Hello, and welcome to Novo Nordisk Conference Call. In the only mode and afterwards, there will be a question and answer session. Today, I'm pleased to present Carsten Knutsen, CFO. Please begin your meeting.
Thank you. Welcome to the Novo Nordisk conference call regarding our decision to initiate Phase III trials within early Alzheimer's disease and an update on our R and D GLP-one strategy. My name is Carsten Munk Knusen, and I'm the CFO of Novo Nordisk. And together with me today on the call, I have Mads Grosgaard Thomsen, our Chief Science Officer and Martin Lange, our Head of Global Development. We will present for around 15 minutes followed by 30 minutes Q and A.
Next slide, please. As you know, the future is uncertain, and we might be making predictions around the future. And especially when we talk about the pipeline will inherently be beyond certainties in this case. Next slide, please. Roughly a year ago, we launched our strategic aspirations for the company towards 2025.
And today, we will be covering our quarter end called innovation and therapeutic focus, again, with the discussion around our decision to enter Phase III development with oral semaglutide in early Alzheimer's disease, which is a serious chronic disease with a high unmet needs. Before we dive into this, let me put a few words on the Hemisphere deal, which we last week. Afterwards, Martin will explain the rationale for initiating development within Alzheimer's. Last week, we closed our Hemisphere acquisition price of USD 1,800,000,000 With the acquisition, we have now full control of the Snag platform and hence are not liable for future Snag related royalties payments. And we have full access to the technology platform, which we'll be using for future pipeline projects, and we'll come back to that in a short while.
The financial impact for the SNAK acquisition is as follows. Our operating profit for 2020 will not change compared to the guidance we issued in conjunction with our 3rd quarter results. So we are basically reiterating our 5% to 8% constant exchange rate operating profit growth. Our tax rate is expected to be slightly impacted, and we still maintain our guidance range of 20% to 22%. But compared to the 20 0.2% we realized in the 1st 9 months, now you should expect us to be more in the middle of our effective tax rate range for the full year.
Our free cash flow, where we guided between DKK 34,000,000,000 and DKK 39,000,000,000 will be reduced by the acquisition price. So you should expect our free cash flow for the year, the range to be roughly DKK 10,000,000,000 lower than what was guided in conjunction with our Q3 announcements. For 20 21, operating profit will be impacted by negatively by less than 1% driven by amortizations offset by eliminated royalty payments. In the medium term, the acquisition is expected to have a neutral to positive net impact on operating profit. And with this, I'll turn to you, Martin, to cover our decision entering early Alzheimer's disease.
Thank you very much, Karsten. So as already mentioned, Karsten, as already mentioned, we based our decision primarily on 2 major points. The first point being that, as we've already discussed, Alzheimer's disease is a serious disease with a substantial unmet need. It's devastating to the patients. And importantly, it's also a it was estimated that the 2020 cost associated with treatment of Alzheimer's disease is to the tune of 3 $1,000,000,000 And these are only the direct costs.
Indirect costs, such as the lost hours of work for associated families and their patients is to the tune of USD 250,000,000,000 on top of this. So a substantial patients, families and society. Our second base is obviously the scientific data that we have both in the preclinical as well as in the clinic. We have real world evidence studies. We have RCT studies.
And we also have an ever growing pool of nonclinical data that have supported our decision. As stated in the announcement, we expect to initiate the Phase 3 program during first half of next year, testing the 14 milligram dose of oral semaglutide versus placebo. Next slide, please. So a few words on the overall Alzheimer's disease. It's constitute a segment of the proportion of dementia, which is an ever growing problem and challenge in across the globe.
This is not a disease specifically for development globally have a diagnosis of dementia. This is expected to more than double over the next thirty years. Alzheimer's disease is a sub segment of this, constituting approximately 60 percent of patients with dementia. So the overall Alzheimer's population is constituting preceded by what we call mild cognitive impairment. Approximately 55,000,000 people treatment approved or available to modify the disease to delay disease progression.
A couple of drugs are approved as symptomatic treatment in already established Alzheimer's. But otherwise, we are back to the substantial unmet need. I think it's important to acknowledge that this unmet need is coming on the background of a very large attrition in drug development, where we've seen approximately 99% of all development programs fail, some of them in Phase II, but also a great number in Phase III. This obviously increases our change. It adds to the risk that we see despite the fact that we believe that we have good data to support us in our decision.
