AstraZeneca PLC (AZN) Earnings Call Transcript & Summary

So welcome. This is the New CVRM: near-term opportunities breakout session. I'm Nick Stone. Obviously, I'm your moderator again for this session and a member of the AstraZeneca IR team. Naturally, I'd like to welcome to this session, a number of my colleagues. So we have Elisabeth Björk, Senior Vice President late-stage R&D; we have John Houghton, who is our global franchise head for roxadustat and again, late-stage R&D; and then Joris Silon, Senior Vice President of Global Products and Portfolio strategy within the BioPharmaceuticals business unit. And we also have the pleasure of Mene also sitting in on this 1 too. I mean, really, this is a session that's around sort of 30 minutes. So a very quick presentation, and then we'll try and give the majority of time over to Q&A. As usual, materials are obviously available on astrazeneca.com/investors. If you've got any questions, then feel free to just e-mail me at [email protected]. Alisa, if you could go to the next slide, please. So this is just the usual forward-looking statements. And now I'll just take the opportunity to hand over to Elisabeth. Please go ahead, Elisabeth.

Thank you, Nick. And it's a pleasure to be here and start with 1 of my favorite medicines, which is Farxiga. It's really an amazing medicine. And it's also very amazing the way we have, in a science-led manner, have developed this drug. It did start as a diabetes drug, now of course approved also for patients with heart failure, and it will be approved for patients also with chronic kidney disease. So we started, as I said, with this as an antidiabetic. The first data going outside that what was when we got the data, showing that we were able to prevent heart failure and chronic kidney disease in patients with diabetes. Then came DAPA heart failure in patients with heart failure and reduced ejection fraction regardless of whether they had diabetes or not. And we now have approvals in all the major markets, U.S., U.K., Europe, Japan and China and in total, 69 markets. Then last year, in the middle of the pandemic, we got the amazing DAPA CKD data that we have now filed as a sister study to the DAPA heart failure, also in patients regardless of whether they have diabetes or not. And we have now find that in many countries, and this is the first approvals are starting to get through. So if you get to the next slide, please. We are getting lots of positive responses from the regulatory bodies around our data [ requests ] which really speaks to the importance of this data. So we have heard now reviewing the U.S. for DAPA CKD and also in Japan. And we have seen the first approval in Ecuador, New Zealand and India. Then towards the end of this year, we will get the result for DELIVER, which is a similar study to DAPA heart failure and DAPA CKD, but in patients with heart failure with preserved ejection fraction. So that's going to be an interesting event towards the very end of this year. We are also working on Phase II combination with the basis of Dapagliflozin. The 1 is the combination with zibotentan, and the other 1 is a combination with an MRA that we call 9977. And if you are interested in those, you should also go to the following CVRM session, where you will get more details around this. So Joris, over to you. What does this all mean from a commercial perspective? And what have you made -- what are you able to do with all this fabulous data?

Thanks, Elisabeth. I must say you and the team have done a fantastic job to unveil the cardiorenal benefits of this drug, way beyond type 2 diabetes where it all started. So on the back of the significant news you presented the total revenue growth to $2 billion in 2020, which represents growth of almost 30%. It further accelerating in Q4 to 40% as you see the momentum building. And what's nice to see is that we see this growth happening across all the major regions. So from the slide, you will appreciate that this is a truly global product, with 70% of revenue being generated outside of the U.S. As an example, the emerging markets, we see growth of 46%. Europe is growing at 36%. U.S. for the year is growing at 6%. However, we do see an acceleration in the U.S. as well, on the back of our approval for the heart failure with reduced ejection fraction indication in May 2020. So the last quarter, the U.S. was growing by 31%. Maybe 1 more point here is the sales that's coming from China. We see high growth there as well, on the back of our NRDL inclusion at the start of 2020. So we do expect to fuel further growth for the product as we continue to roll out the heart failure indication, but also start promoting the CKD indication, hopefully later this year when we get FDA approval based on the unprecedented results demonstrated in the DAPA-CKD trial. So let's turn to Slide 5 and take a deeper dive into the chronic kidney disease. And Ruud alluded to it in his introduction: chronic kidney disease represents this huge unmet medical need, where a significant amount of people are at risk of developing CKD. So mostly people with hypertension and type 2 diabetes. Obviously, they evolve to or could evolve towards CKD. Around 840 million people around the globe suffer from the disease. But unfortunately, only a limited number of patients are getting diagnosed, especially in the less severe stages, with only 12% of patients getting diagnosed in Stage 3. And this contributes to fast-growing population that is reaching end-stage kidney disease. So complications of chronic kidney disease, dialysis, transplantation, they are devastating conditions for patients, obviously, but it also puts a huge financial strain on the health care systems. And as an example in the U.S., the treatment of CKD is likely to exceed [ $48 billion ] per year. So in this round bubble, you can see our 3-pronged approach that we have to improve the care for chronic kidney disease patients. The first one, as I alluded to, we absolutely need to help the health care ecosystem to address the lack of awareness of the disease and drive much earlier diagnosis. Once we've done that, we need to establish Farxiga as the standard of care for patients with chronic kidney disease. And remember this -- and our data is with and without type 2 diabetes, and we've definitely shown that we can slow the progression of this devastating disease. And third with Lokelma and with roxadustat, we have some of the most innovative solutions in our hand to address the most common complications of chronic kidney disease: anemia and hyperkalaemia. So with the 3 drugs in our hand, Farxiga, Lokelma, roxadustat, we have a tremendous portfolio already of innovative solutions and a huge opportunity to change the course of this disease for millions of patients. So on Slide 6, if we move on, we can take a closer look at hyperkalaemia and Lokelma. So maybe a couple of words around hyperkalaemia. It's a frequent complication in patients not only with chronic kidney disease, but also with heart failure. It's particularly present as a side effect of patients taking RAASI inhibition or MRAs, mineralocorticoid receptor antagonists, and these are both life-saving drugs in the disease settings. So physicians, they often treat hyperkalemia by down-titrating or stopping these drugs or providing a low-potassium diet. And we know that there are better ways to treat hyperkalemia with new binders like Lokelma. What we're doing is continuously expanding the science behind Lokelma, informed guidelines, change standard of care. And most recently, as an example, we demonstrated that Lokelma can control hyperkalemia in patients undergoing dialysis. And this is an important setting because for nephrologists, especially after the loan dialysis interval, potassium tends to build up and can cause really life threatening events for patients under dialysis. So our total revenue amounted to almost $80 million in 2020, a steep increase from the [ $14 ] million in 2019. U.S. representing an overwhelming majority of sales, where we continue to lead the new-to-brand prescription market share. Important to mention that Lokelma has now received regulatory approvals in more and more markets, including Europe, China and Japan. And further launches are anticipated to expand our global footprint. The second common complication of CKD, I mentioned before, is anemia and a very important part of treating CKD, and I will hand over to John Houghton, who will explain our progress with roxa on the next slide. John, over to you.

