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Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 1 of 133

Insulin degludec/ (IDegLira)

Treatment to Improve Glycemic Control in Adults with Type 2 Mellitus

NDA 208583

Briefing Document

Endocrinologic and Metabolic Drug Advisory Committee

May 24, 2016

Advisory Committee Briefing Materials: Available for Public Release IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 2 of 133

Table of contents Page Table of contents...... 2 List of abbreviations and definitions ...... 5 1 Executive summary...... 6 2 Introduction...... 21 2.1 Rationale for IDegLira in the treatment of T2DM...... 21 2.2 Development of IDegLira...... 22 3 Product description...... 24 3.1 Key properties of IDegLira...... 24 3.2 Dosage and administration...... 25 4 Nonclinical and toxicology ...... 27 4.1 Overview and nonclinical testing strategy...... 27 4.2 Mode of action...... 27 4.3 Nonclinical efficacy pharmacology of IDegLira ...... 28 4.4 Nonclinical of IDegLira...... 28 4.5 Nonclinical safety pharmacology and toxicology of IDegLira...... 28 4.6 Carcinogenicity assessment for IDegLira...... 29 5 Clinical pharmacology...... 30 5.1 Introduction...... 30 5.2 Pharmacokinetics of IDegLira relative to IDeg and liraglutide...... 31 5.2.1 Single-dose and steady state pharmacokinetics ...... 31 5.2.2 Dose proportionality assessment...... 35 5.2.3 Effect of covariates on exposure...... 36 5.3 Pharmacodynamics and exposure-response...... 38 6 Clinical Efficacy ...... 40 6.1.1 Overview and strategy of the phase 3 trial program ...... 40 6.1.2 Trial designs and endpoints ...... 45 6.1.3 Enrollment criteria ...... 50 6.1.4 Baseline patient characteristics...... 52 6.1.5 Patient disposition...... 53 6.1.6 Statistical Methods...... 56 6.1.7 Efficacy results ...... 58 6.1.7.1 HbA1c...... 58 6.1.7.2 HbA1c target responders ...... 64 6.1.7.3 Fasting plasma ...... 66 6.1.7.4 Postprandial glycemic control...... 68 6.1.7.5 dose ...... 70 6.1.7.6 End-of-trial IDegLira dose and efficacy...... 72 6.1.7.7 Body weight ...... 81 6.1.7.8 Patient-reported outcomes...... 84 6.1.7.9 Efficacy in the U.S. population ...... 85 6.1.8 Persistence of efficacy ...... 87 Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 3 of 133

7 Clinical safety ...... 90 7.1 Safety methods...... 91 7.2 Safety population and exposure...... 92 7.3 Adverse events...... 94 7.3.1 Common adverse events ...... 97 7.3.2 Deaths ...... 99 7.3.3 Serious adverse events...... 99 7.3.4 Adverse events leading to withdrawal ...... 99 7.3.5 Safety areas of special interest...... 102 7.3.5.1 ...... 102 7.3.5.2 Gastrointestinal events ...... 105 7.3.5.3 Pancreatic safety...... 106 7.3.5.4 Cardiovascular safety ...... 108 7.3.5.5 Neoplasms ...... 112 7.3.5.6 Thyroid disease ...... 115 7.3.5.7 Immunogenicity ...... 118 7.3.5.8 Additional adverse event categories...... 119 7.3.5.9 ...... 120 7.4 Adverse events in sub-populations ...... 120 7.5 Drug-drug interactions...... 120 7.6 Post-marketing experience...... 121 8 Plan for continued risk management post-approval...... 122 9 Benefit-risk conclusions...... 125 10 Reference list...... 130 Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 4 of 133

List of appendices

Appendix 1: Summary of characteristics of the individual active components, IDeg and liraglutide

Appendix 2: Results of nonclinical programs for IDeg and liraglutide

Appendix 3: Sensitivity analyses

Appendix 4: Efficacy across subgroups

Appendix 5: Patient-reported outcomes

Appendix 6: Calculation of adjusted AE frequencies and rates

Appendix 7: Event adjudication

Appendix 8: Summary of 120-day safety update

Appendix 9: Safety tables and figures

Appendix 10: Narratives of deaths Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 5 of 133

List of abbreviations and definitions AACE American Association of Clinical Endocrinologists ADA American Diabetes Association AE adverse event ANCOVA analysis of covariance AUC area under the concentration–time curve BMI CI confidence interval Cmax maximum concentration CV cardiovascular DTSQs Diabetes Treatment Satisfaction Questionnaire, status version EAC event adjudication committee EASD European Association for the Study of Diabetes FAS full analysis set FPG fasting plasma glucose GLP-1 RA -like -1 receptor HbA1c glycosylated hemoglobin A1c iAUC incremental area under the concentration–time curve IDeg IDegLira insulin degludec/liraglutide IGlar LOCF last observation carried forward MACE major adverse cardiovascular event MedDRA Medical Dictionary for Regulatory Activities MTC medullary NDA new drug application OAD oral antidiabetic drug OD once daily PYE patient-years of exposure REMS Risk Evaluation and Mitigation Strategy SAE serious adverse event SD standard deviation SF-36v2 Short Form 36 Health Survey, version 2 SOC system class SS steady state SU T2DM mellitus TRIM-D Treatment Related Impact Measure for Diabetes U.S. United States Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 6 of 133

1 Executive summary Several large and comprehensive diabetes outcome studies have demonstrated the importance of tight glycemic control to reduce comorbidities.1-3 Despite the increasing number of therapeutic options available to treat type 2 diabetes mellitus (T2DM), the majority of patients with T2DM nevertheless fail to achieve the recommended levels of glycemic control.4, 5 This may in part be due to insufficient therapeutic response, but may also reflect the treatment barriers associated with current options for intensification of treatment.

Intensification of treatment without adding additional daily injections is an important concept, as adding injections is known from clinical practice to translate into decreased adherence, reduced compliance, reduced satisfaction and clinical inertia. Specifically for the combination of basal insulin and GLP-1 RA, health care providers can be uncertain about how to select the proper starting dose of each of the individual therapies, how to add one of these therapies to the other, and how to titrate each medicine separately. Furthermore, current once-daily options have specific side effects, i.e., hypoglycemia and weight gain with basal insulin therapy and , diarrhea and vomiting with GLP-1 RA therapy, which may represent further barriers for treatment initiation or intensification.

The underlying pathophysiology of T2DM is complex and involves multiple organ systems. The defects include peripheral and progressive relative insulin deficiency as well as impaired secretion and/or action of including GLP-1, leading to the fasting and post-prandial characterizing T2DM.6-8 Optimal glycemic control therefore relies on a multi-faceted treatment approach. One such approach is the combination of basal insulin and GLP-1 RA treatment. The successful outcome of recent trials combining basal insulin and GLP-1 RA treatment as separate injections has led to the inclusion of this treatment combination in the approved labelling for both insulin and GLP-1 RA products.9-19 Thus, concurrent use of insulin and GLP-1 RA is an established treatment regimen and is included in the most recent ADA/EASD position statement on management of hyperglycemia in T2DM.20

Clinical rationale for IDegLira, a fixed ratio combination of two approved drugs IDegLira is a combination of the long-acting basal insulin insulin degludec (IDeg, active substance of Tresiba®), and the GLP-1 analog liraglutide (active substance of Victoza®), each of which have received FDA approval. IDegLira is intended for improvement of glycemic control in adults with T2DM via once-daily . IDegLira is being developed to provide the combined benefits of the two components in a single daily injection.

Basal insulin treatment has the inherent limitation of not addressing fluctuations in insulin demand such as those resulting from meal intake. In contrast, GLP-1 RA treatment stimulates insulin secretion and inhibits glucagon secretion in a glucose-dependent manner when plasma glucose levels are above normal, and this mechanism of action is therefore complementary to that of basal Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 7 of 133 insulin. As shown from the IDegLira clinical development program, the simultaneous introduction of liraglutide to insulin degludec therapy as done with IDegLira adds the benefit of lowering prandial glucose excursions via liraglutide’s glucose-dependent mechanism of action. This allows further improvements in overall glycemic control with IDegLira relative to basal insulin treatment while titrating to equivalent fasting plasma glucose (FPG) targets. Furthermore, the undesired risks of hypoglycemia and weight gain associated with insulin therapy are counteracted. Compared to GLP-1 RA monotherapy, the lower starting dose and more gradual increase in liraglutide dose with IDegLira gives rise to fewer and milder gastrointestinal side effects.

Overall, the combination of IDeg and liraglutide in this titratable product harnesses the complementary actions of insulin and GLP-1 RA to yield clinically relevant improvements in glycemic control relative to either of the components individually, while at the same time addressing the treatment barriers of insulin (hypoglycemia and weight gain) and GLP-1 RA (nausea, diarrhea and vomiting).

Once-daily dosing and simple titration IDegLira is dosed using a pre-filled pen containing a fixed IDeg/liraglutide ratio of 100 units/3.6 mg per mL. The dose of IDegLira is titrated based on fasting plasma glucose, using a simple titration algorithm similar to current practice for basal insulin therapy. The pre-filled pen allows for dose adjustments in increments of 1 unit IDeg and 0.036 mg liraglutide. The fixed IDeg/liraglutide ratio ensures that as the dose of IDegLira is increased or decreased, the ratio between the two components does not change. The dose range is from 1 to 50, with the maximum dose allowed by the device corresponding to 50 units of IDeg and 1.8 mg of liraglutide (Figure 1–1).

Figure 1–1 Principle of dose adjustment for the IDegLira fixed ratio product Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 8 of 133

The number shown on the pen will be the dose prescribed for the patient, as exemplified in Figure 1–2 for an IDegLira dose of 10.

Figure 1–2 Example of IDegLira dose

As applied consistently in the phase 3 trial program, the starting dose of IDegLira is 10 (corresponding to 10 units of IDeg and 0.36 mg liraglutide) in patients initiating IDegLira as add-on to OADs and 16 (corresponding to 16 units IDeg and 0.6 mg liraglutide) when converting from basal insulin or GLP-1 RA treatment. Furthermore, the convenience of administering both components in a single daily injection at any time of the day, using a titration scheme similar to that used for basal insulin products, is expected to facilitate achievement of treatment goals.

Overview of development program The development strategy for IDegLira builds upon the extensive nonclinical and clinical data obtained in the individual development programs that supported the FDA approvals of IDeg (Tresiba®) and liraglutide (Victoza®).

The pharmacokinetics of the components of IDegLira were consistent with those of IDeg and liraglutide when dosed individually, allowing cross-reference to the extensive nonclinical, clinical pharmacology and clinical safety data for the components. For each component of IDegLira, the concentration profile at steady state exhibited exposure coverage over the 24-hour dosing interval, which is consistent with the proposed once-daily administration.

The completed phase 3 program included in the new drug application (NDA) for IDegLira comprises five phase 3 trials, which included a total of approximately 3500 patients with T2DM. The clinical development program was designed to demonstrate superiority on HbA1c reduction with IDegLira versus each of the components (pivotal trials) and to further support use of IDegLira in adult patients with T2DM inadequately controlled on OADs, basal insulin or GLP-1 RA (additional trials).

In accordance with regulatory guidelines for combination therapeutic products,21, 22 two pivotal trials (Trial 3697 in patients inadequately controlled on OAD treatment and Trial 3912 in patients inadequately controlled on basal insulin treatment) were designed to assess the contribution of the individual components of the combination to its primary efficacy effect (i.e., overall glycemic control as reflected in change in HbA1c). Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 9 of 133

 The superiority hypothesis of Trial 3697 was superiority in HbA1c reduction with IDegLira relative to liraglutide, thereby confirming the contribution of the IDeg component of IDegLira to overall glycemic control.

 The primary hypothesis of Trial 3912 was superiority in HbA1c reduction with IDegLira relative to IDeg limited to 50 units (i.e., equivalent to the maximum dose of the IDeg component with IDegLira), thereby confirming the contribution of the liraglutide component of IDegLira to overall glycemic control.

The three additional phase 3 trials (Trials 3951, 3952 and 3851) expanded the investigation of IDegLira in different populations of subjects with T2DM and against other comparator treatments. The completed phase 3 trial program covers the spectrum of proposed use of IDegLira in T2DM, from initiation of injectable therapy in OAD-treated patients (Trials 3697 and 3951) to treatment intensification in insulin-treated patients (Trials 3912 and 3952) or GLP-1 RA-treated patients (Trial 3851) at a more advanced stage of diabetes. An overview of the five completed phase 3 trials is provided in Figure 1–3.

Figure 1–3 Overview of completed phase 3 trials included in the NDA for IDegLira Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 10 of 133

All phase 3 trials were randomized, controlled, parallel-group, multicenter, multinational treat-to-target trials of 26 weeks duration. The treatment period of the pivotal Trial 3697 in patients inadequately controlled on OAD treatment was further extended to 52 weeks for demonstration of persistence of efficacy and long-term safety during extended exposure (hereafter labelled Trial 3697-ext when referring to the entire 52-week treatment period). A ‘treat-to-target’ concept was applied for IDegLira and basal insulin treatment arms of all phase 3 trials, applying the same titration algorithm in all trials.

Clinical efficacy 23 HbA1c is the most widely accepted biomarker of overall, long-term glycemic control, and accordingly the primary endpoint for all phase 3 trials was change in HbA1c from baseline to week 26. In addition, a number of key secondary efficacy endpoints were pre-specified for the phase 3 trial program. An overview of efficacy endpoints including adjustments for multiplicity is provided in Table 6–3.

The results for the primary and key secondary endpoints are presented below. The results were comprehensively evaluated in sensitivity analyses that used various approaches to handling missing data. The applied sensitivity analyses included a repeated measurements analysis (which assumed that data were missing at random), two multiple imputation analyses (in which missing data from the IDegLira group were imputed with data from the comparator arm, hence assuming that data were not missing at random), as well as a tipping point analysis. As shown for the individual efficacy endpoints in Section 6.1.7, the results of the applied sensitivity analyses were similar to those for the pre-specified last-observation-carried-forward (LOCF) approach.

HbA1c The two pivotal trials 3697 and 3912 were designed in accordance with regulatory guidelines21, 22 to confirm the contribution of the individual components of IDegLira to the primary efficacy effect of IDegLira as reflected in change in HbA1c. This objective was achieved by showing superiority relative to the components as outlined below.

 The pivotal trial 3697 was designed to confirm the contribution of the IDeg component of IDegLira to the primary efficacy effect as reflected in change in HbA1c. IDeg and liraglutide comparator treatments were dosed according to product label, with liraglutide dosed at the maximum dose level recommended for the treatment of T2DM. From a mean baseline HbA1c of 8.3% in all groups, HbA1c had on average decreased by 1.91%-point to 6.4% with IDegLira, by 1.44%-point to 6.9% with IDeg and by 1.28%-point to 7.0% with liraglutide after 26 weeks of treatment. Superiority of IDegLira over liraglutide in terms of change from baseline in HbA1c was confirmed from the primary statistical analysis (estimated mean treatment difference: -0.64%-point [-0.75; -0.53]95%CI; p<0.0001), thus confirming the contribution of the IDeg component of IDegLira to overall glycemic control (Figure 1–4). Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 11 of 133

In addition for Trial 3697, the pre-specified hypothesis of non-inferiority of IDegLira relative to IDeg for change in HbA1c was confirmed. In fact, the reduction in HbA1c was greater with IDegLira compared with IDeg (estimated mean treatment difference: -0.47%-point [-0.58; -0.36]95%CI).

Full analysis set. LOCF imputation; mean +/- standard error. Δ = Estimated treatment difference from ANCOVA; ap<0.0001

Figure 1–4 HbA1c (%) by treatment week - Trial 3697

 The pivotal Trial 3912 was designed to confirm the contribution of the liraglutide component of IDegLira to the primary efficacy effect as reflected in change in HbA1c. This evaluation was enabled by limiting the maximum dose of IDeg in the IDeg comparator arm to 50 units, which is equivalent to the maximum dose of the IDeg component with IDegLira. Mean HbA1c at baseline was 8.7% in the IDegLira group and 8.8% in the IDeg group. After 26 weeks of treatment, HbA1c had on average decreased by 1.90%-point to 6.9% with IDegLira and by 0.89%-point to 8.0% with IDeg limited to 50 units. The reduction in HbA1c was statistically significantly greater with IDegLira compared with IDeg (estimated mean treatment difference: -1.05 %-point [-1.25; -0.84]95%CI; p<0.0001), confirming the pre-specified hypothesis of superiority (Figure 1–5). Given that the mean end-of-trial insulin doses were very similar between treatment groups (44.85 units with IDegLira and 44.87 units with IDeg), these results confirm the contribution of the liraglutide component of IDegLira to the primary efficacy effect. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 12 of 133

IDeg limited to 50 units. Full analysis set. LOCF imputation; mean +/- standard error. Δ = Estimated treatment difference from ANCOVA. ap<0.0001

Figure 1–5 HbA1c (%) by treatment week - Trial 3912

The three additional phase 3 trials (Trials 3951, 3952 and 3851) all showed clinically relevant improvements in glycemic control with IDegLira relative to comparator treatments. The completed phase 3 trial program thus confirmed the primary efficacy of IDegLira across the spectrum of proposed use of the product in T2DM, including initiation and intensification in subjects inadequately controlled on OAD and injectable therapy, respectively (Figure 1–6). Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 13 of 133

Estimates with 95% confidence intervals are presented. Missing data are imputed using the last observation carried forward method. Dotted line represents the superiority limit of 0%. The non-inferiority limit used in Trials 3697 and 3952 for the IDegLira vs. basal insulin comparison was 0.3%-point. Abbreviation: EOT = end of trial; ETD = estimated treatment difference; IGlar = insulin glargine; GLP-1 RA = glucagon-like peptide-1 receptor agonist

Figure 1–6 HbA1c change from baseline (%-point) – completed phase 3 trials – plot of estimated treatment differences – FAS

In line with the results for change in HbA1c, 60% - 80% of IDegLira treated patients reached the ADA HbA1c target of <7.0% across trials, and the proportion of patients achieving the ADA HbA1c target of <7.0% (Figure 1–7) and the AACE target of ≤6.5% after 26 weeks of treatment was consistently greater with IDegLira than with comparator treatments, as reflected in the odds ratios for achieving target being statistically significantly greater than unity for all comparisons in all five phase 3 trials. For further details see Section 6.1.7.2. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 14 of 133

Full analysis set. 26-week data. LOCF imputation. IDeg dose was limited to 50 U in Trial 3912. p-value from logistic regression. *p<0.0001.

Figure 1–7 Proportion of patients reaching HbA1c target of <7.0%

With respect to efficacy of IDegLira in the low dose range, the data support that the liraglutide component contributes to the primary efficacy of the product across the entire dose range, including at doses of the liraglutide component below the approved therapeutic dose of 1.2 mg for Victoza® (equivalent to the amount of liraglutide contained in IDegLira doses of <32):  The exposure-response (Section 5.3) and dose-response evaluations of IDegLira against IDeg and liraglutide comparators in Trial 3697 (OAD users) demonstrated the contribution of both components of IDegLira to its overall glycemic effect throughout the dose range.  A dose-response analysis of two dose-ranging trials from the Victoza® development program demonstrated that liraglutide lowered HbA1c at doses below 1.2 mg. The analysis showed HbA1c reductions of 0.28 to 0.99 %-points for doses ranging from 0.36 mg to 1.08 mg.  Finally, the contribution of low doses of liraglutide to the HbA1c-lowering effect of IDegLira was seen in Trials 3697, 3912 and 3952 for the comparison of IDegLira against basal at doses of IDegLira < 32 or basal insulin < 32 units. The results showed that IDegLira effected larger reductions in HbA1c at similar insulin doses, thus reflecting the contribution of the liraglutide component.

Fasting and postprandial glucose control The results for fasting plasma glucose (FPG) and postprandial glycemic control (described in Sections 6.1.7.3 and 6.1.7.4) support the results on HbA1c and furthermore support that the added benefit of IDegLira on HbA1c reduction is a result of the complementary modes of action of the two components as described further above. Similar FPG levels were achieved with IDegLira and comparator insulin treatment in Trials 3697 (IDegLira vs. IDeg in OAD users) and 3952 (IDegLira vs. IGlar in basal insulin users; Section 6.1.7.3), supporting that the observed differences in HbA1c Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 15 of 133 in favor of IDegLira were not the result of titration differences between groups. Instead, the effect of the liraglutide component of IDegLira on postprandial glycemic control (as demonstrated in a dedicated meal test in a pre-specified sub-population of Trial 3697, see Section 6.1.7.4) contributed to the observed improvement in overall glycemic control with IDegLira relative to basal insulin comparators in these trials.

Insulin dose Insulin dose is considered an integral part of the efficacy evaluation due to the insulin-sparing effect of the liraglutide component of IDegLira, which in turn reduces the risks of hypoglycemia and weight gain. The informative trials in this context are Trials 3697 and 3952, in which the insulin dose in the comparator treatment arms was titrated to treatment target with no dose restrictions imposed.

Trial 3697 in patients uncontrolled on OAD treatment showed that the mean daily basal insulin dose after 26 weeks of IDegLira treatment was approximately 15 units lower for IDegLira than for IDeg comparator treatment (38.1 vs. 53.0 units). This difference increased from 15 to 23 units during the extension phase of the trial due to a continued insulin dose increase in the IDeg group. For Trial 3952 in patients uncontrolled on basal insulin, the difference at week 26 for IDegLira relative to insulin glargine comparator treatment was approximately 25 units (40.9 vs. 66.3 units). Given the concurrent improvements in overall glycemic control with IDegLira relative to comparator insulin treatments, these results indicate that the basal insulin requirement with IDegLira is lower than with insulin monotherapy.

Body weight The weight gain commonly observed with insulin treatment was counterbalanced by the weight-reducing effect of the liraglutide component of IDegLira. This resulted in IDegLira treatment being approximately weight neutral when added to OAD treatment. In line with this, a small weight loss was shown when transferring from basal insulin treatment to IDegLira (corresponding to adding GLP-1 RA treatment) and a small weight gain was shown when transferring from GLP-1 RA treatment to IDegLira (corresponding to adding basal insulin treatment); see Figure 1–8. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 16 of 133

§Change for IDeg was 0.0 kg. aEstimated treatment differences with 95% confidence intervals. Full analysis set. Figure 1–8 Change in body weight across phase 3 trials

Clinical safety Across the five completed phase 3 trials, 1881 patients were exposed to IDegLira for a total of approximately 1200 patient-years, and the combined exposure to comparator treatment was of a similar magnitude. The main trial period was 26 weeks for all phase 3 trials, with additional exposure derived from the 26-week extension period of Trial 3697-ext. The rates of AEs and SAEs for IDegLira were similar to the rates for the IDeg and liraglutide comparator arms as well as the other comparator treatments, and no unexpected patterns in the reported AEs and SAEs were observed.

The following is concluded for the key safety areas:

 Hypoglycemia: Severe hypoglycemia occurred rarely in the IDegLira phase 3 trial program and at similar rates across groups. Rates of confirmed hypoglycemia (severe episodes or episodes with a plasma glucose <56 mg/dL) and documented symptomatic hypoglycemia (ADA definition) were reduced for IDegLira by more than 30% relative to IDeg treatment (Trial 3697) and by more than 50% relative to insulin glargine treatment (Trial 3952). Importantly, for both trials the lower rate of hypoglycaemia with IDegLira was achieved while concomitantly demonstrating improved glycaemic control with IDegLira relative to the comparator basal insulin. Conversely, the rates of such hypoglycemia events were higher with IDegLira than with GLP-1 RA comparator treatment (Table 1–1). Confirmed hypoglycemia was a confirmatory secondary endpoint in Trials 3697 and 3952 (i.e., analyzed while controlling for multiplicity). Results of statistical analyses are provided in Section 7.3.5.1.

Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 18 of 133

 Pancreatic safety: No events of were confirmed by the event adjudication committee for patients receiving IDegLira. An increase in mean lipase and amylase activity from baseline to end of trial was observed in the IDegLira and GLP-1 RA groups (Section 7.3.5.3). These findings are consistent with previous observations for liraglutide. In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreatic alone are not predictive of acute pancreatitis,24, 25 and the results for lipase and amylase are not considered indicative of an increased risk of pancreatitis with IDegLira treatment.

 Cardiovascular safety: The IDegLira clinical development program was not designed to generate a cardiovascular outcome assessment. The currently available data indicate that the cardiovascular profile of IDegLira is consistent with that of the individual components. Cardiovascular biomarker changes observed with IDegLira were in line with the well-established effects of each component. FDA approved IDeg (Tresiba®) in September 2015 based on an interim analysis of the ongoing cardiovascular outcomes trial for IDeg (DEVOTE®) comparing IDeg to IGlar in a double-blind trial evaluating over 7000 patients. The cardiovascular outcomes trial for liraglutide (LEADER®) has recently been completed and confirmed the cardiovascular safety of liraglutide compared to placebo when each was added to standard of care. Both trials enrolled a population of T2DM patients at high risk of major adverse cardiovascular events (MACE), ensuring a clinically relevant cardiovascular risk assessment for each of the components based on significant numbers of accrued MACE events. For further information see Section 7.3.5.4.

 Neoplasms: Neoplasm events occurred at similar frequencies across treatment groups in the five completed phase 3 trials pooled, except that there were 6 events of skin neoplasm reported for IDegLira versus 1 event for comparator treatments combined (Section 7.3.5.5). Four of the 6 events with IDegLira (and the one event with comparator treatment) concerned non-serious events of basal cell carcinoma. There is no known plausible mechanistic rationale for an increase in skin neoplasms when combining insulin and GLP-1 RA.

 Thyroid safety: No events of were reported or identified in the development program. Results for were similar between treatment groups (Section 7.3.5.6).

 Immunogenicity: Allergic reactions and injection site reactions occurred at similar rates across treatment groups. The antibody response to IDegLira was low, which is consistent with the low antibody response to IDeg and liraglutide observed in their respective development programs (Section 7.3.5.7).

The safety profile of IDegLira was consistent with the well characterized safety profiles of IDeg and liraglutide as well as the other comparator treatments, and the combination mitigated some of the common adverse effects of basal insulin and GLP-RA when used alone. No new safety signals Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 19 of 133 were identified. The proposed post-marketing risk management program for IDegLira builds upon the ongoing Tresiba® and Victoza® post-marketing programs to address potential and identified risks for IDegLira.

Benefit-risk evaluation In the following, the benefit-risk profile of IDegLira relative to comparator treatments is summarised briefly in the context of the proposed target populations of patients uncontrolled on either OAD treatment, basal insulin treatment or GLP-1 RA treatment.

With all antidiabetic therapies, the benefits of increased glycemic control should be balanced against risks. Relative to basal insulin treatment, the treatment benefits of IDegLira are substantial and highly clinically relevant, both in patients inadequately controlled on OAD treatment and in those who are inadequately controlled on basal insulin. Superior glycemic control is achieved with a once-daily injection while mitigating the main side effects of basal insulin treatment (hypoglycemia and weight gain). The benefits of IDegLira relative to basal insulin treatment should be balanced against the risk profile associated with the liraglutide component of the drug product, including the risk of gastrointestinal side effects. As with any treatment decision, this should be in the context of individual treatment goals and patient characteristics.

IDegLira similarly shows improved glycemic efficacy relative to GLP-1 RA treatment, which suggests that IDegLira may be an appropriate alternative to GLP-1 RA therapy in individual patients, both in patients inadequately controlled on GLP-1 RA therapy and in those who are inadequately controlled on OAD treatment. Specifically in patients uncontrolled on OAD therapy, the reduction in incidence and severity of gastrointestinal events with IDegLira relative to regular GLP-1 RA therapy is clinically meaningful, because these events are typically the ones that are most bothersome to patients starting GLP-1 RA therapy and may lead to withdrawal from treatment. However, avoidance of hypoglycemia remains an important consideration. The benefits of IDegLira over GLP-1 RA treatment should therefore be balanced against the increased risk of hypoglycemia and the differing weight profiles of the therapies due to the insulin component of IDegLira, taking individual treatment goals and patient characteristics into consideration.

IDegLira provides important treatment benefits by enabling the administration of both IDeg and liraglutide in one single injection at any time of the day via a convenient, pre-filled pen. Furthermore, the product allows patients and health care providers to achieve appropriate dose levels for the combination treatment by following a simple titration scheme similar to that used for basal insulin products. It is considered that the availability of this combination product will remove uncertainties for many patients and caregivers with respect to managing transfer to basal insulin + GLP-1 RA combination therapy, including adjustment of the doses of the two drugs during initiation/transfer and maintenance phases. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 20 of 133

In conclusion, IDegLira offers an attractive treatment option for patients with T2DM who wish to intensify glycemic control, both in patients inadequately controlled on OAD treatment and in patients inadequately controlled on either basal insulin or GLP-1 RA treatment. As with any treatment decision, the benefits and risks of IDegLira relative to treatment alternatives should be considered in the context of the treatment goals and characteristics of the individual patient. The availability of IDegLira for the treatment of T2DM allows for further individualization of treatment by providing an effective and safe alternative to the concurrent use of the two separate components for those who wish to limit the number of daily injections. The addition of IDegLira to the range of treatment options for T2DM is thus consistent with the ADA/EASD position statement emphasis on individualization of treatment as being essential for successful .20 A similar emphasis on individualization of therapy based on attributes of both patients and is evident from the most recent AACE consensus statement.26 It is concluded that the benefit-risk ratio is in favor of IDegLira within the investigated patient populations with T2DM. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 21 of 133

2 Introduction

2.1 Rationale for IDegLira in the treatment of T2DM Several large and comprehensive diabetes outcome studies have demonstrated the importance of tight glycemic control to reduce comorbidities.1-3 Despite the increasing number of therapeutic options available to treat type 2 diabetes mellitus (T2DM), the majority of patients with T2DM nevertheless fail to achieve the recommended levels of glycemic control required to reduce long term microvascular and macrovascular complications.4, 5 This may in part be due to insufficient therapeutic response but also reflects the treatment barriers associated with current once-daily injection therapies, i.e., hypoglycemia and weight gain with basal insulin therapy and nausea, diarrhea and vomiting with GLP-1 RA therapy.25-29

The underlying pathophysiology of T2DM is complex and involves multiple organ systems. The defects include peripheral insulin resistance and progressive relative insulin deficiency as well as impaired secretion and/or action of incretin hormones including GLP-1, leading to the fasting and post-prandial hyperglycemia characterizing T2DM.6-8 Optimal glycemic control therefore relies on a multi-faceted treatment approach, and therapies that address the complexity of the disease may allow more patients to achieve treatment targets. One such option is the combination of basal insulin and GLP-1 receptor agonist (GLP-1 RA) treatment, and the successful outcome of recent trials combining basal insulin and GLP-1 RA treatment as separate injections30 has led to the inclusion of this treatment combination in the approved labelling for both insulin and GLP-1 RA products.9-19 Thus, concurrent use of insulin and GLP-1 RA is an established treatment regimen and is included in the most recent ADA/EASD position statement on management of hyperglycemia in T2DM.20 However, increasing the number of required injections may also lead to reduced compliance to treatment, reduced satisfaction, and clinical inertia.