Next slide, please. A few words on the underlying pathology. The of Alzheimer's is an establishment of amyloid plaques. This leads to following accumulation of tangles. And importantly and potentially also a gating event is increased inflammation in the brain.
It's exceedingly important important to understand that these events, in particular the amyloid deposits, is taking place several years up to 20 years before the clinical manifestation of the disease. This obviously leads a change, a diagnostic change for treating physician. But it also is allow us to look at diagnostic and prognostic markers to anticipate which patients would be the right patients to include in both clinical trials and for regulatory purposes. But it's also important to understand that once patients manifest themselves with clinical symptoms, both in the early stage of mild cognitive impairment, but also in the later stage of downright dementia, the underlying pathology is very, very progressed. Mads will come back to specifically where we intend to direct our clinical activities in this disease stage.
But again, important to understand that the underlying pathology allows us to diagnose these patients in a proactive way, which is a support for us in our regulatory purposes. Next slide please. Now as we've already discussed, we have a large pool of evidence to support us in our decision. We have a number of randomized controlled trials. I want to highlight, and I'll come back to that, first of all, our post hoc assessment of our cardiovascular outcome trials with our GLP-one analogs.
In an assessment of those, we see a 53% lowering of the risk of having a dementia diagnosis if patients are on a GLP-one analog versus effect of the semaglutide. As I already mentioned, we now believe that the inflammation part in the brain is an important pathway towards the development of Alzheimer's disease. And having a drug that indicates of semaglutide the potential of decreasing inflammation by up to 50% is an important variable in this space. We have also seen studies demonstrating less decline in cerebral glucose metabolism. This is in some, but in all studies, I'll come back to that right now because a lot of you have mentioned the ALS study.
And also believe that our primary sort of evidence for making this ALS study. I hope to convince you that's not the case, first of all, because the ALS study is only one piece of the puzzle. And second of all, the ALS study is associated with a few caveats and biases that does not allow us to fully conclude on the ALS study. First of all, the ALS study is not in the same population as we intend to investigate in our Phase III program. And second of all, the impact of specifically COVID-nineteen on the ability to collect data led to some missing data in the assessment of endpoint, both on endpoint, both on cognition but also brain pathology, we as assessed by MRI, we actually see positive outcomes of DNA study.
Finally, I think this is important in the discussion of the mechanism of action. We've seen a recent study, granted small study in obesity patients, demonstrating that patients demonstrating that memory function is improved on GLP-one treatment independent of weight loss suggesting that the effects of GLP-one treatment in this space is not necessarily correlated to metabolism or weight loss, but more to the
of GLP-one.
I'll come back to the real world evidence. And specifically, we have seen a number of preclinical, very encouraging data suggesting that the mechanism behind GLP-one improvement in this space is substantial. I've mentioned the decrease in both peripheral, but also central inflammation. We've seen in several animal models a decrease in neuroinflammation. We've seen improvement obviously in cardiovascular space.
We've seen improved synaptic viability. And that basically leads to a decrease in our animal models, amyloid deposition, phosphatap deposition and improved memory function in animals animal models of dementia. All in all, very encouraging data and this supported by next slide, please. Again, our RCT and our real world evidence data. I've just mentioned the pool of our RCT data, our cardiovascular outcomes data, a outcomes data, a total of 15, almost 16,000, 18,000 patients being randomized to either analog or placebo.
We accumulated 47 events of a dementia diagnosis. And what we see is that we have approximately 50% reduction in risk of a dementia diagnosis with the GLP-one analog versus placebo. This is strongly supported from what we see in our real world evidence data. We've seen in a Danish registry that we have in 1 year an 11% lowering risk of a dementia diagnosis. However, in a 2 year period, we see a 25 percent risk reduction.
This is based on almost 500,000 Danish patients and is supporting by almost the same reduction over a 2.5 year period in the Truven claims database with approximately 300,000 patients. As I showed in the previous slide, and there are more data, real world evidence data available. I want to point out a recently reported database study using the FDA database, the FAIR study, again with a large patient number and specifically this time in Alzheimer's disease, demonstrating a 60% have good data to support our decision, both on the clinical side, but certainly also on the nonclinical mode of action side. And this makes us so confident that we are now in a position to announce our Phase III initiative. Very happy to leave the word to Mads
now. Thank you, Martin. And next slide, please. So we have not taken this decision easily. We have liaised with the stakeholders throughout the globe, including regulatory agencies, the FDA, EMA, PMDA and CFDA in even in China.