Thank you very much, Joris. Well, good morning, good afternoon, everybody. Let me begin by saying with roxadustat, it is an exciting new innovation. And you may not be aware, but it's been 30 years since we last saw any innovation in this area for a new treatment of CKD anemia. Current standard of care is really an exogenous infusion of recombinant erythropoietin supplemented with iron. And what I want to point out to you, and I'll do my best to keep the science simple here, is that roxadustat has a totally different mechanism of action. It is actually founded on the Nobel Prize-winning mechanism, hypoxia inducible factor or HIF. And HIF's a transcription factor that regulates expression of genes responsible for returning the body back to an oxygenated state. In normoxic conditions, so normal human beings, HIF gets degraded very quickly and disappears out the body. But when the body becomes hypoxic, HIF stabilizes, and that's what leads to this expression of genes. And what we see with roxadustat, it actually targets the -- and inhibits the enzyme that normally degrades the HIF. So by using roxadustat, you're basically mimicking and leveraging the body's natural response to hypoxia by inhibiting those enzymes and stabilizing the HIF. So what's important then is at that point, what's central to returning to oxygenation is red blood cells. And there's 2 parts to that. The first part is providing endogenous erythropoietin from the body itself, which will drive stem cells down the path to becoming red blood cells. But equally important is to make mature red blood cells. You need iron and hemoglobin. Hemoglobin is the protein that carries the oxygen in the red blood cell, and a key component of that is iron. So if you don't have iron, it's very difficult to make the hemoglobin. And what roxadustat does is it also reduces hepcidin, which is the key regulator of iron in the body and iron homeostasis. So by reducing hepcidin, it makes more iron available. You add that to the coordinated approach with producing red blood cells from the epo, you then end up with a very mature red blood cell. So the theory sounds good. The good news is we can put that into clinical practice and all of our studies shows that it does translate into clinical practice. We've seen consistent hemoglobin control across all patients in all populations. Importantly, there as well, including those patients that have been hyporesponsive to previous standard of care. And I'm thinking like the inflamed patients and again, a little bit of science there. Most people know inflammation increases hepcidin and reduces the iron availability. So as you can imagine, as I've just explained to you, that's why we see good efficacy for roxadustat across all those patient populations. We do reduce the risk of red blood cell transfusion, which is the key endpoint. And of course, given this mechanism, we also see less requirement for iron supplementation, particularly IV iron in the DD population. So I think you can see there are a number of benefits there that roxadustat is bringing to the table from an efficacy perspective. We did previously announce that we've demonstrated CV safety. Our data supports that, particularly in a population that already have a very high level of underlying CV risk, that in the NDD population, we were similar to placebo, that in the DD population, we were similar to epo. And in a population of those new to dialysis and new to [ crectonemia ], we actually saw better outcomes. So I think overall, we've demonstrated that CV safety. And finally, and not to underestimate this, obviously, the oral administration is something of convenience we bring to the table. Obviously, we don't require injection or infusion, and we don't require cold chain storage, which is something [ thakin ] standard of care needs. And I think this, particularly in the NDD population, where they're not going into the physician's office. For patients that are being treated at home, whether it be peritoneal dialysis, or as the U.S. executive order is saying now, they want more patients to be treated them from home. I think this oral convenience will become even more important as we move forward here. Just to highlight in the middle section, yes, obviously, we've made some previous announcements of data, but we continue to support our key messages with more data. I just want to choose a couple for you that came out at ASN a few months ago now. We did show that there's a reduced risk of hospitalization for heart failure versus ESA in the DD patients, a 27% reduction. And we also showed that roxadustat was not associated with an increased risk of neoplasm, again, 2 important endpoints from our perspective. Last but not least, Ruud touched upon this, and I think Joris mentioned it as well. We did launch in China first. I'm pleased to say that things are going very well in China. Our collaborative revenue at the end of last year was $30 million. We continue to focus on ensuring that roxadustat is available to patients and also focusing on getting the hospital listings. Finally, I think most of you are aware, we -- the -- in the U.S., we've been asked to go to an AdCom. We recently announced that. At this point in time, we continue to dialogue with the FDA about what that AdCom will look like. And at this point in time, we don't have a definitive date. But as soon as we do, we will communicate that to you. I will now hand back to Elisabeth, who will cover the near-term opportunities in the CVRM pipeline.

Thank you, John. If I can have the next slide. Here we can see all the exciting news flow that we will see over the next coming year. I'll point out a few things. I spoke to Forxiga before. So we are awaiting the regulatory decision based on the DAPA CKD, both in the U.S., which will come [indiscernible] based on the priority review. Then for the other major markets, Europe, Japan, China, we expect to see that during the rest of the year. Then as I also said before, the DAPA HFpEF study DELIVER will read out towards the end of this year. And finally, we will have the FDA Advisory Committee for roxadustat at a time that we will announce later on. So with that, I take it back to Nick and the Q&A session.

Thank you very much, Elisabeth. Yes. We will now go to Q&A. [Operator Instructions] We'll take our first question from Sachin Jain at Bank of America.

Can you hear me?

Yes, we can, sir.

Perfect. So expected on roxa, if I may, you just commented that you're in dialogue with the FDA regarding topics for the AdCom. Any color you can give us as to what the topics are? Is it the CV safety, statistical design of MDD, any expectations for a pre-approval study?

So I'll take that one, Nick, then. Yes. I mean, we anticipate having a few more meetings with the FDA. There's nothing specific yet, Sachin. Obviously, it's an opportunity actually for us to present all of our data at this meeting, where as you know there will be experts in nephrology and experts in cardiology. So we're actually kind of looking forward to that. It'd be a good opportunity to present that data. Of course, some of the questions will always come back to benefit/risk, and we're looking forward to demonstrating that as well. But again, as we get to know more specifics, Sachin, we will update you. At this point in time, having just come through being transferred from the [ Ochin ] division, which is the 1 that's been doing the discussions around the label so far, we now kind of switch gears a little bit in the FDA. There's a division that actually handles all of the cardiac advisory committee meetings. And that's the group that we're waiting to hear from. So again, once we get more specificity from them, Sachin, obviously, we'll update you. But at the moment, the team are preparing for all of the above. As you can imagine, we want to make sure we're ready no matter what question comes up.

Sam, I believe you're there. So let me just allow you to talk.

Nick, thank you for allowing me to ask a vaccine question, although this is not part of the discussion we just had. And first, I want to thank you all at AstraZeneca for enabling me to have a dose of the AstraZeneca vaccine yesterday. So I'm 32 hours into my dose and feeling great after having felt pretty awful for most of yesterday. Just 2 questions. I know you said 1 but they're all about vaccines. One is the interim analysis on the vaccine was at 75 and we didn't hear anything until you hit 141 cases. I'm assuming this because you didn't hit statistics at 75 and judging by the confidence intervals, that's probably the case. Can you just confirm that, that is what happened? And then I gather about 20% of sites, although I don't know what percentage of cases -- sorry, what the recruitment there is in the U.S. from each of these? Is either in California or New York, where there is the B1526 variant that's pretty significant in the 484 mutation. So could you tell us whether you'd have enough information with regards to the variants that have affected or the virus that's affected your cases to be able to give some feel for efficacy versus 484 mutations? I do have 1 on Forxiga, but you did say one, so...

It's okay. Sam. So I'm just double-checking. Mene, are you there? I know he may have had to step away for a call. So Sam, want to propose -- Perfect. Thanks.

I didn't hear it. Can you just repeat the question quickly?

Please go ahead, Sam.

Yes, yes, sure. So interim for the trial was at 75. You didn't report at 75, you reported 141. I'm assuming this because the stats were just not supportive of a report at 75 given the confidence interval that we see at the 141 or 190 cases. Is that the case? And then do you have...

No, that's not the case. We just to do it 1 at a time. The interim is pre specified, right? And we announced it when we hit the pre-specified analysis of 75 cases. And because it was the first randomized study that demonstrated that we had very high efficacy in under 65s, and because we also had the issue around thrombosis that the DSMB had specifically looked at and we had no indication of increased clots, we felt it important to release the interim results as every other company has done releasing their interim results. We then, obviously, given the letter that was leaked, also prioritized doing the primary analysis just for those 3 endpoints, without looking at all the safety and other things in the primary, as quickly as we could to confirm, as we said in the initial announcement, that the final primary analysis was in line with the interim. So they were both prespecified analysis. One was at 75. We announced it when we hit it. The other was at 150. We announced it when we hit it.

Okay. Okay. And then just on the 484, Mene, in terms of mutations, you have about 20% or so of sites in California and New York, I think where the mutation is. Are you going to be able to do genomic analysis on your cases to get some feel?

Yes. Every case is being sequenced.

So Gary, we're going to come to you next, so just bear with me. I'm just going to unmute you. So Gary, you should be able to ask a question.

I hope you can hear me. So just a quick question on Farxiga from [ MIFID ]. So given that Novartis has kind of carved out the commercial potential for Entresto in the HFpEF setting. Just wondering if you could help us understand the commercial potential that you see for Forxiga in this setting 2, please?

Thank you. Gary, great question. The landscape is moving very fast and have us on the back of the -- both advisory committees with ENTRESTO and [ sperolacto ]. We believe that patients with HFpEF will probably need multiple mechanisms to really decrease the risk of hospitalizations or CV death. So 1 will not be enough and also I remind you that ENTRESTO's indication does point towards the lower ejection fraction of patients with low ejection fraction. So there is still a big space of patients with truly preserved ejection fraction that is -- that has a unmet medical need today. And our trial and maybe a little bit was to comment on that, is a broad trial in patients with [ HFpEF ]. It's powered to show that we can hopefully address that unmet medical need in patients across. So I think it's good news that ENTRESTO is available for patients with lower ejection fraction, but I think we will be able to add more if the trial reads out [ for us then ] Elisabeth, do you want to add something?

