Good evening, everyone. I'm Christine Lindenboom. I'm the head of Investor Relations and Corporate Communications at Alnylam. We're very pleased to welcome those who are joining us here in person at ACC, as well as those who are on the webcast, to talk about some exciting data that we presented earlier this morning from the KARDIA-2 study with zilebesiran. The press release is available on our website, as well as slides from the presentation in the Events section , as they typically are, so I'd encourage you to go take a look at those. During the course of our presentation this evening, we will have Pushkal Garg, our chief medical officer, give some introductory remarks and general context. Dr. Akshay Desai is joining us here from Brigham and Women's Hospital, and we'll go through the KARDIA-2 results.
Then Pushkal will wrap us up with some summary and last, next steps before we get into the Q&A session. During the Q&A, Simon Fox, the program leader for zilebesiran, will join us for the panel, and Weinong Guo from our clinical development organization is here for questions as well. If you do have a question, please submit it in the portal. We'll try to balance the questions between the room and the webcast, to make sure we could get to all of them. And I know it'll be incredibly tempting to ask questions beyond zilebesiran, so I would ask for the first wave of questions that we focus on, the zilebesiran data that was shared earlier today. And then if we have additional time, we'll try to get to any additional questions.
Before we get started, I just have to remind you that our presentation may contain forward-looking statements. Please take a look at this and take a look at our website if you have any additional questions. With that, I'll invite Pushkal up to get us started.
Thanks, Christine. Hello, everybody. Thanks for joining us. And what I want to do is just give a couple of introductory remarks just to put the zilebesiran program in a little bit of context. I think, you know, I think everyone here hopefully is well aware that uncontrolled hypertension is really a global health crisis. We have 220 million people with primary hypertension in the seven major markets. It's the leading addressable cause of cardiovascular morbidity and mortality around the world. Up to 80% of patients have uncontrolled disease. There was some data shown on that earlier today, in terms of poor control. And beyond people not taking their medicines, we have other things: variability in blood pressure, poor nighttime dipping, etc. And all of those, along with adherence, contribute to higher cardiovascular risk.
What we're trying to do with zilebesiran is actually tackle all of those problems really simultaneously with one agent. We're trying to provide an agent that can provide tonic control of blood pressure. That is, bring blood pressure down and maintain it, overcoming variability for an extended period of time. So addressing both the quantity and the quality of blood pressure control. And through that, we think we have a real chance to improve cardiovascular outcomes for patients with cardiovascular disease or at high risk for cardiovascular disease. So zilebesiran is a GalNAc-conjugated siRNA directed towards the liver. It targets angiotensinogen, which is very high up in the RAAS, the renin-angiotensin-aldosterone cascade. And by doing so, we think that it can actually provide 24-hour tonic blood pressure control for an extended period of time.
And that was really most robustly shown in the KARDIA-1 Phase 2 study, that was published in JAMA, very recently, where a single dose of zilebesiran was shown to have good blood pressure lowering out to 6 months. We saw upwards of 16-18 millimeters of systolic blood pressure lowering with a single dose out to 6 months. And you can see on the right the curve of 24-hour blood pressures, and you can see that constant tonic control that's extending over the entire 24-hour period. And what you have to imagine is if you did have people on ambulatory blood pressure monitoring every day for 180 days in a row, you would see that same profile of blood pressure lowering 24 hours a day for 6 months at a time. So that's what we're really excited about.
We're also excited about the safety profile, which showed that this drug was well tolerated. It did have low incidence of injection-site reactions, hyperkalemia, and hypotension, but were, again, well tolerated. And so it was on the basis of that that we decided to kick off the KARDIA-2 study. And I'm really excited to have Dr. Akshay Desai, who's the director of the Cardiomyopathy and Heart Failure Program, and a professor of medicine at the Brigham and Women's Hospital, to walk you through that study and the results.
Well, thanks very much, Pushkal. It's a pleasure to be here to review these results from KARDIA-2. The study designed for KARDIA-2 was a Phase 2 prospective randomized placebo-controlled trial that was double-blind, in patients with add-on therapy with zilebesiran in patients with uncontrolled hypertension. The population recruited was an adult population with either untreated hypertension defined as an office blood pressure between 155-180 millimeters of mercury, or treated hypertension on 1-2 agents with a seated blood pressure of between 145-180 millimeters of mercury. Patients meeting those criteria were randomized in 4 to 7 to 10 fashion to open-label therapy with one of three paradigmatic antihypertensive agents: one indapamide 2.5 mg daily, a thiazide diuretic; the second amlodipine 5 mg daily, a calcium channel blocker; and the third olmesartan 40 mg daily, an angiotensin receptor blocker, a potent one.
The patients who had renal dysfunction or proteinuria were preferentially allocated to the olmesartan arm, and the differential randomization was arranged to secure more than 80% power to detect changes of 8 mmHg from baseline in the indapamide arm, 6 mmHg in the amlodipine arm, and 5 mmHg in the olmesartan arm. At the end of the open-label run-in period, those patients who were still hypertensive, defined as a blood pressure between 130-160 mmHg, and who also had demonstrated 80% adherence to the protocol-specified background therapy, were again randomized to single-dose zilebesiran 600 mg or matching placebo, with randomization stratified by race, baseline blood pressure, and screening eGFR. Patients were then followed for a 6-month interval. At 3 months, the primary endpoint, which was the change from baseline in 24-hour mean ambulatory systolic blood pressure, was measured.
