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

Good day, and thank you for standing by. Welcome to the ALN-AGT RNAi Roundtable. [Operator Instructions] Please be advised that today's conference may be recorded. I'd now like to turn the conference over to Alnylam.

Good morning, everyone. Thank you for joining us today for this RNAi Roundtable, where we'll be discussing zilebesiran, or ALN-AGT, our investigational product in development for the treatment of hypertension. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. I'm joined today by Pushkal Garg, Chief Medical Officer at Alnylam, Dr. Elizabeth Ofili, Professor of Medicine at the Morehouse School of Medicine; Stephan Huang, Senior Director of Clinical Research at Alnylam; and Eric Green, Senior Vice President, Development programs at Alnylam. In just a moment, I'll hand this over to Pushkal, but let me start with a few brief comments. Today's RNAi Roundtable is part of a series of roundtable webinars that we're hosting this summer and early fall to review progress across our various programs. Today's event is expected to run approximately 60 minutes. Pushkal will moderate a Q&A session at the conclusion of the presentations. [Operator Instructions] Finally, as a reminder, we will be making forward-looking statements during this webinar, and we encourage you to read our most recent SEC filings for a more complete discussion of risk factors. And with that, I'd like to turn this over to Pushkal. Pushkal?

Thank you, Christine. My name is Pushkal Garg. I'm the Chief Medical Officer at Alnylam, and I want to welcome all of you as well to this roundtable today. I'm going to just take a couple of minutes to just give a little bit of background on Alnylam, and what we've been working on for almost 2 decades now as a company. And that is to bring forward an entirely new class of medicines based on the science of RNA interference. This is Nobel Prize-winning science that enables us to actually silence any gene in the genome. Importantly, this new class of medicines has some very novel properties that allow for a potent and durable mechanism of action. And as a sustainable engine -- product engine for innovation. As I'll show you now, this engine has actually led us to bring forward a clinical development pipeline that's composed of over 12 molecules in active clinical development. We now have 4 products that are marketed, ONPATTRO, GIVLAARI, OXLUMO, and as this platform has evolved, as I'll share with you in a moment, increasingly into more prevalent indications as marked by the approval in Europe and the review that's ongoing in the U.S. for Alexion and inclisiran for hypercholesterolemia. Today, though, we'll be talking more about zilebesiran in a few moments. The 1 or 2 other points I wanted to bring up was that this sustainable product engine is associated with a high probability of success. This is related to the strategy that we have of pursuing genetically validated targets, programs where there are biomarkers and looking for clear and strategic development programs that meet regulatory and commercial success criteria. And as such, we have an over 60% success rate transitioning from Phase I into the clinic to positive Phase III results. As I just alluded to, as we've advanced this platform and the unique pharmacology of RNAi therapeutics, they are associated with particular properties that enable them to go increasingly into prevalent indications, a very durable mechanism of action associated with clamped pharmacology, a well-tolerated and increasingly well-understood safety profile and these can enable improved access. And as I'll show you, this is particularly important, and as our speakers will, potentially for the treatment of diseases like hypertension. So turning to hypertension. We're really excited about this program, zilebesiran, as a potential way to reimagine the treatment of hypertension. Dr. Ofili will talk to you more in a few moments about the unmet need, but just a couple of points to bring up, this is an incredibly prevalent indication 108 million people in the United States, over approximately 40 million of whom are at high CV risk. The majority of patients have uncontrolled hypertension. And that poor control is exacerbated by variability in blood pressure control, lack of nighttime dipping and poor adherence. And all of these factors contribute to the substantial risk of cardiovascular morbidity and mortality and are potentially addressable by a long-acting RNAi therapeutic such as zilebesiran. So let me now turn it over to Dr. Elizabeth Ofili, who we are really, really delighted to have join us to can expound more on the unmet needs for patients with hypertension. Dr. Ofili is a very distinguished professor of medicine, cardiologist at Morehouse School of Medicine. She is the Chief Medical Officer of the Morehouse Accountable Care Organization. She's the chair of the Association of Black Cardiologists and has really built a national and international reputation as someone who's focused on disparities in cardiovascular health, preventative medicine and women's health, and been addressing that through her clinical trial work, her leadership in various organizations and also as she'll share, advancing technologies to improve cardiovascular health and reduce health disparities. So Dr. Ofili?

