Victoza® (Liraglutide) Injection LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results

Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017

Victoza® (liraglutide) injection LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results

NDA 22341 S-027

Briefing Document

Endocrinologic and Metabolic Drug Advisory Committee

June 20, 2017

Advisory Committee Briefing Materials: Available for Public Release Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 2 of 95

1 Executive summary Introduction Liraglutide is an analog with 97% homology to human glucagon-like peptide-1 (GLP-1) and acts as a GLP-1 receptor agonist (GLP-1 RA). Liraglutide (Victoza®) obtained marketing authorization in the United States (US) in 2010 and is currently approved in over 100 countries worldwide. In the US, Victoza® (for subcutaneous injection 1.2 mg and 1.8 mg once-daily) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM) as mono- or combination therapy.1 The exposure to Victoza® in the post-marketing setting is extensive; as of 30 June 2016, the cumulative exposure was estimated to be greater than 6 million patient-years of exposure to Victoza®.

The LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) was a cardiovascular outcomes trial designed and conducted to determine the effect and long-term safety of liraglutide versus placebo on cardiovascular outcomes as a post- marketing requirement (PMR) for Victoza® in the US and European Union (EU). Based on the robust results from the LEADER trial demonstrating that liraglutide was superior to placebo with respect to the primary endpoint (time to first major adverse cardiovascular event [MACE]), Novo Nordisk is seeking to add an additional indication to the existing indication for Victoza® as follows (new proposed indication in bold):

‘Victoza® is indicated:  as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.  as an adjunct to standard treatment of cardiovascular risk factors to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus and high cardiovascular risk.’

Thus, while Victoza® is already indicated to achieve glycemic lowering in patients with T2DM, the new proposed indication based on the demonstrated benefit to reduce cardiovascular events will provide important guidance to prescribers considering their options to treat T2DM.

Unmet medical need Cardiovascular disease is the leading cause of morbidity and mortality in patients with diabetes.2,3 Despite improvements in T2DM care by early and multi-factorial treatment of cardiovascular risk factors such as hypertension, obesity and dyslipidemia, the risk of cardiovascular disease for patients with diabetes remains at least twice as high compared to that in adults without diabetes.4 Furthermore, patients with diabetes and established cardiovascular disease have a higher risk of additional cardiovascular events and a shorter life expectancy than patients without diabetes.5 Hence, there is a large unmet medical need for additional therapies that can further reduce the risk Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 3 of 95 of cardiovascular disease development and progression in the population with diabetes while ensuring good glycemic control.

LEADER trial design and population (Sections 4 and 5) LEADER was a long-term, multicenter, multi-national, randomized, double-blind, placebo-controlled trial to determine the effect of liraglutide versus placebo on cardiovascular outcomes and long-term safety in patients with T2DM at high cardiovascular risk. Both liraglutide and placebo were used in addition to standard of care therapy. The trial was designed and conducted in accordance with the 2008 FDA guidance for evaluating cardiovascular risk in new antidiabetic therapies.6 As such, an independent external event adjudication committee (EAC) was established with appropriate subcommittees to perform ongoing blinded adjudication of cardiovascular events and deaths, as well as events of nephropathy, retinopathy, neoplasms and pancreatitis.

Patients with T2DM were eligible for trial enrolment if they had an HbA1c ≥ 7.0% at screening (no upper limit) and were antidiabetic drug naïve or were treated with one or more oral antidiabetic drugs (OADs) and/or neutral protamine hagedorn (NPH) insulin, long-acting insulin, or premixed insulin. In addition, patients were to be at high risk for cardiovascular events with either established cardiovascular disease or chronic kidney disease and age ≥ 50 years, or with at least one cardiovascular risk factor and age ≥ 60 years. These cardiovascular enrichment criteria were applied to achieve the required number of MACEs as well as the number of patients with moderate (estimated Glomerular Filtration Rate [eGFR] ≥ 30 to < 60 mL/min/1.73m2 per Modification of Diet in Renal Disease [MDRD]) and severe (eGFR < 30 mL/min/1.73m2 per MDRD) renal impairment (the latter two as per FDA request). As such, this resulted in inclusion of a clinically relevant high cardiovascular risk population for ruling out cardiovascular harm associated with liraglutide, and represented patients who could benefit from either primary or secondary cardiovascular disease prevention. An overview of the key inclusion and exclusion criteria is provided in Table 1 with a complete listing provided in Appendix 2.

Patients were randomly assigned, in a 1:1 ratio, to receive either liraglutide 1.8 mg (or maximum tolerated dose) or placebo once-daily, both in combination with standard of care therapy. The trial was both time and event driven. Thus, the trial ended when all patients had had a minimum treatment period of 42 months (plus a follow-up period off treatment of 30 days) and once at least 611 first events of MACE (primary endpoint defined as the composite of cardiovascular death, non- fatal myocardial infarction [MI; including silent MI] and non-fatal stroke) were recorded and confirmed by event adjudication. The minimum treatment period of 42 months was chosen to provide long-term data for liraglutide on relevant safety parameters. Because of an 18-month recruitment period, those patients first randomized into the trial could have a maximum treatment period of 60 months.

A total of 9,340 patients were randomized (4,668 to liraglutide and 4,672 to placebo) including a total of 224 patients with severe renal impairment at baseline (eGFR < 30 mL/min/1.73 m2 per Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 4 of 95

MDRD). A total of 96.8% of the randomized patients (9,042 patients) were completers defined as patients who during the trial either had a primary event (MACE), died (due to non-cardiovascular causes), or completed the planned follow-up visit. Importantly, the vital status was known in 99.7% of the patients (9,311 patients). Thus, the LEADER trial had a high degree of patient retention ensuring a low amount of missing data for evaluation of the primary endpoint. For details of patient disposition, see Figure 4. The median time of observation in LEADER was 3.84 years in each treatment group (including the follow-up period off treatment) and the median time of exposure to trial product was 3.52 and 3.51 years in the liraglutide and placebo groups, respectively. In the liraglutide group, 85% of the total exposure to liraglutide was to the 1.8 mg/day dose indicating that this dose level was well-tolerated. Demographics, baseline characteristics, and use of concomitant medication were well-balanced between the two treatment groups at baseline.

Cardiovascular outcomes (Section 6) The primary endpoint: time from randomization to the first occurrence of a MACE (cardiovascular death, non-fatal MI [including silent MI], or non-fatal stroke) was analyzed using a Cox proportional hazards model with treatment as factor based on the full analysis set (FAS) that included all randomized patients.

The primary analysis was performed using a pre-defined hierarchy, initially testing if liraglutide was non-inferior to placebo (upper bound of the 2-sided 95% CI for the estimated hazard ratio < 1.3) to establish cardiovascular safety. If non-inferiority was confirmed, it was then tested if liraglutide was superior to placebo (upper bound of the 2-sided 95% CI for the estimated hazard ratio being < 1.0). A number of pre-specified sensitivity analyses were performed to evaluate the robustness of the result; these analyses included a per protocol (PP) analysis and two ‘on-treatment’ analyses (for definitions, refer to Table 5). In addition, a total of 13 exploratory subgroup analyses were pre-specified to evaluate the consistency of the treatment effect on the primary endpoint.

A total of 1,302 first MACE events (confirmed by adjudication) were identified in the trial (608 in the liraglutide group and 694 in the placebo group). The primary analysis of time to first MACE with liraglutide versus placebo resulted in an estimated hazard ratio of 0.87 in favor of liraglutide (Figure 1). The one-sided (α-level 0.025) test for non-inferiority of liraglutide versus placebo for the primary endpoint was statistically significant (p < 0.001) with the upper 95% CI below 1.3, thus confirming non-inferiority. The one-sided (α-level 0.025) test for superiority of liraglutide versus placebo was also statistically significant (p = 0.005), thus confirming superiority of liraglutide versus placebo, with an estimated risk reduction for MACE of 13% compared to placebo.

All 3 components of the primary endpoint (cardiovascular death, non-fatal MI and non-fatal stroke) contributed to the reduction in first MACE observed with liraglutide (Table 13). All pre-specified sensitivity analyses (including ‘per protocol’, ‘on treatment’ and ‘on treatment + 30 days’) supported the robustness of the primary analysis, with all hazard ratio estimates and upper bounds of the 95% CIs < 1 (Figure 1). Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 5 of 95

Time from randomization to first event was analyzed using a Cox proportional hazards model with treatment as factor. Pre-specified sensitivity analyses: for definitions of ‘per protocol’, ‘on-treatment’ and ‘on-treatment + 30 days’, refer to Table 5. Abbreviations: CI: confidence interval; FAS: full analysis set; MI: myocardial infarction; N: number of patients; %: proportion of patients; UAP: unstable angina pectoris. Figure 1 Forest plot of treatment contrasts for time to first EAC-confirmed MACE, expanded MACE, individual components of expanded MACE and other secondary endpoints

The benefit observed with liraglutide compared to placebo for time to first MACE was generally consistent with the primary analysis across the pre-specified exploratory subgroup analyses (by baseline demographic and prognostic disease characteristics including baseline renal function and heart failure status) (see Figure 7 for the detailed results). In two subgroups, the hazard ratio estimate was > 1 with the 95% CI including the point estimate for the primary analysis: the subgroups of patients from region ‘North America’ (estimated hazard ratio [HR]: 1.01 [0.84; 1.22]95% CI) and patients enrolled based on the inclusion criterion #3b (cardiovascular [CV] risk factors and age ≥ 60 years; estimated HR: 1.20 [0.86; 1.67]95% CI). Further analyses performed for the US population (comprising 88% of the population in the North American region) failed to reveal specific covariates that explained the difference from the overall population except for a lower exposure time to trial product compared to patients from outside the US. On-treatment analyses of time to first MACE for the US population yielded hazard ratio estimates consistent to that of the overall population (Figure 9), providing support that the US population is not different from the overall population with respect to liraglutide response. The hazard ratio estimate observed for time to first MACE in patients enrolled based on the inclusion criterion #3b (CV risk factors and Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 6 of 95 age ≥ 60 years) was based on patients with relatively few events due to less advanced disease (contributed 137 out of 1,302 first MACEs). Additional analyses based on a clinically acknowledged cardiovascular risk stratification of patients with or without a medical history of non- fatal MI or stroke provided hazard ratio estimates < 1 for time to first MACE (Figure 10). Although these observations arise from post hoc analyses, these data support a cardiovascular benefit of liraglutide in both primary and secondary cardiovascular prevention.

Supportive secondary endpoints were time from randomization to:  First occurrence of expanded MACE defined as the primary MACE composite in addition to hospitalization for unstable angina pectoris (UAP), hospitalization for heart failure or coronary revascularization  Each individual component of expanded MACE  All-cause death  Non-cardiovascular death

A total of 2,010 first expanded MACEs (confirmed by adjudication) were identified (948 in the liraglutide group and 1,062 in the placebo group). The analysis of time to first expanded MACE resulted in an estimated hazard ratio of 0.88 [0.81; 0.96]95%CI, corresponding to a 12% risk reduction with liraglutide compared to placebo, resembling the outcome of the primary analysis (Figure 1). The hazard ratio estimates for all individual components of expanded MACE were < 1. Importantly, the estimated risk of cardiovascular death was reduced by 22% (estimated HR: 0.78 [0.66; 0.93]95%CI) with liraglutide compared to placebo. This reduction was also reflected in the related secondary endpoint all-cause death (estimated HR: 0.85 [0.74; 0.97]95%CI), while the estimated risk of non-cardiovascular death was similar with liraglutide and placebo (estimated HR:

0.95 [0.77; 1.18]95% CI)( Figure 1).

Microvascular outcomes (Section 7) Secondary time to event analyses were also pre-specified for a composite of microvascular endpoints. The components of the microvascular composite included:  The 4 components of the nephropathy composite: ‘new onset of persistent macroalbuminuria’, ‘persistent doubling of serum creatinine and eGFR ≤ 45 mL/min/1.73 m2 per MDRD’, ‘need for continuous renal replacement therapy’, and ‘death due to renal disease’.  The 3 components of the retinopathy composite: ‘need for retinal photocoagulation or treatment with intravitreal agents’, ‘vitreous hemorrhage’ and ‘diabetes-related blindness’.

The analysis of time to first microvascular event (confirmed by adjudication) resulted in an estimated hazard ratio of 0.84 [0.73; 0.97]95%CI, corresponding to a 16% risk reduction with liraglutide compared to placebo. The difference was driven by an estimated 22% reduction in the risk of the nephropathy composite (estimated HR: 0.78 [0.67; 0.92]95%CI) with liraglutide compared to placebo. An estimated hazard ratio of 1.15 [0.87; 1.52]95%CI was observed for the retinopathy Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 7 of 95 composite, attributable to an imbalance in the small number of patients with events of vitreous hemorrhage (32 vs 22 patients in the liraglutide and placebo groups, respectively). The low incidence of vitreous hemorrhage precludes firm conclusions.

Glycemic control and other cardiometabolic parameters (Section 8) In addition to trial product, all patients in LEADER were to receive best-practice standard of care therapy for T2DM and cardiovascular risk factors according to treatment recommendations issued by a trial specific Global Expert Panel (Table 2).

Formal analyses of glycemic and cardiometabolic parameters were conducted at year 3 (last visit for all patients where the parameters were assessed) and at end of treatment (the end of treatment visit could vary from 42 to 60 months).An estimated treatment difference (ETD) of -0.4% [-0.45; -0.34]95% CI for HbA1c was observed with liraglutide compared to placebo after 3 years; the change in HbA1c was maintained at end of treatment. The improvement in HbA1c was supported by a reduced likelihood of initiating insulin and/or other antidiabetic drugs with liraglutide compared to placebo. Liraglutide was associated with greater reductions in body weight (ETD [in kg]: -2.26 [-2.54; -1.99]95% CI) and systolic blood pressure (SBP; ETD [in mmHg]: -1.20 [-1.92; -0.48]95% CI) compared with placebo after 3 years; changes in both body weight and SBP were maintained at end of treatment. Diastolic blood pressure (DBP) was reduced from baseline in both treatment groups at 3 years, but the reduction was smaller in the liraglutide group than in the placebo group (ETD [in mmHg]: 0.59 [0.19; 0.99]95% CI).Improvements were also seen with liraglutide for total cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL) compared with placebo after 3 years. Consistent with previous clinical experience with liraglutide1, an increase in mean resting heart rate of approximately 3 bpm was observed with liraglutide at 3 years compared to placebo (ETD [in bpm]: 2.98 [2.54; 3.42]95% CI).

Safety results (Section 9) As the safety profile for liraglutide was well-established from the clinical development program for T2DM, a selective and targeted approach to safety data collection was applied in LEADER in accordance with guidance on safety data collection in late stage premarket and post-approval clinical investigations, including cardiovascular outcomes trials.7,8 Thus, only events in LEADER meeting the definition of a serious adverse event (SAE) or a pre-specified medical event of special interest (MESI) were required to be collected and reported according to protocol.

