VICTOZA Q&A JULY 2011

Question 1

What is GLP-1?

Answer 1

GLP-1 (Glucagon-Like Peptide-1) is a natural gut hormone and is part of the body’s own glucose control mechanism. GLP-1 therapy is a major innovation in T2DM; it helps regulate blood sugar levels only when they are elevated, for example, after meals, by stimulating beta cells to secrete insulin and by reducing glucagon secretion. GLP-1 also helps control food intake by slowing gastric emptying and inducing satiety, and it plays an important role in protecting the beta cells, a key to slowing diabetes progression.

Question 2

What drug class does Victoza® belongs to?

Answer 2

Victoza® belongs to the class of human GLP-1 analogues. Human GLP-1 analogues are part of a category of drugs known as GLP-1 receptor agonists that also includes exendin-based therapies such as exenatide and exenatide extend release (ER). GLP-1 receptor agonists and DDP-4 inhibitors belong to a family of T2DM drugs known as incretin-based therapies. An incretin is a hormone made by the intestine that stimulates the pancreas to make more insulin upon food intake and inhibit glucagon.

Question 3

What is the mode of action of Victoza®?

Answer 3

 Victoza® stimulates insulin secretion and inhibits glucagon secretion resulting in a reduction in blood glucose. Both the effects on insulin and glucagon are glucose-dependent, which means that Victoza® only works when glucose levels are elevated. This results in a very low risk of hypoglycaemia in the absence of concurrent sulfonylurea therapy.  Victoza® delays gastric emptying, induces satiety and reduces appetite and food intake, ultimately contributing to weight loss.  Victoza® improves beta-cell function in humans and has been shown to increase beta-cell mass in animal trials. Native GLP-1 has multiple direct and indirect effects on human physiology targeting the pancreas, liver, gastrointestinal system, kidney, fat cells, muscle and central nervous system. Victoza® is expected to share most of these properties.

Question 4

Does Victoza® improve insulin resistance?

Answer 4

GLP-1 receptors are not widely expressed in peripheral insulin-sensitive tissues such as muscle, fat and the liver. Some studies have suggested that treatment with GLP-1 receptor agonists is associated with improvements in insulin sensitivity. Victoza® has the potential to indirectly influence insulin sensitivity by improving glucose control. In LEAD 3, insulin resistance improved more in the Victoza® group than in the glimepiride group; but there also was a substantial improvement in overall glycaemic control achieved with Victoza® compared to glimepiride, as well as a significant weight loss with Victoza® versus the weight gain with glimepiride group. Both the improved glycaemic control and weight loss can favourably influence insulin resistance.

Question 5

Does Victoza® impact postprandial glucose?

Answer 5

Victoza® reduces post-prandial glucose. A reduction in the postprandial increment (blood glucose post-meal minus pre-meal) was demonstrated in meal test studies (Flint A, et al, Adv Ther 2011). In the LEAD 2 trial, Victoza® reduced postprandial glucose by approximately 50 mg/dl (2.3 mmol/l) and brought the majority of people below the ADA-recommended daily maximum (2 h postprandial) glucose level of 10mmol/l (180mg/dl). The impact, however, on glycaemic levels is greater on FPG than on PPG, due to the pharmacokinetic (PK) profile that provides sustained pharmacologically effective drug levels throughout 24 hours.

Question 6

Does Victoza® pass the blood-brain barrier*?

Answer 6

It is unknown whether Victoza® passes the blood-brain barrier in humans. However, investigations have shown the passage of GLP-1 and exenatide into brain of rats and mice. In humans, cells positive for the GLP-1 receptor has been found in several areas of the brain, in particular in the ventromedial part of the hypothalamus responsible for satiety. *The blood-brain barrier is the protective barrier formed along the blood vessels to separate the circulating blood from central nervous system fluid. This protective barrier prevents some substances in the blood from entering brain tissue.

Question 7

Does baseline beta-cell function have a role on Victoza® glycaemic control?

Answer 7

Some data suggest that well-preserved beta-cell function could imply even greater benefits of Victoza® when compared to SU, if treatment is initiated early. In a post-hoc analysis of LEAD-3 results (Garber et al, Diabetes supplement 1, 2010), patients with diabetes duration ≤1 year treated with Victoza® experienced the best reductions in A1c, sustained over 52 wks, whereas patients with diabetes duration >1 yr treated with glimepiride had smallest decrease in A1c. This suggests that use of Victoza® early in the natural history of diabetes may provide the most robust effect on glucose control. Furthermore, a meta-analysis of the LEAD trials examined beta-cell function at baseline (pre-Victoza® administration) by HOMA-B. When the results were stratified into change in HbA1c by quartiles of baseline beta-cell function, similar reductions in HbA1c were observed in all quartiles, further indicating that Victoza® is effective regardless of diabetes duration.

Question 8

Can Victoza® prevent or delay diabetes the progression of the disease?

Answer 8

Beta cell function is an important measure of disease progression in T2DM. As such, human trials have demonstrated that Victoza® improves first-phase insulin response and beta-cell insulin secretory capacity as well as improving (reducing) the pro-insulin/insulin ratio. Furthermore, insulin secretion can be restored to the level of healthy subjects following a single dose of Victoza®. Currently, the longest-term published data from a two-year monotherapy trial (one year blinded and one year extension) with Victoza® (LEAD 3) demonstrate that the improved beta-cell function results in substantial and sustained (over 1 year, hence 2 years in total) improvement in glycaemic control. That was with HbA1c maintained below 7.0% in a large proportion of patients previously treated with diet and exercise (that is, those not previously on pharmacologic therapy). In animal models of diabetes treated with Victoza®, disease progression is delayed. Victoza® inhibits free fatty acid (FFA) and cytokine-mediated apoptosis (cell death) in vitro and increases beta-cell mass in rodent models in vivo. One can speculate that the effect on beta cells may prevent secondary failure to treatment as seen with OAD treatment of T2DM. The above described human, animal and in vitro data give rise to speculation that Victoza® may play a role in potentially delaying disease progression in humans; however more clinical studies will be needed within this area to appropriately document this potential.

Question 9

What are the main in vitro and in vivo findings of Victoza® on beta-cells?

Answer 9

The positive impact of Victoza® on beta cell function includes: • Restoration of beta cell glucose sensitivity • Improved pro-insulin to insulin ratio • Improved HOMA-B • Increased insulin secretory capacity • Increased first phase insulin secretion • Increased beta-cell mass (only investigated in animal studies); Reduced beta-cell apoptosis

Question 10

Can long-term treatment with Victoza® lead to beta-cell hypertrophia?

Answer 10

There are no animal data showing hypertrophia*. *Hypertrophia refers to the general increase in bulk of a body part or organ due to an increase in cell volume; it is not due to tumour formation, nor to an increase in the number of cells.

Question 11

How is Victoza® metabolized and what happens to the fatty-acid side chain once cleaved off?

Answer 11

There is no single organ of elimination. Victoza® is considered almost completely metabolised and degraded into peptides, amino acids and fatty acid fragments, and subsequently completely degraded yielding carbon dioxide and water. The palmitate side chain is metabolised like other fatty acids ingested as part of food and represents a very small amount of fatty acid compared to that generated from food or from endogenous metabolism of fat. As Victoza® is not cleared by one specific organ, renal and hepatic impairment have only a limited effect on the pharmacokinetics of Victoza®.

Question 12

What is the fraction of total albumin saturated with Victoza® in serum?

Answer 12

There is a 120,000-fold excess serum albumin to Victoza® at steady state.

Question 13

At what level of plasma concentration is Victoza® effective?

Answer 13

After subcutaneous administration, about 95% to 99% of Victoza® is bound to albumin. The plasma concentration at which Victoza® is effective has not been determined.

Question 14

Why are patients experiencing nausea on GLP-1 therapy?

