Alnylam Pharmaceuticals, Inc. (ALNY) Earnings Call Transcript & Summary

Hello, everybody, and thank you for joining us. Thanks so much for those of you who are here in the room in Madrid, I made the trip out to ESC and to many colleagues around the world, including those in the U.S. who are celebrating the Labor Day holiday. We really appreciate everyone being here for what's a pretty exciting milestone event, which is the announcement of the KARDIA-3 results and really the kickoff with Alnylam in Roche of a Phase III cardiovascular outcome study for zilebesiran. We're really excited about this because as you're going to hear this afternoon or this evening, we're really excited about the potential for zilebesiran to address one of the most stubborn and intractable health problems that's out there, a public health problem, which is uncontrolled hypertension, which is really the #1 addressable cause of cardiovascular morbidity and mortality. And as you'll hear, cardiovascular disease is the #1 killer of people around the world. So we're going to spend some time talking about that today. I've got some wonderful colleagues here to help facilitate the discussion. I'm going to start with just a little bit of an introduction. We're joined by Professor Bryan Williams from the University College of London, who's going to talk to you about the global burden of cardiovascular disease and why zilebesiran may be prone to be able to address some of the major determinants of why we've not been able to control hypertension as well as we'd like to. Then Dr. Neha Pagidipati from Duke University, who presented in the hotline session at ESC today, is going to come up and reprise her presentation and provide a little bit of additional data talking about the KARDIA-3 results and put them in some context. My colleague, Simon Fox, who leads the zilebesiran program at Alnylam, will provide the perspective on the opportunity here. And then Dr. Manu Chakravarthy from our partner at Roche, will give a partner perspective, and we'll come back and have a short period of Q&A. So we expect the prepared remarks to be about 30 minutes or so, and then we'll launch into Q&A, both from people in the room and on the webcast. These are our forward-looking statements. What I want to show you in the next couple of moments is really what's turned out to be a really remarkable pipeline of therapeutics based on RNA interference. And in particular, how well suited these drugs are for treating a number of factors that sort of contribute to cardiovascular disease and the portfolio now, a number of very transformational or potentially transformational agents that can address major causes of cardiovascular morbidity and mortality. As you all have seen us present before, we've been working for 23 years on developing RNAi therapeutics. And it's a really unique class of medicines with a very, very remarkable pharmacology. We're able to silence any gene in the genome, work upstream of today's medicines, a catalytic mechanism that allows for highly potent medicines that are also highly specific and reversible and importantly, allow us to have infrequent administration once a quarter, once every 6 months or annually. And we think that is really important in addressing many of these chronic diseases. With this technology, we've built really a pipeline that's the envy of the industry across a range of diseases. We have 6 marketed products across both rare and prevalent conditions. And as I said, a number of these really point this technology towards major determinants of cardiovascular health. You're familiar with Leqvio, which is approved for hypercholesterolemia and is now in two large outcome studies being run by Novartis. We had the recent approval of AMVUTTRA in ATTR cardiomyopathy. We're going to be talking about zilebesiran for most of this session. And we have early programs in type 2 diabetes and in obesity. Just one moment on AMVUTTRA, just that you can see the power of this technology in terms of being able to work upstream at knocking down or silencing the disease-causing protein. In this case, TTR resulted in really spectacular results, about a 35% reduction in all-cause mortality, concordant benefits on a whole number of other endpoints. This has now been approved in multiple geographies around the world. And we've had the launch in the United States, which is the first quarter has been quite good with 1,400 patients already on therapy and new results being presented at the ESC talking about extended survival data for HELIOS-B that are being presented at this Congress. But what we're here to talk about is zilebesiran. And the reason we're so excited about this is that we think it really gives us an opportunity to address some of the major things that small molecule or daily drugs can't really address, helping more patients get to goal in terms of the quantity of blood pressure, but also the quality of blood pressure control, reducing blood pressure variability, improving adherence and improving nocturnal dipping. And Dr. Williams is going to talk to you about why we think all of those matter. This summarizes the zilebesiran clinical development program. You can see the Phase II studies, we've had three of them now that have all now IV studies actually, including the Phase I that have all shown repeatedly really impressive effects of zilebesiran in terms of reducing blood pressure. And in KARDIA-1 as a monotherapy and KARDIA-2 with a single other agent. And now in KARDIA-3, Dr. Pagidipati will talk to you about how it performed on top of 2 other agents -- 2 or 3 other agents in a high-risk population. And we are going to be announcing today that we're kicking off a cardiovascular outcome study to study the impact of this mechanism and this approach of continuous control on cardiovascular morbidity and mortality. So with that, I'm going to invite Dr. Williams to come up and talk to you about the burden of cardiovascular disease. Yes, right here.