The combination product insulin degludec/liraglutide (IDegLira) is being developed to provide the combined benefits of the two FDA-approved components insulin degludec (IDeg, a long-acting basal insulin) and liraglutide (a GLP-1 analog) in a single daily injection. As shown from the IDegLira clinical development program detailed below, the simultaneous introduction of liraglutide to insulin degludec therapy as done with IDegLira not only adds the benefit of lowering prandial glucose excursions via liraglutide’s glucose-dependent mechanism of action, but it also counteracts the undesired risks of hypoglycemia and weight gain associated with insulin therapy. Furthermore the more gradual increase in liraglutide dose with IDegLira compared to GLP-1 RA monotherapy gives rise to fewer and milder gastrointestinal side effects. Overall, the combination of IDeg and liraglutide in the proposed titratable product harnesses the complementary actions of insulin and GLP-1 RA to yield clinically relevant improvements in glycemic control relative to either of the components individually, while at the same time addressing important treatment barriers of insulin (hypoglycemia and weight gain) and GLP-1 RA (nausea, diarrhea and vomiting). Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 22 of 133

The convenience of administering both components in a single daily injection at any time of the day, using a titration scheme similar to that used for basal insulin products, is expected to facilitate achievement of treatment goals. The availability of IDegLira for the treatment of T2DM allows for further individualization of treatment by providing an effective and safe alternative to the use of the two individual components for those who wish to limit the number of daily injections. The addition of IDegLira to the range of treatment options for T2DM is thus consistent with the ADA/EASD position statement emphasis on individualization of treatment as being essential for successful diabetes management.20 A similar emphasis on individualization of therapy based on attributes of both patients and medications is evident from the most recent AACE consensus statement.26 In the absence of a single ‘perfect for all’ therapy, such individualization requires therapeutic options with varied attributes to aid in patient/healthcare provider decision making.

2.2 Development of IDegLira The development strategy for IDegLira builds upon the extensive clinical database obtained in the individual development programs for IDeg (Tresiba®) and liraglutide (Victoza®). The program was designed to demonstrate superiority on HbA1c reduction with IDegLira versus each of the components and to support the use of IDegLira in adult patients with T2DM inadequately controlled on OADs alone, basal insulin or GLP-1 RA. The proposed indication is as an adjunct to diet and exercise to improve glycemic control in adults with T2DM.

The completed clinical development program for IDegLira on which the new drug application (NDA) is based comprises two single-dose clinical pharmacology trials and five phase 3 trials:

One clinical pharmacology trial (Trial 3632) investigated to what extent IDeg and liraglutide affect each other’s pharmacokinetic characteristics in the combination product. The other trial (Trial 4026) investigated bioequivalence between two different formulations of IDegLira and is not described further herein. The clinical pharmacology trial program is further described in Section 5.

The phase 3 trial program included two pivotal phase 3 trials (Trials 3697 and 3912) designed to assess the contribution of the individual components of the combination to overall glycemic control. Three subsequently conducted phase 3 trials investigated the efficacy and safety of IDegLira in additional populations of patients with T2DM defined by previous antidiabetic treatment. An overview of the completed phase 3 trials is provided in Figure 2–1. The phase 3 trial program is further described in Section 6. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 23 of 133

Figure 2–1 Overview of completed phase 3 trials included in the NDA for IDegLira

The NDA submitted to the FDA had a data cut-off of 31 March 2015. Additional blinded safety data from the two phase 3 trials that were ongoing at the time of NDA submission (Trial 4119 which is an extension to Trial 3952, and Trial 4056 comparing once-weekly versus twice-weekly titration) as well as from a trial that was subsequently initiated (Trial 4185 testing IDegLira versus basal therapy) were submitted to the FDA in a 120-Day Safety Update with a cut-off date of 30 September 2015. Both the results from the NDA as well as the information from the 120-day safety update are described in this document. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 24 of 133

3 Product description

3.1 Key properties of IDegLira IDegLira is a combination of the long-acting basal insulin insulin degludec (IDeg, active substance of Tresiba®), and the GLP-1 analog liraglutide (active substance of Victoza®). IDegLira is intended for improvement of glycemic control in adults with T2DM via once-daily subcutaneous injection.

The product combines the active substances of two FDA-approved therapies that within their respective drug classes have shown to be safe and efficacious for the treatment of T2DM. IDeg has been designed with a unique ability to form multi-hexamers at the injection site giving rise to a soluble depot from which a slow and steady release of IDeg monomers is achieved (Appendix 1, Section 1.1). The duration of action extends beyond 42 hours at clinically relevant doses, resulting in a stable pharmacodynamic action profile and low day-to-day variability in glucose lowering effect. However, basal insulin treatment has the inherent limitation of not addressing fluctuations in insulin demand such as those resulting from meal intake. In contrast, liraglutide stimulates insulin secretion and inhibits glucagon secretion in a glucose-dependent manner when plasma glucose levels are above normal (Appendix 1, Section 1.2), and this mechanism of action is therefore complementary to that of basal insulin. The glucose-dependent mechanism of action of the liraglutide component of IDegLira facilitates further improvements in overall glycemic control with IDegLira relative to basal insulin treatment while titrating to equivalent fasting plasma glucose (FPG) targets. This is achieved without increasing the risk of hypoglycemia as otherwise seen when adding prandial insulin to control glucose excursions. In fact, the lower insulin requirement with the combination product was associated with a reduced risk of hypoglycemia compared to basal insulin treatment. Liraglutide also shows a distinct effect on reducing body weight through mechanisms involving decreased hunger and lowered energy intake (Appendix 1, Section 1.2), which counter-balance the weight gain commonly observed with insulin treatment.

The distinct molecular structures of stable IDeg di-hexamers and liraglutide heptamers allow for co-formulation. With a focus on securing an appropriate balance between efficacy and safety, the IDeg/liraglutide ratio of 100 units/3.6 mg per mL in the product was chosen such that clinically appropriate doses of both IDeg and liraglutide would be co-administered with this titratable product. This takes into consideration the amount of IDeg and liraglutide in the IDegLira starting dose as well as the maximum approved liraglutide dose of 1.8 mg per day for the treatment of diabetes. The ratio providing 50 units of IDeg and 1.8 mg of liraglutide at the maximum dose level was considered to adequately cover the treatment requirement for the majority of the target patient population. This a priori assumption was in accordance with clinical experience with the co-administration of basal insulin and GLP-1 receptor as separate products.31, 32 The appropriateness of the selected ratio between the two components was subsequently confirmed in the phase 3 trial program, which demonstrated superior efficacy in terms of change in HbA1c with IDegLira relative to IDeg and liraglutide alone as well as a distinct contribution of each of the Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 25 of 133

components of IDegLira to change in HbA1c throughout the dose range (Sections 6.1.7.1 and 6.1.7.6).

3.2 Dosage and administration The IDegLira combination product intended for the market will be provided in a pre-filled pen containing an IDeg/liraglutide ratio of 100 units/3.6 mg per mL, which is equivalent to the IDeg/liraglutide ratio tested in the phase 3 clinical trials.

IDegLira is to be titrated based on fasting plasma glucose, similar to current practice for basal insulin therapy (Table 6–2). The fixed IDeg/liraglutide ratio of 100 units/3.6 mg per mL ensures that as the dose of IDegLira is increased or decreased, the ratio between the doses of the two components does not change (Figure 3–1).

Figure 3–1 Principle of dose adjustment for the IDegLira fixed ratio product

The pre-filled pen allows for dose adjustments in increments of 1 unit IDeg and 0.036 mg liraglutide. The number shown on the pen will be the dose prescribed for the patient, as exemplified in Figure 3–2 for an IDegLira dose of 10. The dose range is from 1 to 50, with the maximum dose corresponding to 50 units of IDeg and 1.8 mg of liraglutide. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 26 of 133

Figure 3–2 Example of IDegLira dose

An overview of recommended IDegLira starting doses and corresponding component drug contents is provided in Table 3–1. These starting doses are the ones used in the phase 3 trial program, which confirmed their appropriateness. The recommended daily starting dose when initiating IDegLira as add-on to OADs is 10 (corresponding to 10 units of IDeg and 0.36 mg liraglutide), which is consistent with the initiation dose of 10 units of basal insulin typically used in insulin-naïve patients with T2DM. The recommended daily starting dose when converting from basal insulin or GLP-1 RA treatment is 16 (corresponding to 16 units IDeg and 0.6 mg liraglutide), which is in line with the recommended starting dose of 0.6 mg/day for Victoza®.

Table 3–1 Starting dose of IDegLira Previous anti-diabetic therapy IDegLira starting IDeg (U)/liraglutide (mg) dose OADs 10 10 units/0.36 mg Basal insulin + OADs 16 16 units/ 0.6 mg GLP-1 RA + OADs 16 16 units/ 0.6 mg

A summary of results for the individual components (IDeg and liraglutide) including results for nonclinical toxicology, clinical pharmacology and clinical efficacy and safety is included in Appendix 1. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 27 of 133

4 Nonclinical pharmacology and toxicology Summary  The comprehensive nonclinical safety programs to support the approval of Tresiba® (IDeg) and Victoza® (liraglutide) are also supportive for IDegLira: – IDeg has a similar metabolic and safety profile compared with human insulin. – Liraglutide dose-dependently induced proliferative changes and neoplasia in C-cells (parafollicular cells) of the thyroid during rodent 2-year carcinogenicity studies. The rodent C-cell findings are considered a class effect caused by a specific GLP-1 receptor-mediated mechanism to which rodents are particularly sensitive. – No signal for pancreatitis or pancreatic cancer was observed in any nonclinical studies – A few fetal abnormalities in rats and were observed in studies with liraglutide. These were likely related to reduced maternal food intake.  The nonclinical safety program using IDegLira showed the following: – General toxicology study findings were mainly dose-limiting hypoglycemia and reduced body weight gain reflecting the known pharmacology of insulin and GLP-1 analogs. – IDegLira caused mild testicular changes in rats, which were considered related to severe hypoglycemia and reduced body weight gain.

4.1 Overview and nonclinical testing strategy The individual components of IDegLira (IDeg and liraglutide) have undergone comprehensive nonclinical efficacy and safety testing. This work has supported the approvals of Tresiba® and Victoza® and is considered supportive for the IDegLira NDA in accordance with guidance given by the International Conference on Harmonization (ICH). The results from the nonclinical programs for IDeg and liraglutide are summarized in Appendix 2.

For IDegLira, the nonclinical efficacy characterization of IDegLira consisted of one pharmacology study, while the general toxicity studies were up to 13 weeks of duration. All nonclinical in vivo studies for IDegLira were conducted in rats.

4.2 Mode of action Insulin is a with well-known pleiotropic effects, which are mediated via binding to specific insulin receptors found in almost all cells of the body. Binding leads to the activation of a series of intracellular signaling events, initiated by the auto-phosphorylation of the on specific tyrosine residues with subsequent activation of kinase B, and resulting in diverse effects on the regulation of glucose, protein and lipid as well as in some cases stimulation of cell growth.

Similar to insulin, GLP-1 is a hormone with pleiotropic effects including glucose-dependent insulin secretion and activation of proliferation in pancreatic beta cells; inhibition of glucagon secretion; Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 28 of 133 delayed gastric emptying; and appetite suppression by acting on various specific brain regions. The pharmacological actions of GLP-1 are mediated via specific G-protein-coupled receptors that, upon binding of GLP-1, initiate intracellular signaling via cAMP, with subsequent activation of protein kinase A and increases in intracellular cytosolic Ca2+ and PI3-kinase.

Based on the current understanding of the molecular and pharmacological modes of action of insulin and GLP-1, these hormones and their analogs activate distinct receptors and act through different mechanisms. In combination, insulin and liraglutide have been shown to result in an additive and not synergistic effect in in vitro cell studies.

4.3 Nonclinical efficacy pharmacology of IDegLira The acute pharmacodynamic effects of IDegLira have been evaluated in normoglycemic male Wistar rats and compared to the individual effects of IDeg and liraglutide at equivalent dose levels. The pharmacodynamic effects of IDegLira on blood glucose, food and water consumption and change in body weight were as expected based on the known effects of IDeg and liraglutide in these normoglycemic animals. Liraglutide had no effect on acute blood glucose lowering in these normal rats, while both IDegLira and IDeg significantly lowered blood glucose. In contrast, IDeg had no effect on body weight and food/water intake while IDegLira and liraglutide had comparable effects on these parameters. Dose-dependent effects of IDegLira were observed for all parameters measured. These results reflect that IDeg and liraglutide work via different mechanisms and that IDegLira recapitulates the actions of the individual components.

4.4 Nonclinical pharmacokinetics of IDegLira The pharmacokinetic profile confirmed that the pharmacokinetics of IDeg and liraglutide following s.c. administration of IDegLira to rats was similar to what was observed for IDeg and liraglutide dosed separately.

4.5 Nonclinical safety pharmacology and toxicology of IDegLira In accordance with the ICH guidance on combination drug toxicity testing, the development approach for IDegLira included pivotal subcutaneous combination toxicity studies of up to 13 weeks of duration in rats to support the clinical development program. These studies did not identify significant toxicities beyond what was observed in the programs conducted for the individual components.

General toxicology in rats Effects related to the pharmacological or exaggerated pharmacological effects of insulin and GLP-1 analogs were seen in the general toxicology studies with IDegLira. These were mainly episodes of lowered blood glucose/hypoglycemia, reduced food consumption and reduced body weight gain. The maximum tolerated dose was exceeded in the 4-week rat study, resulting in the Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 29 of 133 premature sacrifice of several animals due to severe hypoglycemia (< 36 mg/dL) and reduced body weight gain leading to dose reductions.

The histological effects observed in the 4-week study in the (increased rarefaction), adrenal gland (cortical vacuolation) and testis (spermatocyte apoptosis and tubular degeneration) were mild and considered related to the exaggerated pharmacology of insulin and GLP-1 analogs. Similar findings have been reported either with insulin alone or in relation to reduced food consumption,35 reflecting the known pharmacology of GLP-1 analogs.

In the 13-week pivotal toxicity study in rats, doses were reduced compared to the 4-week study. IDegLira was well tolerated throughout the study. There were no macroscopic or microscopic changes of toxicological relevance. Specifically, there were no treatment-related findings in the liver, adrenal gland or testes.

4.6 Carcinogenicity assessment for IDegLira Since individual carcinogenicity assessments of both insulin degludec and liraglutide were performed according to current standards and guidelines, no dedicated carcinogenicity studies have been conducted for the IDegLira combination product. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 30 of 133

5 Clinical pharmacology Summary  The clinical pharmacology program for IDegLira builds upon the clinical pharmacology programs for IDeg (Tresiba®) and liraglutide (Victoza®).  The pharmacokinetics of the components of IDegLira were overall consistent with those of IDeg and liraglutide, although the liraglutide concentration was lower when given as IDegLira versus as liraglutide alone. This is of low clinical relevance as IDegLira is titrated based on individual patient responses.  For each component of IDegLira, the concentration profile at steady state exhibited exposure coverage over the 24-hour dosing interval, which is consistent with the proposed once-daily administration.  Dose proportional pharmacokinetics (in terms of AUC) were supported for each of the components of IDegLira.  Exposure to both components of IDegLira was inversely correlated to body weight, whereas no or minor effects on exposure were observed for the remaining investigated covariates.  Exposure-response analysis showed that both components of IDegLira provide distinct contributions to overall glycemic control throughout the IDegLira exposure range.

5.1 Introduction The clinical pharmacology program for IDegLira builds upon the clinical pharmacology programs for IDeg (Tresiba®) and liraglutide (Victoza®), which have extensively characterized the clinical pharmacology properties of the two active components of IDegLira (Appendix 1). In order to reference the individual development programs for IDeg and liraglutide, the IDegLira clinical pharmacology program has assessed to what extent IDeg and liraglutide affect each other’s pharmacokinetic pattern in the combination product. This was investigated in a single-dose, cross over clinical pharmacology trial in 24 healthy subjects (Trial 3632) comparing the IDeg/liraglutide ratio of 100 units/3.6 mg per mL (i.e., the ratio used in phase 3 trials and intended for the market) against IDeg and liraglutide given alone or as concurrent, separate injections.

Furthermore, population pharmacokinetic analysis based on data from the pivotal phase 3 Trial comparing IDegLira against IDeg and liraglutide (Trial 3697) contributed to the evaluation of steady-state pharmacokinetics, dose-exposure proportionality and the effect of covariates on IDeg and liraglutide exposure levels.

An analysis of change from baseline in HbA1c versus exposure of IDeg and liraglutide in Trial 3697 (with exposure in terms of model-derived AUC values at steady state) was carried out to investigate the contribution of the individual drug components to the overall glycemic control with IDegLira throughout the exposure range. In addition, the postprandial pharmacodynamic effects of IDegLira were evaluated in a pre-specified population of 260 patients from Trial 3697 for whom a 4-hour Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 31 of 133 standardized meal test was performed at baseline and after 26 weeks. Postprandial pharmacodynamics were pre-specified as a confirmatory secondary endpoint in Trial 3697. As considered an integral part of the efficacy evaluation, results for prandial glycemic control are described in Section 6.1.7.4.

The pharmacokinetic and pharmacodynamic properties of IDeg and liraglutide have been extensively studied and are well understood. The key clinical pharmacology findings for IDeg and liraglutide from their respective development programs are summarized in Appendix 1, Sections 1.1 and 1.2, respectively. As described in Section 5.2.1 below, co-formulation of IDeg and liraglutide in IDegLira was shown to have only minor effect on pharmacokinetics, and the clinical pharmacology findings of the IDeg and liraglutide programs are therefore considered applicable for IDegLira.

5.2 Pharmacokinetics of IDegLira relative to IDeg and liraglutide

5.2.1 Single-dose and steady state pharmacokinetics A trial was conducted to estimate the relative (in terms of ratio of AUC) of IDeg and liraglutide when administered as a single dose of IDegLira versus as IDeg and liraglutide given alone or as concurrent, separate injections (Trial 3632).

Steady state pharmacokinetic properties of IDegLira at clinically relevant doses were characterized using model-based evaluation of data from the phase 3 Trial 3697, comparing IDegLira with IDeg and liraglutide. Steady state exposures (in terms of model-derived AUC) for the components of IDegLira were derived based on samples taken at weeks 1, 2, 4, 8, 12, 16, 20 and 26.

IDegLira versus IDeg The serum concentration–time profiles of IDeg obtained after single-dose administration of either IDegLira, IDeg alone or IDeg concurrently with liraglutide are shown in Figure 5–1, upper graph. The general pharmacokinetic pattern for IDeg was similar across the three modes of administration. This observation was confirmed from the model-derived IDeg concentration-time profiles at steady state for IDegLira and IDeg (Figure 5–1, lower graph). Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 32 of 133

Upper graph: mean concentration-time profiles for a single dose of IDegLira (equivalent to 17 U of IDeg), and single doses of IDeg (17 U) given alone and given concurrently with liraglutide (Trial 3632). Lower graph: steady-state IDeg concentration-time profiles, model-derived, in a reference patient* for an IDegLira dose of 50 (containing 50 U of IDeg) and a corresponding separate IDeg dose (Trial 3697). *The reference patient profile was defined as a non-Hispanic White female, younger than 65 years of age with a body weight of 85.8 kg, dosed weeks 1−11 in the thigh Figure 5–1 Concentration-time profiles of IDeg component

Results from Trial 3632 on relative bioavailability and Cmax for the IDeg component are summarized in Figure 5–2. The relative bioavailability (ratio of AUC0-∞) for IDeg administered as IDegLira versus as IDeg alone was 1.03 [0.99; 1.07]90% CI, hence within the limits for equivalence [0.80;1.25, post hoc evaluation]. The corresponding ratio of Cmax for IDeg was 1.12 [0.99; 1.27]90% CI, hence with the 90% confidence interval extending beyond the upper boundary of the equivalence interval, indicating a 12% higher Cmax for IDeg when administered as IDegLira versus as IDeg alone. When comparing the IDeg component of IDegLira relative to concurrent, separate administration of IDeg and liraglutide (shown as ‘IDeg + liraglutide’ in Figure 5–2), the 90% confidence interval for the ratio of AUC and Cmax were contained within the equivalence boundaries. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 33 of 133

The above single-dose observations were confirmed from a covariate analysis based on steady-state data from Trial 3697, which showed an estimated ratio of AUC (IDegLira vs IDeg) of 1.02 [1.00;1.05]90%CI (Figure 5–6).

Values to the right (as well as the symbols) represent estimated treatment ratios and 90% CIs. Endpoints were log-transformed and analyzed using a normal linear mixed model, with treatment and period as fixed effects, subject as a random effect, and a random error term. Comparisons are IDegLira (17U/0.6mg) vs IDeg (17 U) and IDegLira (17U/0.6mg) vs concurrent, separate administrations of IDeg (17U) and liraglutide (0.6 mg) [shown as ‘IDeg + liraglutide’]. Dotted lines indicate the equivalence limits [0.80;1.25], post hoc evaluation.

AUC: area under the curve (infinity). Cmax: maximum concentration. CI: confidence interval.

Figure 5–2 Analysis of relative bioavailability (AUC) and Cmax for the IDeg component – Trial 3632

IDegLira versus liraglutide The plasma concentration–time profiles of liraglutide obtained after single-dose administration of either IDegLira, liraglutide alone or liraglutide concurrently with IDeg are shown in Figure 5–3; upper graph. The general pharmacokinetic patterns were similar, but the liraglutide concentrations were lower with IDegLira compared to liraglutide administered either alone or concurrently with IDeg. This observation was confirmed from the model-derived liraglutide concentration-time profiles at steady state for IDegLira and liraglutide (Figure 5–3; lower graph). Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 34 of 133

Upper graph: mean concentration-time profiles for a single dose of IDegLira (equivalent to 0.6 mg of liraglutide), and single doses of liraglutide (0.6 mg) given alone and given concurrently with IDeg (Trial 3632). Lower graph: steady-state liraglutide concentration-time profiles, model-derived, in a reference patient* for an IDegLira dose of 50 (containing 1.8 mg liraglutide) and a corresponding separate liraglutide dose (Trial 3697). *The reference patient profile was defined as a non-Hispanic White female, younger than 65 years of age with a body weight of 85.8 kg, dosed weeks 1−11 in the thigh Figure 5–3 Concentration-time profiles of liraglutide component

Results from Trial 3632 on relative bioavailability and Cmax for the liraglutide component are summarized in Figure 5–4. The relative bioavailability (ratio of AUC0-∞) for liraglutide administered as IDegLira versus as liraglutide alone was 0.89 [0.82; 0.96]90% CI, hence 11% smaller AUC for IDegLira but within the limits of equivalence [0.80;1.25, post hoc evaluation]. The corresponding treatment ratio for Cmax was 0.77 [0.68; 0.87]90% CI, hence with the 90% confidence interval extending beyond the lower boundary of the equivalence interval, indicating a 23% lower Cmax for liraglutide when administered as IDegLira versus as liraglutide alone. Similar results were Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 35 of 133 obtained when comparing the liraglutide component relative to concurrent, separate administration of IDeg and liraglutide (shown as ‘IDeg + liraglutide’ in Figure 5–4).

The above single-dose observations were confirmed from a covariate analysis based on steady-state data from Trial 3697, which showed an estimated ratio of AUC (IDegLira vs liraglutide) of 0.86 [0.83;0.89]90%CI (Figure 5–7).

Values to the right (as well as the symbols) represent estimated treatment ratios and 90% CIs. Endpoints were log-transformed and analyzed using a normal linear mixed model, with treatment and period as fixed effects, subject as a random effect, and a random error term. Comparisons are IDegLira (17U/0.6mg) vs liraglutide (0.6 mg) and IDegLira (17U/0.6mg) vs concurrent, separate administrations of IDeg (17U) and liraglutide (0.6 mg) [shown as ‘IDeg + liraglutide’]. Dotted lines indicate the equivalence limits [0.80;1.25], post hoc evaluation.

AUC: area under the curve (infinity). Cmax: maximum concentration. CI: confidence interval

Figure 5–4 Analysis of relative bioavailability (AUC) and Cmax for the liraglutide component – Trial 3632

5.2.2 Dose proportionality assessment Dose proportionality for IDegLira was assessed based on IDeg and liraglutide pharmacokinetic data from the IDegLira treatment group of Trial 3697. No clinically relevant deviations from dose proportionality were indicated for the respective components of IDegLira across the recommended dose range of IDegLira using population pharmacokinetic modelling of data from Trial 3697 (Figure 5–5). Hence, dose proportionality as previously established for IDeg and liraglutide was supported for IDegLira, and the conclusions on bioavailability described in Section 5.2.1 can be inferred to be independent of dose and applicable throughout the full IDegLira dose range. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 36 of 133

Blue solid line and dashed blue lines: Model-derived relation between AUC0-24h and dose with 90%CI; including dose as covariate. Red square symbols: geometric mean model-derived AUC with 95%CI for percentiles of dose values. Grey area: 0.80-1.25 boundaries for a model not including dose as a covariate (perfect dose proportionality) Figure 5–5 IDeg AUC (left graph) and liraglutide AUC (right graph) versus dose at steady-state of IDegLira (Trial 3697; population pharmacokinetic analysis)

5.2.3 Effect of covariates on exposure Exposure (in terms of model-derived AUC based on data from Trial 3697) to each component of IDegLira was inversely correlated to body weight, whereas no or minor effects on exposure were observed for the remaining investigated covariates: sex, age (above/below 65 years), race, ethnicity, injection site (thigh, abdomen, upper arm), treatment (IDegLira, IDeg, liraglutide), and time from start of treatment (week 12-26/week 1-11); see Figure 5–6 and Figure 5–7. These results are as expected and are consistent with the results of the individual IDeg and liraglutide development programs. The results do not suggest changes in titration algorithm or regimen based on any of these characteristics.

The pharmacokinetic properties in special population groups such as patients with renal or hepatic impairment have been investigated for IDeg and liraglutide in their respective development programs. Given that the observed differences in pharmacokinetics for IDegLira versus IDeg and liraglutide were minor, the results for these special population groups are considered to also be applicable for IDeg and liraglutide when administered as part of IDegLira. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 37 of 133

Values to the right (as well as the symbols) represent estimated steady state exposure ratios (ratio of AUC0-24h) and 90% CI. Exposures are relative to the reference patient profile*. Dotted lines indicate the equivalence limits [0.80; 1.25]. 41 kg is the lowest body weight in the data set and 156.8 kg is the highest body weight with IDeg. AUC: area under the curve. CI: confidence interval. *The reference patient profile was defined as a non-Hispanic White female, younger than 65 years of age with a body weight of 85.8 kg, dosed weeks 1−11 in the thigh. Figure 5–6 Effect of covariates on IDeg exposure (Trial 3697) Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 38 of 133

Values to the right (as well as the symbols) represent estimated steady state exposure ratios (ratio of AUC0-24h) and 90% CI. Exposures are relative to the reference patient profile*. Dotted lines indicate the equivalence limits [0.80; 1.25]. 41 kg is the lowest body weight in the data set and 144.9 kg is the highest body weight with liraglutide. AUC: area under the curve. CI: confidence interval. *The reference patient profile was defined as a non-Hispanic White female, younger than 65 years of age with a body weight of 85.8 kg, dosed weeks 1−11 in the thigh. Figure 5–7 Effect of covariates on liraglutide exposure (Trial 3697)

Conclusion on pharmacokinetics In conclusion, the pharmacokinetics of the components of IDegLira were consistent with those of IDeg and liraglutide, and only minor pharmacokinetic differences for IDegLira relative to IDeg and liraglutide were observed. These minor differences are of low clinical relevance as IDegLira is titrated based on individual patient responses.

5.3 Pharmacodynamics and exposure-response In accordance with regulatory guidelines for combination therapeutic products,21, 22 demonstration of a distinct contribution from each component is an important element in supporting the selected dose ratio for IDegLira. An analysis of change from baseline in HbA1c versus exposure of IDeg and liraglutide (in terms of model-derived AUC values at steady state) in Trial 3697 was therefore carried out to investigate the contribution of the individual drug components to the overall glycemic control with IDegLira throughout the exposure range. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 39 of 133

Results on change in HbA1c from baseline to week 26 with IDegLira and IDeg treatment are plotted against AUC values for IDeg (model-derived AUC0-24h at steady state, grouped in percentiles and shown separately for IDegLira and IDeg) in Figure 5–8, left graph. The reduction in HbA1c was consistently greater with IDegLira than with IDeg throughout the exposure range. Thus, it can be inferred that the liraglutide component contributes to the effect of IDegLira on HbA1c throughout the exposure range. Corresponding results for change in HbA1c plotted against AUC values for liraglutide (grouped in percentiles and shown separately for IDegLira and liraglutide) are presented in Figure 5–8, right graph. The reduction in HbA1c was consistently greater with IDegLira than with liraglutide treatment throughout the exposure range, demonstrating a contribution of the IDeg component to the overall efficacy of IDegLira throughout the exposure range.

Data are baseline-adjusted mean HbA1c with 95% CI versus exposure (model-derived AUC0-24h at steady state) grouped in percentiles by treatment. AUC: area under the curve

Figure 5–8 Change in HbA1c (%-point) from baseline to week 26 with IDegLira and IDeg treatment plotted against IDeg exposure (left graph) and IDegLira and liraglutide treatment plotted against liraglutide exposure (right graph) – Trial 3697

In conclusion, both components of IDegLira provide distinct contributions to overall glycemic control throughout the IDegLira exposure range, which supports the clinical applicability of the dose ratio selected for IDegLira. For further information on IDegLira dose range and dose response see Section 6.1.7.6. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 40 of 133

6 Clinical Efficacy Summary  The phase 3 clinical program covered the spectrum of proposed use of IDegLira in T2DM, from initiation of injectable therapy in OAD-treated patients to treatment optimization in insulin-treated or GLP-1 RA-treated patients at a more advanced stage of diabetes  Two pivotal trials demonstrated contributions from both components of IDegLira to overall glycemic control by showing superior HbA1c reductions with IDegLira versus liraglutide (pivotal Trial 3697) and versus IDeg (pivotal Trial 3912)

 Consistently greater and clinically relevant reductions in HbA1c (primary endpoint) with IDegLira relative to comparators (including basal insulin and GLP-1 RA) were seen across all five phase 3 trials (two double-blind and three open-label) after 26 weeks of treatment.  Across the five phase 3 trials, IDegLira enabled 60−80% of patients to reach the ADA HbA1c target of <7.0% and 45−70% the AACE HbA1c target of ≤6.5% after 26 weeks  In these treat-to-target trials, end-of-trial fasting plasma glucose was similar between IDegLira and IDeg or IGlar comparators. The similarity in achieved fasting plasma glucose supports that the observed differences in HbA1c were not the result of titration differences between groups  Liraglutide’s efficacy in attenuating postprandial glycemia was preserved in the IDegLira combination product. This was demonstrated in the dedicated meal test and continuous glucose monitoring (CGM) assessment performed in a sub-study of the largest phase 3 trial (pivotal Trial 3697)  With the IDegLira combination product, the weight gain from IDeg is counterbalanced by the weight loss from liraglutide. Addition of IDegLira to previous OAD therapy resulted in little weight change over time. A weight benefit was seen in comparisons of IDegLira with basal insulins and a weight disadvantage in comparisons with GLP-1 RA  The primary and key secondary efficacy endpoints were comprehensively evaluated in sensitivity analyses that used various approaches for handling missing data. Similar results were seen across the pre-specified LOCF approach and the applied sensitivity analyses.  IDegLira’s effect on glycemic control and body weight was sustained up to 52 weeks in the pivotal Trial 3697 while the mean dose remained stable

6.1.1 Overview and strategy of the phase 3 trial program The IDegLira clinical development program includes five completed phase 3 trials designed to evaluate the efficacy and safety of IDegLira in patients with T2DM.