Yes, thanks, Joris. I just want to reassure everybody that we have set up in the delivered HFpEF file that, hopefully, we will be successful and show efficacy across the broad range of expectations that we have in the study. But we also have a setup that even if we are only successful in the ones with an ejection fraction under 60%, the design of the study is such that we will be able to capture that. So we are covering both ends, so to speak. And I think that's a good thing with the design and the execution of this product.

I'm going to take our next question from Eric Le Berrigaud.

Nick. 2 questions on Forxiga, please. First of all, you showed that revenues were already around $2 billion, and I assume it's mainly in type 2 diabetes. And your excitement, starting with PASCAL are increasingly high with cardiology first and even higher in CKD. So in 4, 5 years from now before patent expires, could you share any views about how much you expect cardiology and nephrology to represent out of total sales of Forxiga by then? And second question, if we move to the 2 combinations in the making, do you plan to pursue those combination in all 3 indications? Or is the rationale stronger in any of the 3?

Thanks, Eric. Great questions. And we are definitely excited about the prospects with Forxiga on the trials that Elisabeth has alluded to and the great data that we've shown. But you're absolutely right, the $2 billion step up, if you want, that we did in 2020 was still in majority carried by our type 2 diabetes indication. I think it's fair to say that, obviously, there is a halo effect of the great science in heart failure and CKD, but maybe remember the study that we built since DECLARE was about cardiorenal protection. First, in type 2 diabetes patients, we saw that we were avoiding heart failures and CKD events. And then the specific trials have been proven that we can move from prevention into real treatment both with and without type 2 diabetes. We expect the growth to be fueled with the new indications from this year onwards, and we start to see that in the U.S., which was the first to launch -- first in heart failure. We'll have additional indications with CKD coming in. So obviously, that will add to the overall prospects that we have. And we also assume that, that continued halo effect in our type 2 diabetes indication, which is still the biggest -- will be carrying on, and we will be calling on all the different specialties and the [ chronologists ], nephrologists, cardiologists to make sure patients that need this medicine can reach it. To your question in terms of percentage of sales of those indications, I can probably best allude to the big overlap that there is in type 2 diabetes. Many patients have CKD and heart failure but we're also hoping to get indications outside of type 2 diabetes. So we still believe type 2 overall will remain the biggest indication, because just sheer number of patients that are there. But we do see significant growth coming from the new indications in the next years. And maybe, Nick, I can take the Q&A that was on the -- I saw on the chat because it was similar, right? Quickly take this one's from [ Kerry Holford ]. So the answer is -- I can build on that is, yes, we will access patients with heart failure who have diabetes or not have diabetes, same with CKD. So cardiologists and nephrologists are definitely core to our segmentation. Luckily, we have Brilinta, for example, and that team is very acquainted with cardiologists, and we're tapping into their knowledge to bring this heart failure medicine to cardiologists, and we have a great team that is working on Lokelma and preparing for roxadustat and selling roxadustat in China for the moment, and that team will carry Forxiga to nephrologists. So I think we're nicely set up to really be as good as we can in convincing these physicians of the benefits of Forxiga for their patients.

Maybe continuing with sort of the commercial theme as well. So a question from [ Will Hamlin ]. So what has been the challenge to Lokelma commercially? Are you expecting an inflection in growth given you're highlighting it. I mean, competitor to Lokelma has a study reading out this year, looking at reduction in hospitalization and mortality. If this reads out positively, will it impact Lokelma growth?

Great question, Will. Thanks for asking it. Yes, there -- obviously, there's always challenges with any brand that we launch. With Lokelma specifically, it is about these old entrenched habits of physicians to stop RAAS inhibition or stop MRAs, or/and provide a lousy diet, if I can say it like that, with local fashion in it, which is actually not healthy for patients. And so the issue is not so much that physicians don't recognize your unmet medical need. If a patient comes in with hyperkalemia, I can tell you a physician acts because they're afraid of the sudden death they see the -- [ RME ] they're seeing, and obviously, the mortality that is related to that. So they do something, but what they do is the wrong behavior. And it's obviously built on an era where nothing was available without the new binders that you have currently. So what we're trying to do is unlearn that behavior into embracing new binders, which are easy to use. You have a direct effect. They're very safe. And they get your hyperkalemia controlled in a very intuitive way, and we're obviously also helping guideline committees to understand our data better. There's been 2 guideline changes from [ Codigo ] recently for hypertensive patients or patients with type 2 diabetes where usage of these [ camian ] binders are now been put forward as a better solution than taking away these life-saving medicines like RAAS inhibition and MRA. So that gives you maybe a little bit of color. I think we've always said it's going to be a bit of a slow burner, if you want, but the market is growing. Definitely where we're launching, we're gaining market share very quickly because of the profile of the molecule. And we believe that, that's going to continue to go ahead in the next couple of years.

I'm going to try and take the last 2 questions. So Matt Weston, please go ahead.

Nick. It's a question about commercial strategy in CVRM overall. I mean given the rollout of the new indications, but also, you've highlighted the overlap for a number of the agents that you're bringing to market. How should we think about incremental investment in SG&A in CVRM over the course of '21 and '22? Can you do it all with the people and the funds that you have? Do you need more? Or is the focus on efficiency such that you're doing it all for less?

Great question. For less, I'll probably not acknowledge that one. We have so much science to bring to physicians that we will need the infrastructure that we have today. But I can assure you that we believe we have more or less in place what we need because what I was just saying, the synergies between our Brilenta sales force versus our renal sales force for Lokelma and rox, and then the Forxiga indication CKD. We are well set up to tap into the specialists that need it. If we would do slight increases, it's probably looking at primary care because most of these CKD patients in stage 3, they are managed by primary care. So we're looking at how we could optimize some of our presence there. But remember, also there, we are present with Forxiga in type 2 diabetes, which is a typical primary care sales force. So all in all, I think we are well set up today to maximize what we have in that. Or Nick, I just saw Eric coming back on a question, and I'm really sorry, I forgot to answer that one. About the combinations with Forxiga. The ones that we have in development now and that Regina is covering in the other session, are more pointed towards patients with comorbidities like heart failure and CKD. So you think about [ dapagliflo ] it's really for patients with CKD, and we really believe that's a combination that could really maximize benefits for those patients. The 9977 DAPAs or MRM with DAPA is pointed towards patients with heart failure, but also patients with heart failure and CKD. So those are the 2 ones that we have that are furthest ahead, but we are continuing to look for other solutions for a broader patient population. So stay tuned, more work in progress.

Elisabeth, I just wanted to check if there's anything you wanted to add on some of those comments?

No, I think Joris just covered it really nicely. What we are trying to do here is not just a convenience study. We are trying to see how the science of the 2 molecules together can make a difference. But yes, we are primarily going into the comorbidities that Joris alluded to, as we're also looking for other opportunities where these 2 molecules and the mechanism of action on these 2 molecules can make a difference. So that more things are likely to come in that area as well.

Sachin, given that you've got your hand still up, I'm going to come back to you. So feel free. And then I will have to move on to the next.

Sure. So I just had 1 question on the Forxiga and combos that are in Phase II. I don't really understand how those launch meaningfully ahead of patent expiration, given if you're doing them in these new indications, I guess they likely require outcomes data. So could you just give us some color on time lines of when you think those combinations, if successful, can launch as a patent expiration strategy?

I'm happy to have a go at that. Our ambition is definitely to have them launch at or around the time of patent loss of exclusivity for Forxiga. We are looking at innovative ways of making that happen, looking both at what kind of endpoints we will be looking at. It's also what kind of clinical development that will be needed. But that is definitely our ambition.

I mean just to say to all of our participants today, many thanks. We have about I guess, 8 minutes before the next virtual breakout session starts. So that starts at 4:15 U.K. time. So please again go to astrazeneca.com/investors, where you'll find the information to join the next session. And alongside, obviously, presentations, and then we'll put event recordings there a little bit later. Finally, I just want to say thank you to all of our panelists from CVRM, but also Mene. To the people that are attending, you can please disconnect now. Whereas my colleagues, what we are now going to do is we're going to put ourselves on mute. We're going to turn off our cameras. I'm going to pause the recording, and then we will come back at 4:15 U.K. time for the next session.