The safety results for liraglutide in LEADER generally reflected the well-established safety profile described in the current prescribing information for Victoza®.1 No notable differences were observed between the liraglutide and placebo groups in the incidences of SAEs or non-serious MESIs (62.3% vs 60.8%), SAEs or non-serious MESIs considered severe (32.2% vs 32.8%) or SAEs only (49.7% vs 50.4%). SAEs or non-serious MESIs of gastrointestinal disorders (mainly ‘nausea’) were, as expected, common and occurred more frequently with liraglutide (3.7%) compared with placebo (0.9%). In addition, the proportion of patients who permanently Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 8 of 95 discontinued treatment due to SAEs or non-serious MESIs was higher in the liraglutide group (9.6%) compared with the placebo group (7.3%). The majority of the permanent discontinuations with liraglutide were attributable to events of gastrointestinal disorders (mainly ‘nausea’, ‘vomiting’ and ‘diarrhea’). The incidences of events of acute pancreatitis (confirmed by adjudication) were similar with liraglutide and placebo (0.4% vs 0.5%, respectively), while liraglutide was associated with a higher incidence of acute gallbladder disease (SAEs or non-serious MESIs) compared with placebo. This difference was primarily observed in events of ‘cholelithiasis’ (liraglutide: 1.5%; placebo: 1.1%) and ‘cholecystitis acute’ (liraglutide: 0.8%; placebo: 0.4%). The frequency of malignant neoplasms (confirmed by adjudication) was similar in the liraglutide and placebo groups (6.3% vs 6.0%, respectively). Malignant neoplasms were distributed across several tissue types with some frequencies favoring liraglutide and others favoring placebo; no clustering within specific organ sites was observed for either treatment group. A potential association between GLP-1 RAs, including liraglutide, and development of medullary thyroid carcinoma (MTC; no cases with liraglutide) was not supported by the LEADER data. Furthermore, despite a numerical imbalance observed between the liraglutide and placebo groups in the frequency of malignant pancreatic neoplasms (13 vs 5 patients with confirmed events, respectively), the totality of data (including non-clinical studies, clinical trials and post-marketing experience with liraglutide) does not support an increased risk associated with liraglutide treatment. The rate of severe hypoglycemia (American Diabetes Association [ADA] classification) was lower in the liraglutide group compared with the placebo group with an estimated reduction of 31% (estimated rate ratio [ERR]: 0.69 [0.51; 0.93]95% CI) despite generally lower levels of blood glucose observed for the liraglutide group.

In accordance with the selection criteria, the trial included a substantial number of elderly patients, patients with heart failure and patients with moderate or severe renal impairment. Overall, no notable differences were observed between the treatment groups with respect to the distribution of SAEs or non-serious MESIs across subgroups defined by baseline age (< 65 years, 65−74 years, 75−84 years or ≥ 85 years), baseline renal function (normal renal function [eGFR ≥ 90 mL/min/1.73m2], mild [eGFR ≥ 60 to < 90 mL/min/1.73m2], moderate [eGFR ≥ 30 to < 60 mL/min/1.73m2] or severe [eGFR < 30 mL/min/1.73m2] renal impairment; eGFR per MDRD) or baseline heart failure status (no heart failure, New York Heart Association [NYHA] class I, II or III).

Benefit-risk assessment (Section 10) The LEADER trial demonstrated that liraglutide added to standard of care therapy was associated with statistically significant and clinically relevant reductions in cardiovascular morbidity and mortality in patients with T2DM at high cardiovascular risk. The estimated risk reductions versus placebo were 13% in MACE, 12% in expanded MACE, and 22% in cardiovascular death. The results were consistent across all pre-specified sensitivity analyses, and across a large number of pre-specified subgroups. All individual components of expanded MACE showed estimated hazard ratios < 1, further supporting the robustness of the results. Finally, liraglutide was associated with a 15% clinically relevant estimated risk reduction in all-cause death versus placebo. Based on these Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 9 of 95 data, Novo Nordisk proposes to add an additional indication to the existing indication for Victoza® to include that in adults with T2DM and high cardiovascular risk, liraglutide is indicated as an adjunct to standard treatment of cardiovascular risk factors to reduce the risk of MACE (cardiovascular death, non-fatal MI or non-fatal stroke).

Liraglutide as compared with placebo was associated with a 22% risk reduction in the nephropathy composite, while no improvement in the retinopathy composite was shown. Also, treatment with liraglutide provided substantial and sustained improvements in glycemic control. The effect of liraglutide on HbA1c was accompanied by a reduced likelihood of initiating additional antidiabetic therapies including insulin, and with a lower rate of severe hypoglycemia as compared with placebo. In addition, liraglutide was associated with greater and sustained reductions in body weight and SBP compared with placebo.

The safety results in LEADER reaffirmed the well-established safety profile from the clinical development program for liraglutide in T2DM and the extensive exposure to Victoza® in the post- marketing setting. Liraglutide was generally safe and well-tolerated, but was, as expected, associated with a higher frequency of gastrointestinal adverse events. While a higher incidence of acute gallbladder disease was observed with liraglutide compared with placebo, this finding is consistent with observations from the liraglutide for weight management clinical development program at higher dose (3.0 mg; Saxenda®), and is already reflected in the current Victoza® prescribing information.1 In addition, the results supported the long-term safe use of liraglutide with respect to areas of uncertainty at the time of the New Drug Application (NDA) approval, including pancreatitis and neoplasms.

The LEADER results also support the efficacious and safe use of liraglutide in particularly vulnerable patient groups which has previously not been well studied and for whom treatment options are limited, including: elderly ≥ 75 years of age, patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2 per MDRD), and patients with heart failure (NYHA classes I−III).

Overall, the LEADER results demonstrated clinically relevant cardiovascular benefits of liraglutide as well as long-term safety and sustained improvement in glycemic control, thereby strengthening the established positive benefit-risk profile for liraglutide in T2DM. Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 10 of 95

List of abbreviations ACE angiotensin converting enzyme ADA American Diabetes Association AE adverse event BMI body mass index BPM beats per minute CHMP Committee for Medicinal Products for Human Use CI confidence interval CMC Calcitonin Monitoring Committee CV cardiovascular DBL data base lock DBP diastolic blood pressure DMC Data Monitoring Committee DPP-4 dipeptidyl peptidase-4 EAC event adjudication committee ECG electrocardiogram eCRF electronic case report form eGFR estimated glomerular filtration rate EMA European Medicines Agency ETD estimated treatment difference ETR estimated treatment ratio EU European Union FAS full analysis set FDA U.S. Food & Drug Administration GCP good clinical practice GLP-1 glucagon-like peptide-1 GLP-1 RA glucagon-like peptide-1 receptor agonist HDL high density lipoprotein HbA1c glycosylated hemoglobin HLGT high level group term HR hazard ratio ICH International Conference on Harmonisation LEADER Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results LDL low-density lipoprotein MACE major adverse cardiovascular event MDRD modification of diet in renal disease MedDRA medical dictionary for regulatory activities MEN 2 multiple endocrine neoplasia syndrome type 2 MESI medical event of special interest MI myocardial infarction MMRM mixed model repeated measurement Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 11 of 95

MTC medullary thyroid carcinoma NDA New Drug Application NPH neutral protamine hagedorn NYHA New York Heart Association OAD oral antidiabetic drug PMR post-marketing requirement PP per protocol PYO patient year of observation SAE serious adverse event SAP statistical analysis plan SBP systolic blood pressure SGLT-2 sodium-dependent glucose transporter two SMQ standardized MedDRA query sNDA supplemental New Drug Application SOC system organ class StC Steering Committee SU sulfonylurea T2DM type 2 diabetes mellitus TIA transient ischemic attack UACR urinary albumin-to-creatinine ratio UAP unstable angina pectoris ULN upper limit normal US United States Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 12 of 95

2 Table of contents Page 1 Executive summary...... 2 List of abbreviations ...... 10 2 Table of contents ...... 12 3 Introduction and background information...... 18 3.1 Purpose of this document ...... 18 3.2 Liraglutide ...... 18 3.3 Type 2 diabetes mellitus and unmet medical need...... 19 3.4 LEADER trial regulatory requirements and rationale...... 20 4 LEADER trial design and statistical considerations...... 21 4.1 Trial governance ...... 21 4.2 Trial design...... 22 4.3 Medical events of special interest ...... 25 4.3.1 Adjudication of medical events of special interest ...... 26 4.4 Statistical considerations ...... 29 4.4.1 Sample size calculation...... 29 4.4.2 Analyses related to the primary endpoint...... 29 5 Disposition and characteristics of the trial population ...... 31 5.1 Patient disposition...... 31 5.2 Demographics and baseline characteristics ...... 32 5.3 Concomitant medication at baseline ...... 34 5.3.1 Cardiovascular medication at baseline...... 34 5.3.2 Antidiabetic medications at baseline...... 35 5.4 Observation time and exposure time to trial products...... 36 5.5 Exposure to concomitant medication during the trial...... 37 5.5.1 Concomitant cardiovascular medication started exclusively after baseline ...... 37 5.5.2 Concomitant antidiabetic medication started exclusively after baseline...... 38 6 Cardiovascular outcomes...... 40 6.1 MACE ...... 40 6.1.1 Primary endpoint: time to first MACE...... 40 6.1.2 Analyses of MACE by subgroups ...... 44 6.2 Expanded MACE and individual components of expanded MACE ...... 51 6.2.1 Expanded MACE...... 51 6.2.2 Individual components of expanded MACE ...... 53 6.3 All-cause death ...... 54 6.4 Heart rate...... 59 7 Microvascular outcomes ...... 61 7.1 Microvascular composite...... 61 7.2 Nephropathy ...... 63 7.3 Retinopathy...... 63 8 Glycemic control and other cardiometabolic parameters...... 65 8.1 Glycemic control...... 65 Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 13 of 95

8.2 Other cardiometabolic parameters ...... 67 9 Safety results ...... 69 9.1 General safety ...... 71 9.1.1 Overview of SAEs and non-serious MESIs ...... 71 9.1.2 Most common SAEs and non-serious MESIs ...... 72 9.1.3 SAEs and non-serious MESIs leading to permanent treatment discontinuation ...... 72 9.2 Selected safety areas ...... 74 9.2.1 Overview ...... 74 9.2.2 Neoplasms ...... 76 9.2.3 Pancreatitis ...... 81 9.2.4 Acute gallbladder disease...... 83 9.2.5 Renal safety ...... 85 9.2.6 Hypoglycemia...... 87 9.2.7 Immunogenicity...... 89 9.2.8 Cardiac arrhythmia ...... 89 10 Benefit-risk discussion and conclusions ...... 91 11 References ...... 93 Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 14 of 95

List of appendices

Appendix 1: Membership on LEADER committees and panels

Appendix 2: LEADER inclusion and exclusion criteria

Appendix 3: Definitions and classifications of events sent for EAC evaluation

Appendix 4: MedDRA search criteria

Appendix 5: Supporting tables and figures Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 15 of 95

List of in-text figures

Page Figure 1 Forest plot of treatment contrasts for time to first EAC-confirmed MACE, expanded MACE, individual components of expanded MACE and other secondary endpoints ...... 5 Figure 2 Trial design ...... 24 Figure 3 Overview of the adjudication process ...... 28 Figure 4 Patient disposition...... 31 Figure 5 Kaplan-Meier plot of time to first EAC-confirmed MACE...... 42 Figure 6 Forest plot of treatment contrasts for time to first EAC-confirmed MACE (primary endpoint) and sensitivity analyses of the primary endpoint...... 43 Figure 7 Forest plot of treatment contrasts for to time to first EAC-confirmed MACE according to pre-specified exploratory subgroups ...... 45 Figure 8 Percentage of patients on treatment over time for US and non-US populations...... 47 Figure 9 Forest plot of treatment contrasts for time to first EAC-confirmed MACE in the US population ...... 48 Figure 10 Forest plot of treatment contrasts for time to first EAC-confirmed MACE by prior non- fatal MI or stroke at baseline ...... 50 Figure 11 Forest plot of treatment contrasts for time to first EAC-confirmed expanded MACE and individual components of expanded MACE...... 52 Figure 12 Kaplan-Meier plot of time to first EAC-confirmed expanded MACE ...... 53 Figure 13 Kaplan-Meier plots of time to first EAC-confirmed individual components of MACE and expanded MACE ...... 54 Figure 14 Forest plot of treatment contrasts for time to EAC-confirmed all-cause death, cardiovascular death and non-cardiovascular death...... 56 Figure 15 Kaplan-Meier plot of time to EAC-confirmed all-cause death...... 56 Figure 16 Kaplan-Meier plot of time to EAC-confirmed non-cardiovascular death ...... 59 Figure 17 Forest plot of treatment contrasts for time to first EAC-confirmed MACE and EAC- confirmed hospitalization for heart failure occurring after month 6 by categorical heart rate change...... 60 Figure 18 Forest plot of treatment contrasts for time to first EAC-confirmed microvascular composite endpoint and its components...... 62

Figure 19 Estimated mean HbA1c (%) over time ...... 66 Figure 20 Time to first initiation of insulin or any new OAD...... 67 Figure 21 The 20 most common SAEs or non-serious MESIs by preferred term ...... 72 Figure 22 SAEs or non-serious MESIs leading to permanent treatment discontinuation ...... 73 Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 16 of 95

Figure 23 The 20 most common SAEs or non-serious MESIs leading to permanent treatment discontinuation by preferred term ...... 74 Figure 24 Incidences of EAC-confirmed overall, benign, and malignant neoplasms and malignant neoplasms by tissue type ...... 77 Figure 25 Kaplan-Meier plot of time to onset and stage of first EAC-confirmed malignant pancreatic neoplasm ...... 80 Figure 26 Kaplan-Meier plot of time to first EAC-confirmed acute pancreatitis ...... 82 Figure 27 Mean number of events of acute gallbladder disease (MedDRA search) per patient ...... 84 Figure 28 Mean number of severe hypoglycemic episodes per 1,000 patients ...... 88 Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 17 of 95

List of in-text tables

Page Table 1 Key inclusion and exclusion criteria ...... 23 Table 2 Recommendations provided by the Global Expert Panel ...... 25 Table 3 Evaluation of medical events of special interest ...... 26 Table 4 Events for adjudication...... 27 Table 5 Definitions of sensitivity analyses...... 30 Table 6 Selected demographic and baseline characteristics...... 33 Table 7 Cardiovascular profile at screening...... 34 Table 8 Concomitant cardiovascular medication taken at baseline ...... 35 Table 9 Concomitant antidiabetic treatment regimen at baseline...... 36 Table 10 Overview of observation time and exposure time to trial products...... 37 Table 11 Concomitant cardiovascular medication started exclusively after baseline...... 38 Table 12 Concomitant antidiabetic medication started exclusively after baseline...... 39 Table 13 First EAC-confirmed MACE...... 41 Table 14 EAC-confirmed deaths ...... 55 Table 15 Cause of EAC-confirmed cardiovascular deaths ...... 58 Table 16 Microvascular components...... 61 Table 17 Changes in body weight, blood pressure, heart rate and lipids from baseline ...... 68 Table 18 Overview of SAEs or non-serious MESIs ...... 71 Table 19 Summary of selected safety areas in LEADER ...... 75 Table 20 EAC-confirmed thyroid neoplasms by malignancy status and type ...... 78 Table 21 EAC-confirmed pancreatic neoplasms by malignancy status...... 79 Table 22 Frequencies of EAC-confirmed acute pancreatitis among patients with at least one scheduled post-baseline amylase or lipase value ≥3×ULN or ≥1×ULN ...... 83 Table 23 Events of acute gallbladder disease (MedDRA search) by preferred term with frequency ≥0.1% ...... 84 Table 24 Changes in UACR, serum creatinine and eGFR from baseline to year 3...... 86 Table 25 Events of acute renal failure (MedDRA search) by preferred term ...... 87 Table 26 Summary of severe and confirmed hypoglycemic episodes...... 88 Table 27 Events of cardiac arrhythmia (MedDRA search) by preferred term with frequency ≥0.2% ...... 90 Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 18 of 95

3 Introduction and background information

3.1 Purpose of this document Liraglutide (Victoza® for subcutaneous injection 1.2 mg and 1.8 mg) is a once-daily human glucagon-like peptide-1 receptor agonist (GLP-1 RA) developed by Novo Nordisk and approved by the FDA on January 25th, 2010. In the US, Victoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [T2DM] as mono- or combination therapy.1 Liraglutide (Victoza®) is currently approved in more than 100 countries worldwide.

Novo Nordisk submitted a separate supplemental New Drug Application (sNDA) on October 25th, 2016 providing results from the LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results). LEADER was a cardiovascular outcomes trial designed and conducted to determine the effect and long-term safety of liraglutide versus placebo on cardiovascular outcomes as a post-marketing requirement (PMR) for Victoza® in the US and European Union (EU). Based on the robust results from the LEADER trial demonstrating that liraglutide was superior to placebo with respect to the primary endpoint (time to first major adverse cardiovascular event [MACE]), Novo Nordisk is seeking to add an additional indication to the existing indication for Victoza® as follows (new proposed indication in bold):

This briefing document outlines the key results from the LEADER trial and provides background information for discussion of the trial results at the Endocrinologic and Metabolic Drug Advisory Committee meeting scheduled for June 20, 2017.