Answer 14

Administration of GLP-1 can slower gastric emptying by the stimulation of GLP-1 receptors in the gastrointestinal tract and/or stimulation of the vagus nerve. This means people feel fuller (feeling of satiety), which in some cases may be experienced as nausea (similar to the situation where people have eaten too much and feel really full). It has been demonstrated that the GI side effects are reduced if the time span between the doses (from 0.6mg to 1.2mg for example) is increased to one week.

Question 15

Approvals, launches and brand name

Answer 15

Victoza® approval regulatory agencies and dates are as follows:  European Commission in all 27 European Union member states on 30 June 2009 (Novo Nordisk Company Announcement, 3 July 2009)  US Food and Drug Administration (FDA) on 25 January 2010 (Company Announcement, 26 January 2010)  As of June 2010, approval has also been granted by the Regulatory authorities in Japan (Company Announcement, 20 January 2010; Press Release related to price approval and launch, 2 June 2010), as well as Norway, Mexico, Iceland, Switzerland, Lebanon, India, Macedonia, Brazil, Canada, Croatia, Argentina, Qatar, Israel and Russia.  The Chinese State Food and Drug Administration (SFDA) have approved Victoza® in March 2011 (Company Announcement, 15 March 2011). In those countries where Victoza® has not yet been approved, please call the compound “liraglutide”, previously known as NN2211 with all external parties.

Question 16

Is there evidence of a correlation between efficacy of Victoza® and duration of diabetes?

Answer 16

There are indicators that even better efficacy is seen in early stages of the disease relative to comparators as shown in monotherapy trial in patients previously on diet and exercise.

Question 17

Does the Victoza® formulation contain propylene glycol or latex?

Answer 17

It contains propylene glycol as a tonicity agent, i.e. propylene glycol is added to obtain an isotonic solution for injection. Latex is not included in the formulation of Victoza®.

Question 18

Is it necessary to adjust the doses according to the patient’s weight?

Answer 18

No. Regardless of initial weight, patients should receive a standard dose of Victoza®.

Question 19

How large a volume would a patient have to inject per day?

Answer 19

A small volume (0.2-0.3 ml/dose) is needed for the patient to inject the once-daily dose of Victoza®.

Question 20

Why is the priming procedure (air shot before an injection) for the insulin Flexpen® necessary before each injection and for Victoza® only before the first time a new pen is used?

Answer 20

For insulin, doses are given according to the requirement of the individual patient, i.e. a specific dose must be precise to provide glycaemic control with low risk of hypoglycaemia (especially in type 1 diabetes patients). In contrast, Victoza is given as a “fixed dose” and the properties of the drug do not require the same precise accuracy as insulin dosing. Hence, patients do not need to prime except when taking a new Victoza® pen into use.

Question 21

Does Victoza® therapy require blood glucose monitoring?

Answer 21

Self-monitoring of blood glucose (SMBG) - specifically for the purpose of adjusting dose, is not necessary with Victoza®. However, when initiating treatment with Victoza® in combination with a SU, blood glucose self-monitoring may become necessary to adjust the dose of the sulphonylurea. Please note that SMBG is an important educational feedback tool for people with diabetes and their physicians and should not be disregarded.

Question 22

What are the pharmacokinetic properties of Victoza®?

Answer 22

The duration of action of Victoza® is >24 hours with a half-life (T½) after subcutaneous injection of 13h, time to peak concentration (Tmax) is 10-13h. Absolute bioavailability after sc injection is 55%. In plasma, approximately 99% is bound to albumin, 1% is unbound. Only unbound Victoza® is biologically active.

Question 23

Does glycation of albumin have a role on the pharmacokinetics of Victoza®?

Answer 23

Most probably not. Protein binding (albumin) differences have not been shown between diabetic- and control sera to other drugs.

Question 24

Why is palmitate (C-16) used for Victoza® and not myristic acid (C-14) as for detemir (Levemir®)?

Answer 24

The composition and length of the fatty acid side chain influences the pharmacokinetic properties of GLP-1. The C-16-gamma-glu side chain of Victoza® was mainly chosen to achieve the desired PK profile for once-daily dosing of an analogue of natural GLP-1. The combined absorption and elimination profile after subcutaneous dosing provides a smooth exposure profile that has an excellent fit to once-daily administration.

Question 25

What were the glucagon excursions following Victoza® treatment?

Answer 25

T2DM is associated with inappropriately high glucagon secretion, resulting in high hepatic glucose output. In a Phase II Trial (NN2211-1332), Victoza® lowered blood glucose by stimulating insulin secretion and lowering glucagon secretion. Importantly, Victoza® did not impaired glucagon response to low glucose concentrations (trial NN2211-1224). These effects were glucose-dependent and helped to regulate both fasting and postprandial blood glucose.

Question 26

Does combining Victoza® with a DPP-4 inhibitor cause a cumulative increase in efficacy?

Answer 26

The combination has not been studied in humans but only in mini-pigs, where it was shown that the co-administration of sitagliptin and liraglutide did not alter the pharmacokinetics of liraglutide following SC administration (abstract ADA, 2009).

Question 27

What does LEAD stand for and what are the combinations and comparators in LEAD?

Answer 27

LEAD stands for “Liraglutide Effect and Action in Diabetes”. It is the name of 5 phase 3a and 1 phase 3b clinical programme on liraglutide (Victoza®). Below is an outline of the different treatments used in the trials (different doses of liraglutide are tested) and LEAD 1, 2, 4 and 5 have a placebo arm: LEAD 1: liraglutide + glimepiride vs rosiglitazone + glimepiride, glimepiride + placebo LEAD 2: liraglutide + metformin vs glimepiride + metformin, metformin + placebo LEAD 3: liraglutide vs glimepiride LEAD 4: liraglutide + metformin + rosiglitazone vs metformin + rosiglitazone + placebo LEAD 5: liraglutide + metformin + glimepiride vs glargine + metformin + glimepiride, metformin + glimepiride + placebo LEAD 6: liraglutide + metformin and/or SU (sulfonylurea) vs exenatide + metformin and/or SU.

Question 28

How many subjects were in the LEAD program?

Answer 28

LEAD 1-6 have involved approximately 4,500 subjects of whom approximately 2,700 received Victoza®. (Please note that LEAD 6 was not part of the file in US and EU.) For the purposes of external communication, and in some Company Announcements, Novo Nordisk communicates 6,500 as the entire number of subjects in the whole clinical programme (including Phases 1- and 2) and 4,200 as the number of people who received Victoza®.

Question 29

In LEAD 3, why was SU used as an active comparator instead of metformin?

Answer 29

Metformin affects insulin resistance and is not an insulin secretagogue – whereas SUs are powerful insulin secretagogues. As Victoza® stimulates insulin secretion in a glucose-dependent manner (unlike SUs), it is seen as highly relevant to compare to an SU. Furthermore, first-line SU usage still occurs in certain markets.

Question 30

Why did we see a much better efficacy compared to glimepiride in LEAD 3 (in comparison to LEAD 2)?

Answer 30

Probably due to a better beta-cell-function, treatment earlier in the disease progression, or relatively “clean” population (36.5% untreated and 63.5% monotherapy with OAD).

Question 31

How does monotherapy data of Victoza® (LEAD-3) compare to that of exenatide?

Answer 31

LEAD 3 shows that patients taking Victoza had substantial reductions in HbA1c (-1.6%) which were sustained under 7.0% for 52 weeks. A similar pattern was observed after a study extension to 104 weeks. LEAD 3 also showed that Victoza monotherapy was superior to treatment with a sulphonylurea in controlling HbA1c. A study which examined the effect of exenatide twice-daily administered as monotherapy study demonstrated a mean HbA1c reduction of -1.0% which was sustained for up to 3 years.

Question 32

How does monotherapy data of Victoza® (LEAD-3) compare to that of exenatide?

Answer 32

LEAD 3 shows that patients taking Victoza had substantial reductions in HbA1c (-1.6%) which were sustained under 7.0% for 52 weeks. A similar pattern was observed after a study extension to 104 weeks. LEAD 3 also showed that Victoza monotherapy was superior to treatment with a sulphonylurea in controlling HbA1c. A study which examined the effect of exenatide twice-daily administered as monotherapy study demonstrated a mean HbA1c reduction of -1.0% which was sustained for up to 3 years.