In accordance with regulatory guidelines for combination therapeutic products,21, 22 two pivotal trials (Trial 3697 in patients inadequately controlled on OAD treatment and Trial 3912 in patients inadequately controlled on basal insulin treatment) were designed to assess the contribution of the individual components of the combination to its primary efficacy effect (i.e., overall glycemic Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 41 of 133 control); see Figure 1–3. Accordingly, these trials were designed to demonstrate superiority in HbA1c reduction with IDegLira versus each component. The contribution of the IDeg component was assessed in Trial 3697 (IDegLira vs. liraglutide superiority comparison), while the contribution of the liraglutide component was evaluated in Trial 3912 (IDegLira vs. IDeg superiority comparison). Both trials also assessed the clinical benefit and safety of the IDegLira combination relative to the individual components.

The pivotal Trial 3697 (in patients inadequately controlled on OAD) compared IDegLira relative to IDeg (dosed according to the product label) and liraglutide [Victoza®] (dosed at the maximum approved dose of 1.8 mg). The primary hypotheses were superiority in HbA1c reduction with IDegLira relative to liraglutide and non-inferiority relative to IDeg. A non-inferiority hypothesis was selected due to the IDegLira maximum dose of 50 (50 units IDeg/1.8 mg liraglutide) and no restrictions on the maximum dose of the IDeg comparator (see Section 6.1.6 for more details). The overall clinical benefit of IDegLira versus IDeg was assessed through pre-specified confirmatory secondary analyses (i.e., analyses with an adjustment for multiplicity) of clinically relevant endpoints for insulin-treated patients with T2DM (insulin dose, hypoglycemia, body weight and prandial glycemia).

The pivotal Trial 3912 (in patients inadequately controlled on basal insulin) was designed to evaluate the contribution of the liraglutide component by comparing IDegLira to IDeg at similar insulin doses in both treatment arms. This was achieved by setting the maximum dose of IDeg in the comparator arm to 50 units, i.e., equivalent to the maximum dose of the IDeg component within IDegLira. The primary hypothesis of Trial 3912 was superiority in HbA1c reduction with IDegLira relative to IDeg.

The three additional phase 3 trials investigated the efficacy and safety of IDegLira in different populations of patients with T2DM defined by previous antidiabetic treatment (i.e., uncontrolled on OAD, basal insulin or GLP-1 RA therapy). For these additional trials, comparator treatments comprised insulin glargine (IGlar), continued GLP-1 RA therapy and placebo. The primary hypothesis for comparison of IDegLira with a maximum dose of 50 (50 units IDeg/1.8 mg liraglutide) and IGlar without a maximum dose limit was of non-inferiority (see Section 6.1.6 for more details). In comparisons against continued GLP-1 RA therapy and placebo, the primary hypotheses were of superiority in HbA1c reductions with IDegLira.

The completed phase 3 trial program thus covered the spectrum of proposed use of IDegLira in T2DM, from initiation of injectable therapy in OAD-treated patients (pivotal Trial 3697 and Trial 3951) to treatment optimization in insulin-treated patients (pivotal Trial 3912 and Trial 3952) or GLP-1 RA-treated patients (Trial 3851) at a more advanced stage of diabetes. The program was designed to facilitate informed decision making by patients and prescribers as to when and how to use IDegLira in individualization of therapy. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 42 of 133

Hereafter, patients inadequately controlled on OAD therapy will be referred to as ‘OAD users’, patients inadequately controlled on basal insulin therapy will be referred to as ‘basal insulin users’ and patients inadequately controlled on GLP-1 RA therapy will be referred to as ‘GLP-1 RA users’.

An overview of phase 3 trial designs is provided in Table 6–1. All trials were randomized, controlled, parallel-group, multicenter, multinational treat-to-target trials of 26 weeks duration. The treatment period of the pivotal Trial 3697 was further extended to 52 weeks for assessment of persistence of efficacy and long-term safety during extended exposure. The pivotal Trial 3912 (IDegLira vs. IDeg in basal insulin users) and Trial 3951 (IDegLira vs. placebo in OAD users) were double-blind. The pivotal Trial 3697 (IDegLira vs. IDeg and liraglutide in OAD users), Trial 3851 (IDegLira vs. continued GLP-1 RA therapy) and Trial 3952 (IDegLira vs. IGlar in basal insulin users) were open-label due to differences in treatment regimens or drug administration.

With respect to insulin dosing, the starting doses of IDegLira and basal insulin comparators are listed for each trial in Table 6–1. The maximum dose of IDegLira was set to 50 (Figure 3–1), as this dose contains the maximum approved dose of the liraglutide component for T2DM (1.8 mg). A ‘treat-to-target’ approach was used for IDegLira and basal insulin comparators in all trials, aiming for a pre-defined self-measured fasting plasma glucose target of 4.0−5.0 mmol/L or 72−90 mg/dL 34, (Table 6–2) in order to achieve an HbA1c <7%, as recommended by current treatment guidelines. 35 The fasting glucose target of Trial 3951 was widened to 4.0–6.0 mmol/L (72−108 mg/dL) to decrease the risk of hypoglycemic episodes due to concomitant sulfonylurea (SU) use. In all five trials, titration of insulin-containing trial products occurred twice weekly based on the mean of the three preceding self-measured fasting plasma glucose values. A titration committee composed of Novo Nordisk members surveilled patient adherence to the trial titration algorithm by monitoring the titration doses in a blinded fashion. Significant deviations from the titration algorithm were discussed with the trial site. However, the final decision of dose adjustment was based on the clinical judgement and discretion of the investigator.

With respect to liraglutide dosing in the pivotal Trial 3697, liraglutide was started at 0.6 mg/day and escalated weekly in 0.6 mg increments to a maintenance dose of 1.8 mg/day. GLP-1 RA treatment (i.e., liraglutide or BID) was continued at pre-trial dose levels (see Table 6–1) in the comparator arm of Trial 3851 (GLP-1 RA users).

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1.7 mg/day; ~20% exenatide BID (mean dose: 18.5 μg/day) a A total of 18 patients (3 from Trial 3697 and 15 from Trial 3912) were excluded from analysis (see Table 6–6 footnote for more details). b The full analysis was the same for Trial 3697-ext, covering the 52-week treatment period (26-week main + 26-week extension). Full analysis set is defined in Section 6.1.6. Abbreviations: BID = twice daily; BMI = body mass index; GLP-1 RA = glucagon-like peptide-1 receptor agonist; HbA1c = glycosylated hemoglobin; OAD = oral antidiabetic drug; SU = sulfonylurea, T2DM = type 2 diabetes mellitus

Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 47 of 133 response to a standardized liquid meal-test were evaluated and 24-hour glucose control was assessed using CGM. All patients who completed the 26-week main period were invited to participate in the 26-week trial extension. Patients who chose to participate in the 26-week extension (i.e., signed the informed consent) continued on the same treatment/dosing regimen as they received in the initial 26-week main trial.

The 26-week results from Trial 3697 are intended for demonstrating/comparing the efficacy of IDegLira to its individual components (IDeg and liraglutide) and are presented in Section 6.1.7. The primary trial objective and analysis pertain to the first 26 weeks of the trial. The efficacy results pertaining to the 52-week treatment period provide evidence of persistence of efficacy and are described in Section 6.1.8. The 26 week (main) part of the trial is referred to as Trial 3697 and the 52-week (including the extension) part is referred to as Trial 3697-ext (52 weeks).

‘N’ represents the number of randomized patients. Randomization was stratified by participation in the sub-study, pre- trial treatment (met or met + pio) and HbA1c (≤8.3% or >8.3%). Abbreviations: BMI = body mass index; EOT = end of trial; HbA1c = glycosylated hemoglobin; met = ; IDeg = insulin degludec; pio = Figure 6–1 Trial 3697 design.

Trial 3951 - IDegLira vs. placebo, each as add-on to SU±metformin In this randomized, double-blind, parallel-group, multicenter, multinational trial, insulin-naïve patients with T2DM were randomized 2:1 to treatment with IDegLira or placebo (each administered once daily) in combination with their pre-trial OAD treatment for 26 weeks (Figure 6–2). The SU dose (≥ half of maximum approved dose according to local label) remained unchanged during the trial. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 48 of 133

‘N’ represents the number of randomized patients. Abbreviations: BMI = body mass index; HbA1c = glycosylated hemoglobin; IDeg = insulin degludec; SU = sulfonylurea Figure 6–2 Trial 3951 design Basal insulin users

Pivotal Trial 3912 - IDegLira vs. IDeg, each as add-on to metformin In this randomized, parallel two-arm, double-blind, multicenter, multinational trial, patients with T2DM inadequately controlled on 20−40 units of basal insulin and metformin with or without SU or glinides were randomized 1:1 to treatment with IDegLira or IDeg (each administered once daily) for 26 weeks (Figure 6–3). Pre-trial basal insulin and OAD other than metformin were discontinued at randomization. To enable the evaluation of the contribution of the liraglutide component to IDegLira’s efficacy, the upward titration of both IDegLira and IDeg was restricted to not exceed a maximum dose of 50 or 50 units, respectively.

‘N’ represents the number of randomized patients. Randomization was stratified by pre-trial treatment: basal insulin + metformin or basal insulin + metformin + SU/glinides. Abbreviations: BMI = body mass index; EOT = end of trial;

HbA1c = glycosylated hemoglobin; SU = sulfonylurea Figure 6–3 Trial 3912 design. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 49 of 133

Trial 3952 - IDegLira vs. insulin glargine, each combined with metformin In this randomized, parallel-group, open-label, multicenter, multinational trial, patients with T2DM who were inadequately controlled on 20−50 units of IGlar and metformin were randomized 1:1 to conversion to once-daily IDegLira or upward titration of once-daily IGlar treatment for 26 weeks (Figure 6–4). No maximum dose was specified for IGlar.

‘N’ represents the number of randomized patients. Abbreviations: BMI = body mass index; EOT = end of trial; HbA1c = glycosylated hemoglobin Figure 6–4 Trial 3952 design.

GLP-1 RA users

Trial 3851 - IDegLira vs. continued GLP-1 RA therapy, each combined with metformin ± pioglitazone ± SU In this randomized, parallel-group, open-label, multicenter, multinational trial, patients with T2DM inadequately controlled on combination treatment of GLP-1 RA (once daily liraglutide or exenatide twice daily) and metformin ± pioglitazone ± SU were randomized 2:1 to once-daily IDegLira or continued GLP-1 RA treatment for 26 weeks (Figure 6–5). The GLP-1 RA comparator group maintained the pre-trial dose and dose regimen of liraglutide or exenatide (see Table 6–1). Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 50 of 133

‘N’ represents the number of randomized patients. Randomization was stratified by pre-trial GLP-1 RA: liraglutide or exenatide twice daily. Abbreviations: BID = twice daily BMI = body mass index; EOT = end of trial; GLP-1 RA = glucagon-like peptide-1 receptor agonist; HbA1c = glycosylated hemoglobin; pio = pioglitazone; SU = sulfonylurea Figure 6–5 Trial 3851 design.

6.1.3 Enrollment criteria The completed phase 3 trials cover the spectrum of potential use of IDegLira in T2DM, from initiation in patients who are naïve to injectable therapy to treatment intensification in patients previously treated with basal insulin or GLP-1 RA. The patient populations were chosen to represent adults above 18 years who were in need of treatment intensification to achieve glycemic control as defined by the HbA1c selection criteria for the respective trials (Table 6–4). Selection criteria were established so that pre-trial OAD dose levels corresponded to recommended maintenance doses, thereby ensuring that inadequate glycemic control at baseline was not caused by suboptimal dosing. Pediatric or adolescent patients (< 18 years of age) were not enrolled in any of the trials, whereas patients above 65 years were included.Individuals with a history of recurrent severe hypoglycemia were not excluded from enrollment into the IDegLira phase 3 program.

Patient exclusion criteria for the phase 3 trials were set to exclude patients with clinically significant concomitant illnesses (impaired renal/hepatic function, cardiac disorders, cancer or pancreatitis) as these patients may need individualized therapy with different treatment goals than those specified in the protocol and are more prone to early withdrawal related to their existing disease. In addition and consistent with the Victoza® prescribing information,10 patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 were also excluded.

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Abbreviations: ALAT = alanine aminotransferase; CT = computerized tomography; DPP-4 = dipeptidyl peptidase-4;

FPG = fasting plasma glucose; GLP-1 = glucagon-like peptide-1; HbA1c = glycosylated hemoglobin, IGlar = insulin glargine; MRI = magnetic resonance imaging; MTD = maximum tolerated dose; NYHA = New York Heart Association; OAD = oral anti-diabetic drug; RA = receptor agonist; SU = sulfonylurea; T2DM = type 2 diabetes mellitus; UNR = upper normal range

6.1.4 Baseline patient characteristics Patient baseline characteristics in the five completed phase 3 trials are shown in Table 6–5. In general, baseline characteristics were well matched between the treatment groups of individual trials; therefore, the totals across treatment groups are presented. In the individual trial populations, mean age ranged from 55.0 to 59.8 years. The racial distribution reflected that the phase 3 trials were conducted internationally. Trial patients were on average obese, as evidenced by the mean BMI range (31.2 – 33.7 kg/m2 across the trials). Mean duration of diabetes in the five trials ranged from 6.8 to 11.5 years. As expected, the mean duration of diabetes was longer in patients inadequately controlled on either previous basal insulin or GLP-1 RA treatment (Trials 3912, 3952 and 3851) compared to patients inadequately controlled on previous OAD treatment (Trials 3697 and 3951).

Approximately one-third of patients across the five phase 3 trials were from the United States (U.S.); Table 6–5. In general, the mean baseline characteristics of the U.S. patient population were consistent with the mean baseline characteristics of the total patient population. Exceptions were the proportion of Black or African American patients (10.3−19.3% in the U.S. trial population versus 2.0−7.4% in the total population across trials) and Asian patients (corresponding ranges of 1.5−4.0% versus 1.8−27.9%, respectively, across trials). These racial differences are reflective of the respective racial compositions of the U.S. and non-U.S. regions in which the trials were conducted.

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GLP-1 RA treatment in Trial 3851). The lower proportion of completers in the placebo group (76.0%) relative to the active treatment groups was mainly attributable to lack of trial drug effect.

Trial withdrawal due to the ‘continuously high self-measured plasma glucose’ withdrawal criterion (see Table 6–4) was low and similar across trials in the IDegLira treatment groups: Trials 3697 and 3951 (previous OAD users): 2 (0.2%) and 1 (0.3%) patients; Trials 3912 and 3952 (previous basal insulin users): 1 (0.5%) and 1 (0.4%) patients; Trial 3851 (previous GLP-1 RA users): 2 (0.7%) patients, respectively.

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6.1.6 Statistical Methods The sample size for each clinical trial was calculated to provide adequate power with respect to the primary efficacy endpoint of change from baseline to week 26 in HbA1c. In addition, the sample size for Trial 3697 (OAD users) was calculated to have sufficient power with respect to the main secondary objective of confirming the clinical benefit (i.e., superiority) of IDegLira vs. IDeg on at least one of the following clinically relevant endpoints for insulin-treated patients with T2DM (insulin dose, hypoglycemia, body weight and prandial glycemia). The sample size for Trial 3697 sub-study was calculated to have sufficient power for assessment of superiority of IDegLira vs. IDeg with respect to postprandial glycemic control.

The statistical evaluations were based on pre-specified analyses, using accepted statistical principles and analysis methods across clinical trials for each endpoint. A number of sensitivity analyses (using various approaches for handling missing data) were conducted as described further below and in Appendix 3. The pre-specified primary statistical evaluation of efficacy was based on the full analysis set (FAS), adhering to the intention-to-treat principle.38 The FAS included all randomized patients. The pre-specified safety analysis set included all patients who received ≥1 dose of the trial product.

Primary and confirmatory statistical testing strategy

Standard statistical methods were applied for demonstration of superiority and non-inferiority as applicable for the primary endpoint and pre-specified confirmatory secondary endpoints (i.e., analyzed while controlling for multiplicity/type I error). A non-inferiority margin for change in HbA1c of 0.3%-point was chosen for comparisons of IDegLira to IDeg (Trial 3697 in previous OAD users) and IGlar (Trial 3952 in basal insulin users) based on the recommendation in the FDA guidance for industry on developing drugs for treatment of diabetes.39 This margin provided sufficient assay sensitivity for both comparisons based on the below considerations:

 The margin did not represent a clinically meaningful loss of efficacy with IDegLira relative to the active comparators IDeg and IGlar  The 0.3%-point margin was selected in accordance with the FDA’s recommendation,37, 38 and represented less than 50% of a suitably conservative estimate of IGlar’s treatment effect on HbA1c in a placebo-controlled trial (-0.85%-point [-1.04; -0.66]95%CI versus placebo), which demonstrated IGlar’s superiority 38 – IDeg has previously been shown to yield similar reductions in HbA1c compared to IGlar in patients inadequately controlled on pre-trial treatment with basal insulin and OAD 41

Please refer to Sections 6.1.1 and 6.1.2 for more details on trial designs and analytical strategy.

As the primary hypotheses of Trials 3697 (IDegLira vs. IDeg and liraglutide in OAD users) and 3952 (IDegLira vs. IGlar in basal insulin users) were non-inferiority of IDegLira to basal insulin Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 57 of 133 comparators without maximum titrated dose limits, clinically-relevant pre-specified secondary endpoints/hypotheses were tested to assess the overall benefit of IDegLira treatment. Confirmatory secondary endpoints/hypotheses pre-specified for Trial 3697 (OAD users) examined superiority of IDegLira versus IDeg on body weight, postprandial glucose control, the number of confirmed hypoglycemic events (patient unable to treat himself/herself and/or has a recorded PG < 3.1 mmol/L or 56 mg/dL) and insulin dose. For Trial 3952 (basal insulin users), they examined the superiority of IDegLira versus IGlar with respect to HbA1c, body weight and the number of confirmed hypoglycemic events. Type I error was controlled by applying a hierarchical testing approach combined with the Holm-Bonferroni method.42 Endpoints that were included as pre-specified confirmatory secondary endpoints in one or more of the phase 3 trials were included as pre- specified supportive secondary endpoints in the remaining phase 3 trials. This was done to further establish the clinical validity of findings across the range of investigated patient populations.

Analyses of continuous endpoints

Continuous endpoints (including the primary endpoint of change in HbA1c) were analyzed using a standard analysis of covariance (ANCOVA) method including trial treatment, pre-trial anti-diabetic treatment (Trial 3951 in OAD users), stratification factors (see Figure 6–1, Figure 6–3, Figure 6–5) and country/region as fixed effects and the baseline value of the response as a covariate. The consistency of treatment effect on the change in HbA1c for specific sub-groups was examined for each trial using a standard ANCOVA method similar to the one used in the primary analysis. The model included treatment, sub-group, pre-trial anti-diabetes treatment (as applicable), stratification factors and a treatment by sub-group interaction as fixed effects and the HbA1c baseline value as covariate. For insulin dose analyses, baseline HbA1c was included as a covariate. Baseline insulin dose was not included as a covariate in Trials 3697 and 3697-ext (52 weeks) conducted in patients previously treated with OADs only (i.e., with a baseline insulin dose of 0).

Analyses of categorical and counting endpoints

Categorical endpoints (i.e., HbA1c responder endpoints) were analyzed by logistic regression. Hypoglycemic episodes (i.e., the total number of events during the treatment period) were analyzed using a negative binomial regression model with a log-link function and log of the exposure time as offset (see safety Section 7.3.5.1). Both models included the same fixed factors as the ANCOVA model; responder analyses included baseline HbA1c as covariate. As mentioned above, stratification varied between trials.

Sensitivity analyses At the initiation of the phase 3 trial program, the last observation carried forward (LOCF) method was a standard approach for imputing missing data in diabetes trials. Therefore, LOCF imputation was pre-specified as the primary approach for handling missing data in the five phase 3 trials. The treatment differences estimated based on the LOCF method reflect the effect until the patients stopped treatment. Recognizing the limitations of the LOCF approach,43 several sensitivity analyses Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 58 of 133 using various methods for handling missing data (and yielding separate estimates) were also performed. Sensitivity analyses were performed for the following primary and key pre-specified secondary endpoints: change from baseline in HbA1c, responders for HbA1c target of <7.0%, insulin dose, confirmed hypoglycemia, and body weight.

The applied sensitivity analyses included a repeated measurements analysis (which assumed that data were missing at random), two multiple imputation analyses (in which missing data from the IDegLira group was imputed with data from the comparator arm, hence assuming that data were not missing at random) as well as a tipping point analysis. In addition, the HbA1c <7.0% target endpoint was also analyzed using the assumption that all patients who were not observed to have reached the target at week 26 were non-responders. The repeated measurements analysis estimated an efficacy estimand (i.e., treatment differences assuming that patients remained on trial product until week 26). Two multiple imputation methods were used to estimate effectiveness estimands: 1) a pattern mixture model mimicking an intention-to-treat scenario where withdrawn IDegLira patients were assumed to have switched to the comparator treatment after withdrawal, and 2) a pattern mixture model mimicking an intention-to-treat scenario where withdrawn IDegLira patients were assumed to have been treated with the comparator treatment throughout the trial. For the evaluation of IDegLira’s superiority, both multiple imputation approaches imputed missing data in a way that was less favorable for IDegLira as compared with the repeated measurements method. Conversely, multiple imputation methods imputing data from the comparator arm tend to equalize the treatment effect between groups and be less conservative for non-inferiority comparisons. To mitigate this in the evaluation of IDegLira’s non-inferiority using the two multiple imputation methods, withdrawn patients from the IDegLira group were assumed to have switched to a treatment inferior to the comparator.

For a detailed description of the individual sensitivity analyses and their results, please see Appendix 3.

The outcomes of the sensitivity analyses for HbA1c, insulin dose and body weight are described in the respective results sections, comparing the results for the pre-specified LOCF approach with those from the approach hypothesized a priori to yield the most conservative estimand (multiple imputation method #2). For sensitivity analyses of hypoglycemia, please refer to Appendix 3.

6.1.7 Efficacy results The following sections describe and compare the key results from the five completed phase 3 trials. Results are presented below by endpoint and individual trial across the investigated populations defined by previous antidiabetic treatment.

6.1.7.1 HbA1c 23 HbA1c is the most widely accepted biomarker of overall, long-term glycemic control, and accordingly the pre-specified primary endpoint for all phase 3 trials was change in HbA1c from Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 59 of 133 baseline to week 26. Non-inferiority of IDegLira with respect to the primary endpoint was assessed against basal insulin comparators without a maximum dose limit in the pivotal Trial 3697 (OAD users) vs. IDeg and Trial 3952 (basal insulin users) vs. IGlar. IDegLira’s superiority with respect to overall glycemic control was tested in the pivotal Trial 3697 (OAD users) vs. liraglutide, Trial 3951 (OAD users) vs. placebo, pivotal Trial 3912 (basal insulin users) vs. IDeg, Trial 3952 (basal insulin users) vs. IGlar (in a pre-defined secondary analysis) and Trial 3851 (GLP-1 RA users) vs. continued GLP-1 RA therapy.

Patients inadequately controlled on oral antidiabetic drugs: pivotal Trial 3697 and Trial 3951

From a mean baseline HbA1c of 8.3% in all groups in the pivotal Trial 3697, HbA1c had on average decreased by 1.91%-point to 6.4% with IDegLira, by 1.44%-point to 6.9% with IDeg and by 1.28%-point to 7.0% with liraglutide after 26 weeks of treatment (Figure 6–6 and Table 6–7). Superiority of IDegLira over liraglutide in terms of change from baseline in HbA1c was confirmed from the primary statistical analysis (estimated mean treatment difference: -0.64%-point [-0.75; -0.53]95%CI; p<0.0001). This result demonstrated the contribution of IDeg within IDegLira to the overall glycemic control as the combination product provided superior glycemic benefit as compared to liraglutide 1.8 mg. The estimated mean treatment difference in HbA1c with IDegLira compared with IDeg was -0.47%-point [-0.58; -0.36]95%CI; p<0.0001, thus confirming the primary hypothesis of non-inferiority. This result was obtained with titration towards identical fasting glucose targets for IDegLira and IDeg (see Sections 6.1.1 and 6.1.7.3) and despite no limitation on the IDeg comparator dose, thus attesting to the contribution of the liraglutide component of IDegLira in lowering HbA1c. An evaluation of the contribution of the IDeg and liraglutide components of IDegLira to its HbA1c -lowering effect by end-of-trial titrated IDegLira dose is presented in Section 6.1.7.6.

Trial 3951 investigated the efficacy and safety of IDegLira versus placebo, each added to pre- existing SU ± metformin therapy. Mean observed HbA1c at baseline was 7.9% in both treatment groups and decreased by 1.45 %-point to 6.4% in the IDegLira group and by 0.46 %-point to 7.4% in the placebo group after 26 weeks of treatment. Superiority of IDegLira over placebo in terms of change from baseline in HbA1c was confirmed from the primary statistical analysis (estimated mean treatment difference: -1.02%-point [-1.18;-0.87]95%CI; p<0.0001), demonstrating a significant glycemic benefit of adding IDegLira to existing SU ± metformin treatment.

Patients inadequately controlled on basal insulin: pivotal Trial 3912 and Trial 3952

The pivotal Trial 3912 evaluated the contribution of the liraglutide component of IDegLira to the primary efficacy effect (i.e., the change in overall glycemic control). This was done by comparing IDegLira to IDeg while restricting the maximum insulin dose to 50 units/day for each treatment. In Trial 3912, mean HbA1c at baseline was 8.7% in the IDegLira group and 8.8% in the IDeg group. After 26 weeks of treatment, HbA1c had decreased by an average of 1.90%-point to 6.9% with IDegLira and by 0.89%-point to 8.0% with IDeg limited to a dose of 50 units/day. The reduction in Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 60 of 133

HbA1c was statistically significantly greater with IDegLira compared with IDeg (estimated mean treatment difference: -1.05 %-point [-1.25; -0.84]95%CI; p<0.0001), demonstrating IDegLira’s superiority. Given that the end-of-trial insulin dose was very similar between treatment groups (44.85 units with IDegLira and 44.87 units with IDeg), the results confirm the substantial and clinically relevant contribution of the liraglutide component to the overall glycemic control with IDegLira.

In trial 3952 comparing IDegLira with IGlar, the mean HbA1c at baseline was 8.4% in the IDegLira group and 8.2% in the IGlar group. After 26 weeks of treatment, mean HbA1c had decreased by 1.81%-points to 6.6% in the IDegLira group and by 1.13%-points to 7.1% in the IGlar group. The reduction in HbA1c was statistically significantly greater with IDegLira compared with IGlar (estimated mean treatment difference: -0.59%-point [-0.74; -0.45]95%CI, p<0.0001), confirming both non-inferiority and the pre-specified confirmatory secondary hypothesis of superiority of converting to IDegLira over upward titration of IGlar.

Patients inadequately controlled on GLP-1 receptor agonists: Trial 3851

In Trial 3851 comparing a change from GLP-1 RA to IDegLira with continued GLP-1 RA therapy, the mean HbA1c at baseline was 7.8% in the IDegLira group and 7.7% in the GLP-1 RA group. Mean HbA1c decreased by 1.3%-point to 6.4% in the IDegLira group and by 0.3%-point to 7.4% in the GLP-1 RA group after 26 weeks of treatment. The reduction in HbA1c was statistically significantly greater in the IDegLira group than in the GLP-1 RA group (estimated mean treatment difference: -0.94%-point [-1.11; -0.78]95%CI, p<0.0001), confirming superiority of IDegLira relative to unchanged GLP-1 RA therapy. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 61 of 133

Estimated treatment differences with 95% confidence intervals for IDegLira vs. comparator are presented. Missing data are imputed using the last observation carried forward method. Dotted line represents the superiority limit of 0%. The non-inferiority margin used in Trials 3697 and 3952 for the IDegLira vs. basal insulin comparison was 0.3%-point (solid line). Abbreviation: ETD = estimated treatment difference; IDeg = insulin degludec; GLP-1 RA = glucagon-like peptide-1 receptor agonist; HbA1c = glycosylated hemoglobin; N = number of subjects

Figure 6–6 HbA1c change from baseline (%-point) – completed phase 3 trials – plot of estimated treatment differences – FAS

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diabetes, baseline HbA1c) is presented in Section 6.1.7.9 (U.S. vs. non-U.S. population) and Appendix 4.