After 3 months, rescue medications were encouraged by the protocol to meet guideline-recommended protocol targets in both arms. And then we measured again, the change from baseline, to month 6 in 24-hour mean ambulatory blood pressure and office blood pressure as a time-averaged measure. There was also an additional secondary endpoint of the proportion of patients achieving a blood pressure response criterion that was predefined in the protocol, without rescue medication. If we move forward to the baseline demographics, you can see that the population recruited in KARDIA-2 was, on average, had an age of 59 years, was 42% women, was about 27% African American, roughly 10% of the patients had an eGFR less than 60, 1 in 5 had diabetes, and about 20% of patients had non-treatment-naive hypertension and entered the trial. The balance had been treated by at least one agent.
Patients allocated to zilebesiran experienced a rapid and sustained reductions in serum angiotensinogen levels that peaked at week 2 and were sustained at greater than 95% through month 6. Patients assigned to the placebo group experienced no changes in angiotensinogen levels over time. In parallel with those reductions in serum angiotensinogen levels, we saw incremental reductions in zilebesiran-assigned patients in blood pressure compared with those assigned to placebo. Here is the data for the primary endpoint of change from baseline to month 3 in 24-hour mean ambulatory systolic blood pressure. As you can see, the least squares mean difference in the change from baseline in that blood pressure measurement was 12 millimeters of mercury in the indapamide arm, 10 millimeters of mercury in the amlodipine arm, and 4 millimeters of mercury in the olmesartan arm.
Now, these changes in mean ambulatory systolic blood pressure were mirrored in the changes in office blood pressure from baseline, but the changes were amplified when looking at office blood pressure such that the change in the indapamide arm from baseline between groups was 19 millimeters of mercury, 10 millimeters of mercury in the amlodipine arm, and 7 millimeters of mercury in the olmesartan arm. These data reflect the actual totality of blood pressure reduction from the entry into the run-in period to the month 3 visit in office blood pressure to give you a sense of the aggregate effect of combination therapy with zilebesiran compared to placebo.
You can see that in the indapamide arm, the reduction in the placebo was 14 millimeters of mercury from baseline, whereas in the combination arm with indapamide and zilebesiran, the reduction was almost 32 millimeters of mercury. For the amlodipine plus zilebesiran arm, 26 millimeters of mercury. And for the olmesartan plus zilebesiran arm, nearly 22 millimeters of mercury. Interestingly, across all three background therapies, the reduction was roughly the same of 14 millimeters of mercury from baseline in the placebo groups, despite really what is a very potent dose of olmesartan at 40 milligrams once daily. These data reflect the longitudinal trajectory of blood pressure measurements at each time point during the trial. In office blood pressure, the dashed line is patients assigned to placebo, the solid line, patients assigned to zilebesiran.
We'll focus really on the 3- to 6-month interval here at which time point add-on therapy was encouraged to manage blood pressure to guideline-recommended targets. The percentages reflect the proportion of patients at each time point in each arm who received rescue antihypertensive medications. A few points are notable. One is that 40% of patients in the placebo arm in this indapamide cohort received add-on therapy during that interval compared to only 13% of patients in the zilebesiran arm. Despite add-on therapy, the time-adjusted change from baseline in 24-hour mean ambulatory systolic blood pressure remained significant at the 6-month time point, nearly 11-13 millimeters of mercury, depending on whether you were looking at ambulatory or office blood pressure. The story was very similar in the amlodipine cohort.
Again, a larger proportion of patients allocated to placebo experiencing add-on therapy, nearly 40%-50%, compared to about 20% in the zilebesiran arm, with persistence of the difference between groups in the time-adjusted change from baseline in 24-hour mean ambulatory blood pressure of roughly 8-9 millimeters of mercury, whether you were looking at ambulatory or office pressures. By contrast, in the olmesartan cohort, the changes that were apparent between groups at 3 months were attenuated by month 6 in the context of greater add-on therapy with rescue antihypertensives in both groups of nearly 50% in the amlodipine in the control arm and 40% in the zilebesiran arm. And this meant that by the 6-month mark, the time-adjusted change from baseline in the 24-hour mean ambulatory systolic blood pressure was no longer statistically significant.
However, there was still a persistent difference in office blood pressures averaged over time of nearly 5 millimeters of mercury, at the 6-month time point. Oh. Lost the slide there. Oh, there we are. The secondary response endpoint was, that was the other secondary endpoint that was predefined was the proportion of patients achieving the response criterion that was predefined by protocol. The response criterion was a reduction, to a blood pressure less than 130 millimeters of mercury or more than 20 millimeters of mercury from baseline without the addition of additional antihypertensive agents. And as you can see, the odds of achieving that response criterion at month 6 were dramatically higher in patients assigned to zilebesiran than those assigned to placebo, with an odds ratio of nearly 12 in the indapamide arm, 5 in the amlodipine arm, and 2 in the olmesartan arm.