Nick, can I go to another one now?

Yes, you can.

That was really good, really good.

Can we just stay, yes, Nick? Is that [ possible ]?

Yes, we do, but we are live. So mute comes off, and then I'll come back to you and tell you when we can join.

One more question, Nick. How do I go to another one?

It should be in the calendar. But I will put myself on mute, send it off, and I will send you a link, Mene, and then you all can join.

Thank you, Nick. Thank you.

You're very welcome. Thanks guys. [Break]

Right. I think it's [ past ] now so maybe should kick off this second session. So hi, and welcome, everyone, to this first breakout session called New CVRM: emerging pipeline. I'm Christer Gruvris from the investor -- AstraZeneca Investor Relations team, and I will be the moderator for this breakout session. With me today, I have members of the biopharmaceutical team. We have Regina Fritsche-Danielson, who is the Senior VP for early-stage R&D. We have Tomas Andersson, VP for late-stage R&D; and we also have Lori Kreamer, VP for CVRM from the BioPharmaceuticals business unit. This breakout session will last around 30 minutes. There will be a short presentation followed by Q&A. As usual, the presentations are available on astrazeneca.com/investors, and we have also sent it to people on our distribution list. Before I hand over to today's presenter, I would like to remind you that this meeting is being recorded, and this event is for invited sell-side analysts and institutional investors only. [Operator Instructions] After today's event, recordings from all the sessions will be available on astrazeneca.com/investors. Please turn to the next slide. This is just the usual sort of safe harbor forward-looking statements disclaimer. And with that, I will now hand over to our presenter. Please go ahead, Regina.

Thank you so much, Christer, and good morning and good afternoon, everyone. It's a great pleasure to have the opportunity to take you through some of the exciting programs that we have in the emerging pipeline today. So first, just to reemphasize that we remain committed to the 4 disease areas, and this commitment, of course, is driven by the large number of patients that are in need of novel treatments. And the unmet need continues to increase year-on-year, mainly due to the increasing prevalence of obesity and dyslipidemia, and taken together, these diseases lead to increasing prevalences of chronic kidney disease, cardiovascular disease and liver disease, such as NASH. And in our early research in this disease area, our focus is on developing new medicines by targeting specific disease drivers in specific patient populations where we aim to ultimately stop, reverse and cure disease. But today, I would like to highlight 5 of our programs that are in Phase II in clinical development and which we are aiming to progress into late-stage development later this year or during next year. So we can take to the next slide, please. So the first program I would like to highlight is our AZD8233 PCSK9 antisense oligonucleotide program. And here, we are focusing on the high unmet medical need that remains in terms of getting LDL cholesterol under control. And we know that in the real world, less than 30% of patients reach 70 milligrams per deciliter or less than 10% of patients actually reach the new target goal, which is 50 milligrams per deciliter. So there is definitely a need for improved therapies to control LDL cholesterol, and our ambition here is to develop a new medicine which can get the LDL cholesterol down to target level and keep it low throughout the whole dosing period. And the data you can see here on the slide with this molecule. You can see on the left side that we can achieve 90% PCSK9 knockdown with this antisense oligonucleotide, and this results in a 70% reduction in LDL cholesterol, which you can see in the graph on the right-hand side. And the same level of control in terms of efficacy, in terms of durability is not achieved with the available PCSK9 inhibitors. And we know that the durability of the response to keep LDL low is extremely important since this is what is linked to the overall -- or the overall exposure of LDL cholesterol is really what's linked to see the outcomes in the end. With this program, we are currently completing our Phase IIb dose range finding study, and we are planning to transition into late-stage development later this year. So let's turn to the next slide, please. So the next program I would like to mention is our AZD4831 myeloperoxidase inhibitor project. This is a small molecule which we are developing for treating patients with heart failure with preserved ejection fraction. And as you all know, the unmet medical need in HFpEF is enormous, and there is only one recent approval for ENTRESTO for patients with EF below 57. But the unmet medical need remains huge, and there is no treatment here that really specifically targets disease drivers in HFpEF. And here, we have MPO which we believe is doing this. This is a novel target for HFpEF, which really triggers cardiac and vascular inflammation and fibrosis, and this leads to vascular and cardiac dysfunction in particularly in patients with HFpEF. An MPO was actually selected based on patient data, where we found a strong link between MPO levels and MPO activity to disease progression in patients with HFpEF. And you can see some of that data. In the far left graph, you can see the correlation that we identified between MPO levels and also activity, as shown here, with physical activity, as we measured here in using 6-minute walking distance test. In the next 3 graphs, you can see data from our Phase IIa clinical study, where we treated patients with HFpEF for 3 months, and we could show improvements in 6-minute walking distance as well as improvements in functions and symptoms score, measured using the KCCQ, Kansas City Cardiomyopathy Questionnaire; and the reduction in NT-proBNP, which is a very established heart failure biomarker. So I would say that although these data are from a quite small set of patients, they are increasing our confidence that inhibiting MPO, so the reversibility aspect, has the potential to actually improve functions and symptoms and reduce mortality in patients with HFpEF. And we are starting our Phase IIb clinical trial in Q2 this year, so just about to start dosing patients in that trial. So it's a very exciting program. So let's turn to the next slide, please. So now I want to spend a few minutes and talk about our combination programs with dapagliflozin or Farxiga. And the first program I would like to mention is a combination with our mineralocorticoid receptor modulator, AZD9977. And we are developing this combination as a treatment for patients with heart failure and poor renal function. And in this population, there is a large unmet need since generic MRAs are contraindicated or underused in these patients due to their risk for hyperkalemia. And by combining this novel MRA, which has been optimized to not cause an increase in serum potassium, we combined it with dapa, we can capitalize on the complementary mode of actions that have been demonstrated in outcome trials with both SGLT2 inhibitors and MRAs in terms of efficacy, and we can provide a medicine that is safe to use in patients with impaired renal function. And what you can see on the left-hand side of this slide are data from preclinical studies in rodents, where we show on the far left, a similar effect -- efficacy with our molecule, AZD9977, as eplerenone on cardiac function, and we are measuring cardiac function here as cardiac perfusion reserve. And you can also see on the graph next to that one, that we don't see any effect on serum potassium, which is different with our molecule, which is different from eplerenone, which you can see there on the slide increase in serum potassium in this model as well as in patients. So for this program, we have started Phase IIb, and we are looking forward to seeing data early next year on important biomarkers that can support both heart failure and renal indications in the end. The second program I want to talk about, combination program, is with zibotentan, and that zibotentan combination is being developed for patients with chronic kidney disease. So zibotentan is an endothelin A selective antagonist. And again, by combining these molecules, we are capitalizing on complementary model action to maximize efficacy on renal function. But also here, by combining these 2 molecules, we can mitigate a safety risk that is inherent to all endothelin receptor antagonists, which is a risk of fluid retention. And this risk can be mitigated by addition of dapa, which actually reduces sodium and body fluid. And fluid accumulation is not really acceptable in these patients as it can have severe impacts on the heart and leading to heart failure. So in the right-hand side of this slide, you can see data from another endothelin receptor antagonist, atrasentan in this case. And there was a study called the SONAR trial. And what they showed in that trial in a post-talk analysis, they showed that in patients with DKD that were on SGLT2 inhibitors and then given atrasentan, they had a larger reduction in proteinuria or UACR, which, as you know, is an important biomarker for renal function. So we can really maximize efficacy with the combination here. And you can also see that in these patients on both SGLT2 and ETAs, there was no increase in fluid retention, as measured by changes in body weight as a proxy for this risk in this study. So this really gives us good confidence that we could have complementary efficacy and also mitigate the risk of fluid retention with ETAs. And our Phase IIb study is about to start recruiting patients, and we are planning the transition again here to late-stage development in the middle of next year. So we can turn to the next slide, please. So the last program I want to mention today is our cotadutide program, and this is a dual GLP-1/glucagon copeptide, which we are developing for treatment of NASH or nonalcoholic steatohepatitis. So as you know, NASH remains a huge unmet medical need. There are lots of programs ongoing, and -- but there are currently no approved therapies for this indication. And NASH is really a terrible disease. It's slow in progressing. It starts with fatty liver and then progresses to inflammation, also cell injury and cell death and fibrosis and later stages developing to cirrhosis or scarring and also frequently into hepatocellular cancer. And these later stages of disease have actually become the major cause of liver transplantations in the U.S. and in the EU. So it is a huge unmet medical need and a huge cost to the society. So with cotadutide then, we are capitalizing on 2 well-established -- or we are capitalizing on the well-established effect, I should say, on GLP-1, which is including effects on weight loss. And we know that weight loss indirectly would have an impact on reducing liver fat. But then we have the glucagon component, where we have direct effects of glucagon on the liver. So we don't have any GLP-1 receptors in the liver, but we have glucagon receptors in the liver. And the glucagon effect is what gives us the effect on inflammation and fibrosis in addition to the reduction in fat. So we have completed several Phase II studies with cotadutide. And in the slide here, you can see data from one of our studies in diabetic obese patients. And here, we could demonstrate a really nice significant reduction in liver fat of 33% already after 4 weeks. This is a quite short time and a large reduction. And in the longer study, we could see reductions in the fibrosis biomarker Pro-C3. And it is very important for new medicine in NASH, not only for getting the approval, but also for the patients, of course, that the new medicine reduces fibrosis in addition to liver fat because we know also that it is actually fibrosis that link -- is the link to outcomes, severe outcomes in these patients. So if we can take the next and final slide, please. So in the last slide here, you can see some of the additional programs that we have in early development in CVRM across disease areas. And we have a quite busy portfolio, and we are looking forward to share more about these programs at a future meeting. On the right-hand side, you can see some of the upcoming news flow in terms of data readouts. You've heard about cotadutide in NASH today. We also have a program in diabetic kidney disease with cotadutide. And we also have the FLAP program, which is an anti-inflammatory cardiovascular improvement molecule, which we are developing for coronary artery disease and chronic kidney disease. So there are a lot of important data readouts coming out in the next couple of years. So finally, with that, I would just like to thank you for your interest in the early pipeline, and I hope that you now have a bit more insight into what's coming behind Farxiga and our brands and that you are as excited as we are. And now me and my colleagues are happy to take any questions you may have. Thank you.

