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

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 [ Asher Bond ], 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 2 decades pioneering an entirely new class of medicines based on RNA 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 for more than 2 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 paired this innovation engine with a disciplined strategy for selecting the most compelling opportunities to advance to the clinic. Our therapeutic area agnostic approach focused 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. And you can see the results 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 3 pivotal studies underway and 4 important data readouts expected this year. That momentum will build meaningfully through 2028 with a growing number of pivotal studies, at least 5 key data readouts each year and the potential launch of nucresiran in 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 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 and 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 death 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. And notably, high systolic blood pressure remains 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 1 billion cases prevalent in modern era. And that is defined at a threshold of a blood pressure more than 140 millimeters 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 health care 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 predisposed the development of a range of cardiovascular diseases, including ischemic heart disease, stroke, chronic kidney disease and then a range of other vascular 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 millimeters of mercury, but you can see that even -- that 1/3 of the disability-adjusted life years are associated with blood pressures between 110 and 140 millimeters 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-millimeter 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. And among those who are treated, only 1 in 5 is actually treated to guideline recommended targets. And 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 and 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 millimeters of mercury versus a standard blood pressure target of less than 140 millimeters of mercury, the prevailing recommendation at the time. And 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 my cardial 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% and win the more intensive therapy arm. And 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 a treatment -- to recommend a treatment goal of less than 130 over 80 millimeters of mercury for all adults defining blood pressure more than 130-millimeter mercury as stage 1 hypertension and more than 140 millimeters of mercury, our previous therapeutic target as stage 2 hypertension. So this new guideline recalibrates our estimates of global prevalence of disease and really reassign 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 6 months. This long duration of action pros is a unique opportunity for hypertension that we'll discuss a little bit later in the market but 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 an adequate 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 failed to diagnose hypertension appropriately. And 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've 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 and practice. And then finally, a certain proportion of patients, even with effective therapy remain resistant to anti-hypertensive 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 anti-hypersensive therapy and cardiovascular risk. Amongst young adults in this survey, taking antihypertensive medications. About 63% were nonadherent based on proportion of pharmacy fills of prescribed medications. And those patients who were not adherent not unexpectedly, had nearly 1.6 fold the risk of cardiovascular disease over subsequent follow-up and 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's estimated that nearly half of patients prescribed anti-hypertensive 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 medicine, which means that all the therapeutic effect is lost. Beyond the control of office blood pressure, which is typically our target for clinical intervention, we've 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 maybe important targets for therapy. And 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. And 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've long understood that there is a typical pattern of fall in blood pressure during the nighttime such that blood pressure dips in healthy patients and 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. And 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 has continued through the nighttime. And it's 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. And one way to estimate that long-term variability is looking at the standard deviation of blood pressure between consecutive office visit. And as that standard deviation increases, as you can see here in the slides, looking at deciles, of the standard deviation between -- in between visit blood pressure independent of the mean blood pressure. There's a steady rise in the increase in the risk of stroke, as well as the risk of coronary events that increases -- that is associated with that increasing standard deviation. So more blood pressure variability translates into more strokes, more coronary events. And it's estimated that for every standard deviation increase, there's an 18% increase in cardiovascular death and a 15% increase in the risk of stroke. That variability is also captured in the measure of extremes of blood pressure. And if we look at the relationship between maximum blood pressures measured over serial follow-up and risk, there's also a greater association such that those patients having the widest spikes in blood pressure carry the highest risk of stroke. And this is data from the ASCOT trial the Anglo-Scandinavian cardiovascular outcomes trial, but it's been replicated in other context. And 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's 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. And in this case, that blood pressure target is set by the current guidelines is less than 130 millimeters of mercury. And you can see on the slide that if patients have a higher time in the target range, where they're more in the gray zone of effective control that they have lower risk of cardiovascular events and cardiorenal events, I should say. And then 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. And indeed, when we look in clinical practice at large epidemiologic data sets, there's a tight correlation between the time that patients spend in the therapeutic range and the risk to both renal or kidney and cardiovascular events, with a steady decline in risk associated with heightened time in the therapeutic range. And 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. So 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 any hypertensive 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 in nocturnal hypertension contribute to ongoing CV risk, an effective reduction in cardiovascular risk really requires a strategy then to address therapeutic inertia, treatment nonadherence and blood pressure variability over the short and long term. And 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 and clinical practice to manage hypertension in the comorbidity mode in which it commonly lifts. Thanks very much for your attention.