And we have, of course, spoken to global trialists and key opinion leaders within the Alzheimer's space to make sure that we base the decision on as firm ground as possible in this very high risk area of drug development. Now what I'd like to show you on this slide is that in the shaded area, we have what the FDA calls Stages 34 of Alzheimer's disease. And Stage 3 is the one you can see on the left part of the shaded area where you actually have not only neuropsychological impairment, but the emergence of subtle, but yet detectable also functional impairment in the human being suffering from this. And stage 4 is the first kind of category of overt dementia known as mild dementia even though it is by no means a mild condition. So these are the trials that have been included in the 2 global trials and have been agreed with the regulatory agencies.
Now they have to be of the Alzheimer's type. That means that we will be declaring amyloid positivity either by a PET scan or a lumbar puncture to achieve cerebral spinal fluid, you can say aspiration and positivity. So these are Alzheimer's type patients. And if you take the next slide, I can briefly show you the 2 pivotal trials that we've agreed upon with the agencies. These are 2 trials that in totality include 3,700 early Alzheimer's patients, and we are going to show or trying to show, sorry, to of oral semaglutide 14 milligram, today known as Rybulsus, versus a placebo.
There will be a randomization and the trial's main phase is a full 2 year recruitment where we dose escalate to 14 milligrams of either sema or placebo. And then there will be a confirmatory endpoint readout after 2 years, followed by a, you can say, to the physician and the patient Novo Nordisk company, where we will then follow-up with a more hard outcome measure. And I'll just describe what the endpoints more specifically are. The primary endpoint agreed with the agency is the CDR, also known as the clinical dementia rating sum of boxes score, where you essentially have 6 domains with a maximum score with increasing impairment of the maximum 18, which is very severe dementia, almost deaf, I would say, at that stage. And that is the Pammi, this is a score that is able to detect rather subtle changes and has a good inter reader reliability and is fully accepted by the regulators as a primary endpoint.
However, we also have secondary endpoints that include time to a diagnosis of dementia and also activities of daily living. In terms of the key inclusion criteria, I mentioned these were Stage 3 or 4 category Alzheimer's patients aged between 5585. And one of
the trials will be
pure play Alzheimer's type, either MCI or early dementia, whereas the other one will include around 20% with small vessel pathology. Small vessel pathology has recently emerged as a albeit post hoc analysis as a point of intervention for semaglutide. So we know that small vessel pathology is clearly intervened in by semaglutide and this plays a role in what we call vascular dementia, where will have around or above 20% with this pathology coinciding with Alzheimer pathology. The trial timelines are such that we will, during the first half of next year, initiate both of these pivotal trials and they expect it to complete 3 to 4 years from initiation. The CDR, the clinical dementia rating, sum of boxes scale is explained on the right hand side, but suffice to say that you have neuropsychological elements such as memory, orientation and problem solving, and you have more functional elements such as community affairs, homes, hobbies, personal care and the like.
So this is a very holistic assessment of the patient's situation. Moving to the next slide, I will just mention that as Carsten Hemisphere Corporation very recently, closed it last week. And that means that Novo Nordisk is embarking on a strategy of global leadership within oral biologics of the future. And the only element that we'll touch upon today relates to the GLP-one opportunity that this provides us with more specifically high dose of semaglutide for type 2 diabetes. But on this slide, you can also see that GLP-one is being broadened either in the oral form for cardiovascular protection in the SOUL trial or in the injectable form in the SELECT trial for obesity.
And we are trying to build bridges between the injectable and the oral versions of semaglutide with the endpoints that we have integrated in all of these trials. Likewise, we will be doing semaglutide by the injection route for chronic kidney disease and for NASH, starting pivotal trials during the first half of next year. And as discussed on this slide and during this presentation, Alzheimer's disease by the 14 milligram oral version. But on the next slide, I'd actually like to update you on how we have decided to initiate a Phase III trial, a pivotal trial for high dose oral semaglutide 2550 milligrams in type 2 diabetes in order to allow patients who have been happily treated on Rybelsus 14 milligrams for maybe years, but who at some point in time will need intensification of their therapy, hence the 25 milligram and 50 milligram doses. Is.
The trial is somewhat reminiscent of the SUSTAIN FORWARD trial that we did for 2 milligrams of injectable semaglutide. It includes 2 higher doses and the amount of patients is rather high, 1200 patients with type 2. The classic endpoint is changing hemoglobin A1c from baseline to week 52 with a follow-up where we also get readouts after 68 weeks including on body weight. And I would like to mention that the inclusion criteria, because this is a intensification regimen, calls for patients with an A1c between 8% 10.5%, I. E.
