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Novo Nordisk A/S (NYSE:NVO)

Investor and Analyst Meeting at ADA

June 22, 2013 7:00 pm ET

Executives

Alan Moses - Chief Medical Officer, Senior Vice President and Member of the Senior Management Board

Mads Krogsgaard Thomsen - Chief Science Officer, Executive Vice President and Member of the Senior Management Board

Jakob Riis - Executive Vice President of Marketing & Medical Affairs

Lars Rebien Sørensen - Chief Executive Officer, President and Member of the Senior Management Board

Analysts

Peter Sehested - Handelsbanken Capital Markets, Research Division

Richard Vosser - JP Morgan Chase & Co, Research Division

Peter Verdult - Morgan Stanley, Research Division

Michael Novod - Nordea Markets, Research Division

Alan Moses

Thank you, Mads. You've heard about degludec and the results with degludec, and you've also heard about adding liraglutide onto degludec, and both as a free drug and a fixed combination. What I want to do is bring you back to liraglutide itself and focus on the safety profile for liraglutide, because that's been a topic of quite heavy discussion. In fact, you probably have to be deaf, dumb and blind not to be aware of these activities over the last several months.

Let me first take you through the chronology of the debate over incretin safety. Because it actually started back in 2007, when the FDA alerted to the opt the potential of pancreatitis in patients being exposed, specifically to exenatide and that was a result of some cases of pancreatitis that were reported associated with -- in the post-marketing period with exenatide and then, retrospectively, in the development program as well. In 2008, this was further expanded in label language, and then of course, when liraglutide was approved in the United States in 2010, similar language was included, in part, to -- because a class effect couldn't be ruled out, of course, it couldn't be ruled in either because the data was unclear to that point. In January of 2010, the topic became a little more apparent to many reading the literature with an editorial published by Peter Butler from California, UCLA in California, on the topic of pancreatitis based on exposure to DPP-4 inhibitors or GLP-1 receptor agonists. And he suggested, based on data that he had generated with DPP-4 inhibitors, that this might, in fact, be an issue. That issue was not largely supported by data generated by any of the sponsors in this particular area, and I'll return to that fact.

In March of 2011, so just a little over a year later, a publication, again, from the Butler group appeared, that took the FDA Adverse Event Recording or Reporting System AERS, and used the data from that to suggest that there was, indeed, an increased risk of pancreatitis associated with either exenatide exposure or with DPP-4 exposure, in this case, sitagliptin. However, the FDA has been quite clear that this database is really meant to detect a signal, and not to do comparative studies because the data do not have a denominator. Nonetheless, the paper was published, and raised concern amongst many that maybe there was something going on and scrutiny began to increase. There were articles by Drucker and Buse and others reviewing the scientific evidence that did not support a relationship. But in April of 2012, just a year later, another paper appeared looking at a specific mouse strain, the K-ras mouse, which is susceptible to the development of pancreatic carcinoma, and demonstrating that exenatide exposure in those animals actually increased the rate of histopathologic changes in the pancreas. There was an editorial that accompanied that, by Edwin Gale, again raising the question about whether these agents might indeed produce not only pancreatitis but also, might lead to pancreatic cancer. There was an editorial by Goggins, Michael Goggins, who is a renowned pancreas expert, that didn't quite support that view. And at the same time, or roughly the same time, we published our own data on the preclinical evaluation of liraglutide in mice, rats and monkeys, which demonstrated no evidence of histopathologic changes to the pancreas.

In February of this year, an article, epidemiologic pharmacovigilance study appeared based on a Blue Cross, Blue Shield claims database that suggested that patients exposed to either exenatide or DPP-4 inhibitor, sitagliptin, had a twofold increase in the risk of being hospitalized for pancreatitis. Again, Peter Butler wrote an editorial to that -- on that paper. And so in BMJ, did Edwin Gale. Since that time, there have been other publications that have gone both ways in terms of this discussion. The most provocative of which was a study by Butler, et al. looking at human pancreases obtained from the nPOD program, which is meant to provide pancreases for human study. And in that publication, suggested that there were a number of histopathologic changes induced by either sitagliptin in 7 cases or exenatide in 1 case, compared to control pancreases from people with diabetes or truly control pancreas of people without diabetes. That led to a convening of a number of experts last week at the NIH in a conference convened by NIDDK.