Hi, everybody. So I'm Bryan Williams from London and been presenting at the meeting today. I just wanted to put some of this stuff in context because cardiovascular disease remains the single most important preventable cause of death globally. And currently, about 20 million people die every year from cardiovascular disease. And the tragedy is it's largely preventable. And if we look at the major cause for that, it's high blood pressure. High blood pressure is the most important preventable cause of death globally, accounting for about half of all cardiovascular deaths. That's now -- and this is a projection from the Lancet published just before the pandemic, which suggested that -- the risk factors contributing to loss of life, number one, will remain by 2040 high blood pressure. So we have to take this seriously. There's already a sort of scramble of new activity in this space over recent years. If we look at the ability to control blood pressure at the moment, this is from really many of the better developed health care systems in the world. Less than 40% of women and less than 30% of men -- about 30% of men actually get their blood pressure control to a level below 140 over 90. Now the important thing about that is these are terrible control rates below 140/90, but guidelines now advocate even more aggressive therapy. So all of the guidelines are now suggesting to optimize treatment, we need to get blood pressure below 130/80. So there's a huge treatment gap between what is expected and what is being delivered by current therapeutics. So can we do more to improve blood pressure control? I think we have to do something more. I think we've got to try and do better than we're doing at the moment. So just quickly, the elements of things that we're interested in, and Pang as mentioned this at the beginning, blood pressure levels achieved in the clinic is how we traditionally monitor blood pressure. But actually, the levels over 24 hours are very important. The control of nighttime blood pressure is very important. Speed to control is very important. And increasingly, we're recognizing the consistency of blood pressure control is very important. And that's why I personally got very interested in this drug, having worked in hypertension for 30-odd years. And this is pretty novel or very novel and pretty unique in terms of its mechanism of action. Let me just show you some data we got from a massive study we did on ABPM, ambulatory blood pressure monitoring nearly 60,000 patients. We published in the Lancet a couple of years ago. We're trying to work out which blood pressure is actually the one that we should be most concerned about in terms of measurement. And in the blue, you can see a straight-line relationship very steep. That's the relationship between nighttime blood pressure and risk of death. What we found was that it's nighttime blood pressure that is very powerful predictor of risk of death. And so what you need is something that will control blood pressure, not just when they're in the doctor's office, not just in sporadic moments, but on a consistent basis over a long period of time. And to show you how powerful that effect was, if you look at clinic blood pressure, say that's 100%, 24-hour systolic blood pressure average over 24 hours, that was 4.7x more predictive of risk of death. Daytime, 3.8x more predictive, nighttime almost 6x more predictive. So we've got to control all of these. And at the moment, we've got a lot of fluctuation in treatment. Some of the drugs are not achieving that. The second thing that we discovered back in early 2000s was the variability in your blood pressure, either minute to minute, hour to hour or even week-to-week. All of those parameters have an independent predictive value of risk of premature death and stroke. And so all of this points to the fact that we've got to try and control and smooth blood pressure control if we're to optimize patients' risk. And this is an example for a paper we published very recently on blood pressure variability and risk of death. Every single measurement that we make of how variable blood pressure is, was highly predictive independently of blood pressure itself of risk of death. Finally, just to show you what this phenomenon of persistence of control being important. This, I think, is some data which convinced me that this is a really powerful issue. And it comes from the U.K., but it actually is a typical U.K. study because it involves over 1 million patients. And what we looked at here is the time the patients spent in control, going to their doctor, getting their blood pressure checked, we checked to see was it controlled every time they went, we gave a figure of up to 80% of the time. Or was it controlled only 50% of the time or only 20% of the time. The results were astonishing. That actually, if you happen to be controlled 80% of the time, your risk of cardiovascular death or MI or stroke was reduced by 75% compared to those who had less good control. And this is real-world stuff. This is what's happening out there in millions of patients in the clinic. All-cause death was reduced by half if you had consistent blood pressure control. And to put that into context, one of the big studies in the United States, which had a huge impact on guideline was called the SPRINT trial. And that tried to get blood pressure below 120. So the argument there was if we've got to improve outcome, we've just got to keep going lower. And for people like me who treat these patients, I think we can't go lower. We can't even get to where we need to be now. And what they found is if they went below 120, they got a 25% reduction in cardiovascular death. Well, we got a 75% reduction in cardiovascular death by going below 140, but doing it on a consistent basis. So the message here is that we need treatments that produce smooth and consistent blood pressure control. Now the final issue -- so I think the fact that zilebesiran has the ability to have a single injection, and it's done, job done always on 6 months. That is hugely important in my view and will be important in a clinical trial. The final issue that will be important is adherence. This is the WHO. They say that treatment of chronic diseases worldwide is a massive issue in relation to the adherence to treatment. Now hypertension is an asymptomatic condition. It's even harder to encourage people to take medication. So adherence is really bad. And what we find is about 40% of patients don't take some or all of their medication. I'll skip through that. So this idea that you can give an injection and guarantee adherence to therapy for at least 6 months from a single injection, I think, is really powerful and is often underappreciated as a real novel breakthrough. This morning, I was talking about how new drugs might improve blood pressure control. And one of the things that I emphasize is that we need drugs with a long duration of action to overcome adherence problems. And actually, 6 months is a pretty long duration of action and nothing comes close to it. So that's quite exciting. So in conclusion, I think we have to improve blood pressure control, not just the numbers in the clinic, but the quality of control, the consistency of control over time. There is a great unmet need for treatments that are always on. We don't have any. And this will be, I think, a major advantage in hypertension and to reduce blood pressure smoothly and consistently over prolonged periods to reduce variability and to overcome major problems with treatment adherence. So I'll hand back. But from my point of view, this is a completely novel therapeutic in the field of hypertension.

