Can you hear me? All right. Good afternoon, everybody, welcome to this meeting. Last time we were together was about two years ago, it's really great to have you here. Nice to see a full room, too, such an impressive audience. My colleagues are so impressed, they're all wearing a tie today. Our CMO got himself a new haircut and a new suit. Would you believe it? He's all ready for you. Before we get started, let me tell you a little story, last time we met was almost two years ago, actually, a little bit less than that, 20 months ago or so. I started with AstraZeneca late 2012, before doing this, as you can imagine, I talked to quite a number of people. I talked to a number of people in this room, actually, just to get some advice.
I, of course, went and talked to a large number of doctors, opinion leaders. I remember visiting one of the top oncologists in the world in Boston and having breakfast meeting with him and asking him questions about AstraZeneca in general, but in particular about olaparib, I had been looking at this product from the outside, I was wondering, actually, what exactly is AstraZeneca doing with this product? I went to him and asked him, "What do you think? What should we do? Am I missing something?" He told me what he thought, I will always remember, at some point, he looked at me, he said, "Pascal, what you guys are doing is wrong. This product should already be treating patients.
You absolutely have to do something to bring it to patients." A couple of days ago, one of our major investors told me that a friend of his who was an ovarian cancer patient with a BRCA mutation and was running out of options was treated by olaparib and actually gained two and a half years of life out of this product. I'm telling you this story, for me, this product has had a huge impact on me. I'm telling you this, the work we do matters. The reason we come to work every day, my colleague and I, is we make a difference for patients. I'm also telling you this is only two years, time flies very quickly. Two years ago, we were writing off this product. Today, we are getting ready to launch it. Time has gone very quickly.
The same is true for the next two years. That's one of the messages we'd like to leave you today, is that time goes quickly. Our pipeline is progressing quickly. The value of our company is changing every day, the rerating of this company will continue at an accelerated pace, we believe. Hopefully what we can do at the end of today is convince you that we're not going to make a big announcement today, convince you that we are on track. We're on track with our strategy. We're focused on execution. We need to be absolutely focused, those products do matter. Those products matter for patients, they matter for the company. We've developed AZD9291, our new product for lung cancer, in record time.
I know some people, when we mentioned that in the last few months, some people were a little bit cynical about this. The truth is, we will have gone by the time we file from first-in-man to filing in less than two and a half years. One of the fastest development ever in the cancer world. We are focused on our work, and we hopefully will show you today that we're making good progress delivering on our strategy and in many ways ahead of our plan. No big statement, no big announcement, but we'll show you that hopefully we are focused and delivering. This is the agenda we have for today.
Because we just went through the Q3 call and we gave you an update on our progress from a commercial viewpoint, if you want, we thought we would try to focus the discussion today on the future. Again, as I said, the future will come very quickly. It's not a distant future. It's a future that will become reality relatively soon, at least from the point of view of the valuation of the company, we believe. The first session will be around some of our commercial drivers, our growth platforms. We'll go through this, we'll stop, and we'll answer any questions you have about these growth platforms. From there, we will move fully to the pipeline. The late-stage pipeline to start with our Respiratory Inflammation team, the Cardiovascular Diabetes team, and the Oncology team showing you what we have in development.
We'll stop and have a series of Q&As on these therapy areas. We'll move to the next step. What we wanted to show you today is that what we have is not a one-off, a few projects in late-stage development. What we have is an R&D engine that is productive and a sustainable model. Bahija and Mene will share with you what we have in our earlier pipeline, essentially in the clinical phase, though. We didn't want to go all the way to preclinical, but we wanted to show you what we have in the clinical stage that will rapidly also move to our late-stage pipeline. Finally, Marc will close with a financial picture for you. We showed you this before.
We are on a journey, hopefully you will agree with us that the first phase of this journey, which was 2012 to 2014 until today, we've been rebuilding our foundations. When we were together last time, essentially, people were expecting us to keep declining and to be a $20 billion company by 2020. I will always remember this. Many of you actually forecasted us to be a $20 billion company on a permanent decline by 2020. The good thing is today, the debate is about whether we will be able to achieve $45 billion by 2023. There's still a big debate around this, I accept it, but at least we've sort of moved from $20 billion in 2020.
Essentially, in the last two years, we've been rebuilding our foundations, and we're starting the second phase of this journey, which is 2015-2017. Managing the transition, managing those patent expiries, and continuing to build our growth platforms and preparing for our new launches. Finally, post-2018, we intend to deliver sustainable growth and increasing profitability because of the shape of our portfolio. The $45 billion that we communicated back in May, we didn't pull out of a hat. We said at the time, this was essentially the result of our long-term planning. We are redoing our long-term planning at present like we do every year, and we can reconfirm that this is still our ambition. We had three strategic priorities that we presented to you two years ago.
As far as scientific leadership, our goals were to focus on three core TAs, which we have done and rebuilt, to accelerate some of our pipeline, and to transform our culture. Essentially, we showed you this graph at the time, and I told you that I thought AstraZeneca was a company that has quite a unique position in terms of our capabilities in biologics, in small molecules, in immunology, but also in protein engineering. In the meantime, we've added a fifth capability around devices. Essentially inhaled devices through the acquisitions of Pearl and the Almirall devices. That really positions us very well in terms of managing those products and potentially combining them. We've also been working very hard on building our personalized healthcare capabilities, and you'll hear more from Mene about this.
The last two years have really been full of hard work rebuilding these three core therapy areas. Internally, we told you we would be accelerating a number of projects, and we've done that. Also externally through business development, and you've heard about those quite a bit. I wanted to say a few words about these two therapy areas that we called at the time opportunistic, neurosciences and infection. Opportunistic doesn't mean they're not important. They are very important, but it means that we have to be focused on what we are going to do ourselves and focus our resources. There's a lot we can do in oncology, in autoimmune, respiratory, and also in cardiovascular diabetes. We have a lot of great science in neuroscience and also in the anti-infective fields.
You'll hear from Bahija a little bit later, for instance, about our monoclonal antibodies for the treatment of some infections. We want to create value out of those products and this science. Essentially, our business model is made of therapy areas where we will develop and commercialize ourselves. We might do alliances, we might collaborate, but essentially, we want to do the majority of the work ourselves and through therapy areas where we will partner and create value by licensing out, partnering, sometimes divesting. Public-private partnerships also would be considered. Essentially, it's part of our business model to create value out of these products, even if we don't do it completely ourselves. It's a fundamental point that I'd like you to keep in mind because you will see us do more of those partnerships like we did with the BACE inhibitor. There will be more coming.
Of course, some of this monetizing of our assets, the profit generated out of this, will be reinvested in our core therapy areas. We told you back in early 2013 that we would have 10 projects in late-stage development by 2016. I can tell you something, at the time, we internally debated quite a bit whether we would tell you we would double the number of projects, because we had six, and we said maybe we should double. We were so nervous that we might not be able to achieve this, that we in the end ended up with this 10 you've got there, even though our original ambition was to reach 12. In fact, we've reached 14. From a pipeline viewpoint, you can see we've made more progress than we certainly anticipated at the time.
Importantly, that's what hopefully today we'll show you, is that we have an R&D engine that is sustainable, that is productive, and will keep producing new projects and refilling the pipeline. I could go through many of the things that are on this slide. I just want to say two things. One is we have fantastic scientists in this company. We have scientists that have been historically with the company and have produced great medicines, but we also have new scientists that have joined us and tremendous talent. You'll hear more about some of the people who've joined us recently from Mene and Bahija in particular. It's really a tremendous achievement. The second is we have an organization that is extremely good at collaboration. Externally and internally.
Our Cambridge site in particular is going to be really transformational for us because it's bringing our large molecules and small molecules team together to collaborate on the site internally, but also externally with the great science that exists in the Cambridge area. If you look at our network, in fact, our R&D network, we've simplified it from what it was before. A lot of money has been saved, and Mene will show you this, improving our productivity, but also we've saved a lot of money that was invested in concrete and mortar, and we've redeployed these two projects. We essentially have now three strategic R&D sites. Two of those in Europe, Mölndal and Gothenburg and Cambridge. We intend to really run in an integrated manner.
In fact, we'll even have a daily flight going from Cambridge Airport to Gothenburg, so we can actually attract people who may be willing to come and live in Cambridge, live their family in Cambridge, and commute to work to Gothenburg. We have the ability to run those two sites in an integrated manner and have, again, the best possible talent working there. If I shift gear now and talk to you a little bit about our return to growth agenda. We had three goals at the time. One was to focus on our key growth platforms, accelerate through business development, and start the transformation to a more balanced specialty care, primary care portfolio with more biologics. I'd just like to say one word on the first line, the focus on the key growth platforms. Because the power of focus is actually quite incredible.
The progress we've made, simple example, with Symbicort is quite extraordinary. You'll hear people tell you that we're doing well with Symbicort because we are cutting prices, we are discounting, we're doing this, we're doing this. I'm sure during the Q&A, we'll talk more about it. Paul Hudson, the head of our U.S. business, is here, and you can grill him about what we are doing in the U.S. Of course, it's a competitive field. The truth is, we've actually focused the organization. We've put great people behind the commercialization of this product, the same for Brilinta, which is now getting momentum. We've invested behind these growth platforms, and they have responded. They are doing very well. We've built our pipeline also behind this.
I was at a meeting in Barcelona not long ago with several hundred physicians, and one of the top respiratory physicians in the world looked at me and said, "You guys had disappeared from respiratory medicine for a few years. It's nice to see you being back." This investment we've made in the pipeline also pays back because physicians want to be involved with companies that invest in science and invest in new medicines for their patients. Essentially, this is the shape of our business, and it hasn't. Well, it has improved tremendously. What hasn't changed is we still have a transition to go through over the next couple of years. The good news is the trough is not as low as it used to be because we've been working hard to refill and manage this transition.
The other good news is that, as I said a minute ago, the debate now is about the $45 billion, no longer a $20 billion by 2020. We reconfirm that by 2017, our ambition is to have sales that are broadly in line with 2013, and we do reconfirm the $45 billion. We have the pipeline that will enable us to achieve this. If you look at the launches that will take place over the next two to three years, we have quite a lot. Those are the submissions that we are planning for next year and for 2016. As you can see here, there's a lot of new products, but also a lot of line extensions. Importantly, now is the time to identify oncology for us as a growth platform. That would be our sixth growth platform.
The reason we didn't do it earlier is because to be a growth platform, you have to grow, and to grow, you have to have products that are launched and generate sales. It was too early, and we were not sure how quickly we could actually progress those products. Now we are just about to get approval for olaparib. We are about to file 9291 and then a number of other products. You will see throughout the presentations, we have a very rich portfolio of products in oncology. We believe this will be an important growth platform for this company. I want to say two words about this slide, which is an important one, because I want you to understand the change that is taking place and the fact that our business is going to have a different shape and different look.
First of all, there will be more biologics in our portfolio. About 50% of our pipeline is in biologics. If you have biologics, you tend to have a higher probability of success with these products. Number one. Number two, when you lose patent protection, you don't collapse, you don't evaporate like with a small molecule. You have a more durable asset. The second thing you see here is more devices, in particular respiratory inhaled devices. Again, those have a greater durability. Better probability of success, greater durability after patent expiry. Of course, you lose price power. That's clear. We see it today with Symbicort. You can still defend part of your franchise and turn it into an annuity if you're committed to it. This is really important when you think of the long term of the company.
Finally, there will be a more balanced specialty care, primary care, and therefore, over time, an increasing profitability. We've also done a lot of work around our culture and the engagement of our people and ensuring that everybody shares the same ambition and the same passion for what we do. I wanted to show you those numbers because we ran a survey, like many companies do, every couple of years. We ran it in 2012, we ran it in September, two months ago. These are the results. Essentially what we do, like other companies, we track a number of dimensions through questions that our people answer. This survey went to the entire population of the company, and we track level of engagement, the belief in our strategy, how people relate with their line managers, their leadership, et cetera.
You can see here is the favorable ratings we got are very high. We have 85% engagement, for instance, and we compare ourselves to, of course, 2012. You see here we've made progress. For instance, we went up eight points on this engagement dimension since 2012. We compare ourselves to the pharma norm. Those surveys are done independently, and we are five points above the pharma norm for this one. We compare ourselves across industry to what they call the high-performance norm, the best companies in terms of engagement and cultural dimensions. You can see here that we are either at the level or above the pharma norm and, in fact, even the high-performance norm. There's a couple of places where we can do better, certainly a very engaged organization, very dedicated. We've simplified the structure. We've simplified a number of layers.
We've worked on decision-making accountabilities, we still have a lot of work to do. There's no doubt about it. We've also worked on our systems. There's a lot of work for us still to do, generally speaking, we've made quite a lot of progress simplifying the organization, de-layering it, and providing our people with better systems and support. Essentially at the end of it comes down to this TSR, which we tracked since we rolled out our strategy early 2013. If you look at where we stand, we are certainly above the FTSE 100, also above our peer. Importantly, if you look at the peer group that we compare ourselves to from a TSR viewpoint on this graph, you see the global peer group, global pharma peer group. We are number three in ranking behind AbbVie and BMS.
If you look at the FTSE and you take the top 15 companies, they were the top 15 early 2013 from a market cap viewpoint, the top 15 largest market caps. We have a TSR that is ranked number one ahead of number two, Vodafone, by quite a bit, as this chart can show you. I'll just close here, and I wanted to leave you with only a few key messages. First of all, I just wanted to make sure you see by the end of today that you agree with me that we are on track with our implementation. There's no big announcement. Simply, we are focused on our work and we are making progress with the implementation. Two is we're building a different business, more sustainable, more durable, with durable assets, and more profitable.
The third one, hopefully by the end of today, you'll get a sense for it, is the pipeline value is rapidly increasing, that's what I call the future is coming to us very quickly, the rerating will continue. I think investors need to understand that because, of course, the value of the company will be reflected faster than some can believe. Finally, we continue to work to accelerate our return to growth. Our ambition is, as we said before, to reach the $45 billion by 2023. I'll now ask Luke to take you through the next phase of the presentation. Thank you.
Thank you, Pascal. The bulk of the slides that you're going to see for the rest of the day are really focused on scientific confidence and the evidence behind that confidence in the pipeline. Marc's role and my role is to try and embed that and give you a little bit more color in terms of the commercial consequences if we are successful with that pipeline. Just to recap our business today, it's a business which is concentrated around three therapeutic areas. You can see starting from the bottom there, CVMD, cardiovascular and metabolic disease. You have the business in lipids, which is CRESTOR, which continues to grow in emerging markets. You have BYDUREON, which along with some other products, represents our diabetes business. We also have Brilinta, which is growing nicely as an antiplatelet. The respiratory business today is essentially small molecules which are loaded onto devices.
Oncology is an area that we have not been that active recently. However, we are beginning to reengage for obvious reasons, and we see some opportunities to grow compounds such as Casodex and also Iressa. Geographically, we're also nicely balanced. You can see there the U.S. is a good proportion of our business, so we have critical mass in our operations there. That's attractive for our respiratory business, our CV business, but also in the future if you look at immuno-oncology, this is where you need to win first as a geography. Balancing that as well, we have a very competitive position in emerging markets. We're number two in China, Marc will cover that in more depth. Essentially, the key message of this slide is that we are well-balanced between emerging and established markets.
The pipeline and the commercial business is really built as we look forwards in respiratory based on these inhaled molecules which treat asthma. We also have an emerging pipeline in inflammation autoimmunity. Staying with respiratory, essentially the attractive components of a respiratory business, if you look at it from the position of the customer or the patient, the first thing that you need to compete in this area is a good combination of compounds. We have a strong legacy business in small molecules. We also have some attractive compounds which are coming through, which are small molecules, but we have a very competitive pipeline in biologics. The first one essentially is compounds. The second aspect is combinations. The capacity to have combinations which can be used in devices, and underlying that is the technical ability to put these compounds together and place them on devices.
You also have the access parameters that come from having a strong portfolio in this area. Ultimately, this is a point which is often overlooked, having competitive devices has a lasting benefit on our ability to compete. It's interesting because whilst, in the West and in established markets, there's been a long-term focus on the treatment of asthma and also COPD. You can see from these charts, the left-hand side shows evidence of patients' control and treatment in the G7 markets. This is the U.S. and top five EU, as well as Japan. The same as a measure of the control or progression of the disease in COPD, chronic obstructive pulmonary disease. The key point of these two sets of information shows that firstly, even in established markets, lots of these patients remain undiagnosed.
Secondly, of those patients who are undiagnosed, many of them, despite intensive treatment and a lot of investment on the part of governments and healthcare providers, remain relatively uncontrolled. There's clearly an opportunity here for new compounds which can improve patient care. COPD is another area as well. When you move from established markets and look more closely at emerging markets, this is an enormous challenge for the governments and the patients in these countries. The key parameter of COPD, of course, is a history of smoking. This is an interesting chart here. You can see the level of smoking by geographical region globally, and you can see Russia and countries like China. One statistic just to keep in your mind is one in three smokers live in China. You can imagine that consequence on the likelihood and the prevalence of COPD.
If you add on top of that, the other risk factors for COPD are pollution, either indoor from burning fuels to cook or an environmental pollution which exists in, obviously, societies which are rapidly industrializing. On top of that, the other risk factor is aging. If you look at a country like China or Russia, they have all three of these parameters together. That's ultimately when we look at these inhaled compounds, and also in the biologics which we're developing in this area, you'll see a continuing growth of the number of patients. In addition, we're not standing still. We continue in the middle box there to expand the number of patients in established but also emerging markets who can benefit from our compounds, either through label expansion or the generation of new evidence.
Ultimately, we have a number of new devices that we're developing that will make these compounds more accessible to patients. Many people often ask us, "Why do you continue to invest in devices?" This is a critical component because what's interesting about respiratory is it's both growing, it's a growth business, but it's also fundamentally a defensive business. It's defensive when you look at devices because for a physician to have the time to teach a patient how to use a device, get them using it properly, get them under control, that's a significant investment of their time that they often don't have. What this chart here shows that if you switch patients who are controlled onto a different device, they subsequently have a degrade in their quality of their control. You can see that by the difference of the green bar.
Also, you can see this little acronym SABA, which is the short-acting control that asthmatics use. The higher that use, the less controlled their disease is. Also on the right-hand side, less robust data, but this is surveys that we conduct and also third parties conduct amongst physicians. Clearly, the use and presence of the device is a key factor in their treatment. The point here is if all other parameters remain the same and we're able to be competitive on pricing, we have competitive molecules on devices that physicians know and trust. Looking forwards, we have a high-quality portfolio that Bing will cover shortly. We have an interesting agreement and collaboration with Amgen, which is a very productive interaction, and we're looking at developing compounds there which are potentially best in class for psoriasis and psoriatic arthritis.
Also, we are actively engaged in the development of phase II of compounds in Crohn's disease and ulcerative colitis, and we have some interesting compounds in lupus, which I'll show you shortly, along with RA. There is some unmet need. This is the commercial projection. It says future. It's a 10-year timeframe. You can see today, the bulk of this business is driven by the biologics and rheumatoid arthritis. This is the TNF compounds. Many of these patients are cycling through these agents and are not controlled to is an opportunity for a compound like Mavri to come in and change the way that these patients are treated. The yellow bar shows psoriasis. This is a debilitating condition for patients, a very visible condition for patients, and the treatments are substandard, we have the potential to change how these patients are treated. Ultimately, we have lupus there.
You can see today it's a very small business. A relatively small number of patients, but they really do have profound consequences that are associated with this disease, there's not very much available out there that is effective for these patients, we have a compound that could change these patients' lives. Ultimately, the inflammatory aspects of disease that impact the bowel, we have competitive compounds. This is an element which the investor community hasn't really had a lot of opportunity to see and get a sense of With CVMD, ultimately it is a combination of diabetes and cardiovascular disease. I start here with a slide on diabetes, the numbers here are striking. It's interesting, if I go back 20 years ago when I entered the industry, people were starting to discuss the impact of diabetes, no one really believed the numbers.
In every single conference that we now see, in every single type of report like this, which is from the International Diabetes Federation, shows that this population of patients continue to accelerate. As in the West, obviously, people eat more McDonald's, they're less active. They sit in rooms like this and look at PowerPoints all day. These are the elements that We've got a very healthy break food for you. You can see that there's a lot of change here in these markets. Critically, you start to see populations such as the Middle East, which as they become more wealthy, and you combine that with a genetic predisposition to disease, you start to see significant burdens for these patients. The Western Pacific. 100 million of that 138 million is China. These are diagnosed patients.
There's a whole set of patients who sit out there right now who are in a pre-diabetic stage who may not have been tracked or discovered by healthcare systems. What's interesting about this picture, before we go into our compounds for diabetes, is we have a product for kidney disease. Many of these patients will ultimately end up with kidney disease. That's a compound called roxadustat, and there's elements of this product which we think will be very competitive. In addition, Brilinta, we have a program to explore the efficacy of Brilinta in these patients. One of the other risk factors for diabetics is triglycerides. With Epanova we have a program to explore whether we can lower the risk for these patients. With our business in diabetes, what's interesting is ultimately physicians are looking for drugs which can lower glucose.
Whilst most patients in diabetes actually die of cardiovascular disease, the short-term complications come through high glucose. What physicians are looking for increasingly are compounds which are effective in lowering glucose, but also don't negatively impact the weight of the patient. That's what you see in this picture here. You're starting to see classes like the DPP4, which can lower glucose without raising weight. More importantly, compounds which sit in the classes of SGLT2s and GLP-1s growing strongly on the back of efficacy. We're well-placed with these classes. We have Onglyza, which is also now available in combinations with metformin, which is attractive to patients because they get two drugs in one pill. Payers also like this for many reasons, which I think are obvious. With FORXIGA, which was the first SGLT2 launched globally, we also now have fixed-dose combinations.
The third line there, we're taking these two innovative compounds, Onglyza and FORXIGA, and placing them in a fixed-dose combination, which we think will be very attractive to physicians and patients. We also have a good injectable business dominated by Bydureon, which we've now launched in a new pen, which is doing extremely well after the first few weeks of launch. Brilinta also has received a lot of attention. I won't go into depth on this, but to really comment on this slide is to essentially say we've had a series of good sets of news or evidence which have built the momentum around this compound.
The AHA meeting, which is actually going on right now, has further focused clinicians on our study, which is PEGASUS, which will ultimately show if we can expand the population that can be treated by this drug and also should have some impact in terms of how long patients are treated, broadly, more confidence in Brilinta as a compound to lower the risk for patients. Oncology is a fascinating area. There's a lot of activity naturally in the industry around this disease area. It's very clear if you look at these statistics, this remains a massive burden for healthcare systems. This chart is a combination of data sets, but what it shows is you can see on the bottom of each chart, the burden of these three tumor types in the U.S. and EU. We've also added some data here on China.
Naturally, the Chinese data is less robust, but even if there's some error there, you can see the scale of the challenges which are faced by markets such as China in terms of disease. What is also interesting, though, is these patients increasingly have the capacity to access these compounds and fund access to these compounds. Ultimately, if we're able to successfully commercialize this exciting pipeline, we will see a fundamental shift in our business. We'll go from being essentially a primary care company today to what we believe is the optimal mix between primary care, which is dominated by very focused diseases such as diabetes and respiratory, and also a specialty care business, which has a very healthy component of biologics and which we think overall is very robust and should grow considerably. In conclusion, our core therapeutic areas are aligned with our pipeline.
We believe that geographic structure that we have enables us to maximize these opportunities in a very competitive fashion. Ultimately, if we are successful in commercializing the pipeline that you're about to hear a lot more about, we should be able to generate significant value for shareholders and also patients. Thank you.
Thanks, Luke and Pascal. I'm pleased this morning to give you an update on how we're progressing on two important growth platforms, emerging markets and Japan. I will start with emerging markets and then cover Japan. I think all of you are aware that we've set an ambition, a target, to grow emerging markets business in mid to high single digits in this planning horizon. In 2013, we achieved that with 8% growth, and year to date, we're actually exceeding that ambition with 12% growth. What I'd like to do is share with you why we're achieving those results and why we believe these results are sustainable. The first slide here is, I think, a critical one for all of you to understand.
Of course, I think you're aware that we've had a history of long success in China. We continue to drive very significant growth there, with most of the recent quarters being actually at 20% or above. Critically, outside of China, we are actually now seeing emerging markets return to growth. In fact, in the third quarter, we're achieving our ambition of the mid to high single-digit growth, excluding China from that business. As we said at the last time we were together, that we've made, I think, very smart and targeted investments in both commercial and medical in key markets, in emerging markets. Those investments have paid off. In fact, we have, particularly in Russia and Brazil, which I'll share with you, we've seen strong growth this year.
Actually, we have 17 markets, 17 markets excluding China, that are growing at or above the high single-digit growth area. This growth is certainly driven by our focus on these key markets, but it is, as Luke highlighted, about having the right products in the right disease areas. This is another way to look at, Luke was sharing some of the patient numbers. This gives you a sense of the size and the opportunity from a business perspective in several of the key disease areas in emerging markets. Of course, we have the right portfolio. If I take a look at diabetes, on Luke's slide, it highlighted China with 70 million patients. Some estimates actually take that up to 100 million or more patients. In the Middle East, the prevalence rates in some cases of more than 20%.
Huge unmet need. We're having very significant success. We've launched FORXIGA in 10 markets so far, emerging markets. In eight of those 10, we're actually setting a benchmark for the best launch of a new product in diabetes. In terms of respiratory, particularly with COPD, just an enormous challenge. Luke shared with you some diagnosis and treatment rates in some of the major developed markets. If you think about China and the numbers of smokers that were highlighted, actually only a third of the COPD patients are even diagnosis and only 5% are treated. There's just enormous need to make a difference here. We've got a fantastic portfolio for our emerging markets in respiratory. We're very pleased this year in the maintenance market. We've now become the number one company in emerging markets, driven behind the growth of both Symbicort and Pulmicort.
In particular, we've seen really strong growth this year, in the last two years really, in China, where we're now over 40% market share and continuing to gain share. Brilinta is also a critical product for us in emerging markets. We've launched it in all the major emerging markets. This year our growth for Brilinta will be over 100% in emerging markets. I mentioned when we were together at the previous conference that scientific leadership and medical leadership is also critical for emerging markets. We've substantially increased our investment in that area. As one metric, in 2012, we had 140 MSLs across the emerging markets. We've actually almost tripled that now in 2014. What's even more exciting is the impact that these scientific liaisons are having.
We've seen a ninefold increase in the coverage of KOLs with highly experienced, highly qualified medical leaders, medical liaisons in our core areas of respiratory, diabetes, ACS, and also oncology, as we're also preparing for our future portfolio. What this translates into is actually generation of evidence in emerging markets. Really beginning to, at a much bigger scale, be able to share with physicians how disease is progressing in their countries, how it's being treated, and how our products could fit in and make a difference. In 2012, we just had a handful of investigator-sponsored studies. 2013, we had over 100 that were in process. Today, we're now over 200 investigator or externally sponsored research projects in emerging markets. If you look at real world evidence studies, we had, in 2012, about 44,000 patients in the emerging markets, in real world evidence studies.
