Novartis AG (NOVN) Earnings Call Transcript & Summary

Good morning and good afternoon, and welcome to the Novartis cardiovascular update. [Operator Instructions] And the conference is being recorded today. [Operator Instructions] A recording of the conference call, including the Q&A session, will be available on our website shortly after the call ends. [Operator Instructions] With that, I would like to hand over to Mr. Samir Shah, Head of Investor Relations. Please go ahead, sir.

Thank you very much, and good morning and good afternoon to everybody. A big, big thank you for joining us this afternoon in European time for the Novartis Cardiovascular Update. With us today, we have quite a lot of speakers, but hopefully, we'll leave enough time after the presentation for the questions and answers. We have Dave Soergel, who's the Global Head of Cardiovascular, Renal and Metabolism Development; Rod Wooten, who is the Global Head of Marketing, Novartis Pharmaceutical; Victor Bulto, who's Head of Novartis Pharmaceuticals U.S.; and our external speaker is Matthew Whitty, he's the CEO of Accelerated Access Collaborative, NHS Group, and he'll be talking about the population health program, which we're expecting to start this year. And with myself, Samir Shah, Global Head of Investor Relations. Before we start, I just wanted to read you the safe harbor statement. The information presented today contains forward-looking statements that involve known and unknown risks, uncertainties and other factors. These may cause the results to be materially different from any future results, performance or achievements expressed or implied by such statements. For a description of some of these factors, please refer to the company's Form 20-F and its most recent quarterly results on Form 6-K that respectively were filed with and furnished to the U.S. Securities and Exchange Commission. Now with respect to the slide set, you can follow it on our website. We did post it earlier in the day. And with that, I think I'm going to hand across to Dave Soergel from our development group. Dave?

Great. Thanks a lot, Samir, really appreciate it. Thank you all for joining. It's great to be here to talk about the Cardiovascular, Renal Metabolism portfolio and talk especially about the cardiovascular medicines we have in our portfolio. We have the ambition to reach hundreds of millions of people with these innovative therapies and therefore, improve cardiovascular health. So Rod and I are going to start today with Entresto. So if we flip to Slide 6. As you all know, Entresto has been improving and extending the lives of heart failure patients since 2015. And recently, earlier this year, we expanded Entresto's indication to include patients with heart failure with preserved ejection fraction with below normal ejection fraction. And this then covers about 5 out of every 6 heart failure patients in the United States are now covered by Entresto's label. So if you look at this time line, about 18,000 patients have been enrolled in randomized controlled clinical trials with Entresto across the spectrum of heart failure in rigorously designed active-controlled studies versus the standard of care. And this really, I think, underpins our ambition to transform the care of heart failure. Slide 7. We're going to talk about PARADISE-MI now, which was a landmark study in post-acute myocardial infarction patients, and talk to you a little bit about how PARADISE-MI fits within the clinical trial evidence basis in heart failure. So PARADISE-MI, the aim of this trial was to show whether or not Entresto could prevent the onset of heart failure in high-risk patients after they have had a heart attack. So as many of you are probably aware, in the post-myocardial infarction setting, RAS inhibition, renin-angiotensin system, inhibition with ACE inhibitors like ramipril or with angiotensin receptor blockers are the standard of care. And so we set a very high bar, again, with the ambition to transform the care of these patients to show that Entresto was superior to the standard of care approach. About 5,600 patients were enrolled in this trial. And let me reinforce, these are patients who are within a few days of having a heart attack. So these are patients who are fragile, who are sick and have had a life-changing event. And we have had, therefore, had an opportunity to evaluate Entresto's efficacy as well as tolerability in these fragile patients. The primary composite in PARADISE-MI was cardiovascular death, heart failure hospitalization or outpatient heart failure visit, the first occurrence of any of one of those 3 events. Slide 8 shows you that the results of the primary endpoint from PARADISE-MI, again, cardiovascular death, heart failure hospitalization or outpatient visit for heart failure. And as you can see, despite a trend favoring Entresto in this trial, unfortunately, we did not hit statistical significance for superiority versus ramipril in this study. Slide 9 shows you a bit of context for why the PARADISE-MI trial was setting a high bar for Entresto to transform care. And this shows you a historical view of the care of post-MI patients over the last 30 years. And what you can see if your eyes go to the top of the graphic on the left-hand part of the slide, you see the 1990s, a year after having a heart attack, about 20% of patients would be expected to die. And as you can see, over the last 30 years, care of these patients has improved substantially, so that now that 1-year mortality rate is more in the 5% range. And this has happened for a variety of reasons, renin-angiotensin system blockade is part of it, early percutaneous coronary intervention is another part of it, high-intensity statin use post-MI is another and just quality metrics with respect to how these patients are cared for, I think, have really changed the outcomes in a positive way for these patients after heart attack. So these numerical trends we see in PARADISE are on the basis of already substantial improvements over the last 30 years. Slide 10 shows you other endpoints from PARADISE-MI, again, consistent with the primary end-point where we saw the trend towards an improvement in cardiovascular death, heart failure hospitalization and outpatient heart failure visits. We see the secondary endpoints similarly show a trend towards the benefit for Entresto in a variety of measures. Next slide, on Slide 11, we're calling out 2 additional prespecified analyses that I think provide additional color on the importance of PARADISE-MI in the context of the treatment of heart failure patients. So if you look at the left-hand graphic first, this shows you the total first and recurrent adjudicated primary events in the trial. What this shows you is that the relative risk reduction of 0.79 is better than what we saw on the primary endpoint, which was 0.90. And what this probably reflects is that patients who have a first event of heart failure are starting to perhaps receive some benefit from achieving -- from receiving Entresto as they continue on in the trial. So what you see is future hospitalizations after that first hospitalization are then prevented compared to the placebo group -- compared to the ramipril group, I'm sorry. The next graphic on the right-hand part of the slide shows you that when you look at investigator-reported events, so when -- instead of have -- looking at the CEC-adjudicated events where stringent documentation is required to document a heart failure hospitalization or outpatient visit and instead, you rely on the wisdom of the investigator who, in most cases, is a cardiologist, you see that there are more events and therefore, a nominally statistically significant result with hazard ratio of 0.85. So this gives you confidence that, that trend that we see in the primary analysis may actually be a true incremental effect of Entresto in this population. Slide 12 shows you the adverse event profile. Again, in this very fragile population of individuals who had just had a heart attack, we see that Entresto was well tolerated. And this actually was also despite the fact that there was no run-ins in this trial, so patients were just started on therapy once they were randomized in the trial. And as you can see, there were no new safety findings in this study, as we expect. We see more hypotension events in the Entresto group and more cough in the ACE inhibitor group. But importantly, if you go to Slide 13, you see that actually fewer patients discontinued due to adverse events in the Entresto arm. So again, this gives you confidence that Entresto can be used in these fragile patients and used safely. Slide 14 shows you just that there's a substantial amount of evidence now underpinning the utility of Entresto in the treatment of heart failure. Over 50,000 patients have been enrolled in clinical trials and over 320,000 patients experiences in real-world evidence trials have been tracked now. So this really gives us, I think, a strong basis of support for continued use of Entresto in heart failure. And in addition, probably also reflects the fact that guidelines now support Entresto's standard of care in heart failure with reduced ejection fraction. Slide 15. So what's next? Well, Entresto also could meet major unmet medical needs in Asia in the treatment of hypertension. Very early on in its development path, Entresto was considered for development in hypertension. And what we saw was in Asia where there's an especially high proportion of individuals who are elderly and have a higher sodium intake, they might be particularly amenable to Entresto's mechanism. And indeed, in clinical trials, we showed that Entresto was superior to the then commonly used olmesartan angiotensin receptor blocker in Asian studies. So currently, the hypertension indication is undergoing regulatory review in China and Japan. So now I'm going to pass it to Rod to give an update on the commercial status.