Question 33

Why did Novo Nordisk discontinue the LEAD-3 trial early instead of running 4-year to completion as planned?

Answer 33

Amendment 8, dated October 23, 2009 ended this clinical trial when the last subject completed Year 3 because there were insufficient numbers still enrolled to make meaningful conclusions. Only 8 patients from the glimepiride arm completed Year 3. Because some subjects had entered Year 4 of the study prior to IRB approval of Amendment 8, some data were collected from Year 4. However, no subjects completed Year 4 (i.e., reached week 208) with the last subject completing in week 195. Due to the low number of subjects entering Year 4, no efficacy analyses were performed. The 4-year safety findings presented in this report for the few subjects who entered Year 4 were consistent with the safety findings from Years 1-3. Overall, liraglutide was well tolerated and safe over the long term with a low incidence of hypoglycaemia and gastrointestinal adverse events during the final year of the trial.

Question 34

In all other LEAD trials you have included an active comparator, why not in LEAD 4?

Answer 34

The primary purpose of this trial was to provide prescribers with efficacy and safety information for the use of Victoza® in combination with metformin+TZD and to ensure that this combination use is included in the labelling for Victoza®. This phase 3a trial included 530 subjects who received combination treatment with Victoza® or placebo for 26 weeks.

Question 35

How much did the overall clinical effects found in LEAD 4 differ from what has been seen in the other LEAD trials (LEAD 1, 2, 3 and 5)?

Answer 35

Overall the LEAD 4 study results confirmed the findings of clinical efficacy seen in the other LEAD trials, such as significant and sustained HbA1c reduction, early and lasting weight loss and meaningful reduction of systolic blood pressure, as well as improvement in beta cell function. This study (Victoza® in combination with metformin + TZD) resulted in powerful glycaemic control with a reduction of 1.5% HbA1c and reduction in systolic blood pressure in the range of 6-7 mmHg.

Question 36

How was the insulin glargine dose titrated in LEAD 5?

Answer 36

The patient-driven titration algorithm from the AT.LANTUS trial was used, with a target of 5.5 mmol/L; twice-weekly dose adjustments for the first 8 weeks were based on self-measurement of fasting plasma glucose. After the first 8 weeks, titration was at the discretion of the Investigator, although titration was required at a minimum of 3 visits. The mean end of trial glargine dose was 24 units. In some treat-to-target studies (Riddle et al, Diabetes Care, 2003) with aggressive glargine titration, glargine doses tend to be pushed higher and achieved improved HbA1c reductions compared to doses achieved in LEAD 5, but at the expense of greater hypoglycaemia, weight gain and complex titration schedules. The end-of-study insulin glargine dose in LEAD 5 was nearly identical to the end-of-study insulin glargine dose, 25 units, in a study that compared insulin glargine to exenatide (Heine et al., Ann Intern Med, 2005).

Question 37

What would have been the consequences if LEAD 5 had compared with detemir (Levemir®) instead of glargine?

Answer 37

In T2DM, detemir induces less weight gain than other insulins. Of note, detemir can be associated with weight loss, especially in patients with high BMI. However, the weight loss associated with Victoza® is greater than any consistent weight loss associated with the administration of detemir.

Question 38

What was the purpose and outcome of LEAD 6 comparing Victoza® to exenatide?

Answer 38

The primary purpose of LEAD 6, which was a phase 3b study, was to directly compare the clinical efficacy and safety of Victoza® and exenatide. The study showed that patients treated with Victoza® achieved a reduction in HbA1c of 1.12%, compared to a reduction in HbA1c of 0.79% in the exenatide group. Victoza® treatment led to statistically significantly more patients (54% vs 43%) achieving both the ADA and AACE HbA1c targets of

Question 39

Related to LEAD 6, what were the specific key findings of the 14-week extension comparing effects of patients being switched from exenatide to Victoza® with continued Victoza® treatment?

Answer 39

In that study (Buse JB et al, Diabetes Care 2010), subjects who had previously been taking exenatide for a period of 26 weeks were switched to Victoza® 1.8mg. Patients previously treated with Victoza® continued their treatment throughout the extension period. The results from the extension phase show statistically significant improvements for those subjects who switched from exenatide to Victoza®: - HbA1c further decreased by 0.3 percentage points - FPG further decreased by 0.9 mmol/L - Average body weight decreased by approximately 1 kg - Systolic blood pressure decreased by nearly to 4 mmHg. In addition, the tolerability profile of Victoza® was confirmed.

Question 40

What is the mechanism behind reduced fasting plasma glucose and decreased adverse events versus exenatide in LEAD 6?

Answer 40

The effects on glycaemic control are related to stimulation of insulin secretion, suppression of glucagon secretion by Victoza® under conditions of elevated glucose, and decreased gastric motility. The long half-life of Victoza® ensures that higher steady-state levels are achieved producing a positive effect on fasting blood glucose and producing a more profound decrease in mid-day (post-lunch) glucose levels than exenatide. While we do not know mechanistically why Victoza® produces more rapid resolution of nausea (if it occurs) than exenatide, we hypothesize that this is related to the somewhat diminished effects of Victoza® on gastric emptying than exenatide and the fact that the pharmacokinetics may facilitate tachyphylaxis* to this side effect. *Tachyphylaxis: also known as desensitization, represents a rapid decrease in the response to a drug after repeated doses over a short period of time.

Question 41

How to explain the contrast between equal proinsulin-to-insulin ratios and significant improvement in HOMA-B levels in LEAD 6?

Answer 41

HOMA-B is a model based on serum values of fasting serum glucose and insulin, whereas the proinsulin-to-insulin ration is a calculation dependent on two distinct products of insulin biosynthesis that can be measured directly. The different parameters for beta-cell evaluation may explain the contrasting read-outs.

Question 42

Why was only the 1.8mg dose tested in LEAD 6?

Answer 42

Earlier studies (LEAD 1, 2 and 3) indicated higher efficacy at the 1.8mg dose, with more subjects reaching ADA HbA1c targets leading us to choose the high dose for additional investigations.

Question 43

Is there any additional benefit of 1.8mg versus 1.2mg of Victoza®? Is there any difference in terms of tolerability between the doses?

Answer 43

Victoza®, at either dose 1.8mg or 1.2mg, has shown superior clinical results against all the drugs against which it has been compared. Differences between 1.8mg and 1.2mg dose can be seen:  In the LEAD 3 study which compared Victoza® monotherapy vs glimepiride, there was a significant benefit in the total treated population in regard to HbA1c reduction with 1.8mg dose as compared with 1.2mg of, respectively, 1.14% and 0.84%. This difference was even higher in the subgroup where liraglutide was added on to diet & exercise; reduction with 1.2mg of -1.2% and 1.8mg of -1.6%.  In LEAD 1, 2 and 3 a significantly greater percentage of patients achieved ADA and IDF/AACE targets for HbA1c treated with 1.8mg compared to those treated with 1.2mg.  For LEAD 1 and LEAD 4, the weight loss was significantly greater for the 1.8mg vs the 1.2mg dose. Overall, the 1.8mg dose provides greater efficacy than the 1.2mg dose. When examined separately, the 1.8mg dose showed statistically superior results over all comparators in the LEAD trials except in LEAD 2. Regarding tolerability, the level of gastro-intestinal adverse events (overall tolerability and withdrawal rates) was found to be comparable for the 1.8 and 1.2mg doses of Victoza®.

Question 44

How well does Victoza® lower HbA1c when used as monotherapy or added to one or two OADs?

Answer 44

Overall in the LEAD trials when Victoza® was administered at the 1.8mg dose, we see reductions of HbA1C between 1.3% in combination with metformin to 1.6% in monotherapy. Importantly, the reduced HbA1c levels were sustained in the LEAD 3 extension (2 years), particularly in those patients who previously had not been on pharmacotherapy for their diabetes. The reduction of HbA1c was greatest in the group of patients with the highest level of HbA1c when entering the studies. In fact, patients previously treated with metformin and high baseline (>9.5%) experienced an HbA1c reduction with Victoza® 1.2mg of 2.74%.