That number is now approaching 90,000. A major change in a relatively short amount of time in the science and the evidence that's being generated in emerging markets. Actually, we're now starting to work with leading KOLs and opinion leaders in emerging markets to really push the boundaries of science even. As an example, we've started the iDiscover study, which is a very large 19,000 patients study, looking at how diabetes is really being treated, and now actually across the globe, it was originated in Japan and international, to basically understand where the gaps are and help physicians do a better job of treating their patients. We're really proud and excited about the progress we've made on our medical platform and scientific platform in emerging markets. Now I'd like to just take a look at a couple of key countries.
Of course, we start with China. AstraZeneca continues to be the number 2 multinational pharmaceutical company, number 2 company overall in China. We have the largest sales force in China, and we've expanded our hospital coverage in the last year by 40%. The fastest growth right now in China, of course, is coming not necessarily from the biggest cities and the biggest hospitals, but actually moving into what we refer to as emerging hospitals. These are maybe smaller hospitals, county hospitals, or hospitals in mid-size cities. It has really been impactful in getting medicines to patients that need it and driving our business. We're also very committed to making sure that we take advantage of that full portfolio of products, new medicines, that will be coming out of our R&D organization, which you're going to hear about over the rest of the day.
There is a significant drug lag today in China, which is a challenge for the entire industry. We're absolutely committed, as I said, to make sure we get our new medicines into China as fast as possible. Today, we have over 70 clinical development projects underway. We've just opened our second major manufacturing facility in China to make sure that we have the capacity to meet what has been really strong growth, and that we intend to continue to drive. To put that in context, you can see that the combined commitment and strong commitment and investment with a really strong leadership team in China, local leadership team in China, and our overall capabilities is we're able to derive really outperform the market by a significant way.
Russia is another critical emerging market for one that we do believe continues to hold growth opportunities now and will in the future. It's a large market with a middle class where people and with significant health challenges in the country. One way to think about this, in each year about 600,000 people die from an ACS event in Russia. If you were able to treat those patients like the way we treat them in the Nordics, in Sweden, you'd only have 150,000 people dying. That's a massive opportunity to make a difference. Given that need, you can see, again, we've returned to double-digit growth strongly this year in 2012. That's been driven by our performance in the retail segment, which is the largest segment of the Russian market, and we're the fastest-growing MNC in that segment. We are expanding access to our products.
We now have patient affordability programs running in 27 different regions across the country. We're investing in clinical trials. Russia is participating in most of our overall global programs, we're looking to continue to expand that. We're making a significant investment in manufacturing with a major new facility under construction. Another exciting accomplishment for us this year is in Brazil. In the 2010 to 2012 timeframe, Brazil was impacted with the launch of generics for CRESTOR and NEXIUM and several other key brands. We've worked through that and actually have done a great job of stabilizing that business and have now, through the launches of new products, returned Brazil to growth.
This is a chart that looks at retail market sales, you can see that not only are we growing again, but we're actually now growing faster than the reference market, which is the multinational companies that are promoting innovative brands. As I mentioned, this turnaround is driven by our new products as well. We've had success with Brilinta, significant success with Brilinta in Brazil. You can see we're tripling performance of Brilique. If you look at FORXIGA, which was launched this spring, FORXIGA is on track to be the best launch of any diabetes product ever in Brazil. I'm really excited about the possibilities for this franchise there. I could give you a number of other examples from across emerging markets.
We're not only good at continuing to support and drive our established brands, which are still growing in many markets, but we're showing that we can be fully successful with our new products as well. Now I'd like to move over to Japan, where we will have another example of great ability to drive performance of our products. We're seeing half of it for the last couple of years, we're seeing continued success with our primary care portfolio in Japan. CRESTOR and NEXIUM are already number one and have been in their category. CRESTOR, NEXIUM, and Symbicort are all growing strongly and have helped move AstraZeneca from being outside the top 10 in 2012 to now in the top 10, ranked eighth within the market. Our business in Japan is not just about primary care. We have a very sizable oncology business in Japan.
We have been a leader for many years, actually, in Japan. We're still in the top 3 companies there. We have leadership in breast cancer, in lung cancer, a very important position in prostate cancer, one of the largest sales forces, where we're seeing an erosion of our sales because of generics in for Arimidex and Casodex. We have really the strength, platform, and capabilities, both commercial and from a clinical medical perspective, to really take advantage of the oncology portfolio you're going to hear about later today. As just one example, I wanted to think about the opportunity that AZD9291 represents in Japan. As you probably know, the EGFR mutation is quite prevalent in Asians. Maybe a third of Asians have that mutation. Iressa is the number 1 product in non-small cell lung cancer with really a dominant position in the Japanese market.
To be able to launch a product like AZD9291 into this product can make a real difference for patients. We've done a great job in Japan in diagnosing people with the EGFR mutation. They've gotten very good treatment with many of the patients on TKIs. The number of patients that are either resistant already or going to become resistant to the TKIs is very significant. The potential to make a big difference for patients is huge. We absolutely have the right team and capabilities to make that fully possible. In summary, we are continuing to see strong growth in our emerging markets and through our key brands in Japan. We believe that we can continue to drive this growth based on the underlying need of patients, especially in the emerging markets, and also based on the products and capabilities we have.
As Luke has highlighted, we have a very diversified presence across a broad range of geographies and a broad range of products. We're having success in a broad range of geographies and a broad range of products. We've invested significantly over the last two years to strengthen our commercial and scientific capabilities. I think you can see from the results that we're having, that those investments are really paying off. Thank you.
Thank you, Marc. As I said, we try to give you an overview of where we are with those growth platforms. We could not cover everything, of course. We are here to answer any questions you have about what you saw, also any other products that was not discussed today. I hope there's a microphone close to Paul, because I suspect, Paul, there's a number of questions that are going to come your way. Who wants to get started? I'd like to invite James Faucette. Also Tom, are you joining us? Sorry, Mondher is joining us. Alexandra.
Thank you. Alexandra Hauber from UBS. I have two questions. Starting with you, Pascal. Since 2018 is obviously quite an inflection point for sales, just trying to put your comment into the improving profitability from the new portfolio. Should we expect the inflection point for profitability also to come in 2018, or is that going to come later, given that 2018 may start as a relatively depressed cost space, and therefore require investment? The second question is for either Marc or Luke. Of course, the numbers which you're giving us about the COPD opportunity in China is staggering, particularly looking at the data you just said, 30% diagnosed, 5% of those treated, and I would guess those who are treated probably don't even get modern inhalers. How on earth are you going to tap this opportunity?
Is what we've seen happening on insulin in the last 15 years anything like a guide, or can you just tell us how quickly this opportunity can be tapped?
Do you want to get started, Marc or Luke?
Okay. Sure. I'll take the second question. I think the first thing is that we're doing is that we're not seeing the challenge really for COPD as a China challenge. We're actually seeing it as a global challenge. We're going to be marshaling the resources of the full respiratory commercial and development capabilities to think about how we can expand education, expand diagnosis of COPD in China. I think the best example actually to look for is in our own company, what we've done with PULMICORT RESPULES, and the use of nebulizers in hospitals. We've got almost 4,000 hospitals now that have nebulizer centers that have been built up over the last few years in a very rapid fashion. It's making a huge difference for children primarily, that are suffering from asthma.
In a short amount of time, we've demonstrated that we can really get our messages out and get centers set up in hospitals. I think we're going to take this challenge on with getting the right type of diagnostic equipment, doing the training with primary care physicians, and really drive that forward.
It's very much a question of investment in shaping the medical paradigm in China in particular. Often people say, "We've been told you do well in China because GSK is not doing so well" or whatever. GSK is really not the issue. The issue is, in fact, we need to shape medical practice. In fact, having two companies doing it would be far better. As Marc said, we need to invest. Some of the things we need to do are pretty simple. If you go around China, you visit hospitals or doctors that don't even have spirometers, so they can't even diagnose patients. Very simple things like making sure they have the right tools in place and they're trying to diagnose COPD and et cetera. This is really the priority so those patients can get diagnosed. When they are diagnosed, they will become treated.
It will take some time, but we'll get there. To address your other question, Alexandra, our plan is that you would see a steady increase in profitability starting in 2018 in the years. There's a heavy period of launches, as you saw from the graph we showed you. In particular, if we're successful with our oncology pipeline, we'll see, starting in 2018 to 2023, a profitability improvement over time, yeah. Sorry, Andrew first, and then Sachin.
Thank you. It's Andrew Baum from Citi. Three questions, please. Firstly, I understand that in the U.S., you're marketing FORXIGA with zero copay to some patients. How should we think about transitioning away from that in terms of, given the extraordinary launch you have, how much is price sensitive? Second, could you talk to how you expect SYMBICORT to be impacted by the increased focus on ADVAIR, given the rebating plus the BREO marketing next year? Finally, you referred to spirometry as increasing diagnosis rates for COPD. The industry has been phenomenally unsuccessful in getting spirometry used historically, and I'm thinking of obviously GSK. What are you going to do different in order to get something that's so simple adopted by clinicians? What's the barrier here?
One final thing is just so I understand, is Symbicort on the NRDL in China, if you could remind me? Thank you.
Paul, I knew you were going to get some questions. Do you want to address the first two, and then Luke and Marc may address the other two?
Will do, Pascal. Thank you for reminding people they can grill me at any point. That's very kind of you today. There's a couple of things. Firstly, the diabetes market is incredibly competitive, I think as you know. The SGLT2 market, even more competitive. We've taken a stance to make the co-pay zero, as have the competition, quite frankly. It is not an indefinite promise to the market. It really gets blended into whatever rebates we decide to offer over time. We'll wait and see how the market plays out. We'll wait and see how well SGLT2s are adopted. At the moment, they're the fastest-growing class in type 2 diabetes in North America. Thank you, by the way, for recognizing it's the number one launch since Xeljanz, and it's the number one launch in the U.S. of any product this year, so thank you for that.
Symbicort, it's been an incredible year also. High 20% plus growth in Q3. We've worked very hard at making sure that we're in good shape for next year. There is competition. I can't comment on GSK's decisions on rebates. We make assumptions across our portfolio. The average level of rebate or price decline over 2015, it'll be low single digit. The interesting point, I think, for everybody to watch is what happened after we were unsuccessful in claiming United in July, at midyear this year. In fact, if you look at the data as recently as yesterday, Symbicort is at an all-time high on newer combinations. The team, the level of investment stepped up, the level of prioritization has stepped up, and we're at an all-time high on all leading indicators for Symbicort, irrespective of competitive moves in the marketplace.
Thanks, Paul. James, do you want to comment maybe on COPD in general and Marc specifically in the emerging markets?
I think the issue overall is COPD is poorly diagnosed in a number of places. We see that in the debate, which is taking place at the moment with the overlap syndrome and people trying to diagnose better asthma, COPD, and levels of reversibility of the airways. That is an area where we indeed need to generate more evidence and help physicians better understand where they should be treating patients. I think in China, I have a little experience, as you know, of China myself. I think we are planning an integrated campaign. It's not simply spirometries. Nebulization has been immediately effective, as Marc has said.
We're planning a massive, coordinated, integrated campaign with the national members of the associations, respiratory societies generating more RCT evidence. Demonstrating where you need to have maintenance therapy. Investing clearly in MDI type devices. Patients can leave hospital when they've been treated on a nebulizer, when they may have issues with continuity, and they can use a spacer, for example, for the younger population. It's not one element that we're looking at in China. It's a sustained, integrated campaign, which we're planning over the next three to five years.
Sorry, Marc, go ahead.
Two quick points. Symbicort is on the NRDL and on all of the province reimbursement lists. I think the other key thing that we're going to do differently or need to do differently is we need to go where the COPD patients are. Historically, ourselves and our competitors have focused primarily on the big city, big hospitals, but actually, COPD patients tend to present more in the mid-size to smaller hospitals, county hospitals, emerging hospitals. We now really have the scale to actually go after and educating those physicians. Combined with the integrated program that James has talked about, I think we can make a difference. It is something we have to stick with. It is a harder change process than the asthma, where you get a more sort of an immediate impact.
We believe we've got the resources and the, let's say, the package of integrated resources to make a difference there.
There's a lot of work that needs to be done with patients, and it will take a lot of time. It's a bit like diabetes. 20 years ago, diabetic patients were told by their physician, "If you don't lose weight and if you don't take your tablets, I will put you on the needle." Essentially people felt guilty, and they felt fearful of the needle. It's of course, the wrong way to approach the treatment of diabetes. COPD patients, they feel sort of a bit guilty and hopeless. Guilty because they've been smoking. They think it's their fault, and hopeless because they don't think there is a solution for them. In fact, their life is quite miserable, and there's a lot we can do to help them. It really takes a lot of work to shape this.
It's not going to happen overnight, that's for sure. Sachin?
Thanks. Sachin Jain from Bank of America. Three questions, please. First, you've reiterated your 2017 targets today. When you first published them, I think there was limited pipeline contribution within those. Given the pipeline progress you've had this year and understanding launches will be very early, just wanted to understand whether the mix of that 2017 number has changed at all. Is there more pipeline and you're more cautious on the base? Just any color there. Second question, you've referenced AZD9291 as first patient to filing in two years. You've also talked about six filings in oncology. I just wonder if you could touch on what your stretch target may be. Is there anything in the early stage pipeline that you see fast to market strategies for?
The last question is on Brilinta in China. Memory serves me right, Plavix is selling $400 million-$500 million in China. You're clearly not. We understand the hurdles in the U.S. well. Just what are the additional hurdles in China? Thank you.
Thanks, Sachin. Marc, should we start with Brilinta-
Sure
We'll move to Mondher?
The key, it's actually a very simple barrier. Brilinta is not on the NRDL. Probably many of you are aware that China, there's been a delay in the updating of the NRDL. The last NRDL was published in 2009. We have excellent progress with Brilinta in China. It's actually one of the best launches in the last few years, even though we haven't had the reimbursement. Really well-positioned with KOLs. Really strong coverage of the 1,000-plus PCI centers in China. We're hopeful that in 2015 that the government will in fact update the NRDL. There's a real unmet need. A number of products, not just with AZ, but a number of important products that need to be accessible to Chinese patients.
I believe that once we get that NRDL, we'll be able to really rapidly progress in China time, because you know after you get the NRDL, you have to then get the 30-plus provinces. It's a two-year to three-year process. That's basically the barrier. The acceptance by physicians has been really good.
Mondher, any-
We'll have after the break more deep dive on the oncology pipeline and the different dates. To your question about 9291, yeah, actually the submission during Q2 next year will basically make 9291 the fastest ever drug to be developed and submitted for an ADA approval in the U.S. That speaks to the value of the drug itself and the benefit it brings to patient. Of course, the excitement that physician and the community and regulatory agency have about it. Beyond 9291, I think for the rest of our late-stage pipeline, our strategy is really to develop first-to-market strategy and to be the first and/or best-in-class.
In each and every asset that you will see in the afternoon, we are thinking about smart, and in the same time a fast approach to get the drug approved in a small niche indication before we expand into the other line extension and maximize the value of the asset.
We could revisit your question if you want, Sachin, when we get to the oncology pipeline a bit later. Luke, do you want to cover?
Yeah, I think the 2017, it's broadly what we signaled in the past. There is some movement within the classes, but again, we're very confident about the oncology opportunity as well as the diabetes opportunity in compounds such as Saxa-Dapa.
It's not a huge amount of sales coming from the pipeline by 2017, as you can imagine, starting to ramp up after that, of course.
Thank you. James Gordon from JPMorgan. Three questions, please. One was about the base oncology business, because I saw the comment in the release this morning that you could have 25% of sales from oncology by 2023. If I look what that implies, it implies about $11 billion, whereas your previous risk-adjusted oncology contribution was about $7 billion. Does that mean that the base business in oncology could actually grow from now to 2023?
Mondher, do you want to cover this one?
Yeah. Again, maybe we'll have a better sense once we have the oncology presentation. Clearly, we have ambition to become a leader in this field. The number of NME we plan to launch in the next six years is quite unique and unprecedented, six NMEs in six years. Clearly, for assets like 9291 or Olaparib, but also, of course, the IO, we have a life cycle management plan that plan to develop the molecule in the late stage, but also to expand into the earlier stage in first line, but also in adjuvant. If you think of this potential first, and at the same time, consider that immuno-oncology, there's a consensus today among physician experts and analysts that immuno-oncology will represent the mainstay of cancer treatment in the 20 years to come.
In theory, it's a treatment that could work in any tumor type at any stage of the disease. There is clearly a potential that can range probably from $20 billion-$25 billion, for the more conservative, $20 billion-$25 billion to probably up to $40 billion for the more ambitious forecast that you can think of a market potential. We have an asset that today is considered as behind in terms of the late stage advanced disease. When you think of other new indication, and in particular, when you think of earlier stage of the disease, we are the first mover, and you will see more of this in detail.
overall, if we think of a market that has roughly $30 billion-$35 billion, if MEDI4736, our immuno-oncology is a market leader in some of these assets, yes, I think we are ambitious about the oncology franchise in 2023.
You should also consider that we have now more data around our new product pipeline. The value of the new products in oncology, we see more value there. The numbers we communicate to you, they are risk-adjusted numbers. Of course, from one year to the other, they change because if we have more data, then we become more optimistic. The probability of success goes up, so the risk-adjusted sales go up. It's clear that with a number of our products, we are more confident. A year ago when we did our long-range plan, olaparib was not approved. It's not yet approved, but will soon be. AZD9291 has progressed. You should not compare numbers from last year's plan to this year's plan.
If I understand correctly on that part, it is an upgrade on the pipeline aspiration for oncology rather than that you have high aspirations for what the oncology base business does.
Yeah.
Thank you. The second question was just, you were talking about the stickiness of devices within respiratory and how it sounded like having newer devices could be a protection against generics. Does what we've seen in the U.S. in terms of the speed with which patients have moved from Advair to Symbicort argue against that, as it seems the patients are quite fluid in the device that they'll use?
Yeah. Maybe James, you want to comment on this, but the general comment I would make on this one is that I didn't necessarily mean stickiness. I meant durability. Because for me, a device, the inhaled device is similar to a biologic or closer to a biologic than it is to a small molecule. Of course, you can lose your business if it goes to an analog. Generally speaking, what happens is that if you are ready to compete, you lose price power, so you lose price, but you don't get to pennies and cents like small molecules. You can actually compete and maintain your share, your volume. You lose some volume, of course, but you don't lose 100% of the volume. You lose price and you lose some volume, but you retain a share of the business.
Essentially, the point is, instead of collapsing like happens today or will happen with NEXIUM or CRESTOR in the U.S., you have a slower decline, which enables you to redeploy to new products. You don't have those cliffs to face like NEXIUM and CRESTOR, but there will be some shifts, of course. Having said that, maybe Ruud Dobber could comment with his experience in Europe, because in Europe we're facing analogs left, right, and center, as you know. Maybe you want to share some of the experience we have with SYMBICORT there.
Yeah. We have, as probably most of you know, two analogs available in Europe. One product from Teva, the other one from Orion. We clearly see that there is pricing pressure. So far at least, we see from a volume market share perspective that it is very limited what the competition is doing. It doesn't mean, of course, moving forward, that that is a sustainable position, but we are defending ourselves quite hard to maintain the availability of the product in the marketplace. Wherever it is necessary, we're willing to decrease our price to a reasonable level. So far, the strategy is working quite nicely.
You have to achieve three things. One is that we are ready to compete, we don't let the business go, so including on price. Two is we stay focused and committed to the product. Three is we have good devices because they also help us in this competition. In that context, acquiring Almirall suddenly is very useful for the DPIs because the device, general device, is very well appreciated by patients, and the pearl technology on the MDI front is also a very attractive formulation. That suddenly will help us.
Thank you. Just a final question, which was on emerging markets. Very strong growth, but presumably, your spend in emerging markets is growing quite strongly as well. With the bottom line EPS targets in the medium term, are you going to be able to continue to grow your emerging market promotional spend at the pace you have grown it for the last few years? If not, could that mean a slowdown?
I think you should see this year as a year of. It's a very big investment year. We're launching several things at the same time. We are, of course, continuing to launch Brilinta or relaunch Brilinta. We all know that relaunching costs you typically more than launching a product. Finally, we are gaining traction, including in the U.S. In the last few weeks, we've seen some nice pickup with Brilinta. We're all very excited about this. We're launching Brilinta still. We're launching diabetes. We're still relaunching Symbicort because we had been divesting and with the results we saw. We're launching or we're accelerating growth in the emerging markets. Next year, suddenly, we will have to start optimizing our investment, and we'll gain traction from some of our products.
We don't expect that we'll keep investing to the extent we do over the next two to three years, that's for sure. In the emerging markets, we're also growing and generating profitability improvement market. If you want to comment on this one.
Last year, we said that we would basically broadly maintain our profitability. I think we're still confident we can do that over the planning period. A lot of the investment and the spend in the last two years has been really a catch up or getting the platform in place. You can look at the MSL example. I don't think we need to get to 18,000 KOLs. We've made the investment and significantly expanded the coverage. Now it's going to be about sort of improving what we do with those platforms. In a number of countries, we've also, we're not at scale from a sales force. We've scaled up. Then we should be able to moderate the cost growth over the period.
Thank you.
Really see it as a sort of a launch mode because we have those two massive headwinds coming our way with NEXIUM and CRESTOR generics in the U.S. We've been trying to kind of move the rest of our business as fast as possible. It is under a strong momentum by the time we face NEXIUM and CRESTOR expiries.
Thanks.
Maybe the last question. Thomas, looking to you to tell us. Yeah.
Thank you. It's Matthew Weston for Credit Suisse. Just one question, please, and it's a big picture one. You set out your targets and effectively reiterated 2017 being flat, then clearly the very aggressive aspirational target for 2023. What you've also set out is a lot more pipeline success than you had previously anticipated, also some very high levels of investment in the end market franchises. I guess, for me, the question is going forward in the medium term, so during that 2017, 2018, what's your priority as Chief Executive? For me, it's either about investing for the commercial success of the product effectively irrespective of earnings, and investors should be very comfortable with that potentially because of the long-term possibilities. Is it about being able to pay the dividend?
Are the two actually completely disconnected because we don't need to worry about dividend cover during that period because you can pay the dividend out of the balance sheet? I'd just love to understand where you see the real priority being about investing for commercial success or holding back to make sure you have sufficient earnings to cover the dividend.
Well, it's a great question, and I think for me, the story is pretty simple, is that we're asking our shareholders to be patient because we have a couple of years of transition when, unfortunately, as I said, we're facing NEXIUM and CRESTOR patent expiry. Despite our best efforts, we cannot overnight replace NEXIUM and CRESTOR. Those are tremendous products. They're very profitable. When they go, they really leave a big hole in the till, if you want, in our wallet. Essentially, we're asking people to be patient, and the deal as part of this is we are going to secure the dividend. We are very committed to the dividend. We're going to secure this. As managers, we always have this challenge to manage the long term and the short term, and all of us have to do this.
Of course, this challenge is a little bit more acute in our case because, again, losing NEXIUM and CRESTOR is challenging. Essentially, that's what we're going to do. We are going to protect our profitability, as we said. We're going to deliver the dividend, and we are going to redeploy our resources and launch our new product successfully. I think we should be helped by a few things to do this. One is we'll continue focusing on productivity improvement. Two is we certainly will monetize some of the science, some of the assets that come with our pipeline. We've started with the base. We'll do certainly more of this and reinvest this money and partner when it's required, and certainly make choices and redeploy our resources, reprioritize as we go. To me, it's part of the same story, is be patient. We're managing this transition.
We'll protect our profitability, we'll protect the dividend, and redeploy for future growth.
Thank you.
Okay, we'll go ahead. Thank you very much.
Okay. Should we get started? Yeah. Good afternoon. Glad to be here to see many of you here again. During the Investor Day last year, we shared with you our strategy and our pipeline, and since that time, we have made tremendous progress. I'm really pleased to be here and to give you an update. As Pascal mentioned earlier, respiratory is one of our core therapeutic area. We continue to focus on asthma and COPD, and we are building IPF. These are the diseases with high unmet medical need. Marc and Luke discussed that just earlier today. Our strategy is threefold. First, in the near term, is to deliver inhaled therapies. We're going to expand. Expand with the innovative precision therapies. In the longer timeframe is to transform the disease management. We aim for step therapies in the patient outcome.
That strategy is supported by a very robust pipeline that you can see from here. If you look at the bottom right, there are three marketed products for respiratory. Above that, six phase III programs, all progressed since the last Investor Day. The Almirall and Pearl acquisition brought in three inhaled therapies, and we advanced three biologics into phase III over the last 18 months. If you look at phase II in the middle, there are 11 programs in phase II. This slide here tells you a story about our inhaled therapies for COPD. Our portfolio has the potential to cover all disease severities, from mild to moderate to severe, and the patients with different risks of exacerbation. I would like to walk you through here.
For patients who are mild to moderate, in need of maintenance therapy, and are still at lower risk of exacerbation, we can start them with a bronchodilator, the Symbicort. You see the green box. When the patients get severe, symptoms get severe, it is uncontrolled, you need more bronchodilation. Dual bronchodilators, LABA-LAMA combination, can be offered to this patient population. For patients with high risk of exacerbation or have exacerbations, they need an anti-inflammatory, the ICS. There is LABA and ICS, Symbicort, currently used for patient of that patient population. For most severe population, severe symptoms, also frequent exacerbators, you need all three classes. With LABA, LAMA, and ICS, we are developing a triple combination in one device with a unique formulation from Pearl. That is PT010. The device platform is also discussed earlier, provide choices to our patients.
We are developing both dry powder inhalers as well as the metered dose inhalers, a more active device. The DPI, the dry powder inhaler, is commonly used for patients who are mild to moderate. The more active ones, MDI, preferred by elderly, also by the patients with more severe disease. It is all about choices. We are the only company have both DPI and MDI for LABA and LABA-LAMA. We have a range of different DPIs. This way to ensure we have a better chance to meet the need and the preference for those patients. Now, for asthma. The story is very similar for our inhaled portfolio for asthma. This can potentially cover all disease severities. We have leading brand of the market today. There is Symbicort, LABA and ICS. That is in the middle box, it is red.
We are looking to expand that Symbicort in a mild population where as needed can benefit the patients. In our portfolio, we have options for LAMA and ICS. The evidence for LAMA in the treatment of asthma is strengthening. And there is opportunity also for triple therapies in asthma, in particular in patients who are not well-controlled with a LABA and ICS alone. We have that option also for patients with asthma. Devices, same story. We are developing both DPI and MDI for patients with asthma, provide choices to the patients. In terms of severe asthma, we have a number of innovative biologics. They are targeting distinct patient subsets with diagnostics. I am just showing you one example here. That is from our own data analysis. Using two biomarkers, one of them is periostin that predicts the TH2 disease. That is shown on your Y-axis. Or blood eosinophils to predict your eosinophilic asthma.
