Good morning, everyone. I'm Kelly Cronin, Senior Manager of Investor Relations at Alnylam, and I'm pleased to welcome you to the second event of Alnylam's 10th RNAi Roundtable series. Through this series, we aim to bring greater visibility to select near and midterm pipeline programs that we believe will define the next wave of transformative medicines emerging from our RNAi platform here at Alnylam. Today's event is focused on zilebesiran, our investigational RNAi therapeutic for patients with hypertension and high cardiovascular risk, or established cardiovascular disease, which we are advancing together with our partners at Roche. As a reminder, today's discussion will include forward-looking statements. We encourage you to review our most recent SEC filings for a more complete discussion of our risk factors.
During today's event, you'll hear first from Chief Research and Development Officer, Pushkal Garg, who will set the stage with an overview of Alnylam's organic product engine and the unique potential of RNAi therapeutics to transform cardiovascular care. Dr. Akshay Desai of Harvard Medical School and Mass General Brigham will then discuss the persistent burden of hypertension beyond the office setting, followed by Ishir Bhan, who will review clinical evidence supporting the potential for continuous control with zilebesiran. Simon Fox will then close out our prepared remarks with an overview of the integrated execution underway to realize zilebesiran's full potential. Following the prepared remarks, we will open the discussion for a question and answer session with our speakers, joined by Victoria Silva, who leads zilebesiran commercial strategy at Alnylam.
The Q&A will be moderated by Pushkal, and questions may be submitted at any time through the ask a question field within the webcast platform. With that, I'll turn it over to Pushkal. Pushkal?
Thanks, Kelly, and welcome everyone to today's RNAi roundtable focused on zilebesiran, which we believe has the potential to transform the treatment of hypertension by providing continuous control of blood pressure. As many of you know, Alnylam has spent more than two decades pioneering an entirely new class of medicines based on R NA interference. What makes RNAi so remarkable is the combination of attributes you see here. Like a biologic scalpel, we can silence virtually any gene in the genome and intervene upstream of most traditional medicines. It's a catalytic mechanism, enabling highly potent medicines at low doses while remaining highly specific and reversible. And we can engineer long durations of effect that support very infrequent administration. Taken together, these attributes create an extraordinarily powerful therapeutic profile, and we've already demonstrated what this technology can deliver, translating the science into a growing portfolio of medicines for patients.
We've harnessed this natural phenomenon into a unique and sustainable innovation engine, which we believe will fuel sustained long-term growth. We continue to invest in the power of human genetics with access to data from more than two million lives, helping us identify and validate compelling new targets, advance RNAi delivery to major tissues throughout the body, and optimize our siRNA designs to enable increasingly potent, specific, and durable molecules across a wide range of clinical applications. We pair this innovation engine with a disciplined strategy for selecting the most compelling opportunities to advance to the clinic. Our therapeutic area agnostic approach focuses on diseases with high morbidity and mortality, where we can pursue highly genetically validated targets with a strong biologic rationale.
This integrated approach has enabled us to generate high-quality drug candidates and achieve historical clinical success rates well above industry benchmarks, building a high-value portfolio of programs targeting areas of tremendous unmet need. You can see the result of that strategy here in our industry-leading pipeline of RNAi therapeutics. With more than 25 programs spanning rare specialty and prevalent indications across multiple therapeutic areas, we believe this pipeline underscores the depth of opportunity ahead for Alnylam, and most importantly, our potential to deliver even more transformative medicines to patients. We're entering a period of significant clinical momentum with three pivotal studies underway and four important data readouts expected this year.
That momentum will build meaningfully through 2028 with a growing number of pivotal studies, at least five key data readouts each year, and the potential launch of nucresiran and hereditary ATTR polyneuropathy, assuming positive phase III data and regulatory approval. Cardiovascular disease is one area where the power of RNAi offers the potential to make a major impact on the leading cause of death around the world. With our RNAi-based platform, we've built a diverse portfolio of therapies designed to address major drivers of cardiovascular morbidity and mortality, including obesity, type 2 diabetes, hypercholesterolemia, and hypertension. Zilebesiran is a particularly compelling example of the unique potential of RNAi in cardiovascular disease. Hypertension remains one of the largest and most consequential drivers of cardiovascular risk, yet control remains inadequate for far too many patients.
Together with our partners at Roche, we're exploring whether durable suppression of angiotensinogen can deliver more consistent blood pressure control and ultimately translate into a profound impact on cardiovascular outcomes. The urgency of that work becomes clear when we look at the projected burden of cardiovascular disease. Annual deaths due to cardiovascular disease around the world are projected to rise over 70%, from 20.5 million in 2025 to 35.6 million by 2050. Notably, high systolic blood pressure will remain the leading risk factor, with the CV deaths attributable to hypertension projected to increase from 11 million to nearly 19 million during that period. Despite this enormous and growing burden, hypertension has not seen the same degree of therapeutic innovation as areas such as lipids and obesity. Our aspiration is to bend this curve by investigating whether continuous durable blood pressure control with zilebesiran can reduce cardiovascular risk.
To put the magnitude of this unmet need into clinical context and dive deeper into why we've struggled to effectively manage hypertension in the past, I'll now turn it over to Dr. Akshay Desai.
Thanks very much, Pushkal. In the next 10 minutes, my job is to underscore for you the ongoing threat of hypertension as a global health priority. The burden of hypertension globally has steadily risen since 1990 in the United States and elsewhere, from an estimate of about 440 million prevalent cases in 1990 to more than 875 million cases by 2015, and nearly a billion cases prevalent in modern era. That is defined at a threshold of a blood pressure more than 140 mm of mercury, and we can anticipate that the prevalence would be estimated at the newer reduced thresholds that are recommended by current guidelines. This steady rise in the prevalence of hypertension is related to secular trends and risk factors for the development of hypertension, including normal aging, but also risk factors including obesity, insulin resistance, and diabetes that drive the hypertension epidemic.
Hypertension remains the leading risk factor for cardiovascular disease and associated disability and mortality worldwide, and the leading preventable approach to prevention of cardiovascular disease that we have. 10% of the global healthcare expenditure is estimated to be accounted for by hypertension, and this therefore represents an important target for ongoing attention. We know that hypertension contributes to changes in the vasculature, the heart, and in the kidney that predispose the development of a range of cardiovascular diseases, including ischemic heart disease, stroke, chronic kidney disease, and then a range of other cardiovascular disorders, including heart failure. As this slide shows, the cumulative burden of disability-adjusted life years associated with hypertension is quite substantial. At every blood pressure, the highest burden of disease is contributed by ischemic heart disease, with subsequent contributions by stroke, chronic kidney disease, and other disorders, including heart failure.
