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 CARDIA 3 results, and really the kickoff with Alnylam and 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 number one addressable cause of cardiovascular morbidity and mortality.
As you'll hear, cardiovascular disease is the number one killer of people around the world. 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 University College London, who's going to talk to you about the global burden of cardiovascular disease and why zilebesiran may 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. 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 CARDIA 3 results and put them in some context.
My colleague Simon Fox, who leads the zilebesiran program at Alnylam , will provide a perspective on the opportunity here. Dr. Manu Chakravarti from our partner at Roche will give a partner perspective. We'll come back and have a short period of Q&A. 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. In particular, how well-suited these drugs are for treating a number of factors that contribute to cardiovascular disease, and a portfolio now, a number of very transformational, 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. 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 six months, or annually. 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 six marketed products across both rare and prevalent conditions. 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 and ATTR cardiomyopathy. We're going to be talking about zilebesiran for most of this session. 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.
We've had the launch in the United States, which is the first quarter's been quite good, with 1,400 patients already on therapy, and new results being presented at the ESC, talking about extended survival data for Heliospeed that are being presented at this Congress. What we're here to talk about is zilebesiran. 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. 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, and now four studies actually, including the phase I, that have all shown repeatedly really impressive effects of zilebesiran in terms of reducing blood pressure. In CARDIA 1 as a monotherapy, in CARDIA 2 with a single other agent, and now in CARDIA 3, Dr. Pagidipati will talk to you about how it performed on top of two other agents, two or three other agents in a high-risk population. 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. With that, I'm going to invite Dr. Williams to come up and talk to you about the burden of cardiovascular disease.
Yeah, you got it right here.
Hi, everybody. I'm Bryan Williams from London, and I've 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. Currently, about 20 million people die every year from cardiovascular disease. The tragedy is it's largely preventable. 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. 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 controlled to a level below 140 over 90. The important thing about that is these are terrible control rates below 140/90. Guidelines now advocate even more aggressive therapy. All of the guidelines are now suggesting to optimize treatment, we need to get blood pressure below 130 over 80. There's a huge treatment gap between what is expected and what is being delivered by current therapeutics. 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.
Just quickly, the elements of things that we're interested in, and Bangesh mentioned this at the beginning, blood pressure levels achieved in the clinic is how we traditionally monitor blood pressure. Actually, the levels over 24 hours are very important. The control of nighttime blood pressure is very important. Speed to control is very important. Increasingly, we're recognizing the consistency of blood pressure control is very important. That's why I personally got very interested in this drug, having worked in hypertension for 30-odd years. This is pretty novel, or it's 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. 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 a very powerful predictor of risk of death. 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. 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.
We've got to control all of these. 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 the 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. 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. 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 this phenomenon of persistence of control being important, this, I think, is some data which convinced me that this is a really powerful issue. It comes from the U.K., but it actually is a typical U.K. study because it involves over a million patients. What we looked at here is the time that 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. 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. 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. That tried to get blood pressure below 120. The argument there was, if we've got to improve outcome, we've just got to keep going lower. 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. What they found is if they went below 120, they got a 25% reduction in cardiovascular death. We got a 75% reduction in cardiovascular death by going below 140, but doing it on a consistent basis.
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 six 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. Adherence is really bad. What we find is about 40% of patients don't take some or all of the medication. I'll skip through that.
This idea that you can give an injection and guarantee adherence to therapy for at least six 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. One of the things that I emphasize is that we need drugs with a long duration of action to overcome adherence problems. Actually, six months is a pretty long duration of action, and nothing comes close to it. That's quite exciting. 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. This will be, I think, a major advantage in hypertension.
To reduce blood pressure smoothly and consistently over prolonged periods, to reduce variability, and to overcome major problems with treatment adherence, I'll hand back. From my point of view, this is a completely novel therapeutic in the field of hypertension.
Thank you, Dr. Williams. I'm Neha Pagidipati . I'm a Preventive Cardiologist at Duke. I was very privileged to share these results of CARDIA 3 earlier today at ESC. Just for quick background, and you saw a little bit of this before, the phase II zilebesiran development program has three trials in it: CARDIA 1, CARDIA 2, CARDIA 3, which I'll present to you today. CARDIA 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 mm of mercury for 24-hour mean systolic blood pressure. 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. CARDIA 2, which was the second phase II study, tested zilebesiran on top of a single antihypertensive agent.