Two biomarkers, you can segment the severe population into four segments, four subgroups. A and C patients have high eosinophils, and A and B have high TH2 disease. Benralizumab targeting eosinophils could be potentially used for segments A and C, while tralokinumab and IL-13 could be used for A and B. With two, we can cover potentially 70% of the severe asthma population. But we have others, for example, anti-TSLP. We are co-developing with Amgen, they are upstream. Our portfolio has the potential to cover all the patient subsets for severe asthma. We are quite excited about one of the molecule in the portfolio, the mepolizumab. It is in phase III for severe asthma and diagnostics targeting patient subset. This is the only IL-5 receptor antibody. We have now published our phase II data in The Lancet Respiratory Medicine just recently.
mepolizumab induced potent reduction in eosinophils, and that translated into clinical efficacy, not only of reduction of exacerbation, but also improvement in lung function and also asthma control as measured by ACQ-6. The rate of reduction is shown on your right side. It correlates really well with baseline eosinophils. The higher eosinophils, the higher reduction of the exacerbation. This fit pretty well with how the molecule works. If you look at the cutoff at 300, with the 300 cutoff, we see about 43%-57% reduction in asthma exacerbation in this patient population we tested, which included both patients on medium ICS and LABA, as well as high dose ICS and LABA. When you go higher, you move to 400 cutoff, now we saw 70% reduction in the exacerbation. You go even higher, 500 cutoff, 78% reduction. The range is 43%-78% reduction of asthma exacerbation.
The phase III is ongoing, is on track. We expect to complete phase III in 2016 with a regulatory submission. mepolizumab is also in phase III study for COPD. I would like to highlight that this is a new biology here. This is the first antibody to show eosinophilic inflammation reduction. Traditionally, people think about COPD, they think about neutrophils. What we and others found that one-third of patient populations have elevated eosinophils, therefore, we tested that in our phase IIa clinical study. mepolizumab was the first antibody to demonstrate it can improve lung function in those patient population. That data, along with the strong proof of concept in asthma, led us to move this molecule into phase III in COPD. We are actually recruiting patients in phase III clinical studies. We also advanced tralokinumab to phase III for severe asthma.
This molecule has a potential to target a different patient subset that has TH2-driven disease. In our phase II clinical study, we believe that we have identified a potential responder patient population, and also promising biomarkers. In that responder population, we have seen efficacy across. Across from exacerbation reduction, lung function improvement, asthma control, and quality of life. phase III will further characterize the response in that patient population, and it's on track for completion 2017. tremelimumab is also in phase II clinical study, ongoing study in IPF. That's our respiratory portfolio. You can see from here, equally robust here is our inflammation and autoimmunity portfolio. We have not publicly discussed this portfolio a lot in the past. What you see here to your right side, three phase III programs and seven phase II programs.
Most importantly, we have had a number of positive data from this portfolio, positive phase IIs and positive phase IIIs recently. I'm going to highlight four molecules that we have had more recent data. Starting here is lesinurad, that's for gout. Gout affects about 15 million people in the major markets. Of those, 40%-70% cannot achieve their treatment goal of uric acid less than 60 milligram per deciliter. The disease is associated with the elevation of uric acid. Uric acid accumulate from crystals and depositing the tissues in a joint, for example, kidney, causing damage. lesinurad offers a new mechanism action. It is a uric acide reabsorption inhibitor. It increase the excretion of uric acid, which is different from the standard of care. Standard of care controls the production. We believe that the most appropriate way for treating gout is through a combination approach.
That was tested in phase III, and the top-line data is shown on your right. CLEAR 1 and CLEAR 2 , lesinurad was used as an add-on therapy. Two doses, 200 milligram and 400 milligram as add-on therapy to allopurinol. Both doses met the primary endpoint, and you can see significant higher proportion of the patients can achieve their treatment goal when added on to the allopurinol versus allopurinol alone. Adverse event profile was very similar, including the renal adverse event for the 200 milligram plus allopurinol versus allopurinol alone. We do have observation here to see serum creatinine increase in some patients. However, most of the patients resolved and without interrupting the study drug. The plan is to file before the end of the year for lesinurad as add-on therapy. In lupus, this is a disease where the unmet medical need is extremely high.
We have two innovative molecules. First one, sifalimumab, that's on your left, targeting soluble interferons and utilize the interferon alpha block their functions. We have completed a phase II-B clinical study. This has achieved the primary endpoint and also met multiple secondary endpoints. What you see on your right side is anifrolimumab, which is more broadly targeting. Anifrolimumab targeting the receptor. By blocking the receptor, you can block all the type 1 interferons, not only alpha, but also beta and omega. We have completed the phase I study, open label study, looking at the pharmacodynamic impact of PD markers. Indeed, as we expected, we saw a 70%-90% suppression of the gene signature with anifrolimumab versus 30%-40% for sifalimumab. This give us a potential. Potentially, anifrolimumab could have even better efficacy than sifalimumab. We want to get into some more details.
With the sifalimumab phase II-B data, the primary endpoints and also some of the secondary endpoints. The primary endpoints are looking at SLE Responder Index, as well as some secondaries looking at organ-specific improvement. The green lines highlight the primary and secondary endpoint, SRI-4 as well as secondaries SRI-6 and SRI-8. SRI-6 and SRI-8 are more stringent endpoints. We saw statistical significant improvement for SRI-4, SRI-6, as well as SRI-8. Also in the current study, this is diagnostics. Companion diagnostic incorporates the study looking at the patients who have increased gene signature. Those are interferon alpha positive genes. We saw numerically increase in the effect size, ranging now from 15%-21% for SRI-4 to SRI-8. Once again, they are statistically significant. Right side shows you the organ-specific improvement, is quite obvious. Day 1, before treatment, and six months after treatment. The skin improvement is measured by CLASI score.
We saw a treatment differences of 24.5%. These are for the high dose, the 12 milligram dose. Again, this is significant. The more detailed data will be shared today at a scientific conference. That's our American College of Rheumatology in Boston. It's going to be a late breaker oral presentation by our investigator. In rheumatoid arthritis, we have a first-in-class anti-GM-CSF antibody. Despite the fact that there are multiple biologics on the market today, the remaining unmet medical need is high. For example, if you look at ACR50 is 50% improvement in signs and symptoms. 45%-74% of patients could not achieve ACR50. Mepolizumab has a novel mechanism of action. It blocks the function of macrophage and inhibit the functions, and also blocks the macrophage survival. Macrophage is one of the major drivers in the disease.
Phase II-B in DMARD-IR has been completed with positive data. We met co-primary endpoint. You saw on your right graph, ACR20 at those response, highly statistically significant. Also met the co-primary endpoint at DAS28 , and all of the secondary endpoints, ACR50 and ACR70. The onset of action is quite fast. After single dose, after one week, we begin to see efficacy. We also saw significant improvement in patient-reported outcome. Moving from RA to psoriasis. Just last week, we and our partner, Amgen, announced the second positive phase III for brodalumab in psoriasis. Brodalumab targets interleukin 17 receptor. By binding to the receptor, you can target multiple cytokines at the same time. In addition to psoriasis, brodalumab is also in clinical studies, phase III studies for psoriatic arthritis. Two trials ongoing, remain on track, and also in phase II for asthma.
Both phase III trial clinical studies achieved positive results. You see on your left, there's a first phase III clinical study, AMAGINE-1. AMAGINE-1 compares brodalumab with that of placebo. Primary endpoint is PASI 75, and secondary is PASI 90 and PASI 100. I really want to draw your attention to PASI 100, the blue bar, 200 milligram dose. 41.9% of patients achieved PASI 100. That's total skin clearance. This suggests brodalumab may offer a new level of skin clearance. That's what really patients needed. The second study, AMAGINE-3. Top-line results is shown on your right side. This is a head-to-head study with STELARA or ustekinumab. The reason we choose STELARA, because up to now, STELARA appears to have the best efficacy among the multi drugs.
Two doses, 210 and 140, demonstrate the superiority of the STELARA and with the PASI 100, that's total skin clearance. The study also met the primary endpoint, that's co-primary endpoint, which is PASI 75, comparing with the placebo and other key secondary endpoints. There's a third study, it's going to read out before the end of the year, we report the data as soon as we have them available. Our portfolio molecule also have a rich life cycle opportunity. I'm showing you some of the example here. That's because for immunology, for respiratory inflammation, autoimmunity diseases, they often share biology, they share common disease pathway. Once you demonstrate proof of concept in one disease, you can rapidly expand into other indications.
In addition to leading indication that we're pursuing for some of the molecules you see on the blue column, we're also pursuing some of the secondary indications and some other ones that are in the gray boxes we're considering for the future. This can significantly add the value to our portfolio. Looking to 2015, it's going to be another exciting year. We're looking forward to many milestones with the potential launches to clear, as well as potential approval and regulatory submission and multiple potential phase III starts. All in summary, we have a strong respiratory portfolio that has been further broadened with the Pearl and Almirall acquisition. We're making progress. We're making great progress with positive data from our phase II and our phase III portfolio, and also we're validating the novel pathways with our clinical studies.
We believe that we have one of the most comprehensive portfolio of personalized healthcare for the increase in the benefits to our patients. With that, I'm going to conclude. Thank you very much for your attention. Now I would like to introduce Elisabeth Björk.
Thank you, Bing. I'm really looking forward to giving you all an update on where we are within the cardiovascular metabolic disease area. Starting with the strategy. We have a strategy within our TA aimed to reduce the cardiovascular mortality, morbidity, and organ disease. We are doing that by addressing cardiovascular risk factors within three areas. Starting from the left with patients with cardiovascular disease, here we have a long-standing history. We have been here for quite some time and developed drugs, antihypertensive drugs, and more recently, drugs like CRESTOR and Brilinta. In the middle, we have the diabetes franchise, in my opinion, we have the best non-insulin franchise in the industry. To the right, we have CKD, chronic kidney disease.
We are now moving into that area because these are patients with high unmet needs, many of them also have cardiovascular disease. There is a huge overlap in disease spectrum amongst these three patient populations. Underneath, we have ongoing research activities focusing on really transforming how these patients are being treated with the ultimate goal to change the disease progression per se and not only their symptoms. One part there is focused regenerations, there are also other efforts ongoing. What our focus is and what our aim is within the ongoing late-phase development is to change how patients with diabetes are treated. I'm now starting with the diabetes area, we get back to Brilinta and CKD later on. For diabetes, the goal is to change how patients are being treated towards earlier, more aggressive combinations.
It's a strategy where you don't wait until patients are failing their treatment, instead, much earlier, get them to goal. We're also having a science-led, science-focused approach in how we are expanding our portfolio beyond type 2 diabetes. We have just started with the launch of the phase III development program in type 1 diabetes with FORXIGA, where we dosed our first patient last week. We have a strong ongoing R&D commitment for our broad diabetes portfolio, it was not my intention with this slide for you to be able to read all the individual studies. More to show that we have lots of clinical trials ongoing that will deliver clinical data over the next coming years, including the two ongoing cardiovascular outcome studies, one for FORXIGA and one for BYDUREON; life cycle management program for the Saxa-Dapa combination; regional programs; life cycle management for BYDUREON.
One specific trial I really want to highlight, which is a combination trial in diabetic patients that will be treated both with exenatide and FORXIGA, and it has the possibility to show good effects both on HbA1c reduction and also on weight. I'm personally very much looking forward to the results of that study. In total, we have around 40,000 patients right now in this moment in clinical trials. What is next? I will try now in the next couple of slides to give my perspective on why it is good to have a portfolio versus individual brands and how we can capitalize on that. Type 2 diabetes is a progressive disorder. Over time, patients will deteriorate, and they will need more treatment. We have a portfolio of drugs that can be used across that spectrum.
Regardless of if you are early on in your treatment or later on and on insulin, we have drugs that alone or in combination can be used. If you look at the current guidelines, and here you can see the guidelines issued last year by the American Association of Clinical Endocrinologists. They advocate that you should have more early and aggressive combination treatment, especially in certain cohort of patients. That is not followed by patients and physicians today. We have the portfolio to enable, to help, and make that happen. I will now show you in two slides some data that supports the notion of the benefit of earlier combination. Here are the results of the one study with Qtern, the combination of saxagliptin and dapagliflozin. It's in patients failing metformin treatment, and at baseline, they had very high HbA1c levels, around 9%.
That's a level where most, or at least many endocrinologists, including myself, when I was still treating patients, consider to use insulin instead of oral treatment. Here, that's the red bar up there. If you treat them with the combination of Qtern, you will be able to have a magnificent reduction in HbA1c, here, almost 1.5%, and to be able to get around 40% of the patients to goal. We are working very hard at this moment to put the file together and hope to be able to file the NDA for this fixed dose combination by the end of this year. We are also developing a Qtern metformin fixed dose combination to be able to give that as a once-daily pill, and that work is ongoing. This is another study showing the two-year results of FORXIGA, dapagliflozin, on top of patients treated with insulin and also oral.
Patients here are, for example, also on metformin, around 80% of them. Just remind everybody, Type 2 diabetes is a progressive disorder, and over the two-year period, we expect patients to fail and to get worse and controlled. That's also what you can see on the upper line, which is the placebo-controlled patients. They had to increase their insulin dose over the two-year period here. The patients treated with FORXIGA, not only did they keep their HbA1c levels sustained over time, they lost three kilograms in weight during these two years, and they did not have to increase their insulin doses. All this taken together gives us hope that it is actually possible to not only keep patients at a good glycemic control, but indeed to hopefully impact the disease progression per se.
This is just an illustration, but it is one that many top endocrinologists are very interested in exploring further. It speaks to the notion and tries to summarize what I have been speaking about so far, which is that if you treat patients aggressively early on with combinations, you could be able to keep them under better control for a longer period of time. Moving beyond what we are thinking about doing within the phase II area, we are also using a scientific approach, trying to understand how our drugs can best be used also in other patients, outside the core type 2 area.
As I mentioned, we have started the phase III development program for type 1 diabetes with FORXIGA, and we are also exploring whether our drugs or indeed combinations of our drugs can be used, for example, in patients with NASH, fatty liver disease, heart failure, obesity, or renal disorder. We are there using a scientific platform, or you can look upon this as a toolbox of methods that we have in order to understand how our drugs or combinations of drugs are being used. I will not go through this in any kind of detail, but we are looking at functional data, body composition, insulin sensitivity, and effects on beta cells. Just as an example, looking at the second one there, the body composition.
This is the toolbox that we used when we try to understand whether the weight decrease seen with FORXIGA treatment was due to fat, bad fat, water, and we were able to show that the weight reduction you see there is a reduction in bad fat, visceral fat. The same kind of technology we are now using, looking at lipid content in the liver and see if there is a platform that we can use then for development of drugs in NASH, for example, as I described. Moving from the diabetes area into chronic kidney disease and CKD, and the very exciting ongoing development we have in collaboration with FibroGen and Astellas. The compound is called roxadustat and is currently in phase III development.
It has the potential to be the first oral erythropoietic treatment for renal anemia in patients with chronic kidney disease, be they on dialysis or in pre-dialysis. What you see here to the right is the phase II results, and you can see a clear dose-dependent increase in hemoglobin when these patients were treated. The doses we are bringing forward to phase III, the one milligram per kilogram in the middle, that is what we are starting with the opportunity to increase the dose to get the full aspects of the hemoglobin increase that you need. The phase III program includes around 7,000, more than 7,000 patients and is designed to show cardiovascular safety versus the current erythropoietin treatment that is offered today to patients, and I will get back to why I think we have the potential to show that.
The treatment that is today offered to these patients, it's recombinant erythropoietin, EPO. As you can see on this slide here, if patients are given higher doses of erythropoietin, there's a higher risk of cardiovascular events and higher risk of cardiovascular mortality. This is one of the main blockers for the use of this in patients with renal anemia and CKD. It is not absolutely clear why you have this increased cardiovascular risk when treated with EPO. Some of the topics that are being discussed are indeed the EPO levels per se, that are very high and supranormal when you treat with injectable erythropoietin. There are also discussions around how fast you increase the hemoglobin level, to which levels you get, and also the fact that you have a small increase in blood pressure when you treat them with EPO.
Based on the mode of action with Roxa, which is very different compared to EPO, we aim to avoid these things, and we have designed the program to show that we have a drug that is efficacious, which we believe based on the phase II data I showed you, but also safe from a cardiovascular perspective. One of the key reasons why we believe that there could be a difference in cardiovascular risk is the first point here, the supraphysiological EPO levels you see when treated with injectable erythropoietin. What you have here is a comparison of the erythropoietin concentrations in blood in patients when they are treated with EPO, that's the red one, and when they are treated with Roxa.
The blue one there is the one milligram per kilogram dose I showed you the efficacy of before, and with the potential to go up to the two milligram per kilogram, which is the red one there. Taking all of this together, we think, again, we have a drug that works and that we will be able to show cardiovascular safety based on the mode of action and the program we have designed to show that. Moving then to the last part of my presentation, and that is Brilinta, ticagrelor. We have an ongoing clinical development program for Brilinta called the PARTHENON program. It's our biggest ever outcome study supporting one drug, and it is designed to show the clinical effects of ticagrelor across the spectrum of cardiovascular disease and atherosclerosis.
It includes more than 80,000 patients in total, and we have four major cardiovascular outcome studies ongoing right now that will deliver data every year over the next coming four years. The next one being PEGASUS, that will deliver results hopefully early next year. Following that, we will have SOCRATES in patients with prior stroke, EUCLID in patients with peripheral artery disease, and THEMIS in high-risk patients with diabetes. The next one is PEGASUS, and that is in patients that have had a prior myocardial infarction one to three years before being included in the PEGASUS trial. Taking you back to the PLATO data and reminding everybody about the unique clinical profile we have with Brilinta and ticagrelor. On the left hand, you see the MACE results, which was the primary endpoint in PLATO, the composite of cardiovascular death, myocardial infarction, and stroke.
You see a continuous benefit over the year of the treatment. You see the curves separating over time, and it's in the end, after one year, that's when the inclusion in PEGASUS happens. On the right hand, you see the mortality benefit, which is also unique for Brilinta and ticagrelor, and the same pattern. The curves are separating over time. We think that this unique benefit or this unique clinical profile might be linked to the fact that we have a dual effect. It's not only a P2Y12 inhibition, but also an ENT1 inhibition, giving a local increased concentration of adenosine. This has been recognized also by regulators and has just been included in the European SmPC. The patients included in PEGASUS are patients at high cardiovascular risk. This is data that we presented at the ESC Congress earlier this year.
It's a real-world evidence study that we conducted in five different countries, and these are the results from the U.K. You can see that in patients, like the patients in PEGASUS, that did not have an event the first year following their myocardial infarction are still at a very high risk having a subsequent event. In this study, up to 20%, 1 in 5 patients, PEGASUS-like patients, had another event within the next following three years. That's exactly the kind of patients we have in PEGASUS. We are working very hard on closing that study right now, and I very much look forward to sharing that data with everybody early next year. That brings me to concluding the cardiovascular metabolism side of this.
Our strategy is to reduce mortality, morbidity, and organ damage by addressing the cardiovascular risk factors across these different patient populations that I have described to you. We see a growth in diabetes from earlier, more aggressive combination treatment, and we have a science-led life cycle management and extension strategy. We see a real opportunity to impact and change the lives of patients with chronic kidney disease with treatments like roxadustat that I described to you. We also hope to be able to transform how atherosclerosis is treated across the spectrum throughout our delivery of the clinical data that we have in the PARTHENON program. With that, thank you, and we look forward to the questions.
Thanks, Elisabeth. We're going to focus now on CVMD and respiratory therapeutic area questions. We'll take the first one. I'd like to go to the phone line, actually. We've got Seamus Fernandez, give the guys on the phone lines a chance to ask questions. Hopefully, Seamus, you can hear us. If you'd like to-
Yes, I can hear you fine. Can you hear me?
Yep, got you.
Great. Thanks. Maybe my first question for Bing, a couple things on the respiratory and RIA space. First off, when I look at the data for sifa and compare it to the FDA documents for the effect size versus BENLYSTA, the drug's effect size looks relatively similar to BENLYSTA. Can you please just kind of correct me where I'm wrong on how this drug is differentiated on efficacy from BENLYSTA? I do recall looking in the abstracts at ACR seeing a little bit of a higher adverse event rate at the 1,200 milligram dose. Can you walk us through a little bit of the side effect profile of sifa? Also, remind us again how anifrolumab might differentiate on efficacy and safety. The second question on respiratory.
In the respiratory space, we did have some recent data from a competitor product basically making a lot of the same claims that you make on the anti-IL-5. Can you just walk us through how your strategy on anti-IL-5 and anti-IL-13 will differentiate from the anti-IL-4 alpha? My last question, as we think about the cardiovascular space, can you just remind us on the cardiovascular side, your thoughts on the recent safety questions that were raised very specifically around long-term use of antiplatelet therapies? This was just published at the American Heart Association meeting and met with a safety warning from the FDA. I believe it was specifically associated with a DAPT study which did not involve Brilinta. Just wondering how you're going to respond to that safety question. Thanks so much.
Thanks, Seamus. I think there's at least seven questions in there. If we start with lupus and sifalimumab and anifrolumab, Bing.
Sure. First of all, thank you for the question. I want to remind everyone that for lupus, there's really high unmet medical need. 50, 60 years now, only one approved drug. Clearly, patients need options. For sifalimumab, this is a novel MOA. In fact, we're the first one to demonstrate clinical efficacy targeting interferons can translate into clinical efficacy in autoimmune disease. Cross-trial comparisons in terms of efficacy is going to be very tough. What we have seen with our phase II-B is consistent results. Based on according to our knowledge and also to our clinicians' opinion, this is one of the most consistent phase II results for phase II in lupus. Not only we saw the SLE index four and higher of six and eight, also organ-specific improvement, the six and eight, as well as the organ-based BILAG also. It's most consistent results.
The more data is actually going to be shared today in about probably a few hours, four hours at ACR oral presentation. We're really encouraged by the results. If you have to compare to see BENLYSTA actually failed in the phase II clinical study. In the phase III, to see without cross-trial comparison, the effect size for SRI-4 is nine to 14.2. Additionally, I mentioned that with anifrolumab, because of the MOA targeting more than the interferon alpha, beta, and omega, there's even opportunity for greater enhanced efficacy with the second approach. That's for the efficacy. In terms of safety profile, I think once again, we're going to disclose in details in ACR. The signal we have seen for sifalimumab is increased herpes zoster infection. Higher at higher doses appears to be drug-related.
All the patients responded really well to antiviral therapy. For anifrolumab, we'll have data next year, mid of next year. We expect to share the data in a conference.
Thanks, Bing. Let's go to cardiovascular safety, Tom, and then come back to Bing for the respiratory positioning with the interleukin biologicals.
Yeah. The question relates to DAPT study, which is actually the long-term use of thienopyridines. It did not include Brilinta, but it was presented at the AHA in Chicago on Sunday. I won't go into the detail of the results, but essentially what they say is if you treat 1,000 patients beyond the first year, actually out from 12 months to 30 months, you see a significant reduction in cardiovascular events, a 50% reduction in MIs. Out of 1,000 patients, you would not see 20 CV events. You would reduce stent thrombosis nine cases, but you would increase overall mortality by five deaths, and see 10 increases in moderate or severe bleeding. The debate on Sunday was very much around the risk-benefit of that in the population. Obviously, a lot of focus on those imbalances in death.
The initial hypothesis is that was an imbalance in terms of the number of patients at randomization in the two arms that had cancer. The hypothesis is that's not treatment related. I think the DAPT study in many ways is the perfect curtain raiser for PEGASUS, because if you think historically, I think beyond one year, physicians have systematically underestimated long-term cardiovascular risk, and to a certain extent, they've treated the wrong disease. They're focusing on preventing stent thrombosis, where we believe for high-risk patients, they should be focusing on the long-term treatment of the underlying atherothrombotic disease. I think overall, it raises the clinical debate. This is the reason why we're doing the PEGASUS study, and we very much look forward to the results early in January.
Bing, quick comment on strategy and then relative data from our competitors.
I think, Seamus, I would assume you refer to the dupilumab from Regeneron. They recently announced 12-week interim data. Have to see that with that 12-week data, it's really hard to make a comparison across trial. Again, because they are targeting the IL-4, IL-13, the TH2 pathway, I think it is approach further validated approach we are taking and others are taking, which is targeting the TH2 pathway for a subset of patient population. We remain to be confident of the profiles for our molecules. I mentioned for benralizumab, for eosinophilic asthma. This is a molecule specifically engineered. It has potent property depleting eosinophils. We have in multiple trials, we have phase I-B's, phase II-A's, now phase II-B's consistently deplete very potently eosinophils, hitting the target. That translating to really good efficacy.
Population we're testing in phase II-B quite broad because we included patients with a medium ICS as well as high ICS. We saw a reduction of 43%-78%, depending on the cut level. In phase III clinical design, the way we designed it, we will be able to further characterize the range of eosinophil cutoffs. This way, see which population would be best response to benralizumab. That's for our trial design. For tralokinumab, we have two biomarkers incorporated into our clinical study based on our learnings we have, is also we really enrich for the responder population. What we found in our phase II-B clinical study, the patient needs to be reversible and needs to be not on oral corticosteroids. This will be a separate study.
In that responder population, we saw efficacy across all the different parameters, including asthma control and quality of life, as not seen by other molecules. Phase III, once again, will confirm the efficacy in that population.
Yeah.
We do have two potential diagnostics incorporated in the design too, for tralo.
I'll just add, Bing, if I may. I think there's four elements to this story. One's pure efficacy. The data we saw in our phase II in both benra and tralo was extremely good, both in terms of exacerbations and all on the asthma and COPD, other functions for benra, but also for tralo in exacerbations and symptoms and quality of life. The second one is in terms of personalization. We are focused on the biomarker strategy. We're not looking for all comers. We think it's important with these biologics to focus on specific patients, be most relevant to physicians and to payers. The third one is also convenience. Clearly, we believe with benralizumab, with four-weekly up to eight-weekly dosing, we can have a very convenient and easy-to-use administration.
Finally, we are the only company with a combination of an IL-5, an IL-5R receptor, tralokinumab, an IL-13, and also the TSLP and future biologics. We can provide a range of, and a portfolio, really giving a definitive choice and selection and direction to doctors to understand which patient is going to benefit most. Just remind people on the phone lines, you can ask questions on the Webex, but no more questions here so we'll go into the room. Let's take one from the back so we have some variety. This gentleman here, please.
Hi, it's Mark Clark from Deutsche Bank. Just wanted to ask about lesinurad. The study showed the reductions in serum uric acid as
as you targeted. The secondary endpoints, which were mean gout flares and tophus resolution, showed no significant difference. Speaking as a gout-afflicted pharmaceutical team at Deutsche Bank, we would like to see reductions in gout flares as the primary endpoint. Could you speculate as to why you didn't see those symptomatic improvements? Secondly, does that represent a potential problem with the regulators? Thank you.
Briggs may be the best person to answer. Briggs, do you want to take that question?
Yeah. Thanks very much for the question. I think, the ability of agents that lower serum uric acid to impact both flares and tophi is an area of, it's still sort of evolving science. Nobody's really been able to show with agents that lower uric acid that you get a dramatic decrease in flares until you probably treat for a longer period of time. The studies that we've done so far, probably weren't of long enough duration to see the decrease in the incidence of flares and the decreased incidence of tophi. I think your question about whether that causes any challenges with regulators, I think it's a very fair point and one that, of course, I think they'll raise during the review.