Question 45

Was the period of time sufficient for the wash-out of TZD drugs before initiation of Victoza® trial?

Answer 45

The half-life of rosiglitazone is about 3-4 hr, i.e. wash-out may be completed after 24 hr although the pharmacodynamic effect may last longer. In the LEAD trials, excluding LEAD 1 and 4, there was a period of discontinuation of OAD of 2-3 weeks.

Question 46

The ADA and EASD updated the recommended treatment algorithm for diabetes in October 2008. Can you explain the changes?

Answer 46

The revised algorithm reinforces the early use of basal insulin - and for the first time includes GLP-1 receptor agonists, the class of diabetes treatment of which Victoza® is a member. GLP-1 agonists are included under the 2nd step after lifestyle+metformin failure and in the 2nd tier under less well validated therapies.

Question 47

Is there any investigation on the use of Victoza® in T1DM?

Answer 47

Novo Nordisk is funding and will continue to fund meritorious academic research on liraglutide following stringent review of the concept, the protocol, and the investigator. In addition, NN is in the early phases of planning clinical trials of liraglutide as adjunct therapy to insulin in Type 1 diabetes with a specific focus on the safety of its use for this indication. However, T1DM is NOT an indication in the Victoza® label. NN cannot comment on clinical studies performed with other incretin based therapies or trials not supported by NN. We are aware of two published clinical studies that have explored the effects of liraglutide in combination with insulin in T1DM. Varanasi A et al (in press Eur J Endocrinol, 165, 2011) studied whether addition of liraglutide to insulin in patients with T1D M leads to an improvement in glycaemic control. Fourteen patients with well-controlled T1D M were treated with liraglutide for 1 week, and 8 continued for 24 weeks. In all 14 patients, mean FPG decreased and glycaemic excursions improved after 1 week. Further, mean glucose concentrations decreased, as well as the doses of both basal and bolus insulin. In patients continuing treatment for 24 weeks, mean FPG, glycaemic excursions and insulin doses decreased significantly . Indeed, HbA1c decreased from 6.5 to 6.1% and body weight declined by 4.5 kg. Kielgast U et al investigated the effect of 4 weeks treatment with liraglutide on insulin dose and glycaemic control in T1D patients with and without residual beta-cell function. All C-peptide–positive patients were treated with liraglutide plus insulin, whereas C-peptide–negative patients were randomly assigned to liraglutide plus insulin or insulin monotherapy. The insulin dose decreased per day in C-peptide–positive and C-peptide–negative patients treated with liraglutide but did not change with insulin monotherapy. The % reduction in daily insulin dose was positively correlated with beta-cell function at baseline, and two patients discontinued insulin treatment.

Question 48

What data are available so far that prove sustainable glycaemic efficacy of Victoza®?

Answer 48

In connection with the 2008 full-year financial statement (29 January 2009), Novo Nordisk announced headline 2-year data from LEAD 3 evaluating the efficacy and safety of two different daily doses of Victoza® compared to the sulfonylurea glimepiride in the treatment of T2DM for one year. In LEAD 2, patients treated with Victoza® over a period of two years show sustained HbA1c, a comparable improvement in HbA1c between Victoza® +metformin and glimepiride+metformin, but significantly more subjects reach HbA1c ADA target (

Question 49

What are the background and results of the Victoza® vs Januvia® head-to-head trial?

Answer 49

This was a phase 3b study (Pratley RE, Lancet 2010) with 658 people with T2DM inadequately controlled on metformin. The study compared two doses of Victoza® to Januvia®, a DPP-4 inhibitor. The study was completed in June 2009. HbA1c was reduced by 1.5% with the Victoza® 1.8mg dose and 1.24% with Victoza® 1.2mg compared with 0.9% with Januvia®. Twice as many patients in the Victoza® groups reached the EASD and ADA’s recommended HbA1c goal of

Question 50

What are the key points/conclusions from the trial?

Answer 50

Greater efficacy of Victoza® in terms of absolute reduction in HbA1c and FPG, as well as proportion of patients reaching ADA/EASD and AACE/IDF/NICE targets for glycaemic control with minimal risk of hypoglycaemia. Significantly more patients reaching a composite goal of 1) achieving an HbA1c

Question 51

What are the major differences between Victoza® and DPP-4 inhibitors?

Answer 51

The DPP-4 inhibitors slow the breakdown of the body’s own GLP-1 hormone, but do not add more. They provide a modest, 2-to-3 fold increase in GLP-1. In contrast, the GLP-1 receptor agonists are administered by injection and provide a much greater – or pharmacological - level of GLP-1. In fact, Degn et al show that pharmacological doses of GLP-1 are required for effective treatment outcomes in T2DM (Degn, Diabetes 2004; Agersø H et al, Diabetologia, 2002; Ahrén B & Schmitz O, Horm Metab Res 2004) The first clinical benefit of the GLP-1 receptor agonists is greater blood sugar lowering (as indicated by HbA1c and FPG reductions), and the second is weight loss as result of increase in satiety – or a feeling of fullness that leads to less caloric intake.

Question 52

Why did 25% of the subjects treated with Victoza® 1.2mg drop out of the trial?

Answer 52

While withdrawal rates were similar between Victoza® 1.8mg and sitagliptin, more withdrawals surprisingly occurred with Victoza® 1.2mg. In subjects withdrawing on Victoza® 1.2mg, the primary reason provided by the investigator was “non-compliance” with the protocol or “other”. A typical reason provided in “other” was patients not included in follow up because they relocated or did not attend a follow-up visit. Patients withdrawing due to adverse events were similar across both Victoza® study arms while withdrawals were lower with sitagliptin (2% vs 6-7% due to gastrointestinal adverse events primarily related to nausea). The withdrawal rates due to “ineffective therapy” were low and similar between Victoza® and sitagliptin.

Question 53

How can Victoza®, which is an injectable treatment, result in better patient satisfaction compared to a tablet?

Answer 53

The study was only designed to measure potential differences in treatment satisfaction but not the underlying reasons. It does, however, indicate the stronger clinical benefits (greater blood glucose lowering and weight loss) experienced by patients may outweigh the potential inconvenience experienced with injection. It should be added that Victoza® is injected with a simple pen device and needles as small as the NovoFine® 32G needle; one of the thinnest needles available resulting in minimal discomfort on injection.

Question 54

How was treatment satisfaction measured?

Answer 54

Overall treatment satisfaction was assessed with the Diabetes Treatment Satisfaction Questionnaire (DTSQ), a validated measure used in many diabetes trials. The questionnaire asked participants to answer questions based on a scale of 1-6 to determine their satisfaction with their assigned treatment. According to the Pratley et al study published in Lancet, overall treatment satisfaction was greater for both doses of Victoza®. In addition, no difference in perceived convenience of treatment (injection vs oral) was found between Victoza® (1.2mg) and sitagliptin.

Question 55

Please explain the difference between the results of the 1.8mg and 1.2mg dose in the trial.

Answer 55

In this study, both the 1.2mg and the 1.8mg Victoza® showed superior efficacy in terms of HbA1c compared to sitagliptin. The difference in terms of HbA1c reduction was significant for the 1.8mg dose only. That may be explained by the population studied, which had the disease for a short time. A similar pattern was also observed in the LEAD 3 monotherapy study.

Question 56

What did the preclinical studies in mice and rats show?

Answer 56

In preclinical studies in both mice and rats, Victoza® induced C-cell hyperplasia, C-cell adenomas, and, at the highest dose in female mice and at several doses in male and female rats, C-cell carcinoma. These lesions were accompanied by both acute and chronic increases in calcitonin, a biomarker of C-cell activation and C-cell mass.

Question 57

What did the preclinical studies in nonhuman primates? What was the hypothesis for the discrepancy between rodents and nonhuman primates?