Thanks, Dave. Let me just take a moment and give you some additional context on the PARADISE-MI study to market performance and treatment guidelines as we move forward. So on Slide 16. If we look at the size of the opportunity that still exists in the significant unmet need that exists in congestive heart failure, we have 8 million patients alone in the U.S. and the EU5 that could benefit from Entresto today and achieve and get the standard of care. And if we put the context of the population that Dave described, we've got 1.5 million myocardial infarctions annually and knowing that approximately 1/3 of those patients are likely to develop congestive heart failure, we see that there's a significant opportunity that those patients will eventually develop heart failure, and they will be among the labeled population for Entresto, an opportunity to upgrade into the standard of care. So if you flip to Slide 17, as you see on the left-hand side from the weekly NBRx data, the market performance is incredibly strong. And the trajectory that you see from January post is really driven by 3 main factors. One is the COVID recovery. We're seeing more access to customers again. And actually, patient office visits are exceeding pre-COVID levels. Second major factor is the ACC expert consensus guidelines, which I'll talk a little bit more about in a minute. This had a powerful impact on increasing Entresto first-line use ahead of ACEs and ARBs. And the third major factor is the momentum that we're seeing from the launch of the expanded label and the early positive indicators that we've seen from customers and new prescriptions. So looking ahead at future growth opportunities, we're confident that Entresto can continue to maintain the strong growth trajectory globally. And on the next slide, I -- we've mentioned a number of times the importance of these ACC expert consensus guidelines and they're incredibly clear in terms of focusing on and recommending ARNI as the preferred first-line use ahead of ACE and ARBs and considering the other mechanisms as add-on therapies to ARNI therapy or Entresto in this case. So this really puts Entresto in the pole position for 70% of the HFrEF patients who are still on previous standard of care and not yet receiving Entresto as their foundational treatment. And we know very well from experience in cardiovascular, with cardiologists, that guidelines drive prescription behavior, and we're certainly seeing that with the change in clinical practice particularly from the release of these guidelines in January of 2021. So if we turn to 19 and just summarize where we're at with Entresto overall, it is clearly our anchor brand in the cardiovascular space. It's backed by a very comprehensive evidence package establishing a leadership position in chronic heart failure. And as Dave said, while PARADISE-MI didn't meet the primary endpoint, the results did show incremental benefit versus a high bar and confirmed a very important safety profile in the most fragile patients. So we expect Entresto's momentum to continue very strong throughout the globe as we continue to reinforce and educate on those treatment guidelines, educate our customers on the new expanded label and the opportunity for patients to [receive] Entresto the first approved therapy for this patient population and maintain our strong market access. And with the potential indication in Asia in hypertension, we could see some acceleration of momentum in the case of positive approval and broad reimbursement. So the outlook for Entresto continues to be very strong. Dave, I'm going to hand it back to you to discuss one of our other major assets for the franchise, Leqvio.

Great. Thanks a lot, Rod. I appreciate it. So I'm back again to talk about Leqvio, along with Victor Bulto, Head of Novartis Pharmaceuticals; and Matthew Whitty, CEO of Accelerated Access Collaborative for the NHS. So let's turn to Slide 21. And there have been variations of this slide shown many times and it doesn't change. Despite the advances over the last several decades in cardiovascular care, there is still a huge burden posed by cardiovascular disease, both in terms of morbidity and mortality and in terms of cost for health systems. So if you look on the left-hand part of the slide, we see that about 1/3 of all deaths now are attributable to cardiovascular disease more than any other disease and more than all cancers combined. This poses a huge cost challenge for health systems, expected to exceed $1 trillion per annum by 2025. And of course, the number of lives lost is huge and staggering, 18 million lives lost globally to cardiovascular disease last year and yet -- and about 60 million patients are at risk of having cardiovascular morbidity and mortality due to ASCVD in the U.S. and the EU5. Slide 22. For the last 50 years, we've shown as the medical academic and scientific community shown that there's a strong link between LDL-cholesterol and cardiovascular outcomes and that lowering LDL-C can improve cardiovascular outcomes in actually a rather reliable way. So as you see in the graphic here, about 40 milligrams per deciliter reduction in your LDL-cholesterol reduces your relative risk of having a heart attack or dying of cardiovascular disease by about 20%. So -- and this has been confirmed over many years with many agents in a variety of settings over 500,000 patient lives in this particular analysis. The other important thing to derive from this particular graphic is the importance of adherence and persistence of therapy on outcomes. And what the colored lines represent here is a situation where you have a therapeutic that achieves 100% adherence and full reduction of LDL-cholesterol by 40 milligrams per deciliter. And the fact that that can improve cardiovascular outcomes, as you see on the y-axis, better than other agents that perhaps have more -- that have more administration or patient burden in terms of taking them. So for example, monoclonals or statins. This was an analysis that was published by Kaus Ray and his colleagues in CERC recently. So this relationship is critical. Slide 23 shows you that guidelines have, of course, adopted this recognition and have become more and more specific and more aggressive about lowering LDL as an important way to reduce cardiovascular risk. As you can see in the left-hand part of the slide, the AHA and ACC have -- for individuals at very high cardiovascular risk, recommend an LDL-C reduction to less than 70 milligrams per deciliter. And in Europe, those same patients, less than 55 milligrams per deciliter. So remarkably, despite effective -- what we believe are effective therapies and effective ways of being able to reduce LDL-cholesterol, about 80% of patients are not able to achieve these targets. So if we look at Slide 24, this is where we believe Leqvio fits in. Based on its Phase III profile, we see that Leqvio provides sustained and powerful efficacy on LDL lowering with 2 administrations per year. So as you can see in the graphic in 3 Phase III trials, ORION-9, 10 and 11, we see up to a 52.3% reduction in LDL-cholesterol in patients with ASCVD on top of statin. Next slide, Slide 25. So while we saw this powerful sustained LDL lowering efficacy, Leqvio was also very well tolerated, which is an important factor when you're thinking about a chronically administered medication to sick patients. So as you can see from the adverse event table, Leqvio had a very -- was very well tolerated. And really, the one finding we had was self-resolving injection site reactions that really pose no burden. So this is a game-changing profile that we believe will really be able to improve cardiovascular health. Now I'd like to pass it over to Victor to talk about our plans in the U.S.

