clinical meaningfulness of change would seemingly be strongly affected
`by CPAP use; a patient with severe sleep apnea who used CPAP might gain little
`or no clinical benefit for OSA from liraglutide.
` Secondary endpoints measuring daytime sleepiness (e.g. Epworth), nighttime
`sleep (e.g. wake after sleep onset), and potential biomarkers of cardiovascular
`risk (e.g. blood oxygen saturation) were essentially all negative. This increases
`concern that the AHI finding is of unclear clinical meaningfulness.
` The study was only 32 weeks duration, yet clinical meaningfulness involves
`duration of effect for essentially life-long conditions like OSA. Even if reassurance
`is taken from other studies suggesting that weight loss has sustained benefit over
`several years in OSA (e.g. Kuna et al., Sleep 2013), it is not clear that the
`change in AHI at week 32 predicts a durable effect in the intended patient
`population for this drug.
`
`
`
`Reference ID: 3645660
`
`(b) (4)
`
`

`

`Ronald Farkas, M.D., Ph.D., HFD-120 Medical Review
`
`Page 7 of 7
`
`Reference ID: 3645660
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RONALD H FARKAS
`10/20/2014
`
`WILLIAM H Dunn
`10/21/2014
`
`Reference ID: 3645660
`
`

`

`CLINICAL REVIEW
`
`Application Type NDA
`Application Number 206321
`Priority or Standard Standard
`
`Submit Date 20 December 2013
`Received Date 20 December 2013
`PDUFA Goal Date 20 October 2014
`Division / Office DMEP / ODE2
`
`Reviewer Name Julie Golden, M.D.
`Review Completion Date 18 October 2014
`
`Established Name Liraglutide
`Proposed Trade Name Saxenda
`Therapeutic Class GLP-1 analog
`Applicant Novo Nordisk, Inc.
`
`Formulation
`Injection
`Dosing Regimen Daily
`Indication Chronic weight management
`Intended Population BMI ≥ 30 kg/m2 or ≥ 27 kg/m2
`in the presence of at least one
`weight-related co-morbidity
`
`
`
`
`Template Version: March 6, 2009
`
`Reference ID: 3645293
`
`

`

`Clinical Review
`Golden, J.
`NDA 206321
`Saxenda (liraglutide)
`
`
`Table of Contents
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ....................................... 14
`
`1.1 Recommendation on Regulatory Action ........................................................... 14
`1.2 Risk Benefit Assessment .................................................................................. 14
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies . 18
`1.4 Recommendations for Postmarket Requirements and Commitments .............. 18
`Postmarketing Requirements ................................................................................. 18
`Postmarketing Commitment ................................................................................... 19
`
`2
`
`INTRODUCTION AND REGULATORY BACKGROUND ...................................... 20
`
`2.1 Product Information .......................................................................................... 20
`2.2 Tables of Currently Available Treatments for Proposed Indications ................. 21
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 22
`2.4
`Important Safety Issues With Consideration to Related Drugs ......................... 22
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 22
`2.6 Other Relevant Background Information .......................................................... 23
`
`3 ETHICS AND GOOD CLINICAL PRACTICES ....................................................... 24
`
`3.1 Submission Quality and Integrity ...................................................................... 24
`3.2 Compliance with Good Clinical Practices ......................................................... 25
`3.3 Financial Disclosures ........................................................................................ 28
`
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 28
`
`4.1 Chemistry Manufacturing and Controls ............................................................ 28
`4.2 Clinical Microbiology ......................................................................................... 28
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 28
`4.4 Clinical Pharmacology ...................................................................................... 29
`4.4.1 Mechanism of Action .................................................................................. 29
`4.4.2 Pharmacodynamics.................................................................................... 29
`4.4.3 Pharmacokinetics ....................................................................................... 30
`
`5 SOURCES OF CLINICAL DATA............................................................................ 31
`
`5.1 Tables of Studies/Clinical Trials ....................................................................... 31
`5.2 Review Strategy ............................................................................................... 34
`5.3 Discussion of Individual Studies/Clinical Trials ................................................. 34
`Trial 1807 ............................................................................................................... 35
`Trial 1839 ............................................................................................................... 36
`Trial 1922 ............................................................................................................... 37
`Trial 1923 ............................................................................................................... 38
`Trial 3970 ............................................................................................................... 39
`
`6 REVIEW OF EFFICACY ......................................................................................... 41
`
`Reference ID: 3645293
`
`2
`
`