Answer 57

Similar findings did not occur in nonhuman primates at an exposure of 64 fold that of the human dose of 1.8mg. In vitro experiments supported a mechanism of action for C-cell neoplasia through the GLP-1 receptor. Rats appear to have a much higher density of GLP-1 receptors on their C-cells than humans. Moreover, preclinical experiments have shown that the GLP-1 receptor is a ‘functional receptor’ in rodents, whereas, this is not the case in primates or man.

Question 58

How was the hypothesis for the discrepancy between rodents and nonhuman primates studied in the Victoza development program?

Answer 58

To further assess the potential role of GLP-1 agonists like Victoza® on C-cell function in man, an extensive calcitonin screening program was established and carried out in over 5,000 individuals included in the Victoza® development program. This screening program did not yield any data to suggest that Victoza® activates the human C-cell, supporting that it is not a ‘functional receptor’, as there was no consistent, dose-dependent or time-dependent increase in calcitonin levels compared to active comparator treatments for up to two years of exposure. The cumulative data strongly suggest that rodent C-cells are sensitive to activation by GLP-1 agonists but that nonhuman primate and human C-cells are not.(Refer to Knudsen LB et al, Endocrinolog, 2010 and Hegedus L et al, J Clin Endo Metab 2011)

Question 59

Why does nausea subside quicker with Victoza® than with exenatide?

Answer 59

In LEAD 6, nausea resolved more quickly in patients treated with Victoza® than in those treated with exenatide. By week 6, the proportion of participants having nausea in the Victoza® group had fallen below 10% (8%-1% vs 15%-8% for exenatide), whereas the exenatide group reached this value after 22 weeks. These differences can be related to the pharmacokinetic properties and tolerance mechanisms induced by both Victoza® and exenatide on the GLP-1 receptor.

Question 60

In relation to nausea, how much time should be allowed before increasing the dose?

Answer 60

The worst nausea symptoms are experienced during the first 3 days of treatment. After this period symptoms start to decline. Therefore, it is advisable to wait 1 week before dose escalation.

Question 61

How do you explain the higher rate of nausea occurring in LEAD 4 compared to the other LEAD trials?

Answer 61

In LEAD 4, 30% to 40% of patients on Victoza® experienced nausea during 4 to 10 weeks, which was rated mild in severity and was transient in nature in most cases. Only LEAD 3 showed comparably high rates in nausea. Both studies were conducted primarily in the US where there was already high awareness of GI side effects with exenatide, which might have influenced or biased the tolerability results of theses studies. In the other LEAD trials, the nausea rate was in the range of 5%-15% in Victoza®-treated patients. In all the LEAD trials, nausea with Victoza® was generally transient evaluated of mild or -less often- moderate severity, and the withdrawal rate due to nausea was very low.

Question 62

Does Victoza® cause hypoglycaemia? How did the rates of hypoglycemia compare to glargine, detemir, and NovoMix clinical trials.

Answer 62

The actions of GLP-1 are glucose-dependent, both in terms of the insulin release and the glucagon inhibition. This means that Victoza® should be associated with a low Victoza risk of hypoglycaemia. The LEAD programme has demonstrated that the level of minor (confirmed by BG measurement

Question 63

Why does sulphonylurea (SU) in combination with Victoza® have a higher incidence of hypoglycaemia than Victoza® without SU?

Answer 63

SU is a secretagogue* and can induce hypoglycaemia. SUs act in a glucose-independent manner unlike Victoza®. The glucose lowering effect of Victoza® brings blood glucose levels to normal or closer to the hypoglycaemic threshold. This effect can increase the probability of the SU inducing hypoglycaemia. In addition, it seems that GLP-1 potentiate insulin secretion in synergism with SU at low glucose concentration. *A secretagogue stimulates the secretion of insulin.

Question 64

With rapid improvement of glucose level, can retinopathy or neuropathy status get worse with Victoza®?

Answer 64

While this is a theoretical possibility, there was no evidence in the LEAD trials that retinopathy was accelerated on Victoza®.

Question 65

What is the safety and efficacy of Victoza® in the elderly?

Answer 65

Studies in individuals between 65-80 years old have shown the same HbA1c reduction. No increase in the frequency of hypoglycaemia is seen with advancing age.

Question 66

Does Victoza® induce an antibody response and what is its clinical importance? Why should Victoza® induce less antibody formation than exenatide?

Answer 66

In contrast to the almost human sequence present in Victoza® (97% homology to natural GLP-1), exenatide is derived from the sequence of a reptilian analogue of GLP-1 and only shares 53% homology and therefore, prone to induce antibody responses. Victoza® induces antibodies in a low number of subjects (only 8.6% in LEAD trials) and the antibodies do not change the effect of the drug or have any other clinical impact. Moreover, antibodies against Victoza® or exenatide were measured during the LEAD-6 trial. After 26 wks on exenatide, 61.1% pts had antibodies to exenatide leading to smaller A1C reductions in those with high antibody titers. Importantly, exenatide antibodies that persisted up to 1 yr after switching to Victoza® did not decrease efficacy of Victoza® treatment – indicating absence of cross-reactivity For exenatide it is seen that around half of the people developed antibodies in the AMIGO trials*. The high rate of antibody formation with exenatide is known to neutralize the effect of the drug in a small percentage (~3%) of people (exenatide FDA and EMEA labels). *AMIGO trials, in which exenatide was compared with placebo in patients taking MET (AMIGO 1), SU (AMIGO 2) or MET+SU (AMIGO 3).

Question 67

Does Victoza®-treatment influence CV risk factors?

Answer 67

Diabetic patients have a 2-4 times greater risk for vascular events than their non-diabetic counterparts due to the presence of several risk factors such as hyperglycaemia, insulin resistance, dyslipidemia* (present in up to 73% of people with T2DM), hypertension, and obesity. This altered lipid pattern is associated with an increased risk of cardiovascular events. In a LEAD-1–6 meta-analysis, Victoza® reduced total cholesterol and LDL in patients with T2DM (Plutzky J et al, poster 762, Diabetologia 2009). In addition, obesity and in particular visceral obesity is strongly associated with T2DM and CV disease. Victoza® reduced the average weight by 1.2 kg compared to placebo in trials of 12 to 14 weeks, and up to 2.6 kg in trials lasting 26 weeks. Victoza® improves glucose control and reduces body weight and blood pressure, i.e. clinical and laboratory parameters strongly related to CV risk. In animals, Victoza® has been shown to have beneficial effect on markers of endothelial and myocardial functions. For instance, in a study examining the severity of heart damage after myocardial infarctions in mice, animals treated with Victoza® experienced less severe heart damage than mice not treated with Victoza®. Consequently more Victoza®-treated mice survived the myocardial infarctions. Together, these characteristics support the idea that Victoza® may reduce CV risk. Novo Nordisk is conducting an CV outcome trial (LEADERTM) to fully characterise the CV risk – including VictozaTM mediated reduction in SBP, and/or benefits of Victoza® in a large, high-risk population of people with T2DM (See section 2.4). Yet, results from the UKPDS shows that 1% reduction in HbA1c lead to a 12% reduction in ischemic stroke and 14% reduction in MI. *Dyslipidemia is a change in the amount of lipids in the blood, which can represent an elevation of lipids in the blood, often due to diet and lifestyle.

Question 68

What is the CV risk or Major Adverse Cardiovascular Events (MACE) in the Victoza® program?

Answer 68

The FDA Guidance released in December 2008 provides recommendations on how to demonstrate that a new anti-T2DM therapy is not associated with an unacceptable increase in CV risk. For a new therapeutic agent to be approved without additional pre-approval commitment for assessing CV safety, this analysis should demonstrate that the upper bound of the two-sided 95% confidence interval for the estimated risk ratio is less than 1.8. The clinical development program for Victoza® was designed, executed and completed prior to the development of the FDA guidance (Dec 2008; fda.gov). The results from the MACE Victoza® analyses documented that, based on the available Victoza® clinical safety database, most of the point estimates in the main analyses were below 1 with the upper end of the 95% confidence intervals

Question 69

What is the reason for the increased heart rate seen in some patients?