Thank you so much, Dr. Garg. I'm delighted to be here. And so I'll be addressing the topic of health disparities in treatment gaps in blood pressure control. Next slide. These are my disclosures, I just want to comment that much of my research is funded by the National Institutes of Health. I do serve Advisory Board and consulting, as you see the companies listed and none of those will feature in my discussion today. And also, I hold a patent and as Dr. Garg mentioned, we are looking at technologies to improve access to treatment, especially with small practices that see predominant African American and underserved communities. Next slide. So these are my objectives. I want to outline the disparities in hypertension prevalence and control rates, discuss treatment gaps in hypertension, specifically the declining blood pressure control rates across all demographic groups, the multilevel barriers to treatment adherence and the patient-centered approach to blood pressure treatment. I also want to introduce Health 360x, the culturally congruent coaching for cardiovascular risk management, including blood pressure control and highlight the Association of Black Cardiologists' Cardiovascular Implementation Study, which is a registry that's integrating social determinants of care for underserved patients. Next slide, please. So these are new blood pressure categories put out by several organizations, including the American Heart Association, the American College of Cardiology, the AMA, and been endorsed widely. And these categories essentially redefined blood pressure. So elevated blood pressure now is systolic of 120 to 129 and less than 80. We have now stage 1 defined as 130 to 139 or 80 to 89. And the previous high blood pressure of stage 1 is now stage 2, which is systolic of 140 or higher or diastolic of 90 or higher and also highlighted patients that would need to immediately seek care based on blood pressures higher than 180 systolic or 120 diastolic. Next slide, please. The age adjusted prevalence of hypertension in adults 18 and over -- and I'm just using this to showcase the disparities here in terms of the prevalence of hypertension. And as you can see for both men and women, there's disparities with black hypertensives. But also overall, we can see that percentages of Americans that have higher blood pressure continue to be high, averaging overall over 40%, 43%. Next slide, please. So when we look at the treatment gaps in hypertension, as I mentioned, the 2017 ACC/AHA guidelines lowered blood pressure threshold for diagnosis of stage 1 hypertension, as you can see those levels there, 130 to 139 systolic. This change did result in substantial increase in the prevalence of hypertension, now up to 46%, of course, the United States adult populations, as I just shared. Hypertension control rates, especially among non-Hispanic white adults, 55.7%, significantly higher than non-Hispanic black adults, 48%. In other words, poor control remains a problem, especially for blacks, Asians and Hispanic Americans. Non-Hispanic black adults have especially higher nocturnal blood pressures and less circadian dipping compared to their white counterparts. This is actually important overall for not just control, but also for target-organ damage. Next slide, please. So when we look at this snapshot, this is looking overall at age-adjusted proportion of individuals with blood pressure control. What immediately strikes you is, of course, there has now been -- there was -- while there was a progressive increase up until 2012, 2013, there is a definite decline in control rates now. And there are a number of reasons involved in that, and we will come into that discussion in a couple of slides. Next slide, please. So when we look at adults with hypertension based on the National Health Nutrition survey, which is a survey that's done regularly to look at a snapshot of the nation, you're comparing here 2009 to 2014 versus 2015 to 2018. So the P-values there just show essentially the degree of change. And what is clear is just looking at the absolute numbers, the numbers have gone up between those 2 time periods, higher currently, for both systolic and diastolic, and those are highly significant. The other thing that has increased, and that's important for us when we think about what's going on with control rates, more Americans are obese. And as you can see, the percentage is over 30% BMI, higher now, 53.6% versus 49.6% previously. The other thing that has changed in individuals with a usual source of care that's consistent, generally, that's considered primary care providers. This number is -- that number is lower in the more recent time period. And of course, diabetes prevalence is higher. So we will come back to that in terms of our strategic approach to those individuals as we try to get better at controlling blood pressure. Next slide now looks a little bit into more detail about the demographic breakout. And let me just share, I know it's a little bit busy, all of the sort of signals I have there, whether it's the asterisks or the pluses are just showing the degree of significance of the changes. But just look at it and you can see, the increase in systolic blood pressure is across the board, all demographic groups, Whites, Blacks and Hispanics. Much higher for Blacks, clearly, so is the BMI increase also across the board and the problem with usual source of care, most dramatic for Blacks and Hispanics but certainly declined again across social demographic group. So I think these data, which were just recently published really shed some light into, there are additional determinants to think about when we think about high blood pressure. So on this next slide, we are looking at the backdrop and that's the problem of chronic diseases in America. 6 in 10 adults have chronic diseases, 4 in 10 of them have 2 or more of these chronic diseases. Why is that important? First of all, it's trillions of dollars that are involved, $3.3 trillion in annual healthcare costs. Second of all, it's the important role of high blood pressure. So when you look at 5 or 6 of these chronic diseases have a direct connection between uncontrolled blood pressure and the impact of those diseases. We're talking about heart disease, stroke, Alzheimer's disease and dementia, diabetes and chronic kidney disease. This is why when we think about effective treatment, we also need to be looking at key lifestyle risks for chronic disease, tobacco use, poor nutrition, lack of physical activity, excessive alcohol use, all feed into poor control of high blood pressure as well as, obviously, effective medications. Next slide. I just want to frame this in terms of how I see patients in my practice. So I just want you to meet Brenda. She's a wife, a mother of 2 children. She's employed full-time. She commutes approximately 45 minutes. Occasional travel. She has type 2 diabetes, hypertension and high cholesterol. She has 2 prescribers and has about 5 medications prescribed that she's supposed to take daily. And she sees her doctors on average maybe 3x, 4x a year, maximum. Of course, she's inconsistently controlled. She has no plan for improvement. She is not activated. She's not empowered. She has inadequate knowledge despite of being a very educated woman with obviously high-powered in multiple skills. But her skills are inadequate in terms of healthcare, blood pressure control, and therefore, she is overwhelmed. Next slide, please. So