Yeah. Interestingly, Mark, there is a hypothesis that as you start to break down the crystal burden, the flare rate, typically when you're treating gout, goes up. It's one of these perverse ironies that as you're reducing your serum creatinine and getting the crystals actually into the bloodstream, your flares may go up. As Briggs said, I think we need to look at extended studies for that. The tophi resolution, we had a tough target. Our target was full tophi resolution, in other words, zero evidence of tophi. We weren't able to hit that endpoint, but there was significant reduction in the area of tophi seen, and clearly that data we will be presenting and sharing with regulatory authorities. Martin, maybe you want to comment from a rheumatologist perspective.
Yeah. I want to make a small comment. The other thing is that the lesinurad trials, because if you change treatment, patients are very prone to flare, the patients were, with colchicine, maximally controlled to actually keep their flares down. That actually that design, well, the trial wasn't designed to actually pick up flares. Actually, it was actively treated against it.
Thank you. Yeah. Gentleman in blue.
Thanks very much. This is Jeffrey Holford from Jefferies. On PEGASUS, which you've talked about quite a bit today, how much have you sort of factored in your thinking, the change from first-generation drug-eluting stents to second-generation drug-eluting stents, the data that we've seen around shorter durations of therapy being as optimal as longer generations in those, and how that might impact the outcome? I don't know if you'd care to comment or not, but if PEGASUS were not to read out positively, how much of an impact would that potentially have on your thoughts around where Brilinta could get to in your long-term planning? Thank you.
Tom.
Yeah. Thanks for the questions. We're trying to position Brilinta independent of the stent platform. You know that market moves extremely fast. The PEGASUS study hopefully will deliver results as the PLATO did across a variety of stent platforms. The second part of the question was?
Really just if PEGASUS did not read out as a sort of convincing positive commercial study, what kind of impact would that have on your longer-term management guidance around sales for Brilinta?
I think it depends a little bit of what you mean by read out positive. I think there are various scenarios. As you know, it's a three-arm study. We have a 60 milligram and a 90 milligram arm. We'd need to look at the data from both of those arms and the data together, in terms of statistical significance and also whether we think the data is consistent, what we saw with PLATO. Obviously, there are a range of commercial scenarios which would reflect that. Over the course of the long term, if you put ACS, PLATO, and post-MI PEGASUS together, because of the timing of launches, they do together represent the largest part of our 2023 forecast. We're going to need to take a look at that in the light of the PEGASUS results early next year.
Thanks very much.
Take the risk and see if, Sachin, you can ask one question because it's between you and the break. No, one question. Wait, we need to get the mic working. Still not working. Do we have a live mic?
There's one behind you.
Sachin Jain, Bank of America. I'll focus on roxadustat. CKD is a big enough opportunity in itself, but I wonder if you could discuss potential phase III programs beyond CKD in terms of chemotherapy-induced anemia, other anemias. Any color on differentiation you perceive you have versus the buyer and GSK molecules.
You want me to? Yeah. Clearly the first indication is CKD, but in the life cycle management, it will all depend if the compound deliver on its promises, which is the CV safety. If there is no, as we expect, no issue with the CV safety, other anemia, chemotherapy-induced anemia of inflammatory origins are clearly part of the life cycle management. Your second question was the differentiation. As you know, we are ahead of the competition. Clearly, if you look at the design of the program, we are giving the drug three times a week, and we do believe that the way this class of compound is administered will impact the clinical response. We can provide you more insight when we have seen more data. But to the best of our understanding, I think three times a week is probably optimal dosing regimen.
Thank you very much. Appreciate it. There's a lot more questions in the room. We're going to have a break. The management team will be around for questions. Obviously, there's more time for questions later. Please be back at three o'clock sharp so we can stay on track. Thank you.
Okay. If you could take your seats. I believe we have the phone lines and Webex up and going. For those of you that don't know me, my name is Susan Galbraith. I'm the head of the Small Molecule Oncology Innovative Medicines Group, and I'm delighted to be here today to talk to you about the updates that we had in our oncology portfolio. Our oncology vision is to redefine the cancer treatment paradigm to bring novel medicines that will restore patients' lives and increase the potential to eliminate cancer as a cause of death for an increasing proportion of patients. We're very confident in the ability of our pipeline to deliver, sufficiently confident to promise that we'll be delivering six new medicines to patients by 2020. We're focused on four key biology areas, tumor genetic drivers and resistance mechanisms, DNA Damage Response, antibody drug conjugates, and immuno-oncology.
We're also focused on four core disease areas: lung cancer, breast cancer, ovarian cancer, and hematologic malignancies. Our strategy is focused on three key areas. The first is around combinations. Many novel oncology drugs first get approved as monotherapies. The real progress in terms of improving the survival and outcome of patients with cancer over the last 50 years has been through the development of combinations, and that will continue. We need to put together carefully, individually effective drugs to drive the combinations that will dramatically improve the outcomes for patients with cancer. This is a really important part of our strategy and one that we'll be emphasizing through today's presentation. The second element is personalized healthcare. A core hallmark of cancer is its heterogeneity. We used to define cancer by its site of origin, lung cancer or breast cancer.
Now we know that actually there are many different subtypes of cancer within those terms. By understanding which patients are most likely to respond to treatment because of particular understanding of the genetic drivers in that cancer, we can tailor the right treatment for the right patients. Again, you'll hear that we have developed multiple different diagnostic tests associated with different compounds in our pipeline. The final element is that we need to be smart about how we develop our compounds. We need to understand quickly how to combine them together with the other agents to drive those efficacious regimens. We need to be nimble and agile in terms of understanding how we develop the diagnostic tests to go along with them. We also need to move early into early stages of disease where the potential for cure is highest.
This slide just shows on the left-hand side, the power of combinations. You see three different preclinical experiments looking at combinations of two agents together, where you see better efficacy than you can see with either agent alone. We can do this by putting together different mechanisms that individually kill cancer cells in different ways, you end up with a greater cell kill than you can achieve with either agent alone. We're doing it also by understanding the mechanisms of resistance that can occur to one element of the combination or the other. By so doing, you put together combinations that will overall improve the risk-benefit profile compared to monotherapy. I said the second element of our strategy is personalized healthcare.
Our approach is to have freedom to access to the right diagnostic test by partnering with the right company for the right platform for our individual agents. You can see on this slide, we've got a variety of different platforms. We're using an immunohistochemistry test in partnership with Ventana to identify the right patients to treat with our PD-L1 antibody MEDI4736. We're partnering with Myriad to have BRCA mutational testing available for patients for LYNPARZA. We're the first company to get a circulating tumor DNA diagnostic test as part of the label for Iressa in partnership with QIAGEN, and we're also developing this technology with AZD9291. We're also partnering with Illumina for our next-gen sequencing platform, which is going to be the future of genetic testing, the ability to look at multiple genetic mutations simultaneously with sensitivity and accuracy and depth.
The third element of the strategy is about the smart development. I'll give you several examples. We've been able to move AZD9291, as Pascal told you earlier, very fast from the first time in human in March to the earliest filing, potentially two and a half years from the first dose. We've done that by having They started off with a parallel phase I going in Asia and in the West. You heard as well from Marc that the prevalence of the EGFR sensitizing mutation is much more common in Asia. That enabled us to go very quickly. We also selected patients with the T790M mutation early on in the study, we're very early to get efficacy signals. We've had a seamless transition into phase II and phase III, and we've had the right commercial formulation to go along with that.
All of those pieces of development are critical to enabling this very rapid move to filing and getting this drug to patients. With our PD-L1 antibody, the PACIFIC study in Stage 3 unresectable lung cancer has been able to move this very early into the early stages of the disease, where the potential for cure is highest. I've mentioned the circulating tumor DNA test already. Let me tell you why that's important. It's important because not every patient is able to have a tumor biopsy. If you can't have a biopsy and you can't work out what's the genetic mutation in your particular tumor, some patients will get denied access to drugs that might be effective for them. Having access to circulating tumor DNA enables access to a broader range of patients, and also can be used to actually monitor response to treatment during treatment.
Finally, to put combinations together that are going to make effective regimens, they have to be individually safe and tolerated to be combinable. Mohammed is going to tell you in a moment about the MEDI4736 combination with a BRAF and MEK inhibitor. Other people have tried to do similar combinations, some of them have failed because they weren't tolerated. It just emphasizes how the good combinability is critical to developing novel triplet combinations that will hopefully deliver better efficacy. This slide illustrates the strength and depth that we've got across the four biology areas that I outlined. The area of tumor drivers and resistance, DNA damage repair, immuno-oncology, and antibody drug conjugates. You can see that we have great strength and depth, which enables us to develop those combinations, which are a core part of our strategy.
Now I'm going to tell you a bit about four different programs that come under the classification of tumor drivers and resistance. The cartoon on the left-hand side of this slide outlines some of the signaling pathways that occur in cancer. Cancer is a genetic disease, the mutations that happen in cancer drive abnormal signaling through these pathways. They basically switch on permanently the on switches for growth. Cancers can become addicted to that on switch. By understanding that, you can develop inhibitors to switch the switches off, that causes the cancer cells to die and leads to tumor regression. Because these pathways are often interconnected, some of the cancer cells can have resistance mechanisms, they can subsequently regrow and repopulate the cancer with those resistant cells.
If you can understand the potential resistant mechanisms, you can help develop drugs with combinations that can overcome them. A great example is AZD9291, which is the first of the four programs I want to highlight today. This is our EGFR mutant selective inhibitor in lung cancer. We know that a subsegment of patients with lung cancer have mutations in the epidermal growth factor receptor, which drive that addiction to the on signal that this provides. Drugs like Iressa have a high response rate, about 60%-70% response rate, but patients ultimately develop resistance, which often shows after about 10-12 months on drugs like Iressa. By biopsying those tumors at the time of progression, we now understand that about 60% of those patients develop a second mutation in the epidermal growth factor receptor, the so-called T790M mutation.
What that does is it alters the kinetics of the binding site, so Iressa doesn't bind as well. That's why the on switch is then switched back on again and the cancer grows. What our chemists have done is design a molecule that binds potently both to the original sensitizing mutation with a resistance mutation present as well. It does so with a potency that's 30-fold greater than the potencies with binding to the wild type or normal receptor. That's important because that normal receptor is present on your skin and your gut cells, and inhibition of that normal receptor leads to the side effects that you get with drugs like Iressa of rash and diarrhea. The graph on the left of this slide shows the waterfall plot that was presented at ESMO earlier this year.
Each bar on this graph represents an individual patient, and the bars that go down represent tumor shrinkage. At the 80 milligram dose we're taking forward, we have a 70% response rate in this patient population, which is highly durable. The impressive response rate and the depth and durability of the responses are what have led to the U.S. FDA giving us breakthrough therapy designation. We're continuing to move very rapidly with this program. We have ongoing combinations with MEDI4736, our PD-L1 antibody, with our c-MET inhibitor and selumetinib, which are continuing to dose escalate. We're starting our first-line phase III very shortly, and data readout is expected from that trial in 2017. We're intending to start rolling U.S. filing in January 2015 with completion in the second quarter of 2015. These data were also presented at ESMO.
On the left-hand side is a waterfall plot now from the first-line patients treated with 9291, which also shows an impressive disease control rate and response rate. Obviously, we'll be waiting to see the durability of those responses and the progression-free survival of those data mature. On the right-hand side, I'm quite excited by the anecdotal data we've currently got in the clinic with patients with brain metastases. That's important because the current EGFR inhibitors don't penetrate well into the brain. We have pre-clinical data suggesting at the 80 milligram dose, we do get good brain penetrance, and this is backed up by the currently anecdotal data. We'll be continuing to look at this patient population, which represents a growing unmet medical need since other EGFR inhibitors don't treat this patient population well.
Now I want to move on to the second molecule out of the tumor driver class that I want to talk to you about. This is AZD2014. This is a dual TORC1/TORC2 inhibitor. TORC1 is a clinically validated target. Everolimus is a TORC1 inhibitor and is approved in estrogen receptor-positive breast cancer. The issue with currently available therapies is that you get feedback activation of the pathway actually within hours. One differentiation that we have from everolimus is that by inhibiting both TORC2 and TORC1, you can overcome some of that pathway reactivation. The second point is another example of our smart development. We understand that pathway reactivation is a common issue across all PI3 kinase pathway agents.
We've developed intermittent dosing schedules with this drug so that you can hit the cancer once, kill some cells, allow the pathway to reset, and come in again with the next doses to overcome that feedback inhibition. What we've seen preclinically is that this leads to better efficacy, and we see that better efficacy shown on the left-hand side in a phase I-B study done in heavily pretreated patients. Here, 214 is dosed on a two days a week or three days a week regimen in combination with weekly paclitaxel. Many of these patients had had prior taxane therapy, the response rate we're seeing here and the durability of the responses is encouraging.
This mechanism is important not just in this setting, but it has potential relevance across breast, lung, ovarian cancer, and lymphoma because the PI3 kinase pathway is the most commonly mutated pathway in cancer. Assuming that we have continued encouraging data, not just from this trial that I've shown you, but also from a trial that we have ongoing in combination with Faslodex, which also shows encouraging tolerability and efficacy data, there's a potential for a phase III investment decision for this program next year. The third molecule I want to talk to you about is AZD6094, which is a potent and highly selective inhibitor of MET. MET is another tumor driver, which can be amplified or mutated in some segments of cancers. The molecule that we have is differentiated from a drug you may be familiar with, onartuzumab.
Onartuzumab was designed to interrupt the binding of the ligand for the c-MET receptor, which is hepatocyte growth factor to c-MET. Okay. It's designed to work in settings where the tumor is addicted to that ligand-stimulated signaling. Our c-MET inhibitor is designed to work in the MET-amplified or MET-mutated setting where there can be ligand independence. It's a different setting from onartuzumab, and we have clinical proof of principle from a setting where we have MET amplification in papillary renal cancer, as you can see on the waterfall plot on the left-hand side. We have initiated phase II trial in papillary renal cancer and also in MET-amplified gastric and lung cancer. We have an ongoing combination of this molecule with 9291 in second line EGFR mutant lung cancer because MET amplification is another common resistance mechanism to currently available EGFR inhibitors.
The final molecule out of the group that I want to tell you about in tumor drivers is AZD9496, which is an oral selective estrogen receptor downregulator or SERD. Now, actually, targeting the estrogen receptor is one of the first examples of targeted therapy in cancer from decades ago, and AstraZeneca has a strong heritage here, including our drug Faslodex. But it is possible to improve on the efficacy available for the current therapies. And by designing this molecule, which is orally bioavailable and much more potent than Faslodex, we can have improved knockdown of the estrogen receptor, and that leads to increased cancer cell kill. And what you can see on the left-hand side is a preclinical experiment in tumors with estrogen receptor breast cancer, where AZD9496 shows improved efficacy compared with either Faslodex or tamoxifen.
We've started first-in-human trials with this molecule, and we will be reporting the full pharmacological data at the ACR next year. I'd also like to point out that a large pharmaceutical company with a strength in oncology recently paid substantial amounts of money for a similar molecule, which is the only other competitor in the clinic. Now I'd like to turn to the area of DNA damage response. Abnormalities in the ability to repair DNA are quite common in cancer. In fact, they're one of the reasons why cancers accumulate those genetic mutations that I talked about that help to drive cancer growth. But they also represent an Achilles heel in terms of the ability to kill cancer cells.
If cancers have a deficit in one of the DNA repair mechanisms, and then you inhibit a different DNA repair mechanism, you can selectively kill the cancer cell which has that abnormality and spare the normal tissues which have intact DNA repair mechanisms. AstraZeneca has the most extensive portfolio of DNA damage response agents in the industry with a PARP inhibitor, an ATR inhibitor, and a WEE1 inhibitor all in the clinic, and those are all first-in-class molecules. The principle of selectively targeting cancer cells to produce clinical benefit in patients that have a deficiency in one DNA damage repair pathway is clinically validated now with the data that's come from the LYNPARZA program. And the Study 19 data that's shown on the left showed an improvement in the progression-free survival in patients with BRCA mutation who were dosed with olaparib versus placebo in platinum-sensitive relapsed ovarian cancer.
BRCA mutation produces a deficiency in the homologous repair pathway, which means that patients are then sensitive to inhibition of a second pathway, the base excision repair pathway to the PARP inhibition. We've not just seen activity with olaparib in ovarian cancer, we've seen activity in breast cancer, in gastric cancer, in pancreatic cancer, and most recently shown some exciting data at the ESMO meeting in prostate cancer. We have a broad ongoing phase III program readout from the SOLO2 trial in BRCA-mutated ovarian cancer expected in 2015, from this first line study, SOLO1 in 2016, and from the advanced breast cancer BRCA-mutated setting, the OlympiAD trial, also in 2016. The gastric cancer trial, GOLD, should read out in 2017, and we're starting the pancreatic study in the fourth quarter of this year. I mentioned the prostate cancer data that was presented by Johann de Bono at ESMO.
They showed him in late-stage patients, 10 out of 30 patients responded. These patients had all had prior chemotherapy and more than one androgen receptor antagonist. The data that we've seen from Study 19 has led to the recent positive CHMP opinion, and we're continuing to work with the U.S. FDA and with the PDUFA date expected of 3rd of January 2015. I want to introduce AZD1775, which is our second DNA damage response inhibitor. It's a WEE1 inhibitor. WEE1 is a protein that's important in the control of the cell cycle. There are natural pauses or checkpoints in the cell cycle where a cell literally pauses, checks itself for DNA damage, repairs that DNA damage before it goes on to the next section.
By inhibiting those checkpoints with a WEE1 inhibitor, you force the cell to go through the cell cycle carrying an abnormal level of DNA damage. The cells are more likely to die than they are to successfully complete cell division. We've got preclinical data suggesting that tumors that have a p53 mutation are particularly sensitive to WEE1. We're doing further analyses of the genetic background that will lead to particular sensitivity to this drug so we can treat the right patients with it. We already have data from platinum-sensitive ovarian cancer, which is shown here, and also in platinum-resistant ovarian cancer. We have phase II studies ongoing in both ovarian and lung, which are likely to read out next year. There's also a great rationale to combine this drug with LYNPARZA.
Mene Pangalos in his presentation will show you some of the preclinical data that shows confidence in that approach, leading us to plan to start a combination study in the first quarter of next year. The final compound I want to tell you about today is AZD2811, which is an Aurora kinase B inhibitor. We actually already have proof of concept with this molecule from a randomized phase II trial in elderly patients with acute myeloid leukemia who are unfit to receive intensive chemotherapy. They were randomized to receive the Aurora kinase B inhibitor as monotherapy or low-dose Ara-C, which is the current standard of care, and actually showed a 30% improvement in the overall complete response rate, including the chosen criteria, compared with low-dose Ara-C, and also a trend to improvement in overall survival.
We intend to go and discuss these data with regulators early next year, but we're also developing this molecule in partnership with BIND Therapeutics with a nanoparticle formulation. I think these overall show that our presence in DNA damage response is really strong and is growing. What I'd like to do now is hand over to Mohammed Dar, who's going to talk to you about the progress that's been made in the immuno-oncology portfolio. Mohammed.
Immuno-oncology is one of the four key growth platforms for AstraZeneca Oncology, and in fact, it represents a paradigm shift in how we treat cancer. Rather than targeting the tumor directly, we're targeting the patient's own immune system. What we're learning is that cancer has evolved over time to utilize multiple escape mechanisms to avoid detection and destruction by the immune system. Therefore, our strategy in immuno-oncology is to develop novel combinations that target each of these key escape mechanisms. We believe that this approach offers the best potential for delivering meaningful clinical benefit to patients. Let me share with you in more detail our strategy. The immune response to cancer is actually quite complex, but we can break it down into three key components. The first step is antigen presentation.
Small pieces of protein or antigens are released by the tumor and taken up by professional antigen-presenting cells or the educators. These train T-cells to recognize the tumor. This is the first critical step in generating a potent immune response. As you can see in our portfolio, we already have several molecules that can enhance antigen presentation, and through clinical collaborations, we have access to additional molecules, including vaccines, which are specifically engineered to potently present antigens to the immune system. The next critical step is to actually, once the T-cell has been educated, is to activate the T-cell to cause it to proliferate, to cause it to secrete cytokines, and ultimately for it to mature into a memory cell, which offers actually the greatest potential for durable clinical benefit.
It's actually this step that's garnered the most attention and generated the most excitement, especially because of the success of targeting CTLA-4 and the PD-1 pathway. In addition to these checkpoint inhibitors, which are essentially brakes on the immune system, there are additional receptors on T-cells that actually act as a gas pedal, such as OX40. As you can see, again, in our portfolio, we have multiple molecules targeting both checkpoints as well as the gas pedal, such as OX40. It offers us the potential to pursue rational combinations targeting T-cell activation. Once the T-cell is educated and then ultimately activated, the last critical step is for the T-cell to migrate to the tumor and to recognize the tumor and destroy it. This is actually one of the steps that up until recently hasn't gotten as much attention.
You can imagine a T-cell that's initially been educated and then activated. When it gets to the tumor microenvironment, there can be multiple roadblocks that actually block or stop the T-cell. We actually have been paying attention to this arena, we have several molecules within our portfolio, and through collaborations, we have access to additional molecules that test hypotheses of trying to remove these roadblocks within the tumor microenvironment and to combine it rationally with agents that activate the T-cell or enhance antigen presentation. As you can see, we have a comprehensive strategy in immunotherapy, trying to target multiple immune escape mechanisms and leveraging both the biologics portfolio at MedImmune as well as the small molecule portfolio at AstraZeneca.
In addition, I highlight a number of new molecular entities in each of these categories that are poised to enter the clinic over the next year or so. Let me share with you a couple of examples that highlight each of these components and the strategy that we're taking. The first example that I'd like to share with you is our triplet combination with dabrafenib, trametinib, and PD-L1. As you may know, MEK and BRAF inhibitors have a well-defined place in the treatment of BRAF mutant melanoma, especially frontline melanoma. Emerging clinical data shows that patients, although they achieve high response rates, eventually develop resistance and progress. There is an unmet need in terms of trying to deliver more durable clinical activity with these agents.
Recent published clinical data shows that patients who are treated either with a BRAF inhibitor or the combination actually have significant changes in the tumor microenvironment. What I highlight on the left hand of the slide is before and after biopsies in patients being treated with a BRAF inhibitor, the story is the same with the dual inhibitor of a BRAF plus MEK inhibitor. What you see on the top picture is that the tumor microenvironment is bland. Following treatment with a BRAF inhibitor, you see significant infiltration of immune cells. These are the CD8 positive T cells that is the focus of immunotherapy. The bottom hand before and after biopsy show that following treatment with a BRAF inhibitor, what you begin to see is the tumor is now adaptively trying to resist this immune attack.
It's upregulating one of the key breaks in the tumor microenvironment, which is PD-L1. If you put this story together, this is the perfect rationale for why you would want to add an additional immune checkpoint inhibitor on top of BRAF and MEK. Others have tried to actually combine a BRAF inhibitor with checkpoint therapy such as a CTLA-4 inhibitor or a PD-L1 inhibitor and have run into toxicity. With that background, we're actually quite pleased with the fact that in our initial phase I experience with this triplet combination, we've been able to escalate to full monotherapy doses of each agent and have not exceeded a maximum tolerated dose. We look forward to presenting this data in the first half of next year. Okay. The next example I'd like to share with you is our approach to targeting T cell activation.
Many are familiar with checkpoint inhibitors. The other set of receptors that are important in activating T cells are the agonist receptors. We've made a significant investment in the OX40 pathway with three unique molecules that are differentiated and target distinct biology of OX40. The murine OX40 is actually completed a first-in-human trial. Data was published late last year. I highlight two key data sets. One is on the top, which essentially is a waterfall plot showing that a significant percentage of patients who received a single cycle of the murine OX40 experienced some degree of tumor reduction at the 2-month mark. In addition, looking in the peripheral blood of these patients, we find exactly what we would expect with an OX40 agonizing molecule, which is increased proliferation of the peripheral circulating T cells.
Based on this encouraging preliminary clinical data from the murine OX40 , we've actually initiated clinical combination trials with the murine OX40 plus PD-L1, testing the hypothesis of can you concurrently target both an agonist molecule, a gas on approach, with a checkpoint inhibitor, which is a brakes off approach, to see whether that will be tolerated and what type of clinical activity and pharmacodynamic biomarkers will be activated using that approach. In addition, we have a second OX40 molecule, which is the OX40 fusion protein, which has already entered clinical trials a few weeks ago. We plan to enter a third molecule, which is our OX40 monoclonal antibody, which will enter clinical trials in the first quarter of next year. The last two examples target the tumor microenvironment, a up till recently neglected area.
I want to share with you some data that's been generated with our STAT3 molecule. First of all, on the left-hand side is a diagram that just highlights the multifactorial effect of STAT3 on the tumor microenvironment. It can target those antigen-presenting cells, the educators, and turn them off. It can turn off activated T cells. It can upregulate inhibitory cells known as T regulatory cells. It has multiple effects on the tumor microenvironment. Our STAT3 inhibitor is actually in phase I clinical trials, both in lymphoma as well as in hepatocellular carcinoma. I highlight two patients' scans on the right-hand side of the slide that show these are both diffuse large B-cell lymphoma patients who had failed multiple lines of therapy. Following treatment with the STAT3 inhibitor, experienced significant clinical benefit that's been durable.
We have actually a phase I oral presentation at the EORTC conference this week presenting additional data with the STAT3 inhibitor. In addition, we've generated preclinical data that shows that the combination of a STAT3 inhibitor, a molecule that has the potential to remove some of these roadblocks within the tumor microenvironment with a PD-1 targeting agent could be potentially synergistic. Based on this compelling preclinical data, we are planning to test this hypothesis in the clinic in the first half of next year. The last example I'd like to share with you is a molecule that targets CXCR2, which is a receptor that's found on myeloid cells, which is a type of immune cell that can be present in the tumor microenvironment. One of the myeloid-derived cells that's important when we're thinking about immunotherapy are myeloid-derived suppressor cells, which can again act as a roadblock.
A republished manuscript shows that targeting either PD-1 or CXCR2 with monoclonal antibodies has modest prolongation of survival in tumor models. When you combine the two agents together, you actually see synergistic activity. Based on this data, as well as in-house data looking at a small molecule inhibitor of CXCR2 plus a PD-1 targeting agent that again demonstrates similar synergy, we plan to test this hypothesis clinically of the two agents in the first half of next year. Incidentally, our CXCR2 inhibitor has not been tested previously in the oncology population but was previously tested in the respiratory population and demonstrated proof of mechanism in terms of hitting the target, showing safety, and acceptable PK. With this first part of my talk, I just wanted to highlight several key points. We have a strategy in immuno-oncology of focusing on novel combinations.
What you see here is that we're executing on that strategy with multiple combinations that target each of the key escape mechanisms within the immune response against cancer. In addition, we are in a unique position to leverage both the breadth of the biologics portfolio at MedImmune as well as the small molecule portfolio at AstraZeneca to execute on these combinations swiftly. In addition, we can supplement as needed with clinical collaborations. Some of you may have heard recently with the acquisition of Definiens, which we believe is core to our translational strategy. It offers another dimension that underpins our clinical strategy, which is really to look very carefully at the tumor microenvironment in these ongoing trials. It allows us to look concurrently at multiple markers and understand in a quantitative fashion where their geographic location is and what their numbers are.