A relatively high baseline A1C and a body mass index in the overweight or obese ranges. And they have had to have stable doses of 1 to 3 orals before administration or integration into the trial. So we expect to be initiating the trial during the first half and the total trial completion will take approximately 2.5 years from initiation and will allow us to offer a oral version of semaglutide that can match even the high doses of the injectable counterparts that exist or are going to exist in the market. So very, very exciting. And that leads me to the final slide that actually just summarizes what we've been speaking about, namely that we will conduct 2 pivotal Phase III trials with the same at 14 milligrams oral versus placebo in early Alzheimer's
patients initiated during the first half of next year in both cases because we do believe
initiated during the first half of next year
in both cases because we do believe Alzheimer's is an area with a huge unmet medical need. We also believe, based on margins data, that the modes of action, multiple modes of action, multiple modes of action, we
based on margins data that the modes of action, multiple modes of action of GLP-one indicates a potential beneficial effect in this devastating disease, while acknowledging that there is, of course, a high risk to this program due to the historic failure rate of 99 percent within Alzheimer's clinical development. And the other element we touched upon was the pivotal Phase III trial to upgrade our intensification of patients failing on, for instance, 14 milligram rubribelis or other products for that matter with the use of 25 and 50 milligrams of oral semaglutide. And this is a trial that will assess the efficacy in patients who need improved outcomes despite a long standing type 2 diabetes you can argue. So with that final, over to you, Karsten, for moderating the session.
Great. Thank you, Mads, and thank you, Martin. We're now moving into our Q and A session, and I kindly, as usual, ask all of you to limit yourself to 2 questions per caller. And with that, operator, please take the first Q and A.
Thank you. Question question is from Richard Vosser from JPMorgan. Please go ahead.
Hi. Thanks for taking my question. First question, just on the cost of these trials. How should we think of the cost of the Alzheimer's trials and the higher dose trials? And what burden that would put on 2021 R and D spend and beyond?
Just some idea there, please. And then second question, just on the dose chosen in the Alzheimer's trial and the oral route. I can clearly see oral would be convenient and 40 milligrams is the current oral dose. But why not go to a 2.4 milligram weekly, a high dose sema sort of dose to try and maximize the clinical effect? What's the evidence behind the choice of dose?
Thank you, Richard. So I'll be covering your first questions on impact on our P and L. And Mads, if you take the choices we've made in terms of formulations, that would be great. So Richard, first of all, in terms of cost of trials, this the cost we've built in here, we will contain within the guidance we've already issued and kind of the all capital allocation that I was covering both at our Capital Markets 2021. So clearly, we are pursuing Strategy 1.
So clearly, we are pursuing a growth strategy, and that growth strategy enables us to also make substantial increased investments in D ratio. But the main driver of increased investments in R and D comes from a growing top line. We are not providing specifics on individual trial costs, but just to give you a magnitude for the investment into Alzheimer's, then over the next, say, 4 year period, then it will be in the mid single digits of our total percentage of our total R and D budget that we're investing in this area. And then Mads, on the formulations, chosen? Yes.
First of all, Richard, it has
to be said that we've done quite a bit of research into patient and physician preferences within early Alzheimer's disease. And these are patients who in 8 out of 10 cases will prefer an oral administration rather than a injectable because actually when you have a mild impairment, you are still not as debilitated, of course, as later stages where injections are maybe even more relevant. But I should also bear in mind the PIONEER 4 trial where actually we showed that Rybelsus 14 milligrams given up against Victoza 1.8 milligram was statistically significantly better both on glucose metabolic and weight related parameters, really showing that everything Martin has run through on real world evidence on meta analysis and whatnot has been done with a drug that is actually inferior to what we are going into Phase III with. So I think it's suffice to say that we are happy with the dose chosen. And also, Richard, these are people aged 55 to 85.
They are not with a BMI in the 30 something range that we are seeing for diabetes and obesity. So in terms of exposure, you should not be worried about the exposure in the relevant parts of the brain, in my opinion.
Thank you, Mads. Next question, please.
And the next question is from Martin Parcoy from Danske Bank. Please go ahead.
Martin Parcotte, Danske Bank. Also two questions. And it's actually the first one is a little bit same line as Richard with respect to the chose of the all formulation. Mads, could you maybe also discuss if there's also something with the patent life, given that, of course, the substance patent is going out at the same time in N31, but there are better protection for the oral formulation potentially. Is that also a reason?