But let me just confirm for you the results of our nonclinical studies on liraglutide and the pancreas. Now we have to recognize that animal studies are safety studies that are meant to identify target organs and potential signals of concern for human safety. We did not see that in the liraglutide development program. Indeed, liraglutide did not induce pancreatitis in normal rats or mice dosed for 104 weeks, these are lifetime studies, or in non-human primates dosed for up to 87 weeks. In fact, in the 87-week non-human primates studies, animals were dosed with over sixtyfold the exposure that a human would receive at a 1.8-milligram, the maximum dosage approved for use in diabetes. Liraglutide was not associated with evidence of pancreatic cancer in either the endocrine, alpha beta cells, delta cells or the exocrine, the enzyme-producing part of the pancreas during lifetime rodent studies. And liraglutide was not associated with drug or dose-dependent histopathologic changes in the pancreas of non-human primates.

So in summary, from that rather large body of evidence including, in some cases, 50 to 70 animals per group as opposed to rather small numbers of animals studied by Butler and other academic investigators, there was no evidence that pharmacologic induction of pancreatitis or pancreatic cancer by liraglutide occurred in normal rodents or in non-human primates.

In terms of our clinical development program, there was no clear association of liraglutide to the development of acute pancreatitis and no relationship with pancreatic cancer based on the diabetes development program. Now there was an numeric excess of pancreatitis in the clinical development program. But there was no significant difference in the incidence of reported cases of acute pancreatitis with liraglutide versus comparators, and there was no increase relative to the expected number of cases in this population based on the background increased rate of pancreatitis in type 2 diabetes. Moreover, after the studies were completed, and note that these studies were conducted at a time when pancreatitis was really being associated for the -- its potential association with exenatide, that may have increased the reporting of symptoms and signs in laboratory values that could be considered pancreatitis, but without adjudication or clear confirmation of the diagnosis. So we did post hoc adjudication by a noted pancreas expert. He was unable to confirm a diagnosis of pancreatitis in 6 to 8 -- 6 of the cases in the liraglutide arm. At least, he could not link that to treatments. 2 of the cases, the relationship was unclear, and a single case in a comparator, there was insufficient data to assure documentation. So it's a very uncertain situation.

In regard to pancreatic cancer, there were indeed 3 cases of pancreatic cancer in the program. One of these cases never received drug, that was diagnosed before randomization -- after randomization but before drug was administered. Two cases were diagnosed with pancreatic cancer, in one of these, patient presented 7 days after exposure to liraglutide with metastatic pancreatic cancer, clearly not related to the exposure to liraglutide. And the final case was an individual who presented at 163 days in a disease that has a latency period of 18 years and presented with metastatic disease. Again, highly unlikely to have any relationship to drug exposure.

So that was the background. In the postmarketing period, Novo Nordisk readily agreed with recommendations from the FDA to conduct a variety of studies. One of which was another nonclinical study. This case, in rats, but in rats who had diabetes. So these are ZDF rats who were induced to a state of hypoglycemia, both males and females, and they were treated with liraglutide at 2 separate doses, and with continuous infusion of exenatide at a single-dose. When we looked at the pancreas weight of those animals, whether they be males or females, there was no evidence of increased weight of the pancreas induced by either liraglutide or exenatide in the males or the females.

Indeed, liraglutide did not induce pancreatitis, did not affect the biochemical or histopathologic markers of pancreatitis and did not increase pancreas weight or exocrine or duct cell proliferation or mass. Indeed, as shown on this slide, if we looked at the mass of acinar or duct cells, males on the left, females on the right, duct cell mass in the upper panels, acinar cell mass on the lower panels, again, no evidence that liraglutide in dark blue or exenatide in orange increased duct cell or acinar cell mass. This is very important because it does not support some of the previous data -- by other investigators.