`

`Clinical Review
`Golden, J.
`NDA 206321
`Saxenda (liraglutide)
`
`
`Efficacy Summary ...................................................................................................... 41
`6.1
`Indication .......................................................................................................... 44
`6.1.1 Methods ..................................................................................................... 45
`6.1.2 Demographics ............................................................................................ 45
`6.1.3 Subject Disposition .................................................................................... 49
`6.1.4 Analysis of Primary Endpoints ................................................................... 53
`6.1.5 Analysis of Secondary Endpoints ............................................................... 76
`6.1.6 Other Endpoints ......................................................................................... 96
`6.1.7 Subpopulations ........................................................................................ 101
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .. 105
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects ............... 105
`6.1.10 Additional Efficacy Issues/Analyses ......................................................... 105
`
`7 REVIEW OF SAFETY ........................................................................................... 105
`
`Safety Summary ...................................................................................................... 105
`7.1 Methods .......................................................................................................... 109
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ....................................... 109
`7.1.2 Categorization of Adverse Events ............................................................ 111
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence .................................................................................................. 112
`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 .............................................................. 114
`7.2.3 Special Animal and/or In Vitro Testing ..................................................... 114
`7.2.4 Routine Clinical Testing ........................................................................... 114
`7.2.5 Metabolic, Clearance, and Interaction Workup ........................................ 114
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class 114
`7.3 Major Safety Results ...................................................................................... 115
`7.3.1 Deaths ...................................................................................................... 115
`7.3.2 Nonfatal Serious Adverse Events ............................................................ 120
`7.3.3 Dropouts and/or Discontinuations ............................................................ 124
`7.3.4 Significant Adverse Events ...................................................................... 127
`7.3.5 Submission Specific Primary Safety Concerns ........................................ 127
`7.4 Supportive Safety Results .............................................................................. 250
`7.4.1 Common Adverse Events ........................................................................ 250
`7.4.2 Laboratory Findings ................................................................................. 258
`7.4.3 Vital Signs ................................................................................................ 262
`7.4.4 Electrocardiograms (ECGs) ..................................................................... 262
`7.4.5 Special Safety Studies/Clinical Trials ....................................................... 266
`7.4.6
`Immunogenicity ........................................................................................ 266
`7.5 Other Safety Explorations ............................................................................... 277
`7.5.1 Dose Dependency for Adverse Events .................................................... 277
`7.5.2 Time Dependency for Adverse Events ..................................................... 278
`
`Reference ID: 3645293
`
`3
`
`

`

`Clinical Review
`Golden, J.
`NDA 206321
`Saxenda (liraglutide)
`
`
`7.5.3 Drug-Demographic Interactions ............................................................... 280
`7.5.4 Drug-Disease Interactions ........................................................................ 283
`7.5.5 Drug-Drug Interactions ............................................................................. 285
`7.6 Additional Safety Evaluations ......................................................................... 285
`7.6.1 Human Carcinogenicity ............................................................................ 285
`7.6.2 Human Reproduction and Pregnancy Data .............................................. 286
`7.6.3 Pediatrics and Assessment of Effects on Growth .................................... 288
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound .................... 288
`7.7 Additional Submissions / Safety Issues .......................................................... 291
`
`8 POSTMARKET EXPERIENCE ............................................................................. 291
`
`9 APPENDICES ...................................................................................................... 292
`
`9.1 Literature Review/References ........................................................................ 292
`9.2 Labeling Recommendations ........................................................................... 292
`9.3 Advisory Committee Meeting .......................................................................... 292
`9.4 Narratives of Deaths from the Diabetes Pool ................................................... 296
`9.5 Financial Disclosure Information .................................................................... 300
`
`
`
`Reference ID: 3645293
`
`4
`
`