3.2 Liraglutide Liraglutide is an analog with 97% homology to human glucagon-like peptide-1 (GLP-1) and acts as a GLP-1 RA. Like other GLP-1 RAs, liraglutide binds to and activates specific GLP-1 receptors in the beta-cells of the pancreas and in a number of other tissues. Liraglutide stimulates insulin secretion and inhibits glucagon secretion in a glucose-dependent manner. In addition, liraglutide reduces body weight and body fat mass through mechanisms involving reduced hunger and lowered Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 19 of 95 energy intake. Due to its protracted absorption, liraglutide has a 13-hour half-life and a 24-hour duration of action which makes it suitable for once-daily administration. Accruing evidence supports that liraglutide also has direct beneficial cardio-protective effects including attenuation of the atherosclerotic process via reduced inflammation, increased plaque stability, and improved endothelial function. 9,10,11

Current approved labeling on Victoza® includes comprehensive and detailed information on important aspects of liraglutide.1 The safe and efficacious use of Victoza® in T2DM has been established through an extensive global clinical development program comprising over 55 completed clinical trials in which more than 13,000 patients with T2DM were exposed to Victoza®. The trials were conducted with Victoza® as monotherapy or as add-on therapy to other antidiabetic drugs, including basal insulin. In addition to the effects on glycemia, these clinical trials have shown that Victoza® has beneficial effects on other risk factors associated with cardiovascular disease such as systolic blood pressure (SBP), lipid levels, and body weight.12

Victoza® also has a well-established safety profile. Common adverse reactions as reflected in the prescribing information1 include gastrointestinal side effects such as nausea, diarrhea, and vomiting. As with all long-acting GLP-1 RAs, Victoza® carries a Warning and Precaution for pancreatitis and a Boxed Warning for risk of thyroid C-cell tumors based on findings in rodents, and is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2).

The exposure to Victoza® in the post-marketing setting is extensive; as of 30 June 2016, the cumulative exposure was estimated to be greater than 6 million patient-years of exposure to Victoza®. Furthermore, liraglutide at once-daily dose of 3.0 mg (subcutaneous injection) was approved by the FDA in 2014 as an adjunct to diet and exercise for weight management under the trade name Saxenda®.

3.3 Type 2 diabetes mellitus and unmet medical need In 2015, the prevalence of diabetes was estimated to be 415 million (1 in 11 people) and it is increasing worldwide.3,13 In 2016, more than 29 million people in the US were estimated to have diabetes, with T2DM accounting for approximately 90-95% of the cases.14 According to projections from the US Center for Disease Control, one in three US adults could have diabetes by 2050.15

T2DM is a progressive and complex metabolic disorder characterized by chronic hyperglycemia associated with a high risk of macrovascular and microvascular complications. Cardiovascular disease represents the leading cause of morbidity and mortality in patients with diabetes.2,3 Despite improvements in T2DM care by early and multi-factorial treatment of cardiovascular risk factors such as hypertension, obesity and dyslipidemia, the risk of cardiovascular disease for patients with diabetes remains at least twice as high compared to that in adults without diabetes.4 Furthermore, patients with diabetes and established cardiovascular disease have a higher risk of additional Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 20 of 95 cardiovascular events and a shorter life expectancy than patients without diabetes.5 Hence, there is a large unmet medical need for additional therapies that can further reduce the risk of cardiovascular disease development and progression in the population with diabetes while ensuring good glycemic control.

3.4 LEADER trial regulatory requirements and rationale The initial New Drug Application (NDA) for Victoza® was submitted in 2008 and during the assessment of the application, the FDA issued their ‘Guidance for Industry: Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes’.6

A retrospective post hoc meta-analysis based on a total of 39 MACEs from all completed phase 2/3a trials from the liraglutide in T2DM clinical development program (at the time of the NDA) resulted in an estimated hazard ratio of 0.73 [0.38; 1.41]95%CI for liraglutide versus all comparators (metformin, glimepiride, rosiglitazone, insulin glargine, placebo).16 As the upper bound of the two- sided 95% CI for the point estimate for MACE from this meta-analysis was between 1.3 and 1.8, the FDA (and subsequently the European Medicines Agency [EMA]) required a dedicated post- marketing cardiovascular outcomes trial for Victoza® in accordance with the above-mentioned guidance to demonstrate that treatment with liraglutide is not associated with an unacceptable risk of cardiovascular disease. The Sponsor initiated the LEADER trial to fulfill this PMR for Victoza® for both the US and EU. In addition to assessing cardiovascular safety, the trial fulfilled additional requirements to investigate long-term effects on: MTC, including its biomarker calcitonin, pancreatitis, renal safety, hypoglycemia, immunological reactions, and neoplasms. As per FDA request, LEADER was also to include at least 200 patients with moderate renal impairment and at least 100 patients with severe renal impairment to be treated with liraglutide for at least 1 year.

The LEADER trial was designed to establish cardiovascular safety by demonstrating non-inferiority for the pre-defined primary composite endpoint ‘time to first MACE’ (cardiovascular death, non- fatal MI or non-fatal stroke) for liraglutide versus placebo, both added to standard of care therapy. An additional test for superiority was pre-defined as part of the confirmatory hierarchical testing procedure to evaluate cardiovascular benefit. This was based on the observed suggested favorable outcome of the MACE meta-analysis (as described above), and the observed beneficial effects on cardiovascular risk factors, including HbA1c, SBP, and body weight, associated with liraglutide treatment. By design, the trial was enriched for patients at high risk for cardiovascular disease, including patients with advanced T2DM, elderly patients, patients with moderate/severe renal impairment and heart failure.

The LEADER trial protocol and statistical analysis plan were reviewed by the US FDA and EU Committee for Medicinal Products for Human Use (CHMP) and agreed upon/commented on prior to trial initiation and completion, respectively. Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 21 of 95

4 LEADER trial design and statistical considerations

4.1 Trial governance The LEADER trial was conducted by Novo Nordisk and was governed by 3 committees as presented below:

Steering Committee The Steering Committee (StC) was responsible for designing the protocol and provided scientific and academic leadership for the trial in collaboration with the Sponsor and regulatory authorities. The StC consisted of 11 external experts within the fields of cardiology, diabetology, endocrinology, gastroenterology, nephrology, and statistics, all with extensive experience in conducting cardiovascular outcomes trials. Additionally, 4 employees of the Sponsor were included in the StC. The StC was blinded to trial data and operated under a charter agreed on between the Sponsor and the StC members. A list of StC members is provided in Appendix 1.

Data Monitoring Committee An independent external Data Monitoring Committee (DMC) monitored the safety of the patients and performed ongoing evaluation of safety and effectiveness data from the trial. The DMC was composed of members whose expertise covered relevant specialties including cardiology, endocrinology, gastroenterology and statistics. The DMC received unblinded data from an external independent statistical consulting group (Statistics Collaborative Inc.) for evaluation of the safety of the LEADER trial. During the trial, the DMC provided recommendations on trial continuation, modification, or termination to the internal Novo Nordisk safety committee and to the StC. A list of DMC members is provided in Appendix 1.

Event Adjudication Committee An independent external Event Adjudication Committee (EAC) was constituted to perform ongoing blinded adjudication of pre-defined medical events of special interest (MESIs) and deaths. The EAC evaluated events sent for adjudication using pre-defined definitions and guidelines in accordance with the EAC Charter. The EAC was composed of 4 specialized subcommittees (cardiovascular, microvascular, pancreatitis and neoplasm) with 19 members who were board certified and clinical experts in the diagnosis and treatment of the different endpoints and events of interest in LEADER. A list of EAC members is provided in Appendix 1.

Additional committees/panels In addition, the following 3 committees/panels provided guidance on relevant safety and operational trial-related issues:

 The Global Expert Panel consisted of site principal investigators participating in LEADER from different countries, as well as designated Novo Nordisk employees. The panel advised on Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 22 of 95

global and local operational trial-related issues and could forward recommendations to the StC. A list of Global Expert Panel members is provided in Appendix 1.  An independent blinded external Calcitonin Monitoring Committee (CMC) was established to recommend follow-up actions to the sites for all individual patients with clinically relevant abnormal calcitonin values. A list of CMC members is provided in Appendix 1.  An internal Novo Nordisk Safety Committee was responsible for the overall safety surveillance of liraglutide from all sources including but not limited to ongoing clinical trials and post-marketing data. The Safety Committee worked in a blinded manner.

4.2 Trial design LEADER was a long-term, multicenter, multi-national, randomized, double-blind, placebo- controlled trial performed to determine the effect of liraglutide versus placebo on cardiovascular outcomes and long-term safety in patients with T2DM at high cardiovascular risk. Both liraglutide and placebo were used in addition to standard of care therapy.

The key inclusion and exclusion criteria are shown in Table 1. Patients with T2DM and an HbA1c ≥ 7.0% (no upper limit), and at high risk for cardiovascular events were enrolled to help achieve the required number of MACE as well as the number of patients with moderate (eGFR ≥ 30 to < 60 mL/min/1.73m2 per Modification of Diet in Renal Disease [MDRD]) and severe (eGFR < 30 mL/min/1.73m2 per MDRD) renal impairment (the latter two as per FDA request; Section 3.4). A complete overview of all inclusion and exclusion criteria is provided in Appendix 2.

Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 24 of 95 parameters. Because of an 18-month recruitment period, those patients first randomized into the trial could have a maximum treatment period of 60 months.

A schematic presentation of the trial design is shown in Figure 2.

Abbreviations: EAC: event adjudication committee; OD: once-daily. Figure 2 Trial design

Investigators were instructed to administer best-practice standard of care treatment in addition to trial product, to provide optimal treatment to manage the patient’s diabetes and cardiovascular risk. A Global Expert Panel provided to all investigators written recommendations for standard of care treatment to be used throughout the study, including recommendations for management of hyperglycemia, blood pressure, blood lipids, and treatment with antiplatelet therapy, as shown in Table 2. Recommendations from the Global Expert Panel accounted for local treatment guidelines and the availability of different medications.

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Abbreviations: ACS: acute coronary syndrome; AE: adverse event; Coronary Revasc.: coronary revascularization; CRO: contract research organization; EAC: event adjudication committee; ECG: electrocardiogram; MedDRA: Medical Dictionary for Regulatory Activities; MESI: medical event of special interest. Figure 3 Overview of the adjudication process

The five pathways for identification of events for adjudication were:  Investigator identified deaths and MESIs relevant for adjudication.  Identification via central electrocardiogram (ECG) reading of significant new abnormalities, compared to the previous ECG, consistent with MI.  Out-of-range laboratory values from the central laboratory suggestive of potential nephropathy events. Alerts were based on pre-defined algorithms for serum creatinine and eGFR per MDRD and urinary albumin-to-creatinine ratio (UACR).  Events identified by the EAC or the external contract research organization (ICON) during review of source documents submitted for another event.  Pre-defined MedDRA searches were performed by the Sponsor among all adverse events not reported as MESIs requiring adjudication. Events identified during this standardized preferred term screening process were sent to the external contract research organization company (ICON), who evaluated, in an objective and independent manner, whether the identified event should be sent for adjudication or not.

Each event sent for adjudication was evaluated independently by two primary adjudicators of the appropriate specialty using pre-defined definitions and guidelines (Appendix 3). If agreement could not be reached between the two adjudicators, the event was sent to the EAC Chair who performed Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 29 of 95 an independent review of all data associated with that event, including the assessments of the two primary adjudicators, before making a final determination.

4.4 Statistical considerations

4.4.1 Sample size calculation The sample size calculation was based on the test of non-inferiority for the primary endpoint of time to first MACE using the full analysis set (FAS) (including all randomized patients). Under the assumption of a true hazard ratio of 1.0, at least 611 events were required to provide 90% power to reject the null hypothesis that the hazard ratio is ≥ 1.3 at a 1-sided alpha level of 0.025. Based on previous cardiovascular outcomes trials, an event rate of 1.8 events per 100 patient-years of observation (PYO; i.e., percent events per year) was assumed.22,23 Based on this assumption, 8,754 patients were planned for randomization to provide the required 611 events during 3.5−5 years of patient follow-up. Since all patients were to be followed for a minimum of 3.5 years, the number of events included in the primary analysis could exceed 611 if the observed event rate was higher than that assumed in the sample size calculations.

4.4.2 Analyses related to the primary endpoint The statistical analysis plan (SAP) was discussed and commented upon by FDA prior to unblinding and database lock (DBL). No interim analysis was performed for LEADER. For all adjudicated endpoints, the statistical analyses were performed based on EAC-confirmed events.

The primary endpoint: time from randomization to the first occurrence of a MACE (cardiovascular death, non-fatal MI [including silent MI], or non-fatal stroke) was analyzed using a Cox proportional hazards model with treatment as a factor. The analysis was based on the FAS, including all randomized patients in line with the intention-to-treat principle. The statistical analysis included only EAC-confirmed events that occurred after randomization through the follow-up visit and reported prior to DBL. Patients who did not experience an event between randomization and the follow-up visit were censored at last date of contact.

The statistical analysis was performed using a pre-defined hierarchy: the first test examined whether liraglutide was non-inferior to placebo with respect to the primary endpoint (upper bound of the two-sided 95% CI for the estimated hazard ratio being < 1.3). If non-inferiority was confirmed, a test was performed to examine whether liraglutide was superior to placebo (upper bound of the 95% CI for the estimated hazard ratio being < 1.0). The significance level corresponded to 5% for a two-sided test. Because the hierarchical tests constituted a closed testing procedure, no adjustment of the significance level was required.24,25 No further testing was performed outside of this hierarchical testing procedure.

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5 Disposition and characteristics of the trial population

5.1 Patient disposition The patient disposition of LEADER is shown in Figure 4.

Abbreviations: CV: cardiovascular; FAS: full analysis set, N: number of patients. Figure 4 Patient disposition

Of the 12,076 patients screened, 9,340 patients were randomized 1:1 to either liraglutide or placebo treatment. The FAS included all randomized patients.

In LEADER, a completer definition was specified to describe patient disposition and patient retention in relation to the primary endpoint (time to first MACE). A completer was defined as a patient who during the trial:

1. had a primary event (MACE) or 2. died due to non-cardiovascular causes or 3. had direct contact with the trial site at or after the planned follow-up visit

A non-completer was defined as a patient who did not meet any of the 3 criteria for being a completer. Non-completers could have known or unknown vital status at the time of the planned follow-up visit. A patient who was known to be alive but with whom direct contact could not be Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 32 of 95 established was regarded as a non-completer as it could not be determined if the patient had had a primary event (i.e., non-fatal MI or stroke). Patients with unknown vital status were grouped into 1) patients who had withdrawn informed consent during the trial and 2) patients considered lost to follow-up.

For patients who were potentially lost to follow-up during the course of the trial, the trial site attempted to obtain vital status of the patient at the end of the trial by trying to contact the patient directly or the patient’s primary care giver or next of kin, or contacting public registries if available. If the patient was reported dead, and if the date of the death was no later than the planned follow-up visit, then the patient was a trial ‘completer’. If the death occurred after the planned follow-up visit, the patient was considered a non-completer.

At the end of the trial it was determined that 96.8% of patients were completers and 99.7% were either completers or had known vital status in the two treatment groups combined, demonstrating a high degree of patient retention in the trial for evaluation of the primary endpoint.

5.2 Demographics and baseline characteristics Demographics, medical history, and concomitant illness were collected at screening. Overall, patients randomized to liraglutide or placebo were well-matched with respect to demographics and baseline characteristics (Table 6). The entire trial population was comprised of patients with a mean age of approximately 64 years, a duration of diabetes of approximately 13 years, and at high risk for cardiovascular events.

Approximately 27% of the patients were from the US (2,515 out of 9,340 patients). Of note, the US population had a higher baseline body mass index (BMI), lower SBP and DBP, and slightly lower eGFR when compared to the non-US population (Appendix 5, Table 1).