When we look at the spontaneous reports of either pancreatic cancer on the left on this slide or pancreatitis on the right, since the approval of liraglutide, first, in the European markets, and subsequently, in Japan and the United States, you can see that there is a gradual increase in the number of cases, which would be expected because more patients are being exposed to the drug year upon year. This is shown in the dark blue bars. But if you look at light blue lines which represents the estimated incidence based on those reported cases, there is clearly no increase, and the number of the incidence rates are well below the expected incidence -- background incidence rates in type 2 diabetes for either pancreatic cancer or pancreatitis. So no real signal from the surveillance data that's been reported. Now there are problems with surveillance data, including the fact that cases are underreported. But they're routinely underreported for all diagnoses in all drugs. And these are the best we can do with these data available.

On the other hand, as part of our post-marketing requirements, Novo Nordisk undertook a pharmaco-epidemiology study that was designed in a very different way. In this study, we prospectively identified new initiators of liraglutide therapy. So we only took patients who were starting liraglutide for the first time. This is a claims database, so it has some of the same challenges that other claims databases have. But since the initiation of the study in February 1, 2010, and immediately after approval of liraglutide, until now an interim analysis through June of 2013, we have accrued some 25,000 initiators on liraglutide who are propensity score-matched to individuals with type 2 diabetes treated either with pioglitazone, metformin, sulphonylureas or DPP-4 inhibitors. What does it mean to be propensity score-matched? Every initiator on liraglutide was matched to a patient started with one of these other medications based on: duration of diabetes, age, concomitant medications, hypertension, other conditions, to assure that you've matched as closely as possible to the underlying disease state that these individuals are prone to or susceptible to.

For acute pancreatitis, which is shown on the left here for each of the 4 medications comparative medications, the relative rate ratio is less than 1 for acute pancreatitis. 0.9, 1.0, 0.9, 1.0. For pancreatic cancer, shown on the right, the relative rates are, again, all less than 1 and ranged from 0.6 to 1.0. So based on these data, again, claims data with all of its limitations but prospectively planned and propensity score-matched to other patients, no indication of an increased risk of acute pancreatitis or pancreatic cancer with liraglutide compared to -- for common therapies used to treat type 2 diabetes.

So based on this, we can say that based on the totality of the efficacy and safety information, we can support the positive benefit risk balance for liraglutide. Nonclinical studies do not demonstrate any histopathologic changes in the exocrine or endocrine pancreas in rodents or non-human primates, differing substantially from other independent reports, but rather small in number compared to the weight of the published literature.

Pharmacologic induction of pancreatitis by liraglutide in rats with diabetes, that's in rats with diabetes, was not seen and there was no evidence of dysplastic changes in either the exocrine or endocrine pancreas in these animals. Data from the clinical development program reveal a numeric excess of cases of pancreatitis, but these are not statistically significant, and they can neither confirm nor rule out a causal association between liraglutide and acute pancreatitis. And again, many of these cases may not have been pancreatitis based on post hoc review.

There simply are, in our hands, no animal or human data to support an increased risk of pancreatic cancer following exposure to liraglutide.

And I will remind you that the studies that have been published suggesting a relationship between GLP-1 receptor agonist and those -- that problem, pancreatic cancer, have not included exposure to liraglutide. Interim analysis of the pharmaco-epidemiology studies specifically designed to look at adverse events associated with liraglutide use and with specific focus on pancreatitis and pancreatic cancer, have failed to reveal any evidence of an increased risk in either diagnoses with the use of liraglutide compared to standard therapies, other standard therapies, for type 2 diabetes. So based on the totality of the information we have available, we simply do not see evidence of increased risk with liraglutide for pancreatic cancer, and cannot confirm or rule out an increased risk with pancreatitis. The best hope of actually resolving these situations are twofold: one, to continue the pharmaco-epidemiology studies for the full 5 years as planned, where we will accrue probably more than 50,000 initiators of liraglutide and analyze the data again at that time. And perhaps, even more importantly, to look at our prospective double-blind trial of liraglutide versus placebo to assess cardiovascular outcomes, where we're collecting and adjudicating all cases of pancreatitis in 9,340 individuals, providing the best opportunity to resolve the question about pancreatitis and exposure to liraglutide, and hopefully, provide some insights into any potential risk for pancreatic cancer as well.