The safety profile through month 6 for zilebesiran was actually quite favorable, with all there were more adverse events in zilebesiran-assigned patients, but most of these were mild and, there was no imbalance of serious adverse events between group. When examining the adverse events of particular interest given the mechanism of action of this drug, hypotension was more common in zilebesiran-assigned patients, but most events were mild, transient, and recovered without intervention. Elevations in serum potassium were also more common in patients assigned to zilebesiran, with a higher rate of elevation in potassium to a nominal threshold of 5.5 in the zilebesiran-assigned patients. But on repeat measurement, most of these potassium elevations abated, and there was no signal of severe hyperkalemia.
And then in addition, zilebesiran-assigned patients were more likely to experience a greater than 30% decline from baseline in eGFR, compared to those assigned to placebo. And most of these were, again, transient eGFR declines that were not confirmed on repeat measurement and occurred early after zilebesiran exposure. The patients there given the mechanism of action of the drug and the duration of action, there was some concern about postural changes in blood pressure that might obtain. And this is an effort to examine the difference in blood pressure from seated to standing, which was measured routinely at each office visit.
By the definition of a postural drop in blood pressure of more than 20 millimeters of mercury systolic or more than 10 millimeters of mercury diastolic within 1 to 3 minutes of moving from a seated to a standing position, this is the proportion of patients who had at least one visit with orthostatic hypotension. This is not a formal definition of orthostatic, but a definition of a postural change. And you can see at month 3, there was in the indapamide cohort, actually, more patients in the placebo arm experienced the postural drop. In the amlodipine arm, there was no difference between groups. And in the olmesartan arm, the same pattern obtained. So there's no signal, at least at month 3, of an increase in postural hypotension as defined by this measure.
So the summary of KARDIA-2 is that treatment with a single subcutaneous dose of zilebesiran 600 mg was associated with clinically important reductions in 24-hour mean ambulatory and office blood pressure at month three when added to a diuretic, calcium channel blocker, or maximum-dose angiotensin receptor blocker. These placebo-adjusted differences in blood pressure were sustained to month six despite add-on antihypertensive therapy in most patients, but particularly in the indapamide and amlodipine cohorts. Add-on treatment with zilebesiran was associated with increased rates of mild hyperkalemia, hypotension, and eGFR decline more than 30%, but most of these episodes were non-serious, transient, and resolved without intervention. Although the trial was not adequately powered to ensure long-term safety, these results support the potential, we believe, for combining biannual dosing of zilebesiran with standard-of-care antihypertensives to achieve additive blood pressure reductions.
Moving forward, the Phase 2 KARDIA-3 study, which has already been initiated, will evaluate patients with resistant hypertension uncontrolled by 2-4 standard-of-care antihypertensives who have high cardiovascular risk or advanced chronic kidney disease, expanding the profile for the safety of this drug in clinical practice. So with that, I'll close and thank the investigators and the study staff and collaborators for their work in the KARDIA-2 study and hand it back to Dr. Garg.
Thanks, Akshay. Thank you, Akshay. We're very excited about the KARDIA-2 results. We'll be happy to take some questions in a few minutes. Dr. Desai, in particular, would be happy to address comments around the study. What I did want to do is just talk to you a little bit about next steps for the program.
So I think we've shared this before, but our intent with this molecule is really to bring this forward as an agent that can provide tonic blood pressure control, which, as I said earlier, we really believe, has the potential to reframe the way we think about cardiovascular disease and reduce cardiovascular morbidity and mortality. And so to that extent, we are now moving into the KARDIA-3 study, which I'll describe in a moment, which is really looking at the drug on top of two or more agents in patients who are at higher cardiovascular risk. And then our plan after that is to move into a cardiovascular outcome study where we can actually demonstrate the benefits of tonic blood pressure control in patients at high CV risk in terms of preventing further cardiovascular morbidity and mortality through a MACE type of endpoint.
So this is the, sort of study design, the schematic for the KARDIA-3 study. You can see that there are two cohorts of patients, divided by their entry GFR. But this is a group of patients who are at high CV risk, based on either preexisting cardiovascular disease or high risk. They have office blood pressures over 140 and less than 170, and they have to be on two or more antihypertensive agents. They are then randomized based on their entry GFR; if they have GFRs over 45, they're randomized to placebo, 300 mg or 600 mg every 6 months. And then for patients who have lower GFRs between 30-44, we're exploring those same two doses, but we also are exploring a lower dose of 150 mg. And it's a 6-month study.
The primary endpoint is the change in blood pressure in month three, in office blood pressure, but we'll also be looking at ambulatory blood pressure, as well as some other parameters. That study's kicked off. We're very excited about it. This, as I said, will be gating for the cardiovascular outcome study. In summary, I think we've touched on these points, but it's just a reminder, uncontrolled hypertension represents the leading preventable risk factor for cardiovascular disease. We're excited to be working with our colleagues at Roche to improve outcomes for these patients. I think with that, I'll turn. We can turn to Q&A. We're gonna. I think do we need to get set up? So give us just one second. We're just gonna set up for the Q&A.
TD Cowen. Dr.