About 70% of the disability associated with hypertension and hypertension-related mortality is related to blood pressures that are measured more than 140 mm of mercury. But you can see that a third of the disability-adjusted life years are associated with blood pressures between 110 and 140 mm of mercury, which underscores the need for even more aggressive control of blood pressure to prevent disability and death in clinical practice. It's estimated that nearly $100 billion in global savings could be secured for more aggressive control of blood pressure in clinical practice, and this is really the opportunity for more effective hypertension therapies.
It's well established that blood pressure reduction is an effective way of reducing cardiovascular risk, and this data from a meta-analysis of nearly 123 studies comprising more than 600,000 patients highlights that with each 10 mm reduction in systolic blood pressure, there's about a 20% reduction in major cardiovascular events, a 17% reduction in coronary heart disease, a 27% reduction in stroke, and another 30% reduction in heart failure. These data underscore that with incremental blood pressure reductions, we can expect an incremental reduction in return on cardiovascular risk reduction. That said, we have a lot of effective medical therapies for hypertension, but these are heavily underutilized in clinical practice. When we look at the total burden of hypertension, only 40% of patients are identified as hypertensive and treated in clinical practice. Among those who are treated, only one in five is actually treated to guideline-recommended targets.
This implies that nearly 80% of treated hypertensive patients are still at risk for cardiovascular disease and disability, and there's substantial residual risk that is unattended in the current paradigm. We need a different approach to more aggressive recognition of blood pressure management, and we need more effective therapies for blood pressure control in practice. This problem over time has become even more important because it's recognized now based on data from the SPRINT trial that even more aggressive blood pressure targets are important to prevent cardiovascular disease and disability in clinical practice. The SPRINT trial randomized nearly 9,000 patients with uncontrolled hypertension to treatment with an intensive blood pressure target of less than 120 mm of mercury versus a standard blood pressure target of less than 140 mm of mercury, the prevailing recommendation at the time.
You can see that the trial was terminated early for evidence of overwhelming benefit in the intensive therapy arm at median follow-up of 3.3 years, based on a 25% reduction in the composite outcome of myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death. This effect was also seen in key components of the primary outcome, including overall mortality, which was reduced 27% in the more intensive therapy arm. These data have now driven a change in practice guidelines. The modern ACC/AHA guidelines for blood pressure are outlined on this slide, which highlights that our targets have now been revised to recommend a treatment goal of less than 130 over 80 mm of mercury for all adults. Defining blood pressure more than 130 mm mercury as stage 1 hypertension, and more than 140 mm of mercury, our previous therapeutic target, as stage 2 hypertension.
This new guideline recalibrates our estimates of global prevalence of disease and really reassigns many patients we previously thought were well-controlled with hypertension to an uncontrolled category. After a long lull in the drug development for hypertension, we've now seen an explosion of new therapeutic trials in hypertension and proliferation of new agents for effective management of hypertension since 2019. Most of these therapies are oral agents, some of which are dosed multiple times daily, with only zilebesiran being a parenteral agent that has the opportunity for being dosed once every six months. This long duration of action poses a unique opportunity for hypertension that we'll discuss a little bit later in the market. With this proliferation of therapies, the open question becomes what are the residual barriers to effective control?
If we have so many effective agents for treatment, why is it that blood pressure is not more effectively controlled to the guideline-recommended targets? Well, there are many possible explanations for this. The first is that there is generally poor access to care for many of our patients so that hypertension is underdiagnosed. Amongst those patients, there is also inadequate education and awareness of the importance of blood pressure control. So even when they hear the messages in our clinics about the need to treat hypertension, sometimes it falls on deaf ears. Even when patients are in clinic, we sometimes fail to measure blood pressure at the clinical opportunities that we have it, and therefore we fail to diagnose hypertension appropriately. Even when blood pressure is elevated, many providers fail to act to treat hypertension in clinical practice, and that is the problem of therapeutic inertia.
Once medications are prescribed, providers feel they have done their job, but then many of our patients who are given multiple daily oral medication regimens to take for their hypertension and comorbid medical illnesses struggle with adherence in the setting of polypharmacy and the need for multiple daily dosing of many of the pills, and poor adherence to medications contributes to the burden of uncontrolled hypertension in practice. Finally, a certain proportion of patients, even with effective therapy, remain resistant to antihypertensive treatment, although this is really the minority of patients, estimated to be about 10% of patients with truly resistant hypertension in clinical practice. Examining some of the barriers to hypertension in more detail, this slide focuses on the effects of adherence to antihypertensive therapy and cardiovascular risk.
Amongst young adults in this survey taking antihypertensive medications, about 63% were non-adherent based on proportion of pharmacy fills of prescribed medications. Those patients who were non-adherent, not unexpectedly, had nearly 1.6 fold the risk of cardiovascular disease over subsequent follow-up. There was a direct correlation between the extent of adherence to prescribed medical therapy, and the reduction in cardiovascular risk, with more adherent patients being more protected from the downstream consequences of uncontrolled hypertension. It is estimated that nearly half of patients prescribed antihypertensive therapy discontinue those prescribed medications within a year of initiation, and up to 10% of daily oral medication doses are often omitted in clinical practice, and sometimes these are only once-daily medicines, which means that all the therapeutic effect is lost.
Beyond control of office blood pressure, which is typically our target for clinical intervention, we have understood now that there is a lot of variability in blood pressure outside of the office that needs attention. The mean of office blood pressure readings over several visits is typically utilized to direct therapy, but we know that blood pressure fluctuates a lot over both the short and the long term. Episodic high values or extreme values are often disregarded as aberrations, but emerging evidence suggests that diurnal variation over the full 24-hour cycle and the variability in blood pressure between clinical visits are not just noise, but actually carry prognostic importance, and may be important targets for therapy. This is really the rationale for thinking about opportunities for continuous control of blood pressure in practice.