Thank you, Dr. Williams. So I'm Neha Pagidipati. I'm a preventive cardiologist at Duke, and I was very privileged to share these results of KARDIA-3 earlier today at ESC. So just for a quick background, and you saw a little bit of this before, the Phase II zilebesiran development program has 3 trials in it, KARDIA-1 KARDIA-2, KARDIA-3, which I'll present to you today. KARDIA-1 tested zilebesiran as monotherapy in individuals with mild to moderate hypertension and showed a significant blood pressure lowering as monotherapy on the order of 15 millimeters of mercury for 24-hour mean systolic blood pressure. And what you can see in the graph here is that it really is just like what Dr. Williams said, continuous control through the daytime, through the nighttime, continuous control. Then KARDIA -2, which was the second Phase II study, tested zilebesiran on top of a single antihypertensive agent. Now patients had a run-in and then they were assigned either indapamide, amlodipine or olmesartan and a high dose of olmesartan, 40 milligrams. And what we saw was a significant blood pressure lowering in each of these arms. It was on the order in the office systolic blood pressure of minus 19 millimeters of mercury on top of a diuretic, minus 10 on top of amlodipine and minus 7 on top of olmesartan, which has really never been shown before. Dual Ras Blockade has never been shown to be efficacious or safe before. So that was all very exciting. And now the study objective of KARDIA-3 was to determine the efficacy, safety and optimal dosing of zilebesiran among individuals with uncontrolled hypertension and high cardiovascular risk with or without chronic kidney disease in order to inform the design of the cardiovascular outcomes trial. KARDIA-3 was a Phase II randomized, double-blind, placebo-controlled trial in 5 countries, and it included patients with established cardiovascular disease or at high risk for cardiovascular disease. Uncontrolled hypertension is seen here and who were already prescribed 2 to 4 antihypertensive agents, including a diuretic or a calcium channel blocker. This was the study design. There are 2 cohorts, and I'm presenting today to Cohort A, which included patients with an eGFR of greater than or equal to 45 and Cohort B, which we'll present in the future, included patients with more advanced kidney disease. In Cohort A at baseline, patients were randomized to 1 of 3 arms, a single dose of zilebesiran 300 milligrams, 600 milligrams or placebo at baseline, and then they were followed for 6 months. The randomization was stratified by factors that we a priori thought would impact the effectiveness of zilebesiran, which included race, baseline blood pressure and baseline diuretic use. And patients and clinicians in the first 3 months were encouraged not to change their antihypertensive therapy unless clinically indicated. And then the primary outcome was at 3 months. It was changed from baseline to month 3 and mean office systolic blood pressure. And you can see several of the secondary and exploratory outcomes here. Now to account for multiplicity of looking at multiple doses, if both doses did not have a p-value of less than 0.05, then any single dose needed to have a p-value of less than 0.025 in order to meet statistical significance. These are the baseline demographics of Cohort A. And in the 270 patients, the mean age was in the mid-60s, and this was an appropriately diverse cohort with good representation of females, blacks and Hispanic individuals. And about 20% had a prior cardiovascular event and half had diabetes. The baseline blood pressure, the mean systolic blood pressure was 143 to 144 and the mean diastolic blood pressure was in the 80s. The mean 24-hour ambulatory blood pressure was in a similar range. These are the baseline blood pressure medications that patients were on. And as you can see here, the vast majority, over 90% were on ACE or ARB therapy at baseline. About 2/3 were on a diuretic and over half were on a calcium channel blocker. In terms of the number of oral antihypertensives, about half were on two therapies, about 1/3 were on 3 and the minority were on 4. And these are the results of Cohort A. At month 3, the placebo group had a decrease in systolic blood pressure of 7.3 millimeters of mercury. The zilebesiran group, 300-milligram group had a decrease of 12.3 and the 600-milligram group had a decrease of 10.6, resulting in a placebo-adjusted change of minus 5 in the 300-milligram group and minus 3.3 in the 600-milligram group. And after adjusting for multiplicity, these p-values did not meet statistical significance. In terms of the secondary outcome of office systolic blood pressure at month 6, the placebo-adjusted changes were minus 3.9 and minus 3.6 in the 300 and 600-milligram arms, respectively. And for the secondary outcome of 24-hour mean ambulatory systolic blood pressure at month 3, the placebo-adjusted change was minus 3.6 and minus 2.6 in the 300 and 600-milligram arms. And at month 6, those changes were minus 5.5 and minus 7.4. This slide shows the mean daytime and nighttime ambulatory systolic blood pressure at month 6. And what you can see here is that in the daytime, the placebo-adjusted change in the 300-milligram group was minus 4.9, and it was minus 6.9 in the 600-milligram group. And those corresponding values were numerically greater at nighttime at minus 6.6 and minus 8.2. Now these are some data of the biomarkers that were tested, and that includes NT-proBNP, which many of you may know is related to heart failure and heart failure risk as well as urine albumin to creatinine ratio, which is related to kidney disease, but also a very strong predictor of future cardiovascular disease. And in patients with a somewhat elevated level of NT-proBNP at baseline, just greater than 12 picomoles per liter, you saw on average, 21% and 26% reduction, which is quite impressive in the 300 and 600-milligram arms. And for the UACR, you saw reductions in the 37% and 32% range with the 300 and 600-milligram doses. The safety profile was, I would say, encouraging overall. There were very few serious adverse events, and they were generally comparable between arms and most of the instances of hyperkalemia and worsening kidney function were not confirmed by subsequent measurement and none of them required dialysis or hospitalization. Now as I mentioned, one of the primary purposes of KARDIA-3 was to identify who is most likely to benefit from zilebesiran in order to optimally design the Phase III outcomes trial. And we knew from KARDIA-2 that zilebesiran appears to be most effective in individuals who are on a diuretic therapy, possibly because when you're on a diuretic therapy, your RAS system is upregulated. And so in a prespecified subgroup of KARDIA-3 in those on a diuretic at baseline, the placebo-adjusted change at 3 months was minus 6.6 with the 300-milligram arm and minus 5.1 with the 600-milligram arm. And then if we further look at individuals who are on diuretic therapy, but who are truly hypertensive at baseline with a systolic above or equal to 140, in a post-hoc analysis, you can see a placebo-adjusted change of minus 9.2 or minus 7.0 with the 300 and 600-milligram doses, respectively. So in conclusion, among individuals with cardiovascular disease or high cardiovascular risk who have uncontrolled hypertension on multiple antihypertensives, single doses of zilebesiran 300 or 600 led to respective 5 and 3.3 millimeter mercury reductions in office systolic blood pressure at 3 months compared with placebo. And this was not -- statistical significance was not reached. However, subgroup analyses did suggest that those on a diuretic may experience greater blood pressure lowering with zilebesiran. And we saw an acceptable safety profile with low rates of hyperkalemia, kidney dysfunction and hypotension, consistent with the findings from prior studies. And we're very excited to announce the ZENITH trial, which will evaluate the impact of this novel, long-acting therapy on cardiovascular outcomes in patients with hypertension and established cardiovascular disease or high risk. Thank you very much. And now for Simon.