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Full analysis set. Time from randomization to first occurrence of a MACE (composite of cardiovascular death, non-fatal MI [including silent MI] and non-fatal stroke) was analyzed using a Cox proportional hazards model with treatment as factor. Abbreviations: CI: confidence interval; EAC: event adjudication committee; HR: hazard ratio. Figure 5 Kaplan-Meier plot of time to first EAC-confirmed MACE

Evaluation of all EAC-confirmed MACE (i.e., including both first and recurrent events) resulted in a consistent pattern with a lower number and rate of events with liraglutide (735 events and 4.12 events per 100 PYO) compared with placebo (870 events and 4.90 events per 100 PYO).

Sensitivity analyses The robustness of the primary analysis was supported by the results of the pre-specified sensitivity analyses which consistently showed statistically significant differences in favor of liraglutide (Figure 6). The estimated hazard ratios observed for the ‘per protocol’ and the ‘on-treatment’ analyses (defined in Table 5) tended to be lower than that observed for the primary analysis, supporting that the beneficial effect on MACE was related to liraglutide treatment (Figure 6). Analyses adjusting for additional covariates (sex, region, age, diabetes duration, prior cardiovascular events, anti-diabetic medication, smoking history, eGFR) at baseline or adjusting for variation between investigational sites (with or without random country effects) also resulted in hazard ratios consistent with that of the primary analysis, as did an analysis with stratification for severe renal impairment at baseline (Figure 6).

Post hoc analyses including all events occurring through last drug dosing date + 30 days (i.e., also including events occurring during temporary off-treatment periods), excluding deaths with unknown cause, or excluding silent MIs (the latter two to exclude potential impact of uncertainties related to deaths of unknown cause or silent MIs) provided results similar to the primary analysis (Figure 6). Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 43 of 95

Time from randomization to first occurrence of a MACE (composite of cardiovascular death, non-fatal MI [including silent MI] and non-fatal stroke) was analyzed using a Cox proportional hazards model with treatment as factor. Pre- specified sensitivity analyses: for definitions of ‘per protocol’, ‘on-treatment’, ‘on-treatment + 30 days’ and ‘excl. events after end of treatment, refer to Table 5; additional covariates included sex, region, baseline age, diabetes duration at baseline, prior cardiovascular events at baseline, baseline anti-diabetic medication, baseline smoking history and calculated eGFR (per MDRD). Post hoc sensitivity analyses: for definition of ‘MACE on-treatment + 30 days including drug holidays’, refer to Table 5. Abbreviations: CI: confidence interval; eGFR: estimated glomerular filtration rate; FAS: full analysis set; Excl.: excluding; MDRD: modification of diet in renal disease; N: number of patients; %: proportion of patients. Figure 6 Forest plot of treatment contrasts for time to first EAC-confirmed MACE (primary endpoint) and sensitivity analyses of the primary endpoint

Analysis of missing data Two post hoc tipping point analyses evaluated the potential impact of missing data on the result of the primary analysis. In the first analysis, the 12 patients in the liraglutide group with unknown vital status at follow-up (Figure 4) were added in a step-wise fashion under the assumption that they died from cardiovascular death the day after last contact, while the 17 patients in the placebo group (Figure 4) were assumed to be alive. Even after all 12 patients were added in this way, the results remained significant in favor of liraglutide (estimated hazard ratio [HR]: 0.89 [0.79; 0.99]95%CI) and were in line with the outcome for the primary analysis. In the second analysis, all non-completers in the liraglutide group (i.e., patients who were alive at follow-up, but for whom it was unknown if they had experienced a non-fatal MI or non-fatal stroke, plus patients with unknown vital status at follow-up, Figure 4) were added in a step-wise fashion under the assumption that they had had a Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 44 of 95 non-fatal MI or a non-fatal stroke the day after the last contact. In this analysis, 21 of 139 non- completers in the liraglutide group (15%) would need to have experienced an event versus none of the 159 non-completers in the placebo group before superiority was lost (estimated HR: 0.90 [0.81; 1.00]95%CI). The two scenarios applied in the tipping point analyses are inconsistent with the reporting of events observed in the two treatment groups (3.41 and 3.91 events per 100 PYO in the liraglutide and placebo groups, respectively [Table 13]). Thus, the outcomes of both tipping point analyses further support the robustness of the results for the primary endpoint.

6.1.2 Analyses of MACE by subgroups A total of 13 pre-specified exploratory analyses were performed to evaluate the consistency of the treatment effect between liraglutide and placebo in time to first MACE across subgroups (by baseline demographic and prognostic disease characteristics including baseline renal function and heart failure status). The effects of the subgroups (main effect and interaction with treatment) on time to first MACE were explored separately by adding them to the original model. The trial was not sufficiently powered to detect small or moderate differences between subgroups and no adjustment for multiplicity was made. Hence, these subgroup analyses should be interpreted with caution.

As shown in Figure 7, the benefit observed with liraglutide compared to placebo for time to first MACE was generally consistent across the majority of the pre-specified exploratory subgroups with the exception of: patients from region ‘North America’ and patients enrolled based on the inclusion criterion #3b (cardiovascular [CV] risk factors and age ≥ 60 years). These subgroups are discussed below. Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 45 of 95

a Defined by the inclusion criterion #3, refer to Table 1. Age, BMI, HbA1c, diabetes duration, chronic heart failure (NYHA class II or III), antidiabetic therapy and renal function values are at baseline. The p-value is from the test statistic for testing the interaction between treatment and factor. Abbreviations: BMI: body mass index; CI: confidence interval; CKD: chronic kidney disease; CVD: cardiovascular disease; EAC: event adjudication committee; eGFR: estimated glomerular filtration rate; MDRD: modification of diet in renal disease; N: number of patients; NYHA: New York Heart Association; OAD: oral antidiabetic drug; %: proportion of patients. Figure 7 Forest plot of treatment contrasts for to time to first EAC-confirmed MACE according to pre-specified exploratory subgroups Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 46 of 95

MACE by region As shown in Figure 7, the estimated hazard ratio for patients from region ‘North America’ (estimated HR: 1.01 [0.84; 1.22]95% CI) appeared higher than that observed in other regions, albeit the 95% CI included the hazard ratio estimate for the primary analysis, and the test for interaction yielded a p-value of 0.20. Further post hoc evaluation indicated that the observation for region ‘North America’ was driven by results in the US compared with Canada. The hazard ratio estimate was 1.03 [0.84; 1.25]95% CI for the US and 0.80 [0.42; 1.52]95% CI for Canada. This observation prompted further investigations of the US population, the largest country in the region comprising 88% of the population from North America.

In subsequent analyses comparing the US population with the trial population outside the US, it was investigated whether any factors related to patient characteristics and clinical management, effectiveness or exposure time to trial product were imbalanced across the populations, and therefore potentially could contribute to the potential differential US observation:  Minor differences were observed for demographics and baseline characteristics, and in use of concomitant medication for the US and non-US populations (Appendix 5, Table 1). However, a series of post hoc analyses found that the difference in the hazard ratios for first MACE observed between the US and non-US populations remained after adjustment for each characteristic listed in Appendix 5, Table 2 and its interaction with treatment.  The rate of first MACE in patients allocated to placebo was similar for the US and non-US populations (3.97 vs 3.89 events per 100 PYO, respective), indicating no differences in background cardiovascular risk profile between the populations.  No clear difference in treatment responses between the US and non-US populations for changes

in the liraglutide effectiveness parameters HbA1c, body weight, or SBP was observed (Appendix 5, Table 3).  Analyses of exposure time to trial product showed that the mean proportion of time on trial product was lower in the US population (73%) than in the non-US population (87%). Correspondingly, the proportion of patients on trial product decreased more over time in the US population than in the non-US population in both treatment groups (Figure 8). Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 47 of 95

Full analysis set. Abbreviations: US: United States. Figure 8 Percentage of patients on treatment over time for US and non-US populations

The above suggested that the lower time on trial product in the US population compared to populations outside the US may contribute to the observed regional differences in MACE. Therefore, to further explore the impact of this, post hoc sensitivity analyses of time to first MACE (analogous to those performed for the primary analysis) were performed for the US population. As shown in Figure 9, the results from these analyses investigating the impact of time on trial product all provided estimated hazard ratios < 1 in line to those observed for the primary analysis. Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 48 of 95

Time from randomization to first event was analyzed using a Cox proportional hazards model with treatment as factor. For definitions of ‘per protocol’, ‘on-treatment’ and ‘on-treatment + 30 days, refer to Table 5. Abbreviations: CI: confidence interval; EAC: event adjudication committee; FAS: full analysis set; N: number of patients; %: proportion of patients; US: United States. Figure 9 Forest plot of treatment contrasts for time to first EAC-confirmed MACE in the US population

In summary, the pre-specified subgroup analysis of time to first MACE by region provided no strong evidence to support a regional difference (p for interaction = 0.20). Further analyses of the data for the US population (comprising 88% of the region ‘North American’ population) showed that exposure time to trial product was lower for the US compared to the non-US populations. On- treatment analyses of time to first MACE yielded hazard ratio estimates in the US consistent with that of the overall population. This supports that the US population is not different from the overall population with respect to cardiovascular risk reduction with liraglutide.

MACE by inclusion criterion #3 Patients eligible for enrolment were to be at high risk for cardiovascular events according to inclusion criterion #3a (established cardiovascular disease [CVD] or CKD and age ≥ 50 years) and inclusion criterion #3b (CV risk factors and age ≥ 60 years). These cardiovascular enrichment criteria were applied to achieve the required number of MACEs as well as the number of patients with moderate (eGFR ≥ 30 to < 60 ml/min/1.73m2 per MDRD) and severe (eGFR < 30 ml/min/1.73m2 per MDRD) renal impairment (the latter two per FDA request; Section 3.4). Thus, the criteria were not intended to represent two clinically distinct patient groups at-risk for cardiovascular events. The cardiovascular enrichment criteria resulted in inclusion of a clinically relevant high cardiovascular risk population, which represented patients who could benefit from either primary or secondary cardiovascular disease prevention.26

As shown in Figure 7, the estimated hazard ratio of time to first MACE in patients enrolled based on the inclusion criterion #3a (established CVD or CKD and age ≥ 50 years; estimated HR: 0.83 Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 49 of 95

[0.74; 0.93]95% CI) resembled that for the primary analysis, while the estimated hazard ratio of time to first MACE was > 1 for the patients enrolled based on the inclusion criterion #3b (CV risk factors and age ≥ 60 years; estimated HR: 1.20 [0.86; 1.67]95% CI). The 95% CI for this patient subgroup included the hazard ratio estimate for the primary analysis, and the test for interaction yielded a p-value of 0.04.

To investigate the potential difference in the estimated hazard ratios of time to first MACE by inclusion criterion #3 subgroups, additional analyses were performed as presented below:  No other demographics and baseline characteristics and use of concomitant medication (as summarised in Appendix 5, Table 4) could explain the potential difference.  Approximately 70% and 75% of the patients enrolled based on the inclusion criteria #3a (established CVD or CKD and age ≥ 50 years) and #3b (CV risk factors and age ≥ 60 years), respectively, were exposed to trial product for 90% or more of the observation time. This indicates that the difference could not be explained by exposure time to trial product.  No clear difference in treatment responses between the respective subgroups for changes in

liraglutide effectiveness parameters HbA1c, body weight, or SBP was observed (Appendix 5, Table 5).  Post hoc on-treatment sensitivity analyses (for definitions, refer to Table 5) of patients enrolled based on the inclusion criterion #3b (CV risk factors and age ≥ 60 years) did not result in higher estimated hazard ratios compared to the primary subgroup analysis, as could be expected if treatment with liraglutide was associated with cardiovascular harm (‘on-treatment’ analysis: estimated HR: 1.04 [0.70; 1.54]95%CI; ‘on-treatment + 30 days’ analysis: estimated HR: 1.16 [0.80; 1.69]95%CI).

Of note, the patient group enrolled based on the inclusion criterion #3b (CV risk factors and age ≥ 60 years) accounted for only ~19% of the patients in the trial (1,742 out of 9,340 patients) and, consistent with a group with less advanced disease, for only ~10% of all first MACEs (137 out of 1,302 first MACEs). Thus, the observed effect of liraglutide in this subgroup may be related to the imprecision in the point estimate.

T2DM and the related risk of cardiovascular disease represent a continuum during which patients are at increasing risk for cardiovascular events as they become older and the atherosclerosis progresses. As mentioned above, LEADER included patients who covered this spectrum. Exploratory post hoc analyses of time to first MACE based on a relevant clinical distinction between patients with or without a medical history of non-fatal MI or stroke both resulted in estimated hazard ratios < 1 favoring liraglutide (Figure 10). This supports the benefits of liraglutide in both primary and secondary prevention of cardiovascular disease. Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 50 of 95

Time from randomization to first event was analyzed using a Cox proportional hazards model with treatment as factor. Prior non-fatal MI or stroke is based on cardiovascular history from the case report form with positive response for MI, ischemic stroke or hemorrhagic stroke. Abbreviations: CI: confidence interval; FAS: full analysis set; MI: myocardial infarction; N: number of patients; %: proportion of patients. Figure 10 Forest plot of treatment contrasts for time to first EAC-confirmed MACE by prior non-fatal MI or stroke at baseline

The beneficial effect of liraglutide for primary prevention is further supported by results from the post hoc meta-analysis of MACE based on the phase 2/3a trials in the clinical development program for liraglutide in T2DM, which included trial populations not enriched for cardiovascular events.

This analysis resulted in an estimated hazard ratio of 0.73 [0.38 1.41]95%CI with liraglutide versus all comparators (metformin, glimepiride, rosiglitazone, insulin glargine, placebo).16 This result is consistent with a beneficial effect of liraglutide also in patients at lower risk for cardiovascular events.

In summary, the hazard ratio estimate observed for time to first MACE in patients enrolled based on the inclusion criterion #3b (CV risk factors and ≥ 60 years) was based on patients with relatively few events due to less advanced disease. On-treatment analyses of time to first MACE did not yield higher hazard ratio estimates as compared with that for the main analysis of this subgroup, suggesting that the observed point estimate did not reflect cardiovascular harm with liraglutide treatment. Based on a clinically acknowledged cardiovascular risk stratification of patients with or without a medical history of non-fatal MI or stroke, further analyses of the data provided hazard ratio estimates < 1 for time to first MACE by this patient categorization. Although these observations arise from post hoc analyses, these data support a cardiovascular benefit of liraglutide in both primary and secondary cardiovascular prevention. Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 51 of 95

6.2 Expanded MACE and individual components of expanded MACE

6.2.1 Expanded MACE Expanded MACE was pre-defined as a secondary endpoint and included the three components of MACE as well as hospitalization for unstable angina pectoris (UAP), coronary revascularization, and hospitalization for heart failure.

A total of 2,010 first EAC-confirmed expanded MACEs were identified in LEADER (948 in the liraglutide group and 1,062 in the placebo group).

In line with the results for the primary MACE analysis, the estimated risk of experiencing a first expanded MACE was reduced by 12% (estimated HR: 0.88 [0.81; 0.96]95%CI) with liraglutide compared to placebo, further confirming the cardio-protective effect of liraglutide (Figure 11 and Figure 12). All components of expanded MACE had a hazard ratio < 1 and hence contributed to the reduced cardiovascular risk (Figure 11).