And also given the fact that, of course, we know you have obesity and NASH Phase 2 in injections, but we also know that the production output of the oral formulation been much better than you initially expected. So is that also a reason? And then the second question is on the type II diabetes with the higher doses. And as you compared it with SUSTAIN 4, and in SUSTAIN 4, you did not was not able to show superiority on body weight at the treatment policy estimate. Do you think the study this study will be powered better, so you feel
more comfortable to
show superiority on both dose control and weight on the new higher doses.
Excellent. Thank you, Martin. So first question on choice of formulation again, oral versus injectable and then the design in type 2 diabetes with our high dose
rebaltsis, Mads? Yes. I think a small correction to you, Martin. The IP protection for the injectable version runs until 2,032 rather than 'thirty one, just a minor correction. And you are absolutely correct now that we have the patent estate on snack and we are constantly innovating new and better formulations with higher viability and so on and so forth.
These will, of course, be seeking patent protection that if applied for this year will take us until 2,040. And since Hennig Wolf, our Head of Product Supply, has managed to since we started the production plans for Rybelsus already now beef up the overall output by 3 to 4 fold or so compared to the original plans, we have a situation where this is industrial scale protein manufacturing of a high GMP grade and quality that is going to be very, very difficult to replicate for a competitor, both due to the sheer scale, but also due to all the patents that our innovations will hopefully lead to and are leading to as we speak. So we're really confident that we have made the right choice on the formulation. In terms of the diabetes trial, PIONEER plus 2 elements that differ slightly from the SUSTAIN 40. One is that the duration here is longer than sustained forward.
And we know that the maxing out of bodyweight improvements does not take place within the 1st year, but actually slightly after the 1st year. So these patients are treated for longer. And the high dose 50 milligram with the tablet formulations being used is expected to provide a differentiation versus the existing Rybelsus 14 milligram, but that remains to be seen. And also the BMI, we are only above 25 in this one. And the weight in the cystine photo was not that high.
I recorded as being only 91 or something. So there's also the opportunity that the overall baseline weight is slightly high in this trial. But that remains to be seen, Martin, because we haven't recruited yet.
Thank you.
Thank
you, Mads. Operator, we're ready for the next question.
And our next question is from Peter Schustert from Handelsbanken. Please go ahead.
Yes. Hi, it's Peter from Handelsbanken. Thanks for taking my question. I have 2, mainly to Matt. As you state, Alzheimer's disease that typically emerges 20 years before overt symptoms arise.
And that sort of basically corresponds to just a couple of years before people are diagnosed with diabetes. Have you looked at the potential artifact that, for instance, looking at the Danish population based studies, you saw some beneficial impact from both GLP-one and SGLP-two inhibitors. Have you looked into the artifact that the potential benefit of these drugs could actually be to the fact that they are used late in treatment and have been introduced to the market late compared to, for instance, when metformin has been available for many, many years, etcetera, etcetera. So this artifact could be that patients actually been on some kind of diabetes treatment for a long period of time and then you just come in with a bit more power here and add to that and how that could affect your the patient populations that you have chosen? That was sort of the number 1.
And following up on this, on the mechanism that you actually see, you talk about inflammation, but see. And you talk about inflammation, but since there's also seen some impact with H2P2 inhibitors, are you sort of working from that this is sort of the insulin hypothesis or biological changes in the brain? Thank you very much.
Great. Thank you, Peter. So Martin, first question, I think it is coming your way, which is basically linked to the timing of GLP-one treatment initiation versus the initial onset and signals of Alzheimer's? And then the next question, Mads, on the mechanism of action and related to glucose metabolism. So Martin, if you kick it off.
Thank you very much. So first of all, super good question. Obviously, something that we've also discussed ourselves. When we've been looking into the real world evidence that we have, in some of the studies, you're absolutely right, we also see effect of SGLT2s. And in some of them, we only actually see effects of GLP1s.
That being said, when looking broadly across the real world evidence, the impact of glycemic control appears not to be there. So independent of glycemic control, to the extent that we can correct for that, we don't see similar effects with all other glucose lowering drugs. 2nd of all, just going back to our preclinical studies, we do see that the effects that we have appear to be glycemic control and metabolically independent. Maybe Mads will come back to that. And thirdly, we have data also from RCT coming out showing that even at similar weight loss as compared to a placebo comparator arm, the effect of GLP-one on memory function is significantly better, suggesting that again the effect on cognition, on memory and on Alzheimer's disease appears to be metabolically independent both on the glycemic control and also on the weight loss level.