Thanks, Regina. We'll now go to Q&A. [Operator Instructions] The first question, we can go to Richard Parkes.

And firstly on cotadutide, could you discuss what you hope to see in the head-to-head study that's ongoing versus semaglutide in CKD in diabetes and what the mechanistic rationale is for that? And also remind us what you've seen in terms of tolerability for the drug. So I think that's been a challenge for the class. That's my first question.

Yes. So for the head-to-head with semaglutide, so I don't know if you're referring to the study -- we did a small study in diabetic kidney disease patients with cotadutide and liraglutide, where we could see better improvements in UACR with cotadutide; or if you're referring to another sema study that I may not be quite into the details on. In terms of safety effects, we are seeing quite similar effects on nausea and vomiting as traditional with GLP-1 study. It's dose-related, of course, but it's nothing worse than what is -- what we would expect.

Okay. Could I just take a quick follow-up on the PCSK9? And sorry if I missed it during your presentation. But could you talk about what profile you're looking to see in terms of frequency of injection and what you think you need to demonstrate to compete with inclisiran and where that will fit in? And maybe if you could also talk about cost of goods as well because that's kind of one area where Novartis has talked about potentially having flexibility there, given kind of approaching small molecule type cost of goods.

Yes. Thank you. That's a great question. Yes. So for in terms of dosing frequency, this is going to be a subcutaneous once a month dosing at home, so it's going to be using an auto-injector. So that's different from inclisiran where the patients need to go to a primary care center to get their injection. The dose is low, and cost of goods is acceptable. I will say we are still working on improving the cost of goods and the CMC when it comes to oligonucleotides, but since we have a [ glandular ] conjugated ASO here, so it means it's targeted to deliver, we can get down to fairly low doses, I would say. And in addition, we will differentiate the main -- so the main differentiator, I would say, is on efficacy. So we have a very potent molecule, which gives us 70% reduction in LDL-cholesterol versus inclisiran, where we see 50% LDL cholesterol, looking at the same type of patient population with the same starting level of LDL cholesterol. So of course, it's important what starting level we look at. But -- so basically, efficacy, convenient at-home dosing and cost of goods is reasonable, and we are working on improving that year-on-year to come down further.

Thanks, Regina. Thanks, Richard. We have an e-mail question following up on that actually from Kerry Holford at Berenberg with regards to 8233, and that is, will your Phase III program incorporate similar endpoints? This is in relations to Novartis [indiscernible]. And will you build in an outcome study?

Yes. So we would have some -- I mean, maybe you can talk about that, Tomas, actually, if you like.

Yes, I can take that. Hello, everyone. I'm Tomas Andersson. I'm in late-phase development. And yes, I mean, to register 8233, we will need to demonstrate, as Regina said, the profound and sustained lowering of LDL, obviously, but we will also conduct an outcome study on CV outcomes. And of course, if this holds its promise and we see this increased efficacy on LDL, that will also then translate to the cardiovascular outcomes. So that's what we intend to show.

Yes. So basically 2 studies as we are planning right now, 1 LDL-C for approval and 1 CV outcomes trial to demonstrate that we also have the outcome benefit, and that's likely be superior than to inclisiran. That's what we like to see with a 70% reduction, yes. Okay.

Yes.

The next question is from Seamus.

Great. So on cotadutide, can you just help us understand? I believe this is a once-a-day dosing regimen. Can you just update us? Are you working on weekly dosing such that, that would be competitive with the profile of other incretins in development? And then separately, the 5:1 ratio, I think, that you have GLP-1 to glucagon, are -- any reasons to think that there would be potential benefits to either tolerability or effectiveness to have a more balanced profile as it relates to that? And then a separate question. On the MPO, can you just help us understand maybe a little bit more of whether or not there's an opportunity there more broadly in fibrosis outside of just cardiovascular disease?

Okay. Thank you for 3 great questions [indiscernible]. So let's see. If we start with the QD, so once daily. So we have cotadutide once daily, as you say right now, and it's a great molecule where we have great hopes for good efficacy in terms of natural resolution and reversal of fibrosis. But of course, we know that we want to come with a less-frequent dosing scheme to be competitive. So we are definitely working on that. We have several different angles that we are looking at, but we are -- now the most-promising one is a slow-release formulation. And we are just working on getting all the different aspects right there. But yes, we will definitely plan to launch with QD but come quite soon after with the QW formulation. On the balance in terms of 5:1 GLP-1/glucagon, you are right. And we believe we have done a lot of work to find this right balance. We believe this is critical because we want to have, of course, the GLP-1 targeted effects like on glucose and body weight, et cetera. We want -- but we don't want to -- and we don't want to have too much glucagon because then we know we can get hyperglycemias. So what we have found with this [ B-R ] analysis that we get the right control of glucose. So we have used continuous glucose monitoring in our clinical trials, and we have compared with liraglutide. And we could clearly see that with the glucagon component in addition to GLP-1, we have a more less variable glucose level over the 24-hour interval. So that's been kind of the focus for this balance 5:1, and still not losing out on the glucagon component, which is important for the direct effects on the liver in terms of the anti-fibrotic and the anti-inflammatory effects. And for MPO, yes, MPO is a very exciting targets, and we have, as I said, the [ lead ] program is in HFpEF . What MPO has demonstrated in a lot of preclinical studies and also in epidemiological studies or in clinical cohort studies, is that we have a strong correlation with MPO and microvascular dysfunction. And we have also seen that in HFpEF, in general, microvascular dysfunction is a key disease drivers. And then in lots of preclinical models, we can actually improve vascular function by inhibiting myeloperoxidase. So it's a quite strong link to that. Likewise with fibrosis. So fibrosis is the second disease aspect that is critical in HFpEF, for progression of HFpEF, and MPO is inhibiting fibrosis. So we are also looking at programs in NASH, which we are about to move forward with. We are planning here. And also in chronic kidney disease, we are also looking at MPO in that indication. And we have, of course, preclinical data that support both of those indications. So we believe this can be a quite broad program in the end.