Further details on individual components of expanded MACE are presented in Section 6.2.2. Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 52 of 95

Expanded MACE is the composite of cardiovascular death, non-fatal MI [including silent MI], non-fatal stroke, hospitalization for UAP, coronary revascularization and hospitalization for heart failure. Time from randomization to first event was analyzed using a Cox proportional hazards model with treatment as factor. For the time to first event of any individual component of expanded MACE, all first events are included regardless of whether these contribute to the time-to-first event analysis of the composite endpoint. Abbreviations: CI: confidence interval; EAC: event adjudication committee; FAS: full analysis set; MI: myocardial infarction; N: number of patients; %: proportion patients; UAP: unstable angina pectoris. Figure 11 Forest plot of treatment contrasts for time to first EAC-confirmed expanded MACE and individual components of expanded MACE Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 53 of 95

Full analysis set. Expanded MACE is the composite of cardiovascular death, non-fatal MI [including silent MI], non- fatal stroke, hospitalization for UAP, coronary revascularization and hospitalization for heart failure. Time from randomization to first event was analyzed using a Cox proportional hazards model with treatment as factor. Abbreviations: CI: confidence interval; EAC: event adjudication committee; HR: hazard ratio; UAP: unstable angina pectoris. Figure 12 Kaplan-Meier plot of time to first EAC-confirmed expanded MACE

Evaluation of all expanded MACE (i.e., including both first and recurrent events) resulted in a consistent pattern with a lower number and rate of events with liraglutide (1,721 events and 9.66 events per 100 PYO) compared with placebo (1,958 events and 11.04 events per 100 PYO).

6.2.2 Individual components of expanded MACE The statistical analyses of the individual components included all first events for each of the expanded MACE components.

The estimated risk of cardiovascular death was reduced by 22% (estimated HR: 0.78 [0.66; 0.93]95%CI) with liraglutide compared to placebo (Figure 11 and Figure 13). A post hoc ‘on- treatment’ analysis, including only patients who died from cardiovascular causes while on randomized treatment provided a lower estimated hazard ratio (estimated HR: 0.74 [0.56; 0.96]95% CI) than that for the pre-specified analysis, supporting a treatment effect of liraglutide on cardiovascular death. In addition, a post hoc analysis of cardiovascular death excluding deaths with unknown cause (estimated HR: 0.75 [0.61; 0.93]95% CI) was consistent with the results from the pre- specified analysis of cardiovascular death. Further details on cardiovascular death are presented in Section 6.3.

The hazard ratio estimates for the other individual components, including non-fatal MI and non-fatal stroke, were below 1 (Figure 11 and Figure 13).

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The impact of missing data on the estimated treatment effect for all-cause death was investigated by performing a post hoc tipping point analysis. This analysis remained significantly in favor of liraglutide when up to 11 of the 12 patients with unknown vital status in the liraglutide group (Figure 4) were considered dead versus none in the placebo group. Statistically significant superiority was only lost when all 12 patients in the liraglutide group without vital status at follow- up were included as dead (estimated HR: 0.87 [0.76, 1.00]95% CI). This further supports the robustness of the results for the pre-specified analysis for all-cause death.

Cardiovascular death Time to EAC-confirmed cardiovascular death is discussed in Section 6.2.2.

Table 15 provides an overview of the cause of EAC-confirmed cardiovascular death. If an EAC- confirmed MI or stroke occurred in a patient with an EAC-confirmed cardiovascular death, the EAC Chair evaluated whether any of these events precipitated the cardiovascular death. In such instances the deaths were designated as ‘death due to EAC-confirmed MI’ or ‘death due to EAC- confirmed stroke’. For cardiovascular deaths not classified as ‘death due to EAC-confirmed MI’ or ‘death due to EAC-confirmed stroke’ by the EAC Chair, a plausible cause of death was provided by each of the two adjudicators evaluating the death. This information was reviewed and sub- categorized by the Sponsor after database lock according to the cardiovascular death categories defined in the EAC Charter (Appendix 3). The most frequent causes of these deaths were ‘sudden cardiac death’ and ‘death due to heart failure or cardiogenic shock’ in both treatment groups. Across the sub-categories, the number of patients within each sub-category were either lower with liraglutide compared to placebo or similar between the treatment groups (Table 15).

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Full analysis set. Time from randomization to first event analysis was analyzed using a Cox proportional hazards model with treatment as factor. Abbreviations: CI: confidence interval; EAC: event adjudication committee; HR: hazard ratio. Figure 16 Kaplan-Meier plot of time to EAC-confirmed non-cardiovascular death

Similar to cardiovascular deaths, the plausible cause of death provided by the EAC for the non- cardiovascular deaths was classified by the Sponsor after database lock according to the non- cardiovascular death categories defined in the EAC charter. Based on this, the most frequently reported causes of non-cardiovascular deaths were death due to malignancy (1.4% in each group) or infection including sepsis (0.8% and 0.9% with liraglutide and placebo, respectively) with no evident differences between the treatment groups (Appendix 5, Table 6).

6.4 Heart rate Consistent with previous clinical experience with liraglutide1, an increase in mean resting heart rate of approximately 3 bpm was observed in LEADER. This increase was evident from the first assessment of heart rate at month 6 (see Sections 8 and 8.2). Additionally, a higher proportion of patients in the liraglutide group had an increase in heart rate of ≥ 10 bpm at month 6 compared to patients in the placebo group (1,435 patients [30.7%] vs 750 patients [16.1%]).

To investigate the potential impact of increases in heart rate on cardiovascular safety, exploratory post hoc analyses of time-to-first EAC-confirmed MACE and time-to-first EAC-confirmed hospitalization for heart failure by categorical heart rate change were performed. In both analyses, the results were consistent between the categorical heart rate change subgroups (change in heart rate at month 6 by < 10 bpm and ≥ 10 bpm) as the proportion of patients with first MACE or hospitalization for heart failure was consistently lower in the liraglutide group compared to the placebo group (Figure 17). Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 60 of 95

Full analysis set. Time to first event was analyzed using a Cox proportional hazards model. Only first events occurring after month 6 were included in the analysis. Abbreviations: bpm: beats per minute; CI: confidence interval; N: number of patients; %: proportion of patients. Figure 17 Forest plot of treatment contrasts for time to first EAC-confirmed MACE and EAC-confirmed hospitalization for heart failure occurring after month 6 by categorical heart rate change

No imbalance was observed for events related to cardiac arrhythmia reported by the investigators (presented in Section 9.2.8). Hence, in addition to the overall results on MACE and expanded MACE, these data support that the increase in resting heart rate observed with liraglutide was not associated with adverse cardiovascular outcomes.

Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 62 of 95 one of the criteria defining nephropathy or retinopathy events. Thus, a single event could count in more than one of the analyses of the individual components of the microvascular composite.

The analysis of time to first EAC-confirmed microvascular event resulted in an estimated hazard ratio of 0.84 [0.73; 0.97]95%CI, corresponding to an estimated risk reduction of 16% in the liraglutide group compared to the placebo group. The difference between the treatment groups was largely due to a reduced risk of ‘new onset of persistent macroalbuminuria’(Figure 18).

Microvascular composite is the composite of the nephropathy and retinopathy endpoints. Time from randomization to first event was analyzed using a Cox proportional hazards model with treatment as factor. a Persistent doubling of serum creatinine and eGFR ≤ 45 mL/min/1.73m2 per MDRD. b One (1) patient in the placebo group had 1 EAC- confirmed event of ‘diabetes-related blindness’ versus zero events in the liraglutide group; therefore, the analysis of the component ‘diabetes-related blindness’ is not included in the plot. Abbreviations: CI: confidence interval; EAC: event adjudication committee; eGFR: estimated glomerular filtration rate; FAS: full analysis set. MDRD: modification of diet in renal disease; N: number of patients; %: proportion of patients. Figure 18 Forest plot of treatment contrasts for time to first EAC-confirmed microvascular composite endpoint and its components

Evaluation of all EAC-confirmed microvascular events (i.e., including both first and recurrent events) resulted in a consistent pattern with a lower number and rate of events with liraglutide (429 events and 2.41 events per 100 PYO) compared with placebo (474 events and 2.67 events per 100 PYO). Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 63 of 95

7.2 Nephropathy As shown in Figure 18, the analysis of the time to first EAC-confirmed nephropathy event resulted in an estimated hazard ratio of 0.78 [0.67; 0.92]95%CI, corresponding to a risk reduction of 22% in the liraglutide group compared with the placebo group. To ensure that transient and/or reversible changes in albuminuria or in renal function were not included in the analyses, the EAC Charter (Appendix 3) required confirmatory measurements for nephropathy events (i.e., ‘new onset of persistent macroalbuminuria’ and ‘persistent doubling of serum creatinine and eGFR ≤ 45 mL/min/1.73m2’) and excluded acute reversible causes for ‘need for continuous renal replacement therapy’. The relatively short duration of LEADER in the context of renal disease progression, together with the fact that the majority (approximately 77%) of the patients had normal renal function or only mild renal impairment (eGFR ≥ 60 to < 90 ml/min/1.73m2 per MDRD) at baseline, may explain why the risk reduction in the nephropathy composite was driven mainly by the component ‘new onset of persistent macroalbuminuria’ (Figure 18). Albuminuria is considered a clinically useful tool for predicting prognosis of progression of diabetic kidney disease27 and a reduction in albuminuria has been shown to correlate significantly with a subsequent reduced risk of end-stage renal disease.28

Evaluation of all EAC-confirmed nephropathy events (i.e., including both first and recurrent events) resulted in a consistent pattern with a lower number and rate of events with liraglutide (299 events and 1.68 events per 100 PYO) compared with placebo (369 events and 2.08 events per 100 PYO).

Renal safety as evaluated based on renal laboratory parameters and adverse events related to acute renal failure is discussed in Section 9.2.5.

7.3 Retinopathy As shown in Figure 18, the analysis of the time to first EAC-confirmed retinopathy event resulted in an estimated hazard ratio of 1.15 [0.87; 1.52]95%CI. Analyses of the components ‘need for retinal photocoagulation or treatment with intravitreal agents’ and ‘vitreous hemorrhage’ each resulted in hazard ratios > 1 with liraglutide versus placebo. One event of ‘diabetes-related blindness’ occurred in the placebo group.

The number and rate of events of all EAC-confirmed retinopathy events (i.e., including both first and recurrent events) were higher with liraglutide (130 events and 0.73 events per 100 PYO) than with placebo (105 events and 0.59 events per 100 PYO).

The majority of the events fulfilling the criterion ‘vitreous hemorrhage’ also fulfilled the criterion ‘need for retinal photocoagulation or treatment with intravitreal agents’, reflecting the clinical practice of treating vitreous hemorrhage with photocoagulation or intravitreal agents. To address this overlap, a post hoc time to event analysis investigating the effect of liraglutide on events of ‘need for retinal photocoagulation or treatment with intravitreal agents’ that did not also fulfil the criterion ‘vitreous hemorrhage’ was conducted. This analysis resulted in an estimated hazard ratio Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 64 of 95

of 1.02 [0.74; 1.41]95% CI, indicating that the observed imbalance in the retinopathy composite was driven solely by events of vitreous hemorrhage.

In both treatment groups, the majority of patients with events of vitreous hemorrhage had a medical history of diabetic retinopathy (liraglutide: 75.0%; placebo: 86.4%), a diabetes duration ≥ 15 years at baseline (liraglutide: 71.9%; placebo: 63.6%), and poor baseline glycemic control (HbA1c ≥ 8.5%; liraglutide: 53.1%; placebo: 54.5%), all of which represent risk factors for retinal complications and which reflect the natural history of diabetic retinopathy. 29 In patients with poor glycemic control, diabetic retinopathy may worsen temporarily with (rapid) improvement in glycemic control following insulin treatment.30,31 In both treatment groups, the majority of first events of vitreous hemorrhage occurred within the initial 12−18 months of the trial, with the rates declining thereafter (Appendix 5, Figure 1). This pattern could thus be consistent with some vitreous hemorrhage events having been induced by a rapid decline in blood glucose in both treatment groups. Of note, mean HbA1c at baseline in patients with events of vitreous hemorrhage was higher in the liraglutide group (9.2%) than in the placebo groups (8.7%), and the initial mean decline in HbA1c was greater with liraglutide than with placebo (Appendix 5, Figure 1).

Specifically for liraglutide, no safety concern related to adverse events of retinopathy in general, or vitreous hemorrhage in particular, has emerged based on pooled data of previous completed clinical trials with liraglutide in T2DM (Appendix 5, Table 7). Furthermore, no treatment-related effects associated with the eye were observed in the extensive non-clinical development program for liraglutide, including 2-year carcinogenicity studies in rodents. Apart from LEADER, the PMR for Victoza® also included a 5-year prospective observational cohort study evaluating the safety of Victoza® when used in clinical practice. This study was based on the Optum Research Database, a US commercial health insurance claims database. Based on a comparison of initiators of liraglutide with propensity scored matched cohorts of initiators of exenatide, DPP-4i, metformin, SUs, or pioglitazone, respectively, this study showed no evidence of an increased risk of diabetic retinopathy in liraglutide initiators (Appendix 5, Table 8). Furthermore, based on monitoring of post-marketing reports received for liraglutide, only few cases of diabetic retinopathy have been reported (Appendix 5, Table 7).

In summary, the low incidence of patients with events of vitreous hemorrhage and the small imbalance between the treatment groups in LEADER (32 vs 22 patients) precludes firm conclusions. Taking into account the timing of events, the natural history of diabetic retinopathy, the absence of a signal based on previous liraglutide clinical and non-clinical data, and the extensive post-marketing experience with Victoza® including a large medical claims database study, a direct effect of liraglutide treatment on vitreous hemorrhage does not appear likely.

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Full analysis set. Abbreviations: CI: confidence interval; HR: hazard ratio; OAD: oral antidiabetic drug. Figure 20 Time to first initiation of insulin or any new OAD

8.2 Other cardiometabolic parameters In LEADER, liraglutide resulted in a greater reduction in body weight compared with placebo at year 3. The weight loss observed in liraglutide patients was maintained at end of treatment (Table 17).

Liraglutide resulted in a greater reduction in SBP compared with placebo at year 3. The treatment difference for SBP was maintained at end of treatment (Table 17). DBP was also reduced from baseline in both treatment groups at 3 years, but the reduction was smaller in the liraglutide group than in the placebo group (Table 17). Consistent with US prescribing information,1 treatment with liraglutide in LEADER was associated with an increase in heart rate of approximately 3 bpm (Table 17). Additional information on heart rate in relation to cardiovascular risk in LEADER is presented in Section 6.4.

At year 3, the liraglutide group had greater reductions in total cholesterol and LDL and a greater increase in HDL compared with placebo. However, only the treatment difference for HDL was maintained at end of treatment (Table 17). The decreases in triglycerides were comparable between treatment groups at year 3 and at the end of treatment (Table 17).

Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 73 of 95 permanently were evaluated. The proportion of patients with SAEs or non-serious MESIs leading to permanent treatment discontinuation was higher in the liraglutide group (9.6%) compare d to the placebo group (7.3%). A lower proportion of patients in the liraglutide group (4.2%) as compared to the placebo group (5.3%) reported SAEs leading to permanent treatment discontinuation; thus the overall higher proportion of patients with an event leading to permanent treatment discontinuation in the liraglutide group was attributable to non-serious events.

More SAEs or non-serious MESIs leading to permanent treatment discontinuation were observed during the first few months of the trial in the liraglutide group compared to the placebo group, after which there was no difference between the treatment groups (Figure 22).

Full analysis set. Abbreviations: SAE: serious adverse events; MESI: medical event of special interest. Figure 22 SAEs or non-serious MESIs leading to permanent treatment discontinuation

The observed treatment difference in SAEs or non-serious MESIs leading to permanent treatment discontinuation was mainly attributable to a higher incidence of events within the SOC Gastrointestinal disorders (mainly as ‘nausea’, ‘vomiting’ and ‘diarrhoea’) in the liraglutide group (4.1%) compared to the placebo group (1.2%) (Figure 23). SAEs or non-serious MESIs leading to permanent treatment discontinuation in other SOCs were of low frequency (≤ 1.1%). Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 74 of 95

Full analysis set. Abbreviations: MESI: medical event of specific interest; N: number of patients; %: proportion of patients with events; SAE: serious adverse event. Figure 23 The 20 most common SAEs or non-serious MESIs leading to permanent treatment discontinuation by preferred term

9.2 Selected safety areas

9.2.1 Overview Long-term effects of liraglutide on neoplasms including MTC and its biomarker calcitonin, pancreatitis, renal safety, hypoglycemia, and immunological reactions were also required to be assessed in LEADER per the PMR (see Section 3.4). These safety areas are further detailed in subsections below. Furthermore, assessments of the effect of liraglutide on other event types given specific attention for safety, including acute gallbladder disease and events related to cardiac arrhythmias are presented.