6.1.7.2 HbA1c target responders

Endpoints relating to HbA1c target response at week 26 were pre-specified as supportive secondary in all five trials (Table 6–3). The proportions of IDegLira-treated patients achieving the ADA HbA1c target of <7.0% or the AACE target of ≤6.5% after 26 weeks of treatment ranged from approximately 60 to 80% and 45 to 70%, respectively, across the five phase 3 trials (Table 6–9). The proportions of patients achieving these treatment targets were consistently greater with IDegLira than with comparator treatments, resulting in greater odds of reaching the aforementioned HbA1c targets with IDegLira across all trials (p<0.0001 for all comparisons). The results of the sensitivity analyses for the HbA1c <7.0% endpoint consistently supported the conclusion of the pre-specified LOCF analysis (Appendix 3, Table 1−2). The low responder rate for the basal insulin group of the pivotal Trial 3912 (IDegLira vs. IDeg in basal insulin users) should be considered in light of the fact that the maximum insulin dose in the IDeg comparator arm was limited to 50 units. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 65 of 133

Table 6–9 Patients reaching HbA1c <7.0% or ≤6.5% after 26 weeks – completed phase 3 trials - FAS Trial IDegLira Basal GLP-1 RA Placebo IDegLira vs. IDegLira vs. IDegLiravs. HbA1c target Insulin basal insulin GLP-1 RA placebo n (%) n (%) n (%) n (%) OR [95% CI] OR [95% CI] OR [95% CI] Trial 3697 (OAD users) <7.0% 671 (80.6) 269 (65.1) 250 (60.4) 2.38 [1.78; 3.18]* 3.26 [2.45; 4.33]* ≤6.5% 581 (69.7) 196 (47.5) 170 (41.1) 2.82 [2.17; 3.67]* 3.98 [3.05; 5.18]*

Trial 3951 (OAD users) <7.0% 229 (79.2) 42 (28.8) 11.95 [7.22; 19.77]* ≤6.5% 185 (64.0) 18 (12.3) 16.36 [9.05; 29.56]*

Trial 3912 (basal insulin users) <7.0% 120 (60.3) 46 (23.1) 5.44 [3.42; 8.66]* ≤6.5% 90 (45.2) 26 (13.1) 5.66 [3.37; 9.51]*

Trial 3952 (basal insulin users) <7.0% 199 (71.6) 131 (47.0) 3.45 [2.36; 5.05]* ≤6.5% 154 (55.4) 86 (30.8) 3.29 [2.27; 4.75]*

Trial 3851 (GLP-1 RA users) <7.0% 220 (75.3) 52 (35.6) 6.84 [4.28; 10.94]* ≤6.5% 184 (63.0) 33 (22.6) 7.53 [4.58; 12.38]*

*p <0.0001 Basal insulin comparator: IDeg (Trials 3697, 3912) and IGlar (Trial 3952). GLP-1 RA comparator: liraglutide (Trial 3697) and liraglutide/exenatide (Trial 3851). Missing data are imputed using the last observation carried forward method. Abbreviations: CI = confidence interval, GLP-1 RA = glucagon-like peptide-1 receptor agonist, HbA1c = glycosylated hemoglobin, IDegLira = insulin degludec/liraglutide, n = number of responders, OR = odds ratio Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 66 of 133

6.1.7.3 Fasting plasma glucose

Fasting glycemia is an important indicator of overall glycemic control (e.g., HbA1c level) and was evaluated in the IDegLira clinical development program. Both the IDeg and liraglutide components of IDegLira have demonstrated effective fasting glycemic control in their respective development programs in patients with diabetes.42, 43 FPG was a pre-specified supportive secondary endpoint in all five completed trials (Table 6–3).

Baseline FPG levels were similar between treatment groups within each of the phase 3 trials. The results of statistical analyses on fasting plasma glucose (FPG) are presented in Table 6–10.

The self-measured fasting plasma glucose target to which IDegLira and insulin comparators were titrated was the same for the pivotal Trial 3697 (IDegLira vs. IDeg in OAD users) and Trial 3952 (IDegLira vs. IGlar in basal insulin users). Therefore, no difference between IDegLira and basal insulin comparator was noted for these trials with respect to FPG change from baseline. The similarity in achieved FPG levels supports that the observed differences in HbA1c were not the result of titration differences between groups. The FPG difference in favor of IDegLira relative to IDeg in Trial 3912 (IDegLira vs. IDeg in basal insulin users) should be considered in light of the fact that the maximum insulin dose in the IDeg comparator arm was limited to 50 units.

For both trials that included a GLP-1 RA comparator arm (Trial 3697 in OAD users and Trial 3851 in GLP-1 RA users), the FPG reduction from baseline was statistically significantly greater for IDegLira than for GLP-1 RA treatment (Table 6–10).

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6.1.7.4 Postprandial glycemic control As elevated PPG concentrations contribute to suboptimal overall glycemic control and are targeted by the liraglutide component of IDegLira,44 post-prandial glucose control was assessed in the IDegLira development program. In line with liraglutide’s mechanism of action (i.e., stimulation of insulin secretion in response to increased blood glucose concentrations), reductions in post-prandial glycemia were previously consistently demonstrated with liraglutide doses up to 1.8 mg in the Victoza® development program.42

The postprandial pharmacodynamic effects of IDegLira were evaluated with a meal test and CGM (described later in this section) in a pre-specified sub-population of 260 patients from the pivotal Trial 3697 (IDegLira vs. IDeg and liraglutide in OAD users). In the meal test evaluation, frequent blood sampling was performed during a 4-hour period after consumption of a standardized meal at baseline and after 26 weeks of treatment. The postprandial glucose endpoint was based on the area under the glucose curve 0−4 hours after start of the standardized meal, counting only the area above the glucose reference value collected 10 minutes prior to meal start. The resulting area was divided by the length of the observation period to yield the pre-defined normalized endpoint of change in prandial glucose increment (iAUC0-4h) at week 26. This pre-specified confirmatory secondary endpoint for Trial 3967 was analyzed with an adjustment for multiplicity.

The results of the meal test in Trial 3697 (IDegLira vs. IDeg and liraglutide in OAD users) demonstrated that the liraglutide component of IDegLira contributed significantly to postprandial glycemic control. Mean baseline glucose iAUC0-4h was similar across treatment groups (approximately 74 mg/dL). The reduction in prandial glucose increment at week 26 was statistically significantly greater with IDegLira than with IDeg, thus confirming the superiority of IDegLira for this endpoint (Figure 6–7). The reduction in iAUC0-4h was similar for IDegLira and liraglutide, which demonstrates the preserved contribution of the liraglutide component of IDegLira to postprandial glycemic control when combined with exogenous insulin. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 69 of 133

p = 0.0023 (adjusted significance level: 0.05) vs. IDeg Data are observed means ± SE collected 4 hours after a breakfast meal in a pre-specified Trial 3697 sub-study population of 260 patients. The Holm-Bonferroni method is used to calculate the adjusted significance level for IDegLira-IDeg treatment difference taking into account the analyses of body weight, insulin dose and hypoglycemic episodes. Missing data are imputed using the LOCF method. Abbreviations: CI = confidence interval, IDeg = insulin degludec; LOCF = last observation carried forward; SE = standard error Figure 6–7 Change in post-prandial glucose increment after 26 weeks – Trial 3697 (IDegLira vs. IDeg and liraglutide in OAD users) – sub-study analysis set

In addition to the assessment of postprandial glucose excursions, the effect of IDegLira, IDeg and liraglutide was evaluated by assessing insulin secretion relative to glucose excursion (insulin secretion ratio) during the meal test in Trial 3697 (OAD users). The insulin secretion ratio for IDegLira at week 26 was statistically significantly higher than for IDeg (33.8 versus 25.7 [pmolinsulin/L×min]/[mmolglucose/L×min]; p=0.048) but similar to the ratio for liraglutide (33.8 versus 36.8 [pmolinsulin/L×min]/[mmolglucose/L×min]; p=0.45). These results demonstrate that the effect of the liraglutide component of IDegLira on endogenous post-prandial insulin secretion is preserved when administered in combination with exogenous insulin (IDeg).

CGM was employed in the same subset of 260 patients in Trial 3697 (OAD users) as the above-mentioned standardized meal test to further characterize the glycemic efficacy of IDegLira versus component comparators. The patients wore the CGM device for a minimum of 72 hours for every recording: 3−4 days just before the randomization visit and at weeks 26 and 52. The CGM system recorded interstitial glucose (IG) values every 5 minutes in order to generate individual glucose profiles. The increment in IG across all meals (derived from the CGM data) was a pre-specified supportive secondary endpoint in Trial 3697 (OAD users).

Technical issues with the CGM device resulted in the loss of 26% of data at week 0 (randomization) and 50% of data at week 26 for the U.S. patients who participated in the sub-study. As the CGM data were missing for technical reasons, they were considered to be missing completely at random. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 70 of 133

As such, an analysis based on observed values was considered to be valid and the CGM results are presented based on observed values instead of the pre-specified LOCF approach. Consistent with the findings from the dedicated meal test (Figure 6–7), the increment in IG across all meals (as measured 90 min after individual meal consumption) was reduced to a statistically significantly greater extent with IDegLira relative to IDeg (Figure 6–8). Similar reductions in IG increment across all meals were observed between IDegLira and liraglutide after 26 weeks of treatment.

Data are means from the substudy analysis set. p=0.0290 vs degludec, p-value not significant vs liraglutide. Abbreviations: CGM = continuous glucose monitoring; ETD = estimated treatment difference; IDeg = insulin degludec; IG = interstitial glucose Figure 6–8 Change from baseline at week 26 in post-prandial increment across all meals (based on IG profiles from CGM) – Trial 3697 (IDegLira vs. IDeg and liraglutide in OAD users) - observed values

Taken together, the results for the change in post-prandial increment from the meal test and across all meals (CGM assessment) indicate that the postprandial effect of liraglutide is preserved in the IDegLira combination product.

6.1.7.5 Insulin dose The association of insulin therapy with risks of weight gain and hypoglycemia presents a barrier to the initiation and intensification of insulin-containing therapies. Given the relationships between insulin dose and body weight as well as insulin dose and hypoglycemia, insulin dose was included in the efficacy evaluation of IDegLira. Insulin dose was a pre-specified confirmatory (i.e., analyzed with an adjustment for multiplicity) secondary endpoint in the pivotal Trial 3697 (previous OAD users). It was a pre-specified supportive secondary endpoint in the pivotal Trial 3912 and Trial 3952 (both in previous basal insulin users).

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Trial 3951) were on lower doses of IDegLira at the end of 26 weeks compared to patients previously treated with basal insulin (pivotal Trial 3912 and Trial 3952) or GLP-1 RA therapy (Trial 3851). The mean end-of-trial IDegLira dose ranged approximately 28−38 in Trials 3951 and 3697 (OAD users), 41−45 in Trials 3952 and 3912 (basal insulin users) and 43 in Trial 3851 (GLP-1 RA users), respectively. In total, 2 patients in Trial 3697 (IDegLira vs. IDeg and liraglutide in OAD users) were listed as receiving an IDegLira dose of >50 at week 26 based on LOCF data; both patients were withdrawn prior to the end of week 26 due to non-compliance with protocol.

Overall, 0−12.2% of patients in the five trials had IDegLira doses of ≤ 10 (containing liraglutide component doses of ≤ 0.36 mg) at week 26. The majority of patients in all trials except Trial 3951 (OAD users) had titrated IDegLira to doses of ≥ 40 (Table 6–13). The highest proportions of patients on end-of-trial IDegLira doses of ≤ 10 were seen in Trials 3697 and 3951, in which IDegLira was added on to previous OAD therapy. An evaluation of change from baseline in HbA1c by end-of-trial IDegLira dose in Trials 3697 and 3951 (both in OAD users) demonstrated that IDegLira provided sufficient glycemic control for patients requiring doses of ≤ 10. This was evidenced by the clinically relevant mean HbA1c reductions from baseline (-1.2 to -1.5%-point) as well as end-of-trial mean HbA1c of 6.3% to 6.6% (i.e., below the ADA target of <7.0%).

Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 75 of 133 included in the present analysis). Trial NN2211-1571 had 4 treatment arms, comparing liraglutide doses of 0.65, 1.25 and 1.9 mg against placebo. Pooled together, the trials provided a liraglutide dose range of 0.045−1.90 mg for the dose-response analysis.

In the dose-response Figure 6–9, symbols represent the observed mean changes (95% CI) in HbA1c from baseline at liraglutide doses tested in each trial, while solid and dotted lines represent the model-estimated HbA1c response at the end of each trial throughout the evaluated dose range. For each trial, the table in Figure 6–9 shows model-estimated HbA1c response for liraglutide doses corresponding to those of the liraglutide component within IDegLira doses of 10, 20, 30, 40 and 50. An HbA1c response was evident throughout the investigated liraglutide dose range, including at doses well below the approved therapeutic dose of 1.2 mg (corresponding to the liraglutide component in IDegLira doses of <32). The model-estimated mean HbA1c reductions in the liraglutide dose range of 0.36 mg to 1.08 mg (corresponding to the liraglutide component in IDegLira doses of 10 to 30) ranged 0.28 to 0.99%-points for the two trials. The estimated liraglutide dose which provided half of the maximal glycemic effect (ED50) was 0.60 mg, corresponding to the dose of the liraglutide component within an IDegLira dose of 16. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 76 of 133

a IDegLira dose containing the corresponding shown dose of the liraglutide component. The end-of-trial HbA1c response was estimated with an Emax model, using least squares regression with no imputation of missing data and with additive and multiplicative baseline HbA1c covariate effects. Symbols represent observed mean changes (95% CI) in HbA1c from baseline with liraglutide doses tested in each trial. Solid line corresponds to the model-estimated HbA1c response for Trial NN2211-1310 and dotted line corresponds to the same for Trial NN2211-1571. Trial NN2211-1310: 164 subjects in the ITT, 143 contributing to the analysis. Trial NN2211-1571: 163 subjects in the ITT, 157 contributing to the analysis. Abbreviations: ∆ = change from baseline at the end of the trial; CI = confidence interval; ITT = intent to treat Figure 6–9 Liraglutide dose-response showing observed (symbols) and model-estimated (lines) changes from baseline in HbA1c (%) for Trials NN2211-1310 and -1571 – ITT analysis sets

Efficacy of IDegLira at end-of-trial doses of ≤32

Consistent with the titration of IDegLira according to individual patient needs, the end-of-trial doses in the five completed phase 3 trials were distributed throughout the entire dose range (≤ 10 to 50). As IDegLira doses of ≤32 contain less liraglutide component than the lowest approved therapeutic dose for T2DM (1.2 mg), the maintenance of IDegLira efficacy at doses of ≤32 (as well as the contribution of the liraglutide component to the observed efficacy) was evaluated. An HbA1c-lowering effect of liraglutide at doses below 1.2 mg was previously demonstrated in the Victoza® development program (see previous section). The glycemic efficacy of the liraglutide component at low doses was thus evaluated for confirmation in the IDegLira trials. It should be noted that in the treat-to-target trials described below, patients were not randomized at baseline to different doses of IDegLira, thus limiting the conclusiveness of this post hoc evaluation.

To enable the above-mentioned evaluation, data from three trials with basal insulin comparators (pivotal Trials 3697, 3912 and Trial 3952) were examined. A comparison of baseline characteristics of patients treated with IDegLira doses of ≤32 (approximately 13−33% of patients across the trials) versus >32 at week 26 showed that on average the patient population treated with IDegLira doses of Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 77 of 133

≤32 was older (56−61 years vs. 54−58 years), had a lower percentage of males (37−48% vs. 54−58%), higher percentage of Asian patients (1.5−36% vs. 3.8−23%) and lower mean HbA1c (8.1−8.5% vs. 8.4−8.8%), FPG (144−151 mg/dL vs. 166−179 mg/dL )and body weight (79−89 kg vs. 91−96 kg) compared to the patient population treated with IDegLira doses of >32.

To evaluate whether the benefits of IDegLira are retained in the subset of patients using a dose of ≤32 at week 26, endpoints related to glycemic control, hypoglycemia and body weight were assessed and compared between patients with end-of-trial doses of ≤32 and >32. On average, similar improvements in glycemic control and body weight were seen in the subsets of patients on IDegLira doses of either ≤32 or >32 (Table 6–14 and Table 6–15). Although the rates of confirmed hypoglycemia (patient unable to treat himself/herself and/or has a recorded PG < 3.1 mmol/L or 56 mg/dL) in the three trials were higher in the subset of patients treated with an IDegLira dose of ≤32 compared to the subset treated with >32, they were lower than the event rates seen with basal insulin comparators in the ≤32 subgroup.

In each subpopulation (at week 26 titrated IDegLira doses of ≤32 or >32), greater improvement in overall glycemic control (i.e., HbA1c) and body weight at no increased rate of hypoglycemia were seen with IDegLira versus basal insulin comparators across the three trials (Table 6–14 and Table 6–15). This demonstrates that the liraglutide component contributes to the clinical efficacy of IDegLira, even at doses <1.2 mg (corresponding to liraglutide within IDegLira doses of ≤32). The similar decreases from baseline and end-of-trial FPG values exclude the possibility that the improved overall glycemic control with IDegLira relative to insulin comparator could be due to titration differences between the groups.

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Data are baseline-adjusted mean HbA1c changes from baseline with 95% CI versus dose of IDeg (left) and versus dose of liraglutide (right). Doses are shown in percentiles and by treatment for IDegLira and IDeg (left) and for IDegLira (right). One dose group is shown for the liraglutide comparator group (right) as all patients in this group received a maintenance dose of 1.8 mg. Abbreviations: CI = confidence interval; HbA1c = glycosylated hemoglobin; IDeg = insulin degludec

Figure 6–10 Change in HbA1c from baseline to week 26 plotted against doses at week 26 of IDegLira and IDeg (left) or IDegLira and liraglutide (right) – Trial 3697

In summary, several lines of evidence support the conclusion that the liraglutide component contributes to IDegLira’s HbA1c-lowering effect across the entire dose range, including at doses below the approved therapeutic dose of 1.2 mg (contained in IDegLira doses of <32):

 At the end of the five trials, patient exposure to IDegLira was distributed throughout the dose range (≤ 10 to 50).  The exposure-response (Section 5.3) and dose-response evaluations of IDegLira against IDeg and liraglutide comparators in the pivotal Trial 3697 (OAD users) demonstrated the contribution of both components of IDegLira to its overall glycemic effect throughout the dose range.  A dose-response analysis of two dose-ranging trials from the Victoza® development program demonstrated that liraglutide lowered HbA1c at doses below 1.2 mg. HbA1c reductions of 0.28 to 0.99%-points were estimated for liraglutide doses ranging 0.36 mg to 1.08 mg, respectively.

 Finally, the contribution of low doses of liraglutide to the HbA1c-lowering effect of IDegLira was seen in Trials 3697, 3912 (both pivotal) and 3952 for the comparison of IDegLira against basal insulins at doses of IDegLira < 32 or basal insulin < 32 units. The results showed that IDegLira effected larger reductions in HbA1c at similar insulin doses, thus reflecting the contribution of the liraglutide component. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 81 of 133

6.1.7.7 Body weight The weight gain commonly observed with insulin treatment may present a barrier for initiation and intensification of insulin therapy.31 Change in body weight from baseline to week 26 was therefore included as a pre-specified confirmatory secondary endpoint (i.e., analyzed with an adjustment for multiplicity) for the pivotal Trial 3697 in patients on previous OAD therapy (for IDegLira versus IDeg) and Trial 3952 in patients on previous basal insulin therapy (IDegLira versus IGlar). For the three remaining trials, the change from baseline in body weight was a pre-specified supportive secondary endpoint.

Patients inadequately controlled on oral antidiabetic drugs: pivotal Trial 3697 and Trial 3951

Superiority of IDegLira over IDeg in regard to change in body weight was confirmed in Trial 3697 based on pre-defined secondary confirmatory analysis (Figure 6–11). With IDegLira, the weight- reducing effect of the liraglutide component appeared to counter-balance the weight gain commonly associated with insulin treatment. A comparison of IDegLira to liraglutide 1.8 mg in Trial 3697 demonstrated a weight disadvantage of IDegLira (Figure 6–11). This finding was not unexpected, given the weight gain commonly associated with the basal insulin component of IDegLira.

Viewed solely as a function of time, patients on IDegLira on average experienced little change in weight during 26 weeks of treatment. This can be seen as an average weight loss of 0.5 kg at week 26 in patients treated with IDegLira as an add-on to metformin ± pioglitazone in Trial 3697 (Figure 6–11), as well as an average weight gain of 0.5 kg in patients treated with IDegLira as an add-on to SU ± metformin (Trial 3951). The weight change difference of 1.5 kg in favor of placebo at the end of Trial 3951 resulted from the above-mentioned slight average weight gain in the IDegLira group and an average weight loss of 1.0 kg in the placebo group. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 82 of 133

*p<0.0001, **p<0.001; Change from baseline in body weight was a pre-specified confirmatory efficacy endpoint for Trial 3697 (for IDegLira versus IDeg) and a pre-specified supportive secondary endpoint in Trial 3951. Missing data were imputed using the last observation carried forward method. The Holm-Bonferroni adjusted significance threshold in Trial 3697 (vs. IDeg) was 0.0167. Abbreviations: BL = baseline; CI = confidence interval; ETD = estimated treatment difference; IDeg = insulin degludec; OAD = oral antidiabetic drug Figure 6–11 Change from baseline in body weight (kg) – Trials 3697 and 3951 in OAD users – FAS

Patients inadequately controlled on basal insulin: pivotal Trial 3912 and Trial 3952

The estimated treatment differences for change in body weight show the consistent weight benefit of IDegLira treatment relative to basal insulin comparators (Figure 6–12). Superiority of IDegLira over the upward titration of IGlar with respect to change in body weight was confirmed based on pre-defined confirmatory secondary analysis in Trial 3952. The weight benefit of IDegLira relative to IDeg in Trial 3912 was demonstrated at similar end-of-trial basal insulin doses (see Section 6.1.7.5), reflecting the weight-reducing contribution of the liraglutide component of the combination product. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 83 of 133

*p<0.0001, **p<0.001; Change from baseline in body weight was a pre-specified confirmatory efficacy endpoint for Trial 3952 (the Holm-Bonferroni adjusted significance threshold was 0.0167) and a pre-specified supportive secondary endpoint in Trial 3912. Missing data were imputed using the last observation carried forward method. Abbreviations: BL = baseline; CI = confidence interval; ETD = estimated treatment difference; IDeg = insulin degludec Figure 6–12 Change from baseline in body weight (kg) – Trials 3912 and 3952 in basal insulin users – FAS

Patients inadequately controlled on GLP-1 receptor agonists: Trial 3851

Consistent with the comparison results for IDegLira versus liraglutide in Trial 3697 (OAD users) described above, a weight disadvantage of IDegLira relative to continued GLP-1 RA therapy was also seen in Trial 3851 (Figure 6–13).

**p<0.001; Change from baseline in body weight was a pre-specified supportive secondary endpoint. Missing data were imputed using the last observation carried forward method. Abbreviations: BL = baseline; ETD = estimated treatment difference; GLP-1 RA = glucagon-like peptide 1 receptor agonist Figure 6–13 Change from baseline in body weight (kg) –Trial 3851 in GLP-1 RA users– FAS

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The methodology and results for the above-mentioned PRO measures are described in Appendix 5. A brief summary of the results is provided below.

After 26 weeks of treatment in Trial 3952 (basal insulin users), patients receiving IDegLira demonstrated improvement relative to patients receiving IGlar in the physical component summary score of the SF-36v2 (a general health questionnaire), driven by improvements in all four component scores. Improvements in the total score of the diabetes-specific PRO measure, TRIM-D, were seen with IDegLira versus IGlar and GLP-1 RA comparators at week 26 in Trials 3952 (basal insulin users) and 3851 (GLP-1 RA users), respectively. In Trial 3851 (GLP-1 RA users), the treatment satisfaction score in the diabetes-specific PRO instrument, DTSQs, was better with IDegLira than with continued GLP-1 RA therapy after 26 weeks of treatment. Although these supportive results have limitations due to the open-label designs of both trials, they suggest perceived benefits of IDegLira treatment.

6.1.7.9 Efficacy in the U.S. population The consistency of findings in the U.S. trial population (approximately one-third of the total across the five completed trials) and the non-U.S. trial population in regard to the primary and pre-defined confirmatory (i.e., analyzed with an adjustment for multiplicity) secondary endpoints of insulin dose, postprandial increment (iAUC0−4h) and body weight were examined post hoc and are discussed below. Baseline characteristics of the total and U.S. populations are described in Section 6.1.4.

Overall, differences between the U.S. and non-U.S. populations were quantitatively small across the trials (Table 6–17). Further, the data indicate that all important between-arm differences identified in the full trial cohorts were preserved in the U.S. subpopulation as follows:

 IDegLira effected greater reductions in HbA1c than any comparator (including the individual components)  An insulin sparing effect of IDegLira was demonstrated against basal insulin comparators with no maximum dose limit (IDeg in Trial 3697 in OAD users and IGlar in Trial 3952 in basal insulin users)  In the meal test sub-study of Trial 3697 (OAD users), the reduction from baseline in iAUC0−4h was similar between IDegLira and liraglutide and greater with IDegLira relative to IDeg. This demonstrated the contribution of the liraglutide component of the combination product to post-prandial glycemic control  A consistent weight benefit with IDegLira was seen relative to basal insulin treatment and a corresponding weight disadvantage relative to liraglutide/continued GLP-1 RA treatment

Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 88 of 133 persistence of efficacy, the mean daily dose of IDegLira was essentially unchanged from week 12 until the end of the 52-week trial period. In contrast, the daily dose of IDeg continued to increase during the 52-week treatment period to maintain the self-measured fasting plasma glucose target (Figure 6–14).

Data are means. HbA1c data are presented using the FAS and insulin dose data are presented using the SAS, resulting in different N in the figure. Missing data are imputed using the last observation carried forward method. Abbreviations:

FAS = full analysis set; HbA1c = glycosylated hemoglobin; N = number of patients included in the analyses; SAS = safety analysis set

Figure 6–14 HbA1c and insulin dose during 52 weeks of treatment – Trial 3697-ext (52 weeks) in OAD users –FAS

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7 Clinical safety Summary  Across the five completed phase 3 trials, 1881 patients were exposed to IDegLira for a total of approximately 1200 patient-years, and the combined exposure to comparator treatment was of a similar magnitude. The main trial period was 26 weeks for all phase 3 trials, with additional exposure derived from the 26-week extension period of Trial 3697-ext.  The overall rates of AEs and SAEs for IDegLira were comparable to the rates for IDeg and liraglutide as well as the other comparator treatments, and no unexpected patterns in the reported AEs and SAEs were observed.  In addition to a non-treatment emergent fatal event of gun-shot wound, 4 deaths were reported in the completed IDegLira clinical development program, 3 during IDegLira treatment and 1 during insulin glargine treatment.  Severe hypoglycemia occurred rarely in the IDegLira phase 3 trial program and at similar rates across groups. Rates of confirmed hypoglycemia (severe episodes or episodes with a plasma glucose <56 mg/dL) and documented symptomatic hypoglycemia (ADA definition) were generally lower for IDegLira relative to basal insulin comparators. Conversely, the rates of such hypoglycemia events were higher with IDegLira than with GLP-1 RA comparator treatment.  The gastrointestinal side effects associated with GLP-1 RA treatment (such as nausea, diarrhea and vomiting) occurred less frequently with IDegLira than with liraglutide during the initial weeks of treatment as demonstrated in the pivotal Trial 3697. Similarly, the proportion of patients with gastrointestinal events leading to withdrawal was lower in the IDegLira group than in the liraglutide group. Conversely, the proportions of patients with nausea, diarrhea and vomiting were generally higher for IDegLira than for basal insulin treatment across the phase 3 trial program.  No events of pancreatitis were confirmed by the event adjudication committee for patients receiving IDegLira. Increases in mean lipase and amylase activities from baseline to end of trial were observed in the IDegLira and GLP-1 RA groups, which is consistent with previous observations for liraglutide and not indicative of an increased risk of pancreatitis.  The IDegLira clinical development program was not designed to generate a cardiovascular outcome assessment. The currently available data indicate that the cardiovascular profile of IDegLira is consistent with that of the individual components. Cardiovascular biomarker changes observed with IDegLira were in line with the well-established effects of each component. FDA approved IDeg (Tresiba®) in September 2015 based on an interim analysis of the ongoing cardiovascular outcomes trial for IDeg (DEVOTE®) comparing IDeg to IGlar in a double-blind trial evaluating over 7000 patients. The cardiovascular outcomes trial for liraglutide (LEADER®) has recently been completed and confirmed the cardiovascular safety of liraglutide compared to placebo when each was added to standard of care. Both trials enrolled a population of T2DM patients at high risk of major adverse cardiovascular Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 91 of 133

7.1 Safety methods The development strategy for IDegLira builds upon the nonclinical and clinical data obtained in the individual development programs for IDeg and liraglutide. Therefore, the IDegLira data should be considered in the context of the results derived from the extensive exposure during clinical development of IDeg and liraglutide and subsequent market use of Tresiba® and Victoza® (Appendix 1).

The safety evaluation for the IDegLira clinical development program is primarily based on the safety outcome of the five completed phase 3 trials. These were controlled trials in patients with T2DM in which IDegLira dosing and treatment resembled the intended clinical setting. For details of treatment regimens including comparator treatments, see Table 6–1. Of note, no serious adverse events (SAEs), deaths or other medical events of special interest were recorded in the clinical pharmacology program, which comprised single-dose trials in healthy subjects.

The overall distributions of adverse events are presented separately for the pivotal Trials 3697 and 3912 comparing IDegLira to its components (IDeg and liraglutide) as well as for the five completed phase 3 trials pooled. The safety evaluation of Trial 3697 is based on the entire 52-week treatment period (hereafter called Trial 3697-ext). Results for hypoglycemia and gastrointestinal events are presented on an individual trial basis to account for differences in trial populations. The presentation of results for the remaining safety areas of special interest is based on pooled analyses due to the low number of events within each category.

For the pooled analyses, treatment arms across the five phase 3 trials are pooled into treatment groups of IDegLira (all trials), basal insulin (IDeg in Trials 3697-ext and 3912; IGlar in Trial 3952), GLP-1 RA (liraglutide in Trial 3697-ext and continued GLP-1 RA treatment in Trial 3851) and placebo (Trial 3951). It is recognized that this pooled data approach does not take into account the Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 92 of 133 potential bias caused by differences in trial designs including differences in randomization ratios across trials (Simpson’s paradox). To account for this, adjusted event rates and percentages of patients with events are provided for overall AEs and SAEs as well as for events within each of the safety areas of special interest. For the applied statistical methods see Appendix 6.

Safety areas of special interest were predefined based on the potential and established areas of safety interest for IDeg and liraglutide. Specific types of adverse events within these areas of interest were pre-specified in the phase 3 trial protocols as ‘medical events of special interest’, and additional information was collected for these events to support a comprehensive evaluation of these events. Cardiovascular events (pre-specified event categories; see Appendix 7, Table 11), pancreatitis or suspicion of pancreatitis, neoplasms, thyroid disease requiring thyroidectomy and fatal events were sent for adjudication, which was performed by an external independent event adjudication committee that was blinded to trial treatment. Events eligible for adjudication were identified through reporting of medical events of special interest as well as through pre-defined searches among all reported AEs. In addition, cases of increased calcitonin levels were evaluated by an independent and blinded committee of thyroid experts. The medical events of special interest as well as the process of collection, evaluation and adjudication of these events are described in detail in Appendix 7. In the following, ‘confirmed’ adverse events refer to events that were confirmed via adjudication by the event adjudication committee. As a result, the number of ‘confirmed’ events may differ from the general tabulations of adverse events. Adverse events are treatment emergent events (onset on or after the first day of treatment and no later than 7 days after the last day of treatment) unless otherwise specified.