This allows us actually to select patients that might be more preferentially able to respond to certain therapies, and it can also further accelerate our clinical development. In addition, by acquiring Definiens, we feel like it will offer a competitive advantage in terms of allowing this technology to be incorporated into our clinical decision-making and into our teams. Having covered our strategy in immunotherapy, I'd like to summarize our clinical development strategy with our late-stage immuno-oncology assets, which is really built on three key pillars: speed, differentiation, and leadership. We are committed to taking MEDI4736 and its combination with tremelimumab to the market as quickly as possible. As you'll see in subsequent slides, we're targeting late-line non-small cell lung cancer, as well as second-line squamous cell head and neck cancer in single-arm trials that are designed to garner potential rapid approval.
We're building on that by expanding potential indications and looking at high-value indications such as earlier line indications in lung, such as stage 3 lung cancer that's unresectable, which has been overlooked by the competition. With the recent announcement that we are collaborating with the NCIC, we are launching our adjuvant trial in non-small cell lung cancer ahead of the competition. We're building on the initial monotherapy activity in late-line disease and then expanding to earlier line indications. In addition, we're using our biomarker platform, which was alluded to earlier with Ventana, our PD-L1 assay, in selecting biomarker-negative patients that we think may benefit more from our combination therapy. Then finally, we're aiming to establish leadership in the field of immuno-oncology by developing first as well as best-in-class combination agents.
As an example, we believe that MEDI4736 plus tremelimumab has the potential to be a best-in-class combination therapy. In addition, as you heard, we have initiated combination studies with MEDI4736 as well as AZD9291, which offers the potential to be a first-in-class combination, and I already alluded to our triplet combination with MEK and BRAF. In addition, I shared with you our investment in OX40, where we have the potential to initiate the first combinations of OX40 plus checkpoint inhibitors, as well as monotherapies with the fusion protein and the humanized mAb. Before I provide additional details about the clinical late-stage programs, I want to refresh and represent some data that we recently shared at ESMO in Madrid, which is around our MEDI4736 monotherapy activity, and I'll also highlight data we presented in Madrid for our combination therapy.
MEDI4736 has been included in a large phase I trial where we've enrolled well over 700 patients. In Madrid, we presented updated data with over 300 patients. What I'm showing here is a spider plot. Highlighted in green are patients who are exhibiting some degree of tumor shrinkage, which is approximately a third of all patients that were enrolled on the study. The other key takeaway is that with the Ventana-based assay, we can actually enrich for responders as well as patients who derive durable clinical benefit. This is consistent with the mechanism of action of the PD-L1 targeting antibody. In addition, responders on this trial appear to maintain response for a long period of time, with 90% of patients still maintaining response. This is as a reminder, data that we presented in Madrid six weeks ago on the MEDI4736 combination with tremelimumab.
A few key points to make here. We're actually encouraged by the fact that we've been able to escalate with more than 6 dose levels. We presented data here for 6 dose levels. We have additional dose levels that are open that did not preclude or was not precluded by safety that prevented further escalation. That's one key takeaway. The other is that we've actually seen clinical activity in each of the dose levels, except for the very first dose level, which was the lowest dose of the combination. Finally, in this unselected population, we see a response rate of the combination approaching 30% and a stable disease rate of an additional 30%. A total clinical benefit rate of approximately 60% in this unselected population.
The key point to highlight is that this is still early data with approximately 20 patients, and we need additional follow-up and more experience. The last point about the combination that I'd like to make is the fact that with the limited number of patients that we were able to evaluate for PD-L1 status, what we are finding is that the response rate is actually quite reasonable in the PD-L1 negative with the combination and compares favorably to the monotherapy activity of PD-L1 in PD-L1 negative patients. This highlights the potential for the combination to potentially target patients who have less chance of benefiting from monotherapy. This slide summarizes our development plan in non-small cell lung cancer with MEDI4736. Let me highlight some of the key studies that are ongoing or are about to start.
Beginning with the ATLANTIC trial, this is our single-arm trial that's targeting PD-L1 positive patients with monotherapy, it's designed to try to achieve a faster market access. Building on this study is the ARCTIC study, which will confirm the activity observed in ATLANTIC. This has two components to it, a PD-L1 positive component that looks at monotherapy compared in a randomized fashion to standard of care, a PD-L1 negative component that looks at the combination randomized to standard of care. It builds on the initial ATLANTIC study, confirms it, and expands to a PD-L1 negative population using the combination. In addition, we differentiate from the competition with our PACIFIC trial, which targets previously untapped population, which is an early line of lung cancer, stage III unresectable, looking at following chemo radiation, the benefit of PD-L1 monotherapy versus placebo.
Finally, with the recent announcement with the NCIC, we have launched our adjuvant study, which looks at further earlier line expansion, looking at potentially benefiting a larger group of patients, targeting PD-L1 monotherapy versus placebo following initial surgery and chemotherapy. With this slide, I wanted to highlight the complex nature of the non-small cell lung cancer population, which is that it's now beginning to be molecularly subtyped. Beginning on the right-hand side, what you see is a small sliver that's ALK mutation positive as well as EGFR mutation positive. These are small segments of the lung cancer population that can be benefited by approved therapies that target these mutations. The key message is that the bulk of the lung cancer population does not have targetable mutations with drugs that are currently approved, it represents a clear unmet need.
With the advent of immunotherapy, the top gray portion of patients, which are potentially PD-L1 positive, can benefit from PD-L1 or PD-1 targeting agents as monotherapy. The larger purple box represents a group of patients that are PD-L1 negative that cannot benefit from targeted small molecule therapy or PD-1 targeting monotherapy and represents a potential market for novel combinations such as MEDI4736 plus tremelimumab and future upcoming combinations. This is a reminder of some of the activity that we again shared at ESMO in Madrid, which just drives home the point of the benefit of drugs like MEDI4736. This is a head and neck cancer patient that is 96 years old, who actually progressed on the available biologic therapy and then was entered onto the trial with MEDI4736.
Within four weeks of starting on trial, she had a dramatic response to the drug and actually went on to experience 70% reduction in her tumor. Based on this, as well as a larger data set of PD-L1 monotherapy data, we've initiated a program targeting head and neck that I'll highlight here and summarize. Following a similar paradigm as non-small cell lung cancer, we target a second-line population that's failed platinum, both PD-L1 positive using monotherapy. Again, building on our emerging understanding of the role for the combination therapy in PD-L1 negatives, we look at a similar population that's PD-L1 negative with the combination. These are two single-arm trials designed to try to get faster market approval. In addition, we have a randomized trial that then confirms the activity compared to standard of care using the combination in unselected patients, and that's the EAGLE trial.
What I'd like to leave you with is that MEDI4736 and the combination with tremelimumab are not the only combinations that are poised to enter late-stage development. With the breadth of the MedImmune portfolio along with the AstraZeneca small molecule portfolio, our strategy really is to develop novel combinations that target multiple escape mechanisms. As you can see here, we have multiple not only monotherapy studies but multiple ongoing combination studies that are built around this strategy. I'd highlight several studies on the left-hand side that are ongoing that are not just leveraging large molecule combinations, but also large small molecule combinations, such as our combination with AZD9291, Iressa, and the triplet MEK BRAF. Since ESMO, we've actually initiated planning for several new studies, including ones that target hematologic malignancies such as our combination with CD19 and PD-1, as well as our combination with ibrutinib.
In addition, the studies that I mentioned that target the tumor microenvironment with STAT3 and CXCR2 are in the planning stages to begin early next year. In summary, as Susan mentioned, we have four key growth platforms, drivers of resistance, and that includes drugs such as olaparib. We have drugs that target DNA damage response mechanisms such as olaparib. We also have drugs that target immunotherapy, such as 4736, all poised to potentially get approved in the next year or so. Beyond those initial monotherapy drugs, we have a broad portfolio in which we're able to combine novel combinations and execute on our strategy, which we believe is to provide more clinical benefit for patients through novel combinations.
Finally, we have additional drugs that are in our preclinical portfolio that are poised to enter the clinic in the next year or so, which we are even more excited about that can further synergize with our current clinical combinations. Thank you.
Antoine and Mondher are going to join us and be happy to take any questions.
Yeah. Thank you, Susan. Thank you, Mohammed. As the previous session, we're going to open the Q&A for about 30 minutes. We have questions in the room here, questions on the internet, and of course, by phone. I open the floor with maybe first question here.
Thank you very much. It's Matthew Weston from Credit Suisse. Three quick ones, please. The first regarding the head and neck program. Can you tell us what the HPV status is for those patients? You're targeting all comers or are you specifying HPV status? Secondly, with respect to the circulating DNA test for AZD9291. Apologies, Susan, have you told us about that before or is that new? The third issue, the OX40 program. Again, forgive me, having three in the clinic, is it because they have very different characteristics? Is it because you don't know which one is going to work? I mean, just explain to me why three in the clinic, layman's terms, why that's the right thing to do in an environment with very limited or very significant pressures and demands on R&D spend.
Susan or Antoine, maybe you want to start with the ctDNA, and then we'll leave the.
I can answer the ctDNA one.
Okay.
We did present data at ESMO on the circulating tumor DNA. There was a poster. I think the lead author was Kenneth Thress. If you want to go into the details, I'd be happy to provide it. What that showed, very similar to what we saw with Iressa, is that if you detect patients by circulating tumor DNA as opposed to just by the tumor biopsy, and they are T790M positive, they have a similar response rate either by the tumor biopsy or in the circulating tumor DNA. That was the same data that was from the IFUM trial that was used for the basis of the label update in the EU for Iressa. We have been collecting circulating tumor DNA at baseline and through treatment on all of the patients in the AURA study, and we will be presenting more data on that as things progress.
Mohammed, you take the HPV status for head and neck.
With regards to the head and neck studies, both in the phase I trial and the planned phase II and III trials, we are planning to stratify or collect the PD-L1 status and stratify the patients. HPV status will be collected, and it'll just be used as a stratification factor.
Yeah. I forgot to mention that we have colleagues in the room who are supportive, of course, here for the question. Peter Emtage, the VP of Early Stage Clinical Development for IO, will answer the question on the OX40 program.
Thank you very much. The question is why three? We believe that the pathway is extremely important. Mohammed alluded to its ability as an agonist to drive T-cell responses. From an immunological point of view, it actually is a co-stimulatory molecule, which means that when you're trying to drive antigen-specific responses against the tumor, molecules like this help you to build that army. The question is why three? In the first instance, with the murine antibody, which is in combination with PD-L1, we believe in the science. It recapitulated the biology we had seen in preclinical as well as non-human primate toxicology studies, and hence bringing that together with a checkpoint blockade like PD-L1 allows us to do a couple of things. One, to learn, and two, if you see something, take it forward.
It's not a molecule that we won't take beyond where it is. It has value depending on what we see with it. The fusion protein and the two human and humanized assets tackle specific biologies associated with OX40. One is a pure agonist. The other one has other biological attributes that tackle different aspects of the pathway. From a science-driven point of view, we believe in the pathway is important to our strategy moving forward, we are going to evaluate both and try to understand which pathway, which aspect of the biology brings significant benefit to patients with cancer. Also from a combinatorial point of view, where these molecules come to play. Don't forget, we have a number of assets that are in the clinic. A pretty robust pipeline that's in development.
What we need are molecules such as these that we can, in various permutations and combinations, start to elucidate the best biology for patients with cancer.
Thank you, Peter. Andrew?
It's Andrew Baum from Citi. Three questions, please. Number 1, on CTLA-4 and treme. I'd just like your thoughts on how long do you think CTLA-4 is going to be a standard backbone of immunotherapy. Previously, I might have thought it'd be replaced fairly sharply by alternative agents, but the commentary from Citi might suggest it's going to form more of a backbone for longer than we perhaps have thought. I'd be interested on that. Related to that, where are you in terms of developing a bispecific antibody for CTLA-4 in terms of the toxicity? Second, a broader question. There has probably never been so much complexity in terms of the proliferation of clinical trials with immunotherapy.
Now, I understand the trials are relatively inexpensive compared to cardiovascular, but just how do you manage the bandwidth in order to determine combinations and coordinate? This is just a start, I suspect, of your program. How are you dealing with those challenges, I would be interested to hear. I will hold the final question.
Thank you, Andrew. I may start with the second question and hand over then to Mohammed for the CTLA-4 program. I think you have noticed from Susan's introduction the need for us to focus on a couple of core disease area. We picked those ones, and of course, we are not limited to lung, breast, ovarian, and heme. We would potentially expand to other tumor type. The reason we are doing it actually is to integrate and come with a disease area strategy where we can leverage the potential synergy that you can have from different molecules working in the same tumor type. As a matter of fact, we have a lung cancer disease area strategy where all those assets that could potentially work in lung cancer, IO or non-IO, are being tested and positioned and mapped into this disease area strategy.
Number 2, we have the so-called basket study type of protocol where we pick a number of combination, and of course, we test them at the same time. That is, of course, another way to find the resource, if you are thinking resource. I know it is not only resource that you have in mind, it is the ability to manage the whole portfolio. I think at the end of the day, we may end up with a very complex algorithm that go beyond what we can potentially, as a human being, manage and clinically critical software to help basically design decision tree to pick the right combination is maybe what we can have in the future. I do not know if I convinced you, but I think it is clearly the integration of our portfolio across different disease area that is the way to go in the future.
For the CTLA-4, you want to add something, Mohammed?
Sure. Andrew, if I understood your question correctly, you were asking whether we view CTLA-4 long-term serving as a backbone for immunotherapy. I think based on the emerging data, it appears that CTLA-4 and PD-L1, they're non-redundant. Even though they're both checkpoints, they appear to work independently of each other and certainly synergize based on early clinical data. The other emerging story with CTLA-4 and PD-1 targeting combinations is that it does appear to target a group of patients that were not responding to either agent alone, i.e. mainly this PD-L1 negative cohort that appears to respond to the combination. At least our current thinking is that in the near term, CTLA-4 is here to stay, certainly not as monotherapy, but potentially in combination because it serves as a non-redundant partner to an agent that targets the PD-1 pathway.
Thank you.
Mondher, do you have any?
No, go on.
Thank you. I just wanted to go back to Andrew's question because this combination is actually the biggest opportunity we have, we as a company, the industry, and medicine overall. It's also, of course, our biggest challenge. It's a challenge for us as a company, but it's a challenge for anybody else who actually wants to be in combination. Some of the things we're doing as Mondher described, but I just wanted to also say that this is one of the reasons why we were so excited about Definiens, because any technology, anything that can help us make those choices faster, cheaper, earlier, is something that will help us manage that complexity. There's an enormous complexity here, and we're going to have to do a number of things, but certainly Definiens fits very well in helping us there.
Maybe the other quick comment is OX40, as Peter said, there's a lot of good data, a lot of excitement. We're not going to develop three products in phase III, that's for sure. Just to make sure we don't get everybody panicked about the cost of developing those things.
Thank you, Pascal. Actually, we're going to have one question on the phone. We have two questions on the internet, then come back to the room here. Tim Anderson from Sanford C. Bernstein.
Yes, thank you. Based on what you know today with the combo of 4736 and tremelimumab, can you give us an update on what you think the maximum tolerated dose of tremi will be? Do you continue to stand by your prior claim that you think tremi may end up being a better version of ipilimumab? Last question, you mentioned intermittent dosing with the TORC
That suggests a tolerability or safety issue, and I'm hoping you can characterize the tolerability or safety profile of that drug a little better.
I'll do the combo and Susan, then you take the 2014 question.
Let me comment on the question around the combination and the MTD. As we mentioned at the ESMO conference in Madrid, the combo study is still ongoing. We have multiple cohorts that are being expanded so that we can better define the balance between efficacy and toxicity. As of right now, we have not defined a maximum tolerated dose. We have multiple doses that are in play, and we are going to follow the data, but we still remain confident that we will have a dose either by the end of this year or early next year. With regards to the TREME comparison to ipilimumab. We mentioned earlier there can be small differences mechanistically between tremelimumab and ipilimumab. These small differences, while may not show up in monotherapy comparisons, they may actually make big differences in combination.
I think ultimately the data will tell whether the differences between TREME and ipilimumab in combination will translate. The early data seems to suggest that there is clearly differences in safety of the two combinations.
Thank you.
In regards to the AZD2014, the dual TORC1/TORC2 inhibitor. The data that was presented that I showed you from the Glenn Denning poster from ESMO in combination with weekly paclitaxel showed a very low rate of grade 3 toxicities at the maximum tolerated dose in that setting. One of the things that we see that's different when you dose the drug continuously versus intermittently is a lower rate of mucositis, GI disturbance, and fatigue compared with what you expect to see with continuous dosing of the pathway. That's also a pattern that we're seeing in combination with fulvestrant in the phase I-B that we'll present next year.
I do think it's an important principle, and I think there are also preclinical data coming out of collaborations that we have with Neal Rosen's lab showing that actually you can drive better efficacy as well as better tolerability through the intermittent dosing profile. I think it's important. It does take time and effort to invest in doing this, but I think it's time well spent because I think chronic tolerability in the setting that we're looking to take this compound forward is important.
Thank you, Susan. We have two questions from Steve Scala on the internet. The first one is for you, Susan, to compare our SERD, AZD9496, with the Roche ARN-810, what PK dosing and safety data differentiate the two molecules. There's a second question on the melanoma data. PD-1 IP showed very good one- and two-year overall survival in melanoma. What is the setting in which PD-L1, BRAF and MEK would be used? How we would see these two regimen being sequenced? Maybe I take the melanoma question and then you answer on the SERD. First of all, I think it's important to put this study into the context. It's part of our strategy to really differentiate. We are not really following melanoma just for the sake of getting our PD-L1 approved in melanoma.
We're trying to differentiate our antibody in developing a new combination that could provide benefit and are different from what the others are doing. The first step was to show that our PD-L1 confirmed the very good safety profile that we have seen in the phase I and could be combined easily with small molecules and in particular with BRAF and MEK inhibitors. As Mohammed mentioned, other studies have been in trouble trying to combine either IP or eventually PD-1 with BRAF or MEK. Here we have achieved, I would say, the first goal to show good tolerability and of course, more data about the safety, but the efficacy will be communicated in scientific meetings. The next step would be, of course, to demonstrate the real clinical benefit of this triplet.
Before to think of how to position this versus IP PD-1, we need to really have the experiment and show that this triplet has an addition in terms of clinical benefit, either in terms of tumor shrinkage but also in terms of durability of response. Then, of course, we will discuss with the regulators what's the appropriate way. Melanoma is not clearly our next tumor type, if that's what you have in mind. Susan, do you want to-
Yeah, answer the SERD question. We've started dosing the first in-human study with 9496. It's too early to give you any PK data. We intend to present the preclinical pharmacological package for this data and an update on any clinical data at AACR next year. I'd be happy to follow up in detail at that point. Obviously, we're confident in the selection of the molecule that we've got. We've got a great profile and good oral bioavailability predicted from the preclinical data.
Thank you. We have a question in the back there.
Hi, it's Keyur Parikh from Goldman Sachs. Three questions, please. First, just looking at the kind of chart on planned trials. I see that you're doing a CD19 combination with PD-1 and not a PD-L1. Is there a reason why kind of you've chosen to go with PD-1 rather than the PD-L1 there?
Secondly, if I remember correctly from the data presented at ESMO, and I kind of understand more that you're not stratifying it by HPV status on the head and neck study, but the data presented seem to suggest that the Merck compound works a lot better across both HPV positive and negative, whereas the Astra compound works better in the HPV negative cohort. Is there a mechanistic reason why that might be the case? Lastly, as I look at the combination data, if I'm reading this correctly, you've had a response, an ORR of five out of 18 across the patient population and three out of 10 for the PD-L1 negatives, which would lead us to two out of 18 in the PD-L positive or response rate less about 10%. Is there a reason why your combination seems to not work in the PD-L1 positive?
Thank you. The short answer is no. I'm going to leave Mohammed to answer your question number 2 and 3. Maybe to start with the CD19, PD-1 phase I-B combination, I ask Peter again to give some light on the rationale of this phase I.
Thank you very much. There's a number of opportunities that we have in the portfolio. With respect to CD19 and PD-1, if you look at the axis in heme tumors, the responding cell to anti-PD-1 with respect to the biology of CD19 is blockade. We anticipate or postulate here that by removing the PD-1 inhibition on the responding cell, keep in mind, please, that CD19, our MEDI-551, is an afucosylated antibody that has very exquisite ADCC-inducing potential. The responding cell is going to be either an NK cell or a T cell, potentially a macrophage, which are sensitive to PD-1 blockade. This is not to say that both ends of the spectrum, PD-L1 or PD-1, might not come to play here, but within our preclinical data and modeling, PD-1 suits itself very well with CD19 because of the responding population.
Yeah.
Let me comment on the head and neck data with regards to HPV and the potential differences between what was reported with the Merck compound and ours. I think the bottom line is that the HPV status associations with our data, the data sets are relatively small, and we actually didn't collect HPV status on all patients. I wouldn't draw too many conclusions between potential differences between the Merck data versus ours because the data set overall is small, and we didn't have complete HPV status collection in that phase I trial. With regards to the tremelimumab PD-L1 combination and potentially a lower response rate in PD-L1 positives, I think the important point to take away is that we have not typed every single patient on the combination. We only typed 11 patients. Of those, 10 were negative, one was positive.
Actually, we don't have sufficient data in terms of the response rate of the combination in PD-L1 positive. We're in the process of generating that data, but we don't have it from the data set that was presented in Madrid.
Thank you, Mohammed. Sachin?
Thank you. Sachin Jain, Bank of America. Three short questions, hopefully. Firstly, Mondher, you promised you'd come back to my faster market strategy. I wonder if you could touch on that for some of the assets that Susan touched on, the c-MET, WEE1, and TORC.
Yeah.
Secondly, on the CTLA-4 PD-L1 combo, you've listed new solid tumor starts since ESMO. I wonder if you just give us some color on what tumors you've seen preclinical activity and the breadth of tumors you're looking at there. The third very high-level question for Susan on the DNA damage response portfolio. Just some broad color on what size of market you see, how broadly applicable this is, and I guess some color as to why you're excited by this as a portfolio, whereas others, as you've referenced, potentially are not looking at it as much. Thank you.
You want to start, Susan, with the DDR-
Yeah.
portfolio strategy?
I think it's interesting. I'm a radiation oncologist by training, so causing DNA damage has been something that I've been doing for a little while. I think when you understand that actually there's a large proportion of common cancers that have a deficiency in one or other of these pathways and often have a p53 mutation, which as I described for the WEE1 inhibitor, already means you've got a deficiency in one point in the checkpoint in the cell cycle. I think it's a broadly applicable platform. I think what we've lacked before is the molecular understanding of which patients are likely to be sensitive to which mechanism and the range of really good quality compounds to specifically drive activity. Right?
The reason why we're a leader in the DNA damage response science is because of the KuDOS acquisition and the scientists that came with that KuDOS acquisition, along with olaparib. We've built on that and understood those data. I think in Mene's talk, he's going to talk a little bit about some of the data that come with ATR and ATM. I suspect, clearly there's multiple companies that are interested in PARP inhibitors once there was some clinical proof of principle with PARP inhibition. Obviously, that went through its own wave of enthusiasm and then some lack of enthusiasm after the iniparib data, which was subsequently shown not to actually actively and potently inhibit PARP.
I just think it's one of those things where you require a level of clinical validation, but we're in a fortunate position to be in a leadership place in a mechanism that I think is important. I don't know, Mondher, whether you want to comment on what you think is the commercial potential for the DNA damage response portfolio.
I can. Actually, it's interesting because we have been debating and discussing this, the richness of this portfolio of multiple agent, more or less working around the same mechanism of action, but targeting different subset of patients. The first key message is that any tumor type, potentially, especially if you combine the DDR agent with a cytotoxic certain type of DNA damage, cytotoxic or eventually radiation therapy could potentially be a subject, and we could use the agent. Number two, as Susan said, we have beyond the combination, the ability to sequence those treatments somehow. I can't give you the full potential of the four agent.
If I think of olaparib only and go beyond the fast-to-market strategy that we have in the BRCA-mutating platinum-sensitive ovarian cancer and start expanding to the somatic mutation and then to even beyond the mutation to other sort of ovarian cancer, in particular, you may have in mind the NCI data that were presented in June at ASCO, where the combination of olaparib with cediranib provide a great clinical benefit in all type of patient who have been treated with the platinum but relapse. Clearly the idea is to expand for each and every tumor type. For olaparib, for instance, we have beyond ovarian cancer, a number of other indication. Gastric cancer is one of them. Breast cancer, as you know, both early and late stage. Prostate cancer, as Susan showed you. Potentially also other tumor type that are part of our ESS program.
Very important potential without getting into the detail. Clearly this class of agent that has been somehow forgot about a couple of years ago because people were disappointed after some trial were negative actually with the launch of olaparib is going to be revitalized. There was a question on CTLA-4 PD-L1 antibodies combination. Before I hand over to Mohammed to give you his view. First of all, clearly the differentiation strategy that we have is to push for the combination, and the combination of two IMTs is the first one we've picked, and the signal we've seen in lung cancer is very exciting. It does not mean that we should not explore this combination in other tumor type, first of all, and Mohammed can give you more detail on the different basket study that we have there.
In the same time, I think it's too early to tell whether there will be a differential of activity between PD-L1 negative and PD-L1 positive. I think the PD-L1 negative, we know the scientific rationale there, and we know that CTLA-4 can upregulate PD-L1 and then increase the level of expression and somehow render the tumor cell more sensitive to an anti-PD-L1. We don't know whether the level of activity and the magnitude of the benefit is not the same in the PD-L1 positive. We need to do the experiment, and we will be doing the experiment to show that. Mohammed, do you want to give some highlights on this one?
Sure. I can comment. Our thinking around the development of the combination is in part driven by the fact that the signals that we're seeing from our broad phase I trial just using MEDI4736. As we see signals there that identify tumor types that are responsive to PD-1 targeting, but then obviously it identifies also a subset that are not responding to PD-L1 monotherapy, is to then position the combination to go after those tumor types to see whether we can actually now capture a larger segment of patients that can respond or benefit from the combination. It's learning from the monotherapy experience, but also understanding the biology that as long as that there is a T-cell infiltrate in these tumors, but there's a segment of patients that don't respond to monotherapy, we can potentially rescue those patients with a combination.
Susan will pick up the last question on the first-to-market strategy.
First-to-market strategy. The data that I showed you from the Glenn Denning study included some patients with squamous lung cancer, where we actually saw two out of two patients that had quite impressive and durable responses in that combination with paclitaxel. Clearly two is too small of a denominator to have a high level of confidence, but we're currently expanding that study, and I think that might provide an attractive opportunity. Again, as I said, assuming that the data continues to be encouraging, there's a potential for a phase III investment decision next year. I think for papillary renal cancer, for the c-MET inhibitor also represents an opportunity, and again, it depends a little bit on the response rate and the durability of response in those settings. We have limited data currently. We'll be looking at that as well.