Well, thank you very much, Dave. If we move to Slide #26. I wanted to focus here on the particulars of the U.S. unmet need. And you can see here that we have around 20 million patients treated with statins today, ASCVD patients, and that the vast majority of them are not at goal as of today. Also notable that we see a small penetration of the nonstatin therapies as well. And we have identified 3 main factors that drive this unmet need. The first one being adherence to therapy, the second one being access to these therapies and the third one being patient affordability. And we believe that Leqvio has the potential to uniquely address them. So now if we move to Slide 27, we focus on the first one of these factors being adherence. On the left side, you can see how adherence remains a challenge both for statins and PCSK9s. And on the right side, you can see how different adherence levels may influence the cumulative incidence of events. If we move to Slide #28. Here, we focus on the potential that Leqvio has to address adherence challenges based on 3 factors: the first one, as Dave just shared with us, is the clinical profile and the effective and sustained LDL-C reduction that we see in the clinical trials; and the second one is a twice-yearly dosing in the maintenance phase; and thirdly, the HCP administration. Now if we move to Slide #29, the HCP administration has also implications for access. Leqvio was studied as an HCP-administered drug, and as such, we expect that the majority of Leqvio patients will be covered by the medical benefit which we believe will have the potential to reduce access hurdles. On the table below, we have summarized the main differences between the pharmacy and the medical benefit reimbursement. And here, you can see that Leqvio will have the potential to be acquired via buy-and-bill and that for certain populations like the Part B fee-for-service population that represents around 40% of the CVD population, likely will be covered to label, which means no steps added, no prior authorizations and therefore, much less hassle for HCPs and their offices. Moreover, for buy-and-bill, practices will be reimbursed for their administrative efforts, which is not the case for the drugs covered under the pharmacy benefit. Now one question that we get quite often is the impact of the availability of CV outcomes evidence as a driver for access divisions at launch. And here, you can see that for the Part B fee-for-service population, again, around 40% of the population, we expect access to mirror the FDA label. And then for the rest of the populations, our experience with payers in the U.S. is that the focus is mostly on efficacy, safety and cost. Now moving on to Slide 30. If we move to patient affordability, as you can see on the left side, the out-of-pocket cost for patients has a substantial impact on the abandonment rates in this market, highlighting the importance of patient affordability. And as you can see on the right side, the medical benefit coverage for Leqvio creates the opportunity for a $0 co-pay for up to 2/3 of patients at launch, and we believe this will be a strong driver. Now as we have just seen in inclisiran's clinical profile and the possibility of the medical benefit reimbursement have the potential to address the 3 key unmet needs in the market, being adherence, access and affordability. Now for this to happen, cardiologists will have to grow increasingly comfortable with the buy-and-bill process, which is a new process for them and which will take time and effort to establish. Now if we move to Slide 31. In order to support this process and to comprehensively manage these nonclinical barriers, our U.S. launch focuses on partnering with healthcare systems. As you can see in the graph in the center, the majority of U.S. cardiologists today are employed by healthcare systems. And importantly, these systems have already buy-and-bill infrastructures implemented for other specialties which should help with the process of establishing buy-and-bill in cardiology. Some of these healthcare systems also have centralized prescribing influence and centralized EHR systems that enable granular patient identification. Now importantly as well, when we talk about the top 200 healthcare systems in the U.S. who take care of 2/3 of the ASCVD patients in the U.S., 45% of these systems already have ASCVD as a key strategic priority, which makes them strong partners for this launch. Now moving on to Slide #32. We've here shown the example of one of those systems of care, these large systems of care that we're going to prioritize for the launch. And there's 2 things that are interesting to note here. One is the size of the systems of care. I mean, this one, in particular, has 23 hospitals, 1 dedicated lipid center, 7 advanced cardiac hospitals. They own 40 cardiology groups. And they already have 10 outpatient infusion centers that do buy-and-bill for other therapeutic areas. The other interesting thing is understanding the granular data available to identify the ASCVD population who is not at goal today. And the fact that many of these systems already have population health experts working within the system, trying to address these challenges. Now finally, moving to Slide 33. I wanted to quickly recap this section saying that we believe that Leqvio has the potential to become the leading choice for ASCVD patients. On the one hand, by providing effective and sustained LDL-C reduction. And on the other hand, we believe that Leqvio is uniquely positioned to address the 3 key unmet needs in ASCVD, which are adherence, access and affordability. Now in order to prepare for the launch in the U.S., we have focused on approximately 200 prioritized healthcare systems, and we're deploying a highly experienced reimbursement team to help systems and HCPs navigate the early reimbursement complexity with buy-and-bill. Now with that, I would like to hand it over to Matthew Whitty.

Many thanks. And yes, really grateful for the opportunity to kind of talk through this really exciting partnership work that we, at NHS England, have been working with Novartis on for the last year or 2. And I'll start, if I may, just by briefly introducing the work of the Accelerated Access Collaborative. And so this is a convening board that brings together an industry, government, regulators, patient groups and the NHS. And the aim is to remove barriers to access and to accelerate the adoption of the most important medicines, diagnostics, devices and digital products. And you can see on the slide the range of partners that we bring together, but it's probably just worth highlighting that there isn't really anything else like this in the U.K. where you get the Chief Exec of the NHS England meeting with the Chief Exec of The Medicines and Healthcare Regulatory Products Agency (sic) [ The Medicines and Healthcare Products Regulatory Agency ] with the Chief Exec of NICE with representation from trade bodies and also other parts of government and research and the research infrastructure as well. So it's a really unique group with the really senior buy-in and expertise to help us solve these biggest challenges. And it's hosted by NHS England, as I mentioned as well. So that's just a bit of background to what the Accelerated Access Collaborative is. So it's a really, really important group for driving this work through and other work with regard to the adoption of innovative technologies. Moving on to talk about the population health approach, and I think I won't go through all the detail on these slides, I'll just talk to you the highlights in the interest of time. And I think the important things to note on this are there's a really strong alignment with this work with the aims and the specific commitments in the NHS long-term plan around reducing the impact of cardiovascular disease. And I think when we look at sort of why we, at NHS England, started to -- wanted to sort of undertake this partnership, it was really because there was a strong clinical case for the improved reduction in LDL-cholesterol lowering that really aligned with the long-term plan commitments. We had strong support from the national clinical directors. So we had the key opinion leaders at NHS England, who were supportive of the approach. And we also recognize that other therapies in this area, so specifically the PCSK9 inhibitors had, had lower levels of uptake than we would have liked even though they had approval from NICE and the regulatory and the NICE HCA body. So I think the opportunity to work in an area that was strategically important, had the clinical buy-in and would enable us to -- and the work -- the timing of the work enabled us to actually start planning to overcome some of these obstacles to adoption in a timely manner so that we weren't in a position with NICE approving something and then the uptake being slower than we would have liked. And there are a couple of key areas. There are 3 key areas really that we focus on here. So one is really positioning this treatment as a primary care intervention. So typically, a lot of the uptake for new medicines would be focused in secondary care. Secondly was efficient patient identification. So working with NHS Digital and GP system suppliers to make it easier to identify the patients most at risk. And thirdly, working with our stakeholders and making sure that their consultation and the training program is in place so the education for clinicians is being developed as well. And we're working really closely with delivery partners called Academic Health Science Networks. So this is a network of 15 organizations that have got really good local relationships with NHS organizations but a national level of coordination that we work with them on a range of our implementation programs. And I should say, while, all of these is contingent on or linked into the deal that was agreed with NHS England, which is contingent on the NICE approval as well, but yes, really, really strong alignment and timing wise, makes perfect sense. And moving on to the impact. So we already know and I mentioned the NHS long-term plan that heart and circulatory disease causes 1/4 of all deaths in the U.K. and is the largest cause of premature mortality in deprived areas. And it's already been recognized as the single biggest area where the NHS can save lives over the next 10 years. So in terms of sort of the level of importance of addressing outcomes in this area, and it doesn't really get more important than this. And you can see on the slide here, we've got a program of work where we're looking at kind of what the impact this could have on cardiovascular disease deaths and health inequalities across the U.K. And then moving on to the implementation planning. So we've been working really closely between ourselves and Novartis and the Academic Health Science Networks to agree to the objectives, to agree to the implementation plan, looking at the trajectories and the key performance indicators that we're putting into the agreements with the Academic Health Science Network. And we're taking a local focus to looking at what the implementation looks like in the different geographical regions. And also looking at a targeted rollout in areas where we think that's where we're going to have the biggest impact. I briefly mentioned patient identification already and the collaboration with NHS Digital has been key to being able to effectively identify these patients in primary care and it's something that we haven't done before for outside of COVID. So it's a really good test case for how we can do this. I mentioned education. So it's critical that we're educating the clinicians who are going to be the prescribers for these both in terms of what the intervention does, but also in terms of the model for how this can work. So recognizing that this is slightly different to how the NHS would typically adopt a new medicine, which might be a little bit more cautious in keeping things within BKS setting, so we really kind of see this as a primary care intervention. We've got sort of a rate and engagement program that is kicking off next week. And then finally, we've got adherence support as well, so linking in with the NHS Digital collaboration. So we've got various system prompts that we can build, will be we built into the system as well. So including a recall for patients that have been initiated on treatment. So I think that was everything that I wanted to cover. Hopefully, that's given a good flavor of sort of why we were, from an NHS perspective, interested in this collaboration and how we've gone about it from an implementation planning perspective. And then how this is different from how things have been implemented in the NHS previously. So I think that that's all I wanted to cover really.

