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

Please welcome Chief Executive Officer, Yvonne Greenstreet.

Hello, everybody. It's absolutely fantastic to welcome you all to New York for our R&D Day 2025. And during our time together today, you'll be hearing from some of our key R&D leaders who will describe to you the progress against our R&D strategy. The accelerated pace of innovation with respect to our pipeline and platform. Look, our R&D engine is truly humming. And I could not be more excited about the opportunities that we have ahead for patients. Before I start, I need to remind you that today's presentations will contain forward-looking statements, and they are noted on the slide. Fortunately, for you, I'm not going to be reading through the slide, but I will get on to the presentation. Look, Alnylam is clearly, clearly the leader in RNAi therapeutics. We've demonstrated outstanding R&D productivity. And this has validated an entirely new class of medicines. This does not happen very often. And it's produced an outsized probability of clinical success relative to the rest of the industry and produced a commercial portfolio of 5 medicines. We've delivered a rich pipeline with numerous multibillion-dollar opportunities across diverse indications by the end of 2025. We've also built leading commercial capabilities with a global footprint, and we're now serving patients in 60 countries across the world, 30 with a direct presence. And we've established a robust financial position, where we have growing revenues, strong balance sheet with $2.7 billion of cash and approaching profitability. This is a unique profile that's rarely seen in the biotech industry. Now 2024, was a transformative year for the company. And there are a number of highlights, but I'd like to just touch on a few. Obviously, the highly positive results from the landmark HELIOS-B Phase III study and the submission of global regulatory filings for vutrisiran in ATTR cardiomyopathy. We also advanced continued innovation for ATTR patients with Phase I data with nucresiran, really building durable long-term growth for our TTR franchise. We continue to advance mivelsiran, including initial multi-dose results in patients with early onset Alzheimer's disease and the initiation of the cAPPricorn-1 Phase II study in cerebral amyloid angiopathy. We're also pleased with our progress with zilebesiran in hypertension, where we're going to reimagine the treatment of hypertension. We got positive results from the KARDIA 2 Phase II study showing significant additive blood pressure lowering. And we expanded our clinical pipeline with 4 proprietary CTAs as well as a number of additional CTAs filed by our partners. And we demonstrated exemplary financial performance, achieving combined net product revenues of over $1.6 billion, while maintaining, which is very important to us, our award-winning culture because this has been a critical enabler to our success. Now the achievement of $1.646 billion in combined net product revenue in 2024, I just want to underscore that this was at the high end of our revised guidance and represented growth of 33% compared to 2023. And I think it's also worth noting that since 2019, which is our first full year of being a commercial company, we've seen impressive revenue growth with a 58% CAGR over this time period. Now we believe that the strong commercial performance, coupled with the very solid capabilities that we have built, position Alnylam well for exceptional future growth. At JPMorgan earlier this year, we provided our 2025 net product revenue guidance. Now specifically, we're guiding towards total combined product sales of between $2.05 billion and $2.25 billion. And this represents over $0.5 billion in annual growth at the midpoint of the guidance. And if we're successful in meeting this product revenue guidance, we anticipate achieving sustainable non-GAAP profitability by the end of this year. So wrapping up, here is a full list of our company goals for 2025, which captures key elements of the exciting year ahead. Now I'm not going to walk through all of these. But I think it's worth highlighting 6 commercial products, 3 Phase III study starts. Vutrisiran launched in ATTR cardiomyopathy, KARDIA 2 Phase II results, 3 Phase III study starts, 4 or more new INDs and obviously achieving sustainable non-GAAP profitability. So all of this represents tremendous progress against the ambitious 5-year goals that we launched in early 2021, our P5x25 goals. And we really are now on the cusp of turning these goals into reality, which will set us up not just for the rest of this decade, but for years to come. There's so much more opportunity ahead of us as we look forward to fulfill the promise of RNAi and usher in the next era of growth for the company. So with that, I'd like to turn over to Pushkal, who is going to provide you with some perspectives on our R&D strategy and walk you through the rest of our time together today. Thank you so much, Pushkal.