So with that, let me turn the microphone back over to Jesper Brandgaard to conclude this session. But I hope I've reassured you in terms of our views, our data regarding the pancreatic safety of liraglutide. Thank you.

Question-and-Answer Session

Mads Krogsgaard Thomsen

More surprisingly, towards the end of the trial, in the last 3 months, they actually lose significance and go down to a 4% reduction. So overall, this is -- it is difficult to get much wiser on. The overall performance on the primary end point, A1c, I was a little bit surprised to see that the patients are only dropping the A1c by 0.8%, where in our comparator trial between glargine and Tresiba, we got a 1.3% reduction bringing every other patient to the target. And in spite of the A1c not being so low in this glargine U300 trial, we actually -- or they actually saw approximately 5% or slightly more of the patients reporting severe hypoglycemia in a 6-month period. Whereas we, in a 1-year period in our own trial, in spite of better A1c achievements, didn't even see, only barely saw a 5% occurrence of severe hypos spread over twice the time. It seems that they have slightly more, about 50% more injection site reactions on U300 than U100, but again, that can be a fluke, I think that needs to be investigated further. And since the situation of action, as we've heard it today, is about 3 hours longer than the U100, where we know that Tresiba has twice the compared to U100 glargine, the way I see that, is it's encouraging for the Sanofi colleagues that they may have a product that is -- appears to, perhaps, be modestly better then U100, but I do not see it as something that I would shy away from comparing up against with Tresiba anytime. I don't know, Jakob..?

Jakob Riis

Yes. No, I would say, I think it's -- what's positive about this development is that Sanofi emphasized and is already emphasizing the quality in having a longer duration of action and a lower risk of hypoglycemia, that is spot-on what we are communicating to the market that is important in the basal segment. Where Tresiba is what you measure up against, I wouldn't be concerned from what I hear here. I think an improvement, perhaps, but nothing that matches what we've seen with Tresiba. But I know -- I acknowledge your question was about Levemir, you could say that the place where you could see this as a relevant dynamic to discuss would be in the market where Tresiba is not available, and that essentially means that we are talking a U.S. market, as it looks, from '15 until we launch Tresiba. And I think that's how to gauge from the little we know about U300 and how that would proceed against Levemir. But I think that's a debate a little out in the future and only, hopefully, for a limited period of time. So I would see this as, overall, a positive development because I think we're going to benefit more than we, potentially, are going to have to struggle with U300 with Levemir.

Lars Rebien Sørensen

And I think overall, also, I think it's likely to basically be reassuring for the pricing points of insulins, not only in the U.S. but internationally, that this is highly likely to actually imply that there will be an upgrade opportunity. I think it's clear by what we have demonstrated with Tresiba and also what, potentially, could be in the glargine U300, there's opportunity for treating both type 1 and type 2 patients even better with the basal insulin, and I think that's going to be, long-term, also commercially attractive and it's going to be good for the patients. So we're very reassured with this development. Next question please? We have Peter down there?

Peter Sehested - Handelsbanken Capital Markets, Research Division

It's Peter from Handelsbanken. Regarding the uptick in Japan, could you comment anything about the switching versus capturing of new patients, what is driving that? And secondly, no, I think I'll stick to that one.

Jakob, uptick in..?

Jakob Riis

Yes. It's, by far, driven by switching right now, and predominantly from glargine. It's the preliminary data we have. I think because of glargine's majority of share in the basal segment, mostly analogs in Japan, you could say just a switching pattern reflecting the average position in the markets would, of course, give more glargine patients coming. So that's why we're predominant, and you see them from -- there's not that much dynamic in the insulin market in Japan. So relatively, you could say the contribution in the beginning will be overwhelmingly, it will be switching but of course, over time, that will gradually shift, so it's more the new patients that drives it.