Thanks, Dr. Pagidipati, and congratulations on a great presentation and a well-executed trial. Hi, everyone. I'm Simon Fox. I'm the program leader at zilebesiran, and it's my pleasure to be talking to you about the patient opportunity and the next steps for the zilebesiran program. As Bryan said, it's become increasingly obvious that hypertension is a public health care crisis. It's become well known that even today with the numerous classes of antihypertensives, there are tens of millions of patients with uncontrolled hypertension. Of the 219 million patients that have hypertension across the 7 major markets, 77 million of these patients also have high cardiovascular risk and up to 62 million of these patients are currently uncontrolled. Now these patients with uncontrolled hypertension and high cardiovascular risk have the greatest unmet need. And these patients have comorbidities like diabetes, CKD and established cardiovascular disease. Now moving on to the potential we see in zilebesiran. Dr. Pagidipati presented the findings of the KARDIA-3 study, and we clearly saw an enhanced response in a subgroup of interest. And these benefits seen were both blood pressure reductions and benefits beyond blood pressure control. So putting this into context when reviewing the literature of the various independent risk factors, it's well known that reductions in daytime systolic blood pressure of 5 to 10 millimeters of mercury can result in significant reduction in cardiovascular risk. And we know that nighttime blood pressure is very important. A small additional nighttime blood pressure reduction of around about 1 to 2 millimeters of mercury could result in a risk reduction of cardiovascular death of 1% to 2%. In addition to this, improvements in things like NT-proBNP and UACR can also have additional cardiovascular risk reduction benefits. And finally, improving blood pressure variability over the long term can also help further reduce cardiovascular risk. In conclusion, given zilebesiran's emerging profile, which is exhibiting attributes like sustained daytime and nighttime blood pressure reductions as well as observed effects beyond blood pressure control, we believe this will have cumulative benefit over time, and therefore, zilebesiran has the potential to improve outcomes for the patients with the highest unmet need. Now it's my pleasure to be presenting to you our Phase III pivotal trial design, which is named ZENITH. ZENITH will enroll a total of 11,000 patients. The patients to be enrolled will be the KARDIA-3-like patient population, as mentioned, previously uncontrolled hypertension with either established cardiovascular disease or at high risk of developing cardiovascular disease, including patients both with preserved and impaired renal function. Now these patients will have a baseline office systolic blood pressure of equal to or greater than 140 millimeters of mercury on stable treatment of 2 or more background antihypertensives and one of which will have to be a diuretic. It will be an event-driven trial, and the primary composite endpoint will be a 4-point MACE, which is nonfatal myocardial infarction, nonfatal stroke and cardiovascular death as well as hospitalization for heart failure or urgent heart failure visits, and it will be comparing zilebesiran 300 milligrams to placebo. The trial will have a minimum follow-up of 2 years, and we've already engaged with regulators to seek advice on the specific of the trial design and the target indication. And the conversations have been extremely helpful. And now with the KARDIA-3 data in hand, we have finalized the ZENITH protocol. Both Alnylam and our partners at Roche are thrilled to be initiating the global multicentered cardiovascular outcomes trial, ZENITH. We have already filed ZENITH protocol with multiple regulators to date, and we look to complete these filings by the end of next year. We are planning to activate our first sites in the coming weeks with first patient first dose planned before the end of the year. ZENITH will have a global footprint, enrolling patients from approximately 35 countries across the major regions to ensure the trial reflects a real-world population and a real-world clinical practice. I just wanted to highlight that the global footprint of ZENITH illustrates Alnylam and Roche's commitment to developing innovative treatments for cardiovascular disease as well as our global aspirations for zilebesiran. So what's next for Alnylam and Roche? Our immediate focus operationally will be to initiate and expedite enrollment of our cardiovascular outcomes trial through our clinical operation capabilities as well as our medical affairs capabilities. Once the trial initiates, the medical affairs team will be delivering medical education and scientific engagement. Organizationally, we'll be looking to shape our go-to-market strategies as well as developing an understanding of the organizational capabilities and resources to successfully commercialize zilebesiran. We'll also be continuing to develop REVERSIR, which will further demonstrate the capabilities of our RNAi platform. We've made a very choiceful key strategic choice to evolve our manufacturing capabilities to reduce COGS, given that zilebesiran will be targeting a prevalent disease such as hypertension and given our aspirations to commercialize zilebesiran globally. And finally, the team at Alnylam and Roche are assessing the potential to develop zilebesiran for additional indications. To conclude, Alnylam and Roche fully believe in the potential value zilebesiran has to offer and how we unlock this value is generating the most robust data to optimize the zilebesiran value proposition. Generating cardiovascular outcomes data will ensure favorable guideline positioning and demonstrate the value to health care systems. We believe for HCPs that cardiovascular outcomes data, coupled with the ability to achieve continuous control of blood pressure safely with infrequent dosing will potentially drive rapid uptake and differentiate zilebesiran. And finally, generating this data will also drive confidence and preference amongst patients. And with that, I'm going to hand over to our partner at Roche, Manu Chakravarthy.