Thanks very much, Matthew, appreciate it. If we flip to Slide 38. The current submissions in the U.S. and globally are supported by the trials that have been completed already, ORION-9, 10 and 11. And then as you all know, we expect our cardiovascular outcomes to the ORION-4 to yield data in 2026. But we have a robust evidence generation plan behind those studies as well with the aims of really better understanding how best Leqvio can be used in which patients and in which settings. And as you can see, we're in the process of planning several trials to support this evidence generation. And we'll be providing more information and more detail as time -- in good time as we get more details on the program. So in summary, Slide 39. The burden of cardiovascular disease is indeed rising despite effective therapies. And we know that LDL-cholesterol is one of the most modifiable risk factors to improve cardiovascular outcomes and yet patients are not optimally managed mainly due to adherence, access and affordability challenges, as Victor talked about. The U.S. launch is focusing on partnering with health systems to manage nonclinical barriers. And the U.K., as you just heard, the NHS and Novartis are partnering on a population health approach to impact cardiovascular disease at scale. So we'll now turn to pelacarsen, and Rod and I will walk you through this exciting program as well. So Slide 41, introduces you to lipoprotein(a). Lipoprotein(a), if you haven't heard about it before, is an LDL-like particle, but is highly atherogenic, proinflammatory and thrombogenic. And it is an independent cardiovascular risk factor that's genetically determined. Currently, there are no known therapies that reduce lipoprotein(a) and in fact, diet and exercise, don't improve your lipoprotein(a), statins, et cetera. None of those therapeutic alternatives will improve your lipoprotein(a) or reduce your risk. So we have an opportunity to develop a new therapy for patients with cardiovascular risk that's currently not managed. Slide 42 shows you the evidence that links elevated lipoprotein(a) to cardiovascular risk. And so you see there are a variety of sources of data. On the left-hand part of the slide, we show you epidemiologic data showing you on the x-axis as your lipoprotein(a) concentration, blood concentration goes up, your risk ratio for nonfatal MI and coronary death increases. And on the right-hand panel, you see a Mendelian randomization study showing you similar data, whereas you have elevated -- as your Lp(a) increases on the y-axis, your hazard ratio also goes up. So these -- there are several lines of evidence that link lipoprotein(a) to increasing cardiovascular risk. And indeed, guidelines and -- are increasingly recognizing Lp(a) as an important risk factor to assess in patients with ASCVD. Slide 43 shows you an important piece of information, which is -- so I said at the beginning that Lp(a) looks a lot like LDL-cholesterol. But interestingly, they're not very highly correlated. So the reason why this is important is because if you have a patient with moderately elevated or normal LDL-cholesterol, you still should measure an Lp(a) if they've had a heart attack or they have ASCVD, right, to appropriately assess their risk. So what this tells you is because these 2 risk factors are independent, LDL and Lp(a) are independent, you need to measure both of these risk factors in order to really judge a patient's risk for cardiovascular morbidity/mortality. Slide 44 shows you a potential approach for the treatment of elevated Lp(a) and the reduction of cardiovascular risk and that's pelacarsen. Pelacarsen is an antisense oligonucleotide which specifically reduces Lp(a). And as you see from these Phase IIb data, doses of 20 milligrams a week or 80 milligrams a month, reduce Lp(a) substantially and getting about 90% of patients below the higher risk threshold of 50 milligrams per deciliter. So this is exciting data that shows us that we can target specifically target lipoprotein(a) in the blood and reduce it in patients. And the question then is how this influences a patient's cardiovascular risk. As we also saw in this Phase IIb study, pelacarsen was very well tolerated, again, important when you're talking about treating patients chronically with the medication. On Slide 45, we have 2 studies running right now. On the left-hand panel, we have Lp(a) Heritage, which is a prevalent study which seeks to evaluate Lp(a) levels in patients with established cardiovascular disease. It's a very large trial where we evaluate prevalence and we initiated this trial in April of 2019 and expect results later this year. The Phase III outcomes trial is called Horizon, which is summarized on the right-hand part of the slide. This is a cardiovascular outcome study looking at major adverse cardiovascular events in patients with Lp(a) greater than 70 milligrams per deciliter. This study was initiated in 2019, and we expect the primary outcome in 2024. Next slide, I'll pass it to Rod.

Thanks, Dave. If we flip to Slide 46, and we look ahead to the commercial opportunity that exists for pelacarsen, we'll really build on our strength in cardiovascular and leadership position that we've had in heart failure with Entresto. And we've just shared with you our plans with Leqvio so that we can address another very large significant addressable population and that the potential to impact cardiovascular disease at scale. We see already that 1 in 5 people worldwide have elevated Lp(a), that's 1.4 billion people that have one of the strongest genetic cardiovascular disease risk factors. And while that prevalence can vary globally, in the U.S. and Europe alone, over 200 million people have elevated Lp(a). But the real problem, that if you flip to Slide 47, is the lack of awareness. And since there are currently no treatment options to modify Lp(a) levels, awareness overall is very low, particularly among general practitioners. And what we see from our data, if you look at the middle table, you see that the risk is similar, as Dave shared, to that of elevated LDL-C, but the physicians rank its importance much lower. And many of them misperceive that it could be treated with current cholesterol-lowering therapies, which just isn't the case. So when you combine that low awareness and knowledge, it also translates, as you see on the far right, to incredibly low testing rates. So that's the real challenge and the opportunity because even amongst diagnosed ASCVD patients, the rate is significantly below 1%. And that will really be the focus of our efforts is truly around education to raise awareness and level of testing, leveraging the Heritage study that David just talked about earlier. And on Slide 48, one of the things that we have in our favor and we'll continue to work towards stronger education is the guidelines are very clear and they're progressive on this particular topic. In the U.S. the recommendation is to test patients with a history of ASCVD for Lp(a). And in Europe, it's recommended to test everyone once in a lifetime. So as we prepare for launch and why it's so important that we do this early and educate through medical education and other efforts is really about raising awareness of Lp(a) and the need to test, and that will be our primary focus. The other thing we'll leverage on Slide 49 is clearly, there are synergies that we'll leverage in the marketplace. But the one, as the head of the commercial organization, but I just referenced, for me, it's all about education. It's about education to the key prescribers, the healthcare systems and systems of care that Victor alluded to earlier in the U.S. and that Matthew acknowledged in the U.K. and the importance of working with medical and professional societies and patient advocacy groups. And as Dave alluded to earlier, again, it's so critical that we educate and focus our efforts on making sure that this deadly cardiovascular risk factor is more acknowledged and testing rates dramatically increase, which is why we're focused over the next 4 years in doing that. Leqvio will continue to be our cornerstone in ASCVD management, but pelacarsen has the potential to promote CV health on a completely another level. So if we go to the last slide, just to summarize the opportunity and the focus we have for pelacarsen going forward, Lp(a) is a significant independent and genetic risk factor for ASCVD. And with no current treatment options available, we still need to drive access to Lp(a) testing and at significant increase so that the patient's other cardiovascular risk factors can be optimally managed. And while the awareness of Lp(a) is very low right now and the rate of testing is low, we know that guidelines are very strong and clear in the importance of testing for patients, which will drive our education efforts and ultimately lead us up to the potential launch where we know pelacarsen significantly reduces and modifies Lp(a) in cardiovascular disease patients. And with our strong capabilities that we've built in cardiovascular disease with Entresto in heart failure, the footprint that we have with Leqvio around the globe, we anticipate a significant opportunity for pelacarsen and a leadership in ASCVD long into the future. So now let me hand it back over to Samir for the Q&A.