Patients had a run-in, and then they were assigned either indapamide, amlodipine, or olmesartan, and a high dose of olmesartan, 40 mg. 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 mm of mercury on top of a diuretic, - 10 on top of amlodipine, and - 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. That was all very exciting. The study objective of CARDIA 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.
CARDIA 3 was a phase II randomized double-blind placebo-controlled trial in five countries. It included patients with established cardiovascular disease or at high risk for cardiovascular disease, uncontrolled hypertension, as seen here, and who were already prescribed two to four antihypertensive agents, including a diuretic or a calcium channel blocker. This was the study design. There are two cohorts. I'm presenting today to Cohort A, which included patients with an eGFR of greater than or equal to 45. 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 one of three arms, a single dose of zilebesiran, 300 mg, 600 mg, or placebo at baseline. They were followed for six 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. Patients and clinicians in the first three months were encouraged not to change their antihypertensive therapy unless clinically indicated. The primary outcome was at three months; it was change from baseline to month three in mean office systolic blood pressure. You can see several of the secondary and exploratory outcomes here. 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. In the 270 patients, the mean age was in the mid-60s.
This was an appropriately diverse cohort with good representation of females, Blacks, and Hispanic individuals. About 20% had a prior cardiovascular event, and half had diabetes. The baseline blood pressure, the mean systolic blood pressure was 143- 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. 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 a 1/3 were on three, and the minority were on four. These are the results of Cohort A.
At month three, the placebo group had a decrease in systolic blood pressure of 7.3 mm of mercury. The zilebesiran 300 mg group had a decrease of 12.3 mg, and the 600 mg group had a decrease of 10.6 mg, resulting in a placebo-adjusted change of - 5 in the 300 mg group and - 3.3 in the 600 mg group. 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 six, the placebo-adjusted changes were - 3.9 and - 3.6 in the 300 mg and 600 mg arms, respectively. For the secondary outcome of 24-hour mean ambulatory systolic blood pressure at month three, the placebo-adjusted change was - 3.6 and - 2.6 in the 300 mg and 600 mg arms. At month six, those changes were - 5.5 and - 7.4.
This slide shows the mean daytime and nighttime ambulatory systolic blood pressure at month six. What you can see here is that in the daytime, the placebo-adjusted change in the 300 mg group was - 4.9, and it was - 6.9 in the 600 mg group. Those corresponding values were numerically greater at nighttime at - 6.6 and - 8.2. These are some data of the biomarkers that were tested. 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. In patients with a somewhat elevated level of NT-proBNP at baseline, just greater than 12 pmol/L , you saw on average 21% and 26% reduction, which is quite impressive in the 300 mg and 600 mg arms.
For the UACR, you saw reductions in the 37% and 32% range with the 300 mg and 600 mg doses. The safety profile was, I would say, encouraging overall. There were very few serious adverse events, and they were generally comparable between arms. Most of the instances of hyperkalemia and worsening kidney function were not confirmed by subsequent measurement, and none of them required dialysis or hospitalization. As I mentioned, one of the primary purposes of CARDIA 3 was to identify who is most likely to benefit from zilebesiran in order to optimally design the phase III outcomes trial. We knew from CARDIA 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 up-regulated.
In a pre-specified subgroup of CARDIA 3, in those on a diuretic at baseline, the placebo-adjusted change at three months was - 6.6 with the 300 mg arm and - 5.1 with the 600 mg arm. 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 mg, in a post-hoc analysis, you can see a placebo-adjusted change of - 9.2 or - 7.0 with the 300 mg and 600 mg doses, respectively. In conclusion, among individuals with cardiovascular disease or high cardiovascular risk who have uncontrolled hypertension on multiple antihypertensives, single doses of zilebesiran 300 mg or 600 mg led to respective 5 mm and 3.3 mm of mercury reductions in office systolic blood pressure at three months compared with placebo. Statistical significance was not reached.