just look at this dosing history of 2 different patients. On the left and right, you are looking at patients that are recorded as having roughly 80% adherence to medications prescribed once a day. And so this is sort of the best-case scenario, if you will, and when you have the gray lines and bars or when people have skipped taking their medication. And so what you can see there is, over time, while this is a sophisticated with the monitor based on who's opening that memory pill box, it is pretty clear that there is a problem. Even when you think overall that there's adherence, there's actually inconsistency. And especially when you look at that box to the right, there's a whole week that goes by where a patient did not take their -- that patient did not take their medication. Next slide. And so when we think about adherence, we're looking at several categories of factors that are impacting adherence to prescription medication. So I'm not going to go through all of these in detail, but I just want to highlight its uses because I know you have access to these slides. There are social demographic factors as you see on the left-hand side, minority rates, ethnicity as we just shared, social determinant, and I want to emphasize here, health literacy. Now when we look at the healthcare system or the clinics, the engagement, how are doctors -- how is the patient-clinician relationship? What's that communication style? Is it patient-centered? And does it look for cues relevant to that particular patient, in terms of what they're dealing with, what they're struggling with? There's obviously the therapeutic things and the middle data shows it matters how you -- what kinds of drugs you have the patients on, how are those treatments being taken, is it once a day? Is it a more complex regimen of multiple times a day? That matters. What about individuals with multiple chronic conditions that can effect whether or not they understand the treatment or also how consistent they are. And that includes the symptom severity multiple chronic diseases as we just shared, whether or not they're using alcohol, whether or not they have any cognitive issues, depression, dementia, those all have been mapped. And then what about that patient-related situation? And we need to be very focused on this. Sometimes patients may not understand how effective drugs are. Sometimes they are concerned about side effects. Sometimes they forget to take their medicines and then also there's the issue of are they following up in care, and who is looking out for that? Next slide. So when we look at interventions, they got -- they have to be in these categories. What is happening at the physician level in terms of their ability to assess the barriers to care. Patient level in terms of how they can potentially be engaged with self-monitoring and self-management, and I'll share some examples. What about group sessions, peer group engagement to help them. Medication treatment, it's got to be simplified. We believe single pills or combination medicines, looking at opportunity for long-acting therapies and definitely avoiding high doses and side effects. And the health system, health systems can contribute because they can make it easier to have access to affordable drugs, issues, obviously, beyond health systems such as co-pays, but also the health system can contribute to providing some kind of a talent monitoring that brings the patient into care more frequently even when they are not physically in the clinic. Next slide. So I like this slide that was presented, and I have the reference there for you. It was really based on the broader discussion that was put out by the ACC/AHA. And this is the issue of racial disparities in hypertension. The major factors that are involved are shown in red, and these are -- obviously there are some genetic predisposition individuals with a strong family history, but more important are some of the social determinants, as I just shared. There are the reasons for worst outcomes shown in yellow and that's suboptimal risk stratification tools, but also variability in medication response and adherence. There are then future directions, and I believe we should pay attention to this novel, culturally specific treatment strategies, new therapeutic approaches that allow us to maybe dose less frequently advancing research efforts in ethnic data collection. Next slide, please. I just want to share with you this example we have, which we're very impressed by. And this is Dr. Priscilla Pemu from Morehouse School of Medicine. She was invited to the TED stage to talk about how she's been working with a platform called Health 360x. I did share my disclosure, I'm involved in developing this. But this has been work that was funded by NIH, and you see there the references based on published work. Worked -- this platform worked with African American patients, over 500 of them now through Morehouse School of Medicine and basically determined there are definite approaches that need to integrate cultural congruency. And she gives examples, and I encourage you to look at this TED Talk, if you just enter Priscilla Pemu, P-E-M-U, you'll have an opportunity to listen. And the reason I bring this up is, she mentioned the fact that there is conversation underneath the conversation. Sometimes the 10-minute encounter in the doctor's office is not enough. Sometimes coaches working with the patients, bring out new things in this particular case, patients that have 0 confidence that they can ever get blood pressure control, but working with coaches, learn that it is possible. Next slide, please. So this is the Health 360x. And just to mention very briefly, it is available for free. The patients do some of the research that I said Morehouse has sponsored and the NIH has funded. It allows the health coach to engage with the patient. The platform can be downloaded for free on the -- any of the platforms, whether it's Apple or Google Play. And you can just get more information on health360x.com. Next slide, please. So again, as I said, over 500 African-Americans were rigorously tested in these clinical research studies and have been promoted out there because we noticed that it is possible, as you can see in that lowest panel to go from a baseline blood pressure -- these are diabetic patients, to be quite clear, where they had reduced blood pressure less than 130 by 12 weeks, and we're able to sustain it at about 130 even after 52 weeks, the coaching stopped at the end of 12 weeks. So we know that the intervention was sustained. And I just want to mention that the Association of Black Cardiologists is working very hard with what we call the Cardiovascular Implementation Study which is a registry that integrates social determinants because we believe we have to do that for long-term care. And again, we have various cardiovascular diseases that are included in the registry, but the important thing is we are empowering small practices, looking at what's going on with their electronic medical records, making it accessible so they can use it and work with the Health 360x platform to more significantly engage their patients and consistently engage them in delivering care. And so as I close out, I want to just thank you all for listening. I know, hopefully, I didn't go through the slides very quickly. We welcome your questions, and I will turn it over now to our Chief Medical Officer -- to the Chief Medical Officer, Dr. Garg.