We have some opportunity to measure the efficacy of control of blood pressure over the full 24-hour cycle using 24-hour ambulatory blood pressure monitoring. Although this is not commonly utilized in clinical practice, examination of 24-hour ambulatory blood pressure data gives us some understanding of how variations in the blood pressure over the 24-hour cycle may contribute to risk. We have long understood that there is a typical pattern of fall in blood pressure during the nighttime, such that blood pressure dips in healthy patients. Patients with cardiovascular risk factors, particularly diabetes, obesity, tend to dip less during the nighttime, and that failure of the blood pressure to dip in the nighttime is associated with heightened risk. In fact, some patients have increase in blood pressure during the nighttime, and this nocturnal hypertension is associated with a particularly high-risk phenotype.
If we look at blood pressure in large populations, daytime hypertension certainly contributes risk, but that risk is amplified even further if it is continued through the nighttime. It is this data that really underscores the need for continuous control of blood pressure over the full 24-hour interval to secure effective cardiovascular risk reduction. Beyond that short-term variability in blood pressure, it is important to control long-term variability in blood pressure. One way to estimate that long-term variability is looking at the standard deviation of blood pressure between consecutive office visits.
As that standard deviation increases, as you can see here in the slide, looking at deciles of the standard deviation in between visit blood pressure, independent of the mean blood pressure, there is a steady rise in the increase in the risk of stroke, as well as the risk of coronary events that is associated with that increasing standard deviation. So more blood pressure variability translates into more strokes, more coronary events, and it is estimated that for every standard deviation increase, there is an 18% increase in cardiovascular death and a 15% increase in the risk of stroke. That variability is also captured in the measurement extremes of blood pressure, and if we look at the relationship between maximum blood pressures measured over serial follow-up and risk, there is also a graded association such that those patients having the widest spikes in blood pressure carry the highest risk of stroke.
This is data from the ASCOT trial, the Anglo-Scandinavian Cardiac Outcomes Trial, but it has been replicated in other contexts. The implication of this is that more aggressive blood pressure control, not just in the office, but over the full 24-hour interval and extending between visits such that there is less volatility over time, is critically important to effective cardiovascular risk reduction. One way of capturing the efficacy of blood pressure control is to measure the time that patients spend in the range of target. In this case, that blood pressure target is set by the current guidelines as less than 130 mm of mercury. You can see on the slide that if patients have a higher time in the target range, where they are more in the gray zone of effective control, that they have lower risk of cardiovascular events, and cardiorenal events, I should say.
If you look at the patient on the second panel of the slide, who is spending more time outside of the gray zone, that patient has heightened risk of major adverse events. Indeed, when we look in clinical practice at large epidemiologic datasets, there's a tight correlation between the time that patients spend in the therapeutic range and the risks of both renal, or kidney, and cardiovascular events, with a steady decline in risk associated with heightened time in the therapeutic range. It's really this data that supports the hypothesis that agents that could provide more continuous control of short and long-term variability in blood pressure will return higher benefits with regard to cardiovascular risk reduction. I think at this point, the data suggests that hypertension needs a new approach. Despite effective therapy, many patients with hypertension remain poorly controlled.
Physicians commonly fail to adapt therapy even when blood pressure is high, contributing to poor time in the therapeutic range. Adherence to daily oral antihypertensive regimens is poor in clinical practice and undermines blood pressure control. Even when office blood pressure appears controlled, residual visit-to-visit blood pressure variability and nocturnal hypertension contribute to ongoing CV risk. An effective reduction in cardiovascular risk really requires a strategy to address therapeutic inertia, treatment non-adherence, and blood pressure variability over the short and long term. Although there are a range of novel oral antihypertensives that are coming available in clinical practice, these are unlikely to effectively meet this challenge, particularly given the need for patients to take multiple medications in clinical practice to manage hypertension in the comorbidity milieu in which it commonly lives. Thanks very much for your attention.
Thank you, Dr. Desai. I'm Ishir Bhan, Executive Director of Clinical Research and clinical lead for zilebesiran's phase III study at Alnylam. As Dr. Desai and Pushkal outlined, a significant unmet need exists today and is projected to grow through 2050. This unmet need is driven by multiple factors that leave patients at elevated cardiovascular risk. Despite numerous classes of oral antihypertensives, the underlying contributors of this challenge remain unaddressed. Against this backdrop, I'll discuss the therapeutic hypothesis behind zilebesiran and why we believe it has the potential to address key drivers of cardiovascular risk. Zilebesiran represents a fundamentally differentiated approach to managing hypertension by targeting angiotensinogen, or AGT, the most upstream precursor to the RAS, the body's primary pathway for regulating blood pressure.
By suppressing AGT production, zilebesiran acts upstream of conventional medications like ACE inhibitors, ARBs, and MRAs, potentially avoiding compensatory changes in the pathway that may limit effects on blood pressure and target organ stress. Unlike conventional short-acting medications, zilebesiran has demonstrated the potential to provide continuous control of blood pressure with just twice-yearly dosing. Through this continuous control, zilebesiran has the potential to address critical gaps that contribute to the ongoing unmet need outlined by Dr. Desai and ultimately improve outcomes for patients with high cardiovascular risk or established CVD. I'll now walk us through the clinical evidence that supports this therapeutic hypothesis. Zilebesiran was evaluated across multiple treatment settings in the KARDIA phase II program. KARDIA-1 studied zilebesiran as monotherapy in patients with mild to moderate hypertension, providing an early opportunity to understand the potential of AGT suppression for blood pressure control.
As shown here, patients who received zilebesiran monotherapy achieved an average placebo-adjusted blood pressure reduction of 10 mm of mercury, while also experiencing continuous control of blood pressure throughout the 24-hour period. The lack of sustained long-term blood pressure control is a key contributor to cardiovascular risk. We have also observed in KARDIA-1 that patients who received one dose of zilebesiran every six months achieved sustained 24-hour blood pressure control for an entire year. These results, which demonstrate sustained continuous control of blood pressure, further reinforce our belief in zilebesiran's differentiated profile. Zilebesiran's safety profile has been consistently reassuring throughout phase II, with experience spanning 889 patients treated with zilebesiran. Throughout the phase II program, we observed low rates of adverse events, including hyperkalemia and hypotension. Importantly, most of these events resolved without intervention and did not lead to treatment discontinuation.