Thanks, Regina. Next question is from [ Michael Nedelkovich ].

I'm curious with the recent interest of label expansion, the FDA, to some extent, redefined HFpEF or what they would consider a HFpEF indication. Has that reshaped at all you're thinking about development and how you would move forward with, for example, the MPO inhibitor or maybe other agents?

Yes. So maybe I can start and say my view here from a scientific perspective. So from a scientific perspective, we know that HFpEF -- I mean, first of all, I can just say that to divide patients based on ejection fraction is quite arbitrary. So we know that, for example, HFrEF, when we talk about HFrEF, we usually talk about a ischemic origin of the heart failure. So it's usually post MI, and then patients that do not recover their myocardium, they go into HFrEF. And it's a very different disease biology versus HFpEF. And in HFpEF, on the other hand, regardless of the EF or regardless of the EF being mid-range, 45, being 50, 60 or almost normal up to 70, we know that this disease is very heterogeneous. So there are many different subpopulations in that disease category. So for example, you may have seen that Novo Nordisk and, I think, also Eli Lilly are now going into obese HFpEF with our GLP-1s and -- GLP-1s. So there is a subpopulation of HFpEF patients that have obesity-driven disease pathophysiology, and that's different biologies. We need to target that differently versus lean HFpEF patients, where a key disease biology is fibrosis and microvascular dysfunction, and that's where we think MPO is. So it's more in the non-obese, more in the normal, so to say, HFpEF patients. And that's how we do our science in general. So we have many other molecules in preclinical phase that are also focused on HFpEF. But on specific patient populations where we are aiming for a precision medicine approach and using biomarkers to identify those patients that are most likely to respond to a therapy in the end. So I don't -- I think you should not be hang up by the EF. That's been something that's been clinically used because HFpEF patients have been poorly diagnosed. We haven't paid -- physicians haven't really understood how to diagnose them, and I think that will change as well in the future.

Thanks, Regina. [Operator Instructions] There is an e-mail questions here from Mark Purcell. Please, could you help us understand how you expect to develop cotadutide in F2/F3 and separately, F4 patients? Are you exploring collaborations with respect to a noninvasive diagnosis and combination approaches, especially for F4 patients?

Yes. So how we are -- so in the Phase II program that we are running now, we have F2 and F3 patients. In the Phase III program that we are planning, we will have F1 to F3, and we will have a separate F4 cirrhosis -- going for cirrhosis patients. So that's how we will cover the different patients. For the cirrhotic patients, we know that it's very challenging to reverse basically scar tissue. So here we are definitely -- we believe that this -- there would be like a treatment regimen for these patients, whether it would be fixed dose or in the same molecule or if it would be add-on. I think the way we see this is that these metabolic agents, including GLP-1s but also potentially cotadutide, is like a backbone treatment for NASH patients. And then we likely need to add on other more specific agents or medicines that can target more aggressively the fibrosis mechanism, for example, to really get to a position where we can reverse the fibrosis. So it can also be -- I think another part of this question is that how can we diagnose NASH in an easier way than using a biopsy. So there's a lot of initiatives ongoing using imaging and elastography, for example, to look at how stiff the liver is, and we are part of such consortiums and collaborations where we're looking at that. And the ideal situation would, of course, be if we could diagnose these patients earlier, and maybe when they only have F2, so they're non-cirrhotic, a little bit of fibrosis but mostly fat and inflammation, it will be much easier to reverse the disease. So we are looking at the whole spectrum there.

Next question is from Emmanuel Papadakis.

I just had a quick question on the Farxiga combinations. It looked potentially intriguing. Could you just talk a little bit about the opportunity to put some intellectual property around those combinations? You obviously don't have a huge amount left on Farxiga, its molecule itself. And also as part of the combinations, is there an opportunity to do something more than just combining them in a daily pill? Could you talk a bit more if that is the case?

Yes. So in terms of the IP here. So for the 9977 dapa combination, we are capitalizing on the patent life of 9977, which has a very long patent life. That's going to be a new NME moving forward. For zibotentan dapa, we have -- it's going to be data exclusivity-driven. So there, it's -- and we're going to plan -- we are planning to launch at the time of dapa LOE basically. So we're going to plan for a 30-month extension about 5 years exclusivity. That's the kind of strategy we have right now. And we're also looking into several other indications than the one I presented here today. So the plan is that once we have demonstrated in our trial that is ongoing now, that we can mitigate the fluid retention risk, which is a key data readout. We have several other indications that we're exploring that we could progress in parallel with this CKD indication to launch broadly in the right sequence at -- and get the maximum protection over 7 years.

Thanks, Regina. And there are no new questions. There a few people that asked questions before, so we can go a second round if there are no more questions. Richard Parkes, please go ahead.

I'm just intrigued over zibotentan that you've chosen to go with a selective endothelin antagonist. I know some of your competition, they're confident that with the dual endothelin antagonist, you can avoid the edema issue without kind of using SGLT2. So I just wondered kind of what your thoughts were on that and whether you just don't agree with that or whether you're looking at also dual endothelin antagonist.

No. Yes. I think that is a quite hot scientific debate. Based on the data we have, our own data and how we interpret the data and the literature is that it's actually the ETB that we should avoid because that's what links to the sodium reabsorption in the kidney, which drives the water in. And we have had a lot of [ key ] discussions on this. And actually, most -- I will say that the most common view is that you will not get away from the fluid retention risk regardless of if you are endothelin A selective or endothelin A/B, hitting both A and B. So I think it still needs to be proven. And none of these endothelin receptor antagonist, regardless of their selectivity, have been able to progress into cardiovascular indications. Of course, there has been signs of -- or real data showing an edema risk.

Thanks, Regina. Next question, Seamus, you have another question.

So I just wanted to ask scientifically, as you think about the NASH mechanisms, there are a number of FGF-oriented mechanisms in development, 19, 21. I think Novo is also continuing to develop their program there. Just wanted to get your thoughts on those programs. And there was some recent data presented by Akero with their FGF21, suggesting that there may be some direct fibrosis benefits of treating with an FGF21. I wanted to just get your thoughts there. And then as a separate question, I guess, I'm struggling quite a bit with the desire to conduct this extraordinarily costly program with this PCSK9 ASO. This is more a simple question. How did this pass muster for the magnitude of investment necessary for kind of what looks like a me-too monthly treatment when antibodies approach the market quite well in that context?

Okay. I'll take the first question, and I'll hand over the second one to Lori. So in terms of the new data that has come forward for Akero with the FGF21, I think it is quite nice data they are showing there with -- on the fibrosis component. It's still a quite small study, so I think we need to follow the -- continuously see the data that is coming out from their programs. But both -- I mean, both FGF -- there are some side effects or safety concerns, I should say, there with FGF19, especially on bone and GI tolerability as well. But I think we need to follow the progression in terms of efficacy and safety as well coming out from those programs. Lori, do you want to take the PCSK9 question? I mean, first, we should remember, reiterate that it's a much more efficacious molecule. So it's reducing LDL cholesterol by 70% rather than 50%. For antibodies, of course, you are more close to 65-ish, I will say, but it's a different dosing scheme as well. So maybe, Lori.

Well, Regina, that was going to be my go-to answer. I mean, efficacy is king, right? And we do believe that with this one, this is going to be the strongest LDL lowering agent that will be on the market. And with 53 million uncontrolled high-risk patients [ NGA ] and just a fraction of them on the PCSK9 mAbs, we do think that there's an opportunity, particularly for those patients that are highest risk, to make sure that they achieve those target levels of 55 and 70. And we think that we'll have the agent that best does that. And I think Regina also mentioned I think the dosing regimen can be seen to be advantageous. You don't need to go to your primary care physician's office to have the administration that you would have inclisiran. It's much better efficacy than inclisiran. And so we just think that there's still a lot of unmet need out there. And there are patients that really need a heavy LDL lowering agent in order to achieve those target LDL levels and to reap the benefit in the outcomes. And so that's why we're bringing 8233 forward.

Thanks, Lori. [Operator Instructions] There is a question similar to what we have in last sessions. This is about Alexion, and Mene mentioned his excitement about the Innate system and the complement cascade. How sort of excited are you, Regina, about the Alexion deal?