Thank you very much, team, and perhaps we can go to the question-and-answer session. And if the operator could start taking the questions, please.

[Operator Instructions] And your first question comes from the line of Laura Sutcliffe at UBS.

I've got 2 questions on TQJ, please. Firstly, for the Horizon trial on the 80 mg dose, are you expecting the same sort of efficacy that you've got for the 20 mg once weekly, just with fewer discontinuations? Or is that not the right way to think about it? And then secondly, if you just think about what the outcomes are for these trials, is sort of getting below a threshold as you've named here on your graph, the most important thing? Or is it more about an absolute reduction in Lp(a) for these patients? I think there's some literature that suggests that the latter is important when it comes to changing risk profile.

Thank you very much, Laura. And perhaps I can ask Dave to address both the questions. And the first one with respect to the dosing and the second one with respect to threshold or absolute threshold or not, please.

Yes. Great. Thanks for the question. Yes, so if I understood your first question, you're asking if 20 milligrams q week is equivalent to 80 milligrams q month, and the answer is yes. We saw in the Phase IIb study that it was actually a very nicely designed trial, looking at different doses and intervals, which gave us a very strong ability to be able to predict what was going to happen with the 80-milligram dose. And your second question is a great one. And being first-in-class is a great opportunity, but it comes with some scientific questions that we have to answer. And I think that's -- your question is exactly along those lines. The good news is that pelacarsen is incredibly effective on both angles, so both in terms of percent change and in terms of absolute reduction. So when you see, for example, an Lp(a) of 100, we expect to get that patient down below 30 with pelacarsen. So this is -- it's a very strongly effective agent. And so we think, and no matter how you look at it, whether it's a threshold or a percent decline that we'll be able to achieve that.

And your next question comes from the line of Keyur Parekh at Goldman Sachs.

Thank you team Novartis for hosting this deep dive. Really appreciate it. Two separate questions, please. First one on Leqvio, am I right in interpreting the tone of the launch has been different to your previous tone about being cautious and a slow launch, a lot of the commentary today seems to be very bullish about near term estimates. And perhaps you might want to address that in the context of kind of 2025 consensus of $1.5 billion or kind of Medicines Company's target of $1.7 billion, $1.8 billion when you acquired them. So I guess, simplistically, are you guys kind of more excited about it than the Medicines Company was, do you think consensus is getting it wrong? Kind of any color there would be helpful. And then secondly, as we look at the outcome study for Lp(a), can you help us think about kind of the potential for interim analysis? And what kind of -- when potentially that might happen?

Great. So if I could put the first question to Rod and the second question will then go to Dave. Thank you.

Yes. Thank you for the question. I think if we think about the Leqvio launch and particularly what you saw today from Victor and how we've established it, we know it will take time to establish the infrastructure for buy-and-bill and how we're working with healthcare systems. And so we know that will take a few years in order to be able to develop those relationships and the comfort in working within the flow of their system to identify the patients and treat them. And so that will be a main driver in some of the early launch. We've also acknowledged the fact that as we look at ex-U.S. markets, it will take outcomes data before we get to the build. So I think the most important position for us is to establish those foundational partnerships that we would have with healthcare systems in the U.S. and major healthcare systems like Matthew talked to in the U.K. to ultimately maximize the assets in the long term. So that's how we're continuing to think about it is tackling ASCVD a new way, addressing the nonclinical barriers with these partnerships, access, affordability as well as adherence and continue to be optimistic in the long term.

So Rod, I think the question was also how optimistic are you or how comfortable are you with the consensus in 2025?

I think we continue to be confident in the consensus that we have and the expectations that we have with the outlook for 2025. Thank you, Samir.

And coming back to Dave for the second question on potential interim analysis.

Yes. I love the question because I'm going to assume it's because of the person's confidence in this trial. So as in most cardiovascular outcome studies, there is indeed an interim analysis built in. This is an event-driven trial and the interim analysis is dependent on a certain number of events accruing. So I can't say exactly when that's going to happen yet. The bar is high for an early stopping for a cardiovascular outcome study, especially for a first-in-class therapy where you really want to accumulate long-term efficacy and safety data in the population. So our expectation is that it will run to the end of the trial, but there is an IA built in.

And your next question comes from the line of Emmanuel Papadakis at Deutsche Bank.

A couple, if I may. Just a bit nearer term, Leqvio, the refi you've reiterated Q2, Q3, it does however seem a next year inspection is likely to be warranted whether you file on third party and/or your internal tech transferred facilities, but the FDA does have quite a backlog. So could you just talk to your degree of confidence around timing of approval in the first half of next year and how that regulatory process is proceeding? Second question on the -- thanks for the very helpful on the NHS collaboration. To my knowledge, you haven't actually given us any commercial details in terms of the terms around the arrangements. So is there anything you can say to pricing or value associated with that contract? And indeed, by extrapolation, is there anything you could say in terms of pricing benchmarks we should think relevant to the U.S. market for PCSK9 antibodies, for example, are relevant facts to consider.

Okay. Thanks, Emmanuel. So on the first question with respect to the timing of, a, the refiling; and b, when we like to get FDA to review things, that could be for Dave. And the second question with respect to NHS and how to help Emmanuel model from a pricing, et cetera, and benchmark that I'll give to Rod. So the first question, please, on timing for refiling, Dave.

Yes. Got it. Thanks, Samir. Yes, thanks for the question. So we remain confident in the refile Q2, Q3, as we've said. It's up to the FDA as to whether or not to conduct an inspection. So what we can say is that typically, these reviews take 6 months and that our expectation is to make the refile as we've said.

Thanks. And Rod?

Yes. Thanks for the question, Emmanuel. With our agreements with the NHS at this point, what I can say is we've signed memorandums of understanding. The contract we expect to be signed in July prior to our launch in Q3, and it's still subject to NICE outcome. So I can't share any details in terms of the benchmark or pricing at this time until we've established that contract in the NICE outcome, which is why, at this point, with Matthew and his colleagues were focusing on once those are established, how do we start to identify those patients, work with their -- in their primary care networks and make sure that we're giving the prescribers the confidence and the education they need with patients, but more details to come later following the NICE outcome.