All right. Thank you, Yvonne, and good morning, everyone. My name is Pushkal Garg and I'm the Chief Medical Officer at Alnylam. I want to join Yvonne in welcoming you all to our 2025 R&D Day. My job is actually primarily to focus and introduce you on the agenda, but I'm going to take a few minutes before that to tell you about our overall approach to R&D at Alnylam. Now as you all know, Alnylam has been pioneering an entirely new class of medicines to treat human disease. This generational technology leverages the natural process of RNA interference, which was discovered about 25 years ago. And it's a natural process of gene regulation that occurs in every cell of our body. We couple this novel insight, this natural process with state-of-the-art delivery so that we can get our oligonucleotides into any tissue that we desire with high efficiency and specificity in every cell type that we choose to, to affect disease. Now what's really remarkable is what we've learned about the attributes of RNAi therapeutics that make -- that allow us to create a class of drugs that's actually without any human precedent. So like a biologic scalpel, we can actually silence any gene in the genome, and we can work upstream of all other current modalities of drugs that are out there. It's a catalytic mechanism. That lends itself to highly potent molecules that require low doses to affect biology. The approach is highly specific and entirely reversible, which minimizes safety liabilities. And we're able to engineer long half-lives to enable very infrequent administration, which allows annual, biannually or quarterly administration. So with this technology and our relentless focus on execution, we've already delivered 5 novel medicines in record time. And we believe, and I believe that the best is yet to come. See RNAi enables a sustainable innovation engine. We can use human genetics to identify new novel targets. We can constantly innovate to optimize oligo design, and we can identify targeted and efficient approaches to tissue delivery. So we can couple this innovation engine, which is a flywheel of sorts with a disciplined strategy to pick a subset of opportunities to advance into and through the clinic. So what is that strategy? We only address diseases with high morbidity or mortality. We want to pursue high conviction targets. What's a high conviction target where we have a very strong biologic rationale, particularly informed by human genetics. We look for opportunities to potentially halt or reverse human disease and focus on best-in-class opportunities. We drive to clear and definitive proof -- clinical proof of concept. So that means incorporating biomarkers or other strategies early in development so we can buy down risk early in the development process. And then, of course, we look for encouraging opportunities with regard to market and access dynamics. So this sustainable innovation engine and our R&D strategy have yielded higher rates of success than the industry is known to date. And so it makes abundant sense for us to continue to invest in organic innovation in Alnylam. Our product engine allows us to only advance the best opportunities. And our anticipated strong revenue growth after the launch -- anticipated launch of AMVUTTRA in ATTR-CM will expand the opportunity for us to advance wholly owned programs. So we see ourselves in a very privileged position to deliver transformational medicines to patients. And we fully intend to take advantage of that opportunity and to deliver, relying upon our sustainable innovation engine, our deep knowledge of science and know-how around RNAi therapeutics and a proven track record of successful end-to-end execution. Now while we're disproportionately going to grow our internal pipeline of wholly owned assets, of course, we're going to continue to partner at times in a variety of flavors, when we believe that's the best way to create value. For instance, in the genetics space, where we may be able to have larger and larger data sets that will allow us to generate new insights, with technology partners where we can optimize delivery to various tissue types and cell types or with global pharma partners who can help us build capabilities and get our medicines to help more patients around the world, like we did with zilebesiran and Roche. So with these principles in mind, we've built 1 of the most exciting pipelines in the industry. It spans a range of therapeutic areas and diseases, all stages of development in each of these molecules with the potential to transform the care of patients with particular diseases. So today, we're going to be talking about many of these programs to tell you about why we're excited, how we see the opportunity and also to share new insights and data. But I do want to draw your attention to what we see as 3 potential blockbuster franchises in the making that can deliver in the near to midterm. These are in ATTR amyloidosis, cardiovascular disease and neuroscience. So as you all well know, we've had a lot of great success in our TTR franchise over the past 10 years with approvals of ONPATTRO and AMVUTTRA in hereditary ATTR polyneuropathy and now the pending approval of AMVUTTRA in ATTR cardiomyopathy with the strong HELIOS-B results. And that's now been filed in major territories around the world, and we eagerly anticipate the PDUFA date of