Desai, can you talk about, given the olmesartan data combination data, can you talk about the use case for those hypertension patients that are on background RAAS inhibitors, you know, whether it's intolerance, whether it's noncompliance? And then the follow-up question, given the design of KARDIA-3, why was the office assessment so different than 24-hour ambulatory? Is there any clinical meaningfulness for the difference that was sort of so consistently seen through all the data? Thank you.
Yeah. So taking your questions in order, I think that from the standpoint of the, I was focused on the second question. The first question was around. Oh, the use case. The use case, right? So.
Given the olmesartan.
So, so I think that, you know, there are a few different ways to conceptualize the use case in that circumstance.
I think that the patient who is nonadherent, I think, becomes a straightforward use case because the opportunity here, I think, is plain for a drug with a very prolonged duration of action, in a patient who is missing doses of medication. And as we heard a little bit today in the meeting, there is a large fraction of patients that is prescribed oral medication who simply don't take all the doses. And then a number as high as maybe 17% of patients who take none of the doses of prescribed medication. And so I think securing a safe amount, the requisite amount of blood pressure lowering with zilebesiran would be one strategy for overcoming the adherence barriers. For tolerability, I think there are some questions about exactly how this would work 'cause there is some overlap in the tolerability profile with ARB.
So if there was intolerance, for example, for hyperkalemia or worsening renal function, I think we would be loath to trial a drug like zilebesiran in clinical practice. But I think if the tolerability issue was more an issue with taking the pills or other things, then this would be another opportunity. I think the other question that comes up is the sequencing, right? Does this become primary therapy or add-on therapy? The trial was designed against a maximal dose of a potent ARB with the concept of really demonstrating the safety of combination therapy. And I think that there is reassuring data in KARDIA-2 about the tolerability of the combination without an excess risk of hyperkalemia or worsening renal function.
But in clinical practice, we often don't combine a dual RAAS antagonist because of the legacy of that combination. And I think the real question here is if you have a drug that provides more complete angiotensin suppression, then perhaps it becomes more reasonable to start that up front, and then deploy the other meds in combination. And so I can think one can imagine a paradigm in which this becomes foundational therapy for hypertension and then other drugs are layered on top to minimize the total pill burden for the patient. But that would be the way I might think about it. I think with regard to the question around, what was the second? Was it the office versus ambulatory blood pressure?
I think ambulatory blood pressure has historically been used in a lot of hypertension trials largely because it has been thought of as a favorable path through regulatory approval, but I think also because in the hypertension community, there has been some concern about office blood pressures because they're often confounded by measurement error but also just the circumstances of being in the office and the white coat phenomenon. And so I think that there's been some belief that the ambulatory pressures are more real reflection of blood pressures in the ambient environment. I think that the challenge is that most of our clinical decisions are made based on blood pressures we measure in the office.
So in some sense, from a clinical practice perspective, the office blood pressures are almost more important because I don't often and most clinicians in practice don't routinely order ambulatory blood pressure monitoring. And frankly, access is cumbersome and difficult for some patients. So in some ways, for me, the more relevant measures are the measures that happen in the office, or perhaps those that are taken at home. We do have home blood pressures in these trials. We haven't unpacked that data just yet.
Myles Minter from William Blair. I had a question on, basically the olmesartan group and exactly why in the placebo arm at 6 months, like, the rescue medication use is clearly the highest among the cohorts here, but why that had such a drastic reduction in the placebo arm there whereas the prior two arms didn't.
Is that just an indication of, like, a more severe patient population? Is it a different rescue medication paradigm that those patients are going on? So that's the first one. And then the second one is what happens if you put the 64 patients' worth of data back in the olmesartan group that you censored? And does that change the way we perceive that data? 'Cause I think you censored it if patients were using rescue medication or they came off within two weeks or something. I saw that on the site, and the numbers did not up, so.
So, with regard to the first piece, I think that the important thing to remember is that the drugs that we're looking at in that arm of the trial act in the same pathway.
So we're looking at a potent angiotensin receptor blocker that is dosed at its maximum, which provides fairly effective suppression of renin-angiotensin system in patients who take the medication. And then we're layering on a comparison with a more upstream suppression of the same system by zilebesiran. And so I think you'll notice even in the power calculations, the expected blood pressure reduction in that arm was notably less, and we needed more patients in that arm to achieve it because the thought was that by giving two drugs acting in the same pathway, it would be harder to show a difference, particularly given we went up against a bully in that class.
I think that the expected finding of the lesser difference was not actually the surprise. The surprise was really that we had an incremental 4-mm reduction, and it's almost a 7 in the office blood pressure. So that was pretty impressive. I think beyond that, the add-on therapy you make the point that both arms had more add-on therapy, but I think it stands to reason that if you started high and got a lesser blood pressure reduction at month 3, then it would be that you would need more blood pressure reduction in follow-up to reach guideline-recommended targets. So I think part of this is an artifact of the lesser differential in blood pressure that was seen on top of olmesartan that left more to be treated, if you will.