Subsequent to the NDA submission, blinded safety data (serious adverse events, pregnancies and adverse event leading to dose reduction or withdrawal) from three ongoing phase 3 trials were submitted to the FDA in a 120-Day Safety Update to the NDA. Among the serious adverse events included in the 120-day safety update, a death and a spontaneous abortion were reported, and these two events are described further below. A summary of the 120-day safety update is included in Appendix 8.

7.2 Safety population and exposure Exposure in the completed phase 3 trials is summarized in Table 7–1. In the pivotal Trials 3697-ext and 3912 combined, 1024 patients were exposed to IDegLira for a total of 797.5 PYE, and the combined exposure to IDeg and liraglutide was of a similar magnitude. Trial 3697-ext, comparing IDegLira against IDeg and liraglutide, accounted for the majority of the exposure.

Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 94 of 133 subgroups), the additional exposure in the IDegLira program is considered sufficient to provide information on the safety of IDegLira within investigated ethnic and racial subgroups.

Additional blinded safety data from three ongoing phase 3 trials was submitted to the FDA in a 120-Day Safety Update. Based on the randomization ratio and the number of patients randomized, exposure to IDegLira in these ongoing trials is estimated to have occurred in 529 patients (Trial 4119: 31 patients; Trial 4056: 420 patients; Trial 4185: 78 patients). For further details see Appendix 8.

7.3 Adverse events Frequencies of AEs reported in Trials 3697-ext and 3912 (the two pivotal trials comparing IDegLira to its components, IDeg and liraglutide) as well as in the completed phase 3 trial program are summarized in Table 7–3, Table 7–4 and Table 7–5, respectively. The rates of AEs and SAEs for IDegLira were overall comparable to the rates for IDeg and liraglutide as well as the other comparator treatments, and no unexpected patterns in the reported AEs and SAEs were observed. Severe and serious adverse events were reported for a minority of patients across trials. The lower rate of AEs possibly or probably related to trial product with IDegLira than with liraglutide comparator treatment is partly explained by differences between groups in the occurrence of gastrointestinal events such as nausea, diarrhea and vomiting, which are common side effects of GLP-1 RA treatment (Section 7.3.5.2).

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7.3.1 Common adverse events Overall, the most common adverse events in Trials 3697-ext and 3912 as well as in the five completed phase 3 trials pooled were common infections (‘nasopharyngitis’, ‘influenza’ and ‘upper respiratory tract infection’), gastrointestinal events (‘nausea’, ‘vomiting’ and ‘diarrhea’), ‘headache’, ‘lipase increased’ and ‘decreased appetite’ (Table 7–6).

In addition to the commonly occurring adverse events of headache and infections/infestations, the most frequently reported events were gastrointestinal adverse events of nausea, vomiting and diarrhea, and consistent with the known side effects of GLP-1 RA treatment these gastrointestinal events were primarily reported in the IDegLira and GLP-1 RA treatment groups. For further details see Section 7.3.5.2.

In the five completed phase 3 trials pooled, events of increased lipase were reported with greater frequency in patients in the IDegLira and GLP-1 RA groups (11.4 and 14.6 and events per 100 PYE, respectively) than for patients in the basal insulin and placebo groups (7.4 and 6.5 events per 100 PYE); Table 7–6.

Hypoglycemia (which was reported separately) was the most frequently reported type of event. A safety evaluation of hypoglycemia is included in Section 7.3.5.1.

Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 100 of 133 treatment and 0.7% for placebo (adjusted incidences). The difference in the proportion of patients withdrawing due to AEs between IDegLira and GLP-1 RA groups was mainly attributable to a lower proportion of patients with gastrointestinal events leading to withdrawal in the IDegLira group than in the GLP-1 RA group (0.4% versus 2.7% of patients; adjusted incidences for pooled analysis). The adjusted rates of AEs of elevated lipase and/or amylase leading to withdrawal were low for IDegLira and GLP-1 RA treatment (0.7 and 2.1 events per 100 PYE, respectively), with no withdrawals in relation to elevated amylase or lipase reported for basal insulin or placebo treatment. No other patterns or differences between IDegLira and comparators were noted for AEs leading to withdrawal.

Patients with adverse events leading to withdrawal are presented for event types occurring in > 0.2% of patients in any active treatment group in Table 7–9.

For adverse events leading to withdrawal during the reporting period of the 120-day safety update, please see Appendix 8, Section 1.3.4.

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Table 7–11 Severe hypoglycemia events – completed phase 3 trials

Safety analysis set. N: number of patients with events; %: percentage of patients with events; E: number of events. R: event rate (number of events per 100 PYE).

Results for confirmed hypoglycemia and documented symptomatic hypoglycemia are presented in Table 7–12 and Table 7–13, respectively. In the pivotal Trial 3697 in subjects inadequately controlled on OADs, the pre-specified statistical analysis for confirmed hypoglycemia showed a statistically significant 32% lower rate of confirmed hypoglycemic episodes with IDegLira relative to IDeg (estimated rate ratio: 0.68 [0.53; 0.87]95%CI; p= 0.0023) and a similar and statistically significant 37% lower rate of documented symptomatic hypoglycemic episodes with IDegLira relative to IDeg (estimated rate ratio: 0.63 [0.48; 0.82]95%CI, p=0.0007; post hoc analysis). In Trial 3952 in subjects inadequately controlled on IGlar and OADs, the pre-specified analyses for confirmed hypoglycemia showed a statistically significant 57% lower rate of confirmed hypoglycemic episodes with IDegLira relative to IGlar (estimated rate ratio: 0.43 [0.30; 0.61]95%CI, p<0.0001) and a similar and statistically significant 54% lower rate of documented symptomatic hypoglycemic episodes with IDegLira relative to IGlar (estimated rate ratio: 0.46 [0.34; 0.62]95%CI; p<0.0001; post hoc analysis). For results of sensitivity analyses on hypoglycemia endpoints, see Appendix 3.

Conversely, the rates of confirmed hypoglycemia and documented symptomatic hypoglycemia were higher with IDegLira than with GLP-1 RA comparator treatment. This is as expected, as GLP-1 RA treatment carries a low risk of hypoglycemia due to the glucose-dependent mode of action of this class of drugs.

The overall rate of confirmed hypoglycemia in the IDegLira group of Trial 3951 (receiving concomitant SU treatment) was higher than the rates observed for IDegLira treatment in Trials 3697 and 3912 (Table 7–12), and a similar trend toward increased hypoglycemia rates with concomitant SU treatment was observed for Trial 3851. This is in line with hypoglycemia results for concomitant administration of SU in the IDeg and liraglutide development programs. These results should be considered in the context that treatment with SU per se is associated with an increased risk of hypoglycemia.

Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 105 of 133 component of IDegLira. No differences between treatment groups were noted for severe hypoglycemia, which occurred rarely in the development program.

7.3.5.2 Gastrointestinal events In common with other GLP-1 receptor agonists, liraglutide treatment is associated with gastrointestinal side effects such as nausea, diarrhea and vomiting. These are primarily transient effects that occur most frequently during initiation of therapy.

Trial 3697-ext compared IDegLira against IDeg and liraglutide in patients uncontrolled on OADs, which enabled a comparison of gastrointestinal side effects of starting IDegLira versus liraglutide treatment. Adverse events of nausea, vomiting and diarrhea occurred approximately 50% less frequently with IDegLira than with liraglutide during the first approximately 10 weeks of treatment, after which the proportion of patients with events were similarly low and stable for both treatment groups (exemplified for nausea in Figure 7–1). This finding is likely due to the lower starting dose and more gradual increase in dose of the liraglutide component during IDegLira treatment initiation. Rates of severe gastrointestinal events over 52 weeks were 1.1 and 5.1 events per 100 PYE for IDegLira and liraglutide, respectively. Gastrointestinal events leading to withdrawal occurred in 4 (0.5%) patients in the IDegLira group and 18 (4.4%) patients in the liraglutide group. Most of the gastrointestinal events leading to withdrawal occurred during the first 6 weeks of treatment with liraglutide (Figure 7–2).

Consistent with IDegLira containing a GLP-1 RA component, the proportions of patients with nausea, diarrhea and vomiting were generally higher for IDegLira than for basal insulin treatment across the phase 3 trial program including Trial 3697-ext (Figure 7–1).

Figure 7–1 Percentage of Patients with Nausea by Week – Trial 3697-ext - Safety Analysis Set Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 106 of 133

Figure 7–2 Patients with gastrointestinal adverse events leading to withdrawal – cumulative plot – Trial 3697-ext - Safety Analysis Set

7.3.5.3 Pancreatic safety Based on comprehensive evaluations independently undertaken by FDA and European Medicines Agency, both agencies agree that assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer are inconsistent with the data.47 Similarly for liraglutide, a causal relationship between liraglutide and pancreatitis can neither be established nor excluded based on available data. Irrespectively, all GLP-1 based medicines carry label warnings concerning pancreatitis, and a similar label warning is proposed for IDegLira. Patients with a history of chronic and idiopathic acute pancreatitis were excluded from the IDegLira clinical program, and if a patient was suspected to have pancreatitis they were instructed to immediately discontinue the use of trial product. Across all five trials, the diagnostic criteria for acute pancreatitis required that at least 2 of the following 3 criteria were met: 1) characteristic abdominal pain, 2) amylase and/or lipase above 3×upper limit of normal and/or 3) characteristic findings on imaging of the .50

In the IDegLira trial program, events of pancreatitis as confirmed by the event adjudication committee comprised one event of acute pancreatitis with IDeg (non-treatment emergent) and two events of acute pancreatitis with liraglutide. An additional non-treatment emergent event of acute pancreatitis with liraglutide was not classifiable by the event adjudication committee due to incomplete information. One of the liraglutide-treated patients with confirmed pancreatitis was also diagnosed with pancreatic cancer stage IV. No events of pancreatitis were confirmed by the event adjudication committee for patients receiving IDegLira.

An increase in mean lipase and amylase activity from baseline to end of trial was observed in the IDegLira and GLP-1 RA groups, which is in agreement with previous observations for liraglutide. This is shown for Trial 3697-ext in Figure 7–3. In line with this, the proportion of patients with Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 107 of 133 elevated lipase or amylase levels was highest in the IDegLira and GLP-1 RA groups but was not increased for IDegLira relative to GLP-1 RA group (Table 7–14). In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreatic enzymes alone are not predictive of acute pancreatitis,49, 50 and the results for lipase and amylase are not considered indicative of an increased risk of pancreatitis with IDegLira treatment.

Data are mean +/- standard error of the mean. Lipase reference range: 0 - 60 U/L; Amylase reference range: 20 - 112 U/L Figure 7–3 Lipase and amylase concentrations over time – Trial 3697-ext – safety analysis set Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 108 of 133

Table 7–14 Incidence of lipase and amylase levels exceeding 3, 5 and 10 times the upper limit of normal (ULN) - completed phase 3 trials

Safety analysis set. a: Patient (Trial 3697, liraglutide) developed acute pancreatitis (EAC confirmed). N: number of patients, %: percentage of patients

7.3.5.4 Cardiovascular safety Cardiovascular diseases are the predominant cause of death in people with diabetes, and diabetes confers about a two-fold excess risk for coronary heart disease, stroke and deaths attributed to other vascular causes.3, 51 Cardiovascular events are considered events of special interest from both a clinical and a regulatory perspective.

The IDegLira clinical development program was not designed to generate a cardiovascular outcome assessment. The confirmation of the cardiovascular safety of IDegLira is based on the cardiovascular safety assessment of its components in their substantially larger development programs, including the cardiovascular outcomes trials for IDeg (DEVOTE®) and liraglutide (LEADER®). Key results on cardiovascular safety from the IDegLira clinical development program are summarized below.

Cardiac arrhythmia An increase in pulse of 2-3 beats per minute is a known effect of liraglutide treatment.52, 53 This was confirmed for the IDegLira program, which showed a mean pulse rate increase of approximately 2.5-3.0 beats/min at 26 weeks after initiation of IDegLira or GLP-1 RA treatment, consistent with previous findings for liraglutide. The increase in pulse rate had diminished to approximately 1.5-2.0 beats/min above the baseline level after 52 weeks of treatment in Trial 3697-ext. While no association between liraglutide and an increased risk of cardiac arrhythmias other than sinus tachycardia has previously been observed, cardiac arrhythmias remain an area of special interest for the GLP-1 RA class. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 109 of 133

In the pooled dataset comprising the five completed phase 3 trials, a total of 74 treatment-emergent cardiac arrhythmia events (in 64 subjects) were identified based on the predefined MedDRA search. Adjusted rates of cardiac arrhythmia events were 3.3, 3.1, 5.0 and 4.7 events per 100 PYE with IDegLira, basal insulin, GLP-1 RA and placebo, respectively, with no apparent differences in type of events between groups.

Cardiovascular events confirmed by adjudication Event adjudication was done for pre-specified categories of cardiovascular events in IDegLira phase 3 trial program. These categories were acute coronary syndrome (myocardial infarction, hospitalization for unstable angina); cerebrovascular event (stroke, transient ischemic attack); heart failure requiring hospitalization (new episode or worsening of existing heart failure); and coronary revascularization procedure.

In the five completed phase 3 trials pooled, a total of 36 cardiovascular events were confirmed by adjudication (Table 7–15), resulting in adjusted event rates of 1.3, 3.4, 1.3 and 0.0 events per 100 PYE with IDegLira, basal insulin, GLP-1 RA and placebo, respectively.

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Change from baseline is mean (SD) Missing data are imputed using the last observation carried forward method Figure 7–4 Systolic blood pressure (mmHg) – estimated treatment differences for change from baseline to end of trial - completed phase 3 trials - full analysis set

In conclusion, the currently available data indicate that the cardiovascular profile of IDegLira is consistent with that of the individual components. Cardiovascular biomarker changes observed with IDegLira were in line with the well-established effects of each component. FDA approved IDeg (Tresiba®) in September 2015 based on an interim analysis of the ongoing cardiovascular outcomes trial for IDeg (DEVOTE®) comparing IDeg to IGlar in a double-blind trial evaluating over 7000 patients. The cardiovascular outcomes trial for liraglutide (LEADER®) has recently been completed and confirmed the cardiovascular safety of liraglutide compared to placebo when each was added to standard of care. Both trials enrolled a population of T2DM patients at high risk of major adverse cardiovascular events (MACE), ensuring a clinically relevant cardiovascular risk assessment for each of the components based on significant numbers of accrued MACE events.

7.3.5.5 Neoplasms A possible association between antidiabetic therapy and cancer has been discussed for a number of years, as the incidence of some types of cancer is higher in patients with diabetes than in nondiabetic patients.57 The nature of the higher incidence of cancer in the diabetes population remains unclear. Available data do not indicate an increased risk of cancer with basal insulins, including IDeg. Neither liraglutide nor any of the other approved GLP-1 receptor agonists are mutagenic or genotoxic,10, 19, 58 and based on available clinical data there is no indication that GLP-1 receptor agonists are associated with an increased risk of cancer. Although there is no Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 113 of 133 indication of a causal relationship between neoplasms and treatment with either IDeg or liraglutide, neoplasms were regarded as a safety area of special interest in the IDegLira development program.

In the five completed phase 3 trials pooled, a total of 29 treatment-emergent neoplasms in 25 patients were confirmed by the external EAC. Rates of malignant events were 1.1, 0.5, 0.2 and 0.0 events per 100 PYE for IDegLira, basal insulin, GLP-1 RA and placebo treatment, respectively. In addition to these events, two non-treatment emergent events (‘breast cancer’ and ‘pancreatic carcinoma metastatic’) were reported following IDegLira treatment.

Neoplasm events occurred at similar frequencies across treatment groups, except for a numerical excess of infrequent events of skin neoplasm with IDegLira treatment (6 events reported for IDegLira versus 1 event for comparator treatments combined; Table 7–17). Corresponding adjusted event rates for skin neoplasms were 0.5, 0.2, 0.0 and 0.0 events per 100 PYE for IDegLira, basal insulin, GLP-1 RA and placebo treatment, respectively. Four of the 6 events with IDegLira (and the one event with comparator treatment) concerned non-serious events of basal cell carcinoma (Appendix 9, Table 13). Of note, basal and squamous cell skin cancers were not exclusion criteria in the completed phase 3 clinical trials. Growth of skin cancer cells (both basal and squamous cells) are thought to be primarily dependent on pathways other than insulin/IGF-1 signaling.59-61 Furthermore, no GLP-1 receptors have been detected in epidermal cells.62 Therefore, there is no mechanistic indication of an effect of IDeg or liraglutide on development or proliferation of skin cancers.

Including the non-treatment emergent event of ‘pancreatic carcinoma metastatic’ with IDegLira treatment mentioned above, events of pancreatic cancer confirmed by the event adjudication committee comprised one event each for IDegLira, IDeg and liraglutide. For further information on pancreatic safety see Section 7.3.5.3.

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7.3.5.6 Thyroid disease Thyroid disease was defined as a safety area of interest in the IDegLira development program due to findings in rodent C-cells in the liraglutide nonclinical development program. Medullary thyroid carcinoma is a rare form of cancer originating in the calcitonin-producing parafollicular C-cells of the thyroid gland. In the normal human thyroid gland there is no GLP-1 receptor expression,63, 64 but some medullary thyroid cancers express the receptor.64 Based on the finding of C-cell tumors in rodent studies, all GLP-1 RAs carry a labeled warning related to C-cell tumors including medullary thyroid carcinoma. There are no signals of an increased risk of thyroid disease or medullary thyroid carcinoma from the liraglutide clinical development programs or the ongoing post-marketing surveillance program for Victoza®.

Based on the pre-defined MedDRA query search for all thyroid disease events across the completed phase 3 trial program, adjusted event rates were 0.7, 0.7, 0.8 and 0.0 events per 100 PYE for IDegLira, basal insulin, GLP-1 RA and placebo treatment, respectively (Table 7–18).

One event of thyroid disease was confirmed (an event of ´goitre’ in a liraglutide-treated patient who underwent thyroidectomy). No events of medullary thyroid cancer were reported or identified in the IDegLira development program. Results of calcitonin assessments (a specific biological marker of medullary thyroid cancer and a potential predictor of C-cell neoplasia at levels ≥50 ng/L) were similar between treatment groups, with mean levels well below the upper limit of normal (ULN) for both genders (Figure 7–5). The proportion of subjects who had an incidental increase in calcitonin from <20 ng/L at baseline to ≥20 ng/L during the trial was 0.7%, 1.1%, 0.9 % and 0.7% in the IDegLira, basal insulin, GLP-1 RA and placebo groups, respectively. Of these, only one patient (in the basal insulin group) reported an adverse event related to thyroid disease (nontoxic multinodular goitre).

Figure 7–5 Mean calcitonin levels by treatment group – completed phase 3 trials –safety analysis set Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 116 of 133

Based on the above, there is no indication that IDegLira is associated with an increased risk of thyroid disease events relative to comparator treatments. As part of post-marketing risk management for IDegLira, it is proposed that IDegLira be incorporated into the US national medullary thyroid cancer registry that is already ongoing for the Victoza® program and the Saxenda® (liraglutide for the treatment for ) program.

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7.3.5.7 Immunogenicity Allergic reactions IDeg and liraglutide are peptide-based components, and therefore the potential for allergic reactions such as local reactions and immune-related reactions exists.

In the five completed phase 3 trials pooled, a total of 138 allergic reactions were identified for 116 patients based on a pre-defined MedDRA query search. The rates of allergic reactions were similar across treatment groups, with adjusted rates of 5.3, 6.5, 10.1 and 4.9 events per 100 PYE in the IDegLira, basal insulin, GLP-1 RA and placebo groups, respectively. The corresponding proportions of patients reporting events of allergic reaction were 2.7%, 3.7%, 4.7% and 3.1% of patients. The proportions of allergic reactions that had not resolved by the end of the trial were similar across active treatment groups (11.8−14.1% of events). Four (4) allergic reactions in 4 patients (2 events of ‘injection site rash’ and an event of ‘drug hypersensitivity’ in the IDegLira group and an event of ‘rash’ in the GLP-1 RA group) led to withdrawal from trial.

Single events of anaphylactic reaction and Stevens-Johnson syndrome were reported in the IDeg and liraglutide group, respectively. Both events were considered possibly related to concomitant medications by the investigator. The patients recovered from both events and continued trial product treatment.

Injection site reactions In the five completed phase 3 trials pooled, the adjusted rates of injection site reactions were 9.6, 18.3, 6.5 and 9.5 events per 100 PYE in the IDegLira, basal insulin, GLP-1 RA and placebo groups, respectively. The proportions of patients reporting injection site reactions were similar across the four treatment groups (adjusted proportions were 2.6%, 4.6%, 2.7% and 2.1%, respectively), and the event rate in the IDegLira group was partly driven by a few patients reporting several injection site reactions. Of the total of 183 injections site reactions reported, 161 were mild events. The rate of moderate injection site reactions was low and similar in the IDegLira, basal insulin and GLP-1 RA groups (0.9, 1.0 and 1.2 events per 100 PYE, respectively).

No events were severe or serious. Injection site reactions led to withdrawal by 3 patients, all in the IDegLira group. In addition to the 2 events of ‘injection site rash’ described under allergic reactions above, this total included a single event of ‘injection site pain’ in Trial 3951.

The most common preferred terms were ‘injections site bruising’, ‘injection site pain’, ‘injections site reaction’ and ‘injection site pruritus’. Event of ‘injections site bruising’ occurred with a higher rate in the IDegLira group than in the basal insulin and GLP-1 RA groups (6.3 versus 1.9 and 3.0 events per 100 PYE), which was driven by a few IDegLira-treated patients with multiple events. All events of ‘injections site bruising’ were mild in severity except for 5 events of moderate severity (2 events with IDegLira, 1 with basal insulin and 2 with GLP-1 RA treatment). Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 119 of 133

Antibody development All insulin preparations cause some degree of antibody development in humans, which is generally of no consequence for the efficacy and the safety of current insulin preparations.65, 66 Insulin antibodies arising from repeated drug exposure (IDeg-specific and antibodies cross reacting with human insulin) were investigated in Trials 3697 and 3912. These trials additionally assessed anti-liraglutide antibodies, including assessments for cross-reactivity to native GLP-1 and in-vitro neutralizing effect.

The proportions of patients with an increase in IDeg antibody titer (IDeg-specific antibodies or anti-IDeg antibodies cross-reacting to human insulin) from baseline to end-of-trial were low in both IDegLira and IDeg treatment groups in Trials 3697 and 3912. In the IDegLira groups of each trial a slight increase in the proportions of patients with an increase in cross-reacting antibodies was observed for IDegLira relative to IDeg, which likely reflects the variation in antibody levels generally observed with insulin preparations.

Anti-liraglutide antibody development was limited (< 3% patients). None of the anti liraglutide antibodies exhibited cross-reactivity towards native GLP-1.

Importantly, there was no indication that the presence of either IDeg-specific antibodies, anti-IDeg antibodies cross-reacting to human insulin, or anti-liraglutide antibodies affected the clinical safety of IDegLira as evidenced by the lack of correlation between the development of antibodies and the pattern in AEs. Allergic reactions occurring in patients with IDeg antibodies comprised 3 events in 3 patients treated with IDegLira in Trial 3697-ext (‘injection site erythema’, ‘atopy’ and ‘injection site mass’) and one event of ‘anaphylactic reaction’ with IDeg treatment in Trial 3912. In all 4 cases the patients recovered and continued trial product treatment. Allergic reactions occurring in patients with anti-liraglutide antibodies comprised an event of ‘rash macular’ with IDegLira treatment, an event of ‘abdominal rash’ with liraglutide treatment, and various injection site reactions and a ‘rash pruritic’ on the chest in a patient treated with liraglutide. All allergic reactions occurring in patients with anti-liraglutide antibodies occurred in Trial 3697-ext and were mild or moderate in severity, and in all cases the patients recovered and continued in the trial.

The observed immunogenic response to treatment with IDegLira neither reduced glycemic efficacy nor increased the drug dose requirement for the maintenance of glycemic control.

The low antibody response observed for IDegLira is consistent with the low antibody responses to IDeg and liraglutide observed in their respective development programs.

7.3.5.8 Additional adverse event categories No clinically relevant differences between IDegLira and comparators were noted for altered renal function, immune complex disease, errors, suspected transmission of infectious disease via trial product, hyperglycemia or rare events. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 120 of 133

7.3.5.9 Pregnancies In the IDegLira trials, or the intention of becoming pregnant was an exclusion criterion and women who became pregnant were to be withdrawn and discontinue trial product immediately. Nonetheless, some pregnancies occurred and their outcomes are reviewed below.

A total of 4 pregnancies were reported in the completed phase 3 trials (1 in the IDegLira group of Trial 3912 and 3 in the liraglutide group of Trial 3697). In the IDegLira group, the outcome of the pregnancy was a normal, healthy baby. In the liraglutide group, the outcomes of all 3 pregnancies were spontaneous abortion.

A spontaneous abortion was reported in the 120-day safety update for one patient in the ongoing Trial 4056 comparing two different titration algorithms of IDegLira. The spontaneous abortion occurred at a gestational age of the fetus of less than 2 months. Medical history included substance abuse during pregnancy.

7.4 Adverse events in sub-populations The potential effects of intrinsic factors on safety were evaluated by considering rates of AEs, SAEs and AEs leading to withdrawal across the various intrinsic factor sub-populations. Investigated intrinsic factors comprised sex, age, race, ethnicity, region (U.S. versus non-U.S.), BMI, and baseline renal and hepatic function.

Overall, there were no clinically relevant differences between treatment groups with respect to the distribution of adverse events across intrinsic factor sub-populations. This is in accordance with the results from the IDeg and liraglutide clinical development programs, where none of the investigated intrinsic factors were concluded to have a safety impact that warranted special safety precautions in the prescribing information for Victoza® or Tresiba®.

7.5 Drug-drug interactions The data on drug-drug interactions for the IDeg and liraglutide development programs did not indicate that deviations from the dosing regimen for IDeg and liraglutide were required for drugs administered concomitantly with these drugs. Furthermore, in the IDegLira development program there were no clinically relevant treatment differences between IDegLira and comparator products with respect to the rate of confirmed hypoglycemia or hyperglycemia with concomitant use of a range of tested drugs known to affect blood glucose levels (monoamine oxidase inhibitors, beta-blocking agents, angiotensin converting inhibitors, anabolic steroids, sulphonamides, salicylates, diuretics, danazol, glucocorticoids, thyroid hormones, sympathomimetics, and oral contraceptives, octreotide and lanreotide) or for concomitant use of drugs known to have a high level of plasma protein binding (warfarin , valproate, ibuprofen and acetylsalicylic acid). Furthermore, no clinically relevant interactions were identified between IDegLira and selected drugs with a narrow therapeutic index (digoxin and warfarin). Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 121 of 133

7.6 Post-marketing experience IDegLira (Xultophy®) has been marketed in the EU and Switzerland since January 2015. No new safety signals not already reflected in labeling have been identified from post-marketing data for IDegLira, which adds to the post-marketing experience for IDeg and liraglutide. Post-marketing data for IDegLira pertaining to the period of the 120-day safety update is described in Appendix 8, Section 1.4. This period represents market exposure corresponding to approximately 3003 PYE and adds to the results of the limited post-marketing exposure presented in the NDA. The cumulative market exposure to IDegLira as of the cut-off for the 120-day safety update was approximately 3813 PYE. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 122 of 133

8 Plan for continued risk management post-approval The IDegLira clinical development program included approximately 3500 patients exposed to trial drug across the five completed phase 3 trials, of whom 1881 received IDegLira. These data are in addition to the results derived from the extensive exposure during clinical development and subsequent market use of IDeg and liraglutide. The safety profile of IDegLira is consistent with the safety profiles of IDeg and liraglutide, with no unexpected findings and no new safety signals identified. In addition to routine pharmacovigilance, the post-marketing risk management program for IDegLira will build upon the ongoing Tresiba® and Victoza® post-marketing risk management programs described further below. The program will focus on patient and physician education on the potential risks and will include further investigations as deemed appropriate. Educational activities An educational program targeting health care professionals, pharmacists and patients is planned for IDegLira. The objectives of the educational activities are to support how to initiate, titrate and administer IDegLira. Labeling The packaging for IDegLira will include a physician insert along with a Medication Guide that is targeted to patients. Based on nonclinical rodent findings associated with GLP-1 RAs, IDegLira will include a boxed warning regarding the potential risk of medullary thyroid cancer (MTC), as IDegLira contains liraglutide. The labeling will also include information on pancreatitis. Proposed and ongoing risk management activities related to IDegLira An overview of proposed and ongoing risk management activities for IDegLira and the individual components IDeg and liraglutide is provided in Table 8–1 and detailed further below.

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 REMS website. The REMS website will be accessible directly through a search engine, and users will be unable to directly navigate back to the product website. This non-promotional REMS website will include downloadable versions of the US Prescribing Information, Medication Guide, REMS Letters, REMS Factsheet for Prescribers, REMS Slides and will also be accessible via a REMS-specific link from the IDegLira websites for healthcare professionals and consumers.

Importantly, the activities occurring under this REMS will be integrated with the Novo Nordisk’s pharmacovigilance program to ensure proper surveillance, monitoring, and reporting of adverse events.

In addition, IDegLira will be incorporated into the ongoing national MTC registry. The registry systematically monitors the annual incidence of MTC in the U.S. through the North American Association of Central Cancer Registries (NAACCR) for any signal indicating a possible association between treatment with long-acting GLP-1 RAs and the development of MTC in the U.S. population.

Risk management activities for Victoza® The risk management program for Victoza® includes a REMS, the ongoing national MTC registry mentioned above, and a 5-year prospective medical claims database study (OptumInsight) evaluating the safety profile of Victoza®. Novo Nordisk has recently concluded a cardiovascular outcomes trial (LEADER®) to evaluate the risk of major adverse cardiovascular events with liraglutide treatment. LEADER® is a long-term, multi-center, international, randomized double- blind, parallel group, placebo-controlled trial comparing the cardiovascular safety of liraglutide and placebo in addition to standard care in more than 9000 randomized T2DM patients for at least 3.5 years and up to 5 years. The trial confirmed the cardiovascular safety of liraglutide compared to placebo when each was added to standard of care.

Risk management activities for Tresiba® Novo Nordisk is also conducting a prospective cardiovascular outcomes trial (DEVOTE®) to evaluate the risk of major adverse cardiovascular events in more than 7000 patients with T2DM. DEVOTE® is a long-term, multi-center, international, randomized, double-blind, parallel group, controlled trial to confirm cardiovascular safety of insulin degludec compared to insulin glargine when added to standard of care in male and female patients with type 2 diabetes at high risk of cardiovascular events. The primary endpoint is time from randomization to first occurrence of either cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. The trial is expected to have accrued the pre-specified number of MACEs for the full trial analysis in mid-2016. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 125 of 133

9 Benefit-risk conclusions The underlying pathophysiology of T2DM is complex and involves multiple organ systems. The defects include peripheral insulin resistance and progressive relative insulin deficiency as well as impaired secretion and/or action of incretin hormones including GLP-1, leading to the fasting and post-prandial hyperglycemia characterizing T2DM.6-8 Optimal glycemic control therefore relies on a multi-faceted treatment approach.