In both KARDIA-2 and 3, where zilebesiran was studied in patients receiving background ACE inhibitor or ARB therapy, low rates of hyperkalemia and kidney injury were observed. This is particularly encouraging because therapies that inhibit the RAS are known to increase the risk of hyperkalemia and acute kidney injury, especially when used in combination. Taken together, the efficacy and safety data generated to date support the continued development of zilebesiran and its evaluation in ZENITH, our phase III cardiovascular outcomes trial. The most recent phase II study, KARDIA-3, was key to informing the phase III study population and dose. Just like ZENITH, this study enrolled patients with uncontrolled hypertension on at least two antihypertensives, with either high cardiovascular risk or established cardiovascular disease. A key objective of KARDIA-3 was to evaluate zilebesiran in patients with uncontrolled hypertension receiving treatment with a diuretic at baseline.
This was an important population to study because diuretics are known to activate the RAS by increasing renin levels, potentially amplifying the response to therapies that inhibit this pathway. Based on this biology, we hypothesized that zilebesiran could be particularly effective in these patients. To better understand the importance of these factors, we conducted both pre-specified and post-hoc analyses. KARDIA-3 included a diverse patient population with meaningful proportions of Black and Hispanic patients, as well as patients with established cardiovascular disease, diabetes, and obesity. Notably, the vast majority of the patients were maintained on treatment with ACE inhibitors or ARBs. These patient characteristics were maintained in our post-hoc study population, which closely reflects the patients in our pivotal phase III trial. In the overall KARDIA-3 cohort A population, we observed clinically meaningful reductions in blood pressure.
As expected, the pre-specified and post-hoc analyses confirmed an enhanced blood pressure-lowering response of approximately 9 mm of mercury in patients receiving zilebesiran and a background diuretic, particularly in patients with a systolic blood pressure greater or equal to 140 mm of mercury at baseline. These data demonstrated zilebesiran's ability to achieve clinically significant reductions in blood pressure in our phase III target population. As Dr. Desai outlined, nighttime blood pressure is a powerful indicator of cardiovascular outcomes. Patients who do not experience a normal nighttime dip in blood pressure face significantly higher risk of cardiovascular events. As you can see here, we evaluated the effect of single dose of zilebesiran in both patients with normal nighttime dipping, or dippers, and patients without the nighttime dip, also known as non-dippers. The majority of patients in this study were non-dippers.
In this analysis, we observed that a single dose of zilebesiran achieved clinically significant nighttime blood pressure control, as well as the potential to restore nighttime dipping in patients who were classed as non-dippers at baseline. These results were observed at month six, highlighting the durability of this control with a single dose. These findings provide additional support for zilebesiran's ability to achieve continuous control and suggest an additional mechanism by which zilebesiran could further decrease cardiovascular risk. Beyond blood pressure control, we have observed the impact of zilebesiran on other independent indicators of cardiovascular and renal risk, including NT-proBNP and proteinuria. In patients with modest elevation in these biomarkers, we saw 21%-26% reductions in NT-proBNP and 32%-37% reductions in the urine albumin-to-creatinine ratio. Notably, these clinically meaningful effects were evident as early as month one and were sustained through the six-month dosing interval.
These findings provide additional evidence beyond blood pressure reduction that support the potential of zilebesiran to improve patient outcomes in the phase III cardiovascular outcomes trial. As we conclude this section, I'll return to a key theme from Dr. Desai's discussion. Patients remain at elevated cardiovascular risk because we struggle to achieve and maintain continuous control over time. Contributing factors include poor nighttime blood pressure control, visit-to-visit blood pressure variability, poor adherence, and spending too little time in the target range. Across the phase II program, we've seen encouraging evidence that zilebesiran has the potential to address these needs by providing continuous control of blood pressure with just twice-yearly dosing. We look forward to continuing to test this hypothesis in ZENITH. I'll now pass it to Simon Fox to tell you more about ZENITH and the potential we see for zilebesiran.
Thank you, Ishir, for that comprehensive overview of zilebesiran's clinical profile. I'm Simon Fox, Vice President and Program Lead for zilebesiran at Alnylam. I'll now walk you through the progress we've made to date and how we are positioning zilebesiran for the future. As Ishir highlighted, the robust data generated in phase II reinforced our belief that zilebesiran's ability to provide continuous control with twice-yearly dosing could meaningfully improve cardiovascular outcomes in high-risk patients for whom the urgency to treat is the greatest. To that end, we are executing ZENITH, a trial designed to generate a compelling data package for regulatory review, and if approved, support broad uptake at launch. Importantly, the program has received Fast Track designation from the U.S. FDA and Breakthrough Therapy designation in China, reflecting the significant unmet need and potential of zilebesiran.
ZENITH is an event-driven trial comparing zilebesiran to standard of care in patients with uncontrolled hypertension despite treatment with multiple oral antihypertensives who have established cardiovascular disease or are at high risk of cardiovascular disease. Patients in ZENITH will have a minimum follow-up of two years with a primary outcome of cardiovascular death, non-fatal MI, non-fatal stroke, or hospitalization for heart failure or urgent heart failure visits. ZENITH, Alnylam's largest clinical trial to date, initiated last September. The study will enroll 11,000 patients across 35 countries with a global footprint that reflects Alnylam and Roche's shared ambition of bringing zilebesiran to patients across the globe. We are now actively screening and randomizing patients in all of our 35 target countries. Encouragingly, ZENITH has generated strong enthusiasm among investigators and the broader community, which is translating into strong execution with enrollment very much on track.
We recognize that successfully bringing a medicine like zilebesiran to patients requires time, preparation, and strategic investment, which is why we and our partners at Roche are laying the foundations today. While we focus on strong execution of the phase III trial, we are also advancing a broader strategy to maximize zilebesiran's potential. That includes generating real-world evidence to further characterize the magnitude of unmet need, alongside medical education and scientific exchange to support ZENITH enrollment. Given zilebesiran's potential to provide continuous control of blood pressure, we are also assessing development opportunities in high-need populations such as heart failure and chronic kidney disease. We are also making strategic investments to support future supply and scale. This includes the expanded manufacturing capacity through our siRELIS enzymatic ligation platform, which is designed to increase capacity and support future launches in prevalent diseases.