Well, I'm very excited. And we have our own complement Factor D program, and we're working hard on trying to get a good small molecule. It's a tricky target to get a good small molecule on. But we are very excited about the molecule Alexion has. We think that there are second molecule which has become their front-runner. Looks really good. We have profiled it, of course, before we may started to think about going together with them, but it's really good molecule. And we are starting to see some good data on the complement system in renal indications. So -- and we know that the complement system is playing an important role in disease progression in kidney disease. So their expertise they have there around the complement system and the assets and molecules they have, we are very excited about, absolutely.

So thank you. I don't have any more questions on the web. We can take another e-mail questions with regards to investments in R&D. Obviously, Mene mentioned his 5R framework. From your perspective, Regina, sort of do you get sort of the funds you want? How is the prioritizations done -- being done between your products and sort of from your view?

Yes. No, I mean, it always starts with the unmet medical need, of course; and what is the unmet medical need; where do we see that the clinical pipeline is, not only our own, but also competitors; what's the likelihood of success with different programs; and where should we go in to really help patients that don't have anything today. And then it's the science. So we -- as Mene mentioned, we have invested in a lot of platforms, if I call it that, to have access to all different modalities. So if we find a difficult target that we -- is difficult to modulate with a small molecule, we can use an oligonucleotide approach or a monoclonal antibody. And in addition to that, focusing on unmet medical need is, we have also the investment he mentioned as well in using AI to discover new targets. We can mine a lot of data from patients. And it's a very patient-centric approach as well. So we are also developing very human -- focusing on human models, like using human cells and organoids and 3D printed organs, et cetera, to really look at our mechanisms and validate our mechanisms using human systems and looking at human cohorts, human patients and look at what's driving disease, baked on standard of care. So what is left there to drill the target, to stop the progression of the disease and even reverse disease. And then the investments we made now in cell therapy is -- I'm very excited about, and we have some programs there, which are moving forward, hopefully, in the next couple of years into clinical testing, especially in the cardiac space, where we have been working now for some year on cardiac regeneration using human ventricular progenitor cells that have been demonstrated in pigs actually to be able to regenerate tissue. So the next-generation science is going to be really working on targets that can take us more towards reversal of disease and maybe even curing. We are also investing in therapeutic genome editing to be able to target genetic diseases and cure such diseases by editing the gene, basically. And the third part I want to mention is the precision medicine. So we are also investing a lot in precision medicine. And as I mentioned with HFpEF area and heart failure area, these diseases are easily classified but difficult when it comes to the underlying cause of disease. And it is really different buckets of patients that will need different treatments. So we are even better at giving the right patient, the right treatment as we move forward and have good ways of diagnosing the right patient for the right treatment as well.

Thanks, Regina. Next question is from the Q&A box from Mark Purcell. Please, can you discuss albuminuria and the next steps, Phase II data in both CKD and HFpEF and as well as potential combination approaches?

Yes. Please, Tomas.

Okay. I can take that. I mean, as you probably know, for Verinurad, the -- our URAT1, urate-lowering drug, the SAPPHIRE study in CKD is running. It's fully recruited, and we're waiting for the results. And likewise, the AMETHYST HFpEF study is ongoing and recruiting right now. So we are basically eagerly waiting for the results of that and to bring it into late-phase, Phase III [indiscernible] as soon as possible. Regarding combinations, of course, there's you can -- given that we're looking at HFpEF and CKD, you can easily imagine combining with, for example, dapagliflozin. I mean, that will happen in the clinic, of course. And -- but what we need to see now is, first and foremost, is a confirmation of the efficacy in both HFpEF and CKD.

Thanks, Tomas. We have another question from Seamus. Any thoughts around gene editing as a platform for broader indications like CV diseases? PCSK9 seems to be a target uniquely well positioned. Any other targets towards considering for gene editing approaches?

Yes. So I think the platform, even though I know the PCSK9 data in nonhuman primates showed good promise, I'm not sure that I will go for gene editing approach for PCSK9, to be honest, because most of the patients that have mutations and like the familial hypercholesterolemia, for example, they have LDL receptor mutations, most of them. So even if we would fix PCSK9, they wouldn't be able to take up the LDL cholesterol via the LDL receptors. I think LDL receptors could be an interesting target to edit, if you can identify common mutations. We know that there are several hundred different mutations, so we need to have some kind of commonality in the mutations that we can -- to develop a therapeutic genome editing for those patients. But for familial -- homozygous familial hypercholesterolemia, for example, could be interesting. We're also looking into a lot of the genetic cardiomyopathy indications where we have mutations in sarcomeric proteins that could -- that lead to early death in cardiomyopathy, for example, and that's an area that we are looking at currently. But of course, the therapeutic genome editing platform needs to still mature and especially in terms of delivery and tissue specificity, so we can really get to the right tissue, the right cell to do our gene editing in a safe way. But for sure, it's going to be an important technology for the future. It's definitely something we are investing in, in early research and for certain targets, which is -- which there are very clear monogenetic disease drive on the disease. We can -- we are starting to put -- we have them in the pipeline already, projects. So we will see how they evolve in the coming years.

Thanks, Regina. And we're coming up to time. I probably have time for one more question. Emmanuel, you raised your hand.

I'll try and keep it short. 5718, you put it down as one of your catalysts or, in fact, your only catalyst for the first half of this year, the FLAP in CV, coronary heart disease. If you could just talk a bit about your expectations for that data. It's a mechanism with a mixed development history from other companies. I'd be interested to hear your perspectives on the opportunity and what you're looking for in that result.

Yes. So we will have a complete data set from the small Phase IIa study. So basically, that study is mainly designed for safety and target engagement in a patient -- in the right patient population. So we have good hopes that that's going to be safe and going to be a molecule that has good target engagement in terms of reducing LTB4 and LTE4. Then we are, of course, looking at exploratory efficacy biomarkers in terms of coronary flow reserve, and we are looking at biomarkers of heart failure like NT-proBNP as well. So we need to look at -- see how that data comes out. But based on preclinical data with FLAP in nonhuman primates, we can see really good improvement in ejection fraction in nonhuman primates that have dysmetabolic syndrome and cardiac dysfunction. Likewise, we can see very nice effects on UACR in nonhuman primates with FLAP. So we have nice data supporting the renal indication as well. And the kind of scientific rationale behind this pathway is that the LTC4 is a vasoconstrictor or impacts vascular function, and the LTB4 impacts vascular and also cardiac and tissue inflammation. And we know that both the microvascular function and the tissue inflammation are key drivers in both cardiovascular disease, so to say, coronary artery disease, but also in heart failure as well as in renal disease. So we are very excited. We know it's a very safe molecule, and we have nice preclinical data. Now we just need to see the full data readout from the Phase IIa study that's coming in the second half of this year.

Yes. I think the first question is from Simon Baker.

On the subject of HFpEF, is the -- do you have any data on a potential synergistic effect between Farxiga and 4831? And on a more general point about the utility of SGLT2s in this space, is there any scientific or commercial incentive to look for better SGLT2? Or is that unnecessary or commercially difficult because of the patent life? Some thoughts on that would be very useful.

Okay. So maybe I'll start with the question on the potential -- if I understand -- understood correctly, the synergies potentially between MPO and SGLT2. So first of all, we need to see the SGLT2 trials reading out. And I think we have good hopes that they should read out positive based on the mechanism of action, in particularly in reducing body fluid and blood pressure and also the oxygen carrying capacity that we see and improved energetics and mitochondrial function. So that's important biologies linked to HFpEF. But MPO has a very different mechanism of action. So we could -- we would definitely hypothesize that those 2 could be complementary. We are actually looking into potential combinations between our 4831 with Farxiga as well. And the commercial aspects, I don't know if we have Lori online.

Regina, can you hear me?

Yes.

Yes. I mean, I think the question was whether or not we're pursuing a better SGLT2 than dapagliflozin, and I'd say that the answer to that is no. And as Regina has, and I think many as well, kind of highlighted, CVRM from my perspective is all about innovative science. And we're kind of looking towards the future of new novel mechanisms that will complement that of the SGLT2 to deliver even greater benefit to patients who have residual unmet need.

Thanks, Lori. Next questions is from Steve Scala at Cowen.

Can you hear me?

Yes, now we can hear you.