Thank you, Simon. Really delighted to be joining you all from Boston. Firstly, I want to just thank our Alnylam colleagues for organizing this event. So thank you for that. On behalf of Roche, let me first express a deep gratitude to the patients who actually participated in the whole KARDIA program because without their partnership and volunteering for being in this trial, we wouldn't really have the privilege here to stand before you to share these very exciting results that you heard today. So thank you to that as well. So from our perspective, the whole KARDIA program, particularly KARDIA-3, really represents a paradigm shift. And really in the way that we think about zilebesiran is a fundamentally new way to treat chronic disease. It's a differentiated approach to lower blood pressure and to improve cardiovascular outcomes. You've already heard from Dr. Williams about the importance of blood pressure and adherence, but I want to echo those two points and add a couple of important additions to that, which is really the fact that one of our excitement for this program really resides in the fact that with a single injection, we're able to actually sustain blood pressure lowering for over 6 months. At least to the best of our knowledge, we're not aware of any drug that at this stage of development that can do that. And you've heard how singularly important blood pressure is as the most important predictor of outcomes, if you will. So even a 5-millimeter drop in mercury can potentially translate to about a 10% relative risk reduction in major cardiovascular outcome events. The second point that I think it's totally worth emphasizing because we don't really think about it too much, but in the setting of chronic disease, it's very important, which is adherence. So in the large meta-analysis that Dr. Williams referred to. And when we looked at it a little bit more carefully to look at what the numbers are, it was quite -- at least to me, it was quite striking that for every 1% improvement in adherence, you could actually reduce cardiovascular event rates by another additional 13%. So when you put these two things together, sustained prolonged reductions in blood pressure, especially the reduction in nighttime blood pressure, along with this improved adherence, we believe that we are well poised to really see a very strong impact on cardiovascular outcome benefits when we actually run the ZENITH trial. So that's ultimately the reason why we are also equally excited with our partner, Alnylam, to stand behind them to execute this trial because ultimately, as clinicians and as physicians and as public health stewards, if you will, what matters most to patients is not just the lowering of blood pressure, but ultimately, the changing of the trajectory of their health and an outcomes trial can ultimately prove that. And the final point I want to leave you with is that we see zilebesiran as a cornerstone of our growing cardiovascular, renal and metabolic portfolio that you can see here on this slide as well. At Roche, we now have one of the broadest CVRM portfolios, which gives us the optionality, the ability to address unmet needs across a range of patient segments and importantly, allows us to think about very unique combination approaches. So potentially down the road, in [indiscernible] zilebesiran in combination or other combinations that we may not yet have thought about could be all conceivable. And ultimately, delivering medicines that can have the transformational impact in cardiovascular disease is really the crux of the priority at Roche. So overall, just for me, personally, this is just the beginning, I feel, and we couldn't be more energized to see what comes ahead. So with that, let me say big thanks again and hand it off to Pushkal to bring us home with closing remarks.