`

`Clinical Review
`Golden, J.
`NDA 206321
`Saxenda (liraglutide)
`
`
`Table of Tables
`
`Table 1. FDA-approved Medications for Chronic Weight Management........................ 21
`Table 2. Clinical Inspections ......................................................................................... 26
`Table 3. Model-Predicted Median Exposures and Mean Weight Loss at Tested Doses
`of Liraglutide, Weight Management Program ................................................. 31
`Table 4. Trials Included in the Liraglutide 3 mg NDA ................................................... 32
`Table 5. Weight Management Trials............................................................................. 33
`Table 6. Proportion of Patients Achieving at Least Five Percent Weight Loss, Weight
`Management Trials ........................................................................................ 44
`Table 7. Proportion of Patients Achieving More Than Ten Percent Weight Loss, Weight
`Management Trials ........................................................................................ 44
`Table 8. Demographics and Baseline Characteristics for Patients in the Phase 2 and 3
`Weight Management Trials ............................................................................ 46
`Table 9. Demographics and Baseline Characteristics, Trial 1922 ................................ 47
`Table 10. Demographics and Baseline Characteristics, Trial 1923 .............................. 48
`Table 11. Patient Disposition, Trial 1807 and Extension .............................................. 50
`Table 12. Patient Disposition by Pre-Diabetes Status, Trial 1839 ................................ 51
`Table 13. Patient Disposition, Trial 1922 ...................................................................... 51
`Table 14. Patient Disposition, Trial 1923 ...................................................................... 53
`Table 15. Key Efficacy Endpoints Related to Body Weight by Weight Management Trial
` ....................................................................................................................... 54
`Table 16. Summary of Change in Body Weight (kg), 20- and 52-Week Analyses, Trial
`1807 ............................................................................................................... 56
`Table 17. ANCOVA of Change in Body Weight (kg) after 52 Weeks of Treatment, Trial
`1807 ............................................................................................................... 57
`Table 18. Proportion of Five and Ten Percent Body Weight Loss Responders at 52
`Weeks, Trial 1807 .......................................................................................... 57
`Table 19. Percent Change from Baseline in Body Weight after 56 Weeks of Treatment,
`LOCF, Trial 1839 ........................................................................................... 58
`Table 20. Percent Change from Baseline after 56 Weeks of Treatment, Completers’
`Analysis, Trial 1839 ........................................................................................ 59
`Table 21. Proportion of Patients Losing at Least Five Percent of Body Weight after 56
`Weeks of Treatment, LOCF, Trial 1839 ......................................................... 63
`Table 22. Proportion of Patients Losing at Least Five Percent of Body Weight after 56
`Weeks of Treatment, Sensitivity Analyses, Trial 1839 ................................... 64
`Table 23. Proportion of Patients Losing at Least Five Percent Body Weight by Pre-
`Diabetes Status, Trial 1839 ............................................................................ 66
`Table 24. Proportion of Patients Losing More Than 10 Percent of Body Weight after 56
`Weeks of Treatment, LOCF, Trial 1839 ......................................................... 66
`Table 25. Proportion of Patients Losing at least 10 Percent of Body Weight after 56
`Weeks of Treatment, Sensitivity Analyses, Trial 1839 ................................... 67
`Table 26. Proportion of Patients Losing Greater than 10 Percent Body Weight after
`Week 56 by Pre-Diabetes Status, Trial 1839 ................................................. 69
`
`Reference ID: 3645293
`
`5
`
`