Question on cotadutide. I thought AstraZeneca had been developing it, not only in NASH and diabetic kidney disease, but also in type 2 diabetes as a discrete disease. Is that still the case? And related to that, do you have any thoughts on the data on Lilly's tirzepatide to date? Lilly thinks it ultimately will be a great drug in NASH.

Thank you for the questions. So in terms of the diabetes indication, yes, that was -- that's correct, we had a Phase IIb large program with cotadutide in obese diabetics. And we learned a lot about the safety of the molecule in that program. We didn't pursue it further because we thought that the competition was hard, and we saw more benefit to position this against the high unmet medical need in NASH, where the mechanism of action is a very good fit. On the question related to tirzepatide's data, they have some promising data on biomarkers that are linked to -- they have data on liver fat and they have data on inflammatory and fibrotic biomarkers that looks promising. But we still need to see the histological data to be convinced about if there will be a real effect on NASH resolution and/or regression of fibrosis. We haven't seen that yet, so that remains to be demonstrated. But I believe that with the GLP-1, GIP, you will -- there will be mainly the metabolic effects, the weight loss-driven effects and the indirect effects on the liver in terms of reducing fat because there are no GLP-1, GIP receptors on the liver. So there, we believe with cotadutide, where we have the glucagon component, and we will have a direct effect in the liver, which is really the -- driving the anti-inflammatory and anti-fibrotic effects that are so important to get the full resolution and reversal of fibrosis in these patients.

Thanks, Regina. The next question is from Jean-Jacques at Bryan Garnier.

A quick question on cotadutide. I did not find any data on the ALT enzyme biomarker for NASH. So do you have any idea what is impact of cotadutide on this particularly important biomarker?

It was a little bit difficult for me to hear the question, but if I heard correctly, you asked about ALT and whether there's an effect on ALT with cotadutide. Is that correct? Okay. If that's the question, then I can say that, I mean, ALT is not a very NASH-specific biomarker. It's more a biomarker of liver health in general. But we do see effects on ALT as well with cotadutide because, of course, we are improving liver health with this mechanism of action.

Thanks, Regina. [Operator Instructions] Yes, there's one. Simon got back to us, Simon Baker.

A question on 8233 where you're targeting monthly dosing. How do you think that's going to stack up against some of the longer-acting agents out there like inclisiran? Do you think that the difference between once -- 1 monthly and 6 monthly dosing is not that significant? Or are there other aspects where you think you can differentiate your product?

Yes, that's a really good question. Thank you. So yes, we will differentiate versus inclisiran based on efficacy. So we have clearly a larger reduction in PCSK9 and LDL cholesterol. So with inclisiran, you reach about 50% LDL cholesterol in patients with above 100 milligrams per deciliter. And we have 70% reduction in LDL cholesterol. And the other part of differentiation is that we will have an auto-injector easy-at-home administration once every month, whereas with inclisiran, the patients need to go to a primary care unit to have their injection. So it's going to be a patient -- more patient friendly, and we're going to have better efficacy for sure with our molecule.

Thanks, Regina. I think Steve Scala come back with another question.

There's quite a few drugs in the Astrazeneca pipeline that you didn't touch upon. So I'm wondering if you could provide a few words on them, such as the VEGF-A, the FLAP, the LCAT, the LOX-1 monoclonal antibody, the relaxin product and the anti-IL-33 for diabetic kidney disease.

Yes. That was a lot of molecules. Let me bring up the pipeline here. Yes. So we did -- obviously don't have time to talk about all the programs today. I can mention that VEGF-A, as you know, is an mRNA therapeutic, which we are developing for treatment of heart failure, especially in patients undergoing CABG. And this is a regenerative type of therapy, and we have just completed actually Phase IIa study in patients undergoing CABG. And we are waiting for the data that we will have now in April. We should have the data from that study. And based on what we see there, that will trigger a potential Phase IIb investment decision in the same patient population. FLAP is a novel molecule that we have discovered in AstraZeneca and where we are having really good, strong platform of evidence preclinically. It's an anti-inflammatory mechanism of action. It reduces LTB4, which is inflammatory; but also LTC4, which is vasoconstrictive agent. So taken together, a FLAP inhibitor improves microvascular function. And we know that microvascular function is very -- it's dysfunctional in patients with heart failure, with cardiovascular disease and CKD. So by improving the microvascular function and blood flow to the heart and to the kidney, the glomerular flow, we will improve renal as well as cardiac function. And we have nice data in nonhuman primates, showing that we get a good benefit from this molecule. And it's now progressing nicely into Phase IIb studies in CKD and also in coronary artery disease. We will actually have coronary artery disease data readout, the full data readouts from the first Phase IIa study later in this year. LOX is a novel molecule. It's a monoclonal antibody that is targeting oxidized LDL and effects of oxidized LDL. It's really focusing on NT -- atherosclerosis effects, reducing systemic inflammation. We have nice -- quite nice data, I would say, from a small Phase Ib study in patients with cardiovascular disease, where we see using imaging reductions in atherosclerotic plaques in the noncalcified plaque volumes. We see effects on NT-proBNP and we see effects on systemic inflammatory biomarkers. So we are that's also a program we are excited about. It's progressing into Phase IIb studies, already started dosing actually. What else did you mention there, let's see. We can say something maybe around -- so IL-33, as you know, is a program across many indications in respiratory and also in DKD. And IL-33 is a very specific inflammatory pathway that is expressed locally in the kidney. It has high mRNA expression levels, high activity measured using biomarkers, and it's a strong link to progression of renal disease into end-stage renal disease. So we believe this is an important specific inflammatory pathway for patients with renal disease.

Thanks, Regina. We are coming up to time. Let's see if there's any more questions. I don't see any more questions on the web. There's one e-mail question, Regina. Mene mentioned the Alexion acquisitions and sort of some of the [ rapid ] with the Innate system. Is there anything that sort of excites you then getting Alexion on board as well from your perspective?

Yes. Yes, I'm very excited about the Alexion pipeline and what we have in the complement system there. So they have several assets, including the complement Factor D, but also other parts of the complement system. And we are really excited about dosing for our kidney portfolio because we know that the complement system is a key driver of disease, in particularly in certain subpopulations of CKD, like IgA nephropathy, anti-vasculitis and other smaller indications. And as Mene mentioned, we also have our own CFD program, but that's behind, of course. So if we can get the Alexion portfolio, we would be very excited in -- sorry, we will be very excited about taking those programs on and driving them forward.

Thanks, Regina. We're coming up to time now. I don't see -- well, actually, Steve Scala, one more question perhaps to end with.

If you would allow me, I'd like to ask about 2 other early-stage programs. The relaxin, one of your competitors failed in that, but it seems to not be going away. Other companies continue to work on it. And CD39-L3, what specific cardiovascular disease is that targeting?

Yes. Okay. So the relaxin molecule is a very good molecule. It's a long-acting relaxin, and we are developing that for treatment of heart failure, so it can go actually both into HFrEF and HFpEF, also renal disease. So it has a long half-life, and we can dose once-weekly with that molecule, and we have very nice data from nonhuman primate studies showing that we get improvements in ejection fraction and different cardiac parameters. So it is a clear vasodilator, reducing peripheral resistance, which then makes the -- increases ejection fraction. And we also know that we have direct effects on fibrosis with this molecule. So that's progressing in Phase I studies currently and looking very promising, I would say. And then you asked about the 3366, the CD39 ligand. That's being developed for -- it's a recombinant protein that is going to be IV -- one IV infusion. It's being developed for patients with elevated myocardial infarction. And it's really a rapid onset antithrombotic agent, which has no or minimal bleeding. And in addition to having the rapid onset of antithrombotic effect and no bleeding, it also have clear tissue protective effects. So the ambition here is to reduce acutely the damage made from the MI, from an acute MI, to sandwich the myocardium and, at the same time, block the -- have the antithrombotic effect without any bleeding risk. So that is also a very exciting Phase I program that we have -- are looking forward to see the data coming out from.

Thanks, Regina. We're coming up to time now. You have about 10 minutes now to join the next breakout session. You can find all the breakout sessions on our web page, and you will also find the recordings for each one. So if you attend to live today, you can always see you the other recordings online. With that said, I would say thank you to our panelists, and also thank you to you for showing the interest in AstraZeneca. Please disconnect now. Thank you.