Answer 69

There is no clear explanation. Specialists suggest that it may be a compensatory mechanism that can be related to the increased metabolism autonomic nerve system, or blood pressure. The following facts can be stated:  A minor increase in heart rate was consistently observed in intermediate and long-term trials with no dose-response relationship  There was a trend towards a reduction in the increased heart over time  Heart rate change depends on baseline heart rate value; baseline values above 80, results in a decrease in heart rate  There was no imbalance in the rate of tachyarrhythmia reported as serious adverse events in subjects treated with liraglutide compared to total comparator. A higher frequency of benign tachyarhtmia such as palpitations, extrasystoles was seen compared to total comparator  The MACE analysis on liraglutide conducted for the FDA Advisory Board confirmed no increased CV risk with liraglutide  Limited data exist in patients with cardiac conditions. The long-term CV risk profile of liraglutide will be studied in the LEADER™ trial in a high risk CV profile population

Question 70

Why is systolic blood pressure* reduced with Victoza®?

Answer 70

The mechanism responsible for Victoza®’s effect on systolic blood pressure* (SBP) is unknown. Native GLP-1 has direct effect on sodium excretion and promotes relaxation of the blood vessels. Weight loss is often associated with BP decrease, but Victoza® seems to reduce SBP within the first two weeks of treatment, before significant weight loss occurs. In the LEAD trials, Victoza® at the 1.8mg dose reduced systolic blood pressure by 2-6 mmHg on average. *Systolic blood pressure is the first or top number in a blood pressure reading, which is the maximum pressure produced as the heart muscle contracts and blood flows into the arteries.

Question 71

Is there hypotension seen with Victoza® treatment?

Answer 71

The amount of hypotension events with Victoza® is equivalent to active comparator and placebo.

Question 72

Can you provide a summary related to the incidence of acute pancreatitis and treatment with Victoza® from both a clinical and epidemiological perspective?

Answer 72

In the Victoza® development program there was a numeric excess of cases of acute pancreatitis in subjects receiving Victoza® versus placebo or active comparator. Overall, however, there are too few cases to be able to determine whether or not there is a cause and effect relationship between the development of acute pancreatitis and treatment with Victoza®. Moreover, the incidence among subjects using Victoza® is consistent with what one would expect in a population of patients with T2DM. It is important to note that people with T2DM have a 2.8-fold higher risk of pancreatitis compared to people without diabetes. This is substantiated by a study (Rebecca AN et al, Diabetes Care, 2009) which examined a US managed care claims database including 337,067 people with T2DM and a similar number of people without diabetes. Hence the pancreatitis incidence in people with T2DM is approximately 4.2 cases per 1000 patient years.

Question 73

Have there been any published cases of pancreatitis in the Victoza® development program; if so what are the details?

Answer 73

The published cases of pancreatitis from the Victoza® development program are as follows: LEAD 3 (2 cases), published in The Lancet • 1 patient treated with Victoza® 1.2mg; occurred after 197 days of treatment. Continued on Victoza® without re-occurrence of pancreatitis. • 1 patient treated with Victoza® 1.8mg; occurred after 333 days, discontinued treatment. LEAD 2 (2 cases), published in Diabetes Care •1 patient treated with Victoza® 1.2mg, occurred after 50 days and discontinued treatment. •1 patient treated with glimepiride, occurred after 65 days and discontinued treatment. LEAD 1 (1 chronic case), published in Diabetic Medicine •1 patient treated with Victoza® 0.6mg, occurred after 120 days and the patient continued on Victoza® throughout the trial •At screening, 5 of the randomized patients previously had pancreatitis and did not develop pancreatitis during the trial LEAD 6 (1 chronic case), published in The Lancet •1 patient treated with Victoza® 1.8mg, occurred after 88 days and the patient continued on Victoza® throughout the trial Previous history of pancreatitis •Of patients recruited for the LEAD programme, 17 patients had previously had acute pancreatitis and 7 had chronic pancreatitis. None of these developed pancreatitis again during the treatment with Victoza® (data on file).

Question 74

Is it worthwhile to monitor amylase/lipase in patients on liraglutide?

Answer 74

Amylase might give an early signal of pancreatitis. If a patient has risk factors for pancreatitis, there may be value in monitoring amylase levels; however, there is no specific requirement for monitoring amylase levels in patients receiving liraglutide.

Question 75

What is NN position on Elashoff et al publication (Gastroenterology, 2011) describing pancreatitis with exenatide and sitagliptin?

Answer 75

The approach employed by Elashoff et al.’s publications is unconventional and the methodology is questionable. Extensive preclinical programmes, clinical trials and post-marketing data do not support their findings. Liraglutide data were not included in the paper, and the risk–benefit profile continues to be favourable and no association between liraglutide and the development of pancreatitis has been established. The FDA Adverse Event Reporting System (AERS) contains a mixture of spontaneous reports from HCP and consumers and it is used by FDA to monitor for new adverse events that might occur with marketed products. Importantly, it is not necessarily containing a proven causal relationship between a product and event, not always containing reports with enough detail to properly evaluate an event, and not comprehensive. Overall Novo Nordisk disagrees with this comparative use of the AERS database and cannot reproduce the results presented by Elashoff et al. The AERS database is designed to be used with automated signal detection tools applying validated statistical algorithms for this purpose. Novo Nordisk is committed to continuously and timely evaluate the safety profile of all Novo Nordisk products. For liraglutide, two database studies (GPRD and i3) and the large clinical outcome trial (LEADER™), as well as additional animal studies are currently ongoing. Any possible involvement on external discussions related to this topic should be regarded as reactive only.

Question 76

Were there any carcinogenicity issues with Victoza® pre-clinically or in clinical development?

Answer 76

Conclusions from the pre-clinical safety program were that Victoza® was well tolerated and non-genotoxic (Knudsen LB et al, Endocrinology 2010; Hegedus L et al, J Clin Endo Metab 2011). C-cell (Clear cell) hyperplasia and c-cell tumours were the only treatment related findings seen in 2-year carcinogenicity studies in rodents. In rats, treatment with the highest doses of Victoza® was associated with dorsal sarcomas at the injection sites, something that has been found with other drugs and some inert agents. The human significance of this is not known but thought to be very low. There was a numeric excess of neoplasms in Victoza®-treated subjects compared to active comparator-treated subjects that did not appear to be related to drug exposure. There was no specific pattern of neoplasm identification that could be related to Victoza®. Based on pre-clinical and clinical studies, data do not suggest that GLP-1 receptor activation by Victoza® alters C-cell function or mass in humans. Furthermore, in extensive clinical trials, data showed no clinically relevant changes to calcitonin levels in patients treated with Victoza® for up to 2 years of therapy.

Question 77

What is the function of calcitonin and what do increased levels imply?

Answer 77

Calcitonin is a peptide hormone synthesized and secreted by C-cells, located within the thyroid gland. Calcitonin participates in calcium and phosphorus metabolism however, the physiologic importance of calcitonin in human adults is not known. Calcitonin has, at best, a minor role in regulating blood concentrations of calcium. Calcitonin is well-recognized as a valid biomarker of C-cell activation (such as with drugs that increase gastrin, a GI hormone that directly stimulates calcitonin release) and its serum levels are used to diagnose and monitor patients with medullary thyroid carcinoma. To ensure patient safety, Novo Nordisk has diligently monitored the levels of patients’ calcitonin during its clinical trials.

Question 78

What is the function of calcitonin and what do increased levels imply?

Answer 78

Calcitonin is a peptide hormone synthesized and secreted by C-cells, located within the thyroid gland. Calcitonin participates in calcium and phosphorus metabolism however, the physiologic importance of calcitonin in human adults is not known. Calcitonin has, at best, a minor role in regulating blood concentrations of calcium. Calcitonin is well-recognized as a valid biomarker of C-cell activation (such as with drugs that increase gastrin, a GI hormone that directly stimulates calcitonin release) and its serum levels are used to diagnose and monitor patients with medullary thyroid carcinoma. To ensure patient safety, Novo Nordisk has diligently monitored the levels of patients’ calcitonin during its clinical trials.