Finally, we're building commercial readiness by drawing on Alnylam's proven launch engine and experience navigating buy and bill pathways which will scale for this opportunity. Taken together, these efforts are intended to position us to effectively deliver zilebesiran to patients and healthcare providers if the program is successful. We are making these investments because uncontrolled hypertension remains the leading modifiable risk factor for death and cardiovascular disease worldwide. Across seven major markets, more than 200 million adults live with hypertension, and roughly one-third are at high cardiovascular risk. Despite treatment with multiple oral antihypertensive therapies, up to 80% of patients remain uncontrolled, and this is where we see the clearest opportunity for impact. The consequences of uncontrolled hypertension extend well beyond patients, placing a significant burden on the healthcare system.
Hypertension accounts for an estimated $292 billion in annual costs to the U.S. and the healthcare system, with 61% attributed to uncontrolled hypertension. This underscores that the burden is concentrated in exactly the population we're focused on. Looking ahead, the global economic burden is projected to exceed $500 billion annually by 2050. Generating real-world evidence in hypertensive populations will be critical in characterizing and quantifying the burden of uncontrolled hypertension. This analysis of contemporary U.S. claims data paints a stark picture, showing that even high-risk patients being treated with multiple oral antihypertensives spend most of their time outside of target blood pressure range, leaving them at elevated cardiovascular risk. These findings highlight the significant gap that persists today and reinforce the need to investigate a therapy designed for durable effect like zilebesiran.
We believe the opportunity for zilebesiran is not to simply become another antihypertensive, but to establish an entirely new category in cardiovascular care. That opportunity rests on four pillars, the potential to improve cardiovascular outcomes, continuous control, infrequent twice-yearly dosing, and a well-tolerated profile that can complement existing therapies. Together, these attributes, supported by an outcomes-orientated evidence strategy, have the potential to differentiate zilebesiran from the therapies that rely on daily adherence and are designed primarily to lower blood pressure alone. Our view of the opportunity is reinforced by encouraging signals across patients, prescribers, and payers. Physicians see significant unmet need, with 72% of physicians surveyed agreeing zilebesiran addresses a critical gap in care, and three in four indicating intent to prescribe. Fortunately, they view zilebesiran as a differentiated therapy with the potential to become a cardiovascular protective agent.
Patients are similarly enthusiastic, describing zilebesiran as promising and exciting, with twice-yearly dosing emerging as a key benefit that could help support long-term adherence. Finally, payer feedback is clear. Cardiovascular risk reduction is the critical decision driver, an insight that aligns with our development strategy and reinforces the importance of the outcomes data we intend to generate through ZENITH. As Dr. Desai shared, the lack of durable blood pressure control is significantly contributing to increased cardiovascular risk. The findings from SPRINT provided unequivocal proof of both the benefits and the challenges of achieving durable blood pressure control over the long term. In the controlled clinical trial phase, patients received intensive blood pressure treatment, had a reduced risk of cardiovascular and all-cause mortality compared to those receiving standard treatment.
However, those benefits quickly diminished once the clinical trial ended and patients entered the observational phase, highlighting how challenging it is for patients to maintain durable blood pressure control in the real-world setting. This raises an important question. What if a therapy could provide continuous control of blood pressure with infrequent dosing over the long term to help address these challenges? We believe zilebesiran represents an opportunity to help answer that question with the goal of delivering continuous control through twice-yearly dosing. Before we close, it is important to remember what is at stake. Patients who continue to face significant cardiovascular risk despite today's treatment options, I would like to offer you the opportunity to hear from Bob, a patient living with uncontrolled hypertension and high cardiovascular risk.
Hi, my name is Bob, and I'm living with hypertension and high cardiovascular risk. For years, I felt fine and convinced myself that I had a handle on my high blood pressure. Looking back, that decision nearly cost me my life. At 45, I suffered a heart attack and left permanent damage to my heart. Hypertension is often called the silent killer for a reason, and my experience taught me that even when you feel healthy. Uncontrolled blood pressure can have life-threatening consequences.
It's for patients like Bob that we continue to pursue innovation, driven by the belief that innovation is needed and that we can do more to improve long-term outcomes. With that, I will turn it over to Pushkal to moderate Q&A. Pushkal.
Thanks, Simon. All right. Lots of interest I am seeing from questions. Let us move into the Q&A section. We have already gotten a number of questions coming in, but to those on the call, if you have additional questions, please enter them into the web app. The first set of questions we have gotten are all around this concept of continuous control, and particularly time and target range. A couple of questions maybe for you, Akshay, and then Simon, you should also chime in. Really, how robust is this concept of time and target range? What do we understand from real-world data? Can you just summarize some of your points, Akshay, around that? Then Simon, to you, what gives us confidence coming out of phase II that we might see benefits in that? Then importantly, how do you measure time and target range?
Is that actually something you can measure in clinical practice? Is it something we are measuring in ZENITH? Is that something that could be a competitive differentiator for this kind of a drug?
Yeah. Pushkal, I think important questions. I think one of the points I think that needs to be made is that most of our therapeutic assessment in hypertension has largely been based on single measurements of blood pressure in the office, and we understand the limitations of office-based blood pressure. Sometimes it is not terribly representative of how blood pressure varies in the ambulatory setting. In practice, there is variation, as we discussed, over the full 24-hour cycle and between visits in blood pressure that is not captured in those spot checks in the office. I think we know that blood pressure is a continuous exposure for patients, and it is that continuous exposure that relates to risk.
I think as a concept, it is very appealing to think about what proportion of time in their ambient life patients spend in the optimal range of blood pressure, because we think that is reasonably expected to be a better correlative risk. Now, the evidence for that is largely based on clinical trials, which we have looked at post hoc or even epidemiologic data sets, where we can measure blood pressure serially over time in the office or even at home, and then look at the proportion of those measures that actually fit within our target range. The greater proportion of measurements that are taken over longitudinal follow-up for a patient that fit within that range, the better the outcome seemed to be, both when we look at renal events and we look at composite cardiovascular events like stroke and myocardial infarction.
I think there is a fairly robust belief that the more time you spend in a target range, the better you can expect your outcomes to be. The only limitation has been our ability to continuously measure blood pressure over time to really robustly assess that treatment response.
Fantastic. Simon, you want to just add a little bit from.
Yeah.
Just what we've learned?
Not much more to add, but really what we saw in the phase II, the totality of the phase II data really does speak to that therapeutic hypothesis that Akshay just spoke to. Really that was highlighted by this ability to achieve continuous control of blood pressure throughout the 24-hour period with only two doses a year. That really does speak to that.