Fantastic. Thank you, Manu. Really appreciate you dialing in and those comments and perspectives from Roche. We're really delighted to be partnering with your whole company. The collaboration has been going extraordinarily well. I'm going to close quickly with just some of the keys to success. Look, we couldn't be more excited. I hope you've picked up on that. This is another program that's really a product of our disciplined R&D strategy, where we really pursued with our sustainable innovation engine, diseases where we have high biologic conviction, high morbidity and mortality and the potential to halt or reverse disease be best-in-class. And you see, hopefully, from what everything we've spoken about today that we really believe that zilebesiran can be a paradigm-shifting therapy for patients with hypertension. This is an opportunity to rewrite how blood pressure is managed around the world and maybe even bend the curve on cardiovascular disease. And so we, our partners at Roche, and you've seen our academic collaborators and experts really have a strong level of conviction about this that we can really potentially have a substantial impact on this disease. So hopefully, you picked up on that confidence. We're going to now switch over to Q&A. So I'm going to invite my colleagues to come on up, and we'll be able to take some questions from the room and on the webcast.

We're actually happy to start in the room if anyone who's joining us live would like to ask anything. Great.

Eliana Merle, UBS. Can you elaborate a little bit on why you think you see a synergistic effect with the diuretics and then also your expectations for the proportion of patients on the ZENITH trial that will be on diuretics as well?

Great. So Ellie's question was about the rationale for the synergies potentially between zilebesiran's mechanism of action and diuretic and whether that will -- how that might affect recruitment in the context of Phase III. So Neha, maybe you want to start to address. And Bryan, you may also have some comments there.

Sure. Yes, it's a great question. I think part of the first question that you asked was around the rationale for why we might see this kind of synergistic or complementary effect. And my -- I think that it has to do with the fact that when a patient is on a diuretic, their volume contracts and their blood pressure goes down, and that actually upregulates the RAS system. And the precursor for the entire RAS system is angiotensinogen, which is what zilebesiran is working on. So you're essentially increasing the substrate for zilebesiran to do its job. And so I think that's probably the most likely reason that we're seeing that kind of synergistic effect that we saw both in K2 and K3. In terms of the proportion of patients who will be on it in the cardiovascular trial and the outcomes trial, it will be everybody because we're going to require that patients are on a diuretic because we think we'll see the greatest benefit in those patients. I actually don't think it's going to make it harder to recruit for the trial because even though there is some geographic variation in diuretic use, it is probably the single most well-used antihypertensive globally. It is very well available and in most guidelines is a Class I indication. So I actually don't expect it to be difficult to recruit.

Thanks, Neha. Bryan, anything to add?

Yes. I mean, I think we've known for years that if you use a single drug, it often gets counteracted by another mechanism. And so as Neha said, if you try and offload sodium and water, which is what diuretics do, you activate the reading system, which limits the effectiveness of the diuretic. So if you can block the renal system, what you're doing is you're pulling out more -- even more effectiveness from that strategy. The other thing I would add actually is that as you move into more complex patients with -- who are often on multiple drugs and they've got underlying cardiovascular or kidney disease, you almost invariably need a diuretic as part of treatment because all of those conditions and aging are associated with increased sodium retention. So I think it's not a bad idea anyway for those patients to be on a diuretic. They probably should be on a diuretic if they're hypertensive. And then zilebesiran on top. So I'm very confident that combination will produce a much more robust and consistent response across the patient population that's going to be studied.