March 23. John Vest, who's been leading the program for 10 years, will discuss what we see as the broad impact of this drug on this disease and why we believe it can become a new standard of care for patients with ATTR cardiomyopathy. This is going to be supported or affirmed by updated survival data that he's going to share with you today, which includes updated data going into the open-label extension period, which reaffirms the importance of this drug in being able to actually prevent mortality and save lives in patients with ATTR cardiomyopathy. He's also going to preview upcoming ACC presentations. But he's going to spend the most of his time, the bulk of his time today talking to you about how we and Alnylam are continuing to innovate and want to do even better by patients with this disease. So we're going to -- he is going to talk about how we're going to advance our next-generation molecule nucresiran, which we believe can offer better efficacy and better convenience for patients with this disease. So today, he's going to share our development plans in ATTR polyneuropathy and ATTR cardiomyopathy which we believe enables a fast-to-market approach and a best-in-class profile. After John, Simon Fox will come up to talk about a second blockbuster franchise in the making, zilebesiran for hypertension and atherosclerotic cardiovascular disease. Now I want to highlight, this is an area that is ripe for innovation. There has been no real innovation for over 4 decades in this space. And cardiovascular disease remains the leading cause of mortality around the world. We believe that zilebesiran's profile of continuous blood pressure control with twice a year dosing can improve both the quality and the quantity of blood pressure control and thereby potentially save lives, lots of lives. So he's going to provide an update on our ongoing Phase II program. He's going to preview our Phase III cardiovascular outcomes trial that we expect to start in the second half of this year and how we see this drug fitting in to the therapeutic armamentarium. And we'll close the first half of the morning by talking about our potentially third blockbuster franchise using RNAi to treat neurodegenerative diseases of the brain. You'll hear from Julia Shirvan about our mivelsiran program, targeting APP for cerebral amyloid angiopathy and Alzheimer's disease. And she's going to share some updated multi-dose data that, again, gives us a lot of confidence in this program but also in our C16 delivery platform for the CNS. And then you'll hear about Kevin Sloan about a very exciting program, ALN-HTT02, which uses a very unique approach to targeting the Huntington's gene. And we're actually very, very fortunate today to have 1 of the world's leaders in Huntington's disease. Professor Sarah Tabrizi from the University College of London, who's going to be joining us here to talk about the disease and our approach. In the second half of the morning, we'll talk about our mid- to longer-term growth drivers, new disease areas and platform technologies. My colleague, Kevin Fitzgerald, our Chief Scientific Officer, will tell you a little bit more about those shortly. But we're going to talk about new programs and metabolic diseases, a universal hemostatic inhibitor as well as new program in diabetes. But also our ambition to actually deliver RNAi to every major tissue in the body by 2030, so that we can help as many patients as we can. So look, of course, we're going to need to grow in scale to take on such an audacious aspiration and a large and complex pipeline. But we're confident that we can do it. We're going to build on our successes, agile content-driven leadership, enhancing the probability of success by disease and target knowledge and innovative trial design, a seamlessly integrated R&D organization and an award-winning culture focused on making lives better. And we're going to continue to grow as well. We've already increased our oligonucleotide throughput. We're enhancing our clinical trial efficiency and predictability. We're doing manufacturing innovation that you're going to hear about later today to actually improve yields and efficiency and bring down the cost of goods. And we continue to build deep expertise in new disease areas. So in sum, I hope you'll emerge today, as convinced as I am that Alnylam's pipeline is spring-loaded for tremendous growth. We have 4 priority focus areas rapidly gaining approval of vutrisiran around the world, delivering on our mid-stage pipeline, which has multiple blockbuster opportunities with 3 Phase III starts this year, investing in our platform and new targets to drive the next wave of innovation and scaling our capabilities with continued emphasis on bold clinical development and flawless execution. So here's today's agenda. You can find it through the QR code that's on your tables. You'll see that we have an intermission about halfway through and 2 Q&A sessions to answer any questions that you might have. And I'm also really excited that you're going to get to meet a good number of my colleagues this morning, highlighting the deep bench of expertise that we've built at Alnylam. So before we start the rest of the morning, I thought maybe we'd share this video with you all so you can see why we do what we do. [Presentation]

All right. Well, thank you, and let me introduce John Vest. John?