Thank you very much, Dr. Ofili. Really appreciate your really great overview of the unmet needs in hypertension, particularly affecting minority and disadvantaged populations, underserved populations. I'm going to turn it over now to Dr. Stephan Huang, who's Senior Director in Clinical Research, who's going to talk about the zilebesiran development program.

Thanks, Pushkal, and thanks again to Professor Ofili for her wonderful presentation. My name is Stephan Huang. I'm a clinical -- I'm a Senior Director of Clinical Research at Alnylam and in this section, I'll present our current Phase I data and introduce our global Phase II program. As background, this slide summarizes the therapeutic hypothesis of zilebesiran. Zilebesiran acts at the level of angiotensinogen or AGT, which is the first substrate in the renin-angiotensin system or RAS because AGT is the precursor of all vasoactive angiotensin peptides and because most circulating AGT is produced in the liver, zilebesiran's hepatocyte-specific silencing of AGT is predicted to be sufficient to inhibit the systemic renin-angiotensin system and to confer the therapeutic benefits of conventional RAS blockade. This includes the lowering of blood pressure in patients with hypertension. As shown on the right side of this slide, in contrast to conventional agents, zilebesiran has the advantage of tissue specificity for the liver, which is expected to spare local RAS signaling and extrahepatic tissues such as the kidney. Another important mechanistic advantage is zilebesiran's prolonged duration of action, which may achieve consistent and durable blood pressure lowering even within frequent dose administration. This has the potential to resolve the adherence problems inherent to daily oral antihypertensives and to also achieve more constant photonic blood pressure control. The data I'll present today is from Part A of our Phase I first-in-human study, which explores single ascending doses of zilebesiran versus placebo given to cohorts of 12 patients. This trial is a multicenter study in the U.K. And as shown on the left side of this slide, we studied patients with hypertension rather than healthy volunteers to enable an assessment of therapeutic blood pressure reduction. Other than the diagnosis of hypertension, patients were selected to be healthy with exclusion criteria in place for diabetes, low GFR or history of cardiovascular event. As shown in the center, we've dosed 7 cohorts using zilebesiran doses ranging from 10 to 800 milligrams. This corresponds to a total of 84 patients, 56 of whom have received active drug, an unusual feature of our trials is that because it's designed to evaluate antihypertensive effects over the course of weeks or months, our key blood pressure assessments, our 24-hour ambulatory blood pressure measurements or ABPMs, conducted in the setting of the patient's usual activity and dietary intake. As a Phase I study, our primary endpoint shown on the right side of this slide is safety and tolerability, PK and PD are secondary endpoints and change in blood pressure is analyzed as an exploratory end point. This study has enrolled a diverse population. As shown in this table, the median age of the study population is in the mid-50s with approximately 40% of participants being female and about 1/4 of participants being black. At baseline, the median 24-hour systolic blood pressure was in the high 130s, which corresponds to the mild to moderate hypertensive range. No important differences were observed in demographic features between the active and placebo groups. For safety, zilebesiran has been well tolerated. Approximately 3/4 of zilebesiran-treated patients have reported at least one adverse event, most of these events have been mild and resolved without intervention. There have been no deaths or AEs leading to study withdrawal or treatment-related serious adverse events. No patient has required intervention for low blood pressure from excessive pharmacology, and there have been no clinically significant elevations in Alanine aminotransferase, serum creatinine or serum potassium. Minority of patients have reported injection site reactions. All these were mild events that resolved in 1 to 2 days. Pharmacodynamic data showed dose-dependent and durable reductions of circulating angiotensinogen after single doses of zilebesiran. After doses of 100 milligrams or higher, reductions greater than 90% were achieved by week 3 and persisted through the end of the protocol's 12-week treatment period. The greatest reductions in serum AGT were observed in the 800-milligram group where all patients achieved more than 95% lowering. After the 12-week treatment period, our protocol requires patients to return for safety follow-up every 3 months until their serum AGT recovers. Data from these visits show meaningful AGT knockdown up to 24 weeks after higher doses, further supporting that infrequent dosing will be possible. These reductions in serum AGT were accompanied by corresponding clinically significant reductions in blood pressure. The graph on the left shows change from baseline in blood pressure, assessed by 24-hour ABPM performed at 8 weeks after single dose administration, after doses of 100 milligrams or higher, mean reductions in 24-hour systolic blood pressure greater than 10 millimeters of mercury were observed with the mean reduction of 17 millimeters of mercury in the 800-milligram group. Once we observed these positive results, we amended the protocol to perform an additional ABPM at the end of the 12-week treatment period. And as predicted from the serum AGT data, this confirmed persistent antihypertensive effect through week 12, illustrated in the graph on the right. Looking at individual patient responses. This slide shows a waterfall plot, comparing the individual responses of all patients who received placebo shown here in blue, to the responses observed in the pooled group of all patients who received a zilebesiran dose of 100 milligrams or higher, shown here in red. Even 8 weeks after dosing, clear differences in the change from baseline in 24-hour blood pressure are evident between the groups. As shown on the right, the majority of active patients responded to zilebesiran with a median treatment effect of approximately 10 millimeters of mercury. To begin exploring the concept of constant 24-hour blood pressure control, this slide shows the mean 24-hour blood pressure profile of all patients in the Phase I, who received a single dose of 800 milligrams of zilebesiran, shown here in blue versus those who received placebo, shown here in red. Consistent with constant or tonic antihypertensive effect from zilebesiran, blood pressure is reduced relative to placebo at every hour of the day and nighttime periods. The planned potential dosing regimen data from the single ascending dose study have been used to generate clinical pharmacology modeling. As illustrated here, the model predicts the potential for both quarterly and biannual dosing regimen, showing that reductions in systolic blood pressure greater than 10 millimeters of mercury to be maintained throughout these dosing intervals. In the remaining slides, I'll summarize the current status of our ongoing Phase I study and then introduce our plans for Phase II. Starting with Phase I. Dosing in the single ascending dose study, I just presented, is now complete. Given the long-term knockdown of serum AGT, safety follow-up of individual patients will continue, and we anticipate sharing updated data from these assessments later this year. The Phase I has 2 parts that are designed to assess the tolerability of zilebesiran during potential augmented pharmacology induced either by a low-salt diet or by co-administration of the conventional RAS inhibitor, irbesartan. These cohorts have completed dosing with data readout expected later this year. Finally, a Phase I multidose cohort in obese patients to assess the effect of repeat dosing and the potential impact of body weight on PK and PD is currently enrolling with the goal of completion by the year's end. Moving to Phase II clinical development. Two global studies are planned named KARDIA-1 and KARDIA-2. KARDIA-1 is designed to evaluate the efficacy and safety of zilebesiran as a monotherapy. I'll describe the study in more detail in the next slide. Our IND opened in May with study initiation earlier this month. KARDIA-2 is designed to evaluate the efficacy and safety of zilebesiran as an add-on therapy in patients with hypertension despite treatment with a potent RAS inhibitor, a calcium channel blocker or a diuretic. We are targeting steady initiation in late 2021. Looking at the KARDIA-1 trial in more detail, it's designed as a randomized, double-blind, placebo-controlled dose-ranging study. As shown on the left, compared to Phase I, the Phase II population has been expanded to include individuals up to 75 years of age and those with diabetes or GFR as low as 30. After a washout period, patients will be equally randomized to placebo or to 4 active regimens of zilebesiran, evaluating both quarterly and biannual dosing regimens. The primary endpoint is changed from baseline in systolic blood pressure at month 3, which corresponds to the end of a strict placebo-controlled period. Additional blood pressure assessments, including at month 6, are secondary endpoints. As in the Phase I, ABPM will be used to evaluate the consistency of blood pressure control over the 24-hour period. In addition, repeated blood pressure assessments by both ABPM and office measurements will be collected to evaluate the consistency of blood pressure control over the entire multi-month intradosing period. We're excited to share that we've activated our first site and that the KARDIA-1 trial is now open. In summary, single doses of zilebesiran have been well tolerated in Phase I. Doses of 100 milligrams or more achieved more than 90% reductions in serum AGT and more than 10 millimeters of mercury reduction in systolic blood pressure. These data support the potential for infrequent quarterly or biannual dosing regimen, which will be evaluated in Phase II. The Phase II KARDIA-1 trial is now open, and we're looking forward to opening the KARDIA-2 trial later this year. Now I'm happy to hand the presentation over to Eric.