Lars Rebien Sørensen

Thanks. The next question please.

Richard Vosser - JP Morgan Chase & Co, Research Division

Richard Vosser from JPMorgan. Just a couple of questions on your prospectives given we really saw a favor earlier this -- or a week ago, I'll say. Just how you think and how that result impacts your thinking around the potential for a positive result around LEADER? And ally to that, Lilly discontinued their 3 mg dose of dulaglutide because of a heart rate increase of 5 beats per minute or something like that. I think your average is 3 beats per minute increase. How do you think that affects the results, as well, in terms of potentially a positive result of LEADER? And then, just another, a final question, just on the FDA. I think you alluded to, on the call, about having to do maybe double-blind trials with -- for -- to prove hypoglycemia or efficacy trials essentially. Could you just give us an update what you've submitted to the FDA there and what you're thinking?

Lars Rebien Sørensen

Okay. there are 2 questions. First, I guess, Mads, an update on what are the prospectives for LEADER from the trial that we reported last week and what implications do you read from the decision by Eli Lilly of not doing the 3-microgram (sic) [3-milligram] dulaglutide dosing in their Phase III trials?

Mads Krogsgaard Thomsen

Okay. Well, first of all, Richard, 1 slight correction, if I may. I think what happened in the dulaglutide that the Lily colleagues entertained in Phase II and then, switched the patients further into Phase III was actually more that they saw a slight blood pressure increase, the pulse rate you see with all GLP-1 agonists. It is essentially a slight blood pressure increase that was so much surprising and that kicked in, at least, at the 3 milligram dose, and I think that is what caused the folks at Lilly to discontinue and only do the 1.5 and 0.75. As regards to read from Seva and the Onglyza or sitagliptin into Victoza, there's no correlation. A DPP-4 inhibitor, even though people love to call this the incretin class of agents, you have to bear in mind that what a DPP-4 inhibitor does is essentially increase the, indulging the circulating levels of GLP-1 by 1.5 to twofold, whereas, when we use pharmacotherapy with a human GLP-1, and a lot like liraglutide, we are maybe sevenfold up. What does this mean? Well, it means, for instance, that in the cardiovascular risk biomarkers, we systematically, both in diabetes but also in obesity, see highly significant, very often, with p values of 100 naughts before the first digit kicks in, in favor of liraglutide on important risk markers such as CRP, C-reactive protein, which is an inflammation marker, acute-phase reactant. We do see improvements, small but statistically significant, across trials in lipid profile, increases in HDL, decreases in LDL and triglycerides. We do see that pie 1 goes down as you would hope for, adiponectin goes up as you would hope for. When you actually then look at the pulse rate, you actually -- you're right that it goes up by a couple of beats per minute. But what the measure of myocardial oxygen consumption in reality is the pulse pressure product. Where you simply multiply the systolic blood pressure with the heart rate, the pulse rate, and get the pulse pressure product, which is a direct readout of the individual myocardial cardiomyocytes oxygen consumption and hence, stress level, and that, if anything, goes down on liraglutide rather than up. So I would not take any reads from Seva or dulaglutide for that matter into liraglutide.

Lars Rebien Sørensen

And then, Mads, I forgot, there was also a question from Richard on the trials we are going to undertake in terms of Tresiba in the U.S. and whether the double-blinding, if you had any comments on what we have submitted to FDA in terms of the design of those trials?

Mads Krogsgaard Thomsen

Yes, so I think it is absolutely true that we could also hear that at the advisory committee meeting that the FDA was not, you can say, appropriately impressed by the hypoglycemia data to the extent that we have seen Europeans and Japanese regulators be. So it is true that one of the things that we would do is, indeed, even more robust and firm assessment, ideally, in a blinded setting between glargine and Tresiba, because that will be proof to the pudding that the data that we've been showing you for the last years are indeed highly replicable and robust and valid, also, in the blinded setting where, if anything, I think that will give us a favor that people would not know which agent they would be titrating, whereas, in an open-label setting, many patients are familiar with the use of glargine and how to titrate it, unlike in new experimental products such as Tresiba. Okay. Yes, Peter?