With regard to the censoring question, I'll, you know, I believe that the data that we're showing you reflects all of the patients with blood pressure measurements available at each time point. And then the time-averaged measure is really an area under the curve assessment, divided by the time interval over which the measurements happen. But I'll let Dr. Guo answer that one. Yeah. I'm gonna call up Weinong. You may not come up. Okay. Just here. I'll call up Weinong Guo, who heads up our cardiometabolic franchise in clinical research. You wanna come over here.
Okay. So, let me clarify. So in the primary endpoint slides analysis, that is indeed done with the censored, right? Those patients received the rescue meds. However, when you look at the time-course longitudinal data, that is reflected to all patients. That is all patient data, and there's no censor.
That is actual, actual data. Yeah. Thank you.
Thanks, Weinong. I was just thinking a quick one: how are you controlling for olmesartan usage in KARDIA-3?
So KARDIA-3, we're allowing actually it's much more of a usual care type of paradigm where patients who meet the entry criteria have to be on two or more medications. We expect the large majority, based on what we understand in terms of just general practice and use, are likely to be on a diuretic or calcium channel blocker plus potentially, an ACE or an ARB. It's unlikely that a lot of that is gonna be at the highest dose of olmesartan just given what the use is. We, again, as Dr. Desai was mentioning, we really wanted to test in the most stringent conditions, what was, one, the efficacy add-on, but particularly what was the safety profile of combining zilebesiran.
So we put it through the most stringent test we could.
We've got a number of questions that have come in through the webcast, so I wanna make sure to get to some of them here. Maybe just as a follow-on to the questions we've been getting about the combination with olmesartan, can you comment at all on the degree to which the weaker effect size in the ARB cohort is a risk to either approvability or the market opportunity with zilebesiran?
Yeah. Maybe I can start touching on that. You know, I think, first of all, I think it's important to recognize that, you know, blood pressure, at least from a regulatory perspective, is a validated surrogate, because of its such a tight correlation across multiple classes of agents with cardiovascular outcomes. And maybe just as a guide, as Dr.
Desai presented, you know, the add-on effect here is about 4-7 millimeters. I would just point out that, you know, a recently approved drug actually had a 3.8-millimeter blood pressure systolic blood pressure benefit and a black box warning, and got approved. And so I think that should highlight in particular, how important blood pressure reduction is and even, you know, what someone might consider a modest change, can be considered clinically important, from a regulatory perspective. Again, our focus here, though, I, I would just wanna bring back, is not about the add-on effect on top of one particular agent. It's really about looking at zilebesiran added on to a usual care sta, you know, panoply of medicines that are used and actually ultimately reducing blood pressure. And you saw on a on the cumulative slide that Dr.
Desai presented that there was probably 20-30 mm Hg of overall blood pressure effect in that whole regimen, and then showing a benefit on cardiovascular outcomes. So I don't know, Akshay, if you wanna say anything more.
Yeah. No, no, no. I think the only thing I would add is just that I think it's probably worth highlighting that most of the patients that we see in clinical practice, who have hypertension are managed with multiple medications, right? It's 1-2 would be on the milder moderate end of hypertension, but many of our patients with more longstanding hypertension are on 3 or even 4 medications to manage their hypertension. And so I think the challenge, in hypertension management is the sort of accumulated polypharmacy of drugs and multiple daily drug dosing and overlapping side effects.
So I do think that there is opportunity here to add to deprescribe in the context of a drug that provides more important, more sustained background or tonic control. And I think the other feature here that shouldn't be lost is that we shouldn't treat this class, this agent really as simply another more potent method of inhibiting the renin-angiotensin system. I think we tried to highlight that there are other features of this approach beyond adherence that might be unique. One is the potential for consistent 24-hour control of blood pressure. We know that nocturnal blood pressure is a potent predictor of risk, and many patients even have treated daytime blood pressure, have persistent nighttime hypertension. And so an agent that can more effectively suppress nighttime blood pressure may be quite useful in clinical practice in reducing long-term cardiovascular risk.
And I think beyond that, we know that visit-to-visit variability or volatility in blood pressure, across visits has associated with quite long-term risk. And so if we can reduce the standard deviation of that variation by an agent that provides more consistent blood pressure control, we might also be able to mitigate long-term cardiovascular risk. And so I would say that even in the worst-case scenario that you thought that the data was not as compelling, in relation to the olmesartan group, I think I would say that there's still a potential advantage to this approach over even potent dose of olmesartan, in patients. But, that's really one of the goals of really the next phase of studies.
Tommy Goldman Sachs.
Continuing on that point about alleviating the pill burden here, what, how are you thinking about the best ways to potentially get patients to taper off their current therapies and maybe transfer to a situation where it's zilebesiran plus one other treatment, for instance? And what are you hearing about fear of injections? And I believe that this was brought up a little bit in the meeting, but if we could also get clarity on whether zilebesiran could actually be administered at home. Thank you.
Yeah. So I'll take the first two, and then I'll let I'll get the clarity.
But I will say that I think that there was a time period where we had a lot of anxiety about use of subcutaneous medications for daily administration because, you know, there is a needle fear that many patients have, and there is an activation barrier to getting a patient to move from an oral to an injectable medication. But I think we've begun to normalize injectable therapies in clinical practice. I think the growth of the obesity therapies has really facilitated that, because there's such interest in access to those medications that I think the willingness to trial a regularly administered subcutaneous therapeutic is there.