I think as a general principle across all of the agents that we've got, that we're looking for settings where there is a selected patient population that's going to be particularly sensitive in seeing if there's a route forward that would enable more rapid approval in that segment.
Thanks. Antoine?
Thank you.
We have time to one more question. Alexandra?
I've only got two left. One of it's actually a follow-up. Before we talked about the safety of the combination of MEDI of the triplet. Given that this is the second time we're seeing MEDI being easier combined with something else than, for instance, nivolumab, can we now safely assume that's always going to be the case, or whether it's just a safer thing to use? You have other ongoing studies, for instance, with Iressa. Is that just something which is easier to combine with a TKI than nivolumab? The other quick question is, how much follow-up will you have for AZD9291 when you will complete the filing in the second quarter next year?
Okay. Antoine, start with the AZD9291, Mohammed, you conclude on the safety of
Okay. When we complete the filing, the last data cut we will submit will be in the early first quarter. We have already engaged the agency to provide them with an updated data set at the chosen time points so that we have a maximum duration of response evidence. Which obviously the response rate is here to stay, and the big question is how durable is this response? We currently have 9.6 months and continuing to accrue. Yeah. It was at the last data cut in August.
Thank you. Mohammed, the question on the safety of the combination, in particular the safety of PD-L1 antibody.
I would make two comments. One, if you look at the monotherapy safety of PD-L1 in general compared to PD-1, I think there are some differences that are beginning to emerge that suggest that the overall safety profile of PD-L1 targeting agents, especially ones that the FC function has been disabled, appears to be more favorable than PD-1. Again, it's still early days, but now we have several hundred patients treated with both PD-1 and PD-L1 in phase I trials, and the safety profile appears to be different. With regard to your specific question around the triplet, I would highlight one other difference about that study is that the previous attempts to combine immuno-oncology agents with BRAF, it was with BRAF alone. We know from experience that the combination of MEK plus BRAF at least ameliorates some safety issues with BRAF alone.
It could be the combination of the fact that PD-L1 may generally have a safer profile than PD-1 and the fact that this is a triplet where MEK tends to down-regulate some of the tox profile of BRAF alone.
Yeah, just one other characteristic we like in the antibody, it's just going to at least translating into maybe safer, at least we like it. Especially for combination, it's really important because we don't see ADA. We don't see anti-drug antibody with this, which makes it a lot easier when you do it with combination.
Thank you, Bahija. We are exactly on time. Thank you for your question. We'll be around after the session for informal discussion. It's now time for a break. No. Sorry.
Briggs, sir. Well done. Well done. Very well done.
No. Thank you, guys.
Okay. Why don't we go ahead? I'm going to just do my presentation, then we'll take a break, then we'll come back with many of Bahija. If you have questions for me, just save them. We'll address them after the break. I'm Briggs Morrison. I'm the Head of Development and the Chief Medical Officer for the company. I see many familiar faces that were at the session we held like this in New York in March of 2013. Those of you who were at the session in March of 2013 will remember that I introduced myself by telling you a few stories about from my days when I was treating patients. I told you a couple of stories, very gratifying stories, about what it's like to be a practicing physician and see your patients do well.
I also told you some sort of haunting stories of patients who didn't do well. Patients in their 20s, 30s, 40s, who died prematurely because we didn't have effective therapies for their disease. I told you that kind of remembering those sorts of stories and those patients is what brings me to work every day. We've tried to capture that passion for patients in our ambition. What we said in our ambition is that we hope to improve the lives of 200 million patients. Now, if you pause for a minute and think about what does that mean that you're going to improve the lives of 200 million patients? What it means is that 200 million times you're going to have an interaction like you see in the picture on the side here.
An interaction between a healthcare professional and a patient, where the healthcare professional is going to talk to the patient about their disease and about different treatment regimens that we can offer for their disease. If we've done our job well, in fact, I would argue only if we've done our job well, that healthcare professional will recommend to their patient an AstraZeneca product. That's really the business that we're in. We have a very heavy burden that puts on us to generate information that healthcare professional needs and to generate information so that healthcare professional feels confident both in the quality of the way we manufacture our products and in the information that they have so they can make a recommendation to use an AstraZeneca product. That has to happen 200 million times around the world in clinics in multiple countries.
That's what we come to work to do every day. Now, we've tried to use pictures like this and stories like this to inspire our people to do great things, to do things, to be honest, that they didn't think was possible. In fact, to do things that even some of us didn't think were possible. I think if you look at our performance as a company over the past couple of years, what you see are for some reason it's working. People are actually doing great things that they didn't believe were possible. You've heard multiple stories about the 9291 program. I think if you asked people, "Was that possible?" They would say no, but our people delivered it.
If you think about the 4736 program, just to put it in context, when 4736 went into phase I, one of our competitors was already in phase III. Yet we now have a leading position in the adjuvant space. We have a leading position in the PACIFIC trial in a population of patients that they haven't gone after. Our people have done really remarkable things.
If you think about, at the 2013 session, I told you about SAVOR and how we finished our outcomes trial long before Merck did. That exact same passion and energy is being brought to the PEGASUS trial. We asked the team to do something that they didn't think was possible. I wasn't even sure it was possible, but Elisabeth and her team are now mobilized the whole organization. They've been energized, and they're going to deliver that study probably 4 months sooner than they would have otherwise. That's the kind of passion that we're trying to bring to everything that we do. I think what that's led to are my three key points. Number one, I think we are doing an excellent job in delivering the pipeline, and I'll show you more detail around that. We are focusing our spend on our core therapeutic areas.
Now we're going to pivot for you all. You've been tracking our progress of rebuilding our phase III portfolio. What we want our organization to do, what we want you to do is to pivot and focus now on submissions and approvals. We want to take this great phase III pipeline that we've built and now bring it all the way through to approvals so that we can have information and a marketed drug for a healthcare professional to recommend an AstraZeneca product to their patient. Let me just say one comment about who are the people that are doing all this wonderful work. Since 2013, when we met with you in March, if you look at the 9,000 people in our R&D organization, about 20% of the people are new. Some of those people have come through the acquisitions.
Chuck Bramlage and his group from Pearl, from Thera, from Almirall, from other acquisitions. These people have come into the company, and to be very honest, they've shown us new ways of working and inspired us by the kind of work that they did as entrepreneurs setting up their companies and then bringing those into AstraZeneca. If you look on the other pie chart, that's the top leadership of the R&D organization. The top leadership of the R&D organization, about a quarter of the people are new from March of 2013. Many, and Bahija will give you some examples of very accomplished academic physician scientists who have come into our company because they love what we're doing, they love what we're building, and they're very excited about working with us. These are the people.
The other interesting I would say is, of course, 80% of the people are people who were at AstraZeneca before we started our journey. I think what we have seen is that by having a clear vision and having a clear strategy and clear priorities, our people have really rallied around those priorities and are delivering remarkable results. Pascal showed you this slide today. We showed you this slide in 2013. These are the things that we said we would do in terms of achieving scientific leadership. I'm going to start off with focusing on our core therapeutic areas. This is the slide that Pascal showed you earlier about the three core therapeutic areas and the two opportunistic areas, and including the technology that sort of underpins our overall strategy. There's this old saying that how you spend your money is your strategy.
The question is, how are we allocating our money within the R&D units? If we look at 2013, what you saw was about 80% of the R&D spend was allocated to our three core therapeutic areas, 20% went to the two opportunistic areas, infection, vaccines, and neurosciences. As we plan for 2015, what you can see is now 90% of the money we plan on spending in our core therapeutic areas, only 10% in the two opportunistic areas. That 10%, to be honest, we're getting really very good return for. Many, and Bahija will again give you some examples of the really creative work that's going on in those two units. You can see that 90% is now focused on our core therapeutic areas, and you can see the ascendancy of oncology in terms of the way that we're spending R&D dollars.
A number of people during the day have asked, "How are you affording all this?" You can see that clearly about half of that 90% is going to oncology, and that's underpinning the hope that oncology will be, in fact, our next growth driver for the company. In 2013, we also laid down for you three major markers that we said you should track and that we have tracked to see how we're doing on our journey to achieve scientific leadership.
The three markers were, number 1, that we would advance five to seven new molecules into phase III from internal work, that we would have 10 potential NME submissions between 2013 and 2016, and that we would grow the pipeline from the six molecules we had in late-stage development, as Pascal said earlier, to eight by the end of 2013 and potentially 12 by the end of 2016. Let me just talk through how we have done with regards to these three markers, and I'm pleased to report to you that I think it's very fair to say we have either met or exceeded all three things that we told you that we would do that served as markers for our journey towards scientific leadership. The first is the five to seven NMEs. We've actually advanced nine molecules into late development from inside.
Again, consistent with the focus on oncology, six of them are oncology compounds, two of them are the severe asthma compounds that Bing talked about, and roxadustat, which Elisabeth talked about. We clearly have exceeded our goal of five to seven by having nine. When we look at the goal of having 10 potential submissions between 2013 and 2016, we already had three in 2013. We're on track to have a fourth in 2014. We already have the data in hand for three more in 2015. That's CAZ-AVI, durvalumab, and AZD9291. I think the odds are quite high that we will get seven, then we still have eight more opportunities to get to the 10. Again, I think we're going to exceed the 10, but clearly, we're on track for that.
Pascal touched on this slide of how we have rebuilt the portfolio and now have 14 molecules in late-stage development. I talked to you a little bit about how we have reshaped the R&D spending so that 90% of it is focused on our core therapeutic areas. Even within the R&D spending, we also had to make an additional adjustment, which is how much do we spend on early development and discovery versus late development. The panel on the far side is the exact panel that I showed you in 2013. At the time, in 2013, about 40% of our total R&D spend was on late development and about 60% was on early development. We planned that by the end of 2016, we'd be at about 50/50.
What's happened as the pipeline has progressed so rapidly is that in fact, 2014, this year, we're going to probably end the year at about 50/50, and planning for next year, we're going to have completely inverted it. Now we'll have 60% of the spend in late development, 40% of the spend in discovery and early development. Some people in the room and some people have asked us, "Well, is that really the right thing to do? Aren't you sort of starving your seed corn? Are you still going to be able to produce things to have a sustainable model?" I think what's remarkable in that regard is that we've actually done a great job of building the early pipeline as well as the late pipeline. This is what the pipeline looked like in 2013, and again, just to orient everybody, phase I, phase II, phase III.
On the far side are the small molecules, and on the near side are the biologics in each one of those categories. This is what the pipeline looked like in 2013. When you look at what the pipeline looks like now, not only have we built our phase III portfolio, but we've also added tremendous breadth in our phase I and phase II, and Mene and Bahija will tell you a little bit about the breaking science that we think does underlie a sustainable model that we can sustainably generate great molecules and progress them through our pipeline. Remember, the goal isn't just to put things into late development. The goal is to get things from late development through registration, get approval, and put them in the hands of healthcare professionals so they can hopefully recommend our products.
With the substrate that we had when we started in 2013, I think we've done a good job of progressing those things through their next milestones. First, of course, are the data readouts that help us to understand the profile of our drug. Both Casodex and lesinurad had positive phase III readouts. I think it's fair to say that for lesinurad, the efficacy might have been a little bit less than we were hoping for, but the safety was a little bit better. It's a profile that we're still, and there's been some questions already about that profile and what's it going to look like, but it's clear to say both of those agents had positive trials, and at least now we know what the profile is.
In the cardiovascular metabolic space, we've delivered approvals that are critical products that will underpin the growth of the company over the next period. So you've heard about the BYDUREON dual-chamber pen. The early days are that that's doing quite well. FORXIGA itself, of course, approved in the U.S. and Japan. Xigduo, the only once-a-day SGLT2 metformin combination therapy approved in the U.S. and in Europe. Epanova approved in the U.S. And the top-line results, which Elisabeth talked through with you on the combination of saxagliptin and dapagliflozin. In oncology, of course, we have the positive CHMP opinion for LYNPARZA, which is the trade name for olaparib, for those of you who just want to make sure you're following along. At the mid-year, I said I was modestly optimistic that we would get approved in the U.S. I've sort of upped my ante on that one.
I think I'm a little bit more optimistic that we will get approved in the U.S. because of the interactions we've been having with the FDA. And of course, to talk about things that we didn't think were possible, we got MOVANTIK approved in the U.S., and I have to say, when we first filed that drug, the feedback we got from FDA, it did not seem to us that that was a likely scenario. But again, our people did things that nobody thought was possible. They got it approved both in the U.S. and of course, the positive CHMP opinion. You've heard a lot of presentations from people about a lot of things that are going to be coming over the next year.
What I thought I would do is simplify that for you in one slide, so sort of the key news flow that we believe as a company are going to be quite important to your perceptions of us as a company over the next period. So we have a combination of regulatory submissions and data readouts, and I'll just go through these so everybody's clear on what they are. So first, of course, is brodalumab. Bing showed you the data from the first head-to-head trial versus STELARA. The second trial should read out before the end of this year. And again, assuming that that all is consistent, we'll be on track to file that next year. The PT003, which is the LAMA/LABA from Pearl, that data will read out at the beginning of next year. And again, if positive, we will be on track to file that next year.
Just want to make a point about the LAMA/LABA. Some have asked, is the LAMA/LABA itself a critical product for you? One thing I think is very important to remember, this is the part of the foundation for the triple. Some people have asked us as we've gone around and visited with you, to do this triple, don't you have to do every combination of A plus B, plus B plus C, and all that? And the answer is, yes, you do. But a lot of that is done in the LAMA/LABA program. So the LAMA/LABA program reading out positive gives us a very firm foundation to now build on the triple. anifrolumab for lupus. The phase II data will be presented sometime next year. And of course, the lesinurad submissions.
If lesinurad, the submission goes in before the end of this year, it is conceivable, I'm not saying it's assured, but it's conceivable it could actually be approved before the end of 2015. In cardiovascular metabolic, I think everybody now who's been in the room all day knows the importance of PEGASUS, and that will read out early next year. If positive, we're on track to have regulatory submissions for that. The Qtern fixed-dose combination, the regulatory submission should go in by the end of this year. If the review goes well, that could be approved by the end of 2015. In oncology, we already talked about the approval for olaparib both in the U.S. and in Europe, but also the SOLO2 data.
The SOLO2 data is the phase III trial that replicates what was done in Study 19, really a critical trial for us. AZD9291 submission, I will say the submission is on track to be in the second quarter. If we get accelerated review by the FDA and the review goes well, it is possible that AZD9291 could get approved before the end of 2015. I just want to be very clear with people about this MEDI4736 PD-L1 third line non-small cell lung cancer. That's the so-called ATLANTIC trial, I just want to make sure that people are clear. The ATLANTIC trial is a potential opportunity for accelerated approval. It is in patients who are PD-L1 positive with non-small cell lung cancer. There are two cohorts.
One is a cohort of people who have either EGFR mutations or ALK rearrangements, the second cohort is the people who don't. Either one of those cohorts could potentially be an opportunity for accelerated approval, but the conditions around that are, first of all, the data have to be strong enough to warrant accelerated approval, it depends on none of our competitors blocking us. If a competitor already has full approval in its subsegment that we're trying to get accelerated approval, that's a bit of a challenge. It is potentially, I emphasize potentially, a registration program. Depends on the data, it depends on the competitive environment.
I think Mohammed did a very nice job of explaining to you the MEDI4736/TREMI combination in that unique population of non-small cell lung cancer patients where, to be honest, there really doesn't seem to be a whole lot of competition. It's those people who are PD-L1 negative and do not have one of the mutations that makes them available for EGFR or ALK therapy. It's a very large population of lung cancer patients. I think next year at ASCO when we read out what the dose is that we've landed on and maybe some early data on larger numbers of patients, I think that's going to be an important point for us. We're still trying to work through the cediranib data and analyze that and find out whether it's going to be suitable for regulatory submissions. I want to set your expectations.
We do not believe that that's going to be appropriate for a U.S. submission. Depending on how the data comes through, it could be appropriate for a European submission. Finally, the descheduling and launch of MOVANTIK both in the U.S. and Europe. Those are some of the key news flow. You've heard many other things today, but I think those are ones that you should keep your eyes on. Finally, I just want to lay out again for you the new set of markers that we would ask you to keep your eyes on, we as an organization are keeping our eyes on as we go through the next two years. The key thing at this point, we want to focus our organization and the innovation and the energy in our organization around taking this pipeline and getting it through to submissions and approvals.
We anticipate that between 2015 and 2016 we will have between 14 and 16 submissions. Half of those will be new molecular entities and half of those will be new indications for established medicines. For example, the PEGASUS filing for Brilinta would be a line extension. Of the 14-16, half we anticipate will be new molecular entities, half we anticipate will be line extensions. Depending on the timelines for regulatory review and when we get those in and putting a little bit of probability around it, we anticipate that during that same time period, we'd have 8-10 approvals. Again, half of those we think will be new molecular entities, half of those will be new indications for medicines that we already have approval for.
To make sure that we also have a sustainable business model and that there are great molecules coming through, we've also given ourselves the task of making sure that we're having significant number of, I want to be very careful here, high-quality phase II starts. Mene and Bahija will talk to you about the work that's been going on in the discovery and early development group so that we understand the science. If we can have phase II starts with molecules like 9291, we'll be very happy. That's what we keep telling them over and over again. Give us those ones where it's very clear, and we can move them along quickly. Those are the markers that I would ask you to keep your eye on over the next two years to judge us on our next stage of the journey towards achieving scientific leadership. This is a substrate.
Again, on the bottom, you have the molecules that could potentially be NME submission opportunities in 2015 and 2016. On the top are those new indications for molecules that would potentially already be approved. In closing, I just want to again say I think we've made tremendous progress on our pipeline. It's just overwhelming to see the work that the people in our organization can rally around when you focus them and give them clear objectives. We clearly are now focusing our resources on our key therapeutic areas with again the ascendancy of oncology as we spend our R&D dollars. Again, I've shown you the potential 14-16 submissions and 8-10 approvals for NME and major life cycle extensions. I'll stop there. I think the clock just ran out. We're going to take a break now.
If people could be back by five minutes before the hour. Mene and Bahija will talk, then we'll take your questions. Thank you very much.
Okay. We're on the finishing stretch. What I hope Bahija and I will be able to talk to you about over the next 40 minutes or so is to really give you some insight into some of the earlier programs we have in our pipeline and in our research labs to give you a flavor for what we think is some of the cool science that's going on in our labs. We'll start with the iMed Biotech unit first, which I lead. Some of you will be aware of a paper that we published earlier in the year in Nature Reviews Drug Discovery. There were probably three key learnings from a study that we did looking at our progress between 2005 and 2010 in terms of how we moved our programs and what that did in terms of the quality.
The first is that our teams are focused on quality and not quantity. We're not measuring them by numbers of candidates or numbers of INDs. We're focusing on the quality of the science and the rigor of their scientific thinking. The second thing is this fundamental focus on understanding disease pathophysiology, the mechanisms that we're working on, and trying to validate or invalidate hypotheses. That leads to what we call truth-seeking behavior, not milestone-driven behavior. That transformation, I think, in our organization, runs through the veins of every scientist in AstraZeneca and MedImmune. It's very, very important because it really shifts the focus of our programs and our science. Of course, what that does is it also makes it easier for us to recruit great talent.
You've seen some of it on show today, there are many fantastic scientists that are excited about the fact that we're a science-led organization with a really exciting pipeline, and we have the truth-seeking behavior, trying to understand fundamental disease biology. If I take two examples, Tim Eisen, who's just joined us from University of Cambridge, a preeminent clinical oncologist, M.D., Ph.D., who's joined our early clinical development group. Ralf Knoll, who's joined us from Imperial College, where he was a full professor, he's moved to Gothenburg to our Mölndal site to work in our Cardiovascular & Metabolic Disease group. Both these scientists are incredibly well-regarded internationally, fantastic publications, they elevate the level of all of our science, not just because of what they bring, but because it rubs off on all of the people that we have in our organization. Very, very important.
As a consequence of this, we're also publishing more. As a scientist, I think one of the best ways of recognizing the quality of the science in your labs is peer review, whether it be in publications or internationally recognized academic conferences. What you can see here is the pressure that we've put on our organization to really publish high-quality papers, to publish in high-impact journals. Of course, this attracts great scientists again because they have a chance to do great science, to publish and talk about it, and to enhance their reputation, and to ultimately, I think, lead to much better drug discovery. The other piece that Pascal touched on right at the beginning of the day is the fact that I think we have a real opportunity.
We're consolidating in Cambridge, which is one of the most exciting places to be a scientist in the U.K. We're bringing our MedImmune colleagues together with our AstraZeneca colleagues. We're also going to make it very easy for our scientists to commute between Gothenburg and Cambridge. There'll be four flights a day, so you'll be able to go back and forth in a day. It means the scientific exchange between those groups is going to be really, really easy. What that means and the opportunity that I think we have is really to create a European scientific powerhouse. I think we have the science to do this, I think we have the people, and I think we have the networks. I think it's a real opportunity for us that we're going to try and capitalize on over the coming months and years.
Okay, let me talk a little bit now about a couple of areas. First one will be in the respiratory space. You've heard from Bing about the impact with the acquisitions we've had over the past year or so with Almirall and Pearl have had in terms of the flexibility we have and the complementarity with our own internal capability in terms of devices and formulation. What does this mean if you're a respiratory scientist? It means that as you come up with really neat molecules that are selective and potent, you have a choice of formulations and device to put them into to enable us to test hopefully more mechanisms and get those drugs into the lung and avoid systemic side effects. Let me give you a flavor. This is really just picking three programs.
These are obviously early, but I could have picked a number of different projects. The first one is our JAK inhibitor, AZD0449. Bing told you about the importance of IL-4, IL-13, TSLP, pathways that are validated in asthma. We have a small molecule inhaled JAK1/3, JAK1/TYK inhibitor, which basically modulates the IL-4, IL-13, and TSLP pathways. It's an inhaled molecule, so we can limit the systemic exposure not see any of the liability you get with systemic exposure. On the graph on the bottom, I'm just showing you some of the preclinical data in mice, where we challenged the mice with IL-13 to drive the inflammatory pathway in the lung. The animals take increasing dose of inhaled AZD0449. You can see that we completely drive down activation of the pathway as measured by phosphorylation of STAT6 to the same degree as an anti-IL-13 antibody.
On the panel on the left, I'm showing you some world-leading, I think, first-in-class biology around toll receptors. This is a TLR9 agonist, inhaled oligonucleotide, AZD1419, that we're doing in collaboration with Dynavax. As you know, asthmatic patients, when challenged with an allergen, have a preponderance to get exacerbations, and they have an overstimulation of their TH2 cells, creating more pro-inflammatory cytokines such as IL-5 and IL-13 in their lungs. What we're trying to do with our TLR9 agonist is reset that TH2 balance to bring down that TH2 drive and equilibrate the lung in these patients when they get challenged with an allergen. In the experiment, I'm showing you what I mean. This is, again, in preclinical in mice. We're challenging the animals with an allergen called ragweed. We challenge them every week, and they only get a dose of the TLR9 agonist for the first five weeks.
We keep on challenging the animals for another 11 weeks, and then we measure their immune response when there's no drug on board. What we can see is that following five weeks of administration of a TLR9 agonist, at week 12, we can see a complete knockdown of IL-5 and IL-13 signaling. Basically recalibrating the system. The way that a patient would use this is a short few weeks course of treatment, and then it'd be hopefully free of exacerbations with their asthma. I think, again, very novel, first in class, and we've already got proof of mechanism in the clinic with this particular molecule. P38, and many of you will know it's a very well-validated pathway. It's one of the central players in inflammation. It drives both IL-1 biology and TNF-alpha.
I remember working on a P38 program when I was at GSK in the 1990s, and there were some great molecules. The problem was systemic tolerability, hepatotoxicity, toxicity in the joints. What we've developed is a very potent, very selective P38 inhibitor that we can again dose through inhalation. We know that P38 is activated in macrophages in the COPD lung. We know using human alveolar macrophages that we can completely inhibit the pro-inflammatory drive of these macrophages in vitro. We have data now in vivo in LPS-challenged healthy volunteers that we can actually activate the mechanism. We can block both the activation of neutrophils and the production of TNF-alpha in response to LPS. Proof of mechanism, the molecule does what it says on the tin, and it's now going into a phase IIB study to see if it can have an impact in COPD patients.
That gives you a flavor of what we can do in the respiratory space. Let me talk to you a little bit about oncology. Again, Susan's covered quite a bit around our DNA damage response portfolio. It is world leading. We acquired the biology and the chemistry from KuDOS, but we've continued to push. One of the things I would say that is quite unique in AstraZeneca, we have got phenomenal chemistry. We're able to make exquisitely potent and selective molecules, and we're good at this. I think this is another reason why we're able to get so many of these molecules through the clinic and ultimately through proof of concept. You've heard about olaparib, you've heard about WEE1. Let me talk to you a little bit about one of those DNA damage response genes, which is called ATR.
ATR is activated following single-strand DNA breaks, such as, for example, through ionizing radiation. What this molecule does, AZD6738, is inhibits this ATR is a PI3 kinase. It inhibits the activation of this pathway, which is induced following single-strand DNA breaks, which basically enables a cell to deal with replicative stress. If you block the pathway, the cell can no longer deal with this replicative stress, it goes into mitotic catastrophe and dies. In the top panel, where you can see these little blue spots, we have two different cell lines. We've tested a number of different cell lines. It shows you that when you radiate these cells with radiation, you get an increase in replicative stress. Those little blue dots are a marker of protein called 53BP1, which basically is an indicator of replicative stress.
When you inhibit at the same time as you're inducing ionizing radiation, what you can see is the cell isn't able to remove this replicative stress basically is under stress and will die. In the bottom panel, what you see is that the more replicative stress that you get in the cells, the more susceptible the cells are to cell death. What does that translate to? When you put this molecule in vivo, this is actually in the colorectal cancer model, we can see that with increasing dose, we can get complete tumor stasis or regression, depending on the model that we use. The plans for this molecule, which went into man last year, are to start working with it in combination with chemotherapy such as carboplatin.
It's a very novel molecule, first in class, I think we have a real chance to also combine it with other molecules as well. Susan touched on this about the potential of combining molecules. This is actually just showing you some preclinical data in a triple-negative breast cancer model where you combine olaparib and WEE1. What you can see here, the lower the graph, the more we're shrinking the tumors, the lower the points in the graph. What you can see in blue is the bars, the dosing with olaparib, you can see that the tumors initially regress, they gain resistance, they start to grow back after a period of weeks. In the green bars, you can see treatment with WEE1, with our WEE1 inhibitor.
Again, we see regression, after a period of weeks, the tumors start to grow back. When we combine olaparib and WEE1 together, we see complete knockdown of the tumor. That, I think, gives you the possibility, the potential to have more profound benefit in the patients that we treat with a combination. We've touched on small molecules. Let me spend a little bit of time talking about oligonucleotides, because I think we're building, again, a leading position working with some of the best companies in the world in this space. We have three partnerships in the oligonucleotide space. The first one is with a company called Moderna, which is working in the modified RNA space. The second one is with a company called Regulus, working in the microRNA space. The third one is working with Isis in the antisense oligonucleotide space.