Peter Verdult - Morgan Stanley, Research Division

Pete Verdult, Morgan Stanley. Jakob, can we come back to the launch of Tresiba in Japan. I realize, only about 15 weeks, both wouldn't understand that value chart you put out because it seems that Levemir's value share has been absolutely maintained flat, and you've taken everything from Lantus, which seems to me somewhat odd. So I suppose the question is, can you give us a bit of a sense as to what percentage of patients you're getting as new starts versus the switch patients? Or secondly, have you done anything with the Levemir price either up or down?

Jakob Riis

Yes. First, when you see the data, it's weekly data. So you could say, there's -- we have to be a little careful how accurately we sort of add them up because there are some weekly fluctuations. So we've taken, by far, the majority from switch and of that, the vast majority for glargine. And I'll be hesitant to put percentages on, but we're sort of probably in the 80%, 90% range. And so you could say, yes, that's why you don't see any significant impact on Levemir, but of course, there has been some switching from Levemir, no doubt about that. So -- but you won't be able to take that right now. I think the main conclusion on why we're pleased with the uptake is, the entry curve for Tresiba is very steady, reaching a satisfactory level at this point. So for us, the recipe is very clear, we just keep going. And at some point, the majority is going to be on Tresiba and of course, you're going to see the glargine share come down significantly. But of course, over time, that will also be somewhat visible on our Levemir curve. So I think I said that's why it's early days, and the dynamics are hard to pick up in the weekly data. But if we just continue the current penetration, it's going to work out really nice. That's how the math works for that.

Lars Rebien Sørensen

Just to confirm that there's been no adjustments to our pricing of Levemir in Japan as a consequence of the launch of Tresiba. So we're quite reassured by what we see, and we hope that, that will lean over into the other markets that we will basically capture from the current players in the market and we'll do that proactively. So there's no specific conversion of Levemir patients towards Tresiba, it's a general capture in the market that we see. Next question please? We'll give another one to...yes?

Richard Vosser - JP Morgan Chase & Co, Research Division

Richard Vosser from JPMorgan again. Just following up from that, what's the price premium that degludec is or Tresiba is in Japan, just quickly? And then, I'll just add, the DPP-4 are slowing, are you seeing any measurable increase in uptake in the GLP-1 class in the U.S. as a direct result of that? Or is it -- yes, I'll stop there.

Lars Rebien Sørensen

Thanks, Richard. First, on the premium of Tresiba in Japan, it's launched at a slight premium to the definitely approximately at low single-digit premium. And in terms of the impact on the GLP-1 market, that was U.S.-specific, you're right, you referred to. Jakob, maybe some comments on that?

Jakob Riis

Yes. No, curves seem to be fairly steady. But again, would be difficult to pick up a dynamic like that. There's a lot of things going on at the same time with the [indiscernible] launch, [indiscernible] launches and so on. But no, I would say, we're not seeing anything, sort of, significant to the curves.

Lars Rebien Sørensen

Okay. We had one question. Michael?

Michael Novod - Nordea Markets, Research Division

Michael from Nordea. Just regarding obesity and also, Alan's presentation regarding pancreatitis and all that discussion. Do you see any impact on the filing in obesity from these discussions, so -- or should we just expect that everything regarding that will be on track? And then, secondly to dulaglutide, there's been a lot of speculation also feet in the market that they will actually be able to show superiority against Victoza in the head-to-head trial reading out late this year. Maybe you can give us some thoughts on how you read the data being presented at the conference?

Lars Rebien Sørensen

Okay. First, the obesity and pancreatitis issue, Alan, if you could comment on that and if you see any implications for our filing approach for obesity? And then, Mads, if you could deal with how we see dulaglutide doing in a head-to-head trial up against liraglutide?