A summarized overview of the results for the selected safety areas discussed is provided in Table 19. For results on hypoglycemia refer to Section 9.2.6.

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Full analysis set. The proportions (%) are calculated based on the number of female patients only for breast, cervical/vaginal, uterine and ovarian neoplasms, and based on the number of male patients only for malignant prostate neoplasms only. Estimated hazard ratios are derived from the Cox model with treatment as only covariate. Abbreviations: CI: confidence interval; EAC: event adjudication committee; N: number of patients; %: proportion of patients. Figure 24 Incidences of EAC-confirmed overall, benign, and malignant neoplasms and malignant neoplasms by tissue type

As per the EAC charter (Appendix 3), a pathological diagnosis, either by histology or cytology, was considered of foremost importance for confirmation of neoplasm events, albeit other source documentation could be used. This ensured an adjudication process of high specificity for the confirmation of a neoplasm, but potentially with lowered sensitivity. To evaluate the robustness of the result of malignant neoplasms, additional supportive post hoc analyses of investigator-reported adverse events of malignant neoplasms captured with the standardized MedDRA query (SMQ) ‘malignant tumors’ were performed, including an analysis of events that were not confirmed by the EAC neoplasm subcommittee as malignant neoplasm events. The overall distribution of investigator-reported malignancies was similar to the distribution of EAC-confirmed malignant neoplasms (Appendix 5, Table 15).Investigator-reported malignancies not confirmed by the EAC were overall well-balanced, though there was a treatment discordance in the frequency of non- confirmed malignant pancreatic neoplasms (presented in below subsection) (Appendix 5, Table 16).

In summary, the results for neoplasms did not support an increased risk of overall, malignant or benign neoplasms associated with liraglutide treatment. Due to concerns raised during the original

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Full analysis set. Figure displays first EAC-confirmed malignant events only. Roman numbers in plot represent stage of the malignant event according to the AJCC staging system.34 Stage was unknown (marked as ‘Unk’) for one malignant event in the liraglutide group. Abbreviations: AJCC: American Joint Committee on Cancer; EAC: event adjudication committee; Unk: unknown. Figure 25 Kaplan-Meier plot of time to onset and stage of first EAC-confirmed malignant pancreatic neoplasm

Based on the analysis of investigator-reported adverse events of malignant neoplasms (as presented above), 4 additional potential malignant pancreatic neoplasms were identified (all occurring in the placebo group) which were not confirmed by the EAC neoplasm subcommittee. Details of these 4 cases are provided in Appendix 5, Table 18 and summarized in the following. Histopathology was not available for any of the 4 cases. Imaging documenting suspicious lesions in the pancreas was present for all 4 cases, and for 3 of the 4 cases relevant tumor markers were noted. The outcome of all 4 events was fatal. These deaths were confirmed as non-cardiovascular deaths by the EAC cardiovascular subcommittee, with the plausible cause of death being either malignancy or pancreatic cancer (based on clinical judgment; no strict diagnostic criteria were required).

Given that pancreatic cancer is a rare cancer type, an evaluation of other data sources than LEADER was assessed for completeness. No safety concern related to malignant pancreatic neoplasms has emerged based on pooled data of previous completed clinical trials with liraglutide in T2DM, though this was only based on few events (Appendix 5, Table 19). Apart from LEADER, the PMR for Victoza® also included a 5-year prospective observational cohort study evaluating the safety of Victoza® when used in clinical practice. This study was based on the Optum Research Database, a US commercial health insurance claims database. Based on a comparison of more than 35,898 initiators of liraglutide with a propensity scored matched cohort of initiators of other antidiabetic agents, this study showed no evidence of an increased risk of pancreatic cancer in liraglutide initiators. The intention-to-treat analysis using Poisson regression models resulted in a rate ratio of 0.6 [0.3; 1.3]95% CI for liraglutide versus comparator agents (metformin, SUs, pioglitazone) (Appendix 5, Table 19). Furthermore, based on monitoring of post-marketing reports

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Full analysis set. Abbreviations: EAC: event adjudication committee. Figure 26 Kaplan-Meier plot of time to first EAC-confirmed acute pancreatitis

A medical history of pancreatitis was not an exclusion criterion in LEADER and a total of 267 patients with a medical history of pancreatitis (acute or chronic) were enrolled in the trial; of these, 2 out of 147 patients (1.4%) in the liraglutide group and 6 out of 120 patients (5.0%) in the placebo group had an EAC-confirmed event of acute pancreatitis during the trial.

An increase in geometric mean lipase and amylase levels from baseline to end of treatment was observed in the liraglutide group, which is consistent with previous observations with liraglutide. 42,43,44 The post hoc statistical analyses (MMRM; liraglutide vs placebo) of the ratio of the 3-year lipase or amylase values to baseline values resulted in estimated treatment ratios of 1.28 [1.25; 1.30]95% CI and 1.07 [1.06; 1.09]95% CI, corresponding to a 28% and 7% greater increase in lipase and amylase, respectively in the liraglutide group than in the placebo group. Few patients in either treatment group with at least one post-baseline lipase or amylase value ≥ 3upper limit normal (ULN) or ≥ 1×ULN had an event of acute pancreatitis, with no notable differences between the treatment groups (Table 22).

Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 85 of 95 treatment groups, the event of acute gallbladder disease led to hospitalization (liraglutide: 91 of 145 patients; placebo: 56 of 90 patients) and for approximately 56% of the patients in both treatment groups, the event resulted in surgery (liraglutide: 81 of 145 patients; placebo: 52 of 90 patients). Thus, while an increased risk of developing acute gallbladder disease was observed with liraglutide, the clinical implications for the individual patients with an event did not seem to differ between the treatment groups.

In summary, an imbalance in acute gallbladder disease (cholelithiasis and cholecystitis) disfavoring liraglutide was observed in LEADER. This finding is consistent with observations from the liraglutide for weight management clinical development program at higher dose (liraglutide 3.0 mg; Saxenda®). A similar imbalance was not observed in the liraglutide for T2DM clinical development program which may be due to the shorter duration of the trials in this program and differences in the trial populations when compared to that in LEADER. The increased risk of gallbladder disorders is already reflected in the adverse reactions section of the Victoza® prescribing information, and findings from LEADER are consistent with the current label language.

To explore the mechanism for the increased incidence of gallbladder-related events with liraglutide, a mechanistic study to assess the effects of liraglutide on gallbladder emptying is currently ongoing as a PMR for Saxenda®.

9.2.5 Renal safety Renal safety was evaluated based on renal laboratory parameters (UACR, serum creatinine and eGFR) and events potentially related to acute renal failure captured by a MedDRA search among all SAEs or non-serious MESIs (see Appendix 4 for details on search terms).

Table 24 shows the results from statistical analyses (MMRM) of the ratio of the 3-year UACR, serum creatinine and eGFR per MDRD values to baseline, respectively (the statistical analyses were performed post hoc for UACR and serum creatinine). The increase in UACR was smaller in the liraglutide group compared to the placebo group, with an estimated treatment difference of 19%. Small treatment differences were observed for serum creatinine (1% smaller increase with liraglutide) and eGFR (2% smaller decline with liraglutide), indicating less renal deterioration in the liraglutide group than in the placebo group (Table 24). In Appendix 5, Table 20 results for renal laboratory parameters across subgroups defined by baseline renal function (normal renal function [eGFR ≥ 90 mL/min/1.73m2], mild [eGFR ≥ 60 to < 90 mL/min/1.73m2], moderate [eGFR ≥ 30 to < 60 mL/min/1.73m2] or severe [eGFR < 30 mL/min/1.73m2] renal impairment; eGFR per MDRD) are provided. These were overall consistent with the results for the overall population.

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9.2.7 Immunogenicity Consistent with the immunogenic properties of protein and peptide pharmaceuticals, patients exposed to liraglutide may develop immune responses including development of anti-liraglutide antibodies. Immunogenicity was evaluated based on events of allergic reaction, injection site reaction and immune complex disease, respectively, captured by pre-specified MedDRA searches among all SAEs or non-serious MESIs (see Appendix 4 for details on search terms). Further, in US patients, anti-liraglutide antibodies were assessed, including assessment for in vitro neutralizing effect.

In both treatment groups, events of allergic reactions (1.3% and 0.9% with liraglutide and placebo, respectively) occurred at low incidences (Table 19). There were no notable differences between the treatment groups for the most frequently reported events which included ‘angioedema’ (liraglutide: 0.1%; placebo: 0.2%),‘drug hyper sensitivity‘ (liraglutide: 0.1%; placebo: <0.1%) and ‘rash’ (liraglutide: 0.1%; placebo: <0.1%). A total of 3 SAEs (2 events with liraglutide and 1 event with placebo) of ‘anaphylactic reaction’ were reported. All 3 patients recovered and an alternative etiology existed for all 3 events (multiple wasp stings, cinnamon and sesame seeds).

The incidence of injection site reactions was low both with liraglutide (0.7%) and with placebo (0.3%) (Table 19). The most frequently reported events included ‘injection site reaction’ (liraglutide: 9 events; placebo: 2 events), ‘injection site erythema’ (liraglutide: 6 events; placebo: zero events) and ‘injection site pruritus’ (liraglutide: 5 event; placebo: 1 event).

Events of immune complex disease were few and occurred at similar incidences in the treatment groups (<0.1% and 0.2% with liraglutide and placebo, respectively) (Table 19). The 3 events reported in the liraglutide group included ‘polymyalgia rheumatica’, ‘chronic pigmented purpura’ and ‘granulomatosis with polyangiitis’.

A total of 11 out of 1,247 patients (0.9%) with antibody measurements had low-level anti- liraglutide antibodies to liraglutide (titres < 9%B/T for all positive samples). None of the patients had antibodies with in vitro neutralizing effect. The observed immunogenic response to treatment with liraglutide impacted neither glycemic effectiveness nor the frequency of immunogenicity- related AEs.

In summary, the incidence of events related to immunogenicity was low, and the findings from LEADER are consistent with current label language.

9.2.8 Cardiac arrhythmia Consistent with previous clinical experience with liraglutide in T2DM1 an increase in mean resting heart rate of approximately 3 bpm associated with liraglutide was observed in LEADER (presented in Section 8.2). Events potentially related to cardiac arrhythmia were evaluated based on events captured by a MedDRA search among all SAEs or non-serious MESIs (see Appendix 4 for details

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10 Benefit-risk discussion and conclusions Cardiovascular disease is the leading cause of morbidity and mortality in patients with T2DM 2,3 and there is therefore a large unmet medical need for therapeutic agents which may concomitantly reduce the risk of cardiovascular disease while ensuring good glycemic control.

LEADER was designed and conducted in accordance with the 2008 FDA guidance for evaluating cardiovascular risk in new antidiabetic therapies.6 As a meta-analysis of data from the previous liraglutide in T2DM clinical development program suggested a cardiovascular benefit associated 16 with liraglutide (estimated HR: 0.73 [0.38; 1.41]95% CI) , the LEADER trial was designed to evaluate not only non-inferiority, but also superiority of liraglutide to placebo for the primary endpoint time to first MACE (composite of cardiovascular death, non-fatal MI and non-fatal stroke). In the context of the cardiovascular risk reductions provided by well-defined and well- executed standard of care therapy, liraglutide was superior to placebo in reducing the risk of first MACE in patients with T2DM at high cardiovascular risk with an estimated clinically relevant risk reduction of 13% (estimated HR: 0.87 [0.78; 0.97]95% CI). With these results, the requirements set forth in the 2008 FDA guidance were fulfilled. The result for MACE was consistent across all pre- specified sensitivity analyses, and across a large number of pre-specified subgroups. The estimated risk of expanded MACE (primary MACE composite, in addition to hospitalization for UAP, hospitalization for heart failure or coronary revascularization) was reduced by 12% with liraglutide compared to placebo, with all individual components showing estimated hazard ratios < 1, further supporting the robustness of the results for the composite MACE endpoint. Specifically, the risk of cardiovascular death was lowered by 22% with liraglutide compared to placebo (estimated HR: 0.78 [0.66; 0.93]95% CI). The beneficial effect of liraglutide on cardiovascular death was also reflected in the related secondary endpoint all-cause death (estimated HR: 0.85 [0.74; 0.97]95% CI). Importantly, these cardiovascular benefits of liraglutide in LEADER were observed in a clinically relevant targeted T2DM subpopulation at high risk for cardiovascular events. This population represented patients in need of primary or secondary cardiovascular disease prevention.

The LEADER trial design, including choice of primary endpoint and targeted at-risk population, was applicable to a trial designed to evaluate cardiovascular effectiveness.47,48 Further supporting the robustness of the MACE result, the LEADER trial was characterized by a high patient retention (> 99%) ensuring a low amount of missing data for the primary endpoint, and was of sufficient duration ensuring substantial exposure to trial drug and accrual of a large number of MACE events. Hence, LEADER was an adequate and well-conducted trial and is considered sufficient to demonstrate the effect of liraglutide on the risk of cardiovascular events. Furthermore, the MACE result from LEADER was consistent with the previous clinical experience with liraglutide from clinical programs in T2DM16 and in weight management (liraglutide 3.0 mg; Saxenda®; estimated 49 HR: 0.33 [0.12; 0.90]95% CI). Therefore, based on the extensive and robust results from LEADER, Novo Nordisk proposes to add an additional indication to the existing indication for Victoza® to include that in adults with T2DM and high cardiovascular risk, liraglutide is indicated as an adjunct Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 92 of 95 to standard treatment of cardiovascular risk factors to reduce the risk of MACE (cardiovascular death, non-fatal MI or non-fatal stroke).

Liraglutide as compared with placebo was associated with a 22% risk reduction in the nephropathy composite (estimated HR: 0.78 [0.67; 0.92]95% CI), while no improvement in the retinopathy composite was shown (estimated HR: 1.15 [0.87; 1.52]95% CI). Also, treatment with liraglutide provided substantial and sustained improvements in glycemic control. The effect of liraglutide on HbA1c was accompanied by a reduced likelihood of initiating additional antidiabetic therapies including insulin, and with a lower rate of severe hypoglycemia as compared with placebo. In addition, liraglutide was associated with greater and sustained reductions in body weight and SBP compared with placebo.

The safety results for liraglutide in LEADER reaffirmed the well -established safety profile from the clinical development program for liraglutide in T2DM and the extensive exposure to Victoza® post- marketing. Liraglutide was generally safe and well-tolerated but was, as expected, associated with a higher frequency of gastrointestinal adverse events. While a higher incidence of acute gallbladder disease was observed with liraglutide compared with placebo, this finding is consistent with observations from the liraglutide for weight management clinical development program at higher dose (liraglutide 3.0 mg; Saxenda®), and is already reflected in the current Victoza® prescribing information.1 In addition, the results supported the long-term safe use of liraglutide with respect to areas of uncertainty at the time of the NDA approval, including pancreatitis and neoplasms. The risk of pancreatitis was similar between the two treatment groups, and was not impacted by observed increases in lipase and amylase levels. The incidences of malignant neoplasms were comparable between the treatment groups with a well-balanced distribution across various tissue types. A potential association between GLP-1 RAs, including liraglutide, and development of MTC (no cases with liraglutide) was not supported by the LEADER data. The potential risk of MTC will continue to be monitored in the ongoing national MTC registry in the US (a Victoza® PMR; includes all approved long-acting GLP-1 RAs). Further, despite a numerical imbalance observed between the liraglutide and placebo groups in the frequency of malignant pancreatic neoplasms (13 vs 5 patients with confirmed events, respectively), the totality of data (including non-clinical studies, clinical trials and post-marketing experience with liraglutide) does not support an increased risk associated with liraglutide treatment. Considering the rarity of pancreatic cancer, surveillance and monitoring of this malignancy will continue through routine pharmacovigilance.