Makes sense. Can I ask another question. There were some comments when the presentation was made in terms of interpreting the results in the context of KARDIA-1 and 2 about how there was maybe sizable proportion of patients between screening and randomization that no longer had hypertension. Could you just elaborate on those comments a little bit and how we should interpret these results in that context?

Yes. So Ellie's question was really about understanding sort of the treatment effect that we observed here versus, for example, in KARDIA-2, where we were somewhat more sizable. And I think probably there's a couple of points that I can start with, and then I can ask Neha to follow up, right? In the KARDIA-2 program, obviously, it was a somewhat milder population without sort of the severity of cardiovascular disease. But importantly -- so -- and also being used in earlier line of therapy but probably the most important factor was that actually there was a run-in period that was incorporated into that study to ensure what baseline blood pressure was as patients entered into the study. So you may want to speak a little bit more about what we observed in KARDIA-3 relative to KARDIA-2 around baseline blood pressure, et cetera, that may have predicted that.

Sure. Absolutely. So that's exactly right. And obviously, in KARDIA-2, there was a run-in period. And here, for the purposes of being more generalizable and applicable to the cardiovascular outcomes trial, there was not a run-in. And what we saw was that for inclusion, patients had to have a systolic blood pressure greater than or equal to 140 at screening. Then there was a screening period during which they had their ambulatory blood pressure monitored, then they returned for their baseline visit and got randomized. At that time, when they return for their baseline visit and at the time of randomization, about 40% of them no longer had a systolic blood pressure greater than 140, but they were still included in the trial. And then about 25% didn't have a systolic blood pressure above 135. Anytime you take a population that isn't truly hypertensive, it is that much harder to show an antihypertensive effect. And so I think that clearly had something to do with the differences between the two trials.

So an important -- this was an important learning for us as we kind of go into the cardiovascular outcome study. And so one of the refinements that we've made working with the investigators is to ensure that patients have an elevated blood pressure at screening. But then at the time of randomization, it has to be confirmed that they have an elevated blood pressure. So with that extra precaution, we're confident now that we'll be enrolling patients in this longer-term CVOT who've got elevated blood pressure at the time that they get randomized to drug or placebo.

Let's hop over to the webcast. We have a number of questions that have come in already. So one of them is around K3 baseline characteristics. The percent of patients with previous CV event or CVD history in the 300 mg cohort has almost doubled compared to the 600 mg. Do you think this difference has any potential impact on the results?

So maybe, Neha, you can speak to that. But look -- the question is really about the 300 and 600 milligrams and whether any of the baseline characteristics may have led to why we didn't see more of a dose response between those 2.

Yes, it's a great question. I'm eager to hear what Dr. Williams thinks as well. There were some -- it is a relatively small Phase II study. And so there will be some imbalances in randomization, and that's one of the areas where we saw some of the imbalance. I'm not sure that, that necessarily contributed to the results. It is helpful to understand what the risk of the underlying population is. But in general, it was a pretty homogenously high-risk population across all of the arms. So I'm not sure the small kind of variations that we saw in the Table 1 and in the baseline demographics really contributed all that much. But I don't know if Dr. Williams or Simon has other thoughts.

No. I mean -- and also, it's quite difficult to do between dose comparisons in relatively modestly sized studies. I mean generally, we don't do that. We're looking to see whether there's an effect, but it's often not powered to try and actually detect an effect. I was just going to add to the first point. I mean, trials are difficult. And sometimes you get a perfect patient population and sometimes some of the patients in the trial are not quite what you wanted in terms of the way they behave. And you can't really control that very easily, and that's just the nature of what we do. I'm pretty confident when you go into a large-scale outcome trial that those kind of things become less important because, first of all, the scale, there's a huge number of patients involved. Secondly, the duration. And if you've got a treatment that they're going to be getting on a 6-monthly basis that is going to guarantee that there's going to be an element of blood pressure control. Even if they don't take all their other medicines, the blood pressure and the blockade of the renal system in that population is always going to be superior to the placebo because we have to accept that the background medicines will get messed about with by the patients and sometimes by their doctors. I mean that's just the nature of trying to do something over a 3-, 4-, 5-year period. So I wouldn't get too hung up on the KARDIA-3 side of things. You've got two very good trials, KARDIA-1, KARDIA 2. KARDIA-2 studies, which are just spectacular results. And there's no reason to sort of push that aside because of the sort of challenges around some of the patients recruited into this particular study.