Question 79

Please elaborate on the calcitonin findings in the LEAD studies (compared to baseline levels and placebo).

Answer 79

Using validated assays with high specificity and sensitivity, calcitonin, the biomarker of C-cell activation and C-cell mass, was measured every 3 months in more than 5,000 subjects in long-term phase 3 trials. Moreover, a calcium stimulation test was performed in a sub-population of subjects from long-term Trials 1573 and 1574. This represents the largest program assessing calcitonin levels in humans without a history of underlying thyroid disease or increased risk of C-cell neoplasia (familial medullary carcinoma of the thyroid (MTC) or multiple endocrine neoplasia 2 (MEN2). Estimated levels of calcitonin throughout the duration of the trials were approximately 1 ng/ml, ie. in the very low end of the normal range values for calcitonin. There was no clinically significant difference between the Victoza® treated and active control treatment groups at any point in time, whereas both of these treatment groups differed significantly from placebo at week 26. At week 52, the 1.2mg and the 1.8mg doses were significantly different from placebo, and no difference was found between Victoza® treatment and active comparators. At 76 weeks, no significant differences were found between any treatment groups, i.e. no clinically relevant increases in mean calcitonin or cases of medullary thyroid carcinoma detected in LEAD 3 trial.

Question 80

Why does Victoza® affect the levels of calcitonin?

Answer 80

Victoza® does not increase the levels of calcitonin in humans. Preclinical findings show that Victoza® increases the levels of calcitonin in rodents but not in non-human primates. Intensive monitoring of calcitonin in the clinical development programme has not suggested a Victoza® treatment related effect in humans on calcitonin. Victoza® activates GLP-1 receptors on the rodent C-cell, which induce calcitonin secretion in rodents. The number of GLP-1 receptors on C-cells differs significantly among different species with much higher levels in rodents. Experiments have shown that rats and mice have more C-cells than humans. In contrast, humans have fewer of these C-cells, and they are not sensitive to Victoza®. In addition, our preclinical studies have found that only rodent C-cells express a functional GLP-1 receptor and human C-cells do not. This was one of the central discussions of the FDA Advisory Committee meeting. The discussion focused on whether Novo Nordisk data showed this is only relevant to mice and rats - and not to humans.

Question 81

To your knowledge, have increased levels of calcitonin been seen in other studies with other treatments?

Answer 81

Increased levels of calcitonin have been seen with histamine-2 receptor blockers (H2RB) and proton pump inhibitors (PPI). The gastrointestinal-hormone gastrin, stimulates C-cells and elevates serum calcitonin levels. Gastrin levels may be elevated when drugs like histamine-2 receptor blockers (H2RB) and/or proton pump inhibitors (PPI) are used.(Erdogan et al, J Endocrinol Invest, 2006). Calcitonin levels also may be elevated in patients with pernicious anaemia a condition in which gastrin levels are very high.

Question 82

Does Novo Nordisk believe that either pancreatitis or elevated C-cells can be considered class effects? If so, what kind of impact would a class warning label have on Victoza®?

Answer 82

At the EMA Pre-Authorisation Evaluation, the risk of pancreatitis was evaluated and addressed in the Summary of Product Characteristics (SPC), in the Risk Management Plan and as post-authorisation follow-up measures. As could be expected based on the C-cell findings in rodents, the EMA has made an in-depth review of the findings and their relevance to humans. The relevance to humans has been considered likely to be low, and based on this assessment there are no label restrictions in regard to human C-cell and thyroid safety. The EMA commitment includes submission of the two-year follow-up report from the Data Monitoring Committee on the cardiovascular outcome study containing conclusions from the analyses conducted for all relevant safety parameters: primary and secondary end-points, adverse events. These will include pancreatitis, neoplasms, thyroid-related events, and laboratory parameters. The FDA granted the approval of Victoza® in January 2010 on the basis of careful consideration of the drug’s benefits, weighed against several safety related concerns. The FDA concluded that increases in the incidence of carcinomas among rodents translated into a low risk for humans. However,, the FDA required additional studies in animals and the establishment of a cancer registry to monitor the annual incidence of medullary thyroid cancer over the next 15 years. Regarding pancreatitis, the FDA required the manufacturers of exenatide and sitagliptin to investigate the possible risk and conduct additional studies in animals. In this respect, Novo Nordisk is committed to perform post approval mechanistic studies in animals and to conduct an epidemiologic evaluation using an insurance-claims database.

Question 83

Does Novo Nordisk expect this to impact sales at launch?

Answer 83

We cannot speculate on the impact of any findings or the effects they may have on projected sales figures for Victoza®. Of interest is the fact that the three most widely prescribed OAD classes (metformin, SU and, TZD) all carry a boxed warning as part of their label. All drugs must be considered within the context of the benefit/risk ratio, which we consider to be highly positive for Victoza® given the need for safe and efficacious diabetes drugs. The efficacy data from Victoza® demonstrate that a high percentage of treated subjects achieved their glycaemic targets with good overall tolerance and a low risk of hypoglycaemia.

Question 84

What was the outcome of the 2 April 2009 FDA Advisory Committee meeting?

Answer 84

To summarise: - The panel found that Novo Nordisk provided appropriate pre-approval evidence of cardiovascular safety. - The panel unanimously supported approvability of Victoza® with regard to (lack of) risk of papillary thyroid cancer. - The panel found that Novo Nordisk had not ruled out the human relevance of preclinical C-cell tumour findings and was split on whether the available data on C-cell tumours supported approvability.

Question 85

What is the name of the large CV outcome study? Why is Novo Nordisk conducting it?

Answer 85

It is called the LEADER trial (Liraglutide Effect and Action in Diabetes: An Evaluation of Cardiavascular Outcome Results). Novo Nordisk aims to assess and confirm the cardiovascular safety of the company’s new once-daily human GLP-1 analogue Victoza® and potentially show the ability of Victoza® to improve cardiovascular outcomes. The trial also satisfies the new FDA guideline for T2DM treatments.

Question 86

What is the cardiovascular event rates reported for background therapy?

Answer 86

The risk of cardiovascular disease in people with diabetes is 2-4 times higher than for the general population and the incidence varies depending on the population and the events included in the definition of ‘cardiovascular disease’.

Question 87

Please describe the LEADER™ design of the protocol

Answer 87

LEADER™ (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) is a long-term, multicentre, international, randomised, double-blind, placebo-controlled, phase 3b trial which will include around 9,000 patients over a five-year period. The trial will compare Victoza® added to standard of care with standard of care alone in people with T2DM who are at high risk of cardiovascular events. Overall trial duration is planned as 18 month of recruitment period followed by 42 month from last subject randomized. After 2-3 weeks of open label run-in period on placebo the subjects will be randomized in a 1:1 manner to receive a once daily dose of maximum 1.8mg of Victoza® or equivalent placebo as add-on to their standard of care treatment. The primary objective will be to asses the primary end-points: Time from randomization to first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (a composite cardiovascular end-point). Further information on LEADER™ can be gathered at the LEADER™ portal.

Question 88

Is this a non-inferiority trial or a superiority trial?

Answer 88

The LEADER trial is designed as a non-inferiority trial with a non-inferiority margin versus placebo of 1.3 for the upper limit of the 2-sided 95% confidence interval. If non-inferiority is detected a second analysis for superiority will be conducted.

Question 89

Does the Victoza® pen-injector need to be ’primed’ between doses?

Answer 89

Priming, or the process of removing air bubbles in the cartridge before injection, is not necessary in between doses with the Victoza® pen-injector. It is however necessary at first-time use of each pen-injector. The potential minor fluctuations in the amount of GLP-1 delivered due to lack of priming will not impact glucose control in any meaningful way or have any acute risks to patients, who have T2DM. (The situation is different with insulin, where small variations in amount can give rise to important clinical variations in glucose levels, particularly among people with type 1 diabetes.)