Fantastic. Maybe the follow on, I guess, Akshay to you is, could we just accomplish the same things by just intensifying and combining more oral therapies for patients? Do you think the aldosterone synthase inhibitors might help in that regard?
Yeah. It's an appealing thought, and I think obviously we are extremely excited about the proliferation of new drugs for hypertension, the resurgent interest in this field. I think that the challenge has never been in hypertension that we don't have enough drugs to treat our patients. We have very effective therapies. It's that the drugs aren't deployed to complete effect in clinical practice, and that's either a problem with access to care, or it's a problem with physician use of the medication, or it's a problem with patient adherence. I think when we integrate this concept of control outside of the office and that longitudinal control over the 24-hour interval in between visits, then I think we have an even larger problem because we have these very stringent blood pressure targets that we know mitigate long-term risk of cardiorenal outcomes.
We know that on the whole, we haven't done a great job of controlling blood pressures even with the arsenal that we have. I think the problem is really not likely to be solved by stacking additional oral antihypertensives. I think that may indeed exacerbate the problem because some of the problem for patients is this huge array of medicines that they have to take each day and the difficulty with doing it. There's this data that I highlighted shows that most patients prescribed a medicine, about half of them by a year stop taking it. That adherence problem, I think, is a real challenge for us moving forward, and I don't think it's solved by even a more effective oral agent.
Very helpful. Victoria, for you, how do you see. Let me introduce Victoria Silva, who heads up our commercial team for zilebesiran. Thank you for joining us for this portion. Building on what Akshay said, how do you think about these new branded therapies like aldosterone synthase inhibitors that are coming forward in a very highly genericized market, and how zilebesiran might ultimately, if it does bear out in ZENITH, compete in that space?
Yep. What we really see about zilebesiran is that we are creating a new category. We believe we are a cardiovascular protection agent. We are not just another blood pressure lowering agent, and we believe that exact design is what differentiates us and sets us apart from the other existing therapies. To a lot of the points made, this will allow us to establish continuous control, will allow us to overcome the adherence hurdles that we see with the oral therapies today. We think those things combined are really what sets us apart, and that in addition, the uptake of emerging therapies really helps validate the need for this innovation. What we are seeing in the marketplace is actually encouraging to us that there is absolutely space for zilebesiran to enter the market.
Gotcha. Yeah.
If I could even just jump in, I would just say that one of the real opportunities here is to completely reinvent the paradigm for prevention, right? Which is that rather than waiting for patients to show up in the office, identify the blood pressure is out of range, and then react to that observation. Whatever the genesis of that problem is, here is an opportunity to intervene early to provide continuous background control of blood pressure and secure blood pressure lowering and cardiovascular risk reduction without the need to rely on the stochastic nature of how patients take their medications.
That is a really important point. I imagine with wearables and things like that is only going to sort of accentuate that identification of patients in their normal lives. Ishir, maybe I can turn to you. There are a number of questions you kind of walked through in your presentation about the learnings from KARDIA-3. I think there are a number of questions that have come through in terms of, okay, given the study did not sort of meet its threshold benefit that we were looking for, but then there is a series of analyses that look for an enriched population.
What gives us confidence? Can you just speak a little bit more to the idea about the diuretics? Was that just a subgroup that was identified, or is there a biologic rationale for that? The cutoff of 140 that was employed to sort of look for an enrichment in KARDIA-3.
Can you just explain a little bit more about that and what gives us confidence that the choices that we made coming out of KARDIA-3 are likely to translate into a sizable or meaningful blood pressure benefit in ZENITH?
Based on our known biology and prior research with both zilebesiran and other RAS agents, even prior to KARDIA-3, we suspected we might see an enhanced response to zilebesiran in patients on diuretics, as well as patients with a blood pressure of at least 140, which is the standard threshold for stage 2 hypertension. Both blood pressure and background diuretic use were included as pre-specified stratification factors in KARDIA-3, and both were also included in pre-specified post hoc analysis. I would say KARDIA-3 met its objective in three keyways . First, it helped identify the population most likely to benefit from zilebesiran. That is patients receiving two or more background antihypertensives, one being a diuretic with a systolic blood pressure of at least 140 mm.
In this population, zilebesiran achieved an enhanced response of 8 - 10 mm in office and 24-hour systolic blood pressure out to month six. Second, it confirmed the safety of zilebesiran in combination with two or more background antihypertensives in patients with high cardiovascular risk. Third, it established the dose for the phase III, a twice yearly 300 mm injection. In conclusion, KARDIA-3 helped optimize the design, the target patient population, and the dose for the phase III cardiovascular outcome trial, ZENITH. Taken together, the KARDIA-3 results give us and our partners at Roche the confidence to advance zilebesiran into this pivotal phase III cardiovascular outcome trial.
Thank you, Ishir. That's really great and clear. Maybe building on that, Simon, we've questions coming. You've shown blood pressure benefit already with this drug. Blood pressure's a registrable endpoint. Ishir talked about how important that continues to those. Why not just register on blood pressure? Why the investment in a sizable outcome study?
Yeah. It is a great question, Pushkal, and look, you heard from Ishir that we saw really encouraging results in our phase II studies and illustrated by zilebesiran's ability to achieve continuous control of blood pressure with only twice yearly dosing. We believe for all of the salient points that Ishir mentioned, that this has the potential to improve cardiovascular outcomes. It is worth acknowledging that it is an entrenched generic oral antihypertensive market.
Yeah.
Outcomes data will be required to differentiate zilebesiran beyond blood pressure alone. Alnylam, our partners at Roche, we really do believe that zilebesiran could potentially become a category creator, as Victoria said, in cardiovascular risk management and not just another antihypertensive. Generating the outcomes data for initial launch is key to our strategy. Just to repeat again, it is worth mentioning that zilebesiran was awarded Fast Track designation by the FDA, a Breakthrough Therapy designation in China, which we believe really illustrates how regulators view both the unmet need and the potential of zilebesiran to improve outcomes.
Good. Then I think a follow-up from there, Ishir just highlighted why there was a biologic rationale for requiring background diuretics. We saw a larger treatment effect in that population. But are we at all concerned, Simon, and maybe that this is going to constrain the label in some way? Two, and maybe more importantly I guess to you, Akshay , can you just talk about this population that we have highlighted, Ishir has highlighted, and Simon that we are enrolling in ZENITH. How representative is that of the patients that you see? Are these zebra patients as we talk about medicine, or are these what you see? How common is this type of patient that we are targeting? So maybe Simon, you can start and then we will go to Ishir.