The LEADER results also supported the efficacious and safe use of liraglutide in particularly vulnerable patient groups which has previously not been well studied and for whom treatment options are limited, including: elderly ≥ 75 years of age, patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2 per MDRD), and patients with heart failure (NYHA classes I−III).

11 References

1. Novo Nordisk A/S. Victoza® (liraglutide), US prescribing information (PI). 22 Apr 2016. 2. American Diabetes Association. 9. Cardiovascular Disease and Risk Management. Diabetes Care. 2017;40 (Suppl. 1):S75-S87. 3. International Diabetes Federation. IDF Diabetes Atlas 7th edition. 2015. 4. Gregg EW, Li Y, Wang J, Burrows NR, Ali MK, Rolka D, et al. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med. 2014;370(16):1514-23. 5. Di Angelantonio E, Kaptoge S, Wormser D, Willeit P, Butterworth AS, Bansal N, et al. Association of Cardiometabolic Multimorbidity With Mortality. JAMA. 2015;314(1):52 -60. 6. Food and Drug Administration, CDER. Guidance for Industry. Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Trial Type 2 Diabetes. Dec 2008. 7. Food and Drug Administration, CDER, CBER. Guidance for Industry: Determining the Extent of Safety Data Collected Needed in Late-Stage Premarket and Postapproval Clinical Investigations. 2012. 8. Food and Drug Administration, CDER, CBER. Guidance for Industry: Determining the Extent of Safety Data Collected Needed in Late-Stage Premarket and Postapproval Clinical Investigations. 2016. 9. Drucker DJ. The Cardiovascular Biology of Glucagon-like Peptide-1. Cell Metab. 2016;24(1):15-30. 10. Gaspari T, Liu HB, Welungoda I, Hu YS, Widdop RE, Knudsen LB, et al. A GLP-1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE(-/-) mouse model. Diab Vasc Dis Res. 2011;8(2):117-24. 11. Gaspari T, Welungoda I, Widdop RE, Simpson RW, Dear AE. The GLP-1 receptor agonist liraglutide inhibits progression of vascular disease via effects on atherogenesis, plaque stability and endothelial function in an ApoE(-/-) mouse model. Diab Vasc Dis Res. 2013;10(4):353-60. 12. Davidson MH. Cardiovascular effects of glucagonlike peptide-1 agonists. Am J Cardiol. 2011;108(3 Suppl):33B-41B. 13. National Center for Chronic Disease Prevention and Health Promotion. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014. Atlanta,GA: US Department of Health and Human Services: 2014. 14. US Department of Health and Human Services, Centers for Disease Control and Prevention. Atlanta, GA. National Diabetes Facts Sheet: National estimates and general information on diabetes and prediabetes in the United States, 2016. 15. U.S.Department of Health and Human Services, Centers for Disease Control and Prevention. Atlanta, GA. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014. 16. Marso SP, Lindsey JB, Stolker JM, House JA, Martinez Ravn G, Kennedy KF, et al. Cardiovascular safety of liraglutide assessed in a patient-level pooled analysis of phase 2-3 liraglutide clinical development studies. Diab Vasc Dis Res. 2011;8(3):237-40. 17. World Medical Association. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, Fortaleza, Brazil. October 2013. Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 94 of 95

18. ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R1), Current Step 4 version , including the Post Step 4 corrections. 10 Jun 1996. 19. Food and Drug Administration. Code of Federal Regulations (21 CFR 312.120) Foreign clinical studies not conducted under an IND. 1 Apr 2013. 20. Food and Drug Administration, CDER. Standardized Definitions for Cardiovascular Outcomes Trials: Draft Recommendations. Division of Metabolism and Endocrinology Products. 22 Jul 2009. 21. Food and Drug Administration, CDER. Standardized Definitions for Endpoint Events Cardiovascular Trials: Draft Recommendations. 20 Oct 2010. 22. Gerstein HC, Miller ME. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-59. 23. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008; 358(24):2560-72. 24. Hung HM, Wang SJ. Multiple testing of noninferiority hypotheses in active controlled trials. J Biopharm Stat. 2004;14(2):327-35. 25. EMEA: Points to consider on switching between superiority and non-inferiority (CPMP/EWP/482/99). 27 July 2000. 26. Hobbs FDR. Cardiovascular disease: Different strategies for primary and secondary prevention?. Heart. 2004;90:1217-1223. 27. Tuttle KR, Bakris GL, Bilous RW, Chiang JL, de Boer IH, Goldstein-Fuchs J, et al. Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes Care. 2014;37(10):2864-83. 28. Heerspink HJ, Kröpelin TF, Hoekman J, de Zeeuw D, Consortium RAaSER. Drug-Induced Reduction in Albuminuria Is Associated with Subsequent Renoprotection: A Meta-Analysis. J Am Soc Nephrol. 2015;26(8):2055-64. 29. Wong TY, Cheung CM, Larsen M, Sharma S, Simó R. Diabetic retinopathy. Nat Rev Dis Primers. 2016;2:1-16. 30. Dahl-Jørgensen K, Brinchmann-Hansen O, Hanssen KF, Sandvik L, Aagenaes O. Rapid tightening of blood glucose control leads to transient deterioration of retinopathy in insulin dependent diabetes mellitus: the Oslo study. Br Med J (Clin Res Ed). 1985;290(6471):811-5. 31. van Ballegooie E, Hooymans JM, Timmerman Z, Reitsma WD, Sluiter WJ, Schweitzer NM, et al. Rapid deterioration of diabetic retinopathy during treatment with continuous subcutaneous insulin infusion. Diabetes Care. 1984;7(3):236-42. 32. Egan AG, Blind E, Dunder K, de Graeff PA, Hummer BT, Boucier T, et al. Pancreatic safety of incretin-based drugs—FDA and EMA assessment. N Engl J Med. 2014;370(9):794-7. 33. Constante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S, et al. Predictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab. 2007;92(2):450-5. 34. Edge S, Byrd D, Compton C, Fritz A, Greene F, Trotti A, et al. AJCC cancer staging manual. 7th ed. New York: Springer. 2010. 35. Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467(7319):1114-7. Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 95 of 95

36. Lewis JD, Habel LA, Quesenberry CP, Strom BL, Peng T, Hedderson MM, et al. Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes. JAMA. 2015;314(3):265-77. 37. Brodovicz KG, Kou TD, Alexander CM, O’Neill EA, Engel SS, Girman CJ, et al. Impact of diabetes duration and chronic pancreatitis on the association between type 2 diabetes and pancreatic cancer risk. Diabetes Obes Metab. 2012;14(12):1123-8. 38. Johnson JA, Bowker SL, Richardson K, Marra CA. Time-varying incidence of cancer after the onset of type 2 diabetes: evidence of potential detection bias. Diabetologia. 2011;54(9):2263-71. 39. Nyborg NC, Molck AM, Madsen LW, Knudsen LB. The human GLP-1 analog liraglutide and the pancreas: evidence for the absence of structural pancreatic changes in three species. Diabetes. 2012;61(5):1243-9. 40. Vrang N, Jelsing J, Simonsen L, Jensen AE, Thorup I, Soeborg H, et al. The effects of 13 wk of liraglutide treatment on endocrine and exocrine pancreas in male and female ZDF rats: a quantitative and qualitative analysis revealing no evidence of drug-induced pancreatitis. American Journal of Physiology-Endocrinology and Metabolism. 2012;303(2):E253-E64. 41. Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, et al. Classification of acute pancreatitis-2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62(1):102-11. 42. Steinberg W, DeVries JH, Wadden TA, Jensen CB, Svendsen CB, Rosenstock J. Longitudinal Monitoring of Lipase and Amylase in Adults With Type 2 Diabetes and Obesity: Evidence From Two Phase 3 Randomized Clinical Trials With the Once-Daily GLP-1 Analog Liraglutide. Gastroenterology. 2012;142(5):S850-S1. 43. Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjøth TV, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA. 2015; 314(7):687-99. 44. Rosenstock J, Rodbard HW, Bain SC, D’Alessio D, Seufert J, Thomsen AB, et al. One-year sustained glycemic control and weight reduction in type 2 diabetes after addition of liraglutide to metformin followed by insulin detemir according to HbA1c target. J Diabetes Complication s. 2013;27(5):492-500. 45. Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 2005;28(5):1245-9. 46. UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia. 2007;50(6):1140-7. 47. Food and Drug Administration, CDER, CBER. Guidance for Industry. Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products. May 1998. 48. European Medicines Agency. Points to consider on application with 1. meta-analyses; 2. one pivotal study (CPMP/EWP/2330/99). 31 May 2001. 49. Novo Nordisk A/S. Saxenda®, (liraglutide), EU Summary of Product Characteristics (SmPC). 31 Mar 2016 Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017

Novo Nordisk

Victoza® (liraglutide) injection LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results

NDA 22341 S-027

Briefing Document Appendix 1

Membership on LEADER Committees and Panels

Endocrinologic and Metabolic Drug Advisory Committee

June 20, 2017

Advisory Committee Briefing Materials: Available for Public Release Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 2 of 6

Table of Contents Page Table of Contents...... 2 1 LEADER committee/panel members ...... 3 1.1 LEADER Steering Committee members ...... 3 1.2 LEADER Data Monitoring Committee members ...... 3 1.3 LEADER Global Expert Panel ...... 4 1.4 LEADER Calcitonin Monitoring Committee members ...... 5 1.5 LEADER Event Adjudication Committees ...... 5 1.5.1 Event Adjudication Committee Chairperson ...... 5 1.5.2 Cardiology Event Adjudication Committee members ...... 5 1.5.3 Microvascular Event Adjudication Committee members ...... 6 1.5.4 Pancreatitis Event Adjudication Committee members ...... 6 1.5.5 Neoplasm Event Adjudication Committee members ...... 6 1.5.6 Electrocardiogram reviewers ...... 6

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1 LEADER committee/panel members

1.1 LEADER Steering Committee members  Richard Bergenstal, Park Nicollet Institute, International Diabetes Center, Minneapolis, MN, USA  John Buse, The University of North Carolina School of Medicine, Chapel Hill, NC, USA  Gilbert Daniels, Massachusetts General Hospital, Boston, MA, USA  Johannes Mann, Friedrich Alexander University of Erlangen, Erlangen, Germany  Steven Marso, UT Southwestern, Clinical Heart Center, Dallas, TX, USA  Michael Nauck, Medizinishe Klinik, St Josef Hospital (Ruhr-UniversitätBochum), Bohum, Germany  Steven Nissen, Cleveland Clinic, Cleveland, OH, USA  Stuart Pocock, London School of Hygiene and Tropical Medicine, London, UK  Neil Poulter, International Centre for Circulatory Health, Imperial College, London, UK  William Steinberg, George Washington University Medical Center, MD, USA  Bernard Zinman, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada  Kirstine Brown Frandsen, Novo Nordisk A/S, Søborg, Denmark  Peter Kristensen, Novo Nordisk A/S, Søborg, Denmark (2015-2016)  Alan Charles Moses, Novo Nordisk A/S, Søborg, Denmark (2009-2014)  Lasse Steen Ravn, Novo Nordisk A/S, Søborg, Denmark (2011-2016)  Mette Stockner, Novo Nordisk A/S, Søborg, Denmark  Marcin Zychma, Novo Nordisk A/S, Søborg, Denmark (2009-2011).

1.2 LEADER Data Monitoring Committee members  Allan Flyvbjerg, Aarhus University, Aarhus, Denmark  Ian Ford, University of Glasgow, Glasgow, United Kingdom  Richard T. Kloos, Veracyte, Inc, South San Francisco, CA, USA  Peter Sleight, John Radcliffe Hospital, Oxford, United Kingdom  Karl Swedberg, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden  Scott M. Tenner, State University of New York, NY, USA

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1.3 LEADER Global Expert Panel  Sema Akalın, Marmara University Medical FacultyIstanbul, Turkey (2010)  Rosario Arechavaleta, Colonia Monraz,Guadalajara, Mexico  Steve Bain, Swansea University Medical School, Swansea, UK  Miguel Camafort Babkowski, Comité Español Interdisciplinario de Prevención Cardiovascular España, Sociedad Española de Medicina Interna, Madrid, Spain (2010–2011)  Marian Benroubi, Athens Polyclinic General Hospital, Athens, Greece  Lori Berard, Health Sciences Centre Winnipeg, University of Manitoba, Winnipeg, Canada  Abdurrahman Comlekci, Dokuz Eylul University, Izmir, Turkey  Leszek Czupryniak, Medical University of Lodz, Lodz, Poland  Björn Eliasson, Sahlgrenska University Hospital, Gothenburg, Sweden  Mats Eriksson, Karolinska University Hospital, Stockholm, Sweden  Vivian Fonseca, Tulane University Health Sciences Center, New Orleans, LA, USA  Edward Franek, Central Clinical Hospital MSW, Warsaw, Poland  Jorge Gross, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil  Khadija Hafidh, Rashid Hospital, Dubai, United Arab Emirates  Martin Haluzik, Charles University, Praha, Czech Republic  Frances Hayes, Dept. of Endocrinology, St. Vinent's University Hospital, Dublin , Ireland (2010-2013)  Yu-Yao Huang, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan  Stephan Jacob, Kardio Metabolischen Instituts, Villingen-Schwenningen, Germany  Linong Ji, Peking University People’s Hospital, Beijing, China  Ghaida Kaddaha, Rashid Hospital, Dubai, United Arab Emirates (2011-2014)  Ali Khalil, Center for Diabetes and Endocrinology, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates (2010)  Bente Kilhovd, Oslo University Hospital, Oslo, Norway  Markku Laakso, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland  Lawrence Leiter, St. Michael's Hospital, University of Toronto, Toronto, Canada  Nebojsa Lalic, University Medical Center and Belgrade School of Medicine, Belgrade, Serbia  Joerg Luedemann, Medicine and Nutrition Diabetes and Foot Care Centre, Falkensee, Germany  Eduardo Mannucci, Diabetes Section Geriatric Unit, Careggi Hospital, Florence, Italy  Michel Marre, Groupe Hospitalier Bichat, Paris, France  Luis Masmiquel, Universitat de les Illes Balears, Palma de Mallorca, Spain  Maria Mota, University of Medicine and Pharmacy of Craiova, Craiova, Romania  Mahomed Omar, Nelson R Mandela School of Medicine, University of KwaZulu Natal, South Africa  Donal O’Shea, St Vincent’s Hospital, Dublin, Ireland Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 5 of 6

 Changyu Pan, Chinese PLA General Hospital, Beijing, China  John Petrie, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK  Thomas Pieber, Medical University of Graz, Graz, Austria  Richard Pratley, Florida Hospital, Diabetes Institute, Orlando, FL, USA  Itamar Raz, Hadassah Hebrew University Hospital, Jerusalem, Israel  Rosangela Rea, Clinical Hospital of the Federal University of Parana, Curitiba, Brazil  Guy Rutten, University Medical Center Utrecht, Utrecht, The Netherlands  Ilhan Satman, Istanbul University, Istanbul, Turkey  Marina Shestakova, Endocrinology Research Centre and M.I., Sechenov First Moscow State Medical University, Moscow Russia  Richard Simpson, Eastern Clinical Research Unit, Monash University and Eastern Health, Victoria, Australia  Diarmuid Smith, Beaumont Hospital, Dublin, Ireland  Cornelis Tack, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands  Lise Tarnow, Nordsjællands Hospital, Hillerød, Denmark  Nihal Thomas, Endocrinology, Diabetes and Metabolism, Christian Medical College and Hospital, Vellore, Tamil Nadu, India  Luc Van Gaal, Antwerp University Hospital, Antwerp, Belgium  Florence Travert, Groupe Hospitalier Bichat, Paris, France (2010-2015)  Josep Vidal, Hospital Clínic de Barcelona, Barcelona, Spain  Mark Warren, Endocrinology and Metabolism Physicians East, PA, Greenville, SC, USA  Kun-Ho Yoon, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea

1.4 LEADER Calcitonin Monitoring Committee members  Robert Michael Tuttle, Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, Brewster, NY, USA  Stephen I. Sheerman, The University of Texas MD Anderson Cancer Center, Houston, TX, USA  Laszlo Hegedüs, Odense University Hospital, Odense, Denmark

1.5 LEADER Event Adjudication Committees

1.5.1 Event Adjudication Committee Chairperson  C. Michael Gibson, Harvard Medical School, Boston, MA, USA

1.5.2 Cardiology Event Adjudication Committee members  Anjan K. Chakrabarti, Eastern Virginia Medical School, Chesapeake, VA, USA Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 6 of 6

 John Francis Dashe, St. Elizabeth’s Medical Center, Boston/Waltham, MA, USA  Judith Hinchey, St. Elisabeth’s Medical Center, Boston, MA, USA  Megan Carroll Leary, Lehigh Valley Hospital, Allentown, PA, USA  Yuri Pride, Gwinnett Medical Center, Lawrenceville, GA, USA  Steve Wiviott, Brigham and Women’s Hospital, Boston, MA, USA

1.5.3 Microvascular Event Adjudication Committee members  Samuel Allen, Tallman Eye Association, Lawrence, MA, USA  Ali Poyan Mehr, Beth Israel Deaconess Medical Center, Boston, MA, USA  Walter P. Mutter, Newton-Wellesley Hospital, Newton, MA, USA  Samir Parikh, Harvard Medical School, Newton, MA, USA  Subhransu Ray, Bay Area Retina Associates, CA, USA

1.5.4 Pancreatitis Event Adjudication Committee members  Adam Cheifetz, Beth Israel Deaconess Medical Center, Boston, MA, USA  Daniel Leffler, Beth Israel Deaconess Medical Center, Boston, MA, USA  Sunil Sheth, Beth Israel Deaconess Medical Center, Boston, MA, USA

1.5.5 Neoplasm Event Adjudication Committee members  Erik Alexander, Brigham and Women’s Hospital, Boston, MA, USA  Jason L. Gaglia, Harvard Medical School, Boston, MA, USA  Wolfram Goessling, Harvard Medical School, Boston, MA, USA  Carol Rosenberg, Harvard Vanguard/ Boston University School of Medicine, Boston, MA, USA  Andrew Wagner, Dana-Farber Cancer Institute, Boston, MA, USA

1.5.6 Electrocardiogram reviewers  Sameer Bansilal, TMI Study Group, Boston, MA, USA  Clifford J. Berger, Steward Physician Group, Brockton, MA USA  Anjan K. Chakrabarti, Cardiovascular Associates, Chesapeake, VA, USA  Nihar Desai, Brigham and Women’s Hospital, Boston, MA, USA  Travis Hinson, Brigham and Women’s Hospital, Boston, MA, USA  Payal Kohli, TMI Study Group, Boston, MA, USA  David E. Leeman, Beth Israel Deaconess Medical Center, Boston, MA, USA  Venkatesh L. Murthy, Brigham and Women’s Hospital, Boston, MA, USA  Benjamin A. Olenchock, Brigham and Women’s Hospital, Boston, MA, USA  Gregory Piazza, Brigham and Women’s Hospital, Boston, MA, USA  Yuri Pride, Gwinnett Medical Center, Lawrenceville, GA, USA Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017

Novo Nordisk

Victoza® (liraglutide) injection LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results

NDA 22341 S-027

Briefing Document Appendix 2

LEADER Inclusion and Exclusion Criteria

Endocrinologic and Metabolic Drug Advisory Committee

June 20, 2017

Advisory Committee Briefing Materials: Available for Public Release Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 2 of 5

Table of Contents Page Table of Contents...... 2 1 Patient selection criteria ...... 3 1.1 Inclusion criteria ...... 3 1.2 Exclusion criteria ...... 4

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1 Patient selection criteria

1.1 Inclusion criteria The following inclusion criteria were specified in the protocol and amendments:

1. Informed consent obtained before any trial-related activities. (Trial-related activities were any procedure that would not have been performed during normal management of the subject) 2. Men or women with type 2 diabetes 3. Age ≥ 50 years at screening and at least one of the below criteria (from a to h below): a) prior myocardial infarction b) prior stroke or prior transient ischemic attack (TIA) c) prior coronary, carotid or peripheral arterial revascularization d) >50% stenosis on angiography or other imaging of coronary, carotid or lower extremity arteries e) history of symptomatic coronary heart disease documented by positive exercise stress test or any cardiac imaging, or unstable angina with ECG changes f) asymptomatic cardiac ischemia documented by positive nuclear imaging test or exercise test or dobutamine stress echo g) chronic heart failure NYHA class II-III h) chronic renal failure, having clinically reached a stage corresponding to a glomerular filtration rate < 60 mL/min/1.73 m2 per Modification of Diet in Renal Disease (MDRD) or < 60 mL/min per Cockroft-Gault formula OR

Age ≥ 60 years at screening and meeting at least one of the below criteria (from i to l below) i) microalbuminuria or proteinuria j) hypertension and left ventricular hypertrophy by ECG or imaging k) left ventricular systolic or diastolic dysfunction by imaging l) ankle/brachial index <0.9

4. Antidiabetic drug naïve or treated with one or more oral antidiabetic drugs or treated with human NPH insulin or long-acting insulin analogue or premixed insulin, alone or in combination with OAD(s) 5. HbA1c ≥ 7.0% at screening

Note that subjects who were randomized in error because they did not meet the age criterion at the time of screening (violating inclusion criterion 3) should discontinue trial products and could be reintroduced on originally randomized treatment when reaching the required age.

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1.2 Exclusion criteria The following exclusion criteria were specified in the protocol and amendments:

1. Type 1 diabetes 2. Use of a GLP-1 receptor agonist (exenatide, liraglutide or other) or pramlintide or any DPP-4 inhibitor within the 3 months prior to screening 3. Use of insulin other than human NPH insulin or long-acting insulin analogue or premixed insulin within 3 months prior to screening. Short-term use of other insulin during this period in connection with intercurrent illness was allowed, at Investigator’s discretion 4. Acute decompensation of glycemic control requiring immediate intensification of treatment to prevent acute complications of diabetes (e.g., diabetes ketoacidosis) in the previous 3 months 5. An acute coronary or cerebrovascular event in the previous 14 days 6. Currently planned coronary, carotid or peripheral artery revascularization 7. Chronic heart failure NYHA class IV 8. Current continuous renal replacement therapy 9. Estimated glomerular filtration rate (eGFR) (as per MDRD) < 30 mL/min/1.73 m2 at screening. The criterion was applicable after a target number of 220 subjects with eGFR < 30 mL/min/1.73 m2 were randomized 10. End stage liver disease, defined as the presence of acute or chronic liver disease and recent history of one or more of the following: ascites, encephalopathy, variceal bleeding, bilirubin ≥ 2.0 mg/dL, albumin level ≤ 3.5 g/dL, prothrombin time ≥ 4 seconds prolonged, international normalized ratio (INR) ≥1.7 or prior liver transplant 11. A prior solid organ transplant or awaiting solid organ transplant 12. Malignant neoplasm requiring chemotherapy, surgery, radiation or palliative therapy in the previous 5 years. Patients with intraepithelial squamous cell carcinoma of the skin (Bowen’s disease) treated with topical 5-fluorouracil and subjects with basal cell skin cancer were allowed to enter the trial 13. Family or personal history of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma 14. Personal history of non-familial medullary thyroid carcinoma 15. Any acute condition or exacerbation of chronic condition that would in the Investigator's opinion interfere with the initial trial visit schedule and procedures 16. Known or suspected hypersensitivity to trial product(s) or related products 17. Known use of non-prescribed narcotics or illicit drugs 18. Simultaneous participation in any other clinical trial of an investigational drug. Participation in a clinical trial with investigational stent(s) was allowed 19. Previous participation in this trial. Participation is defined as randomized 20. Females of childbearing potential who were pregnant, breast-feeding or intended to become pregnant or were not using adequate contraceptive methods (adequate contraceptive measures as required by local law or practice) UK: Adequate contraceptive measures are defined as Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 5 of 5

established use of oral, injected or implanted hormonal methods of contraception, sterilization, intrauterine device or intrauterine system, or consistent use of barrier methods. Germany: Adequate contraceptive measures are implants, injectables, combined oral contraceptives, hormonal IUD (intrauterine device), sexual abstinence or vasectomized partner. Mexico: Adequate contraceptive measures are defined as birth control pills, Depo-Provera, Norplant, an hormonal IUD, a diaphragm with spermicide or abstinence. Condom with spermicide must be used during sexual intercourse. Romania: Adequate contraceptive measures are defined as established use of oral, injected or implanted hormonal methods of contraception, sterilization, intrauterine device or intrauterine system, or consistent use of barrier methods 21. Receipt of any investigational medicinal product (IMP) within 30 days prior to this trial. Brazil: receipt of any investigational drug within one year prior to screening visit (visit 1), unless there is a direct benefit to the research subject at the Investigator’s discretion

Subjects discontinuing from randomized treatment due to violation of exclusion criteria 2 and/or 3 (disallowed medication at or less than 3 months before screening) could be reintroduced on randomized treatment according to their original treatment allocation if the disallowed medication was discontinued. In order to avoid a potential carry-over effect of the disallowed medication and to ensure continual antidiabetic treatment, reintroduction to randomized treatment was to be executed after the following wash-out periods:

 1 day for subjects on fast acting insulin or pramlintide  5 days for subjects on once daily GLP-1 analogues or DPP-4 inhibitors  4 weeks for subjects on once weekly GLP-1 analogues

Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017

Novo Nordisk

Victoza® (liraglutide) injection LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results

NDA 22341 S-027

Briefing Document Appendix 3

Definitions and Classifications of Events Sent for EAC Evaluation

Endocrinologic and Metabolic Drug Advisory Committee

June 20, 2017

Advisory Committee Briefing Materials: Available for Public Release Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 2 of 13

Table of Contents Page Table of Contents...... 2 Table of Tables...... 2 1 EAC evaluation definitions and classifications of events ...... 3

Table of Tables Page Table 1 Event definitions and classifications ...... 4 Table 2 Appendix C: Guidance for adjudication of neoplasm events ...... 13 Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 3 of 13

1 EAC evaluation definitions and classifications of events

During the event adjudication committee (EAC) evaluation, individual members of the designated EAC subgroups performed the adjudication based on the definitions and classifications described in Table 1. Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 4 of 13

Table 1 Event definitions and classifications

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* Additional guidance for adjudicating neoplasms is available in Appendix C (Table 2). Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 13 of 13

Table 2 Appendix C: Guidance for adjudication of neoplasm events

Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017

Novo Nordisk

Victoza® (liraglutide) injection LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results

NDA 22341 S-027

Briefing Document Appendix 4

MedDRA Search Criteria

Endocrinologic and Metabolic Drug Advisory Committee

June 20, 2017

Advisory Committee Briefing Materials: Available for Public Release Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 2 of 4

Table of Contents Page Table of Contents...... 2 1 MedDRA search criteria ...... 3 1.1 Acute gallbladder disease ...... 3 1.2 Acute renal failure ...... 3 1.3 Allergic reactions ...... 3 1.4 Injection site reactions ...... 3 1.5 Immune complex disease ...... 3 1.6 Cardiac arrhythmia ...... 4

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1 MedDRA search criteria For the pre-specified medical events of special interests (MESIs) which did not undergo event adjudication, the safety evaluations were based on events captured from pre-specified MedDRA searches among all serious adverse events (SAEs) or non-serious MESIs. For other event types given specific attention for safety, MedDRA searches were similarly made among all SAEs or non- serious MESIs.

The MedDRA search terms for the safety areas presented in the briefing document are included in the below sections. The search was conducted at Preferred Term (PT) level based on the below listed High Level Terms (HLTs) and Standard MedDRA Queries (SMQs). All searches were made using MedDRA version 18.0.

1.1 Acute gallbladder disease  SMQ Functional, inflammatory and gallstone related biliary disorders  SMQ Infectious biliary disorders

1.2 Acute renal failure  SMQ Acute renal failure (narrow terms only)

1.3 Allergic reactions  SMQ Anaphylactic reaction (narrow terms only)  SMQ Anaphylactic/anaphylactoid shock conditions (narrow terms only)  SMQ Angioedema (narrow terms only)  SMQ Severe cutaneous adverse reactions (narrow terms only)  SMQ Hypersensitivity (narrow terms only)

1.4 Injection site reactions  HLT Administration site reactions NEC  HLT Application and instillation site reactions  HLT Infusion site reactions  HLT Injection site reactions

1.5 Immune complex disease  SMQ Systemic lupus erythematous (narrow terms only)  SMQ Vasculitis (narrow terms only)  SMQ Guillain-Barre syndrome (narrow terms only) Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 4 of 4

1.6 Cardiac arrhythmia  SMQ Cardiac arrhythmia (narrow terms only) Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017

Novo Nordisk

Victoza® (liraglutide) injection LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results

NDA 22341 S-027

Briefing Document Appendix 5

Supporting Tables and Figures

Endocrinologic and Metabolic Drug Advisory Committee

June 20, 2017

Advisory Committee Briefing Materials: Available for Public Release Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 2 of 25

Table of Contents Page Table of Contents...... 2 Table of Figures ...... 2 Table of Tables...... 2 1 Supporting tables and figures...... 4

Table of Figures Page

Figure 1 Individual HbA1c curves for patients with first events of EAC-confirmed vitreous hemorrhage ...... 10

Table of Tables Page Table 1 Key patient characteristics – US and non-US populations ...... 4 Table 2 Characteristics evaluated as potential contributors for impact on time to first MACE in US population and non-US populations...... 5

Table 3 Changes in HbA1c, body weight and systolic blood pressure from baseline to year 3 by US and non-US populations ...... 6 Table 4 Key patient characteristics – inclusion criterion #3 subgroups...... 7

Table 5 Change in HbA1c, body weight and systolic blood pressure from baseline to year 3 by inclusion criterion #3 subgroups...... 8 Table 6 Cause of EAC-confirmed non-cardiovascular deaths ...... 9 Table 7 Retinopathy from liraglutide in T2DM clinical trials and post-marketing data...... 11 Table 8 Diabetic retinopathy diagnoses from medical claims database (Optum Research Database study)a,b ...... 11

Table 9 HbA1c (%) change from baseline to year 3 by age group ...... 12

Table 10 HbA1c (%) change from baseline to year 3 by baseline renal function ...... 13

Table 11 HbA1c (%) change from baseline to year 3 by baseline heart failure status...... 14 Table 12 Overview of SAEs or non-serious MESIs by baseline age group...... 15 Table 13 Overview of SAEs or non-serious MESIs by baseline heart failure status...... 15 Table 14 Overview of SAEs or non-serious MESIs by baseline renal function...... 16 Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 3 of 25

Table 15 Investigator-reported SAEs or non-serious MESIs in SMQ ‘Malignant tumors’...... 17 Table 16 Investigator-reported SAEs or non-serious MESIs in SMQ ‘Malignant tumors’ not confirmed by EAC ...... 18 Table 17 Case details – patients with EAC-confirmed malignant pancreatic neoplasms ...... 20 Table 18 Case details – patients with investigator-reported malignant pancreatic neoplasms not confirmed by EAC ...... 22 Table 19 Pancreatic neoplasms from liraglutide in T2DM clinical trials and post-marketing data ...... 23 Table 20 Changes in UACR, serum creatinine and eGFR from baseline to year 3 by baseline renal function...... 24 Table 21 Events of acute renal failure (MedDRA search) by baseline renal function ...... 25

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A. Liraglutide group

B. Placebo group

Each line on the plots represents HbA1c over time for an individual patient. Time points of vitreous hemorrhage are marked. Abbreviations: EAC: event adjudication committee; HbA1c: glycosylated hemoglobin; VH: vitreous hemorrhage.

Figure 1 Individual HbA1c curves for patients with first events of EAC-confirmed vitreous hemorrhage