Thank you, Stephan. Hello, everyone. I'm Eric Green, Head of Development Programs here at Alnylam. Today, I will provide a brief view of the commercial opportunity we see for zilebesiran as a potential treatment for patients with hypertension. Based on the data that we have just reviewed, we believe we have the opportunity to reimagine the management of hypertension, a highly prevalent disease that has been devoid of significant innovation for decades. Dr. Ofili already spoke to some of the challenges of adherence, especially for the treatment of chronic diseases that are generally asymptomatic. On the left here is another depiction of the various barriers between a prescription being written and a patient taking their medication correctly and for an extended period of time. Although these data are not specific to hypertension medications, the general trend would obviously hold. Several of the potential features of zilebesiran, such as the infrequent dosing and ability to reduce the daily pill burden could help improve patient adherence. The final bullet focusing on tonic blood pressure control over the dosing period, for example, 3 or 6 months is a good segue to the next slide. In this framework from Kario et al, there are 3 components to 24-hour blood pressure control: The 24-hour blood pressure levels, nocturnal blood pressure dipping and blood pressure variability such as the morning BP surge. The quantity of BP reduction is important, for example, lowering blood pressure by 10 to 15 millimeters of mercury. But ideally, that reduction is consistently maintained throughout the 24-hour period and doesn't wane during the night. The challenge with some oral medications that have peak to trough effects every day. Restoring normal nocturnal dipping and avoiding exaggerating morning blood pressure surges are more qualitative aspects for blood pressure control, but also have an impact on CBD risk. Achieving all 3 of these objectives could reduce the risk of organ damage and cardiovascular disease events. Given zilebesiran's profile of potential features, we have -- we may have a positive impact on each of these 3 areas. We look forward to seeing additional data from the KARDIA studies to further understand the profile of this product. When considering the future commercial populations for zilebesiran, we are considering 2 patient segments, assuming a successful clinical development and ultimately, regulatory approvals. The first segment includes patients with uncontrolled blood pressure at high risk for major adverse cardiovascular events. We have estimated the U.S. prevalence of this population to be approximately 38 million people, of which approximately half have uncontrolled blood pressure despite treatment with currently available therapies. The population is defined as patients with a cardiovascular risk or a previous medical history of a cardiovascular event. The current treatment landscape in this therapeutic area is dictated by well-established treatment guidelines, with different classes of medicines being prescribed based on hypertension severity, specific comorbidities that, that patient may have. As many of these patients are taking medications to address their multiple comorbidities, as Dr. Ofili pointed out earlier, as an example, with Brenda, daily pill burden can be significant and medication adherence is often suboptimal, also, as you heard earlier. Lack of adherence is of utmost concern in these patients at high risk for cardiovascular events, where uncontrolled blood pressure can lead to poor clinical outcomes. An antihypertensive medication with tonic blood pressure control and infrequent dosing could be advantageous in treating this population. The disease burden of hypertension is significant. Uncontrolled hypertension is a major risk factor for cardiovascular disease morbidity and mortality. And annually, approximately 1.5 million people in the U.S. suffer from myocardial infarction and stroke, with approximately half of these major adverse events attributed to hypertension. The burden of hypertension and healthcare cost is also quite significant. Annual direct and indirect cost of hypertensive disease and stroke is estimated to be approximately $55 billion and $45 billion, respectively. While only approximately half of the stroke costs are attributed to hypertension, additional healthcare costs are also incurred due to hypertension within the broad category of heart disease. Given the unmet medical need for treatments that provide further blood pressure reduction that is durable and less variable in patients at high risk for major adverse CV events, we estimate zilebesiran could achieve revenues of greater than $4 billion a year at peak. The market for broad hypertension treatment is also significant. As Pushkal mentioned earlier, over 100 million patients in the U.S. have hypertension and despite availability of multiple classes of antihypertensive medications, approximately 3/4 of these hypertensive patients do not achieve the controlled blood pressure. The general treatment paradigm and disease burden is the same as described on the high CV risk population in the previous slide. However, given the endemic adherence issues associated with uncontrolled blood pressure and primary hypertension, zilebesiran has the potential to be a foundational antihypertensive medication that would be infrequently administered and provide sustained and durable blood pressure lowering in patients that have difficulty in achieving their blood pressure goals. Given this, we believe that the treatment of primary hypertension could also be a $4 billion market opportunity at peak. Of course, these 2 populations do have some overlap, so the commercial potential isn't necessarily additive. Briefly summarized, we are quite excited about the continued development of zilebesiran as a potential treatment for patients with hypertension. We believe there remains a significant unmet need in this disease, particularly in patients with uncontrolled blood pressure at high risk for cardiovascular events or even potentially in patients with primary hypertension. The initial Phase I data are encouraging, demonstrating meaningful blood pressure reductions at higher zilebesiran doses and robust pharmacodynamic effect showing durable reductions of serum AGT that supports the potential for quarterly or even biannual dosing. And with the initiation of the KARDIA clinical development program, we are moving into the next important phase of this program. I'll now turn it back to Pushkal to moderate the Q&A session. [Operator Instructions] Pushkal?