Thanks, Pushkal, and good morning, everyone. I'm John Vest, Senior Vice President and the Global Development Lead for our TTR franchise at Alnylam. Following on from the steady stream of data that we released over the course of 2024 and the summary of that data that we shared at our TTR Day last fall, today, what I'd like to do is to again recap our work to date in the space but more importantly to share our vision for the future of this franchise, which we are extraordinarily excited about. As many of you are now familiar with ATTR amyloidosis is a rare progressively debilitating disease that's caused by aggregation of transthyretin protein is amyloid fibrils that deposits in various tissues of the body, most notably the heart and the peripheral nerves, then manifesting clinically as devastating cardiomyopathy and peripheral neuropathy. The true prevalence of this disease is difficult to know, but it's estimated that the hereditary form of the disease is around 50,000 worldwide while prevalence for the wild type form of the disease is far more common, about 300,000 patients worldwide. Now both forms of this disease present with multisystem manifestations, a high burden of disease and are often fatal. Now our therapeutic hypothesis holds that in ATTR amyloidosis, RNAi therapeutics work by rapidly knocking down transthyretin in the liver, thus directly targeting the pathophysiology of the disease by reducing the fundamental disease-causing protein. This in turn diminishes or halts clinical manifestations of the disease. And ultimately can improve outcomes. So in the context of this therapeutic hypothesis, Alnylam now has 3 RNAi therapeutics targeting transthyretin, ONPATTRO, AMVUTTRA and now nucresiran. And we believe that collectively, this franchise will enable us to build a market-leading position that is truly durable. So starting with ONPATTRO, we established leadership in hereditary polyneuropathy. And then with AMVUTTRA, we continue to lead this leadership in hereditary polyneuropathy. But now have brought forward a compelling data package that we believe underscores our potential in ATTR cardiomyopathy. And finally, with nucresiran, we will drive the next great chapter in this franchise's journey, and we believe this reflects our long-term and unwavering commitment to innovation for patients. I'll come back to nucresiran later in the program. But first, I want to start with ONPATTRO and AMVUTTRA, both of which are approved in hereditary ATTR polyneuropathy and thus have enabled us to validate our therapeutic hypothesis and to deliver a life-altering treatment to patients with this devastating form of the disease. Indeed, as we think about the opportunity to meet unmet need in ATTR amyloidosis, this experience with ONPATTRO and AMVUTTRA has been profoundly important. As highlighted in the right-hand panel since 2019, we have grown the polyneuropathy category by greater than fivefold, and we've more than doubled the HCP's prescriber base and established a true leadership position with ONPATTRO and AMVUTTRA accounting for greater than 80% of ATTR polyneuropathy category in competitive markets. Now first and foremost, this has allowed us to address unmet need by delivering the transformational profile of RNAi therapeutics to patients with this devastating form of the disease. But importantly, it's also provided a solid foundation from which we can now seek to address the growing category of patients with ATTR cardiomyopathy, of which there are currently an estimated 300,000 patients diagnosed globally. But -- it's believed that 80% of patients who live with this disease are currently undiagnosed, underscoring a substantial opportunity to meet unmet medical need in these patients. We feel that the results of the HELIOS-B study that were presented at the ESC Congress in London last fall and simultaneously published in the New England Journal of Medicine, demonstrated a profoundly impactful profile of AMVUTTRA and underscore the potential that it has to impact patients who suffer from ATTR cardiomyopathy. The editorial that accompanied that publication of the primary results summarized at best, where 1 of the true luminaries in this field stated that the results demonstrated with AMVUTTRA "has the potential to establish a new standard of care." So before reviewing the key outcomes from the HELIOS-B study, it's important to put the results in the proper context. Because this study enrolled a population reflective of today's patients who have milder disease across multiple clinically relevant metrics, and this is highlighted in the left-hand panel. And as shown in the right-hand panel, we're on substantial background therapy. Most notably, this included about 50% of patients who received tafamidis during the double-blind period of that study. 