And your next question comes from the line of Andrew Baum at Citi.

Yes, sorry about that. A couple of questions to John and Victor. Firstly, in relation to the PARADISE-MI data set, with PARADIGM, it was clear that the FDA was keen for you to file despite the 0.06 p-value for the primary endpoint. In relation to the PARADISE-MI data set, how much push is there compared to pull in relation to the dynamic between Novartis and the FDA, given the interactions you've had to date? And then second, I'm sure that you've done very comprehensive cardiology survey in terms of the desire to use inclisiran in the absence of outcome data. Perhaps you could share with us the differences in the U.S., in particular how much reluctance is there and how much do you believe you could overcome once you're out in the market given it's going to be a while before the outcome data comes through?

Thank you very much, Andrew. So on the first one about PARADISE and push versus pull from the FDA. Dave, would you like to take that one, please?

Yes. Sure, Samir. Thanks for the question, Andrew. So the data from PARADISE are still relatively fresh. We're still doing analyses, the first presentation was just at ACC this past weekend, as you know. We -- so we continue to do analyses and we will update you on any future discussions with FDA as warranted. At this point, we do plan to share the ACC presentation with FDA, and we will see their feedback.

Great. And then with the second question, I think we've split it into 2 parts. And first, I'll go to Victor. The importance of outcome data for the U.S. and perhaps what could then subsequently take outcomes data for Europe. So the importance for uptake, Victor, of outcomes data.

Yes. Thank you very much, Andrew, for the question. So we don't believe this will be a challenge at launch, having discussed and surveyed cardiologists. On the one hand, there is a strong body of evidence linking LDL-C and outcome. And when talking to cardiologists, the linkage between LDL-C and outcomes is really clear. On the other hand, inclisiran works within a pathway of the LDL-C lowering that has already been shown to improve outcomes. Now on the access front because we will be routed to the medical benefit mostly for 40% of that population, the coverage is to label, and therefore, we don't expect an impact on the CV outcomes evidence. And for Medicare Advantage and commercial population, the focus is mostly on efficacy, safety and cost.

Thank you, Victor. And then Rod, importance of outcomes in Europe, please?

Yes. Thanks, Andrew. I think we can acknowledge that the importance of outcomes and for reimbursement and broader access overall outcomes are important. We have launched in Germany and Austria already, but that's to a limited population of patients with very high CV risk. And while the feedback has been physicians are impressed with the immediate drop that they see in LDL-C that Dave spoke to and the sustained efficacy that they see. Our strategy, including Europe is for Leqvio to benefit a much broader number of patients and overcome those nonclinical barriers. So while we will pursue the outcome study and know those markets look at it as an important piece, we are actively exploring commercial partnerships like we talked about today with Matthew in a number of countries around the world and making sure that LDL-C and targeting a larger population that ultimately could be benefit is a cornerstone of our cardiovascular disease health promotion strategy. So the first of which obviously will be the U.K. when we would expect that launch in Q3.

Your next question comes from the line of Graham Parry at Bank of America.

So firstly, going back to Entresto. So just to be clear, what are the -- what's the base case for Novartis or the range of possibilities you see on PARADISE-MI label inclusion? So do you see there's a possibility if you could get a label inclusion of the data? Or possibly even an indication? Or do you just see this as a sort of not negative positive trends that helps the overall perception of Entresto and safety, particularly in fragile patients. And secondly, a question for Matthew Whitty. There are obviously approved and reimbursed antibody-based PCSK9 inhibitors available in the market already. So why wasn't a collaboration like this possible with one of those products and their manufacturers? Was this just proactivity from Novartis that led to the current collaboration? Or is it just the less frequent dosing? If you just help us understand the reason why this product is treated -- could be treated differently? And then lastly on pelacarsen. You flagged LP(a) as being a causal risk factor for MI stroke and PAD. Can you just remind us how causality has been established given today to think we're just looking at observational epidemiological data? And so what are the risks that modulating levels doesn't have the impact on outcomes as we've seen with some other CV biomarkers? And you just stand a bit of this being a coincident finding?

Thank you very much, Graham. So perhaps we can start with the first question from Matthew. And I think the key points from Graham was, why are you working now with inclisiran with Novartis where it didn't work with -- not you, the NHS didn't come up with population health for PCSK9. Matthew?

And it's a great question. I think there's a couple of things to note. So firstly and as part of the voluntary scheme, so the pricing scheme that was put in place, there was an agreed element of that for NHS England to produce something called the commercial medicines framework that was published in January, but we actually started using it about a year or so ago. So timing-wise, it fitted really well with sort of a newer and more innovative approach to commercial models that NHS England was looking for. So that was a big part of why we were able to sort of use that greater commercial innovate -- there's more innovative commercial approaches for this drug where which wasn't in place at the time for the PCSK9 inhibitors. But also I think there was a sort of a proactive approach as well in that the other companies when they approached NICE went down a different route for looking at how they would use their commercial freedoms in a more traditional approach, if you like. So it was sort of a partly timing in terms of the new flexibilities afforded to us under the commercial medicine framework and partly, Novartis having a more innovative approach to pricing than the competitors.

Thank you, Matthew. And Dave, I think the other 2 questions are for you. So the first one relates to the range of possibilities, which you could get vis-a-vis the label. And I think Graham was also trying to work at what do you think is most likely, so be careful with that one. And the second part of his question, apart from the interest of potential label is with respect to pelacarsen. So he said, yes, a number of potential markers, which suggest increased disease activity. But how confident are you that reducing Lp(a) will be established as a therapeutic agent.

Yes. Okay. Great. Yes, I got it. So I guess, first, Graham, on Entresto and PARADISE-MI, I mean, clearly, we saw numerical trends favoring Entresto on the primary endpoint, but we didn't reach the prespecified superiority statistical threshold, so we did not succeed in the trial. And the P value, as you saw on the slide was 0.17, so I think we have to acknowledge that. There are clearly supportive analyses through the secondary endpoint hierarchy that support the numerical trend. But at the end of the day, the trial was neutral. So I think what we see from this study is that patients post MI have much better care than they did 30 years ago. And Entresto may have an incremental benefit on top of that but this trial did not prove that finding. What we did see is that in these patients who, again, are very sick patients a few days after having a heart attack, Entresto was well tolerated. So the data from PARADISE in terms of safety and tolerability, complement trials like PIONEER in transition in heart failure patients who have been hospitalized to give practitioners confidence that this drug can be used in fragile patients. Turning then to TQJ230 and pelacarsen, you raised a great point. And again, coming back to a comment I made earlier, is when you're first-in-class, you weigh the scientific evidence supporting your target and the likelihood of success. And so why do we believe in this case, that we have a greater likelihood of success than previous efforts? Well, first of all, it's the weight of the evidence. So I showed you 2 lines of evidence, of immunologic data, Mendelian randomization data. There's also data from statin trials, the meta-analysis of some statin trials. Again, all showing us that elevated Lp(a) confers higher cardiovascular risk. And then the question is, if you reduce that pharmacologically with pelacarsen, the scientific question is and medical question is when you reduce Lp(a) pharmacologically, do you achieve an outcomes benefit? And what we see from pelacarsen is that the degree in Lp(a) lowering and some of the other salutary effects that they saw on other lipids in Phase IIb gives us more confidence that we're going to have beneficial effects in this population. But at the end of the day, that's why we run the trial.