I think that here we're talking about a medication that could be administered on a q6-month basis, and I think the willingness to take two subcutaneous injections a year might be a lot higher than that to take, say, every 14 days, as you might with evolocumab or, or, or alirocumab in practice. And so I think the activation barrier there maybe is more imagined than real. With regard to, I'm sorry. I lose these questions 'cause I keep talking. But, the, the first question about the, the way in which you would think about deprescribing, I think that's an important consideration.
I don't know that I've thought through exactly how that would happen because 'cause I think what would likely happen, though, is that as you initiate therapy, on the background of existing therapy, one would begin to monitor blood pressure and then begin to peel back medicines as blood pressure declined. I think that it would be the most ready use case would be if a patient was already on a RAAS-active therapy. I think one could do what was done in KARDIA-2, which is to simply stop the therapy and initiate zilebesiran, and then track blood pressures over time. But I think a lot of this would largely depend on some serial monitoring of blood pressure and the response to zilebesiran, which obviously might vary from patient to patient.
Yeah.
Then, Simon, do you wanna just, Simon, he heads up our zilebesiran program within Alnylam. Do you wanna just speak about how we're thinking about administration at home versus the office?
Yeah. Sure. So, right now, I guess, very much like in inclisiran, we're thinking of zilebesiran to be a HCP-administered treatment. I do wanna add a little bit to the fear of injections as well. You know, we spend a lot of time speaking to investigators, and we travel around speaking to sites as well. And, you know, right now in Phase 2 , we have over 600 patients dosed on zilebesiran.
The feedback from investigators about the patients that are involved in these trials, and we thank them for that, is that there is a real positivity about zilebesiran knowing that the fact you can take it biannually. And I think that's one of the biggest things. These patients that are taking multiple therapies for their hypertension are very positive about that.
Thanks, Simon. Is the concept behind HCP's office administration that, you know, if one wants to secure the adherence issue, then leaving patients to self-administer at home leaves them at risk for the same nonadherence? So I think that might be a piece of it, right?
Yes. Yep. Yeah. Absolutely. And when, say, even beyond that, it's HCP administered. So it can be administered by a healthcare professional like a visiting nurse or someone at home.
And that's what we've done in certain other programs. But again, we have some time to explore that. But, you know, when something's given as infrequently as every six months, I think it's also important it's hard sometimes to train patients to sort of do that, and it sort of becomes sometimes easier to sort of facilitate that through either an office visit or a home visitation. But again, we've got some time also to explore that in the future and can evolve that.
Let's take another from the webcast. This is in regards to safety. How does the safety profile of zilebesiran shown in the study stack up versus the historical data seen with other dual RAAS blockade agents? How concerning would you say the risk of hypotension is, particularly if this drug has a roughly six-month duration of actio
n? Yeah. So both important questions.
I think, with regard to the safety in comparison with other dual RAAS agents, I think this, the preliminary data here from KARDIA-2 is quite reassuring. If you look at the rates of hyperkalemia and worsening renal function, which were the principal signals of concern with dual RAAS inhibition with aliskiren and ARB, for example, or ACE inhibitors and ARBs in combination, the rates of hyperkalemia in the zilebesiran and olmesartan arm in KARDIA-2 were not dissimilar from those in the zilebesiran plus amlodipine arm. So we take that as evidence that the dual combination in this case was relatively well tolerated, from the standpoint of potassium. And the same is true with regard to changes in renal function.
So I think with regard to the signals that we'd be most sensitive to, that dual RAAS signal, it does look like the drug appears to be well tolerated. I think in fairness, one, these are 6-month, this is a 6-month exposure. One needs longer duration exposure to understand that more completely. And so I think further data from other trials will be important in that regard. With regard to the second part of that question, which really has to do with the question of hypotension, I think even with any long-acting antihypertensive, that is a theoretical concern, and it is certainly the concern that we went into the trial with.
That said, the signal of the accumulative experience across the Phase 1 data, KARDIA-1 and KARDIA-2, suggests that at least in the populations with mild to moderate hypertension that have been studied, or here patients with uncontrolled hypertension despite 1-2 medications, there does not appear to be a signal of significant hypotension. Hypotension happened relatively infrequently over the course of the trial, although it did happen more in zilebesiran-assigned patients. And it was generally transient and did not require intervention. So I think that so far, the signal appears to be mild. The other feature, I guess, of hypotension is what happens if it occurs. I think that we have some data from the Phase 1 experience that suggests that patients who, that the hypotensive effects of zilebesiran can be antagonized by salt loading.
There are reasons to believe that volume resuscitation would be effective. And in the preclinical data, we know that other pressor agents that are active, for example, sympathomimetics, angiotensin II infusions, all these should still be quite effective in rescuing blood pressure. So I think that there is some security that hypotension doesn't happen as frequently as we might have feared. And it should be manageable, should it happen. We'll see what happens in higher-risk populations as we move the program forward to KARDIA-3, and other trials.