Thank you, Eric. Thanks, Stephan. Thanks again to Dr. Ofili, for all of your great presentations. And as Eric said, we're now going to open it up for question and answer. And if you do have questions, please enter them into the webinar portal. So the first question that came in is just -- is for Dr. Ofili. So Stephan reported about 10 to 15 millimeters of systolic blood pressure lowering with zilebesiran. Dr. Ofili, can you just comment on what is considered a clinically meaningful reduction in blood pressure, systolic or diastolic. How do you think about that?

Right. In general -- thank you so much for the question. In general, when we look at single drug therapy, obviously, reductions of 5-millimeter is considered important. And then when we add combination therapies, we may get more. But usually, between 5- and 7-millimeter reduction. Most antihypertensive agents are in that range.

Thank you, Dr. Ofili. Stephan, a question came in around a concept on the study diagrams for KARDIA-1 and KARDIA-2, where you've talked about time-adjusted average blood pressure. And some questions about what does that exactly mean? How do you look at that? And why is it important?

Thanks, Pushkal. So this refers to the time-weighted average of multiple blood pressure measurements collected over time, which can be calculated as an indicator of overall blood pressure control over an extended period. And we include this as an endpoint in our trials to study the concept of durable and constant antihypertensive effect for weeks or months after dose administration, which we see as a potential novel feature of zilebesiran.

Interesting. So then this actually, I think, may relate to some other questions that have come in, which is you presented these 24-hour plots of blood pressure. Why does the -- we talked about clam pharmacology. Why does the blood pressure go up and down then over a 24-hour period? Is that, that the AGT reduction is changing, or what does that represent?

Sure, Pushkal. I'll start with the comment about change from day to night. So reduction of blood pressure at nighttime relative to daytime is a normal physiologic pattern called dipping, that's observed in healthy individuals without hypertension. So even with optimal pharmacology, the goal of optimal 24-hour blood pressure control includes the restoration of this normal circadian pattern, and we will, in fact, assess the restoration of dipping in our Phase II trials. If you'd like me to comment on the 24-hour blood pressure profile, the profile of zilebesiran we showed indicates reduced blood pressure relative to placebo at every hour of the day and nighttime periods. In contrast to this, some commonly used oral antihypertensives that are short-lived and administered once daily have reduced efficacy towards the end of their 24-hour dosing interval. This can manifest as reduced separation from placebo on that type of 24-hour blood pressure profile. Depending on the timing of administration, which can be variable, as shown by Dr. Ofili's presentation, this reduction of control with short-lived oral antihypertensives can lead to nocturnal hypertension or to an exaggerated morning blood pressure surge.

So just to follow up, are you suggesting that if you took -- if you looked at that same profile for a conventional agent, that gap between placebo and active would actually be fluctuating more over time is what you would expect to see based on the pharmacology?

That's correct.

Interesting. All right. Dr. Ofili, there was a number of questions and interest in some of the work that you presented around adherence. You presented a narrative of a patient named Brenda, but I think one of the questions that came up is it seems that a number of patients fill prescriptions, but then they stop taking them over time. Can you expand a little bit more on why -- what are some of the common reasons that people stop taking medicines over time after they're initially prescribed?