Alan Moses

Surely, from a filing perspective, I think we see no impact of the data that's out there at the moment. Obviously, we will focus on both our preclinical studies that were conducted during the diabetes development for liraglutide, which is the core of the preclinical or nonclinical studies, and also, for all of the pancreas safety data that were developed during the obesity development program. Will there be emphasis by the agency at an advisory committee on this? I would suspect there probably would be just because it's a topical issue, unless that topic becomes further dampened over time. I think it's important to note that from an FDA perspective at the NIH meeting last week, they were rather clear about their remarkable lack of concern, given the huge amount of data that they've had a chance to look at across multiple drugs, multiple sponsors, multiple species, including man. So is it a part of a safety file or a safety review? Of course it is. Are we particularly concerned about it? No, we are not.

Lars Rebien Sørensen

Mads?

Mads Krogsgaard Thomsen

Yes, Okay. I was waiting for the T2 to tell me to speak.

Lars Rebien Sørensen

No, but I've already given you the clue. You want it again?

Mads Krogsgaard Thomsen

Okay. So no, it's fine. So just one further, I totally agree with what Alan is saying. I would like to add that from an approvability perspective, because the pancreatitis potential risk is mentioned for all these drugs already in the label, what really has been in the graveyard for obesity products, as some of us will listen to today at the session this afternoon, is obviously the risks that they have been of a neuropsychiatric character, suicidal ideation behavior and depression and that kind of thing, as well as, the risk of cancers or cardiovascular disturbances. And in all these 3 major, major draculas, we did not see any untoward signs at all for liraglutide, 3 milligram. I think that's important to notice. As regards to dulaglutide, we have all along actually said that we felt that dulaglutide was, indeed, a serious candidate in the GLP-1 field, and I'll confirm that with what I've seen today. But when that is said, it's as if there has been a slight shift from some of the Phase II data to the Phase III data, such that now that we are seeing even Metformin and placebo and sitagliptin having relatively sizable weight losses in the comparative trials. So maybe it's the way the trials are being performed and designed and so on. So I would not, so to speak, put too much weight on the weight data because the deltas are interesting. And on the weight side of things, I think the deltas are in our favor for liraglutide. Whereas in A1c, we look pretty similar.

Lars Rebien Sørensen

Okay, well, that was amazing. This is the first time, I, as a mere bookkeeper, has been trying to be a teacher or an adjunct professor. That's actually great. Do we have any final questions? Yes, Peter?

Peter Sehested - Handelsbanken Capital Markets, Research Division

Peter from Handelsbanken again. When you look at the recruitment for Lily on their vial or blinded study, with the novel insulin and the recruitment for the insulin, the PEGylated insulin alone. You actually see that the recruitment of patients recruited percent is much lower in their vial study, suggesting that, I mean, it's slightly a bit more difficult to get hold of those patients. And I think the average is around 11 patients per trial in their vial studies. That means that for you to accrue at least 6,000 patients with, I mean -- depending on whether you go for 122 or more patients in the interim analysis, I mean, are you confident that you can get that many centers running so you can meet the timeline that you have suggested? And secondly, probably for Lars, in terms of the pricing strategy for Tresiba in Europe, it seems that you're betting that the Sanofi will actually price some of their new products at a premium. What if they don't, are you willing to lose out Tresiba in Europe completely just to make sure that premium is intact?

Lars Rebien Sørensen

Okay, thanks, Peter. First, on our ability to recruit insulin patients using vial administration for the Tresiba cardiovascular trial, outcome trial, Mads, if you can comment on that? And then, maybe I can give a few comments on pricing in Europe and maybe, Jakob, if you have a few comments to add also?