That's very helpful, Bryan. And I think that's our belief, right, that the real benefits of what we're trying to do is going to be in outcomes. And that's where over 3, 4 years, we're going to be starting to see these substantial benefits. Every bit of science that we have in epidemiology that Bryan covered really well suggests all these benefits should come together really in accrue and maybe in somewhat of an additive or synergistic effect to result in outsized outcomes benefits. And that's what we're all super excited about. I'll just add one more point on the dose response, which is I think when if you look at all the data that we've accumulated over time, the 300 and 600-milligram arms have actually performed reasonably similarly across studies. They actually both give us very high levels of AGT silencing, about 95%. And so it's not really too surprising that we didn't see a difference, but we certainly wanted to make sure before we kick off this very large study that we've picked the correct dose. And so we're very convinced that 300 milligrams, which is a single injection every 6 months is the right dose to pursue in the cardiovascular outcome study.

Yes, sounds great. How is the efficacy in KARDIA-3 in the population that was on background angiotenosin 2 receptor blockers. Was there different efficacy in that group as in KARDIA-2?

Yes. So maybe I can -- the question was really about how is the efficacy on patients who are basically on another RAS inhibitor, either an angiotensin receptor blocker or an ACE inhibitor. In this case, 90% of the patients, so pretty much the entire study population was on an ACE or an ARB. And so the efficacy that you're seeing both in the overall population as well as in the enriched subgroup that Neha talked about, that's the target for the cardiovascular outcome study are already being treated with a RAS inhibitor. And I think that's actually pretty remarkable as well if you think about the prior history of combined RAS blockade where I think the effect sizes actually in those settings have been quite small. And Bryan is nodding in no. So maybe, Bryan, you want to speak to that a little bit as well as the safety. So...

Yes, I would agree with you, actually. I think when you combine the drugs, as you have done, I was surprised initially because I think as a clinician, I kind of believe that we had blocked the system at the receptor level with angiotensin receptor blockers. And clearly, we haven't blocked it completely because we're seeing breakthrough in terms of the ability of this drug to take blood pressure further. So it's certainly adding to the existing level of RAS blockade. I guess in the future, what will happen is if this drug is as successful as many people think it will be, it will replace these drugs. People won't need to take an ARB on a RAS blocker on a consistent basis. They will just use this drug to block their renal system. So to some extent, the main issue about dual blockade is about the concern initially about whether there would be a hazard [indiscernible] because there has been a hazard in the past with ACE inhibitor and ARBs together. But fortunately, that hasn't been seen.

That's right. Thank you.

And we actually have a question for our colleagues at Roche with Manu. So what excites Roche about zilebesiran within the context of your broader CV portfolio? And maybe more specifically, what about this data gives the conviction to advance to a global outcome study?

Manu, did you hear that question?

Also do you want me to repeat the question?

No, no, I just want to make sure you heard the question. It sounds like you did. So please go ahead.

Yes. Yes. So the question was really about what excites us about the data overall and convinces us to go forward with the large outcome study. We asked that question, obviously, quite a bit as well. So I think there are several things. I think some of them I touched on in my remarks, but happy to sort of reiterate a couple of them. The first is really the magnitude of the blood pressure response in the population that has been very nicely outlined as the population of interest. It's the high-risk population. It's people that are on at least one single RAS agent and then they'll all be on diuretics. This is the key population at risk. And so we feel very confident based on the data that we saw, 9 millimeters of mercury reduction in that population with all the things that we would want to see, sustained lowering, nighttime lowering, both office and ambulatory lowering. So there is lots of different things that are all highly consistent. And then the final piece is, of course, the biomarkers, too. I know that we don't over-index on it right now, recognizing it's a small study. It's obviously biomarkers, et cetera, but those biomarkers are actually really, really highly predictive. So NT-proBNP and UACR, really well-established biomarkers, almost as good as blood pressure to some extent in predicting cardiovascular risk. So when you take the totality of the whole data set, along with the big question of adherence, which I alluded to as well as Dr. Williams alluded to, to us, that over a long period of time, will accumulate to provide that type of benefit that we anticipate roughly around the 15% to 20% relative risk reduction range, which is going to be highly meaningful from a patient perspective and a value-generating perspective. So that's the gist of why we felt very confident and very excited about the data that we saw. I think your second question was about how does this fit into the Roche portfolio. So hopefully, I showed and alluded to that on my slide as well. But again, to emphasize, we've always approached cardiovascular, renal and metabolic diseases as one continuum, right? Because it's a very common underlying pathophysiology for many of these diseases. And so we are -- what we're trying to do here is to change the fundamental risk profile. So in this case, blood pressure, in the case of diabetes, it's blood sugar. In the case of other things, it's lipids, et cetera. So we're really going after fundamental pathophysiological perturbations that we can modify in a meaningful way. And so zilebesiran really fits squarely into that way that we approach addressing chronic disease. And as I alluded to before, it also lets us the -- gives us the optionality for potential combinations down the road and to also explore other indications beyond just reduction of major cardiovascular risk events.

Thanks, Manu.

So let's stay on ZENITH for a moment. A question here about with 11,000 patients planned for ZENITH, what percent power is that to detect a 15% reduction in MACE and how about a 20% reduction in MACE?