Thank you, Dr. Desai. I'm [ Asher Ban ], 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 it's 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 CBD. 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 millimeters of mercury, while also experiencing continued 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 libiziran every 6 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 2 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 continued development of zilebesiran and its valuation 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 2 antihypertensives, with either high cardiovascular risk or established cardiovascular disease. A key objective of KARDIA 3 was to evaluate flibisiran in patients with uncontrolled hypertension receiving treatment with a deretic at baseline. This was an important population study because diuretics are known to activate the RAS by increasing read-in 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 prespecified 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, obesity, Notably, the vast majority of the patients were maintained a treatment with ACE inhibitors or ARBs. These patient characteristics were maintained in our post-tax 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 prespecified and post hoc analyses confirmed an enhanced blood pressure lowering response of approximately 9 millimeters of mercury in patients receiving zilebesiran and the background diuretic, particularly in patients with a systolic blood pressure greater or equal to 140 millimeters 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 the powerful indicator of cardiovascular outcomes. Patients who do not experience a normal nighttime dip in blood pressure faced a 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 a nighttime dip, also known as non dippers. The majority of patients in study were non-dipper. In this analysis, we observed that a single dose of zilebesiran achieved a clinically significant nighttime blood pressure control as well as the potential to restore nighttime zipping in patients who were classed as non-dippers at baseline. These results were observed at month 6, letting 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 the blood pressure control, we have observed the impact of zilebesiran on other independent indicators of cardiovascular and renal risk, including NT-proBNP and pro-urea. In patients with modest elevation in these biomarkers we saw 21% to 26% reductions in NT-proBNP and 32% to 37% reduction in the urine albumin creatinine ratio. Notably, these clinically meaningful events were evident as early as month 1 and were sustained through the 6-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 for nighttime blood pressure control, visit-to-visit blood pressure variability, core adherence and spending too little time in the target range. Across the Phase II program, we've seen encouraging evidence that sibisiran 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 the 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, Asher, for that comprehensive overview of zilebesiran's clinical profile. I am 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 positioned zilebesiran for the future. As Asher 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 paints with uncontrolled hypertension despite treatment with multiple oral antihypertensives who have established cardiovascular disease or at high risk of cardiovascular disease. Patients in ZENITH will have a minimum follow-up of 2 years with a prior outcome of cardiovascular death, nonfatal MI, nonfatal stroke or hospitalization for heart failure urgent heart failure business. 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 earn our partners at Roche alleging 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. It includes generating real-world evidence to further characterize the magnitude of unmet need alongside medical education and scientific exchange to support ZENITH enrollments. 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 expanded manufacturing capacity through our siRELIS Enzymatic Ligation platform, which is designed to increase capacity and some future launches in prevalent diseases. Finally, we're building commercial readiness by drawing on Alnylam's proven launch engine and experience navigating buy-and-build pathways, which will scale for this opportunity. Taken together, these efforts are intended to position us to effectively deliver zilebesiran to patients and health care 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 7 major markets, more than 200 million adults live with hypertension and roughly 1/3 are at high cardiovascular risk. This by 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 health care system. Hypertension accounts for an estimated $292 billion in annual costs to the U.S. and a health care system with 61% attributed to uncontrolled hypertension. This underscores that the burden is concentrating exactly the population we're focused on. And looking ahead, the global economic burden is projected to exceed $500 billion annually by 2050. Generating real-world evidence in hypertensive relations 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, spent 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 4 pillars: the potential to improve cardiovascular outcomes, continuous control, infrequent twice-yearly dosing and a well-tolerated profile that can come from existing therapies. Together, these attributes supported by an outcomes 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 3 and 4 indicating intent to prescribe. Fortunately, they view salbisiran 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. And 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 walk 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 convince 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 silent killer for a reason and my experience talking to that even when you feel healthy. uncontrolled blood pressure can have life-threatening consequences.

As 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. And all right. Lots of interest I'm seeing some questions. So let's move into the Q&A section. We've 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. So the first set of questions that we've gotten are all around this concept of continuous control, particularly time and target range. And so a couple of questions maybe for you, Akshay, and then Simon, you should also chime in. But 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? And then Simon, to you, what gives us confidence coming out of Phase II that we might see benefits in that. And then importantly, how do you measure time and target range? Is that actually something you can measure in clinical practice? Is it something we're measuring in ZENITH? Is that something that could be a competitive differentiator for this kind of a drug.

Yes. So 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 heart and hypertension is largely based on single measurements blood pressure in the office, and we understand the limitations of office-based blood pressure, sometimes it's not terribly representative of how blood pressure varies in the ambulatory setting and practice there's variation, as we discussed over the full 24-hour cycle in between visits and blood pressure that's not captured in those spot checks in the office. And so I think the -- we know that the blood pressure is a continuous exposure for patients and that's that continuous exposure that relates to risk. So I think as a concept, it's very appealing to think about what proportion of time in their ambient life patients present -- 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've 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. and the greater proportion of measurements that are taken over longitudinal follow-up for a patient that fit within that range the better the outcomes seem to be both when we look at renal events and we look at some positive cardiovascular events like stroke and myocardial infarction. So I think there's a fairly robust belief that the more time you spend in a target range the better you expect our outcomes to be. And the only limitation has been our ability to continuously manage blood pressure over time to really robustly assess that treatment response.