`

`Clinical Review
`Golden, J.
`NDA 206321
`Saxenda (liraglutide)
`
`Table 27. Percent Change from Baseline in Body Weight at Week 56, LOCF, Trial 1922
` ....................................................................................................................... 70
`Table 28. Percent Change from Baseline in Body Weight at Week 56, Completers
`Analysis, Trial 1922 ........................................................................................ 71
`Table 29. Percent Change in Body Weight after 56 Weeks of Treatment, by BMI, Trial
`1922 ............................................................................................................... 72
`Table 30. Proportion of Patients Losing at Least Five Percent Body Weight after 56
`Weeks of Treatment, LOCF, Trial 1922 ......................................................... 72
`Table 31. Proportion of Patients Losing at Least Five Percent Body Weight after 56
`Weeks of Treatment, Sensitivity Analyses, Trial 1922 ................................... 73
`Table 32. Proportion of Patients Losing More than 10 Percent of Body Weight after 56
`Weeks of Treatment, LOCF, Trial 1922 ......................................................... 73
`Table 33. Proportion of Patients Losing More than 10 Percent of Body Weight after 56
`Weeks of Treatment, Sensitivity Analyses, Trial 1922 ................................... 74
`Table 34. Percent Change in Body Weight at Week 56, Trial 1923 ............................. 75
`Table 35. Percentage of Patients Maintaining at Least Five Percent Weight Loss, Trial
`1923 ............................................................................................................... 76
`Table 36. Proportion of Five Percent Responders from Randomization, Trial 1923 ..... 76
`Table 37. Change in HbA1c (%) after 56 Weeks of Treatment, Trial 1839 ................... 77
`Table 38. Change in Fasting Plasma Glucose after 56 Weeks of Treatment, Trial 1839
` ....................................................................................................................... 78
`Table 39. Summary of Fasting Glycemic Parameters, Trial 1839 ................................ 79
`Table 40. Summary of Lipid Profile Parameters, Trial 1839 ......................................... 81
`Table 41. Percentage Point Change in HbA1c at Week 56, LOCF, Trial 1922 ............ 85
`Table 42. Proportion of Patients Achieving HbA1c Below Specific Thresholds at Week
`56, Trial 1922 ................................................................................................. 86
`Table 43. Diabetes Medication Changes, Trial 1922 .................................................... 88
`Table 44. Glycemic Rescue, Trial 1922 ........................................................................ 88
`Table 45. Mean Changes in Blood Pressure, Trial 1922 .............................................. 88
`Table 46. Mean Percent Changes in Lipids, Trial 1922 ................................................ 89
`Table 47. Mean Percent Changes in Cardiovascular Biomarkers, Trial 1922 .............. 89
`Table 48. Mean Changes in Patient Reported Outcomes, Trial 1922 .......................... 90
`Table 49. Exposure, Weight Management Pool ......................................................... 113
`Table 50. Exposure, Trial 1839 Ongoing Extension ................................................... 113
`Table 51. Exposure, Diabetes and Combined Pools .................................................. 114
`Table 52. Treatment-Emergent Deaths, Weight Management and Diabetes Programs
`Combined (Main Treatment Period) ............................................................. 115
`Table 53. Summary of Fatal Adverse Events, Weight Management Phase 2 and 3
`Trials ............................................................................................................ 116
`Table 54. Deaths, Weight Management Program ...................................................... 117
`Table 55. Summary of Fatal Adverse Events, Diabetes Pool ..................................... 119
`Table 56. Fatal Adverse Events, Diabetes Pool ......................................................... 119
`Table 57. Serious Adverse Events, Main Treatment Period, Weight Management Pool
` ..................................................................................................................... 120
`
`Reference ID: 3645293
`
`6
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`

`

`Clinical Review
`Golden, J.
`NDA 206321
`Saxenda (liraglutide)
`
`Table 58. Serious Adverse Events by System Organ Class and High Level Group Term
`or Preferred Term (Selected), Ongoing Portion of Trial 1839 ...................... 121
`Table 59. New Serious Adverse Events Not Reported in the ISS (02 Jul 2013 to 11 Nov
`2013), Ongoing Portion of Trial 1839 ........................................................... 123
`Table 60. Serious Adverse Events, Diabetes Pool ..................................................... 124
`Table 61. Adverse Events Leading to Withdrawal by System Organ Class and High
`Level Group Term, Weight Management Pool ............................................. 125
`Table 62. Pancreatitis Events by EAC Category in the Main Treatment Period of the
`Phase 3 Weight Management Trials ............................................................ 129
`Table 63. Treatment-Emergent Adjudicated Pancreatitis or Suspicion of Pancreatitis
`Sent and Confirmed by System Organ Class and Preferred Term .............. 129
`Table 64. Details of Pancreatitis Events ..................................................................... 132
`Table 65. Details of EAC-Confirmed Events of Pancreatitis, Ongoing 1839 Extension
` ..................................................................................................................... 135
`Table 66. Percentage of Patients with Amylase at Least Three Times the Upper Limit of
`Normal, Weight Management Phase 3 Trials .............................................. 137
`Table 67. Percentage of Patients with Lipase at Least Three Times the Upper Limit of
`Normal, Weight Management Phase 3 Trials .............................................. 138
`Table 68. Pancreatitis or Suspicion of Pancreatitis (Predef