However, subgroup analyses did suggest that those on a diuretic may experience greater blood pressure lowering with zilebesiran. We saw an acceptable safety profile with low rates of hyperkalemia, kidney dysfunction, and hypotension, consistent with the findings from prior studies. We are 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. 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 Lead 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 antihypertensive agents, there are tens of millions of patients with uncontrolled hypertension. Of the 219 million patients that have hypertension across the seven major markets, 77 million of these patients also have high cardiovascular risk, and up to 62 million of these patients are currently uncontrolled. These patients with uncontrolled hypertension and high cardiovascular risk have the greatest unmet need. 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 CARDIA 3 study, and we clearly saw an enhanced response in a subgroup of interest. These benefits seen were both blood pressure reductions and benefits beyond blood pressure control. 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 mm- 10 mm of mercury can result in significant reduction in cardiovascular risk. We know that nighttime blood pressure is very important. A small additional nighttime blood pressure reduction of around about 1 mm- 2 mm of mercury could result in a risk reduction of cardiovascular death of 1%- 2%. In addition to this, improvements in things like NT-proBNP and UACR can also have additional cardiovascular risk reduction benefits.
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. 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 CARDIA 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.
These patients will have a baseline office systolic blood pressure of equal to or greater than 140 mm of mercury on stable treatment of two or more background antihypertensive agents, and one of which will have to be a diuretic. It will be an event-driven trial. The primary composite endpoint will be a four-point MACE, which is non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, as well as hospitalization for heart failure or urgent heart failure visits. It will be comparing zilebesiran 300 mg to placebo. The trial will have a minimum follow-up of two years. We've already engaged with regulators to seek advice on the specifics of the trial design and the target indication. The conversations have been extremely helpful. Now, with the CARDIA 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 the ZENITH protocol with multiple regulators to date. 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 Pharmaceuticals and Roche's commitment to developing innovative treatments for cardiovascular disease, as well as our global aspirations for zilebesiran. 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 Reversia, 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. 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. 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. Generating this data will also drive confidence and preference amongst patients. With that, I'm going to hand over to our partner at Roche, Manu Chakravarthy.
Thank you, Simon. I'm very delighted to be joining you all from Boston. Firstly, I want to just thank our Alnylam colleagues for organizing this event. Thank you for that. On behalf of Roche, let me first express a deep gratitude to the patients who actually participated in the whole CARDIA 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. Thank you to that as well. From our perspective, the whole CARDIA program, and particularly CARDIA 3, really represents a paradigm shift. In the way that we think about zilebesiran, it 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. 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 six months. At least to the best of our knowledge, we're not aware of any drug at this stage of development that can do that. You've heard how singularly important blood pressure is as the most important predictor of outcomes, if you will. Even a 5 mm drop in mercury can potentially translate to about a 10% relative risk reduction in major cardiovascular outcome events.
The second point that I think is 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. In the large meta-analyses that Dr. Williams referred to, and when we looked at it a little bit more carefully to look at what numbers are, it was quite, at least to me, it was quite striking that for every 12% improvement in adherence, you could actually reduce cardiovascular event rates by another additional 13%. When you put these two things together, sustained prolonged reductions in blood pressure, especially the reductions 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.
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. An outcomes trial can ultimately prove that. 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.
Potentially down the road, in inclusions, zilebesiran combination, or other combinations that we may not yet have thought about could be all conceivable. Ultimately, delivering medicines that can have the transformational impact in cardiovascular disease is really the crux of the priority at Roche. Overall, just for me personally, this is just the beginning, I feel. We couldn't be more energized to see what comes ahead. With that, let me say a big thanks again and then 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, and be best in class. 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. 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. Hopefully, you picked up on that confidence. We're going to now switch over to Q&A. I'm going to invite my colleagues to come on up. We'll be able to take some questions from the room and on the webcast.
Happy to start in the room if anyone who is joining us live would like to ask anything. Great.
Thank you, guys. Ellie 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? Thank you.
Great. Ellie's question was about the rationale for the synergies potentially between zilebesiran's mechanism of action and a diuretic and how that might affect recruitment in the context of phase III . Neha, maybe you want to start to address. Bryan, you may also have some comments there.
Sure. Yeah, 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. 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. That actually upregulates the RAS system, and the precursor for the entire RAS system is angiotensinogen, which is what zilebesiran is working on. You're essentially increasing the substrate for zilebesiran to do its job. 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'll 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, it is a class 1 indication. I actually don't expect it to be difficult to recruit.
Thanks, Neha. Bryan, anything to add?
Yeah, I mean, I think we've known for years that if you use a single drug, it often gets counteracted by another mechanism. As Neha said, if you try and offload sodium and water, which is what diuretics do, you activate the renin system, which limits the effectiveness of the diuretic. If you can block the renin system, what you're doing is you're pulling out even more effectiveness from that strategy. The other thing I would add, actually, is that as you move into more complex patients 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. 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. 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.