Yeah. So I will just deal with the diuretic. Look, we fully believe at launch we will have a broad indication and label, and it will be something like indicated to reduce the risk of cardiovascular events in patients with hypertension, with either established cardiovascular disease or it is a higher risk of cardiovascular disease.
Good.
Yeah, no, I think if you look at the population of patients that I see in my clinical practice, I would say that the vast majority are diuretic treated. The epidemiology says that about half of patients with hypertension are treated with a diuretic. When you look at the high-risk population, the uncontrolled hypertensives, the more elderly patients with hypertension, the vast majority are on a diuretic, an ACE diuretic or ARB diuretic or calcium channel blocker diuretic combinations are far and away the most common combinations that are used in clinical practice. I think when I look at the ZENITH design, I think we're talking about patients with uncontrolled hypertension on two or more medications who are including a diuretic, who are at high cardiovascular risk. Those are the patients that we see in a large proportion of a cardiology practice that's focused in hypertension.
I don't think these are zebras at all. I think this is the meat of the patients who have the most urgent need for hypertension treatment.
Yeah. It's absolutely worth mentioning, you mentioned first line guideline recommended diuretics are, and for the specific target patient population we're studying in ZENITH, obviously they're on background diuretic. It's around about 80% of the patients.
Yeah.
With high cardiovascular risk.
Yeah.
Are on background diuretics. That is why we believe that ZENITH really does represent a contemporary population.
Good. Maybe we can then turn now then a little bit to ZENITH. We got a number of questions. I guess first of all, what level of MACE benefit, and maybe Ishir, you can start, and Victoria, it would be good to get your comments, would be clinically meaningful and commercially compelling? Are we powered? What level of effect are we powered for? Then, how do you guys handle in the study patients who might be starting new therapies, et cetera, or down titrating their background medicines? Does that compromise our ability to see an effect if people start a new therapy in the context of the study, et cetera? So a number of questions there.
But maybe, Ishir, we can start from you in terms of just how you think about the clinical effect size we are looking for, powering, and how background medicines are handled in the context of this study.
Given the blood pressure reductions we saw in the KARDIA-3 in this enriched population, we feel it is realistic to expect a 15%-20% reduction in MACE, and we are conservatively powered to assess this magnitude of an effect in ZENITH, our phase III cardiovascular outcome trial. With regard to background medications, we do allow those to be titrated in the ZENITH trial, and we do not expect that is going to have a sizable effect on our impact. We also believe this magnitude of effect will be compelling to regulators, and maybe I will let Victoria speak to what that means for us commercially.
Thanks, Ishir. From a commercial perspective, we believe a benefit in that range would be highly compelling. A 15%-20% MACE reduction is exactly the type of benefit that resonates with cardiologists, and we believe would position zilebesiran as a cardiovascular protected agent, not just another blood pressure lowering therapy. The physician response in our research is strong, and it tells us that we're targeting the right bar. A benefit at this level supports strong access and premium positioning. We feel good about where this lands us with payers for whom MACE reduction is the number one decision driver, and the value it could ultimately command.
Fantastic. And maybe, Ishir, building on your point, I think we've designed ZENITH really to be, in some ways, representative of real world practice kind of study. Because of the infrequent administration, these are not patients who are coming in every month or every couple of weeks to get their blood pressure checked. You guys have designed this as almost acute six-month type of visit schedule in the study, which mirrors real world where, I think Akshay has already highlighted, adherence and titration is not always as vigorous or as we would sort of see in sometimes a much more tense short-term clinical trial setting. Is that fair?
That's exactly right, and that's why we don't expect that we'll see a lot of changes in these background medications. We know that from what happens in clinical practice, and that's where zilebesiran's long-acting nature will really be advantageous.
Yeah. I think one of the real opportunities in ZENITH is to examine our practice, right? I think what we can see from the work that's been done so far is that clinicians often confronted with an elevated blood pressure in clinic choose not to engage it. And it's largely for many reasons, but I think often it's the suspicion that it may not be accurate, and it may not reflect what's going on in day-to-day practice at home. I think as much as you might be concerned that there would be aggressive utilization in the control arm of ZENITH of other medicines, that hasn't borne out in practice. In general, people are pretty lackadaisical about blood pressure therapy.
Yeah. No, it's a really important point, and hopefully something we can help address. Maybe just building on this concept of the MACE reduction that we're looking for, and I think Simon highlighted, actually, you've highlighted that there's an element of blood pressure management that is guideline driven.
I guess it would be helpful to understand from your perspective as an academic thought leader in medical societies, if this study delivers a 15% or 20% MACE reduction, or what else would be needed to kind of put this in guidelines, again, given there are a lot of generic medicines and guidelines do drive a certain amount of clinical practice?
Well, I think it's an important question. It's probably an important question both especially for payers and other things, because a lot of how we elect to select therapies and prioritize therapies is driven by how the guidelines are written. I think that the key message here is that guidelines are heavily driven by the weight of evidence and by the science. I think if we look at blood pressure as a target, it's probably not enough to simply show that agents reduce blood pressure, even if they do it over the full 24-hour cycle. That's true for many agents. It's been true for agents that we've had available for a long time. I think the point of differentiation here is really the randomized outcome trial that will show that effectively addressing CV risk reduction through this strategy will actually translate into long-term outcomes.
I think with that data and the projected 15%-20% reduction, I think that would be compelling to differentiate this approach from others that exist in the literature and perhaps motivate recommendations in that regard.
Super helpful. Ishir, back to you. A couple questions just around safety. We have a long-acting medication to treat hypertension, so I think a couple things. You did touch on the safety profile. Maybe you can just recap and were there any surprises from a safety perspective? Then I guess more importantly, the questions coming through is, how do physicians, are they expected to manage if some intercurrent event happens, like low blood pressure, et cetera? Are they able to stop their other medications? What does that mean? How do you manage those? Or if someone needs to have something happen in terms of managing their blood pressure because they are having an operation or something like that.