Basal insulin treatment has the inherent limitation of not addressing fluctuations in insulin demand such as those resulting from meal intake. In contrast, GLP-1 RA treatment stimulates insulin secretion and inhibits glucagon secretion in a glucose-dependent manner when plasma glucose levels are above normal, and this mechanism of action is therefore complementary to that of basal insulin. As shown from the IDegLira clinical development program, the simultaneous introduction of liraglutide to insulin degludec therapy as done with IDegLira adds the benefit of lowering prandial glucose excursions via liraglutide’s glucose-dependent mechanism of action. This allows further improvements in overall glycemic control with IDegLira relative to basal insulin treatment while titrating to equivalent fasting plasma glucose (FPG) targets. Furthermore, the undesired risks of hypoglycemia and weight gain associated with insulin therapy are counteracted. Compared to GLP-1 RA monotherapy, the lower starting dose and more gradual increase in liraglutide dose with IDegLira gives rise to fewer and milder gastrointestinal side effects.

Benefits of IDegLira The results of the clinical development program demonstrated that each component of IDegLira contribute to the effect of IDegLira on HbA1c throughout the dose range. As reflected in the primary endpoint of change in HbA1c across the phase 3 trials, this resulted in clinically relevant improvements in glycemic control with IDegLira relative to comparator treatments for patients currently inadequately treated with a number of different antidiabetic agents. This was shown for all trials and comparisons, including the comparisons of IDegLira against IDeg in Trial 3697 and IGlar in Trial 3952. Importantly, in these two trials no dose limitation on comparator insulin treatment was imposed while successfully titrating to the same FPG target for both IDegLira and basal insulin comparator. The results point to the ability of the liraglutide component of IDegLira to lower HbA1c through its impact on prandial glucose peaks. The added reduction in HbA1c with IDegLira relative to comparator treatment ranged from approximately 0.5 to 1.0 %-point across trials and comparator treatments. In line with the results for change in HbA1c, the proportion of patients achieving the ADA HbA1c target of <7.0% and the AACE target of ≤6.5% after 26 weeks of treatment was consistently greater with IDegLira than with comparator treatments.

Weight gain is a significant barrier for initiating or intensifying insulin treatment.31 The weight-reducing effect of the liraglutide component counter-balanced the weight gain commonly associated with insulin treatment. This resulted in approximate weight neutrality with IDegLira treatment in insulin-naïve patients and weight loss in patients converting from basal insulin to Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 126 of 133

IDegLira. As expected when adding insulin, patients converting from GLP-1 RA treatment to IDegLira on average gained weight.

The improved glycemic control with IDegLira was attained at a lower insulin dose relative to basal insulin comparator treatments administered according to product label. This was shown to be clinically relevant by reducing the risk of hypoglycemia as outlined below.

IDegLira provides important treatment benefits by enabling the administration of both IDeg and liraglutide in one single injection at any time of the day via a convenient, pre-filled pen. The fact that treatment intensification is enabled while limiting the number of daily injections is important from a patient perspective, as adding injections is known from clinical practice to be a major barrier to treatment intensification. Furthermore, IDegLira allows patients and health care providers to achieve appropriate doses for the combination treatment by following a simple titration scheme similar to that used for basal insulin products. The availability of this combination product could remove uncertainties for many patients and caregivers with respect to managing initiation of basal insulin + GLP-1 RA combination therapy, including dose adjustment of the two drugs during both initiation/transfer and maintenance phases.

Risk evaluation for IDegLira Overall, the risk profile of IDegLira reflected the well-known side effects of insulin and GLP-1 RA treatment, and no new safety signals were identified.

The following is concluded for the key safety areas:

 Hypoglycemia is a key safety consideration for diabetes treatment. When considering intensification of treatment, worry or fear of hypoglycemia is a significant treatment barrier that discourages patients and caregivers from adding insulin and/or pursuing appropriate glycemic targets during insulin treatment.67 The results of Trials 3697 and 3952 showed clinically relevant reductions in event rates for both confirmed and documented symptomatic hypoglycemic episodes of approximately 30% and 55% for IDegLira relative to IDeg and IGlar, respectively. With existing therapies, major improvements in glycemic control are most often achieved at the cost of an increased risk of hypoglycemia. Therefore, the fact that glycemic control was improved with concurrent reductions in rates of hypoglycemia with IDegLira relative to basal insulin treatment is highly clinically relevant. In contrast with the above, higher rates of hypoglycemia were observed for IDegLira relative to GLP-1 RA treatment for both confirmed hypoglycemia and for documented symptomatic hypoglycemia. This is as expected, as GLP-1 RA treatment carries a low risk of hypoglycemia due to the glucose-dependent mode of action of this class of drugs. Severe hypoglycemia occurred rarely in the phase 3 trial program (12 events in total) and at similar rates between treatment groups. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 127 of 133

 The adverse gastrointestinal side effects associated with GLP-1 RA treatment occurred less frequently with IDegLira than with liraglutide during the initial weeks of treatment as demonstrated in the pivotal Trial 3697. This is likely due to the lower starting dose and more gradual increase in dose of the liraglutide component during IDegLira treatment initiation. Similarly, the proportions of patients with gastrointestinal events leading to withdrawal were lower in the IDegLira group than in the liraglutide group. Conversely, the proportions of patients with nausea, diarrhea and vomiting were generally higher for IDegLira than for basal insulin treatment across the phase 3 trial program.  No events of pancreatitis were confirmed by the event adjudication committee for patients receiving IDegLira, and no increase in the risk of pancreatic cancer was seen with IDegLira. An increase in mean lipase and amylase activity from baseline to end of trial was observed in the IDegLira and GLP-1 RA groups. These findings are consistent with previous observations for liraglutide. In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreatic enzymes alone are not predictive of acute pancreatitis,24, 25 and the results for lipase and amylase are not considered indicative of an increased risk of pancreatitis with IDegLira treatment.  The IDegLira clinical development program was not designed to generate a cardiovascular outcome assessment. The currently available data indicate that the cardiovascular profile of IDegLira is consistent with that of the individual components. Cardiovascular biomarker changes observed with IDegLira were in line with the well-established effects of each component. FDA approved IDeg (Tresiba®) in September 2015 based on an interim analysis of the ongoing cardiovascular outcomes trial for IDeg (DEVOTE®) comparing IDeg to IGlar in a double-blind trial evaluating over 7000 patients. The cardiovascular outcomes trial for liraglutide (LEADER®) has recently been completed and confirmed the cardiovascular safety of liraglutide compared to placebo when each was added to standard of care. Both trials enrolled a population of T2DM patients at high risk of major adverse cardiovascular events (MACE), ensuring a clinically relevant cardiovascular risk assessment for each of the components based on significant numbers of accrued MACE events.  Neoplasm events occurred at similar frequencies across treatment groups, except for a numerical excess of infrequent events of skin neoplasm with IDegLira treatment (6 events reported for IDegLira versus 1 event for comparator treatments combined). Four of the 6 events with IDegLira (and the one event with comparator treatment) concerned non-serious events of basal cell carcinoma. There is no known plausible mechanistic rationale for an increase in skin cancer when combining insulin and GLP-1 RA.  No events of medullary thyroid cancer were reported or identified in the development program. Results for calcitonin were similar between treatment groups.  Allergic reactions and injection site reactions occurred at similar rates across treatment groups. The antibody response to IDegLira was low, which is consistent with the low antibody response to IDeg and liraglutide observed in their respective development programs. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 128 of 133

The proposed risk management program will focus on patient and physician education on the potential risks and will include further investigations as deemed appropriate. For further information see Section 8.

Summary of benefits and risks relative to treatment alternatives With all antidiabetic therapies, the benefits of increased glycemic control in reducing late-stage complications of diabetes should be balanced against risks. In the following, the benefit-risk profile of IDegLira relative to comparator treatments is summarized.

IDegLira as an alternative to basal insulin treatment Relative to basal insulin treatment, the benefits of IDegLira are substantial and highly clinically relevant, both in patients inadequately controlled on OAD treatment and in those who are inadequately controlled on basal insulin treatment. Superior glycemic control is achieved with a once-daily injection while mitigating the main side effects of basal insulin treatment, i.e., hypoglycemia and weight gain (Figure 9–1).

Figure 9–1 Benefits and risks for IDegLira relative to basal insulin treatment

The benefits of IDegLira relative to basal insulin treatment should be balanced against the risk profile associated with the liraglutide component of the drug product, including the risk of gastrointestinal side effects. As with any treatment decision, this should be in the context of individual treatment goals and patient characteristics.

IDegLira as an alternative to GLP-1 RA treatment IDegLira similarly shows improved glycemic efficacy relative to GLP-1 RA treatment. This suggests that IDegLira may be an appropriate alternative to GLP-1 RA therapy in individual patients, both in patients inadequately controlled on OAD treatment and in those who are inadequately controlled on GLP-1 RA therapy. Specifically in patients uncontrolled on OAD therapy, the reduced incidence and severity of gastrointestinal events with IDegLira relative to Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 129 of 133 regular GLP-1 RA therapy is clinically meaningful, because these events are typically the ones that are most bothersome to patients starting GLP-1 RA therapy and may lead to withdrawal from treatment. However, avoidance of hypoglycemia remains an important consideration. The benefits of IDegLira over GLP-1 RA treatment in terms of better glycaemic control and fewer withdrawals due to gastrointestinal side effects should therefore be considered against the increased risk of hypoglycemia associated with the insulin component of IDegLira, as well as the differing weight profiles of the therapies (Figure 9–2).

Figure 9–2 Benefits and risks for IDegLira relative to GLP-1 RA treatment

Benefit-risk conclusion IDegLira offers an attractive treatment option for patients with T2DM who wish to intensify glycemic control, both in patients inadequately controlled on OAD treatment and in patients inadequately controlled on either basal insulin or GLP-1 RA treatment. IDegLira provides important treatment benefits by enabling the administration of both IDeg and liraglutide in one single injection at any time of the day via a convenient, pre-filled pen. Furthermore, the product allows patients and health care providers to achieve appropriate dose levels for the combination treatment by following a simple titration scheme similar to that used for basal insulin products. As with any treatment decision, the benefits and risks of IDegLira relative to treatment alternatives should be considered in the context of the treatment goals and characteristics of the individual patient. The availability of IDegLira for the treatment of T2DM allows for further individualization of treatment by providing an effective and safe alternative to the concurrent use of the two separate components. The addition of IDegLira to the range of treatment options for T2DM is thus consistent with the ADA/EASD position statement, which places an emphasis on individualization of treatment as being essential for successful diabetes management.20 A similar emphasis on individualization of therapy based on attributes of both patients and medications is evident from the most recent AACE consensus statement.26 It is concluded that the benefit-risk ratio is in favor of IDegLira within the investigated patient populations with T2DM. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 130 of 133

10 Reference list 1. 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; 2008 2008. p. 2545-59. 2. 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. 3. Emerging Risk Factors C, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215-22. 4. Kilpatrick ES, Das AK, Orskov C, Berntorp K. Good glycaemic control: an international perspective on bridging the gap between theory and practice in type 2 diabetes. Current Medical Research and Opinion. 2008;24(9):2651-61. 5. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999;281(21):2005-12. 6. Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005;365(9467):1333-46. 7. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia. 2003;46(1):3-19. 8. Nauck MA, Baller B, Meier JJ. Gastric inhibitory polypeptide and glucagon-like peptide-1 in the pathogenesis of type 2 diabetes. Diabetes. 2004;53 Suppl 3:S190-6. 9. Tresiba (insulin degludec) EU prescribing information (SmPC), August 2015. 10. Victoza (liraglutide) US prescribing information, March 2015. 11. Victoza (liraglutide) EU prescribing information (SmPC), November 2015. 12. Levemir () US prescribing information, February 2015. 13. Levemir (insulin detemir) EU prescribing information (SmPC), February 2016. 14. Byetta (exenatide) EU prescribing information (SmPC), January 2016. 15. Trulicity () US prescribing information, March 2015. 16. Trulicity (dulaglutide) EU prescribing information (SmPC), March 2016. 17. Tanzeum () US prescribing information, May 2015. 18. Eparzan (albiglutide) EU prescribing information (SmPC), January 2016. 19. Lyxumia () EU prescribing information (SmPC), November 2015. 20. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-9. 21. U.S. Department of Health and Human Services, Food and Drug Administration. Code of Federal Regulations Title 21, Sect. 300.50. Fixed-combination prescription drugs for humans. 1 April 2014. 22. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Guideline on clinical development of fixed combination medicinal products (CPMP/EWP/240/95 Rev. 1). 19 February 2009. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 131 of 133

23. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus (CHMP/EWP/1080/00 Rev.1). 14 May 2012. 24. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College og Endocrinology on the comprehensive type 2 diabetes management algorithm - 2016 executive summary. Endocr Pract. 2016;22(1):84-113. 25. Khunti K, Wolden ML, Thorsted BL, Andersen M, Davies MJ. Clinical Inertia in People With Type 2 Diabetes A retrospective cohort study of more than 80,000 people. Diabetes Care. 2013;36(11):3411-7. 26. Dale J, Martin S, Gadsby R. Insulin initiation in primary care for patients with type 2 diabetes: 3-year follow-up study. Prim Care Diabetes. 2010;4(2):85-9. 27. Peyrot M, Rubin RR, Lauritzen T, Skovlund SE, Snoek FJ, Matthews DR, et al. Resistance to insulin therapy among patients and providers - Results of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study. Diabetes Care. 2005;28(11):2673-9. 28. Kunt T, Snoek FJ. Barriers to insulin initiation and intensification and how to overcome them. International Journal of Clinical Practice. 2009;63(164):6-10. 29. Peyrot M, Skovlund SE, Landgraf R. Epidemiology and correlates of weight worry in the multinational Diabetes Attitudes, Wishes and Needs study. Curr Med Res Opin. 2009;25(8):1985-93. 30. Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet. 2014;384(9961):2228-34. 31. Buse JB, Bergenstal RM, Glass LC, Heilmann CR, Lewis MS, Kwan AYM, et al. Use of Twice-Daily Exenatide in Basal Insulin-Treated Patients With Type 2 Diabetes A Randomized, Controlled Trial. Annals of Internal Medicine. 2011;154(2):103-12. 32. DeVries JH, Bain SC, Rodbard HW, Seufert J, D'Alessio D, Thomsen AB, et al. Sequential intensification of metformin treatment in type 2 diabetes with liraglutide followed by randomized addition of basal insulin prompted by A1C targets. Diabetes Care. 2012;35(7):1446-54. 33. Rehm S, White TE, Zahalka EA, Stanislaus DJ, Boyce RW, Wier PJ. Effects of food restriction on testis and accessory sex glands in maturing rats. Toxicol Pathol. 2008;36(5):687-94. 34. Ryden L, Standl E, Bartnik M, Van den Berghe G, Betteridge J, de Boer MJ, et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J. 2007;28(1):88-136. 35. American Diabetes Association. Standards of medical care in diabetes (2013). Diabetes Care. 2013;36 Suppl 1:S11-66. 36. International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. E9. Statistical Principles for Clinical Trials. 2/5/1998. 37. U.S. Department of Health and Human Services, Food and Drug Administration. Guidance for Industry. Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and Prevention, Draft Guidance. 2008. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 132 of 133

38. Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia. 2009;52(10):2046-55. 39. Wang F, Carabino JM, Vergara CM. Insulin glargine: a systematic review of a long-acting insulin analogue. Clin Ther. 2003;25(6):1541-77, discussion 1539-40. 40. Holm S. A Simple Sequentially Rejective Multiple Test Procedure. Scandinavian Journal of Statistics. 1979;6(2):65-70. 41. National Academy of Sciences (NAS). The Prevention and Treatment of Missing Data in Clinical Trials. Washington D.C.: The National Academies Press. 2010. 42. Blonde L, Russell-Jones D. The safety and efficacy of liraglutide with or without oral antidiabetic drug therapy in type 2 diabetes: an overview of the LEAD 1-5 studies. Diabetes, obesity & metabolism. 2009;11 Suppl 3:26-34. 43. Vora J, Christensen T, Rana A, Bain SC. Insulin degludec versus insulin glargine in type 1 and type 2 diabetes mellitus: a meta-analysis of endpoints in phase 3a trials. Diabetes Ther. 2014;5(2):435-46. 44. Monnier L, Colette C. Targeting prandial hyperglycemia: how important is it and how best to do this? Curr Diab Rep. 2008;8(5):368-74. 45. Rubin RR, Peyrot M. Quality of life and diabetes. Diabetes Metab Res Rev. 1999;15(3):205- 18. 46. Van der Does FE, De Neeling JN, Snoek FJ, Kostense PJ, Grootenhuis PA, Bouter LM, et al. Symptoms and well-being in relation to glycemic control in type II diabetes. Diabetes Care. 1996;19(3):204-10. 47. Egan AG, Blind E, Dunder K, de Graeff PA, Hummer BT, Bourcier T, et al. Pancreatic safety of incretin-based drugs--FDA and EMA assessment. N Engl J Med. 2014;370(9):794- 7. 48. Banks PA, Freeman ML, Practice Parameters Committee of the American College of G. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 2006;101(10):2379-400. 49. 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. 50. Jensen TM, Saha K, Steinberg WM. Is there a link between liraglutide and pancreatitis? A post hoc review of pooled and patient-level data from completed liraglutide type 2 diabetes clinical trials. Diabetes Care. 2015;38(6):1058-66. 51. Macisaac RJ, Jerums G. Intensive glucose control and cardiovascular outcomes in type 2 diabetes. Heart Lung Circ. 2011;20(10):647-54. 52. Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, et al. Liraglutide versus monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373(9662):473-81. 53. Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel- group, multinational, open-label trial (LEAD-6). Lancet. 2009;374(9683):39-47. Novo Nordisk IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 133 of 133

54. U.S.Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry, Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. December 2008. 55. Dungan KM, Povedano ST, Forst T, Gonzalez JG, Atisso C, Sealls W, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet. 2014;384(9951):1349-57. 56. Diamant M, Van Gaal L, Stranks S, Northrup J, Cao D, Taylor K, et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet. 2010;375(9733):2234-43. 57. Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, et al. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33(7):1674-85. 58. Bydureon (exenatide extended-release for injectable suspension), US prescribing information, January 2012. 59. Fogarthy GB, Conus NM, Chu J, McArthur G. Characterization of the expression and activation of the epidermal in squamous cell carcinoma of the skin. Br J Dermatol. 2007 Jan;156(1):92-8. 60. Toll A, Salgado R, Yébenes M, Martin-Ezquerra G, Gilaberte M, Baró T, et al. Epidermal growth factor receptor gene numerical abberrations are frequent events in actinic keratoses and invasive cutaneous squamous cell carcinomas. 2010. 61. Shimizu T, Izumi H, Oga A, Furumoto H, Murakami T, Ofuji R, et al. Epidermal growth factor receptor overexpression and genetic aberrations in metastatic squamous-cell carcinoma of the skin. Dermatology. 2001;202(3):203-6. 62. List JF, He H, Habener JF. Glucagon-like peptide-1 receptor and expression in mouse skin. Regul Pept. 2006;134(2-3):149-57. 63. Korner M, Stockli M, Waser B, Reubi JC. GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J Nucl Med. 2007;48(5):736-43. 64. Waser B, Beetschen K, Pellegata NS, Reubi JC. Incretin receptors in non-neoplastic and neoplastic thyroid C cells in rodents and humans: relevance for incretin-based diabetes therapy. Neuroendocrinology. 2011;94(4):291-301. 65. Fineberg SE, Kawabata TT, Finco-Kent D, Fountaine RJ, Finch GL, Krasner AS. Immunological responses to exogenous insulin. Endocr Rev. 2007;28(6):625-52. 66. Lindholm A, Jensen LB, Home PD, Raskin P, Boehm BO, Rastam J. Immune responses to and biphasic insulin aspart in people with type 1 and type 2 diabetes. Diabetes Care. 2002;25(5):876-82. 67. Mitchell BD, Vietri J, Zagar A, Curtis B, Reaney M. Hypoglycaemic events in patients with type 2 diabetes in the United Kingdom: associations with patient-reported outcomes and self-reported HbA1c - art. no. 59. BMC Endocrine Disorders. 2013;13. Novo Nordisk IDegLira NDA 208583 Appendix 1 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 1 of 6

Novo Nordisk

Insulin degludec/liraglutide (IDegLira) Treatment to Improve Glycemic Control in Adults with Type 2 Diabetes Mellitus

NDA 208583

Briefing Document

Endocrinologic and Metabolic Drug Advisory Committee

May 24, 2016

Appendix 1 Summary of characteristics of the individual active components, IDeg and liraglutide

Advisory Committee Briefing Materials: Available for Public Release Novo Nordisk IDegLira NDA 208583 Appendix 1 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 2 of 6

1 Summary of characteristics of the individual active components, IDeg and liraglutide

1.1 IDeg IDeg is a long-acting basal insulin modified such that the amino acid residue threonine in position B30 of human insulin has been omitted, and the ε-amino group of in position B29 has been coupled to hexadecanedioic acid via a glutamic acid spacer. Upon injection, this structure allows IDeg to form soluble and stable multi-hexamers, resulting in a depot in the subcutaneous (s.c.) tissue. The gradual dissociation of IDeg monomers from the multi-hexamers results in a slow and continuous delivery of IDeg from the s.c. injection site into the circulation, leading to the observed protracted pharmacokinetic and pharmacodynamic profiles. Furthermore, binding of the moiety of IDeg to contributes to the prolonged pharmacodynamic effect. At the target tissues, IDeg monomers bind to and activate insulin receptors in the same manner as human insulin and trigger the same cellular effects such as promoting glucose uptake.

IDeg is indicated for once-daily (OD) injection, covering the basal insulin needs in patients with diabetes mellitus from early to late stages of the disease, either alone or in combination with prandial insulin and/or other anti-diabetic agents.

IDeg has been evaluated in a series of nonclinical studies and clinical trials. IDeg (Tresiba®) is approved for use in the US, EU, Japan and more than 40 additional countries worldwide. As of 30 September 2015 a total of 7,584 patients with diabetes have been exposed to IDeg in completed clinical trials, which is in addition to approximately 320,000 patient-years of exposure in the market as of this cut-off date.

Nonclinical toxicology of IDeg No safety concerns have been observed in nonclinical safety pharmacology studies, including in vitro receptor profiling and an assessment of the effect of IDeg on major organ systems. The tolerance and toxicity of IDeg have been investigated in a series of general toxicity studies with s.c. administration of IDeg. Based on the results from the nonclinical development program, it is concluded that IDeg is similar to human insulin with respect to nonclinical biological actions and nonclinical safety.

Clinical pharmacology of IDeg The terminal half-life of IDeg after s.c. administration is 25 hours, which is twice as long as that of insulin glargine (12 hours). The slow absorption provides consistent pharmacokinetic profiles at steady-state. Steady-state is achieved following 2-4 days of once-daily dosing with no further increase in exposure thereafter. Total exposure of IDeg increases proportionally with increasing dose, and total glucose-lowering effect of IDeg increases linearly with increasing dose in T2DM. Novo Nordisk IDegLira NDA 208583 Appendix 1 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 3 of 6

At steady state, both the IDeg concentration and the glucose-lowering effect are evenly distributed across the 24-hour dosing interval. IDeg can be administered subcutaneously in the abdomen, upper arm (deltoid) or thigh with equal effect. In addition, IDeg was associated with a four-times-lower day-to-day variability in total glucose-lowering effect compared with insulin glargine.

The protracted pharmacokinetic and pharmacodynamic properties of IDeg are preserved across various demographic and disease factors (age, BMI, renal or hepatic impairment, race and ethnicity).

Clinical efficacy and safety of IDeg The efficacy and safety of IDeg for the treatment of T2DM is supported by a comprehensive phase 3 clinical trial program. IDeg was shown to be efficacious and safe when used alone, combined with bolus insulin or used as add-on therapy to the most commonly used OADs, including metformin, DPP-4 inhibitors, SUs, pioglitazone and α-glucosidase inhibitors. IDeg effectively improved long- term glycemic control and was non-inferior to insulin glargine and insulin detemir in reducing HbA1c across all treat-to-target trials. IDeg can be dosed at any time of the day, with the possibility to advance or postpone the injection time if necessary, ensuring a minimum of 8 hours between consecutive injections.

IDeg is well tolerated with an AE profile similar to that of other marketed insulin products, and no unexpected findings or unacceptable risks have been identified. In 2012, the US FDA concluded that a signal of increased cardiovascular risk associated with IDeg and IDegAsp (Ryzodeg®, a combination product of IDeg and insulin aspart) relative to comparators could not be excluded based on the clinical development program. Based on agreement with the FDA, Novo Nordisk initiated the DEVOTE® cardiovascular outcomes trial (CVOT) in October 2013. The DEVOTE® trial is designed to confirm the cardiovascular safety of insulin degludec compared to insulin glargine when added to standard of care in male and female subjects with T2DM at high risk of cardiovascular events. Randomization of 7,637 T2DM patients has been completed, and the required number of major adverse cardiovascular events (MACEs) for a pre-specified interim analysis was accumulated during the first quarter of 2015. Based on the review of the Class II Resubmission of the NDAs (including the DEVOTE® interim analysis), FDA approved Tresiba® and Ryzodeg® for the treatment of diabetes mellitus in adults on 25 September 2015. In order to preserve the integrity of the ongoing DEVOTE® trial, only a small dedicated team within Novo Nordisk has access to the data. Thus, no additional safety information is available from DEVOTE®. The trial is expected to have accrued the pre-specified number of MACEs for the full trial analysis in mid-2016. Novo Nordisk IDegLira NDA 208583 Appendix 1 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 4 of 6

1.2 Liraglutide Liraglutide is a once-daily human GLP-1 analog, obtained by derivatizing GLP-1 with a fatty acid. This results in stable heptamers in the formulation and in the subcutis after injection, ensuing pharmacokinetic properties suitable for once-daily injection. Following s.c. administration, the protracted action profile is based on three mechanisms: self-association, which results in slow absorption; binding to albumin; and higher enzymatic stability towards the dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase (NEP) enzymes.

Liraglutide improves glycemic control by lowering fasting and postprandial glucose. Liraglutide stimulates insulin secretion and inhibits glucagon secretion in a glucose-dependent manner when plasma glucose levels are above normal and furthermore shows an effect on reducing body weight through mechanisms involving decreased hunger and lowered energy intake.

Liraglutide (Victoza®) was approved for the treatment of T2DM in the US in January 2010. The maximum approved dose for the treatment of T2DM is 1.8 mg. During the liraglutide clinical development program where liraglutide was the primary investigational medicinal product, more than 60 clinical trials have been completed as of 30th December 2015, which includes more than 21,000 patients (healthy subjects, patients with T2DM, patients with T1DM and obese patients without diabetes). Of these, more than 14,000 were treated with liraglutide. Some were treated with doses up to 3.0 mg daily in the liraglutide obesity development program, which is the approved maximum dose of liraglutide for (Saxenda®). Estimated world-wide, post- marketing exposure to Victoza® (based on sales volume) as of 30th December 2015 is approximately 4.2 million patient-years. Nonclinical toxicology of liraglutide Toxicology data revealed no safety issues for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, or genotoxicity.

Liraglutide dose-dependently induced proliferative changes and tumors in C-cells (parafollicular cells) of the thyroid during the mouse and rat 2-year carcinogenicity studies. Low grade proliferative C-cell changes were also identified in rodent repeated dose toxicity studies. The rodent C-cell findings are considered a class effect caused by a specific GLP-1 receptor-mediated mechanism to which rodents are particularly sensitive. While some residual uncertainty as to the relevance of these findings remains, the totality of the nonclinical and clinical experience with this class of drugs suggests that the rodent C-cell findings are not predictive of human risk.

In the 2-year carcinogenicity study in mice, a treatment-related increase in the incidence of fibrosarcomas was seen on the dorsal skin and subcutis in the area of the micro-chip implant and the injection site area in males in the 3 mg/kg/day group. Repeated subcutaneous injections of non- genotoxic compounds and solutions as well as implantation of solid material such as micro-chips in Novo Nordisk IDegLira NDA 208583 Appendix 1 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 5 of 6 the subcutis are known to cause development of skin sarcomas in rodents,1 which suggests that the observed fibrosarcomas in male mice are of no human relevance.

Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. The US package insert for Victoza® states that ‘Victoza should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus’.

Clinical pharmacology of liraglutide Unlike native GLP-1, liraglutide has a pharmacokinetic and pharmacodynamic profile in humans suitable for once-daily administration. The terminal half-life of liraglutide is 13 hours, with steady state reached in 2-3 days. Liraglutide exposure increases proportionally with dose. The glucose- lowering effect of liraglutide is observed throughout 24 hours following dose administration.2

No differences in liraglutide pharmacokinetics were found between geriatric and younger patients or between patients of different race or ethnicity. Exposure (AUC) was shown to increase with decreasing body weight and was higher for women than for men. The differences were not considered of clinical relevance, and no dose adjustment is required.

Liraglutide exposure was reduced in subjects with mild to severe hepatic impairment and mild to severe renal impairment in single-dose pharmacokinetic trials. No dose adjustment is recommended for patients with renal or hepatic impairment, but liraglutide should be used with caution in these populations due to limited available data. The drug-drug interaction program investigated the influence of liraglutide on the absorption of concomitantly given oral drugs. Liraglutide did not affect absorption of the investigated compounds to any clinically relevant degree, and dose adjustment is therefore not required. Liraglutide did not produce QT prolongation.

Liraglutide improves glycemic control by lowering fasting and postprandial glucose. These effects are primarily mediated through stimulation of insulin secretion and inhibition of glucagon secretion, both in a glucose-dependent manner, i.e. only when plasma glucose levels are above normal. Liraglutide also causes a minor delay in gastric emptying, thereby reducing the rate at which postprandial glucose appears in the circulation.

Clinical efficacy and safety of liraglutide The efficacy and safety of liraglutide for the treatment of T2DM is supported by a comprehensive phase 3 clinical trial program. The trials showed a robust effect of liraglutide on glycemic control (as measured by HbA1c and FPG). Liraglutide was superior to placebo for the primary efficacy endpoint of HbA1c change from baseline and was superior or non-inferior to a number of established therapies. Liraglutide was also confirmed to be associated with body weight loss and reduction in blood pressure. Novo Nordisk IDegLira NDA 208583 Appendix 1 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 6 of 6

The most frequently reported adverse reactions during clinical trials were gastrointestinal disorders. Adverse reactions (reported in ≥5% of patients treated with Victoza® and more commonly than in patients treated with placebo) comprise nausea, diarrhea, vomiting, dyspepsia constipation and headache. Patients receiving Victoza® in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia. Severe hypoglycemia has primarily been observed when liraglutide is used in conjunction with sulfonylurea. The available safety information from market exposure is consistent with the known safety profile of Victoza®.