Great. Makes sense. I'm going to ask another question. There were some comments when the presentation was made in terms of interpreting the results in the context of CARDIA 1 and 2 about how there was a 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? Thanks.
Yeah, so Ellie's question was really about understanding sort of the treatment effect that we observed here versus, for example, in CARDIA 2, where it was somewhat more sizable. I think probably there's a couple of points that I can start with, and then I can ask Neha to follow up. In the CARDIA 2 program, obviously, it was a somewhat milder population without sort of the severity of cardiovascular disease, but importantly, and also being used in an earlier line of therapy. 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. You may want to speak a little bit more about what we observed in CARDIA 3 relative to CARDIA 2 around baseline blood pressure, et cetera, that may have predicted that.
Sure, absolutely. That's exactly right. Obviously, in CARDIA 2, there was a run-in period. Here, for the purposes of being more generalizable and applicable to the cardiovascular outcomes trial, there was not a run-in. What we saw was that for inclusion, patients had to have a systolic blood pressure greater than or equal to 140 mg at screening. There was a screening period during which they had their ambulatory blood pressure monitored. They returned for their baseline visit and got randomized. At that time, when they returned for their baseline visit and at the time of randomization, about 40% of them no longer had a systolic blood pressure greater than 140 mg, but they were still included in the trial. About 25% didn't have a systolic blood pressure above 135 mg. Any time you take a population that isn't truly hypertensive, it is that much harder to show an antihypertensive effect.
I think that clearly had something to do with the differences between the two trials.
This was an important learning for us as we kind of go into the cardiovascular outcomes study. One of the refinements that we've made working with the investigators is to ensure that patients have an elevated blood pressure at screening. At the time of randomization, it has to be confirmed that they have an elevated blood pressure. With that extra precaution, we're confident now that we'll be enrolling patients in this longer-term CVAT 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. One of them is around CARDIA 3 baseline characteristics. The percentage of patients with previous CV event or CVD history in the 300 mg cohort is almost doubled compared to the 600 mg. Do you think this difference has any potential impact on the results?
Neha, you can speak to that. The question is really about the 300 mg and 600 mg and whether any of the baseline characteristics may have led to why we didn't see more of a dose response between those two.
Yeah, it's a great question. I'm eager to hear what Dr. Williams thinks as well. It is a relatively small phase II study, so there will be some imbalances in randomization. That's one of the areas where we saw some of the imbalance. I'm not sure that necessarily contributed to the results. It is helpful to understand what the risk of the underlying population is. In general, it was a pretty homogeneously high-risk population across all of the arms. 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. I don't know if Dr. Williams or Simon has other thoughts.
No, I mean, it's quite difficult to do between-dose comparisons in relatively modestly sized studies. 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. Trials are difficult. Sometimes you get a perfect patient population, and sometimes some of the patients in a trial are not quite what you wanted in terms of the way they behave. 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.
If you've got a treatment that they're going to be getting on a six-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 renin 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. That's just the nature of trying to do something over a three, four, five-year period. I wouldn't get too hung up on the CARDIA 3 side of things. You've got two very good trials, CARDIA 1 and CARDIA 2, CARDIA 2 studies, which are just spectacular results.
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. I think that's our belief, right, that the real benefits of what we're trying to do are going to be in outcomes. That's where over three, four 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 a crew and maybe in somewhat of an additive or synergistic effect to result in outsized outcomes benefits. That's what we're all super excited about. I'll just add one more point on the dose response, which is I think, you know, if you look at all of the data that we've accumulated over time, the 300 mg and 600 mg arms have actually performed reasonably similarly across studies. They actually both give us very high levels of angiotensinogen silencing, about 95%.
It's not really too surprising that we didn't see a difference. We certainly wanted to make sure before we kick off this very large study that we've picked the correct dose. We're very convinced that 300 mg, which is a single injection every six months, is the right dose to pursue in the cardiovascular outcomes study.
Yep, sounds great. How was the efficacy in CARDIA 3 in the population that was on background angiotensin II receptor blockers? Was there differing efficacy in that group as in CARDIA 2?
Yeah, so maybe I can answer. The question was really about how was the efficacy on patients who were 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. 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. 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. Bryan's nodding and Neha. Maybe, Bryan, you want to speak to that a little bit as well as safety.
Yeah, 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. Clearly, we hadn't blocked it completely because we're seeing breakthrough in terms of the ability of this drug to take blood pressure further. It is 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 or a RAS blocker on a consistent basis. They will just use this drug to block their renin system.