Yeah. With any therapy that targets the RAS, one would expect to see some degree of elevated potassium, reduced eGFR and low blood pressure. But in our phase II program, we were really struck by what we found. We were pleased to see that the rates of these were quite low, and even though zilebesiran has this six-month duration of action, when these events did happen, they were transient and really addressable with just standard of care intervention. That is what we would expect to see in our clinical trial and in the real world. Overall, I think we have been very encouraged by the safety profile generated in the phase I and phase II with almost now 1,000 patients exposed to zilebesiran across really multiple settings, including monotherapy and in combination with other antihypertensives.
These have included patients already on ACE inhibitors and ARBs and patients with moderate to severe chronic kidney disease, as well as patients who have received multiple doses of zilebesiran.
Very helpful. Actually, some questions for you Akshay that I think you are best positioned to answer is just the ZENITH study and zilebesiran being developed really to focus on this secondary prevention indication in high-risk patients. But let us assume it is successful. Where would you be interested in understanding if this kind of a modality or mechanism would actually be useful? Are there other spaces in hypertension? Are there other diseases? We know RAS inhibition is used in other cardiac conditions and clinical conditions. So what would be of interest to you as a clinician and as clinician scientist in terms of thinking about where you might take a medication like this, assuming it continues to look favorable?
Yeah. I think there are two areas that immediately come to mind. I think if you think about the role that hypertension plays in the pathogenesis of heart failure development, the role and progression of heart failure in patients with established heart failure, then you think about chronic kidney disease and the role that hypertension plays. Hypertension is a leading driver of disease progression in both those disease states. The renin-angiotensin system is a key mediator of disease progression in both of those states. We've known for a long time that patients with CKD and those with heart failure across the ejection fraction spectrum benefit from renin-angiotensin system inhibition.
I think those are two very high profile and high priority areas for expansion of a drug that is effective because we would imagine that a drug that provides blood pressure reduction, better time in the therapeutic range, longitudinal control, and overcomes some of the adherence challenges of daily oral medications would equally benefit, if not more so, those high-risk patients with established CKD and heart failure. I think that would be a super exciting next step. Another way to think about this is even moving more proximally in the hypertension treatment armamentarium because I think we're now looking at a second intervention in high-risk patients. But one could imagine this as a backbone for hypertension management to secure initial blood pressure lowering.
It might be the case that for some lower-risk patients with hypertension, this might be all you need to control blood pressure in the range. If not, it would be a scaffold on which to stack fewer oral medicines to achieve blood pressure targets. I think another direction to potentially take this.
Fascinating. Lots of opportunity potentially ahead. Victoria, maybe a question for you that's come in is, another siRNA sort of in a prevalent condition is inclisiran, Leqvio, that was originated here, but now being marketed by Novartis. What have we learned from that experience that helps us think about how, again, assuming ZENITH is positive and that we would potentially launch a drug like zilebesiran, what challenges might we face, and what have we learned from that experience that we can address?
One of the original challenges Novartis faced actually informed our phase III and exactly why we did a cardiovascular outcomes trial with ZENITH. We believe that this outcomes trial will actually create that differentiated profile, drive physician uptake, support broad access, and establish the value of the medicine. We learned exactly from what inclisiran did not initially do to design our phase III. Today, though, inclisiran is starting to be a tailwind for us. While another challenge for Leqvio early on was that cardiologists were not yet comfortable with buy and bill, that has really changed significantly as customers have gained experience. In the U.S., Leqvio sales grew 55% last quarter, so it is a blockbuster that is really matured the whole channel. Unlike a first-time entrant, we are also not entering this from scratch.
Through AMVUTTRA's cardiomyopathy launch, Alnylam is already running buy and bill in cardiology, with 90% of patients able to get treated close to home. We are, with zilebesiran, stepping into an established pathway with our own cardiology track record behind us. We are clear that we will have more work to do ahead, but we like where this positions us.
Fantastic. I think maybe this will be our last question. We got an interesting question, which is there an increased risk for ZENITH? The questioner is asking about a number of recent setbacks in terms of cardiovascular outcomes trials, whether it is Lp(a) , the eplerenone study, IL-6, et cetera, and whether that poses now a risk in terms of ZENITH and how we think about that.
Maybe I can start, but Akshay or others, I would invite you to add as well. I think as we look at it from Alnylam, A, we have really tried with our colleagues at Roche to really look at risk in a number of different ways, right? There is molecule risk, there is biology risk, there is study design risk. I do think that in this particular instance, I think we are quite well-positioned. I think zilebesiran has now been studied in over 1,000 patients.
I think we have a pretty good understanding of its pharmacology. We are able to pick the right dose. We have very high levels of knockdown, good tolerability. That is one piece. I think the second piece then is around biology risk. We have now shown, I think, repeatedly, that we can reduce blood pressure in a variety of settings. The monotherapy is this year highlighted in combination with single agents and then in the intended patient population. I think hypertension itself, I think is very strongly correlated with outcomes. I do not think there is a lot of biologic uncertainty about predictiveness of blood pressure results translating into outcomes benefits.
I think the last piece is study design. I think what you have heard is that the team really has sweat a lot of the details in terms of basically running KARDIA-3 as almost a run-in type of study to basically optimize the patient population, some of the study procedures, et cetera, to manage challenges that have plagued other hypertension outcomes trials. I think all in all, we feel quite good about what we have designed and quite confident about that. That is how I would sort of summarize it. I do not know, Akshay, Simon, Ishir, anyone have anything to add?
No, I think you have said it very well. I think my only add would be that in those other examples that you highlighted, I think we have had a little less certainty about the relevance of the biomarker for predicting cardiovascular outcomes. There is no uncertainty in hypertension that if you can effectively lower blood pressure to a greater extent with zilebesiran than you do in the standard of care arm in ZENITH, that that should translate reliably into a cardiovascular outcome benefit. There has been a linear dose response between achieved blood pressure and outcomes in these trials. I am quite confident that if we can deliver on that premise, which we have every confidence we can do. I think as you said, the study design is tuned really to deliver that outcome. I think there is every expectation of benefit.
Fantastic. Well, then I think we will leave it there with that. Thank you to Ishir, Simon, Victoria, and Dr. Desai. Thank you for joining us today for all your insights and contributions to today's discussion. That is going to be the end of today's RNA Roundtable. You can access the replay of the webinar and view the slides in the Capella section of Alnylam's website later today. We will welcome all of you back on October 26th for our next and final session, which is focused on ALN-HTT02, our investigational therapy for Huntington's disease. Thank you all for joining, and have a great day.
The meeting is now concluded. Thank you all for joining, and you may now.