I think it's important to say also that in our clinical trials and as Mass alluded to, we will also see patients with obesity and diabetes. So we will cover the spectrum as well.
Yes. And then on the other one, Peter, first of all, the preclinical work we've done, the animal models we've been using of accelerated sedescence, etcetera, etcetera, they have all been done in the non diabetic state, just a small notice. But in terms of why we are optimistic, albeit this is a high risk endeavor, we acknowledge. Then GLP-one has shown a multitude of different activities that might all be relevant in Alzheimer's disease. Do bear in mind that the progression that Martin showed you happens over decades of life.
They actually start being relatively specific with the abeta accumulation and fibril formulation. But then you have this spreading of multitude of inflammatory phenomena in the brain and that ends up also giving big neuronal damages and problems with transmission and so on. And just let me remind ourselves that it is true that there is insulin resistance towards glucose metabolic effects in the brain, not towards other substrates, but only towards glucose metabolic effects in the brain. And that seems to be independent of whether or not you have diabetes or not in Alzheimer's disease. We believe this might be impacted by GLP-one, as we spoke about.
And then there are numerous inflammatory mechanisms that we can only study in animals, but when microglia and other cells start releasing cytokines and damaging the synapses and the plasticity of the neuronal circuits in the brain. And we have shown a modulatory and inhibitory effect on this microglial activation. And of course, we will publish some of these data over time. We should also remind ourselves that GLP-one is produced in the brain and is de facto a neurotransmitter in its own right. So by having sema enter into the brain, it might in its own right provide some increased with the addition of GLP-1s to cell cultures and even that tau phosphorylation can be decreased.
So there are many different elements here. Some are metabolic, such as glucose metabolism and blood flow improvements. Some are more of an anti inflammatory agent. And we believe that might be a better shot on goal than having a very single mechanism of action that might be overruled by the multitude of cascades that kick into the different stages of Alzheimer's disease.
Thank you.
Thank you. Operator, we're ready for the next question.
And our next question is from Peter Verdult from Citi. Please go ahead.
Yes. Thanks for doing the call. Peter Verdult, Citi. Just one on timing. Just in terms of base case planning, I realize things can change, but what filing time line are you working to as it relates to Alzheimer's?
Number 2, just on capacity, the €2,000,000,000 plant coming online in Clayton, you already mentioned that Henrik's done a great job in terms of increasing production volumes. If your GLP-one strategy as a whole is fully successful, including the high risk, high reward Alzheimer's, would that Clayton facility be able to meet the demand? Or do we need to think about the need for further expansion? And then forgive me feel to give me a red card because the 3rd question, but it's a quick one. In terms of the Alzheimer's studies that you're running over and above the inclusion and exclusion criteria that you've laid out in the slide deck, is there anything else we should be aware of in terms of would it be a real for all comers population, a mix of diabetics, non diabetics, high and low cardiovascular risk?
Is there basically any other inclusion or exclusion criteria we should be aware of? Thank
you. Great. Thank you, Pete, for these very relevant questions. And since it is Christmas, then I think it's a good time for taking trial design, both and time line versus filing and inclusion criteria. I think, Martin, if you would take the lead on that one, then I'll be covering and combine the 2, then I'll be covering the capacity expansion approach.
Yes. So I don't really want to specifically on the filing time line. But if you imagine a 12 month recruitment period and a 2 year treatment period and then obviously we had to buy it together, then you can sort of calculate from first half of next year. I think Mads also mentioned the 3 to 4 years. To your second point, actually to your third question, we do have obviously in an exclusion criteria, but most of the inclusion criteria are to define the Alzheimer's disease.
So we allow patients with diabetes. We allow patients with obesity. We also, if they can participate in the study, allow patients with myocardial vascular disease. So I don't want to call it a completely all common study, but fairly broad in an exclusion criteria.
Great. Thank you, Martin. Then to your question on having sufficient capacity. And as you correctly, Eduardo, then we are constantly working on improving our manufacturing and our efficiencies in manufacturing. And furthermore, then Mads and team are also doing some very interesting work in R and D and in TMC also in terms of improving our oil platform.
So what you should be expecting in terms of capacity and CapEx, I'd say, 1st of all, this is what we see as a positive problem because this is the top line driven attractive growth from GLP-1s. So we will be working on expanding our API manufacturing for GLP-1 in the existing footprint. So this will be more, I would say, in line extensions in both in Clayton, North Carolina potentially and in Kalemburg in Denmark. So you should expect a CapEx to sales ratio in still, I'd say, in the mid single digits percentages. So with that next question, please.