To some extent, the main issue about dual blockade is about the concern initially about whether there would be a hazard of doing that, because there has been a hazard in the past with ACE inhibitors and ARBs together. Fortunately, that hasn't been seen.
That's right. Thank you.
We actually have a question for our colleagues at Roche with Manu. What excites Roche about zilebesiran within the context of your broader CV portfolio? More specifically, what about this data gives a conviction to advance to a global outcomes study?
Manu, did you hear that question?
Do you want me to repeat the question?
I just wanted to make sure you heard the question. It sounds like you did. Please go ahead.
Yes. 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. 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're all beyond diuretics. This is the key population at risk.
We feel very confident based on the data that we saw, 9 mm of mercury reduction in that population, with all the things that you would want to see, sustained lowering, nighttime lowering, both office and ambulatory lowering. There are lots of different things that are all highly consistent. 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. Those biomarkers are actually really, really highly predictive. NT-proBNP and UACR, really well-established biomarkers, almost as good as blood pressure to some extent in predicting cardiovascular risk. 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%- 20% relative risk reduction range, which is going to be highly meaningful from a patient perspective and a value-generating perspective
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. Hopefully, I showed and alluded to that on my slide as well. Again, to emphasize, we've always approached cardiovascular, renal, and metabolic diseases as one continuum, because it's a very common underlying pathophysiology for many of these diseases. What we're trying to do here is to change the fundamental risk profile. 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. We're really going after fundamental pathophysiological perturbations that we can modify in a meaningful way. Zilebesiran really fits squarely into that way that we approach addressing chronic disease. As I alluded to before, it also 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.
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? How about a 20% reduction in MACE?
Maybe I can speak to that. ZENITH is going to be an 11,000-person study. It's event-driven. We'll be actually looking at the number of events. The study will terminate when we have that appropriate number of events. What I can say is that it's actually very highly conservatively powered. Both Roche and Alnylam want to ensure, and the investigators, that this is a successful study. We're testing a paradigm-shifting approach. We've really conservatively powered the study to be able to yield those kinds of meaningful results.
Great. With that data in hand, can we talk about how we would see zilebesiran fitting into clinical practice alongside other antihypertensive agents? What lines of treatment? Is it mono? Is it combo?
Yeah, maybe I can start. Simon, you can start with how we're thinking about that from the company's positioning. I think it'd also be important to hear from Neha and Bryan about how a therapy like this might be used initially and over time, where you might see it fitting in, assuming the results are positive.
Yeah, great. That's a great question. Clearly, you can see the design of the trial. Patients will be on a background of two or more antihypertensive agents. These are going to be the patients with the highest unmet need, high cardiovascular risk, established cardiovascular disease, and those patients at high risk of cardiovascular disease. That's where we believe, firstly, we can create the most value for patients, payers, and physicians. I think we all have aspirations for zilebesiran to go to earlier lines of therapy. That's where we're going to start. We're going for a broad indication. It'll be something like zilebesiran is indicated to reduce cardiovascular risk in patients with hypertension and high cardiovascular risk. I think the opportunity is sizable.
Yeah, maybe Neha, do you want to dig in? If something like this was available, how would you think about using it, assuming again positive results? We'll ask Bryan the same question.
Yeah, it's a great question, actually. I think all drugs start with the highest risk population for many reasons. First, that's the greatest unmet need. Those are the patients that we as clinicians, when we're enrolling in clinical trials, we are most eager to get our highest risk patients into trials because the potential benefit for them is that much greater. You also generate more events, frankly, for the cardiovascular outcome. There's a practicality to that as well. In clinical practice, though, we tend to start to use what is most effective and easiest to get over time. That doesn't necessarily only end with the high-risk patients. If you have a therapy that is very easy for patients, it is something that decreases their pill burden. They don't have to think about it.
It's not only having them take less pills, which makes them happy, which makes you happy, because when they're not happy, I promise you the clinician's not happy, because we hear about it. It also provides you some measure of reassurance that they are getting continuous blood pressure control, whether they take their medications that day or not. I could certainly see, presuming that the outcomes trial will be positive, which we hope and expect that it will be, I could certainly see over time that zilebesiran kind of edges its way forward earlier in the line of therapy.
Bryan, anything to add?