Yes. So, thank you again for that question. So what we find is that sometimes the most common reason is patients may have a side effect or what they consider to be a side effect, right? Remember, many patients with high blood pressure do not have just one condition. So they've got different medicines they're taking. And sometimes, if they think they have a side effect -- at least what my patients tell me, sometimes they stop everything. And I have to really get into discussion with them that, that is really not -- there are some side effects that we can anticipate. So you can address that upfront by sharing some potential side effects with them. But I do believe that one of the biggest difficulties patients have is that they now have all these multiple medications, the regimens are complex. There's polypharmacy. Is if you've got -- Brenda has only 2 conditions as you saw, but she already has 4 prescribers. And she's probably taking 5 or 6, including stuff that she's taking over the counter. And so I think the more we can simplify and then couple that with clear education upfront about what patients can expect and then especially for high blood pressure for patients with high-risk cardiovascular disease, they cannot stop taking their medicines without risking a rebound and then potentially problems with cardiovascular exacerbation. I just had a patient yesterday in my office, where she thought -- she said, "I'm confused. I think I'm not taking my medicines correctly. Should I -- I usually start in the morning, and I finish taking anything by 2 or 3 in the afternoon". So you see patients just think if I take all 5 right upfront, I'm going to get sick. So again, that requires education and patients need to know that some of the medicines, because you take them, doesn't mean that you'll have magnified side effects. And then there are things where they need to know, okay, you need to shift this to bedtime. So those kinds of communication are important before we outright just dismiss a patient as just not wanting to take the medication.

That's really helpful context. Maybe just building on that, what are some of the tactics that you've employed. You talked about some technology solutions that you're involved, and your colleagues are involved in developing. But specifically in terms of talking to patients about adherence, are there specific tactics that you've pursued or employed that you find helpful?

Yes. I really -- and I appreciate that question because it speaks to what I deal with every day with my patients. Patients actually obviously want to get better. That's why they came. But they don't know what they don't know. And what I try to explain to my patients is you are not alone. Over 85% of Americans do not have appropriate health literacy. And as defined by the National Academy of Medicine, that means this -- the patients that have low health literacy do not have the ability to comprehend instructions that are provided, whether it's at the pharmacy or in the doctor's office and act on it in a consistent manner for the benefit of their health. So when we start with that premise and make everybody comfortable and say, this is not saying you are ignorant. Health literacy is not about ignorance. Health literacy is about understanding how things potentially interact with your disease condition, with your own makeup and how that could lead to better outcome depending on how you take the therapy. So once we clear that hurdle, then I say to them, the next thing is what's going on inside your body? How are you detecting that? Don't assume that you're going to have a headache when your blood pressure is elevated because by the time you get the headache, you're probably about ready to have a stroke, which means you should be in an emergency room. So I explained to them that there is no substitute for tracking your own health. It is your activity, it is what you put in your mouth. It is the actual blood pressure that you're measuring. And now we have all these technologies. But people get confused what should I follow? What about my sleep? And I explain that sleep actually also has relevance, but it is about how well and the quality of your sleep. So before you get all carried away with all of the devices, focus on your blood pressure. And then I show them example of me, and I say, look, this is what happened. This is how my blood pressure varies, and I don't have high blood pressure, but it is varying in a physiologic range, but sometimes it goes into an elevated range. So you need to know that. And as for me, when I don't have enough sleep, or when I'm not as active or not eating a certain diet, it affects that. So when people know that about themselves, especially patients that are hypertensive where this variation is really more marked and more prominent, as you heard from the discussion. And I think they then integrate that into their behavior. The most excited patients I have are patients who come back and say, "Oh, my goodness, look what happened. I took my medicine, blood pressure didn't drop like I thought it would, but it was in a good range, but even when I went for a walk and came back, I saw the change in my blood pressure." So it's just understanding that these ranges, but also bringing them to the discussion about what a pathologic variation versus something that they can expect so they don't freak out. So that kind of -- it's an ongoing process, and that's why for us, we also bring in our team approach where we bring in coaches because the doctor only has, whatever, 10, 15 minutes with the patient, the way our health system is designed and most patients are spending the majority of their time going about it in the community. So having that help just gets them more comfortable, more confident in their ability to help manage their own health.

That's really elucidating, Dr. Ofili. I think you highlighted what I think many people may take for granted as being somewhat simple with all the medicines that are available, but really, it is a very complex milieu that you have to negotiate with patients and health systems, et cetera. So that's really helpful. And just one other question came through. Does telehealth play a role? This is what you've described, it really highlights perhaps a lot of touch points with patients and frequent check-ins has -- how does telehealth play a role in any of this?

Again, an excellent question. So what we found, and this was actually a revealing moment during the pandemic because people were not going to the hospitals, they were not coming to the doctors, they were having more heart attacks and strokes. And so when the reimbursement allowed us to bill for telehealth, the stuff just went through the roof. Now what happened with us because we already had this platform. We basically told patients -- for some patients, their technology doesn't allow them to get in a video conference, we told them that's not the key thing. The key thing is what have you monitored that you can share with us, right? So then patients were able to, in our model, they can just -- we connect with them once they have the platform through a link and they just then -- they don't need to do anything other than enter their data into the platform. And then we get to communicate because they say -- they give us permission as their doctor or coach to have this communication. So it kind of gives them that sense of security, say that, okay, my doctor is looking at this. And if it's in the dangerous zone, they'll tell me what to do. And then that is our classification, we call it telemonitoring and telehealth because it's not just about just going in and doing something. It's responding to something that the patients collected, essentially, and sent in. And so that has really been very, very helpful, and it's not as -- the numbers are not as high as when we were in the middle of the pandemic, but then there are many practitioners that now want to do this in an ongoing manner for patients. Especially those that have multiple comorbidities, helps to control blood pressure, they're not going to be coming into the office every month or every week, so we just then use this as a way to get that blood pressure controlled, and also when we change medications because you kind of want to know and that give patients confidence that, okay, I can take that new medicine because somebody is watching, somebody is monitoring what's going on with me.