Thank you.
And our next question is from Trung Hyung from Credit
Suisse.
I have 2 if I can. So just on your recruitment of the Alzheimer's patients, you noted that you're going with a PET scan or a lumbar puncture to identify that they
have
they have quite mild disease? And my second is just a follow-up on Peter's capacity question. So on your ESG call, you said you now see a 3 to 4 fold improvement on Sema's yield. Is that the ceiling? Or do you think you could potentially improve on that in the future?
Thank you, Trung. So Mads, on our PET scans and Alzheimer recruitments and whether that poses any limits to attracting patients into our clinical trials, if you'll take the first one. And then on capacity strong, I think I'll field that one just from the get go. Then for those of you who have followed Novo Nordisk over the years, then it's a Novo Nordisk classic to continue to improve productivity within existing footprints. So no, we have not reached the end.
We are on a constant basis working on productivity enhancements and getting more out of our existing facilities. Have decades of experience in this field, and you should expect us to continue to do so, which is also why we expect to be able to stay within our current sites in terms of DF-one capacity yet, of course, invest in rebuilds and additional facilities, but still in our current footprints, as I covered before. So Mads, on L time recruitments and any limitations to attracting patients? Yes. Well, first
of all, I think it goes right now without saying that there's been a lot of disappointments. And even though there is a sizable Alzheimer's pipeline out there, we have noticed a high level of engagement and enthusiasm from all the investigators and keeping in this we've been speaking to around the potential of semaglutide. So they are already, I would say, very eager to participate in the trial per se. Then you can say what are the technological differences or difficulties in getting in there. We have 2 technologies for assessing amyloid positivity.
1 is the PET scanning technology where there are 2 particular PET ligands ants that can detect the A beta presence in the human brain via PET scanning. And they are based on FLUOR 18 that we can via a vendor deliver on-site in such a way that despite the relatively short half life of the radio it is actually being produced just an hour or so before the PET scan. And even though each investigator doesn't have their own PET scans, then there are centers, for instance, in the U. S. Where we don't use so much cerebral spinal fluid puncture for a number of reasons where this can clearly be done and the investigators have access to these PET scanning sites without any doubt.
And we are making sure the ligands are made available via this vendor. And then in Europe and certain other countries, lumbar puncture to obtain supraspinal fluid for a, you can say, CSF biomarker assessment of A beta is fully doable. And you can say that's one of the 2 options. And we don't see any hindrances towards either one or the other of these 2, you can say, amyloid positivity assessments taking place in any of the
countries.
And our next question
It's Michael from Nordea. Two questions or 2.5 questions. So the first one, if you look at North America and Europe and you sort of funnel patients down to your inclusion criteria. Is it possible to sort of give us a feeling what the total size of number of patients you're looking at? And in that question, when you're going straight for Alzheimer's and not necessarily only Type 2 diabetes and Alzheimer's, is this something that you will do alone or do you have the option to sort of co promote this with an external party?
And the second one, given the inclusion criteria in the 25 and 50 milligram oral sema trials, is there a way that you can quickly bridge into?
Great. Thank you, Michael. So question around bridging on high dose to obesity and then a question around the patient population. So Martin, if you take the old patient population and the number of diagnosed patients as we know it today, and Mads, you can talk to the bridging to obesity.
Yes. So what we know today in U. S. As we see in Europe, which more or less corresponds to what we intend to do in our clinical trials.
So I have a great number of trial sites outside of U. S. Which the label between the two administration forms. And we have some pre and we, of course, have to back that up by data from real life kinetics that we do in some of these trials. That means that we want to that we do in some of these trials.
That means that we want to bridge and have a really broad label with over time, not only cardiovascular protection claims, but also, hopefully, renal protection claims and what have you, even NASH
claims, but also, hopefully, renal
protection claims and what
have you, even NASH claims, hopefully renal protection claims and what have you, even NASH claims. The things we are doing in the trials I showed you on one of the slides, we seek to bridge as much as possible through formulation variance of somaglutide, so to speak.
Thank you, Mads. And Michael, to your last question around on this at this point in time. However, still worth noting that with our GLP-one franchise in most of our key markets, but needless to say, that would need to be reached in some way or form when we knock on wood would potentially get to the market. So with that, we're ready for the next question.