And the next question comes from the line of Jo Walton at Credit Suisse.

I've got 3 questions, please. Firstly, on Entresto. We know that patients with heart failure tend to be old. They tend to be on lots of medicines, they're rattling around, and Entresto is one of the branded products, which is more expensive for them. So do you have any real-world adherence data showing how may -- what proportion of patients are still taking the drug 1 year on, given that particularly, in the U.S., they are still having to pay a reasonable amount of co-pay. Secondly, on inclisiran. I wonder, just so as I understand this, do you not have a deductible with your medical benefit? You talk about patients being able to get this drug essentially free from the point of launch. But wouldn't they have to go through some form of deductible to get that beforehand before it became free? And my third question -- I don't know if you can still hear me.

We can hear you, Jo, yes.

Oh, perfect. Good. My third question is on the U.K. side of things. So just so I can understand this, how has the system worked so that if a doctor puts the patient on this in the U.K., this is budget neutral for the local trust because I'm assuming that this is a little bit more expensive than some of the other treatments that they might choose to use. And is there something built in whereby the doctors get some reimbursement so that there's an actual pull from the economics from the U.K. doctor's practice as well to get involved? And can I understand, just finally, I think you said that the deal was going to be based on how NICE appraise this. So the deal will be set irrespective of what happens when you get the final outcome data. So it's not a price that will be set. And then when we get the outcomes data and then hopefully, you find this linear relationship and a fantastic reduction in cholesterol give a great reduction in cardiovascular death. At that point, does the pricing change? Or is the price set now? I'm assuming that Novartis gets the benefit of using this data. Is there any way that this could bring forward the global knowledge about cardiovascular risk? It could -- U.K. data, real-world data get there faster than the clinical study that you're otherwise doing.

Jo, thank you very much. I deciphered 4 questions there. So what I'm going to do is, first of all, I'm going to ask Rod to talk about the pricing issue with respect to the UK partnership. Then I'll ask Matthew to specifically talk about the trust versus the doctor practices and how the economics works there? And the other 2 questions which you had both with respect to Entresto, in terms of adherence in the U.S. at 1 year as well as the deductible will go to Victor. So the first question, Rod, simple one. Can you talk anything more about what happens from a pricing perspective post outcomes, pre outcomes?

Yes, Jo, thanks for the question. And as it relates to the U.K., and we have Matthew on as well, we -- throughout this process, whether it was The Medicines Company or now through Novartis, NICE has been a critical player at the table as we've continued through the process. And we've always acknowledged and expected that the NICE outcomes were still an important part of the evaluation that will occur prior to the final agreements and contract signing. Now to your specific question, we -- another expectation has been as we would get the availability of the data of the outcomes trial, we would relook that, and that's been part of the agreement, the pricing and the cost effectiveness analysis in the populations that we've studied, and so that is an expectation that we would revisit at the appropriate time. I think the important thing that Matthew acknowledged and what we're excited about is with this program, particularly addressing some of those nonclinical barriers, we'll be able to generate strong evidence, real-world evidence as we lead up to those outcomes data with our colleagues in the U.K. and NHS England and see the real impact that we're making on the disease as we address both the clinical and nonclinical barriers. So it's an exciting opportunity.

Thank you, Rod. And Matthew, if you could perhaps address the issue of the local trust versus the doctor practice and the economics and how that would work, please?

Yes. Thanks. I think one thing to note really is that the typical launch for a new product, as I mentioned earlier, really, would be sort of focused around specialists in secondary care initiating and then that practice and the prescribing sort of slowly diffusing into primary care. And we really saw this as a primary care intervention, so a lot of the incentives and the payment flows that we've been looking at are sort of how we can support that money flowing through to primary care. So that's in a number of ways that we're looking at the whether there's a more efficient way to identify the patients, as I mentioned, through the NHS Digital work in primary care. We're looking at the payment flows to GP, so we're looking at exploring whether or not we can actually have a direct payment to prescribers as part of the way that we get the drug out to patients. And we're also looking at some other areas, particularly around other incentives for primary care clinicians. So we've got something called the quality outcomes framework. So this is whereby a payment mechanism for GPs where if they hit a particular clinical outcomes, they get additional points, which add up to additional payments. And so we're also looking to see whether we can include a cholesterol target within that as well. So sort of a range of measures we're looking to get those incentives right. But again, it's primary care focused, not secondary care focused.

Great. Thank you. And Victor, the first of your questions was related to adherent state in the real world in the U.S. for Entresto. And the second question relates to the issues about deductibles for inclisiran et cetera.

Great. So thank you very much for the question. So if I start with Entresto, we have worked really hard over the past years to make access Entresto both affordable and easy for patients and HCPs. And that has been of the key pillars of our growth of what we've seen. And as of today, more than half of the Entresto patients pay no more than $10 per month. And most of them have preferred access, 99% in the Part D space and 80% in the commercial patients. This is translating in around 70% of the patients remaining on therapy at 12 months, and reinforces our strong position in heart failure to continue to grow. And just highlighting, for example, that in the rest population, we just penetrated around 30%. So we see tremendous space there to continue to grow with Entresto. On the inclisiran side, in terms of out of pocket -- for patients, it depends on the population that we would have for the Medicare Part B population, which represents 39% of the ASCVD patients, 80% of those patients will pay as little as $0 per month because they have supplemental insurance. For the commercial population, which is around 34%, they would be eligible to pay as little as $0 because of our support. And then finally, the Medicaid and federal population will pay less than $10. The only population that would be left with a little bit of a higher co-pay would be the Medicare Advantage population where it varies depending on the plan and the coinsurance. But all in all, 2/3 of the patients at launch would be having a $0 co-pay, which we believe is a very important factor in the uptake of drugs in this phase.

And your next question comes from the line of Kerry Holford at Berenberg.

I have 3, please. On Leqvio, in your associated cost you see in the U.S.? I'm looking at Slide 33, where you mentioned developing trust, injection sense networks, you aiming to do that within each of your target 200 healthcare systems at launch? And if so, is funding that, is that something that you are funding? Or is it in conjunction with these healthcare systems? And from a promotional perspective, what's the overlap with the Entresto prescribing physician pace? And have you already recruited additional sales or medical reps in order to launch Leqvio, is that required? And then TQJ. I wonder if it's impossible to talk about potentially extending the dosing frequency even further than once monthly is once every 6 months dosing are you similar to Leqvio realistic opportunity? And is there actually any value in a combination with Leqvio I think perhaps the answer is no given that correlation you talked about, we will be interested to hear your thoughts on that. And then finally, a question for Matthew Whitty. You mentioned how CVD was already a sort of ditty target area within your team's long-term objectives here in that new proposition with a nice overlay with that. I would be interested to hear whether there are any other chronic diseases that are on your target list? Perhaps obesity where you might be interested in or indeed actively working on similar partnerships with our metro manufacturer.

Thank you. So if we just take each of those questions in turn, I think you had some operational-related questions with respect to Leqvio, which I will hand across to the U.S. I think it was about who actually does the injection or setting up of the clinics as well as the potential overlap with the interest of field force, so that will be for Victor. And with respect to the TQJ question, which I know Dave spend days, nights, weekends thinking about both with respect to, can you go from monthly to 6 monthly as well as combo. I'll let Dave answer that. And of course, Matthew with other areas other than Leqvio for potential population health. So Victor first, please.