I'm going to spend most of my time talking about Moderna and Isis, but we actually have some very interesting preclinical data with Regulus as well. We're hoping to have our first candidate nominated towards the end of this year, early next year in the cardiovascular diabetes space. The molecule that actually has very broad activity across a number of preclinical models. In the interest of time, I'll focus on Moderna and Isis. Let's talk about Moderna first. If anyone had asked me five, 10 years ago, would anyone be able to create a stabilized messenger RNA that you can express in the cell and actually produce either an inch of the protein, a transmembrane protein, or a secreted protein, I would've said, "You're nuts.
No one will be able to crack that." What the Moderna guys have done is actually generated a chemistry platform or chemistry technology that really stabilizes the messenger RNA, enables you to transfect it into cells and express whatever protein, fusion protein, antibody, vaccine that you want. It's incredibly powerful. We have a five-year collaboration with them, working in the cardiovascular metabolic space and the oncology space. We have more than 20 targets in early research working on this platform. The data in the middle panel shows you some of the data that was generated by Kenneth Chien, who's a professor at Harvard, who's recently moved to Karolinska, showing some data from a modified RNA VEGF protein. What he's done is he's dosed this in an acute myocardial infarction model.
What he saw was that the modified VEGF RNA was able to stimulate both cardiomyocyte proliferation as well as blood vessel formation in the injured heart. What you can see in the top panel is vehicle-treated animals. In the bottom panel, you can see the VEGF mRNA-treated panel, and you can see those bright orange lines. Those are functional blood vessels that are basically oxygenating the tissue and preventing death and necrosis in the heart. What this results in is a functional heart, so better function, better outflow from the heart, and of course, if we could translate this into humans, it would be phenomenal. You're talking about cardiac regeneration. I hope that this type of approach will be the first approach we're able to take into clinic sometime in 2016. The panel on the far right just shows our ability to replicate some of this data.
We've taken a number of human cell types, whether it's fibroblasts, epicardial progenitor cells, or endothelial cells, and with every cell type, we're able to get very good expression of VEGF using this modified RNA. A very exciting platform that really opens up a whole toolbox of therapeutics that we could apply across the cardiovascular, metabolic, and oncology space. You've heard already from Mohammed about our STAT-3 program. This is a great collaboration, again, using generation 2.5 chemistry with Isis. We have five potential programs. The STAT-3 program is the one that's in the lead. We also have an androgen receptor program that's in phase I and currently going through dose escalation. What's exciting here, there's maybe two points I want to talk beyond the efficacy we've seen initially in DLBCL. Just to remind you, there were two patients in particular that we had partial responses with.
One was resistant to R-CHOP, had become sensitive to R-CHOP, became resistant, had gone into a hospice and went onto AZD9150, and actually, one and a quarter years later is still alive. The second patient actually had the worst prognosis, had been completely resistant to R-CHOP at the beginning. Went on to AZD9150, became well enough to have a bone marrow transplant and is still alive and in remission. That's why we come to work, I have to say. It's absolutely phenomenal. We learned from this experiment because we had actually defined some very clear go criteria for this molecule in terms of being able to knock down STAT3 in tumor cells for us to go forward to either a phase II or a phase III trial.
What we saw as we were doing the proof of mechanism studies was that we were actually knocking STAT3 down in the tumor microenvironment, in the circulating T cells. We weren't knocking down STAT3 in the tumors themselves. Of course, what this led us down in terms of the pathway was this is probably working through an immunomodulation pathway, not through a tumor cell killing pathway. We then did some experiments combining with PD-L1, and this just shows you some data in a colorectal xenograft model as well. You can see that PD-L1 on its own, or anti-PD-L1 on its own, has effect or efficacy in some animals, but not all. When you combine it with the anti-STAT3 oligonucleotide, we completely knock down the tumors. They melt away.
When we look at the tumors, we can see a very high level of infiltration of CD8 positive T cells. We're modulating the immune system as we want with an immuno-oncology agent, and the combination of these two molecules is better than either one on its own. This is the trial that we're currently doing, and I think very exciting. We're going in DLBCL and actually head and neck cancer now. Again, the message here is actually the learning of the organization. Because we're focused on science, because we're focused on mechanistic understanding, we're changing course as we're doing our experiments based on what the data's telling us. A few words on personalized healthcare, and again, Susan covered some of this, we don't have a diagnostics business, we are a personalized healthcare company.
Our teams think about this from the very first idea when we start a target in our research labs. More than 50% of our launches between now and 2020 are going to have a personalized healthcare approach to them, trying to identify the most responsive patient population for that particular mechanism of action. As Susan alluded to, the first company to get a circulating tumor DNA diagnostic approved and will be the second company with AZD9291. More than 70% of our clinical programs have a personalized healthcare approach to them. If you look at our scientific reputation in the personalized healthcare space as measured by publications, by our presence at scientific conferences, we're ranked number 2 to Roche, and we're catching up very fast. This is an area of intense focus for us across MedImmune and the iMed and is incredibly important for our future success.
Just to show you, this is showing you the iMed pipeline. Every program with a green dot has a personalized healthcare strategy. If programs don't have a green dot, our teams are working very hard to put a green dot on that program because they know how important it is for us to be able to define the best and most responsive patient population. Just finally, to maybe tell you a little bit about the journey that we've been on in the iMed. We've reduced our investment in the small molecule iMed biotech unit since 2010 by about 40%. Through that time, we've never been more productive. The number of backup programs in our pipeline has gone down from being almost half to less than 2%. Our cost per candidate is industry leading of between $50 million and $60 million per candidate.
Our probability of success from first GLP toxicology dose to end of phase II has gone from 6% to 16%, which puts us in top quartile performance in terms of productivity. We delivered five phase III programs to the organizations since 2012. I'm a scientist, and I'm very lucky to work with great scientists. It's never been a better time to be a scientist in AstraZeneca. We truly are open to collaboration. We're creating environments in our labs where scientists thrive and where they're really enjoying themselves and doing some really neat, exciting work. I hope I've convinced you that we really have a sustainable flow of innovation that's coming out, not just for tomorrow, not just for next year, but actually for the years to come. With that, I'll hand on to Bahija, and she can tell you about what we're doing in MedImmune.
Thank you, Mene. Good afternoon. I'm really excited to share with you MedImmune's early pipeline. I will talk about the foundation of our science and then show you what's next. For me, the foundation, as Mene said, starts and finishes with people. As we sit here today in London, actually a few weeks ago, we just celebrated the 25th anniversary of Cambridge Antibody Technology. That's 25 years for me in the combined organization of expertise in biologics. As a matter of fact, the people and the pioneers who invented some of the drugs that are helping patients today are still with us today. As Mene, you know, we have been also attracting scientists that really, as the pipeline was growing, are helping us bring new capabilities into the organization and move the pipeline forward.
The most important thing is absolutely to provide an environment where the science can thrive and where the scientists can have their Or free to innovate. One way we measure it, obviously, has to be the pipeline. Another way is definitely the publications, as you saw from Mene. This is just an example, and it's the quality of the publications. This is an example for what some of the output this year. When I go to the foundation, I can put it in three pillars. You heard that from Pascal. One is our expertise in immunology. The second one is our expertise in technology and protein engineering. The third one is that what we built the last seven years is the translational science.
If I go to immunology, you have seen, and I think I was really happy that we shared with you today, the breadth in our portfolio in the RIA space, so to the autoimmunity. Just to tell you that MedImmune was founded by an immunologist, and you can still feel it in the company. That's why we're taking that expertise into the immuno-oncology, and we intend to really go deeper in there and understand even more. As you know, there is the inflammation or chronic inflammation is the underlying cause of several diseases, not just immunology, not just autoimmunity, and the immuno-oncology. That provides an environment where all the therapeutic areas can benefit from each other and talk to each other. The second thing is the expertise in protein engineering.
Most of what you have seen today in the pipeline are monoclonal antibodies. I call them simple monoclonal antibodies. If we want to go beyond that because we believe there is a power of the biologics to go into even bigger space, you have to be working today on the new technologies for the future. We have pretty comprehensive toolkit. I would say, if we look into the preclinical pipeline and even in the early clinic, but in the preclinical pipeline, 50% of our pipeline is non-simple monoclonal antibodies, as I call it. The third part is translational. This is an area where I feel extremely passionate about because the desire here was to build in the organization, even the mindset, and build the translational as a real philosophy, then we can discuss again the OX40 and why.
This is part of that. Right? How can we not only bring the projects late bring them to Briggs with higher probability of success, but as importantly is how to identify very early if we can make the right experiments and stop the projects early in phase I, but have the tools and go hypothesis-driven. Let me tell you and show you a little bit what's coming. The first question you have to ask, do we have a sustainable pipeline and how is the early pipeline looks like? I'm showing you here the Usually we don't show, but just to give you a flavor of the early pipeline. At my left, you can see the preclinical pipeline. It's pretty solid. It's very diversified. You can see it. We have projects in all the therapeutic areas we're in.
You see also a solid phase I and phase II. It's not only about the numbers, as Briggs said, it's about the quality. I'm going to give you a little bit flavor of what's coming. I have to confess, this was the hardest part for me, to try to choose which ones to show. I try to keep every therapeutic area happy. Let me share with you this one. This is really the case where our therapeutic area or disease area folks basically give a challenge to our protein engineering. CD40, this is very known ligand, it's very validated. We know it's almost like a master switch in the inflammation pathway. The early antibodies went in there. They showed some activity in phase I. However, there was a safety problem, and that's basically because there was clotting.
The challenge was, how can we attack this pathway, especially for inflammation, without having the clotting problem? That's exactly what the protein engineering folks came up with, is now a proprietary technology for us, which is a multi-domain protein. The Tn3, what we call them tenascin 3 scaffolds. What you see on my right, I am directionally very challenged to tell you right and left, so I'm going to keep with mine. If you look at, this is on my right, in the left, on the lower panel, you can see if you see clotting, this is a preclinical model. If you see clotting, you see the curve going this way. If you don't have clotting, it's completely linear. That has been extensively tested in preclinical. This is non-human primates. You could see that we absolutely get rid of that safety.
Now the project is in phase I. We have tested two cohorts, at least, in the clinic, and so far so good. We will tell you more about it, hopefully, in the next year or so. The second project, we talk a lot about the immunotherapy, and we are excited, and we are absolutely pushing very hard. There is the other platform that we are taking, again, advantage of what we have in the organization, is the antibody-drug conjugate. This platform obviously has been validated in the clinic, and we believe it's very powerful. Last year, if you remember, we acquired Spirogen. Because they had what we believe one of the best warhead in the industry, and only recently was also validated in the clinic. This, I'm showing you just one representative. This is a cancer stem cell target.
You can see just with one single dose, this is the right. This is a xenograft model with the right curve. You completely kill the tumor. What it is, the antibody-drug conjugate, just to tell you, this is an antibody, and basically you put a warhead, which is a cytotoxic monoclonal antibody, so you can very specifically go to the tumor and kill the tumor. The Spirogen folks as well received the best scientific innovation just two weeks ago. To show you what's coming in here, we've been working in this area, not only in identifying, using our phage display novel targets, our proprietary targets to us, but also using the PBD technology, but also our own tubulin-targeting technology. We have both.
I'm happy to report that by the beginning of 2015, which is next year, we will have our first antibody-drug conjugates to enter the clinic. I wanted to show you what we're doing in the infectious disease because it represents several things. Several points. One is, this is an area that's really close to my heart, but at the same time, there's some great learning of the science that's going on there and also the entrepreneurial spirit going on in this area. As you know, we have one product on the market right now that's called Synagis. This is an antibody against the RSV virus. This is a respiratory virus, basically, that the premature babies, if they get infected by this virus, that could be even lethal.
Right now, the RSV season is around five months, you have to take, or if you're a premature baby, you can have five injection of Synagis. There is no vaccine. This is a prophylaxis, this is an antibody. It's the only thing that exists, actually, for this population. One of the idea was, can we utilize some of our technology to bring the next generation of Synagis or the RSV antibody? That technology is actually extending the half-life of the antibody. Basically, making the antibody stay in the body a little bit longer. What does it mean? It means instead of giving five injection in the season, you actually are able to give only one, which is more convenient. That's not only that you can actually give it to more kids as well. We have this technology.
We made the antibody against the RSV. We actually showed pre-clinically that we extend the half-life. This is the purple curve that you see. It by three times, what's the half-life of the normal monoclonal antibody. We also did the phase I studies, and we can confirm in human that we can extend the half-life as well, and this project is moving into phase II. Taking this idea from the antiviral, what we are, so far as I know, the only ones who actually managed to have prophylaxis in antiviral. We took this idea to antibacterial. As you know, this is a real problem right now for all of us that bacterial resistance. We go from one infections to the other, and we have the bacterial resistance.
Taking from what we've done with the antiviral is we basically hypothesized maybe we can do it in the antibacterial as well. If we go after that and make some prophylaxis, instead of dealing with the resistance, how can we actually not have the infection to start with? Why this is important? Most of the infections happen when you go to the hospital. You go for something else, and actually, you end up with infection. What we did first is an antibody against Pseudomonas. Pseudomonas is what we call the hospital-acquired pneumonia that's caused by Pseudomonas. You also get colonization for cystic fibrosis patients. They get colonized by Pseudomonas or Staph as well. We said, if we can have a prophylaxis antibody, that would be something good for society altogether. This is a really cool project.
I wish I could talk about it for a while, Let me just give you some highlight here. What we've done is you have to attack. The bacterias are not easy, you have to attack them in multiple ways. Here in this slide, just to show you, we attacked, we've made antibodies against both 2 types of virulence factors in the bacteria, and we put that in one single antibody. That's what we call the bispecific antibody. There are several things that are exciting. One of them is not only we can actually show that we can have a prevention, you can prevent the infection. We were also happy to see that not only that, but it's also active in treatment. The most intriguing one, and it's also exciting, is that we see synergy with the antibiotics. Okay.
It's a really exciting monoclonal antibody. It's in phase I, and actually, we received, which is for me at least, was a big surprise, we received a happy surprise, a fast track designation from the FDA before we even started the trial. We have same antibody with the Staph, and we received in the same month that antibody is in phase II-B, and we received in the same month the fast track designation from the FDA. I said this area is very entrepreneurial. Most of these studies are being also done in collaboration with the IMI, and the IMI actually is paying for definitely the Staph and parts of this one. The last one, I just want to give you a flavor because I believe that there is a huge opportunity for biologics in the metabolic disease area.
As you know, when a diabetic patient comes and actually is diagnosed with type 2 diabetes, they have already lost 50% of their beta cell health. Here we're looking at, we just said, okay, can we go and find factors that can restore that beta cell health? I'm giving you just a little bit of a flavor, and just to really tell you to watch the metabolic disease space because we will be hopefully bringing more molecules in the next 12 to 18 months. In this case, this is a secreted protein. Not only we see these are early, this one is the earliest that I'm showing you, but in animal studies, we see that we restore some of the pancreatic health, if you will, and then also it has an impact on the glucose.
If this is successful, it's going to be hopefully making a huge difference in type 2 diabetes. Those are just as early as we have in the pipeline. I just wanted to give you a little bit of a flavor, a little bit what's the strategy, where we're going, and also showing you that we have pretty balanced pipeline. We have, I think, very exciting science going on and also very exciting pipeline for the years to come, as Mene shared with you. For me, what's also exciting, we're moving beyond just a simple monoclonal antibody, which is allowing us to even widen the space where you can be in biologics. I just want to finish where I started, which is, you can't do any of this without the people.
It starts with people, finishes with people, and we have really I'm grateful for all the scientists who are day in and day out pushing the boundaries of science. I would say, like Pascal said, it is so much fun doing what we do because we are helping patients. I'll stop here.
I think the floor is open for questions. I guess I'm supposed to facilitate this with the lights up. We'll start right back here.
Hi. Thanks. It's Jeffrey Holford from Jefferies. I just want to go back to your discussion a bit earlier, Briggs. On ATLANTIC, we see a prime endpoint readout on ClinicalTrials.gov around April 2015. Just wondering why you pointed to 2016 for the filing timeline for that in your pack. Just if you could maybe comment also more specifically on some of the other data readouts and competitor activities that might prevent that filing. Just another data readout we would think would be very exciting, and that would just be when would we likely see first phase I data for the PD-L1 OX40 combination? Just lastly, maybe comment a bit on strategy around you don't have anti-cancer vaccines that you're talking about. You don't have any CAR T approach that you're talking about. Just your thoughts around that. Thank you very much.
Sure thing. Let me take ATLANTIC. Perhaps Mohammed, you want to talk about PD-L1 OX40 combo? Bahija, you want to talk about anti-cancer vaccines and the other technologies, CAR technologies? Let me be very clear on ATLANTIC. It is in a way a little bit like the phase II study that's going on with AZD9291, where you're enrolling patients. We're gathering data both on response rate and on durability of response. Essentially, you can cut the data at various times along the way. I think in order to have enough patients with enough follow-up that we would feel comfortable we have a good sense of both the response rate and the durability. That's why I think that's coming probably later in 2015, which would lead to a filing maybe in 2015, but I think right now we're estimating more 2016.
The question about the competitor landscape. I'm sorry, I don't want to go through the entire competitor landscape because I'll give you the principles of what we're concerned about. Of course, the question is, if someone were to have full approval in third-line non-small cell lung cancer for patients who are PD-L1 positive, that would be the challenge for us. I think probably others of you know the competitive, what Merck is doing, what BMS is doing, what Roche is doing. That's the piece. Now, there is, of course, in ATLANTIC, two cohorts. There's the EGFR ALK mutant cohort, and there's the wild type cohort. I think the EGFR ALK mutant cohort may perhaps be a little safer territory relative to competition than the wild type cohort. That's strategically what we would be worried about should somebody have that.
Maybe Mohammed, do you want to take the question about PD-L1 OX40 combo?
Sure. The PD-L1 murine OX40 combination has started. We've dosed patients this year. It's a dose escalation study, there's always some degree of uncertainty in terms of the number of dose levels that you will have to ultimately explore. If things stay on track, we anticipate we can plan to present data in the latter half of next year.
Bahija, you want to comment on other technologies?
I think on vaccine, you've seen we have one on collaboration with Advaxis. We talked about that one, for the HPV cervical head and neck. We have our own efforts going on. Remember, we've been in the vaccine area. You'll see some things hopefully next year.
Let me quick go. I think, is this the phone? Seamus, is that you on the phone? You have a question?
Yes. Actually, thanks for taking the question. Maybe, Briggs, can you talk a little bit about just generally how the process of research is changing and if you think that companies with broad combination opportunities may start to develop a bit of an advantage versus kind of the single agent development. Typically, you see with biotechs, you have more of a single agent that's developed, and maybe it's a good target, but would be interesting to just know your thoughts there. Secondly, the second question for Bahija. Bahija, when you think about the opportunities and you think about sort of the phase I data that you are asked to generate and bring forward along with the technologies, what kinds of signals are you really looking for?
Are you looking for now more the very big signals in phase I for an on-target antibody as the driving force to move forward or is it more of a portfolio thought process? Thanks.
Seamus, thank you for your question. I'll take a stab at it and then Bahija, you can jump in as well. I think the question about combinations and whether it's best, I think what I would say is by focusing in our core three therapeutic areas, we can look for those opportunities, and I think you've heard that theme across all of the people who've presented. In respiratory, we talked about the ability to have a triple combination in a proprietary and an important device. That's one example of a combination. You had heard Elisabeth talk about the potential that if you could combine, say, metformin plus a DPP4 inhibitor plus an SGLT2 inhibitor very early, you might change the natural history of diabetes. Of course, you've heard in oncology, I think, many examples that we've talked about.
I think, Seamus, your question about combination therapy, I think the hope that there'll be a single drug like a Gleevec that will transform the natural history of a disease, those are still possible, and we'll still see that. We've seen examples. I do think as we get into more complicated systems biology, you do need multiple agents and having those all in-house. Again, I think it's the focus on understanding the core science that, again, I'll let Mene and Bahija, because I think they're the ones who are doing this early on and then bringing it to us late in the clinic.
Thank you for the question. I think it really depends on the therapeutic area. What's underlying everything is basically what's the hypothesis you're bringing to the clinic. Our teams are not going to move if they don't have a real hypothesis. I'll give you an example. The antibody that we showed you for the anti-Pseudomonas or for the RSV, one of the hypothesis was that we can extend the half-life. If we don't see that in phase I, that's the first thing we look at. If the PK is not good, we're not going to go. For something like the respiratory, which is you're not going to be able to see activity in phase I, what you're looking for is the minimum. Are you hitting the target the way you really want to see?
I think what you see in benralizumab, we actually ask these questions very early. Not only do you deplete eosinophils in the blood in phase I, we actually did the study to look how much we're depleting in the lung because that's very important before we invest even more. It depends. Where you want to see signal of activity even early, that's oncology, because you can actually see activity early. It depends on the therapeutic area, but I think just that discipline of actually knowing what you're looking for and testing that in the clinic is very important. The other just last point is also the population you're going to and testing it. That's how we did it for asthma for everything that we do. Sometimes it's easy, sometimes it's not as easy as we are learning more in immunotherapy.
Questions here in the room. In the back, we have a few.
Hello. Amit Roy from Foveal. Just a question on CTLA and PD-L1 again combinations. Two questions. Firstly, a commercial one. If I'm correct, Pfizer's licensed tremelimumab in monotherapy. What is the commercial relation we have then with a combination with a PD-L1? That doesn't appear to be clear. Secondly, you alluded to the timings of CTLA versus PD-L1. It's quite clear the timing seems to make a difference in terms of combination cohorts or phased delivery. What's your data telling us to which one should come first or should be given completely together? What do you think?
I don't know who wants to take the question about the commercial arrangement with Pfizer? Yeah.
Yeah, I can answer this one. We have the freedom to do basically what we license from Pfizer, we can do with the CTLA-4 what we want. I think the only things that they can do is in the vaccine area. That's all. The second part is, I don't think we'll share with you in ASCO which one, but basically what we said even at JP Morgan a long time ago, that we believe the sequencing, the dosing, the dosage schedule is going to be extremely important, and that's why we're really. Well, I don't want to say we're taking our time, but we are doing the experiments correctly to look at these three components, which I believe are extremely important.
Thank you.
Okay. I think there was another question in the back.
Yeah. Simon Baker from Exane. A couple of questions, if I may. Firstly, you've given us a lot of data on the changing split of R&D spend, and you've also given us data on cost savings in R&D. I wonder if you would care to share any more information on how that manifests itself at the group level over the next few years as you go through this transition. Secondly, a quick question on the antisense STAT3. Any comments on the tox profile of that? Finally, we talked quite a bit about 9291 and the fast clinical development. It looks like the preclinical development was also impressively swift. I wonder if you'd care to share any changes that you've undertaken in lead optimization and preclinical to accelerate development programs. Thank you.
Great. I can take the question on the R&D spend at the group level. The chart I showed you of the distribution of early versus late and across the different therapeutic areas was really just in percentages terms. As you can imagine, I think we've already communicated. This year's R&D spend is up a bit from 2013. Marc,
14.
14%. I think as we go into 2015, there may be, again, we may need to have a little slight increase as well, but I think it's sort of staying in about the ballpark that we're at now. Marc, I think, will cover that in more detail in his presentation. Is that fair? You guys want to talk about preclinical development?
There was a question on STAT3, which Susan might want to answer in terms of tolerability. I can do it, but she can do it better than me.
In terms of the STAT3, the data was presented at ASCO on the phase I program in lymphoma, and the data will be presented on HCC at the Barcelona meeting, which has started now. At a high level, we do see on-target thrombocytopenia with STAT3. We think that's an on-target mechanism of action inhibition. I would say that the dose escalation with the AR antagonist is getting to a level where we've gone beyond where we could dose escalate with the STAT3 molecule. Suggests, again, that that's a mechanism-related toxicity.
The HCC trial, I'd just say when you look at the tolerability, and I'm not going to go into details because it's just going to be presented at the scientific meeting, bear in mind that this is a patient population with substantial baseline abnormalities in hepatic function because of the hepatocellular carcinoma and the background of cirrhosis that many of these patients have as well. Overall, what we see is a molecule that can be tolerated at the dose levels where we are seeing the mechanism of down modulation of the STAT3 in the tumor microenvironment that many alluded to.
There was a question on the preclinical tox, I would say there's a couple of things at play here. One, I think Pascal alluded this in the very first presentation. We're a much simpler organization, both in terms of decision making and governance and the number of sites that we're on. Moving our programs swiftly and learning about the toxicology early on through lead optimization actually helps us move fast once we've nominated a candidate. The other piece is we've just actually simplified the safety function. It's now on one site, one core site, and we have a set number of partners that we work with. It's a very streamlined process for how we get from candidate nomination through GLP tox.
Any other questions in the room? I don't see any other questions on the call. Thomas, should we move on? Marc, you're next. We're done.
Good afternoon. We have shown in the last few hours how exciting our portfolio was and what underpins the outlook of our business. Before I move into the translation of science into value for the company, I'd like to spend some time to review the financial performance of the company over the last 10 years. Looking at this first slide, you can see that we have returned $53 billion over the last 10 years to our shareholders. Returns have been achieved through a combination of dividends, growing dividends, but also buyback. As you can see that the dividend has been the foundation of our shareholder value. While delivering this shareholder value, we have also seen a growth in the TSR.
You can see on this slide the comparison of AstraZeneca in dark red with 12.9% average TSR in comparison to our peers, which is, if I can read properly, 9.7%, and for the FTSE, 107.2%. Basically, our TSR has grown by more than 3% higher than the competition. On this slide, on the left, you have the dividend. On the left, the dividend growth, and on the right, the dividend yield. As I said earlier on the first slide, the dividend policy has been at the core of our shareholder value creation. You can see that on the left, the chart shows that our dividend is now three times higher than it was in 2004, the start of the horizon. On the right, for the dividend yield, we are presently at 4%.
Our peers are averaging today at 3.5%, and you also have on this chart the average of the last 10 years. That's for the retrospective of the financial performance and financial metrics for the company. I'm now going to turn to a slightly more prospective part of the presentation. Let me spend some time to explain what this slide projects. This is looking at the four-year forward volume revenue CAGR. On the left of this slide, you have the scale, 5%, 10%, and so on. You have in this dark color, the actuals, and the dotted line represent the market consensus, the current market consensus. The arrow points to you the 2014-2018 Growth rate. That's four-year forward growth rate. That's what we are measuring on this curve.
Obviously, AstraZeneca is in a turnaround situation. For us, the return to growth is clearly one of our key objectives. We can see that from the period of 2006 to 2010, the growth has started to decelerate. 2010 and 2011, the yearly growth sales were close to zero. 2012 and 2013 were two years of a substantial decline. As I said, the dotted line represents the market consensus. You can see that the market is expecting the four-year growth rates to be around zero in the 2014-2018 period. The four-year rolling forecast is an important parameter. The change of a few points in that parameter is often correlated with a re-rating by the market. As an indication, we believe that a change in 3 to 4 points in this four-year forward growth rate is usually sufficient to cause a change in the multiple.