Question 90

What is our commercial strategy and positioning?

Answer 90

Victoza® is positioned as the once-daily human GLP-1 analogue that both provides excellent glycaemic control and has the potential to delay disease progression* in T2DM for patients uncontrolled on metformin alone because it delivers significant and sustained: • reductions in blood sugar levels • reductions in weight • reductions in blood pressure • improvements in beta-cell function. Our brand strategy focuses on two points: to redefine and grow the GLP-1 class and to differentiate Victoza®. * Important: Delay of disease progression is part of our positioning strategy and thus not used externally as a claim. The potential to delay disease progression is constituted by beta cell improvement and by sustained glycaemic control and slower increase towards baseline level than comparator. Speak about delay of disease progression in the context of the other benefits, and please keep the benefits in this order. Please do not talk about disease progression in isolation.

Question 91

Why should I choose Victoza® over Januvia®?

Answer 91

They’re both incretin-based therapies, and Victoza® is an injection. Mode of Action Both DPP-4 inhibitors and GLP-1 analogues like Victoza® leverage the same basic biological system to enhance insulin secretion and decrease glucagon secretion in a glucose-dependent manner, but they do it in different ways. In order to get full glucose control and achieve weight loss a high, pharmacologic level of GLP-1 is needed that can only be obtained with an injection of GLP-1. DPP-4 inhibitors work indirectly to prevent natural GLP-1 in the body being broken down by the DPP-4 enzyme. This indirect approach only provides a modest increase in GLP-1 level, resulting in moderate glycaemic control typically without weight loss. Clinical efficacy The superior efficacy of the once daily GLP-1 analogue Victoza® over the DPP-4 inhibitor Januvia® was reported by Pratley et al (Lancet, 2010) and details can be seen in Section 5.2 Head to Head trial: Victoza® vs. Januvia® (sitagliptin) (NN1860). Weight loss as differentiator The main benefit of Victoza is superior glycaemic control, as demonstrated across many clinical trials. This is relevant to T2DM patients who qualify for Victoza regardless of their weight or BMI. For example, Pratley et a. demonstrated that Victoza® provided greater reductions in HbA1c with a low rate of hypoglycaemia, bringing twice as many patients as sitagliptin to the EASD/ADA goal of 7% with Victoza®. The weight loss effect of Victoza is a welcome benefit for many patients with T2DM who struggle to get their weight under control or would cope with the weight gain triggered by many commonly used diabetes drugs.

Question 92

Byetta ®was the first in class GLP-1 analogue. How does Victoza® compare?

Answer 92

Victoza® has a number of advantages over Byetta®: •Superior HbA1c and fasting plasma glucose control due to the true 24-hours drug profile •Once-daily dosing vs. twice-daily dosing with Byetta® •Flexible dose timing at any time of the day; Byetta® must be taken within 1 hour before breakfast and within 1 hour before dinner Importantly, Victoza® is a human GLP-1 analogue with high homology (97%) to native GLP-1; Byetta® is an exendin-based GLP-1 receptor agonist with lower homology to native GLP-1 (53%). The result is high rates of antibody formation with Byetta® which in a small percentage of individuals neutralizes the effect of the drug. (3% as per FDA and EMA exenatide labels). A major clinical trial called LEAD 6 compared Victoza® to Byetta®. The study showed that the human GLP-1 analogue Victoza® administered once daily, was significantly more effective at improving glycaemic control (as measured by HbA1c) than Byetta® administered twice daily. In the LEAD-6 study less than 3% of patients developed anti-liraglutide antibodies with Victoza® versus more than 60% of patients who developed anti-exenatide antibodies with exenatide BID.6 Unlike with liraglutide, high levels of anti-exenatide antibodies were correlated with significantly smaller HbA1c (Buse JB et al, J Clin Endocrin Metab, 2011) In the LEAD 6 extension study, in which subjects entered a 14-week non-randomised extension period after switching from Byetta® to Victoza®, the results show significant improvement in glycaemic control (HbA1c: -0.3% and FPG: -0.9 mmol/L), improvement in beta-cell function, further weight loss (-0.9 kg), and reduction in systolic blood pressure (-3.8 mmHg). Importantly, continued treatment with Victoza® over a total of 40 weeks resulted in HbA1c sustained below 7.0%, maintained improvement in beta-cell function, further weight loss (-0.4 kg), reduction in systolic blood pressure (-2 mmHg) and a low rate of adverse events.

Question 93

How does Victoza compare to exenatide ER, in particular isn’t exenatide ER more effective than Victoza®?

Answer 93

Victoza® offers an excellent clinical profile with significant benefits in glucose control, weight loss, systolic blood pressure and beta-cell function. The preliminary results from DURATION-6 has recently been announced by Eli Lilly (press release 3 March 2011). DURATION-6 study design: DURATION-6 was a 26-week, head-to-head, open-label, superiority study in patients with type 2 diabetes who were not achieving adequate HbA1c control with diet and exercise in conjunction with metformin, a sulphonylurea, metformin plus a sulphonylurea, or metformin plus Actos® (pioglitazone HCI). Primary end point was reduction in HbA1c. Differences in HbA1c reductions: Victoza® provided greater reduction in HbA1c compared with exenatide ER (1.5% vs 1.3%). A 0.2% reduction in HbA1c on its own may not be clinically relevant; however, incremental advantage in HbA1c reduction is always preferred. This needs to be considered as a part of the entire risk/benefit profile and patient satisfaction assessment for any drug. Differences in side effect profiles: Reported rates of gastrointestinal adverse events in DURATION-6 with Victoza® (20% nausea, 11% vomiting, 13% diarrhoea) are somewhat higher compared with what has been observed in the LEAD programme that included more than 3000 patients. In these studies most episodes were mild to moderate and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased in most patients who initially experienced nausea. Furthermore, recent studies have demonstrated high patient satisfaction with Victoza®. Overall patient satisfaction was significantly better with Victoza® compared with both sitagliptin (a DPP-4 inhibitor) and exenatide (Pratley RE et al, Lancet, 2010; Buse J et al, Lancet, 2009). Importantly, skin nodules were reported in 1% of patients on Victoza® and 10% of patients on exenatide ER in the DURATION-6 trial. In the long-term and intermediate trials with Victoza® (October 2010) only a few nodules have been reported. Administration: Victoza® is administered as a simple, once-daily injection and taken any time of day, independent of meals, and therefore offers convenience and flexibility that similar treatments do not. We cannot comment further on the clinical profile of exenatide ER before we have seen the complete results from the DURATION-6 study sponsored by Eli Lilly.

Question 94

Will Victoza® still be relevant after once-weekly GLP-1 like exenatide ER become available?

Answer 94

Victoza® is providing 24h duration of action in a simple, convenient option for once-daily management of T2DM and the results from the DURATION-6 study shows that Victoza® provides greater reduction in HbA1c than exenatide ER (1.5% vs 1.3%). We are convinced that Victoza due to it’s clinical profile will continue to be a relevant treatment option for physicians and patients in the future. Approval of exenatide ER in US is still pending with FDA and we cannot speculate on what FDA will decide.

Question 95

Exenatide ER phase 3 data shows HbA1c reduction of 1.9% vs baseline. How does this compare to Victoza®?

Answer 95

There has been no direct comparison of Victoza® and exenatide ER in clinical trials. However, comparing like-for-like trials in their respective phase 3 programs hints at similar efficacy and weight effect of these 2 drugs. Comparing side-by-side 2 well-matched trials, LEAD-6 and Duration-1 we can see that very similar effects of exenatide BiD were achieved in both studies. In Duration-1, LAR was more effective at reducing A1c compared to exenatide BiD. In LEAD-6, Victoza® was also more effective at reducing A1c than exenatide BiD by the same margin. Similar findings could be derived for weight and fasting blood glucose. However, we cannot draw definitive conclusions from an indirect comparison as the study design and populations were different in e.g. duration of diabetes, weight or prior medication.