Yeah, I think it's fascinating because it is a completely different therapeutic than anything else we've got. In many ways, it's reassuring that there are others in different areas, like the whole spectrum of them being developed in the lipid field with triglycerides, LPA, cholesterol. At some point, the payers and the regulators are going to have to face up to the fact that there is a different paradigm for treatment coming down the track. For prevention, I think eventually it's dawning on everybody that patients generally don't like taking medications every day, particularly if it's not producing symptomatic relief and doesn't seem to be doing anything. If you think about it, some sort of program of biannual, twice-a-year injection to act as a cardiovascular prevention strategy would be very attractive.
We know that there are ongoing trials within inclisiran, which I would anticipate will be positive in high-risk patients for cholesterol. The health systems are going to have to get around the idea that they're going to have to work out how to do this. You could imagine that the two most important things you can probably do is lower blood pressure, lower cholesterol. The idea that you could give a jab once every six months, and who knows, potentially less frequent than that, depending on what we learn about the duration of effect of things, that would be very attractive as a strategy to prevent cardiovascular disease. You might do it initially in the high-risk groups. Eventually, you could see many patients saying, well, I would like a bit of that. That sounds quite interesting and better than what I've been used to using.
I think we have to accept that it's going to require a lot of discussion and a lot of people to start thinking in a slightly different way. I think they will, because I think this type of approach is going to catch on. I mean, who'd have thought patients would have been happy going around jabbing themselves for weight loss?
For weight loss, everybody.
I remember when people started talking about that, saying people saying patients will never inject themselves like that. They can't get enough of the stuff. I think people will do what's easy and will be less inconvenient to them.
Yeah, no, I think really well. I mean, look, again, we're going to start in this high-risk population. As Neha said, this is really where there's the urgency to treat and from a practical perspective how we have to do an outcome study. Over time, it would be wonderful if this drug could be used in earlier lines of therapy. Hopefully, the data will support that. I was actually meeting with patient advocates in the cardiovascular field this morning. One of their big points was, I think you said this, patients don't like to be reminded that they're ill every day by having to take pills. That's really not a nice feeling. This may be a way for patients to not have to remember that and be reminded of it on a daily basis.
When you're talking about prevention, many of them are not ill. I mean, that's the point.
Yeah, that's not the point. Yeah.
We're trying to maintain health. It feels alien to them that you should say you're healthy and we want to keep you that way, but you've got to take tablets.
Right. Yeah, it's like a vitamin at that point.
Maybe a slightly built question on top of the one that was just asked. When we talk about the profile that Simon had to describe, what do we think that total addressable patient population could potentially be? Given the refinement in the phase III population, does zilebesiran still represent a significant opportunity for Alnylam Pharmaceuticals within their pipeline?
That's great. Maybe, Simon, you can speak just about what we understand as the addressable population. Maybe Manu might have something to add as well from the Roche perspective.
Yeah, I mean, I think we've had others make comments about this. I shared a slide. $62 million was on there. Those are the estimated number of patients that have uncontrolled hypertension and high cardiovascular risk. Given the refinements, the use of a diuretic in the inclusion criteria, many of these patients are already on a diuretic. It's a first-line therapy. We saw the AHA/ACC guidelines recently come out for hypertension. They were speaking to diuretics. They were talking about earlier prevention for patients with risk factors for hypertension. I think the opportunity for us has not changed. Perhaps Neha, if you want to give some more flavor to how you see it as well.
My god, there's so many patients. It's like everyone. I can't imagine that the issue is not, are there enough patients for this to be useful? The issue will be, if this outcomes trial is positive, the issue will be, how will we get this therapy to everybody who needs it? Yeah, I don't see a concern.
Manu, did you have anything to add?
No, I can't stop the answer from Neha. I mean, I think that's exactly right. Everything that you guys have said about going into high risk first, all going to make sense. Comments are all.
Thank you, Manu.
Great. For those of us here at ESC, we saw Dr. Williams present the BAX data earlier today. There's a question about whether we could give a sense on how CARDIA 3 compares to the phase III result from BAX and resistant hypertension. They had a median of three background antihypertensive and most on RAS blockade and showed pretty impressive placebo-adjusted blood pressure improvements. Just wondering how zilebesiran would compare.
Yeah, really important question. I think people are seeing the results of two large studies on antihypertensive agents that read out in the same hotline session. We have the two presenters here. While we can't do cross-study comparisons, we'll do a little bit of qualifications. Bryan, you want to start and then Neha?