Mads Krogsgaard Thomsen

Yes. Well, first of all, you can see if this were the first ever cardiovascular trial that Novo Nordisk are going to conduct, we would have relatively little insight into which of the many, many hundreds or even thousands of investigator sites that are relevant to do at the outcome trial that would hold the most promise. I would have to say, though, the performance we've had in the needle trial has documented to ourselves that we are indeed able to pull off, highly professionally and at great speed, a CV outcome for an -- albeit on another drug. It is true that the share effect that you're giving a buzz is compared to pin systems in many countries in the world will pose, you can say, a challenge and that is also why you may see that there's a different country allocation for this trial, where in the U.S, we still see a high degree of willingness to use vials. In particular for patients who are offered for a multitude of years or at least up to several years of treatment with what is potentially an analog, a new and improved analog such degludec or a well-established analog such as glargine that they, in many situations, may not have had access to because of, you can say, managed car considerations and so on and so forth. So I think we can pull this off. Will it be a little bit challenging? Probably will be so, but the area where Novo Nordisk actually, in particular, stands out in terms of clinical performance is in patient recruitment and more specifically, in diabetes, so we are confident.

Lars Rebien Sørensen

And then, on the pricing in Europe for Tresiba. I think, first, one have to bear in mind that the pricing levels in Europe are actually very low and even with the pricing that we are currently pursuing with -- for Tresiba, the cost per day is significantly lower than the price you, for example, have for a novel treatment like GLP-1. So we do believe that there is a meaningful value provided in giving the type 2 patients an insulin at a total cost paid typically of around EUR 2, EUR 2.5 per day, we think that's a great opportunity for patients to significantly lower their risk of hypoglycemia, and we are seeing that we are able to gradually obtain reimbursements, U.K. and Switzerland being in our example there. It'll be a longer haul. We're certainly not, neither Jakob or I are going to speculate on what Lantus potentially will do or Sanofi potentially will do if they potentially get a certain product on the market. And history has shown that predicting how regulatory processes proceeds can be highly challenging, so I'm not going to give any comment on that. I don't whether, Jakob, if you have additional comments there?

Jakob Riis

No, I'll just add that very recently, this week, we got confirmation that the Swedish authorities have come to the conclusion that Tresiba is worth the premium over glargine. That's the national assessment in Sweden, and of course, now we have to discuss this with the regions in Sweden and have them put on the formulary. But the reason why I mentioned that is that before we talk about giving up anything, I think we will focus on arguing for the value with all the players in Europe and it's way, way too early to come to any conclusion that we're giving up on anything. So far, actually, we look like we are progressing quite nicely. Last, you could say, since I was told not to speculate and I won't do that, but the thing is where pricing could become a trigger of patterns of prescribing and purchasing is, obviously, when you have comparable solutions. And as soon as you're differentiated, it's really, really hard to drive any uptake with price. And so as long as we build in and have the market acknowledge that Tresiba is differentiated from anything else, and there is value behind that differentiation, then, I think pricing will not be a primary driver in the marketplace. And that's not to say, of course, that with a price upon the premium you've chosen, that you won't see a slower conversion to Tresiba over the coming decade, and we'll probably remain to see quite a lot of consumption of the model insulins as we have been today. And that's a deliberate choice pricing, you can say, for not only the next, but the coming 20 years.

Lars Rebien Sørensen

And also, bearing in mind that the pricing chosen in Europe will be referenced for the pricing applied in a lot of the international operation markets, and that's also crucial for us. And that's where we see a lot of the opportunities emerging, and that's why we are very aggressive in pursuing a global rollout of Tresiba like we have also been quite successful in being very rapid in the rollout of Victoza globally. You'll see the same here and hence, it's important for us that we have a meaningful price reference point in our home markets. So with those comments, I will end the Q&A. And I'll just lead you to the final slide that I have been granted by Investor Relations, which is one, highlighting that if you have any more questions, you can contact our Investor Relations officers. But I also would like to highlight that, actually, we do have an upcoming investor event, not only at EASD, with an investor presentation in September, but do also note and kindly put into your diaries that we plan to have a Capital Markets Day in Denmark on the 3rd of December, where we'd like to invite you to our diabetes facilities in Hillerød, north of Copenhagen. So with that said, I thank you for your interest in Novo Nordisk and for your questions here today.

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