Can I ask a quick follow-up on that? Yeah. Let's just get the mic. Let's get you the mic grid too. Just a very quick follow-up on that. Pushkal, can you talk about the status of Reversir 'cause that was brought up during the discussion during the discussants.
and also, another thing that was brought up was the potential to track organ damage even within KARDIA-3, even before you got to the outcome study. Can you talk to some of the potential further downstream secondary endpoints in KARDIA-3?
Yeah. So let me start on the Reversir . So, you know, we do have the technology within Alnylam to actually develop a molecule that can reverse, and in animal models, we know that within a matter of days, we can actually reverse the effects of an siRNA and specifically, zilebesiran. So that is a molecule that's currently in preclinical development. We're formulating and finalizing our plans in terms of the clinical development plan. And we'll have updates, you know, very shortly in terms of what we're doing in terms of that program. But that is something that, again, as, as Dr.
Desai mentioned, we think there's a number we're very reassured by what we're seeing so far in terms of the safety profile, from a hypotension perspective. But certainly, that is a risk with any blood pressure-lowering agent. And so we think there's a number of interventions, and we think the Reversir here will be something that we'll hopefully have available as well for patients, if that sort of as a safety net, if necessary.
So you haven't reached that go-no-go point on Reversir, whether you'll even need it or not to go?
No, no. We intend to bring it forward into development. It's absolutely moving forward into development.
Got it. Okay. And then, organ damage?
Yeah. So, I think at a high level again, this is gonna be a relatively short study, you know, from a—and our intent is to actually use this study primarily to establish the dose for the cardiovascular outcome study, which will be, you know, the definitive study. So it's not gonna be a very long study. It doesn't have a lot of additional endpoints, etc., and assessments. We're trying to move, you know, rapidly through this study to establish the dose regimen and help design and power the cardiovascular outcome study. That said, there may be some assessments, for example, in terms of renal dysfunction, proteinuria, etc., as an indicator of end-organ damage that we can measure in KARDIA-3.
And then right now, as you talk to Roche, are there any plans to initiate a corresponding study to VICTORION-INITIATE that we saw at the beginning of the conference, the one where you use Leqvio early on and show sort of real-world polypharmacy management of lipids, so like the hypertension equivalent of that?
Yeah. So like, look, right now, our plans right now are very much I mean, look, we've established certainly that there is a monotherapy effect from a blood pressure perspective, right? We established that in KARDIA-1 quite robustly. As we think, again, about where this medicine we believe between Alnylam and Roche is most likely to sort of have that immediate impact, it's in these patients who are at high cardiovascular risk, right, either because they've had an event. There's a real urgency to treat in that patient, right?
If you have a patient who's had an MI, had a stroke, has elevated blood pressure despite being on multiple medicines, or is a very high risk because they're diabetic or have other, other causes, we think there's a real urgency to treat. And again, our goal is less about treating the number in terms of blood pressure. It's really about trying to reduce cardiovascular events. So that's our initial focus. As Akshay mentioned, I think, you know, there's a lot of reasons to think that this might be something that might be used in earlier lines of therapy. But that's not our immediate focus right now.
Back to the webcast. Sticking with future plans, some questions on KARDIA-3. Can you talk a little bit about the key differences between the patient populations in KARDIA-2 and KARDIA-3? And then is there any meaningful read-through from K2 to K3?
And also, have you looked at or are you planning to look at data from patients in KARDIA-2 who meet the entry criteria for KARDIA-3?
Okay. So a number of questions there. I think what we're seeing, I think really what KARDIA-2 showed us is that zilebesiran can be effectively added on to one, a single agent. And really, the difference between KARDIA-2 and KARDIA-3 is that we'll now be looking at it on a combination of background therapies on two or more medications. And second, we're gonna be going, and we've kind of had this progression going from KARDIA-1, KARDIA-2 to KARDIA-3 to sicker populations of patients. So KARDIA-3 will include more patients with, for example, diabetes or impaired renal function and other risk parameters that we know get to a higher risk, higher cardiovascular risk population.
We'll certainly want to establish sort of the safety profile, the efficacy profile, and the appropriate dose for those, those types of patients. We think those, those three pieces of information will allow us to effectively design the cardiovascular outcome study.
It would be difficult to read through too much from KARDIA-2 to KARDIA-3 because the populations won't overlap all that much because, e.g., here, we're in KARDIA-2, we're really looking at one background medication. And the prevalence of renal dysfunction, which is enriched in KARDIA-3, is actually fairly modest in KARDIA-2. It's about 10% of the population and essentially nobody with an eGFR less than 45. So I think that the, I'm sorry, eGFR less than 30. So I think that the, the overlap is not sufficient to read through too much.
And I think the real question is, Pushkal has said, will really be understanding, not only efficacy but also safety in that population.
Yeah. Just a couple on safety. There was a little bit of a discussion about the timeline of the hypotension, hyperkalemia, the eGFR decreases. So, my question's more about whether the incidents or the, the time course of those, changed at all when patients were not on rescue medication versus in the last three months of the trial where they were allowed to receive rescue medication 'cause I believe the safety data you report is over the entirety of the six months.
So Weinong, do you wanna take that one? Come on up, Weinong.
Yes. Good question. Good questions. And we find is, what Dr. Desai shows you, the laboratory abnormalities of interest mostly happen majority happens in the first three months.