Yeah, I mean, look, I don't usually cross-compare studies because they're done for different reasons, and they include different types of patients. Although in this case, you know, we have probably got high-risk patients and background diuretics. The interesting thing about the BAX study, when we designed it, I wanted everybody to be on a diuretic, even though we were giving a diuretic as well, because actually, aldosterone synthase inhibition is effectively a natriuretic agent. We were going for sort of bumper diuretic because I had long believed that once you get into these resistant cases, there's a lot of resistance to get salt off, and this is a good mechanism to do it. We ended up with 90% of people on a diuretic. The thing I would say is that absolutely, the strategy presented is right.
You have to do that for this population, and actually, the study you mentioned shows that you can do it because we did this globally. I remember going to Bangkok or India and people saying to me, nobody takes diuretics here. I said, they will have to now if they want to get their blood pressure controlled. If you explain the rationale, you can get very high rates of uptake. I'm very confident the study will be delivered. We gave that drug, Baxdrostat, on top of RAS blockade, and you could imagine a scenario going forward where, if you need a diuretic, that could be used in combination potentially with zilebesiran as a diuretic combination as part of treatment going forward. I think it's exciting that we've got new drugs being developed in hypertension.
I can see many of these drugs being used in combination, and they all bring something different to the table. They're all necessary mechanisms to try and get the most difficult patients controlled.
Fantastic. Neha, anything you wanted to add?
Yeah, maybe just a couple of points. I think it really is, you know, the trials are presented one right after another. I think it really is important to remember that CARDIA 3 was a phase II trial, not a phase III trial. Along with that comes a lot of differences. I think the other thing from my perspective as a clinician, we have had, and Bryan, you've spoken so well about this, we have had a complete dearth of innovation in this space for decades. Forget the fact that it is the single greatest contributor to cardiovascular disease and death worldwide. Yet nothing was done new in the space for decades. Now we have this kind of explosion of excitement. This is only a good thing. This is only the right thing for patients. It is only a good thing to have more options for our patients.
I think the innovation that we're seeing with zilebesiran is so exciting because it is a totally new mechanism of action. It is a totally different way to deliver drug. It's a totally different way to think about prevention. Regardless, having more options is a good thing, not a bad thing.
Well said.
We have one final question. I know we've just gotten started, but people are curious on enrollment projections and timelines. There is specifically a question about whether we're planning to include the reverse year in the Phase 3. Do we still think launching 2030 is feasible?
Yeah, so a couple of questions there. Look, we're just getting kicked off, as Simon highlighted. Obviously, there's real urgency for us to enroll this study with the right patients and do that. We're working with our colleagues at Roche, colleagues at DCRI, and our CRO partners to really get this study up. There's a lot of enthusiasm. We met with the investigators and the national coordinators at this meeting. There's a lot of enthusiasm, and we're all going to be working as hard as we can to get this enrolled. We haven't projected specific timelines. We still anticipate that around 2030 is when we'll get top-line results from this study. We'll give updates at the appropriate time. Simon mentioned that we do have a reverse year program. I think what the remarkable thing about this product is we've actually now dosed almost 1,000 patients with this drug.
I will say, before we put it into the clinic, there were a lot of questions about what might be the impact of lowering blood pressure for six months at a time. What's been remarkable is whether as a monotherapy or in combination over almost 1,000 patients, the incidence of symptomatic hypotension has been negligible. It's really quite remarkable. We're really delighted by that. There are many ways that people can actually have their, if they do experience low blood pressure in an emergency situation, it can be managed. That works very effectively on this drug. We do, as Simon said, have the capability to develop a reverse year. We are developing in parallel, and we'll see what the need is. We don't expect there to be any substantive need for something like that. We want to be cautious, and we're doing that in parallel. We'll keep you posted.
We're very, very excited about this program.
That's what we have time for. Back to you just to thank everyone and wrap us up.
All right. Thank you to colleagues who made it here to beautiful Madrid. Thanks to all of you who joined in on the webcast. Very heartfelt thanks to Neha, Bryan, and Simon for joining up here and Manu for joining on the Zoom. I hope you all sense that there's really something very, very exciting here in terms of an entirely novel way to treat such a serious and intractable problem. We just couldn't be more delighted about the opportunity to really shift the entire curve and be a paradigm-shifting therapy for hypertension and cardiovascular disease. Thanks for joining us. We'll keep you updated in the future. Enjoy the rest of your weekend.