And our next question is from Simon Baker from Redburn. Please go ahead.
Thanks for taking my two questions. Firstly, just going back to the question on dosing. I fully get the preference for oral, but it's obviously very difficult to do a dose ranging study ahead of greater spread of dosing within the study. And then second question, looking at the retrospective analysis in the patient registries, a lot of them talk about dementia. And presumably, that covers both your your confident that the finding in those retrospective analyses is clean
for Alzheimer's? Thanks so much. Great.
Thank you, Simon. So your question on additional doses, Mas, if you would cover that and our Phase III trial design And Martin, then you spoke about the retrospective studies and signals in between Alzheimer and vascular dementia, so O2MS?
Yes. So do bear in mind, Simon, that the dose of 14 milligrams of oral semaglutide is well known and well documented from the entire PIONEER program, albeit in people with diabetes. So since we know that there are no safety observability concerns, we know from PIONEER 4 that it exerts more pharmacological action than does 1.8 milligrams of uraclutide, which is all from the basis for a lot of the data that Martin was alluding to, that there's no reason to include a number of other doses. We can, of course, include in the protocols the ability of patients who, for some reason, might not be tolerating 14 milligrams equally well on a given occasion to titrate down and then go back to the dose again. This is normal in long clinical trials of 2 years duration as we've also done it in our CVOTs.
But there's no need to introduce a number of different doses with all the evidence that we already have behind the 14 milligrams of oral semaglutide? And then the other one, Martin,
you can. Yes. So, really good question. And I think what alluding to is obviously when you do real world evidence that there are a lot of data that you have access to, you have volume, but there are also data that you don't have access to. And 3 of the 4 real world evidence studies that we've talked to today, we don't have a clear sort of differentiation on dementia diagnosis.
We call it dementia. But we as we discussed in a data pool of almost 1,000,000 patients, it's fair to assume that the 60% that constitute all Alzheimer's in a broader population would also be present in those populations. That obviously calls for us to evaluate is Alzheimer's then the right place to be. First of all, as Mads alluded to, we in one of our studies look at both patients with Alzheimer's disease, but also patients with small vessel disease. And secondly, I just want to point your attention to the 4th of the real world evidence studies.
It's a 66,000 patient study conducted out of U. S. From the U. S. FDA database.
And this is specifically conducted in patients with Alzheimer's disease. It's a retrospective study collecting data from 2,004 to 2018, as I said, 6,000 patients. And in those patients, all with Alzheimer's disease, an observed So So strongly suggesting that DRP-1 analogs have a place not only, so to speak, in the unspecified space of dementia,
last set of
questions. And our next question is from Andrew Fotz from UBS. Please go ahead.
Hi, thanks for taking my questions. Two very quick ones for me. I'm just wondering how the 3,700 recruitment number that you outlined earlier on, how does that compare to other recent Alzheimer's trials that we've seen? And then my second question, I think you showed some data earlier from the 2 registry studies that dementia risk seems to continue to drop as the treatment exposure continues. So do you have any indication of how far that benefit could go?
Thank you.
Great. Thank you, Andrew. So, Mads, our trial design and how that compares to the recent trials. And I didn't really get the second question about margin. Assuming you got it, then I'll give that to you.
So Mads first.
Yes, Karsten Martin is so young. He remembers much better than you and I do. Well, actually, you're young too. Sorry. So if we compare to aducanumab, the most recent we discussed project from Biogen EyeSci, then our trials are actually slightly larger than theirs, and we are using the same outcomes measures, the CDR, some of boxes, etcetera.
So you can actually say our statistical power, which we've calculated relatively carefully, should be in a really good place to show a clinical effect of oral semaglutide pending, of course, that there is an effect. And that's what the trials are going to investigate starting next year. Then finally, Maarten, on the real world evidence studies?
Yes. And I think I want to expand beyond the real world evidence studies and maybe also to other disease areas. There's no doubt, I would talk cardiovascular prevention, but also potentially in this space, the longer exposure, the better the patients seem to be off. We've made the same observation and this is specifically also to Matt's point. I mean, first of all, the 2 years is a reasonably lengthy story.
However, we also do the extension obviously also because, as management needed to, we want to be able to show an impact on the harder endpoints
Thank you, Andrew. This marks the closing of our Alzheimer's call and our R and D GLP-one strategy update. In case you have any further questions, do not hesitate to reach out to you for the interest and taking time to listen into this call and wishing you all a peaceful
holiday season.