A cardiovascular outcomes trial for liraglutide (LEADER®) has recently been concluded. The trial results are currently being analyzed and will provide further data on the safety profile of liraglutide in a high CV risk T2DM population. For the primary endpoint of time to first major adverse cardiovascular event (MACE), the trial showed a significantly reduced risk with liraglutide compared to placebo when added to standard of care in the investigated population of T2DM patients at high risk of MACE.

References

1. Greaves P. Integumentary system in Histopathology of Preclinical Toxicity studies. Ed. 3 ed. Amsterdam: Academic Press; 2007. p. 38-42. 2. Degn KB, Juhl CB, Sturis J, Jakobsen G, Brock B, Chandramouli V, et al. One week's treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes. 2004;53(5):1187-94. Novo Nordisk IDegLira NDA 208583 Appendix 2 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 1 of 7

Novo Nordisk

Insulin degludec/liraglutide (IDegLira) Treatment to Improve Glycemic Control in Adults with Type 2 Diabetes Mellitus

NDA 208583

Briefing Document

Endocrinologic and Metabolic Drug Advisory Committee

May 24, 2016

Appendix 2 Results of Nonclinical Programs for IDeg and Liraglutide

Advisory Committee Briefing Materials: Available for Public Release Novo Nordisk IDegLira NDA 208583 Appendix 2 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 2 of 7

Table of contents Page Table of contents...... 2 1 Results of nonclinical programs for IDeg and liraglutide ...... 3 1.1 Nonclinical pharmacokinetics and Absorption, Distribution, Metabolism and Excretion ...... 3 1.1.1 Insulin degludec...... 3 1.1.2 Liraglutide...... 3 1.2 Nonclinical safety pharmacology and toxicology data...... 4 1.2.1 Insulin degludec...... 4 1.2.2 Liraglutide...... 4 1.3 Carcinogenicity assessments...... 5 1.3.1 Insulin degludec...... 5 1.3.2 Liraglutide...... 5 2 Reference list...... 7 Novo Nordisk IDegLira NDA 208583 Appendix 2 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 3 of 7

1 Results of nonclinical programs for IDeg and liraglutide

1.1 Nonclinical pharmacokinetics and Absorption, Distribution, Metabolism and Excretion

1.1.1 Insulin degludec The fatty di-acid side chain of IDeg allows it to bind strongly but reversibly to albumin, resulting in a plasma protein binding of >99%. As a result, the total concentration of IDeg is relatively high in the bloodstream, with the majority of circulating IDeg bound to albumin, and thus unavailable for receptor binding. The distribution of IDeg was studied in rats with radiolabeled IDeg. Following s.c. administration, absorbed IDeg was distributed mainly to the serum compartment.

The results of in vitro protein binding studies demonstrated that common protein-bound drugs such as ibuprofen, warfarin, acetylsalicylate and salicylate do not affect IDeg binding to human serum albumin at therapeutically relevant drug concentrations. The opposite effect, IDeg displacement of other albumin-bound drugs, is considered unlikely, as the concentration of IDeg is very low compared to the albumin concentration (>10,000-fold lower). Therefore, the pharmacokinetic properties of IDeg would not be affected in vivo by other albumin-bound drugs including liraglutide or by even very large changes in albumin concentration.

As with any other insulin product, elimination of IDeg is primarily via insulin receptor-mediated internalization and degradation. The peptide cleavage of the IDeg insulin backbone is the same as seen for human insulin. The fatty acid side chain is extensively metabolized similarly to other naturally occurring fatty acids.

1.1.2 Liraglutide Liraglutide is also highly bound to albumin (98%) in all species. No special target organ was identified in tissue distribution studies, where the highest concentrations were observed in well- perfused organs.

The metabolism and excretion pattern of liraglutide was highly similar across species, including humans. Liraglutide was fully degraded in the body, with no single organ as a major route of elimination. The metabolism/catabolism of liraglutide, which consists of a peptide moiety with a fatty acid attached via a glutamate spacer, results in amino acids and a fatty acid. Similar to native GLP-1, metabolism occurs via sequential cleavage of N- and C-terminal peptide fragments and amino acids involving the peptidases dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase (NEP), resulting in CO2 and H2O when fully metabolized. No active metabolites have been identified. In vitro, binding to albumin was demonstrated to control the rate of liraglutide metabolism by limiting free-drug availability. Changes in albumin concentration from 10-50 g/L (which are considered to cover clinical variations) result in only minimal changes in metabolic rate due to the very high excess of albumin relative to liraglutide. Novo Nordisk IDegLira NDA 208583 Appendix 2 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 4 of 7

No clinically relevant induction or inhibition of cytochrome P450 activity was observed in human or rat hepatocytes.

1.2 Nonclinical safety pharmacology and toxicology data

1.2.1 Insulin degludec IDeg is a specific and full agonist at the human insulin receptor, with the same mode of action as human insulin. IDeg nonclinical safety pharmacology studies showed no adverse effects on cardiovascular or respiratory function, function, or the autonomic or central nervous systems in studies in rats and dogs. The nonclinical toxicology program revealed no safety signals based on studies assessing single and repeated dose toxicity, reproductive and development toxicity, local tolerance and carcinogenic potential, see also Section 1.3.1. The nonclinical studies have thus demonstrated that the modifications introduced in IDeg have not changed its metabolic actions or its safety profile compared with human insulin.

1.2.2 Liraglutide Safety pharmacology/effect on vital organs systems The organ-specific nonclinical safety pharmacology program assessed the effect of liraglutide on cardiovascular and respiratory function, kidney function, and the autonomic and central nervous systems in pharmacologically responsive animals (mouse, rat, , guinea-pig and cynomolgus monkey). No safety concerns for humans were raised in these studies.

Perfusion with liraglutide caused a small increase in heart rate (6%) in the rabbit isolated Langendorff heart preparation, but a similar increase in heart rate was not observed in animal studies.

Toxicology findings The majority of findings in the short-, medium- and long-term toxicity studies were attributed to dose-dependent primary pharmacology via GLP-1 receptor-mediated effects (i.e., decrease in food consumption and a decrease in body weight gain).

The pancreas was examined macro- and microscopically in all toxicology studies in mice, rats and cynomolgus monkeys. In a 52-week study with liraglutide, a dose-related increase in absolute pancreas weight was observed in female monkeys only.1 A similar dose-related increase was not found in studies of 4, 13, or 87 weeks’ duration. There were no findings related to the drug suggestive of inflammation or any other toxicology in the pancreas in any of the studies, including the 104-week carcinogenicity studies in mice and rats, an 87-week study in cynomolgus monkeys, and a 3-month study in diabetic rats.1

In the combined fertility and embryo-fetal development study in rats, reduced maternal body weight gain and food consumption were observed at the 1.0 mg/kg/day dose. No effects on male fertility Novo Nordisk IDegLira NDA 208583 Appendix 2 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 5 of 7 were observed. In female rats, an increase in early embryonic deaths occurred at 1.0 mg/kg/day (28- fold human exposure based on AUC). No spontaneous abortions in terms of total litter loss were noted. A few fetal abnormalities were observed in fetuses from both rats and rabbits dosed with liraglutide. These findings are reflected in the product label for Victoza®.

The carcinogenicity assessment for liraglutide is summarized in Section 1.3.2.

1.3 Carcinogenicity assessments

1.3.1 Insulin degludec A thorough assessment of IDeg in in vitro assay systems has been conducted to test the molecular mechanisms involved in the cell proliferative effects of insulin. On the basis of the overall in vitro characterization of insulin degludec, including receptor profiling for both insulin and IGF-1 receptors, intracellular signalling as well as metabolic effects in the major insulin target tissues, and mitogenic effects in both neo-plastic and non-neoplastic cell types, it can be concluded that the molecular pharmacological profile of insulin degludec does not differ from that of human insulin. Insulin degludec has a mitogenic/metabolic potency ratio similar to human insulin, confirming that the balance between the metabolic and proliferative actions of insulin degludec is similar to that of human insulin.

IDeg showed no carcinogenic potential in a 52-week toxicity study in Sprague Dawley rats. Specifically, no treatment-related changes in mammary cell proliferation were found using BrdU incorporation in the female mammary gland in this 52-week study. Furthermore, IDeg treatment did not increase the incidence of hyperplastic or neoplastic changes in dogs or rats treated for up to 26 and 52 weeks, respectively.

Based on this nonclinical package of in vitro and in vivo studies addressing the carcinogenic potential of insulin degludec, it is considered that the totality of the evidence supports the conclusion that the carcinogenic potential of insulin degludec is similar to that of human insulin.

1.3.2 Liraglutide Liraglutide was not genotoxic in a full range of genotoxicity studies. Two-year carcinogenicity studies were performed in CD-1 mice and Sprague-Dawley rats.

The number of dorsal skin sarcomas at the injection site were significantly increased in male mice at the highest dose of 3 mg/kg/day in the two-year mouse carcinogenicity study. The percentages of male mice with dorsal skin sarcomas in controls and 3 mg/kg/day animals were 2.5% and 20%, respectively. The no-observed-adverse-effect level (NOAEL) for skin sarcomas was 1.0 mg/kg/day. The tumors were located in the area of the micro-chip implant and the injection site area. Repeated subcutaneous injections of non-genotoxic compounds and solutions as well as implantation of solid Novo Nordisk IDegLira NDA 208583 Appendix 2 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 6 of 7 material such as micro-chips in the subcutis are known to cause development of skin sarcomas in rodents.2-5

Thyroid C-cell tumors were seen in the 2-year rodent studies and were shown to be of non- genotoxic origin. Based on published literature and further substantiated with experimental data, the mode-of-action behind the C-cell findings in rodents can be summarized in the following sequential key events:

 Circulating liraglutide binds to and activates GLP-1 receptors on C-cells, resulting in calcitonin release.  Persistent stimulation of GLP-1 receptors on the C-cells is followed by C-cell hyperplasia.  Long-term, C-cell hyperplasia may lead to C-cell neoplasia in rodents.

In the mode-of-action studies, calcitonin was demonstrated to be an important biomarker for C-cell activity and mass. Consistent with this, calcitonin is known to be biomarker for C-cell activity and a predictor for C-cell hyperplasia/neoplasia in rodents.6

The key events in this proposed mode-of action and lack of relevance for humans have been substantiated with experimental data6, 7 and literature. Both in vitro and in vivo data substantiate that a profound species difference exists between rodents and primates, including man, with respect to GLP-1 receptor density8-11 and GLP-1 receptor agonist-mediated stimulation of thyroid C-cells.8 Neither normal nor hyperplastic human thyroids containing parafollicular C-cells express GLP-1 receptors. Papillary thyroid cancers do not, and medullary thyroid carcinomas rarely express GLP-1 receptors.11 The consistent demonstration of similar effects from the two GLP-1 receptor agonists, liraglutide and exenatide, at each key step in the sequence of events and the lack of C-cell proliferation in GLP-1 receptor knockout mice confirm the GLP-1 receptor-mediated mechanism.

Thus, this effect on C-cells proliferation in rodents is considered to be a class effect for GLP-1 RAs.12, 13 Rodent C-cell findings are reflected in the product label for Victoza®14 and other GLP-1 RAs. Novo Nordisk IDegLira NDA 208583 Appendix 2 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 7 of 7

2 Reference list 1. Gotfredsen CF, Molck AM, Thorup I, Nyborg NC, Salanti Z, Knudsen LB, et al. The human GLP-1 analogs liraglutide and : absence of histopathological effects on the pancreas in nonhuman primates. Diabetes. 2014;63(7):2486-97. 2. Greaves P. Integumentary system in Histopathology of Preclinical Toxicity studies. Ed. 3 ed. Amsterdam: Academic Press; 2007. p. 38-42. 3. Tillmann T, Kamino K, Dasenbrock C, Ernst H, Kohler M, Morawietz G, et al. Subcutaneous soft tissue tumours at the site of implanted microchips in mice. Exp Toxicol Pathol. 1997;49(3-4):197-200. 4. Blanchard KT, Barthel C, French JE, Holden HE, Moretz R, Pack FD, et al. Transponder- induced sarcoma in the heterozygous p53+/- mouse. Toxicol Pathol. 1999;27(5):519-27. 5. Elcock LE, Stuart BP, Wahle BS, Hoss HE, Crabb K, Millard DM, et al. Tumors in long- term rat studies associated with microchip animal identification devices. Exp Toxicol Pathol. 2001;52(6):483-91. 6. Bjerre Knudsen L, Madsen LW, Andersen S, Almholt K, de Boer AS, Drucker DJ, et al. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010;151(4):1473-86. 7. Madsen LW, Knauf JA, Gotfredsen C, Pilling A, Sjogren I, Andersen S, et al. GLP-1 receptor agonists and the thyroid: C-cell effects in mice are mediated via the GLP-1 receptor and not associated with RET activation. Endocrinology. 2012;153(3):1538-47. 8. Boess F, Bertinetti-Lapatki C, Zoffmann S, George C, Pfister T, Roth A, et al. Effect of GLP1R agonists and liraglutide on primary thyroid C-cells from rodent and man. J Mol Endocrinol. 2013;50(3):325-36. 9. Korner M, Stockli M, Waser B, Reubi JC. GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J Nucl Med. 2007;48(5):736-43. 10. Waser B, Beetschen K, Pellegata NS, Reubi JC. Incretin receptors in non-neoplastic and neoplastic thyroid C cells in rodents and humans: relevance for incretin-based diabetes therapy. Neuroendocrinology. 2011;94(4):291-301. 11. Waser B, Blank A, Karamitopoulou E, Perren A, Reubi JC. Glucagon-like-peptide-1 receptor expression in normal and diseased human thyroid and pancreas. Mod Pathol. 2015;28(3):391-402. 12. Exenatide extended-release (Bydureon), FDA pharmacology review. 2011. 13. Lyxumia (lixisenatide) EU prescribing information (SmPC), November 2015. 14. Victoza (liraglutide) US prescribing information, March 2015. Novo Nordisk IDegLira NDA 208583 Appendix 3 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 1 of 11

Novo Nordisk

Insulin degludec/liraglutide (IDegLira) Treatment to Improve Glycemic Control in Adults with Type 2 Diabetes Mellitus

NDA 208583

Briefing Document

Endocrinologic and Metabolic Drug Advisory Committee

May 24, 2016

Appendix 3 Sensitivity Analyses

Advisory Committee Briefing Materials: Available for Public Release Novo Nordisk IDegLira NDA 208583 Appendix 3 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 2 of 11

1 Description of the sensitivity analyses performed

1.1 Methodology

1.1.1 Background Recognizing the limitations of the pre-specified last observation carried forward (LOCF) imputation method, a number of sensitivity analyses using different approaches for handling missing data were performed to evaluate the robustness of findings/conclusions based on the LOCF data. Of the sensitivity analyses performed for the primary and key secondary endpoints discussed below, the multiple imputation analyses for all five trials as well as completers and per protocol (PP) analyses in Trials 3951 (OAD users), 3912 (basal insulin users) and 3851 (GLP-1 RA users) were defined post hoc. All other sensitivity analyses performed for the primary endpoint were pre-specified in the trial protocols/statistical analyses plans. All sensitivity analyses of secondary endpoints were defined post hoc.

Two types of estimands were considered that estimated the effectiveness and efficacy of IDegLira. The effectiveness estimand investigated the influence on the treatment effect of withdrawn patients not necessarily complying with the treatment they were randomised to; this is equivalent to an ITT (intent to treat) or de-facto estimand. The efficacy or de-jure estimand investigated the full effect of IDegLira treatment, using the assumption that all patients randomized to IDegLira remained on treatment until week 26. This estimand assessed the glycemic benefit of continuing treatment with IDegLira versus continuing treatment with the comparator under similar conditions as observed in the trials. This type of estimand has clinical relevance since it can provide information on the glycemic efficacy attributable to IDegLira to clinicians treating patients with T2DM.

In the analyses discussed below, the multiple imputation methods and the ”observed to reach HbA1c <7.0% target” analysis estimate an effectiveness estimand whereas the repeated measures, PP, and completers analyses estimate an efficacy estimand. The pre-specified primary approach for handling missing data (the LOCF method) can to some extent be considered an efficacy estimand as it reflects the treatment effect until the patients stopped treatment. In each trial, the number of patients with imputed values in the LOCF analysis of the primary endpoint corresponds to the number of patients withdrawn from the trial as shown in the Briefing Book Section 6.1.5, Table 6-6.

1.1.2 Sensitivity analyses Repeated measures All non-imputed measurements at planned post-baseline visits were analyzed assuming an unstructured covariance matrix across visits, with testing performed at week 26. For the analysis of insulin dose, a compound symmetry covariance matrix was assumed due to the more frequent assessment of this endpoint. Novo Nordisk IDegLira NDA 208583 Appendix 3 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 3 of 11

The repeated measures analysis was expected to estimate what would have been the result at the end of the trial had all patients remained in the trial and on drug. The model relies on the assumption that data are missing at random (e.g., that the HbA1c response trajectories for patients withdrawing from the trial prior to completing 26 weeks are comparable to those for patients completing 26 weeks of treatment). The validity of this assumption was evaluated through the multiple imputation methods described below. The repeated measures analysis included all patients with at least one post-baseline observation. This analysis is more conservative in the non-inferiority setting than in the evaluation of superiority.

The model included the same fixed factors and covariates as the primary analysis model and additionally the interaction terms between visit and all other factors and the covariate. Patient was included as a random factor when fitting the model. For sensitivity analyses of HbA1c responder endpoints, logistic regression was based on the estimates from the repeated measures analyses.

Multiple imputation Method 1 The treatment effect of IDegLira was assumed to wear off gradually after the drug has been discontinued. Hence, this analysis was expected to estimate the treatment effect if patients who withdrew from the IDegLira group were switched to the comparator treatment after withdrawal. Patients treated with the comparator were assumed to have remained on their assigned treatment after discontinuation. This approach does not rely on the assumption that data are missing at random, includes all randomized patients and imputes missing data in a way that is less favorable for IDegLira compared to the repeated measures analysis and hence more conservative in the superiority assessment.

This estimation of IDegLira’s effectiveness was performed using a pattern mixture model based on sequential regression methodology for continuous and responder endpoints and a posterior Bayes approach for hypoglycemic episodes, where available post-randomization data from the IDegLira arm were used for model building and for imputation.

For the evaluation of IDegLira’s non-inferiority against basal insulin comparators without dose limit in Trials 3697 (OAD users) and 3952(basal insulin users), patients who withdrew from the IDegLira group were assumed to have switched to a treatment inferior to the comparator used in the trial. This was done to avoid bias toward the null hypothesis when imputing from the comparator arm. The switch to a treatment inferior to the comparator was simulated by adding a penalty corresponding to the non-inferiority limit of 0.3 HbA1c %-point to the withdrawn patients’ parameter values at the last visit.

Method 2 Instead of the assumption of gradual treatment effect disappearance after withdrawal from the IDegLira arm used in method #1, this method’s assumption was that the treatment effect of Novo Nordisk IDegLira NDA 208583 Appendix 3 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 4 of 11

IDegLira ceased immediately after trial withdrawal. To simulate the immediate cessation of treatment effect after withdrawal, patients in the IDegLira arm were assumed to have the same mean response as the patients treated with the comparator throughout the trial. Patients who withdrew from the comparator group were assumed to have remained on their assigned treatment during the entire treatment period. The results obtained using this method are more conservative and less realistic than with method #1 since the treatment effect (particularly on HbA1c) is unlikely to wear off immediately after trial withdrawal.

The estimation of IDegLira’s effectiveness was performed using a pattern mixture model based on a sequential regression methodology for continuous and responder endpoints and a posterior Bayes approach for hypoglycemic episodes similar to method #1 described above. To simulate the immediate cessation of treatment effect after withdrawal from the IDegLira group, the only differences between this method and method #1 were: (1) for patients withdrawn from the IDegLira group, data measured post randomization were excluded from the analysis of continuous and responder endpoints; (2) for hypoglycemic episodes the event rate before and after withdrawal was assumed to be the same as in the comparator group.

For the evaluation of IDegLira’s non-inferiority against basal insulin comparators without dose limit in Trials 3697 (OAD users) and 3952(basal insulin users), patients who withdrew from the IDegLira group were assumed to have received a treatment inferior to the comparator used in the trial. This was done to avoid bias toward the null hypothesis when imputing from the comparator arm. The assumption of receiving treatment inferior to the comparator was simulated by adding a penalty corresponding to the non-inferiority limit of 0.3 HbA1c %-point to the withdrawn patients’ parameter values at the last visit.

Observed to reach HbA1c target of <7.0%

An additional post hoc sensitivity analysis of the HbA1c <7.0% responder endpoint was conducted in which patients without an observed HbA1c <7% response at end of the trials were treated (i.e., imputed) as non-responders.

Tipping point analysis To further evaluate the robustness of the conclusions based on statistical significance in favor of IDegLira, a tipping point analysis based on the multiple imputation (method #2) approach, was performed. In this analysis patients who withdrew from the IDegLira arm were assumed to have received a treatment inferior to the comparator. The extent of the inferiority (also termed a ‘penalty’) was gradually increased to evaluate at which point IDegLira was no longer statistically significantly better than a comparator. This penalty value, also known as the tipping point, corresponded to a hypothetical degree of efficacy deterioration in withdrawn patients needed to shift the treatment effect of IDegLira from being statistically significantly better than the comparator to a statistically non-significant effect. Novo Nordisk IDegLira NDA 208583 Appendix 3 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 5 of 11

PP analysis This analysis was performed using the PP population (defined prior to un-blinding) and estimated an efficacy estimand. Patients included in the PP population had to meet the following criteria:  no violation of any inclusion/exclusion criteria

 actual HbA1c measurement at screening/randomization

 ≥ 12 weeks of treatment exposure with at least one non-missing HbA1c measurement after 12 weeks

Completer analysis This analysis was performed using only patients who completed the trial and estimated an efficacy estimand.

1.2 Results Results of the sensitivity analysis on the pre-specified primary, confirmatory (i.e. analyzed with an adjustment for multiplicity) secondary and supportive secondary endpoints are presented in Table 1–1 to Table 1–6. The sensitivity analyses evaluated several more or less conservative scenarios based on different causal assumptions and handling of the missing data. Similar results were seen across the pre-specified LOCF approach and the applied sensitivity analyses.

Novo Nordisk IDegLira NDA 208583 Appendix 3 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 11 of 11

Table 1–6 Tipping point analyses of the most conservative sensitivity analysis, multiple imputation method #2 Efficacy parameter by trial Penalty needed to reverse MI (method #2) conclusion of statistical significance in favor of IDegLiraa

HbA1c Trial 3697 +2.8%-point vs. IDeg EOT value of 6.9% +3.8%-point vs. lira EOT value of 7.0% Trial 3951 +4.2%-point vs. placebo EOT value of 7.4% Trial 3912 +5.4%-point vs. IDeg EOT value of 8.0% Trial 3952 +3.8%-point vs. IGlar EOT value of 7.1% Trial 3851 +7.4%-point vs. GLP-1 RA EOT value of 7.4%

HbA1c <7.0% or ≤6.5% Statistical significance in favor of IDegLira was maintained even when all withdrawn patients from the IDegLira treatment arms across the five trials were considered to be HbA1c target non-responders Insulin dose Trial 3697 125−150 U higher compared to IDeg EOT value of 53.0 U Trial 3952 >300 U higher compared to IGlar EOT value of 66.3 U FPG Trial 3697 +11.5 mmol/L vs. liraglutide EOT value of 7.3 mmol/L Trial 3951 +10 mmol/L vs. placebo EOT value of 8.8 mmol/L Trial 3912 +1 mmol/L vs. IDeg EOT value of 7.0 mmol/L Trial 3851 +19 mmol/L vs. GLP-1 RA EOT value of 8.8 mmol/L Body weight Trial 3697 +14 kg higher vs. IDeg EOT value of 89.0 kg Trial 3912 +12 kg vs. IDeg EOT value of 93.5 kg Trial 3952 +20 kg vs. IGlar EOT value of 89.1 kg Confirmed hypoglycemic episodes Trial 3697 +3.9 events per PYE vs. IDeg EOT value of 2.6 per PYE Trial 3952 +11.6 events per PYE vs. IGlar EOT value of 5.1 per PYE aPenalty was applied to the end-of-trial values of withdrawn IDegLira patients. In the Multiple Imputations Method 2, patients who withdrew from the IDegLira group were evaluated as ‘being treated with the comparator throughout the trial’. Abbreviations: EOT = end of trial; FPG = fasting plasma glucose; GLP-1 RA = glucagon-like peptide-1 receptor agonist; HbA1c = glycosylated hemoglobin; IDeg = insulin degludec; MI = multiple imputation; PYE = patient years of exposure; U = units Novo Nordisk IDegLira NDA 208583 Appendix 4 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 1 of 7

Novo Nordisk

Insulin degludec/liraglutide (IDegLira) Treatment to Improve Glycemic Control in Adults with Type 2 Diabetes Mellitus

NDA 208583

Briefing Document

Endocrinologic and Metabolic Drug Advisory Committee

May 24, 2016

Appendix 4 Efficacy Across Subgroups

Advisory Committee Briefing Materials: Available for Public Release Novo Nordisk IDegLira NDA 208583 Appendix 4 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 2 of 7

1 Efficacy across subgroups

To evaluate the consistency of treatment effect on HbA1c, efficacy of IDegLira vs. comparators was compared post hoc across sub-groups defined by demographic factors (e.g., age group, sex, BMI group, race, ethnicity and population [U.S. and non-U.S.]) and disease factors (including duration of diabetes and baseline HbA1c).

aThe ’Other’ category included American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander and other races. Data are estimates with 95% confidence interval. The shaded areas denote the 95% CI for the treatment difference in the total population. All treatment by subgroup interactions tested p>0.05 except for race (p=0.0063) and ethnicity (p<0.0001). Missing data are imputed using the last observation carried forward method.

Figure 1–1 Efficacy of IDegLira vs. IDeg on HbA1c across subgroups – Trial 3697 (oral antidiabetic drug users) Novo Nordisk IDegLira NDA 208583 Appendix 4 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 3 of 7

aThe ’Other’ category included American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander and other races. Data are estimates with 95% confidence interval. The shaded areas denote the 95% CI for the treatment difference in the total population. All treatment by subgroup interactions tested p>0.05 except for race (p=0.0147). Missing data are imputed using the last observation carried forward method.

Figure 1–2 Efficacy of IDegLira vs. liraglutide on HbA1c across subgroups – Trial 3697 (oral antidiabetic drug users) Novo Nordisk IDegLira NDA 208583 Appendix 4 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 4 of 7

aThe ’Other’ category included Black or African American and other races. Data are estimates with 95% confidence interval. The shaded areas denote the 95% CI for the treatment difference in the total population. All treatment by subgroup interactions tested p>0.05. Missing data are imputed using the last observation carried forward method.

Figure 1–3 Efficacy of IDegLira vs. placebo on HbA1c across subgroups – Trial 3951 (oral antidiabetic drug users) Novo Nordisk IDegLira NDA 208583 Appendix 4 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 5 of 7

aThe ’Other’ category included Black or African American, Native Hawaiian or Other Pacific Islander and other races. Data are estimates with 95% confidence interval. The shaded areas denote the 95% CI for the treatment difference in the total population. All treatment by subgroup interactions tested p>0.05, except for BMI (p=0.0024). Missing data are imputed using the last observation carried forward method.

Figure 1–4 Efficacy of IDegLira vs. insulin degludec on HbA1c across subgroups – Trial 3912 (basal insulin users) Novo Nordisk IDegLira NDA 208583 Appendix 4 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 6 of 7

aThe ’Other’ category included Asian, Black or African American and other races. Data are estimates with 95% confidence interval. The shaded areas denote the 95% CI for the treatment difference in the total population. All treatment by subgroup interactions tested p>0.05. Missing data are imputed using the last observation carried forward method.

Figure 1–5 Efficacy of IDegLira vs. insulin glargine on HbA1c across subgroups – Trial 3952 (basal insulin users) Novo Nordisk IDegLira NDA 208583 Appendix 4 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 7 of 7

aThe ’Other’ category included Asian, Black or African American, American Indian or Alaska Native, and other races. Data are estimates with 95% confidence interval. The shaded areas denote the 95% CI for the treatment difference in the total population. All treatment by subgroup interactions tested p>0.05. Missing data are imputed using the last observation carried forward method.

Figure 1–6 Efficacy of IDegLira vs. GLP-1 receptor agonist on HbA1c across subgroups – Trial 3851 (GLP-1 receptor agonist users) Novo Nordisk IDegLira NDA 208583 Appendix 5 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 1 of 5

Novo Nordisk

Insulin degludec/liraglutide (IDegLira) Treatment to Improve Glycemic Control in Adults with Type 2 Diabetes Mellitus

NDA 208583

Briefing Document

Endocrinologic and Metabolic Drug Advisory Committee

May 24, 2016

Appendix 5 Patient Reported Outcomes

Advisory Committee Briefing Materials: Available for Public Release Novo Nordisk IDegLira NDA 208583 Appendix 5 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 2 of 5

1 Patient-reported outcomes Patient-reported outcomes (PRO) listed below were assessed as pre-specified supportive secondary endpoints in two open-label trials: Trial 3952 (IDegLira vs. IGlar in basal insulin users) and Trial 3851 (IDegLira vs. continued GLP-1 RA therapy in GLP-1 RA users).

 Short-Form 36, version 2 (SF-36v2 ) questionnaire in Trial 3952  Treatment Related Impact Measures-Diabetes (TRIM-D) in Trials 3952 and 3851  Diabetes Treatment Satisfaction Questionnaire, status version (DTSQs) in Trial 3851

The SF-36v2 questionnaire used in Trial 3952 (IDegLira vs. IGlar in basal insulin users) is the mostly widely used patient-reported health outcomes measure.1 This generic (i.e., not disease- specific) questionnaire assesses general health status and well-being. The SF-36v2 includes 36 items that assess 8 domains of functional health and well-being as well as 2 component summary scores (i.e., overall scores) of physical and mental health. The SF-36v2 domain scores are calculated using Norm-Based Scoring using the 1998 U.S. general population norm (mean = 50, SD = 10). Higher values on all domains and component summary measures indicate better functional health and well-being.

At the end of Trial 3952 (conversion to IDegLira vs. IGlar optimization in patients inadequately controlled on IGlar), mean scores improved with IDegLira across all physical and mental domains, but worsened with IGlar for 3 out of 4 physical domains and remained relatively unchanged for most mental domains (Table 1–1). After 26 weeks, patients receiving IDegLira demonstrated statistically significant improvement relative to patients receiving IGlar treatment in the overall physical score (i.e., physical components summary score) of SF-36v2, driven by improvements in all four component domain scores: physical functioning, role-physical, bodily pain and general health.