That's really helpful to hear. And it's wonderful if there's advances in this space that have actually been spurred on by the pandemic, so maybe at least one positive outcome there. A number of questions that have come, maybe Stephan and Eric, for you 2 around therapeutic positioning of zilebesiran. Will it be used as a first-line therapy? Will it be used as add-on therapy? Will it be used in treatment-resistant patients? And will there be studies in that population? And then likewise there, what might be the payer sort of requirements? Will there be step-throughs, et cetera? So do you see it being used as a first-line agent or a later-line agent? What's our thinking around those topics?

I'll let Stephan start on the design of our KARDIA studies and the data we're starting to generate to help inform some of those answers.

Sure. Thank you, Eric. So our initial thinking for positioning focused on patients with unmet need with current therapies, including patients with resistant hypertension, patients with high cardiovascular risk, who aren't able to achieve adequate control despite treatment with multiple conventional antihypertensives. So we are developing trials like KARDIA-2 to understand how our drugs could combine with conventional agents in those sorts of populations. However, as we've seen that data develop from Phase I, observed a very constant and durable control of blood pressure. And as we learned from experts, like what Dr. Ofili taught us about how adherence challenges exist at all stages of disease, we've actually also started to think about the possibility of being used earlier in the treatment paradigm, possibly as a foundational therapy.

Great. And so once we learn more, obviously, from our 2 Phase II studies, we'll then inform our development of our pivotal Phase III studies, all of which data will inform which patient population may benefit most and initially and then over time, as we continue development. So we highlighted 2 potential populations in the slides. Those patients at high CV risk, those have had at a prior event or have prognostic factors indicate they may be at high risk, could be a very appropriate patient population, the first use of zilebesiran. As far as what health payers and governments may think about this, this is a huge healthcare burden, the treatment of hypertension or lack of control of the hypertension is a huge cost. We believe with an innovative profile like zilebesiran hopefully will continue to generate, we have the chance to change health at a population level and lower that catastrophic risk across an entire population, whether it's government or region or even a particular commercial payer. We do recognize that as we address a much more prevalent population, price will be aligned with other innovative drugs in a very prevalent population. And we will build on our history over the last number of years of being innovative in our pricing and our interactions with payers and with governments and value-based agreements that we really hope that we will be able to make zilebesiran available broadly for patients that may benefit.

Very, very helpful. Thank you, both. I think we have time for one last question. So there were a couple of questions that I'll sort of bundle together. Stephan, maybe you're in the best position to answer, which is around the emerging safety profile of this mechanism. One was, have we seen episodes of hypotension in the Phase I study? Can you lower AGT too much? And then will we -- do we expect with this RNAi approach that we would see other common side effects that are associated, for example, with ACE inhibitors, whether it be renal safety concerns or angioedema. Can you just comment on a couple of those things?

Sure, Pushkal. So the possibility of hypotension from excessive pharmacology is something that's important, and we tried to gain early insight from that -- into that with animal models. So in those preclinical models, deep knockdown of circulating AGT, even in normotensive animals was not associated with hypotension, our trials monitor carefully for low blood pressure. And as I mentioned in our presentation, no patient in the Phase I study has developed a hypotensive event even at the highest doses. We'll continue to monitor carefully going forward for low blood pressure, but it's worth noting that we have also conducted preclinical experiments to confirm that standard treatments for low blood pressure, such as increasing dietary salt intake, and use of common vasopressor agents will remain effective in individuals who have been treated with zilebesiran. For the other types of renal safety events associated with conventional RAS blockers, here, our feature of tissue specificity is important. So with our approach of renal sparing, we only target liver angiotensinogen, and that's notable because there are data to indicate that one of the reasons patients who are treated with conventional ACE inhibitors or ARBs, may experience nephrotoxicity is due to the local effects of those drugs in the kidney. So we view zilebesiran's ability to target liver-specific angiotensinogen without impacting the kidney to be a novel opportunity to potentially avoid the renal injury that's associated with conventional drugs.

Very helpful, Stephan, thank you. I think that's all we have time for in terms of questions today. I'm going to turn it over to Christine, but I just want to thank all of our presenters and thank all the participants who dialed in and asked questions, and we look forward to giving you more updates on zilebesiran in the coming months. Christine?

Thanks, Pushkal. And thank you to Dr. Ofili, Stephan and Eric as well. So this will conclude our RNAi Roundtable for today. We'll be posting the replay and the slides on the Capella section of our website at alnylam.com/capella. And we'll also plan to post a transcript once that becomes available. We hope you can join us for our next RNAi Roundtable on July 16, where we'll be discussing patisiran and vutrisiran in the development for ATTR amyloidosis. Thank you, everyone, and have a great day. Goodbye.

Thank you. Buh-bye.