And even with the add-on of the rescue medications, we have found very few of those lab abnormalities. Yeah. Thank you.
Yeah. And I would just add, you know, beyond the happening in the first couple of months, as we showed, as Dr. Desai showed in his presentation, in the majority of the times when we repeated those laboratory assessments within 1 to 2 weeks and again, this is because of the long-acting nature, there's ongoing pharmacology of the drug, they were not reconfirmed, right? So these were somewhat in many in most instances, actually transient changes, that were detected. It's also probably worth mentioning that, you know, the predefined safety threshold here was of 5.5 for potassium.
But many of those, even in clinical practice, particularly those who treat, you know, patients with CKD or those who treat cardiovascular patients are quite comfortable with potassiums that reach the range of around 5.5. So really, the question and or the actionable threshold is probably much higher, around 6 milliequivalents or 6 milliequivalents per liter, for many patients. I think it's useful to set a safety margin that's a little lower than that, not to test it. But I think the number that exceeded six is actually quite small, over the course of the trial. So I think even those cases were often not seen on repeat measurements.
So I do think there's some certainty that in this population at least, that the RAAS signal of hyperkalemia is pretty modest, and consistent with what one would expect based on mechanism of action.
We've got a few more minutes. We've got a lot of questions on the webcast. Here's one about the actual payer perspective. Can you talk about how you think payers would view adding multiple therapies for this patient population and if there's any potential pushback for combo therapy, and also in light of the fact that it's a market largely filled with generics?
Yeah. I mean, maybe I can start, Simon, and then you can add on if you want. Look, I think we certainly recognize that this is a market that has a lot of generic medicines of multiple classes.
I think despite that, unfortunately, as we've talked about extensively, there's a tremendous unmet need. Those medicines aren't fully fulfilling that need. There's a huge and it's based on multiple parameters, not just nonadherence to those medicines but, as Dr. Desai mentioned, variability in blood pressure, lack of nighttime control of blood pressure, etc., visit-to-visit variability. And so our intent here is to bring forward a medicine that we think can really address both the quality and quantity of blood pressure control and actually result in a cardiovascular outcomes benefit. And it's possible that we may see because of the benefits of tonic control, and this has to be tested, you know, an outsized benefit in terms of cardiovascular impacts. And that's something that we'll be testing in the CVOT study.
So at the end of the day, we do know that we will need to show the value of this therapy to patients, to providers, to payers, and to society. And that's our intent. Yeah.
Yeah. And I only have the red light. Strategically, we're looking at the high-risk patient population, that where the unmet need is, those high-value patients. And we wanna reduce risk there. And that's why we're doing a cardiovascular outcomes trial, right? So we have the most robust data set in order to file and also launch for both, you know, regulators, payers, physicians, and patients so, you know, the patients can access the medicine.
But, you know, the other sort of general comment from a clinical perspective on hypertension is that, you know, the failure to control blood pressure in clinical practice is not a failure of the therapies that are available.
It's a failure of the application of those therapies in practice, either by providers or by patients. I think that what we are seeing of late is sort of a renaissance of therapies in hypertension. There's now interest in FDA approval for renal denervation. There is zilebesiran. There are other agents active in the therapy of primary hyperaldosteronism that may be quite relevant in clinical practice. I think for the first time in a long time in cardiovascular medicine, we're seeing resurgence of interest in hypertension as a problem, which we're grateful for, because it's such a huge unattended risk in most of our patients.
And so I think it's very possible that the availability of newer therapies that may address some of the previously unattended aspects of hypertension care may force us to renovate our perspective on management of these patients, even in the face of generic options, to better mitigate long-term cardiovascular risk. 'Cause I think much of that the way that lipid therapy has evolved, to really think about patient risk and modification of risk over time, not just LDL targets, I think we may need to think about how we manage patients with hypertension at high risk, and take a different approach.
Anything you can say on what you're thinking about regarding zilebesiran pricing, given many of the treatments are currently generic? And what would need to be demonstrated to secure payer coverage?
Yeah. It's obviously much, much too early to be talking about price at this point.
But certainly, again, we intend to bring forward a medicine that we think will provide value, and we'll price it accordingly.
Okay. And perhaps we have time for one more. There's a question here, about the way the trial on the study design slide, it showed the randomization, and it said the randomization to background medication was 10 to 7 to 4. Can you clarify the reasoning behind that approach?
Yeah. So, this, the KARDIA-2 trial was really three trials in one, zilebesiran versus placebo against three cohorts of background medical therapy. And the expectation of treatment response of zilebesiran on top of the different background therapies was different.
And the study was independently powered in each of the arms to achieve a blood pressure reduction of 8 millimeters of mercury in the indapamide arm, 6 millimeters of mercury in the amlodipine arm, and 4 millimeters of mercury in the olmesartan arm. And so that's how the sample size power calculations for each arm were done. And that's where the differential randomization works out. So, it wasn't a random ratio. It was really the individual components were powered for specific blood pressure reductions.
Next one, we'll just I think we're just about at time. So I think we will thank our speakers and thank everyone here on site as well as all of those on the webcast for attending. Thank you.