Fantastis. Simon, do you want to just add a little bit from what we've learned...

Yes, 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. And really, that was highlighted by this ability to achieve continuous control of blood pressure throughout the 24-hour period with only 2 doses a year. So that really does speak to that.

Fantastic. And maybe the follow-on I guess, Asa, to you is could we just accomplish the same things by just intensifying and combining more oral therapies for patients. And do you think the aldosterone synthase inhibitors might help in that regard?

Yes, 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. But 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, it's a problem with physician use of the medications or it's a problem with patient adherence. And 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. And we know that on the whole, we haven't done a great job of controlling blood pressures even with the arsenal that we have. So 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 is that most patients prescribed the medicine about half of them by a year have stopped taking it or -- and 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 correlation.

Very helpful. And Victoria, I mean, for you, how do you kind of see -- let me introduce Victoria Silva, who heads up our commercial team for zilebesiran. Thank you for joining us for this portion. How -- building on what Akshay said, how do you think about these new branded therapies like aldosterone 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?

Yes. So what we really see about zilebesiran is that we're creating a new category. We're going to be -- 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 the other existing therapies. And to a lot of the points made will allow us to establish continuous control will allow us to overcome the adherence hurdles that we see with the oral therapies today. And so we think those things combine are really what sets us apart. And that, in addition, the uptake of emerging therapies really helps validate the need for this innovation. So what we're seeing in the marketplace is actually encouraging to us that there is absolutely space for zilebesiran to enter the market.

And if I can 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 pressures out of range and then react to that observation, whatever the genesis of that problem is here's 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 clastic nature of how patients take their medication.

So that's a really important point. And I imagine with wearables and things like that, that's only going to sort of accentuate that identification of patients, right, in their normal lives. Ashir, maybe I can turn to you. There's a number of questions that have come through in terms of -- okay, given the study didn't sort of meet its threshold benefit that we were looking for, but then there's a series of analyses that look for enriched population. What gives us confidence? Can you just speak a little bit more to like the idea about the diuretics. Was that just a subgroup that was identified? Or 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.

So based on our known biology and prior research with both sivisiran and other RAS agents, even prior to KARDIA-3, we suspected we might see enhanced responses zilebesiran in patients on diuretics as well as patients with a blood pressure of at least 140, which is a standard threshold for Stage 2 hypertension. And both blood pressure and background diuretic use were included as prespecified stratification factors in KARDIA-3 and both were also included in prespecified post-hoc analyses. So I would say KARDIA-3 met its objective in 3 key ways. First, it helped identify the population most likely to benefit from zilebesiran that is patients receiving 2 or more background antihypertensives, 1 being a diuretic, with the systolic blood pressure at least 140 millimeters. In this population, zilebesiran achieved an enhanced response of 8 to 10 millimeters in office and 24-hour systolic blood pressure out to month 6. Second, it confirms the safety of zilebesiran in combination with 2 or more background anti-hypertensive in patients with high cardiovascular risk. And third, it established the dose for the Phase III, a twice yearly 300-milligram injection. So in conclusion, KARDIA-3 helps optimize the design the heart 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.

Akshay, that's really great and clear. So maybe building on that, Simon, we questions coming, you've shown blood pressure benefit already with this drug, blood pressure is a registerable endpoint Akshay talked about how important that continues to go. So why not just register on blood pressure. why the investment in the sizable outcome study?

Yes. So it's a great question Pushkal, and look, you heard from Asia, we saw really encouraging results in our Phase II studies. And illustrated by a zilebesiran ability to achieve continuous control of blood pressure with only twice yearly dosing. And we believe all of the salient points that Akshay mentioned, that this has the potential to improve cardiovascular comes. And it's worth acknowledging that it's an entrenched generic oral antihypertensive market. And outcomes data will be required to differentiate zilebesiran beyond blood pressure alone. And Alnylam and our partners at Roche we really do believe zilebesiran potentially come at creator. As Victoria's said, in cardiovascular risk management and not just another antihypertensive and generating the best outcomes data for initial launch is key to our strategy. And just to repeat again, it's worth mentioning that zilebesiran was awarded Fast Track designation by the FDA breakthrough therapy designation in China, which we believe really illustrates how it leads us view both the unmet need and the potential of zilebesiran to improve outcomes.

Good. And then I think a follow-up from there, as you just highlighted, why there was a biologic rationale for requiring background diuretics, we saw a larger treatment effect in that population. But all concerned, Simon, and maybe that this is going to constrain the label in some way? And two, and maybe more importantly, I guess to you, Akshay, can you just talk about this population that we've highlighted, Asher highlighted and Simon that we're enrolling in ZENITH, how representative of that is that of the patients that you see? Are these Zebra patients as we talk about medicine? Or are these kind of what you see -- how common is this type of patients that we're targeting. So maybe, Simon, you can start and then we'll go to Akshay.