Supporting the above-mentioned findings, greater improvement with IDegLira relative to IGlar in Trial 3952 (basal insulin users) was also reported with a diabetes-specific PRO measure, the TRIM-D. The TRIM-D survey includes 28 items that assesses 5 domains shown in Table 1–1. The domain scores, as well as the total score, have a range of 0 to 100 with a higher score indicating a better health state. After 26 weeks, IDegLira treatment was associated with a statistically significantly greater improvement in the TRIM-D total score compared to IGlar, driven by improvements in the treatment burden and diabetes management domains. Similar findings with the TRIM-D instrument were also seen in Trial 3851 which compared conversion to IDegLira to continued GLP-1 therapy in patients inadequately controlled on GLP-1 RA. After 26 weeks of treatment, the total score as well as all 5 domain scores of the TRIM-D (including treatment burden and diabetes management domains) showed statistically significantly greater improvement in the IDegLira group than in the GLP-1 RA group (Table 1–1). Novo Nordisk IDegLira NDA 208583 Appendix 5 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 3 of 5

Greater treatment satisfaction with IDegLira relative to continued GLP-1 RA therapy was demonstrated with another diabetes-specific PRO measure, the DTSQs. The instrument consists of 8 items, 6 of which assess treatment satisfaction and are summed to produce a total score (ranging 0−36) for which a higher value indicates greater treatment satisfaction. The remaining 2 scores assess perceived frequency of hyperglycemia or hypoglycemia. These scores can range from 0 to 6, with lower scores indicating lower perceived frequency. Statistically significantly greater improvement in the treatment satisfaction score was seen 26 weeks after conversion to IDegLira than with continued GLP-1 RA therapy in Trial 3851 (GLP-1 RA users); Table 1–1. Consistent with the trial’s clinical findings for overall glycemic control and hypoglycemia, the ‘perceived frequency of hypoglycaemia’ score was greater (i.e., worse) in the IDegLira group compared to the GLP-1 RA group, while the ‘perceived frequency of hyperglycaemia’ score was lower (i.e., better) with IDegLira.

Novo Nordisk IDegLira NDA 208583 Appendix 5 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 5 of 5

Perceived 0.8 (1.4) 0.3 (0.1) 0.8 (1.4) -0.1 (0.1) 0.4 [0.1 ; 0.6] 0.006 hypoglycaemia

*Comparators: IGlar in Trial 3952 and GLP-1 receptor agonists (liraglutide or exenatide) in Trial 3851. Missing data are imputed using the last observation carried forward method. Abbreviations: CI=confidence interval; DTSQs =Diabetes treatment satisfaction questionnaire, status version; ETD=estimated treatment difference; GLP-1 RA = glucagon-like peptide-1 receptor agonist; LSMean=least square mean; SE=standard error; SF-36v2= Short-form 36, version 2; TRIM-D= Treatment related impact measures-diabetes.

1. Scoggins JF, Patrick DL. The use of patient-reported outcomes instruments in registered clinical trials: evidence from ClinicalTrials.gov. Contemp Clin Trials. 2009;30(4):289-92. Novo Nordisk IDegLira NDA 208583 Appendix 6 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 1 of 2

Novo Nordisk

Insulin degludec/liraglutide (IDegLira) Treatment to Improve Glycemic Control in Adults with Type 2 Diabetes Mellitus

NDA 208583

Briefing Document

Endocrinologic and Metabolic Drug Advisory Committee

May 24, 2016

Appendix 6 Calculation of Adjusted AE Frequencies and Rates when Pooling Trials

Advisory Committee Briefing Materials: Available for Public Release Novo Nordisk IDegLira NDA 208583 Appendix 6 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 2 of 2

1 Calculation of adjusted AE frequencies and rates when pooling trials Naïve pooling of AE data from trials with different treatments and/or different randomization ratios may introduce bias when comparing treatments, e.g. due to Simpson’s paradox. To minimize such bias, a method was used that 1) adjusted the AE frequencies and rates in each trial based on the respective pooled AE frequency and rate for IDegLira, and 2) weighted the trials according to the number of patients in the IDegLira group in each trial. The method is described in four steps below for AE frequencies. The same method was applied to AE rates. Steps 1-3 adjust for trial effect, assuming that the true IDegLira frequency is the pooled IDegLira frequency and that any deviation from this is a trial effect. Step 4 adjusts for the trial sizes and differences in randomization ratios.

Step 1 derived the pooled frequency for IDegLira. This was calculated from the naïve pooling of trials, i.e., as the total number of IDegLira-treated patients with the event divided by the total number of patients treated with IDegLira.

Step 2 calculated the relative risk (RR) for the event with comparator vs IDegLira for each trial. For trials with no events in the IDegLira arm the RR was set to 0.

Step 3 calculated the adjusted fraction of patients with the event in the comparator arms of each trial based on the trial-specific relative risks vs. IDegLira and the pooled frequency for IDegLira.

Step 4 pooled the adjusted fraction of patients with the event in the comparator arm across trials, assigning weights according to number of patients in the IDegLira arm in each trial.

The frequencies and rates calculated from this adjusted pooling have the following properties:  The pooled frequency and rate for IDegLira is the naïve pooled frequency/rate.  The relative risks and relative rates for comparators vs. IDegLira are preserved within each trial.  The pooling of trials is weighted according to the size of the IDegLira treatment group in the trial. This implies that the Simpsons paradox type of bias, arising from differences in randomization ratios, is avoided.  The adjusted pooled frequencies and rates can be interpreted as the frequencies/rates that would have been observed if 1) the IDegLira group of all trials had the same frequencies/rates, and 2) patients were evenly randomized to treatment groups in all trials. Novo Nordisk IDegLira NDA 208583 Appendix 7 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 1 of 5

Novo Nordisk

Insulin degludec/liraglutide (IDegLira) Treatment to Improve Glycemic Control in Adults with Type 2 Diabetes Mellitus

NDA 208583

Briefing Document

Endocrinologic and Metabolic Drug Advisory Committee

May 24, 2016

Appendix 7 Event Adjudication

Advisory Committee Briefing Materials: Available for Public Release Novo Nordisk IDegLira NDA 208583 Appendix 7 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 2 of 5

1 Event adjudication Medical events of special interest Medical events of special interest were pre-defined for the 5 completed phase 3 trials. A medical event of special interest (serious or non-serious) is an event related to a specific scientific and medical area that Novo Nordisk continues to assess on an ongoing basis. A medical event of special interest does not necessarily have a causal relationship with the trial product. The medical events of special interest were selected based on the known and potential risks of insulins and GLP-1 RAs, as well as requirements from regulatory agencies for the development of drugs for the treatment of diabetes, and were predefined in the protocol to ensure collection of relevant and timely information for an in-depth evaluation of these events.

A medical event of special interest was to be reported by the investigator following the same reporting requirements and timelines as for SAEs, irrespective of whether the event fulfilled the SAE criteria. Specific forms in the electronic case report from (eCRF) for each type of medical event of special interest were to be filled out. These forms were designed to optimize the relevant clinical information collected for each type of event. Additional adverse events potentially relevant for adjudication was captured through preferred term query (PTQ) searches. If the event was not already reported on a dedicated form in the eCRF, the investigator was asked to reconsider if this AE was a medical event of special interest.

Event Adjudication Committee (EAC) An external EAC was constituted to perform ongoing adjudication of pre-selected events. The EAC was composed of permanent members who represented required medical specialties. The EAC members disclosed any potential conflicts of interest and were independent of Novo Nordisk. The EAC worked in accordance with written guidelines included in the EAC charter that describes in detail the composition, tasks, responsibilities, and work processes of the committee.

The EAC was composed of 3 individual subcommittees that evaluated the events according to their areas of expertise:

 Cardiovascular events (2 cardiologists and 2 neurologists)  Pancreatitis events (2 gastroenterologists)  Neoplasms and thyroid disease requiring thyroidectomy (2 oncologists and 1 endocrinologist)

Event adjudication by the EAC was completed based on a blinded review of source information collected from the sites. The source data were blinded to treatment assignment and anonymised of personal identifiers. The EAC reviewed translated copies in English of medical documentation received in the adjudication packages (for example X-rays, ECGs, ultrasound images, discharge summaries, pathology reports, and death certificates). The investigator was to provide these Novo Nordisk IDegLira NDA 208583 Appendix 7 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 3 of 5 documents as soon as possible upon receiving a request from Novo Nordisk. The EAC classified the cardiovascular events consistent with FDA guidance.

The adjudication process was managed by an external, independent company, ICON Medical Imaging. ICON managed the collection of relevant information from the clinical trial sites for adjudicated events and ensured that it was blinded with respect to treatment assignment and anonymized before forwarding it to the EAC.

The role of the EAC was solely to adjudicate events. The EAC had no authorization to impact trial conduct, trial protocol or amendments. The assessments made by the EAC were included in the clinical trial reports, and so were assessments made by the investigator. The outcomes of adjudication were kept in the Novo Nordisk clinical trial database.

Selection of events sent for adjudication Events to be adjudicated could follow different paths (Figure 1–1):

1. The investigator reported a medical event of special interest within one of the pre-defined categories relevant for adjudication. This reporting on a dedicated form in the eCRF triggered that the event was directly sent to ICON, which then forwarded the event together with relevant source information to the EAC, whose members performed an independent, blinded adjudication and classification of the event based on the collected information. 2. Events, potentially eligible for adjudication and not reported as described above, were identified by Novo Nordisk applying a broad, pre-defined search (a ‘preferred term query’ [PTQ] based on standardised MedDRA queries [SMQs] and relevant terms from the MedDRA hierarchy) on all reported AEs. These events were sent to ICON, where medically qualified personnel reviewed the events to decide whether the case was appropriate for referral to adjudication. Events relevant for adjudication were forwarded (together with source information) to the EAC for adjudication, as described above. In addition, to identify potential cases of pancreatitis not reported by the investigator, Novo Nordisk searched for reported events of pancreatic enzyme elevations that occurred within 30 days of predefined gastrointestinal signs or symptoms.

Novo Nordisk IDegLira NDA 208583 Appendix 7 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 5 of 5

Table 1–1 Classification of adjudicated events by the external event adjudication committee (EAC) Event type EAC category Death  Cardiovascular death  Non-cardiovascular death Acute coronary syndrome  Acute myocardial infarction (MI) - ST-elevation myocardial infarction (STEMI) - Non-ST-elevation myocardial infarction (NSTEMI)  Unstable angina pectoris requiring hospitalisation (UAP) Cerebrovascular events  Stroke  Transient ischaemic attack (TIA) Heart failure requiring hospitalization (no sub-classification) Coronary revascularisation procedure (no sub-classification) Pancreatitis (or suspicion of pancreatitis)  Acute pancreatitis  Chronic pancreatitis Neoplasms Malignancy status, organ/system of origin and stage

Thyroid disease  Thyroid disease requiring thyroidectomy  Thyroid neoplasm Novo Nordisk IDegLira NDA 208583 Appendix 8 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 1 of 8

Novo Nordisk

Insulin degludec/liraglutide (IDegLira) Treatment to Improve Glycemic Control in Adults with Type 2 Diabetes Mellitus

NDA 208583

Briefing Document

Endocrinologic and Metabolic Drug Advisory Committee

May 24, 2016

Appendix 8 Summary of 120-day Safety Update

Advisory Committee Briefing Materials: Available for Public Release Novo Nordisk IDegLira NDA 208583 Appendix 8 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 2 of 8

Table of contents Page Table of contents...... 2 1 Summary of 120-day safety update ...... 3 1.1 Scope of the 120-day safety update ...... 3 1.2 Exposure ...... 4 1.3 Analysis of adverse events...... 4 1.3.1 Overview of SAEs ...... 4 1.3.2 Fatal adverse events...... 4 1.3.3 Other serious adverse events...... 5 1.3.4 Adverse events leading to withdrawal ...... 5 1.3.5 Pregnancy ...... 6 1.4 Post-marketing data ...... 6 Novo Nordisk IDegLira NDA 208583 Appendix 8 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 3 of 8

1 Summary of 120-day safety update

1.1 Scope of the 120-day safety update The NDA submitted to the FDA had a data cut-off of 31 March 2015. Additional blinded safety data from two phase 3 trials that were ongoing at the time of NDA submission (Trials 4119 and 4056) as well as from a trial that was subsequently initiated (Trial 4185) was submitted to the FDA in a 120 Day Safety Update with a cut-off date of 30 September 2015. A brief overview of the ongoing trials included in the 120-day safety update is provided in Table 1–1. The 120-day safety update included available blinded safety data from these trials on deaths, other serious adverse events, pregnancies (including updates for pregnancies reported as ongoing in the NDA) and adverse events leading to withdrawal.

Table 1–1 Overview of the design and status of the ongoing phase 3 trials in the IDegLira 120-day safety update Trial Trial description Trial Concomitant Randomisation Duration and randomised treatment population Antidiabetic ratio/ Status treatment estimated exposure

4119 Subjects inadequately controlled on T2DM subjects Metformin: 1:1 IDegLira + metformin in Trial 3952. in the IDegLira arm of ≥ 1500 mg/day or 31 patients 26 weeks Treatment intensification with 1–3 Trial 3952 (HbA1c ≥7% maximum injections of bolus IAsp vs. IDegLira up at week 26 of Trial tolerated dose to a maximum of 80 dose steps (80 units 3952). IDeg and 2.9 mg liraglutide) (open- label). 4056 Once weekly versus twice weekly T2DM subjects Metformin: ≥ 1:1 titration of IDegLira, both in (screening HbA1c 1500 mg/day or 420 patients 32 weeks combination with metformin ± 7.0−10.0%, both maximum pioglitazone (open-label). inclusive). tolerated dose ± BMI ≤ 40 kg/m2 pioglitazone: ≥30 In both treatment arms, the starting dose mg of IDegLira is 10 dose steps (corresponding to10 units IDeg and 0.36 mg liraglutide). 4185 Subjects on existing IGlar + metformin T2DM subjects Metformin: 1:1 26 weeks treatment given IDegLira + metformin (screening HbA1c ≥ 1500 mg/day or 78 patients vs IGlar +IAsp +metformin (open-label). 7.0−10.0%, both maximum inclusive). tolerated dose BMI ≤ 40 kg/m2

BMI: body mass index; HbA1c: glycosylated haemoglobin A1c; IAsp, insulin aspart; IDeg: insulin degludec; IDegLira: insulin degludec/liraglutide; IGlar: insulin glargine; T2DM: type 2 diabetes mellitus Novo Nordisk IDegLira NDA 208583 Appendix 8 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 4 of 8

1.2 Exposure As of the cut-off date for the 120-day safety update (30 September 2015), exposure to IDegLira in ongoing clinical trials was estimated to have occurred in 529 subjects (Trial 4119: 31 subjects; Trial 4056: 420 subjects; Trial 4185: 78 subjects), based on the randomisation ratio and the number of subjects randomised.

1.3 Analysis of adverse events

1.3.1 Overview of SAEs An overview of SAEs is given in Table 1–2. The events reported in this 120-day safety update also include an SAE of peripheral arterial occlusive disease that had an onset date of 12 March 2015, and one case with 2 SAEs (hypotension and colitis), both with onset on 31 March 2015. These events were included in the 120-day safety update because they were reported after the ISS data lock-point.

Table 1–2 Overview of SAEs reported in this 120-day safety update Categorisation Number of events SAEs prior to trial product treatment 1 Treatment emergent SAEs 22  Trial 4056 21  Trial 4119 0  Trial 4185 1  Treatment emergent SAEs reported as 19 recovered/resolved by 30 September 2015  Treatment emergent SAEs reported as not 2 recovered/resolved by 30 September 2015  Fatality 1 Exposure during pregnancy 1 SAE, serious adverse event

1.3.2 Fatal adverse events One fatal AE (in Trial 4056) was reported in the 120-day safety update ((recorded cause of death: ‘natural death and cardiovascular collapse’). A narrative is provided in Table 1–3. Novo Nordisk IDegLira NDA 208583 Appendix 8 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 5 of 8

Table 1–3 Fatal event in the ongoing phase 3 trials (120-day safety update) Trial/ Study Preferred Investigator Relevant medical Short narrative Age/ day Term causality history Sex/ BMI/ Country Death 4056/ 194 Death Unlikely Hypertension, The subject had a recent abnormal ECG showing 63/ hyperlipidaemia, a history of coronary artery disease, mid-left Male/ ischemic heart ventricular hypertrophy, ejection fraction of 65.3 27.2/ disease, carotid and diastolic dysfunction. The subject died whilst US plaque bilateral sleeping. The death certificate was not available at the data lock-point (30 September 2015), however a subsequent update confirms that no autopsy was performed and ‘natural death and cardiovascular collapse’ are the specified causes of death on the death certificate. ECG, electrocardiogram; SAE, serious adverse event.

1.3.3 Other serious adverse events A total of 23 SAEs (22 treatment emergent) in 17 subjects were reported in the 120-day safety update; 21 SAEs were reported in 15 subjects participating in Trial 4056 and a total of 2 SAEs were reported for 2 subjects in Trial 4185. One of the SAEs reported in Trial 4185 had an onset prior to treatment with trial product.

Within the reporting period for the 120-day safety update, no SAEs, categorised by SOC or preferred term, occurred in ≥1% of the subjects. The SOCs with the highest occurrence of SAEs were ‘infections and infestations’ (4 SAEs), ‘gastrointestinal disorders’ (4 SAEs) and ‘renal and urinary disorders’ (3 SAEs). There were 2 SAEs in each of the SOCs ‘general disorders and administration site conditions’, ‘metabolism and nutrition disorders’ and ‘vascular disorders’; there was 1 SAE in each of the SOCs: ‘pregnancy’, ‘cardiac disorders’, ‘nervous system disorders’ and ‘musculoskeletal and connective tissue disorders’.

Of the 21 non-fatal treatment emergent SAEs, 19 were considered recovered by 30 September 2015. The two SAEs that had not resolved by 30 September 2015 comprised events of ‘salivary gland mass’ and ‘haematoma infective’.

No safety concerns were raised based on this limited additional data.

1.3.4 Adverse events leading to withdrawal For trials that were ongoing during the 120-day reporting period, adverse events leading to withdrawal were summarised for the entire period from trial initiation and up until the cut-off date Novo Nordisk IDegLira NDA 208583 Appendix 8 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 6 of 8 for the safety update. In total, 9 subjects withdrew from Trial 4056 due to AEs. The 9 AEs leading to withdrawal from trial were reported with 9 different preferred terms (‘endometrial adenocarcinoma’, ‘death’, ‘hypertriglyceridaemia’, ‘headache’, ‘paraesthesia’, ‘gastroenteritis’, ‘nausea’, ‘arthralgia’ and ‘pancreatitis’) distributed across 7 system organ classes. There were no withdrawals from Trials 4119 or 4185 due to AEs during this period.

1.3.5 Pregnancy A spontaneous abortion was reported in the 120-day safety update for one patient of the ongoing Trial 4056 comparing two different titration algorithms of IDegLira. The spontaneous abortion occurred at a gestational age of the fetus of less than 2 months. Medical history included substance abuse during pregnancy.

There are no new updates to pregnancies reported in the 5 completed phase 3 trials, as the pregnancies were concluded.

1.4 Post-marketing data Since the cut-off date of this 120-day safety update (30 September 2015) is shared by the Periodic Safety Update Report/Periodic Benefit Risk Evaluation Report (PSUR/PBRER) for Xultophy® (IDegLira), the PSUR details the most current and relevant critical analysis of the benefit-risk balance for Xultophy®. This PSUR evaluation is supported by a cumulative summary tabulation of SAEs from clinical trials and adverse reactions by preferred term from post-authorisation sources.

No safety concerns were identified from post-marketing data during the period from 31 March 2015 up until the cut-off date for data in the 120-day safety update (30 September 2015). A summary of the post-marketing experience reported in the PSUR, for the interval of 1 April 2015 to 30 September 2015 is given in Table 1–4. Novo Nordisk IDegLira NDA 208583 Appendix 8 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 7 of 8

Table 1–4 Summary of post-marketing data with IDegLira (Xultophy®) reported during the period of 01 April 2015 to 30 September 2015 No. of Summary of post-marketing period experience cases Off label use 5 2 cases of switch from GLP-1 RA therapy to Xultophy®,a 1 case where Xultophy® was added to existing treatment of Victoza® and glargine;a 1 case of co-treatment with Xultophy® and a sodium- glucose co-transporter 2 inhibitor ().a No AEs were reported with these 4 cases.

There was 1 case of use in moderate renal impairment, where Xultophy® replaced Victoza®. When the Xultophy® dose in this case was titrated from 46 to 50, this was associated with 1 AE each of 'diarrhoea’, ‘nausea’ and ‘vomiting'. This improved when the Xultophy® dose was lowered to 46. Misuse, abuse or overdose 0 Adverse drug reactions (ADRs) 2 serious 45 ADRs in 21 spontaneous case reports were reported with the 43 non- use of Xultophy®: 2 serious ADRs and 43 non-serious ADRs serious Medication errors 0 serious; Four reports of medication errors have been received from the 4 non- post-marketing setting. Overall, these do not alter the medication serious error risk for IDegLira significantly. Gastrointestinal disorders 0 serious; Further details not yet available 14 non- serious Hypoglycaemia 0 serious; Further details not yet available 3 non- serious Immunogenicity 0 No cases related to immunogenicity have been reported from the post-marketing data sources with Xultophy® Pancreatitis 0 No cases related to pancreatitis have been reported from the post- marketing data sources with Xultophy® Altered renal function 0 No cases related to altered renal function have been reported from the post-marketing data sources with Xultophy® Cardiovascular disorders 1 serious 1 serious case (PT ‘Myocardial infarction’) 0 non- serious Lack of efficacy due to anti-IDeg or 0 No cases related to lack of efficacy due to anti-IDeg or anti- anti-liraglutide antibody formation liraglutide antibody formation have been reported from post- marketing experience Medication errors, including errors 0 serious Further details not yet available with transfer from injectable diabetes and 4 therapy non- serious cases Novo Nordisk IDegLira NDA 208583 Appendix 8 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 8 of 8

No. of Summary of post-marketing period experience cases Medullary thyroid cancer 0 No cases related to medullary thyroid cancer have been reported from the post-marketing experience. Neoplasm 0 No cases related to neoplasms have been reported from the post- marketing data sources with Xultophy® Pancreatic cancer 0 No cases related to pancreatic cancer have been reported from the post-marketing data sources with Xultophy® ADR, adverse drug reaction; PT, preferred term a These cases were reported according to the European Union (EU) label at the time of data cut-off; the EU label has since been updated to include switching to Xultophy® from GLP-1 RA.

Cumulative and interval patient exposure from marketing experience The sales figure representing the total volume (including samples) of IDegLira released from Novo Nordisk A/S to external customers (with distribution outside the US) up until 30 September 2015 is approximately 54 million units. Exposure data have been calculated from the total released volume of IDegLira. The average daily dose at the 120-day safety update cut-off date was estimated to be 39 dose steps based on the average daily dose in the 5 completed phase 3 clinical trials and is used to estimate the patient years of exposure (PYE). A crude estimate of exposure (currently from Europe) is 3,003 PYE during the reporting period and 3,813 PYE cumulatively. Novo Nordisk IDegLira NDA 208583. Appendix 9 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 1 of 5

Novo Nordisk

Insulin degludec/liraglutide (IDegLira) Treatment to Improve Glycemic Control in Adults with Type 2 Diabetes Mellitus

NDA 208583

Briefing Document

Endocrinologic and Metabolic Drug Advisory Committee

May 24, 2016

Appendix 9 Safety Tables and Figures

Advisory Committee Briefing Materials: Available for Public Release Novo Nordisk IDegLira NDA 208583. Appendix 9 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 2 of 5

Table of tables

Page Table 1–1 Exposure by demographics – completed phase 3 trials ...... 3 Table 1–2 Exposure by baseline characteristics - completed phase 3 trials ...... 4 Table 1–3 Patients with skin neoplasms - completed phase 3 trials...... 5 Novo Nordisk Appendix 9 IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 3 of 5 1 Safety tables and figures Table 1–1 Exposure by demographics – completed phase 3 trials ————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— IDegLira Basal insulin GLP-1 RA Placebo Total N (PYE) N (PYE) N (PYE) N (PYE) N (PYE) ————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Safety analysis set 1881 (1200.8) 890 ( 575.2) 557 ( 400.2) 146 ( 62.1) 3474 (2238.4) Sex Male 990 ( 624.9) 442 ( 288.6) 276 ( 197.7) 73 ( 31.2) 1781 (1142.3) Female 891 ( 576.0) 448 ( 286.7) 281 ( 202.6) 73 ( 30.9) 1693 (1096.1) Age group (yrs) >=18 - <65 years 1506 ( 976.2) 703 ( 461.8) 465 ( 337.5) 99 ( 43.1) 2773 (1818.6) >=65 years 375 ( 224.7) 187 ( 113.5) 92 ( 62.7) 47 ( 19.0) 701 ( 419.9) >=65 - <75 years 323 ( 198.3) 162 ( 96.5) 81 ( 55.5) 38 ( 14.8) 604 ( 365.1) >=75 years 52 ( 26.3) 25 ( 16.9) 11 ( 7.2) 9 ( 4.2) 97 ( 54.8) Race White 1411 ( 865.2) 672 ( 417.4) 387 ( 277.3) 111 ( 46.0) 2581 (1605.9) Asian 327 ( 243.2) 165 ( 122.5) 117 ( 88.0) 20 ( 9.3) 629 ( 463.0) Black or African American 116 ( 72.0) 38 ( 23.8) 40 ( 23.5) 13 ( 6.3) 207 ( 125.5) Other 24 ( 17.9) 12 ( 9.1) 12 ( 10.5) 2 ( 0.6) 50 ( 38.0) American Indian or Alaska Native 3 ( 2.5) 2 ( 2.0) 5 ( 4.5) Native Hawaiian or Oth. Pacific Islander 1 ( 0.5) 1 ( 1.0) 2 ( 1.5) Ethnicity Not Hispanic or Latino 1582 (1022.1) 665 ( 446.4) 486 ( 344.5) 130 ( 55.8) 2863 (1868.8) Hispanic or Latino 299 ( 178.8) 224 ( 128.8) 70 ( 55.5) 16 ( 6.3) 609 ( 369.4) Missing* 1 ( 0.0) 1 ( 0.2) 2 ( 0.2) Region(continent) Europe 733 ( 467.9) 367 ( 229.3) 164 ( 127.2) 57 ( 25.0) 1321 ( 849.4) North America 661 ( 396.4) 247 ( 157.2) 232 ( 149.7) 71 ( 28.8) 1211 ( 732.2) Asia 248 ( 187.9) 117 ( 90.5) 85 ( 67.7) 18 ( 8.3) 468 ( 354.5) South America 99 ( 53.6) 91 ( 49.3) 10 ( 10.0) 200 ( 113.0) Africa 88 ( 60.0) 52 ( 34.9) 33 ( 20.9) 173 ( 115.8) Australia 52 ( 34.9) 16 ( 14.0) 33 ( 24.6) 101 ( 73.5) Region(US/non-US) non-US 1284 ( 848.7) 660 ( 432.3) 338 ( 261.0) 85 ( 37.5) 2367 (1579.5) US 597 ( 352.1) 230 ( 143.0) 219 ( 139.2) 61 ( 24.6) 1107 ( 658.9) ————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— N: number of patients; PYE: patient-years of exposure (1 PYE = 365.25 days).* No information provided. Novo Nordisk Appendix 9 IDegLira NDA 208583 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 4 of 5

Table 1–2 Exposure by baseline characteristics - completed phase 3 trials —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————

IDegLira Basal insulin GLP-1 RA Placebo Total N (PYE) N (PYE) N (PYE) N (PYE) N (PYE) —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————

Safety analysis set 1881 (1200.8) 890 ( 575.2) 557 ( 400.2) 146 ( 62.1) 3474 (2238.4)

Duration of diabetes < 10 years 1196 ( 806.3) 554 ( 382.6) 370 ( 276.3) 88 ( 38.2) 2208 (1503.5) >= 10 years 685 ( 394.5) 336 ( 192.6) 187 ( 123.9) 58 ( 23.9) 1266 ( 735.0)

BMI group(kg/m2) [30;35[ 652 ( 406.6) 312 ( 196.9) 194 ( 140.2) 53 ( 23.8) 1211 ( 767.5) [25;30[ 551 ( 356.3) 255 ( 165.6) 150 ( 110.2) 47 ( 19.3) 1003 ( 651.4) [35;[ 518 ( 327.8) 250 ( 160.0) 162 ( 114.0) 40 ( 16.6) 970 ( 618.3) [0;25[ 160 ( 110.2) 73 ( 52.7) 51 ( 35.9) 6 ( 2.4) 290 ( 201.2)

Renal function Normal 944 ( 610.3) 474 ( 306.4) 294 ( 213.9) 60 ( 26.8) 1772 (1157.4) Mild impairment 820 ( 522.3) 358 ( 231.1) 226 ( 163.9) 73 ( 29.9) 1477 ( 947.2) Moderate impairment 116 ( 68.2) 58 ( 37.8) 37 ( 22.5) 13 ( 5.4) 224 ( 133.8) Severe impairment 1 ( 0.0) 1 ( 0.0)

ALAT <75th percentile 1392 ( 869.0) 677 ( 429.8) 395 ( 279.1) 112 ( 47.8) 2576 (1625.6) >=75th percentile 489 ( 331.9) 213 ( 145.5) 162 ( 121.2) 34 ( 14.3) 898 ( 612.8)

ASAT <75th percentile 1387 ( 863.9) 702 ( 446.9) 398 ( 281.9) 110 ( 45.6) 2597 (1638.3) >=75th percentile 494 ( 336.9) 188 ( 128.3) 159 ( 118.4) 36 ( 16.5) 877 ( 600.2)

—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————

Data are based on trials NN9068-3697 (including extension part), NN9068-3912, NN9068-3851, NN9068-3951 and NN9068-3952. N: number of patients; PYE: patient-years of exposure (1 PYE = 365.25 days). Renal function is classified using creatine clearance estimated using the CKD-EPI equation.

Novo Nordisk IDegLira NDA 208583 Appendix 10 Endocrinologic and Metabolic Drug Advisory Committee, May 24, 2016 1 of 2

Novo Nordisk

Insulin degludec/liraglutide (IDegLira) Treatment to Improve Glycemic Control in Adults with Type 2 Diabetes Mellitus

NDA 208583

Briefing Document

Endocrinologic and Metabolic Drug Advisory Committee

May 24, 2016

Appendix 10 Narratives of Deaths

Advisory Committee Briefing Materials: Available for Public Release