Well, thank you very much, Kerry, for the question. So as we've stated, one of the key challenges at launch will be to establish the buy-and-bill processes within cardiology offices because today, it's not a reimbursement pathway, they use often. And for that, we will be working on the one hand with these systems of care because they already have established processes to buy-and-bill other products in other therapeutic areas. So our efforts are mostly connecting the dots within those systems that cardiologists can utilize those efforts. And on the other hand, we've mentioned that we're developing an alternative injection center network to provide this acquisition and administration flexibility for those cardiologists who cannot or do not want to establish buy-and-bill within the center or in their office. And basically, those are independently own injection center networks. The only thing we're doing is helping connect the dots and helping cardiologists understand that they would be able to send their patients to these systems. Now in terms of your question on the overlap, there's a very substantial overlap, of course, from a health care professional, both on the cardiology front and those primary acquisitions that do take care of those patients. Also around 60% of the key Entresto targets are affiliated with these prioritized healthcare systems for Leqvio. Answering your question on whether we've recruited more reps, the answer is no. We believe that the current footprint that we have with our interest of field team will suffice. What we are doing and we have done already is hire and develop a strong field reimbursement team that will work with these offices and the healthcare systems. As I said, on the one hand, to connect the dots within the system and to, if needed, established relationships with third-party injection sites.

On the TQJ question, Dave, with respect to perhaps more prolonged dosing as well as the possibility of a combination.

Yes. No. I mean thanks for your enthusiasm on that, Samir. I really appreciate it. As of today, we don't see a way to easily increase the durability of Leqvio -- I'm sorry, of TQJ, and increase its duration of action to match the Q6 month administration of Leqvio. But we're continuing to turn this one around and see if there is a way to make that happen. As of today, we don't have a way of designing a way to achieve that.

I was only kidding, Dave, anyway. So Matthew, the last part of the question was in relation to any other areas where you may think about population health.

Yes. I'm afraid I can't talk about sort of active deals that we are either pursuing or considering at the moment. But I would say that the NHS long-term plan gives a really good indicator about the areas that we're prioritizing and one of those other areas being earlier diagnosis of cancer. And so we've got a specific target in the long-term plan to diagnose more cancers at stage 1 or stage 2. So currently, the NHS is at about 56%, 57% of cancers being diagnosed at stage 1 or stage 2, and there's a commitment to increase that to 75% of cancers. And we published information on a deal that we did with a company called GRAIL on a new cancer diagnostic back in -- the deal was done back at the end of November 2020. So yes, so the long-term time a really good idea about kind of the areas we're interested in and how that's driving a particular focus for future deals as well.

Great. Thank you, Matthew. As we've only got about 5 minutes left, and there are still 3 people in the queue for question. Could I just ask that each person limits themselves to 1 question, please.

And your next question comes from the line of Florent Cespedes at Societe Generale.

So I will ask one on pelacarsen. What is the level of efficacy you're targeting with the Horizon trial on the primary endpoint? What is the level of positive risk reduction in the design of the trial? Is it 20% relative risk reduction? Or more that you are targeting, please?

Thank you, Florent. Dave?

Yes. Thanks, Florent, for the question. We're actually in the process of preparing the study design paper now, which will give you a lot more information. But what we've already talked about is we have 2 tiers of Lp(a) level that we're evaluating as co-primary endpoints: 70 milligrams per deciliter, which would be the total population; and 90 milligrams per deciliter. So we have 2 ways of being able to achieve success. We haven't publicly stated what level of MACE reduction we're looking at within the population at this point. But I think if you -- again, if you look at the evidence that, that indicates Lp(a)'s role in cardiovascular risk, and the degree to which pelacarsen reduces Lp(a), you can infer that there will be a clinically important benefit at the end of the trial.

Your next question comes from the line of Charles Pitman at Redburn.

Just on inclisiran, I was wondering how will the rollout be communicated? And will this be done by the NHS or by Novartis primarily? And just in terms of the pandemic, how has this affected the plan, given that on one hand, cardiovascular disease is a risk factor for severe COVID and the other has created significant disruption and backlogs within primary care.

Okay. So 1 question becomes 2, I think. So in terms of communications, Rod could address that and in terms of impact of pandemic and COVID perhaps Matthew could talk to that. So the first question is for Rod.

Yes. Thanks for the question. I think that's the important element, and Matthew can speak to it, too, from the beginning of the working relationship and the unique nature of the agreement as our teams are really working very closely together co-creating what that education plan and implementation will look like within the primary care network. So it truly will be a joint effort and how we work together within the NHS system. And importantly, identify the right patients, the right education process and the right follow-up so that patients can ultimately get the outcome and benefit. Matthew can speak to it as well, but it's been one of the unique relationships to tackle this together.

Thank you. And Matthew?

Yes, agreed. I mean it's been one of the sort of the key -- it's been about bonded agreement really that it's been sort of a collaborative effort, and it will continue to be so in terms of the communications. And in terms of the second part of the question, in terms of COVID, clearly, it's -- we've seen that patients with comorbidities having worse outcomes from COVID. So it's really only heightened the importance of this work. I should also flag that my boss has led the rollout of the vaccine program as well. So as part of his work, we had the -- we also had the minister who is overseeing that sort of feed into our work program, so we could understand some of the lessons, which we've sort of fed in and that is around sort of easier identification of patients. It's around primarily the importance of primary care leadership as well so we're feeding in those lessons. So yes, it's impacted it in terms of the sort of the ability of GPs to engage early on in the process, I would say. But we've also learned the lessons from the vaccine rollout program. We've fed those into the -- into our work plans, and it's only really heightened the importance of us delivering.

Thank you, Matthew. And operator, we have time for the last question.

And your final question comes from the line of Richard Parkes at Exane BNP.

I've got 2, but I'll just ask the 1, and if there's time for the second, then we can squeeze in. It's just one for Matthew. I just wondered if you could give us a sense of what kind of levels of uptake you're planning for -- within the 300,000 patient target population? I don't know whether you're making any input into the NICE budget kind of impact assessment. So maybe you could talk about that what you feel is the biggest barrier to achieving that.

So Matthew, over to you in terms of the question.

Yes, it's probably best to pass to Novartis colleagues really on specific uptake here, only to say that we've got kind of a shared interest in getting this out to as many patients as possible from both a clinical perspective but also on a commercial perspective.

Okay. So Rod, do you want to give a final word on that?

Yes. I think the ambition is high from both teams, obviously, to try and identify these patients. We know there will be learnings along the way. And that's why the important aspect of the relationship is really focusing on the nonclinical barriers, the identification of the right patients initiating on therapy and the follow-through and follow-up at their regular appointment. So while we're very enthusiastic about the partnership and encouraging how we're approaching it, the uptake we'll have to see as we go. But we both created ambitious targets for ourselves through the first 3 years through the implementation science that we'll also be doing so that we can identify are there other factors that limit uptake and how do we address those, of course, through the course of the relationship and the agreement. So it's really meant to be implement together, learn and continue to work for new ways that we can make sure we get the right treatment like in the hands of the right patients.

Great. So thank you very much. And this brings us to a close for our conference call. I'd like to particularly thank all the participants and those who specifically asked those questions. I'd also especially like to thank our external guest, Matthew, for helping us to explain what population health is and also to our Novartis colleagues, Rod, Dave and Victor. Have a great evening or a great lunch depending on which side of the world you are. Thank you, everybody.