I take this opportunity to mention that we are confirming our sales target of above $45 billion for 2023. If this point was represented on this chart, it would place us above the dotted line. This parameter is very important because I think it gives you an idea of the speed of the value creation. I will now turn to two different phases for AstraZeneca in an illustrative form. The first period covers 2013, 2017. It is a period of replenishment. You have the strong headwinds of the loss of exclusivity on CRESTOR, NEXIUM, and SEROQUEL. You can see that the revenues of 2017 on these slides plan to be broadly in line with 2013, thanks to the contribution of the growth platforms and to a limited extent, the contribution of the late-stage pipeline. The second period is a period of harvesting.
From 2017, the headwinds of generic are abating and are mostly behind us. Our growth platform continues to deliver. Therefore, you have a strong growth trajectory from 2017. We expect, as I said earlier on, that our late-stage pipeline will help us drive the revenue towards the $45 billion long-term target. I'm now going to turn to the model we are using to monitor our value creation. On these three bubbles on the left, these are representing the revenues. You have revenues coming from established products, revenues coming from growth platforms, and revenue coming from the pipeline, which is being developed in the course of this 10-year horizon.
Through operating leverage, obviously from this revenue and through operating leverage, we get onto cash flows, which are used for the pipeline, the R&D necessary to create the pipeline and business development opportunities, but also to provide a return to our shareholders and in line with our progressive dividend policy and also make sure that we have an efficient capital structure. The CapEx and the business development are obviously very important as the progressive dividend policy. As we move towards from primary care to specialty care progressively, the operating leverage will increase as well as long as our focus increases, the operating leverage also increases. You have this sort of feedback arrow coming from the pipeline and in turn, providing the next wave of new products.
You can see under the bubble for the pipeline, the products that have been described in the course of today, the approvals and the submissions, and even beyond that, upstream for the phase III, phase II, and phase I. Coupled with our strategy of value creation through our rapidly progressing pipeline, we also need to ensure that the company long-term priorities and objectives and the shareholders' interests are closely aligned. This slide explains how the management incentive, which are both the STI and the LTI, are constructed. On the left of the slide, this is a construction, and on the right part of the slide, this is more the alignment with the shareholders' interest.
The STI itself is composed of 14 different individual measures, which are not represented for simplicity on this slide, but they are regrouped around scientific leadership, return to growth, and achieving group financial targets. The LTI part is itself composed of 12 measures. It is also based on scientific leadership, return to growth, and financial targets. In the case of long-term incentive, the financial targets are the TSR and the cumulative cash flow. On the right, we have tried to depict how these objectives are aligned with the shareholders' interest. You can see that obviously the scientific leadership is linked with the delivery of pipeline. The return to growth is basically the measurement of the growth platform, which we have talked to you about today, and the group financial targets obviously are very aligned with those of the shareholders.
What we need to remember from our management incentive is that they are aligned with our strategic priorities, but they're also very consistent with the figures that we have presented, and we are presenting regularly about our long-term plan. Let me turn now to the way we deploy our capital in the pursuit of scientific leadership, but also to generate long-term revenue growth. In this slide, Briggs showed you a similar slide earlier on. The only difference is mine incorporates both R&D spend, the internal spend and the business development capital allocation. This is the aggregate of those two costs. You can see that 92% of the aggregate of R&D and business development over the last two years have been allocated to the three core areas. Only 8% have been spent on the infection, vaccines, and neuroscience.
This, on the CVMD, the largest spend has been, as you know, done on the diabetes alliance with BMS. On the respiratory area, we had two critical acquisition, Pearl and the respiratory franchise of Almirall, and Oncology, our capital allocation was mostly devoted to the own clinical spend. This slide was also used by Pascal and by Briggs. It shows how fast we have replenished our late-stage pipeline, and as we have commented during the course of today, we have seen the results which have been accomplished in the last 18 months. You can see at the end on the right of it, that we are progressing towards a target of 13 to 15 new programs in phase III or registration by 2016.
If you worried about the potential value of our pipeline, this table classifies the products according to their peak year sales and their probability of launch. The date in brackets represents the year of launch. You have on the vertical axis, the potential, and on the horizontal, the scientific evidence or the probability of launch. You can see that on this slide, we have included most of our phase II or beyond. Not all of them, but most of them. You will note that two-third of these assets are projected to reach sales above $1 billion. In conclusion, I'd like to say that we are rapidly coming to a period of harvesting and value creation for our shareholders. We have in the past 10 years, returned $53 billion, delivered a TSR of 13%, provided superior dividend growth and yield.
Now the ship is turning, and the speed of the turn is rapid. We should see an inflection in the four-year forward rolling rate. Just as a last word from me, we remain committed to the policy of progressive dividend and to a sustainable value creation for our shareholders. I will now take your questions and ask Briggs and Luke to join me on the podium. We have no question on the James?
Thank you. Can you hear me? Thanks. James Gordon from JPMorgan. A couple of questions on SG&A. In terms of looking in the medium term, if you do have a flat top line and if R&D is growing, you've got to make some SG&A cuts. Just in terms of how much can you cut when CRESTOR goes? Is there a lot of spends still attached to CRESTOR? Are there other areas that you can make big cuts? How low could SG&A, as a percentage of revenues, actually make sense for Astra? Could you get down to the low 30s, or would that be cutting too far?
Okay. First of all, in 2014, our SG&A has been increasing by 14%, as we mentioned earlier on, the same rate as for the R&D. Obviously, this is not going to be continuing forever, and we will need to more actively manage our expenses, our OPEX from next year on, or when NEXIUM sort of disappears. We are ready for this time. I've seen a note by an analyst talking about a 27% of cost reduction in the next three years for SG&A. We do not have exactly the same numbers, but directionally, this is going to be in the right direction.
Thank you. Just one follow-up question, which was in terms of other things that could support the bottom line, in terms of whether you would divest other pipeline assets in non-core areas, are you already in advanced discussions with other partners potentially, or other people who might want to buy some of your assets in infection or neuroscience? Should we expect other assets beyond metreleptin in 2015 to be divested?
Thank you. Yes. I think we are going to do 3 types of things. First of all, we are going to redeploy our resources even more aggressively or dramatically than we have done. Briggs has already shown you today that in the course of the last 2 years, we have moved late-stage development from 40% to 60%. Also within R&D, we have moved from, I would say, project related from sort of brick and mortar to project related. This has been done very actively, in particular, by the discovery units. We have also moved projects across franchises and so on. We are going to continue to do that more aggressively. The second avenue is, as you describe it, are you going to sort of monetize the produce of your discovery? The answer is yes. We have already in 2014 had 2 examples of this.
The BACE inhibitor is 1 type of partnership, the recent announcement of the disposal of metreleptin is another example. We are actively working on several other projects which have the same purpose. In other words, to relieve our P&L and to enable us to continue having our discovery engine fully in force.
Thank you.
Yes.
Thanks. Mattias Häggblom, Danske Bank Markets. 3 questions, please. Pascal, could you help us understand with 8-10 medicines likely to be launched in 2015 into 2016, what we should keep in mind when modeling the ramp-up of those introductions, in particular in light of payers' inability to embrace innovative medicine recently. Secondly, with regards to your 2014 Focus employee survey, you shared with us a lot of parameters where AstraZeneca comes out favorably. I am sure there are parameters where you do not come out as good as well. I would be curious to hear what those would be and what you intend to do to change that. Thirdly, and lastly, can you remind me how many breakthrough designations the company has as of today, how that compares with peers, and whether that is a good measure to measure return to scientific leadership? Thank you.
Thank you. The third question relates to want to think about it to understand some of the other two. You can count maybe. The Focus results, it is a great question. In fact, I would have commented, but I realized I was running out of time, so I was actually speeding up a little bit. We are very excited. We got, as you saw, very good results. There are two things that people told us we are not really where we should be. One is complexity. We have made quite a bit of progress, I think, simplifying, as you have heard today, but we are still too complex. Part of it is the nature of a large company. Part of it is our history. Complexity is clearly something that people tell us, complexity of our systems, IT in particular, complexity of the way we operate.
We certainly need to do more there. The second is people development. There is certainly more we can do there, too. Those are two of the priorities that we, as a senior executive team, have decided to give ourselves for 2015. Not that reducing complexity was not a priority. It is, of course, but we certainly have to do a lot more. As far as your first question, I am not really 100% sure I got it. It was more like what kind of ramp-up can we expect for new products? I guess the answer to this is really it depends, because it will depend on what product. There is some products where we expect pretty rapid ramp-up provided we can get access. It is partly in our hands, of course, because we decide the price at which we sell our products.
I think for a number of our products, we should expect a relatively good ramp-up. Now, one of the questions we get from time to time is the respiratory field. Are we going to be able to succeed with LAMA/LABA, our triple combination in a context of a very difficult environment, intensifying competition, difficult access, et cetera? I think the answer is yes, we can. We need to be focused, and we need to really educate the market around COPD in particular. But we have shown you what we can do with Symbicort. Quite frankly, the access we have for Symbicort next year in the U.S. is still pretty good, actually. A little bit reduced compared to what it is this year, but still very strong and better than many of our competitors. I think we can do the same with our new products, yeah.
What I'll do, I'll take maybe a question on the telephone. Seamus, would you like to ask your questions?
You just answered the question.
Sorry. There was another response that we were in.
I'm looking at my colleagues to correct me if I'm wrong. I think 9211 is the only breakthrough therapy designation we have. As Bahija alluded to, we have a couple of fast track designations, which is different from breakthrough.
Okay. Seamus, would you like to ask your question?
Sure. My question is just more, can you again, Marc, you mentioned a target of 27%. Was that in terms of the threshold for SG&A? What are we thinking about in terms of the time frame within which I presume that you were saying that a realistic target for SG&A might be somewhere in the kind of high 20s for SG&A over time. I'm just trying to get a better sense of when should we anticipate that that might be possible. Are we talking about immediately post CRESTOR, or should we be thinking about a bit of a period where the numbers may run a little bit below that as you're launching new products and SG&A could even be higher as a % of sales?
Okay. I was not indicating any company strategy for the 27%. I was mentioning that I read it in an analyst note not so long ago, I just was alluding to it. In 2014, what we are trying to do is to manage our top line and also our bottom line. As we had provided guidance, we try to sustain our pipeline progression as well as our commercial investment as much as we could. I think we are going to finish the year as we had planned or slightly better. We are going to give the same principle for 2015 and 2016. However, the condition may change. We may have to reduce the level of the progression of the spend on R&D and the same on SG&A.
Overall, in a few years' time, when we go to specialty care, we expect that the level of spend of G&A will be substantially lower than where we are today. We believe that 2015 will be also lower than what we are going to finish in 2014. I'm not going to give you any %. We may be able, next year, to provide you some indication in February for the guidance, but not for today. I'll take another question in the room, and then I'll go to the telephone again.
Thank you very much. It's Matthew Weston from Credit Suisse. Two questions, if I can. In Pascal's introductory slides, one of them was entitled, "Driving a simpler and more productive business." At the bottom, it highlighted process and systems, IT enterprise systems delivering in 2014 and 2015, and business processes with a focus in 2015. I'm just curious, given that you're investing heavily in that at the moment, is there an element of your cost base today which is effectively duplicated as you run legacy systems and invest in new systems? If so, can you quantify how much, and how much do you anticipate that both those investments will save in 2015 and 2016 going forward? Thank you.
The second question, you've alluded a number of times, and Pascal has, that selling non-core assets will be an element of funding the internal investment in your business during this replenishment phase. When it comes to guidance, are you going to give us an indication at the beginning of the year how much of your cost budget is effectively going to be covered by those divestitures? Are you just going to leave us to wonder how that's going to play out over the course of the year? Thank you.
Pascal, you want to take the first one? I take the second one.
Well, yeah, the first one is yes, certainly the investment we're making in systems is going to drive a reduction of cost over time. We've done a lot of this already. Mene mentioned the cost reductions we've been able to achieve in the IMED, and a lot of this is, in fact, due to reduction of our infrastructure cost. There's more to come from an IT perspective. Our primary goal is really to make our people more effective. We've got an IT, quite frankly, that is today in a much better place than where we were two years ago. Was historically a function where we hadn't invested, and we had very clunky systems that were quite irritating, frustrating for everybody, and in fact, creating more cost than necessary. Our IT costs were higher than the benchmarks in the industry.
Essentially, we have a new leadership in IT who have been working really hard to reduce the cost rapidly and increase the service level. They've done quite a lot of progress this year. We still have a long way to go, which is why our people are telling us we are still too complicated. Part of this is their experience with some of our systems. There's more to come. More to come to make our people more efficient with better systems. We'll also reduce the cost of IT, and we have certainly goals for cost reductions there. Of course, we don't give any guidance for those, but we certainly, directionally, again, you can expect that we'll get some savings out of this. As far as the other question, it's hard to answer today. We'll have to decide what kind of level of guidance we give for 2015.
I just would like to correct something you said, Matthew, is that we're not necessarily going to divest products. Sometimes it may be a divestment. Metreleptin is a divestment, but mostly it's going to be creating value in a different way through partnering or licensing products. Trying to get some short-term value out of those, but retaining long-term value as well for royalties or partnerships. It's not really totally divesting those products, it's really retaining some of the economic value, getting a little bit of it today and some other part of it later on.
Sachin?
Thank you. Sachin Jain. Just one question on the balance sheet. You mentioned you wanted to retain an efficient capital structure. How do you define efficient? On the assumption you're moving to inefficient through the course of next year, if there's no further M&A, what's your preferred route of return of cash dividend, or would you restart a buyback? Thanks.
We still have our net debt position for the time being, and probably by the end of next year, we'll still be there or thereabout. If we have no, we'll obviously prefer the dividend in relation to buyback. If there is surplus left, we will be open to resuming the buyback. Alexandra?
There have been various questions trying to fish for some sort of long-term guidance. I understand you don't want to give us that, I'm going to ask a related question, but actually asking for something different. The issue really is that until recently or until last week, I thought it's actually fairly simple because if you're giving us 420, that needs, unless you do buybacks, about $7 billion operating profit. That's the 2017 base, which you're going to grow. Since last week, understanding that how you get to that operating profit number, which you need to do the 420, that will contain some elements of what you call monetizing assets. Some milestones, some other components, which may be non-recurring. Basically now I'm less sure whether you're really going to have a $7 billion operating profit in 2007 that you can grow.
It may be a different figure. I'm not going to ask you what that figure is. I'm just going to ask you, have you got good visibility what the number is actually going to be in 2017? Is that still in your internal plan, a range that is this wide?
We have a very clear visibility. I know maybe it's a little bit frustrating that we don't give you this midterm guidance and we just let you do your job, I guess. We give you some pieces of information, but not the whole picture. That you can have fun doing your job as well. Otherwise, you put numbers in spreadsheets. No, I accept that you'd like to hear more because there is a certain amount of uncertainty for sure out there. No, we have a clear visibility and you should not put such a big emphasis on divestments or whatever. What we're trying to message to you is that there's many ways to create value, and there are places where we're going to create the value ourselves as much as we can. We're going to develop, commercialize those products ourselves.
There are other places in the organization where we have great science, we have great people, but we can't do everything ourselves. Rather than say we're going to shut down those activities, which would be a pity because we really have great science, what we decided to do is continue creating value for patients and for the company by partnering or licensing out some of those assets. The other thing we achieve doing this is we retain the optionality to rebuild at some point in the future to keep building those areas to do things ourselves. We maintain this optionality and we create value. That's really what we're trying to signal to you. Fundamentally what we're going to do is manage our cost base to reduce our SG&A ratio in particular.
I think you've got to look at this company, this business as an innovative business. That tells you an idea of what is the R&D spend as a percentage of sales and the kind of range where we think we're going to stabilize. Certainly, as we move to a more specialty care portfolio, our SG&A ratio will decline. Let me just make one last point again, repeating what I said earlier. This year is a really massive investment year in terms of several launches. The emerging markets, China, diabetes, Brilinta, Symbicort, et cetera. This is paying off because you see the kind of growth we're experiencing in China with Symbicort, et cetera. It's actually good value, good investment. It is not going to last like this. Essentially by 2017, we will have managed our cost base.
We're not going to live off selling assets, I guess, is what I'm trying to say. Maybe I'll take one question on the telephone. There is Terence McManus from Credit Suisse.
Hello, it's Jo Walton, in fact. Just two quick questions. Emerging markets, you've just touched upon that as an investment period for at the moment. If we look through to 2017, presumably milking your established brands into those markets is going to continue to be an important part of your growth. Do you think you can actually reduce your cost base and continue to get growth in emerging markets? I'd be intrigued on your attitude to the general view of a slight slowdown in emerging markets. The second question is just one on cash flow. I wonder if you could give us some help on what sort of proportion of your core earnings we should expect to see converted through to cash. I know you've got royalty payments out. You've got restructuring charges and things like that.
Just some help on how we should be looking at the cash flow coming through as well as the sales and profits would be helpful.
First of all, the first question for the emerging market. We will probably maintain our level of investment more than reduce it. It will probably be a ratio that is slightly lower in the future. Marc Dunoyer has explained to you how much investment we had done in China over the course of 2014, and you have seen in his presentation how successful this investment has been. We are not going to continue investing at that pace, but we are certainly going to maintain a strong presence in the emerging markets. Regarding your second question on the level of cash flows, obviously, we'll give you a bit more visibility of the cash flow for 2015 and maybe possibly 2016 when we talk to you in February 2015. You are aware of all the milestones or
Sales-related payments that when we do an acquisition or a business combination, we are usually very transparent with what we commit to do with our partners. I think it's relatively simple for you to anticipate what these payments are going to be. We do provide every three months on the quarterly accounts, these details. I'll take another question in the room there.
It's Keyur Parikh from Goldman Sachs. Pascal, just a little bit of clarification. My understanding was that when you issued the guidance for 2017 revenues in March 2013, that was based on a purely organic measure, and did not include any M&A contribution. Given the Bristol diabetes addition and Almirall, should we now think of that being an upside to your 25.7 number in 2017? Are we consensus thinking about it wrongly, or has something changed on the rest of the business? That's one. Secondly, Marc, as you very helpfully provided a preview for 2015. In response to an earlier question, you kind of suggested that you were in late stage negotiations with a few of your other compounds for potentially having another strategic value to it. How should we think about whether that's been already included in the preview that you provided?
Will that likely stuff that has not been announced, will that be an upside to your preview, or is that already included?
Okay. For the first question regarding the 2017 sales guidance, we had provided this guidance in January of 2014. When we provided this guidance, we mentioned that it was at constant exchange rate. We said it would be broadly in line, that the 2017 sales would be broadly in line with those of 2013. We had said at that time that it could possibly include small, regular business development activities, but it was not including any major acquisition.
Maybe just to add, Keyur, I think you've got the wrong assumption with diabetes, because if you remember, when we communicated our plan, we said that we used our long-range plan. The only adjustment we made to it was to add the other half of the diabetes business. Essentially, the 2017 guidance included diabetes. The one thing it didn't include is the Almirall acquisition, but it did include the totality of the diabetes business. When we said we would be broadly in line, which means, it could be exactly the same number, a bit below, a bit higher. Almirall is suddenly going to be additional to what we had in our plan, but diabetes is totally included.
The next question is, if we are monetizing asset or partnering asset next year, is this already considered in your preview of 2015? The answer is yes, this are anticipated. If we do more, obviously it will be an upside, but it is anticipated.
Just to follow up on that. Beyond the $325 that you already announced, what is anticipated? Can you quantify that for us?
Not today. Okay, maybe a question on the telephone. Timothy Anderson, would you like to ask your question?
Yes. Thank you. A couple of questions. How much of a focus is there by management on trying to pull forward the year in which AstraZeneca returns to growth, which you usually describe as 2018, through M&A, deals that would add to revenues and earnings in the intermediate term? Second question, on your guidance for 2023 revenues, can you just remind us what proportion is assumed to come from acquisitions or in-licensing by the company? Or are these two activities assumed to be zero, and all of that $45 billion is based on what you already have in-house today?
First of all, I will take the second question first. When we explained about our long-range plan, 2023 sales above $45 billion, this did not include any major acquisitions. They are, as we said, traditional or regular acquisition that we do along the way, complementing our portfolio or doing one partnership or the other. There was no major acquisition considered in the $45 billion for 2023. Your first question was on the, you mentioned, are we considering M&A? Did I get your question right or?
It's really, I think one of the stumbling blocks for investors is sometimes the fact that you don't return to growth even by your own admission until 2018. Here we sit, in 2014. My question is, how much of a focus is it by management to try to pull forward that year, through mergers and acquisitions? Acquiring revenues and earnings growth so that you can suddenly say that growth is going to return in 2016 and not 2018, for example.
What I can say that we are constantly looking for good opportunities, we want absolutely to make sure that any opportunity would be aligned with our strategy, would be accretive and consistent is what we do. There are not many opportunities. We do believe that we can maintain our sales around the 2013 level until 2017, after which we are expecting a period of rapid growth. We don't see it as an absolute must. If we did find a great opportunity which would be in our line of business and accretive with our company, we would obviously consider it.
Yeah. The only thing I would add is that the price has to be right, of course, we have to be able to execute on it. When you combine all of this, it leaves you with a limited number of opportunities, as Marc said. Also, this execution dimension is an important one. I think what we try to show you today is that we're creating value organically through our own pipeline. We're complementing this through business development. We're making rapid progress. A merger or an acquisition of large size that would be disruptive would certainly help in the short term, potentially create long-term disruption. It doesn't mean we will not consider it if we found one that addresses the criteria Marc just described, strategically aligned, feasible, the right price, we would do it.
It is not easy to find, and we also have to consider the disruptive dimension that one of those things could bring to the organization and to this value creation we are trying to achieve. Essentially, we're trying to do it through midsize acquisitions. If we found more of the Almirall or the diabetes acquisition of the BMS alliance, if we find more of those, we will certainly do them because they are easy to absorb and easy to align with our business.
I think we have run out of questions.
No, we've got one there, Marc.
Sorry.
Hopefully the last one then. Danny Serumpet from Barclays. Just a very quick question regarding the 2023 guidance. When you laid out your long-range plan, you identified a third of that $45 billion approximately was going to come from pipeline and the remainder from the mature existing franchises and the growth platforms. Can you confirm that that is still your expectation? If so, within that, how has anything been changed for what seems to be a dramatically changed pricing environment, particularly within the fields of respiratory and diabetes that we've witnessed this year? Was this part of your long-range planning assumptions at the time? From our perspective, it would seem that has been something that's changed. What's compensated for that?
Basically, as Pascal was mentioning earlier on, we are now in the process of finalizing our plan for the year 2014, the next 10-year plan. We do not see any dramatic change or evolution in our planning, it's more or less in line with what we had last year. There are slightly ups and down. Pricing is one evolution, we had always anticipated a gradual decrease of prices in some regions. There's nothing surprising, I would say, in the pricing environment that we are confronted with today. The pricing that we had in our plans last year and this year are still valid.
As you can imagine, there are moving parts, ups and downs, as Marc says. Overall, the totality of the plan is very much aligned with what we had before. In some areas, for sure, our plan reflects the changing environment and the price pressure, but we have other products that we think can do better than we expected before. That's why we feel comfortable reconfirming the $45. I'd like to maybe go back to the previous question because I wouldn't want you to think we ignore this aspect. I mean, we completely recognize the fact that there's a couple of years where we are fighting pretty substantial headwinds with NEXIUM and CRESTOR. If we actually were able to address this, we would do it, and we're constantly looking.
We don't want you to think we are not considering this and not trying to address it, we will not do it. We are trying to be an organization that is not risk averse. We're trying to progress some of our projects fast and take educated risks. We also want to be disciplined in the way we manage the business, we will not do anything that leads us to overpay for business or consider a business just for the sake of filling this gap. We want to build a sustainable company, and we want to do it with a strategic approach, not sort of buying stuff left, right, and center just to create short-term earning acquisitions. That we will not do. We certainly will continue very actively to look for opportunities.
Regarding your last question, the size of the pipeline and the $45, the sort of indication of about one-third is still valid.
We're done. Sorry. All right. Thank you so much. We're on the last stretch. It was quite a long day. I hope you found it interesting. I hope you enjoyed it. Certainly, I did enjoy it a lot personally. For two reasons. First of all, because your questions are always very insightful, and they help us. Often, really, we go home, and we have more to think about. Also personally, I must say, because sitting here in the audience and seeing this fantastic team in action is always very energizing. I was really excited to listen to them over the last few hours. Hopefully, we gave you a good sense of what we're trying to do. We covered the progress we're making with the growth platforms.
We try to cover the pipeline and the progress we've made with the pipeline, we also try to give you a sense of what's next, what's in the early pipeline in research and early development. I certainly didn't expect one minute that you would actually believe that all early projects we showed you will work. We completely realize that some of those will work and others won't work. The goal was not really so much to convince you that every single of these projects is going to make it. It was more to give you a flavor of what we're doing. Hopefully, you could touch the science and the kind of science we're pursuing and the kind of projects we're pursuing. Hopefully, you get a sense for the people who are doing it and how aligned the organization is in terms of progressing those projects.
We are on a journey, and the journey is still made of another couple of years, and we just talked about this. It is clear that there's two years where we're facing headwinds. In the long term, we believe that by 2017, 2018, we'll be in a very good place. We certainly will keep working, looking for solutions for this two-year period that we're facing of headwinds. I think the message I also wanted to leave you with is two years is a very short period of time, unfortunately, because it means we're all getting older very quickly. Last time we talked to you was almost two years ago and sort of look at the progress we've made, and so another two years, and we'll be in 2016, and we'll be almost done with our patent expiries.
If we find the magic solution, the magic bullet for this 2015-2017 period, we'll certainly pursue it. Again, at the same time, it's a relatively short period of time. I'll just go back to the key messages that I wanted you to leave with. One is we're very focused on implementation. We're very focused on execution. We have a strategy, and our entire energy is on executing as quickly as we can and as effectively as we can. We are very much on track. We're building a sustainable business, and hopefully, that's what we showed you. We have an R&D engine that is effective and sustainable and is looking for constant improvement in productivity. We have a portfolio of products that are durable. We have more biologics, we have more devices.
Even though we didn't give you the guidance you're looking for, you can assume that it's going to become more profitable and certainly, as soon as the specialty care part of the portfolio starts ramping up, you will see us continue investing in R&D and maintain a relatively healthy level of investment as a percentage of sales. You will see the SG&A ratio suddenly decline and the profitability go up. The pipeline value is rapidly increasing, and there's a rich news flow for 2015. Finally, we reconfirmed the $45 billion. I'll leave you with this. This is basically our investor proposition. That's what we think we have to offer. With, as I said, a productive R&D engine, a strong business. I think we cannot underestimate this. The scale of the organization, the fact that we have a strong presence in the emerging market.
The fact that our businesses, diabetes and respiratory in particular, are perfect products, perfect portfolio of products for the emerging markets. Hopefully, you got also a sense for the opportunities in diabetes, of course, but also in respiratory medicine. COPD is an enormous problem that is totally underestimated, and we have the products to address this. Oncology, of course, will also help us. We have a very strong business with a global scale. Finally, we are continuously building a culture of innovation and a culture where people enjoy what they're doing. We are recruiting strong talent. Certainly, the kind of changes we're bringing to the business is helping us do this even more effectively.