1/3 of the patients started SGLT2 inhibitors and 80% of the patients were on diuretics at baseline with about half of those patients either starting or intensifying the use of those diuretics, this is relevant for multiple reasons. First, and perhaps most importantly, in a rapidly evolving patient landscape. It speaks to the relevance of these results to the patients who are being seen in clinics around the world today. Second, it underscores the magnitude of the treatment effect, given that these effects were observed in the context of this substantial effective therapy. This inherently raises the bar to observe efficacy. Finally, this is relevant in informing and giving confidence in the design of the nucresiran Phase III program, which we'll discuss a little later on. So with this background in mind, the HELIOS-B study demonstrated a therapeutic profile for AMVUTTRA that's highly supportive of first-line potential. Specifically, rapid knockdown of the disease-causing protein transthyretin led to profound benefit on CV outcomes, including up to a 36% reduction in all-cause mortality compared to placebo, as well as broad effects across a range of important disease manifestations, including biomarkers, cardiac function, functional status and quality of life and very importantly, vutrisiran demonstrated an acceptable safety profile, which is consistent with the profile that's been established. And vutrisiran had these effects with an attractive quarterly dosing schedule, that aligns with doctor visits and support strong adherence. I'll talk a little bit more about that later on, too. As I just alluded to, in addition to the benefit on outcomes, vutrisiran demonstrated impact on multiple important measures of disease progression with the first clinical benefits occurring early and then subsequent benefits cascading in a temporal fashion that was biologically rational. The impact on cardiac biomarkers, including NT-proBNP, which is a well-established biomarker of cardiac risk were seen as early as 6 months with relative stability then maintained over 30 months on the study compared to the steady decline, the expected decline that was seen in the placebo-treated patients. This was followed by improvement compared to placebo on key echocardiographic parameters of cardiac function, both systolic function and diastolic function, which reflects the impact on the underlying pathophysiology of this disease. And in turn, by benefit on clinical parameters, including functional capacity or relative stability in 6-minute walk test was observed in patients on treatment over 30 months. Collectively, these findings, along with the impact on outcomes suggests the potential for a disease-modifying effect. So now I want to share the results of an exciting new analysis based on a new data cut with near complete data through month 42. As you'll recall, as we're showing on the left-hand side here, at our primary analysis time point, we looked at all-cause mortality as a component of the primary endpoint. This reflected data from the double-blind period from 33 to 36 months, where we saw an approximate 30% reduction compared to placebo in both the overall and monotherapy arms of the study. As shown in the middle panel, our primary analysis, and this is as previously reported, we also looked at all-cause mortality through 42 months as a prespecified secondary endpoint. On this analysis, which included data from the double-blind period and up to 6 months of data from the open-label extension, we saw a reduction of approximately 35% in both populations. At the time of these primary analysis, it's important to recognize that we had excellent data ascertainment where we knew the vital status, meaning whether the patients were alive or dead for over 99% of patients on the study speaking to the robustness of this analysis. However, as per the planned design of the study and as outlined in the statistical analysis plan at the time of the primary analysis, the follow-up time varied from 33 to 42 months depending on when the patient was enrolled in the study. Those who were enrolled earlier, completed all the way through 42 months while later enrolled patients completed only 33 months. So now on this right-hand panel, we're showing a new data cut that was performed with near complete data through 42 months and follow-up time varied from 39 to 42 months. As you can see with further follow-up on this new data cut, there was 36% and 39% reduction in all-cause mortality in the overall and monotherapy populations, respectively, compared to placebo. And again, as with the primary analysis, we had outstanding data ascertainment here. The vital status was available again for over 99% of patients on the study, again, underscoring the robustness of the result. So these data are important as they corroborate the results of the primary analysis. And as you can see, the treatment effect is consistent across time points and is potentially even growing over time. Before I conclude the discussion of vutrisiran, I just want to highlight that as we continue to dig deeper into the HELIOS-B data set, we anticipate sharing a steady flow of exciting data over the course of 2025 and beyond. As we'll start with the ACC Congress at the end of March, where we'll have multiple presentations that continue to support the compelling profile of AMVUTTRA. So in summary, we believe that AMVUTTRA has now demonstrated an outstanding profile across the development program. We've seen that this RNAi therapeutic, which rapidly knocks down the fundamental disease-causing protein, reduced hospitalizations, saved lives, helped people to feel and function better, demonstrated the potential to be disease-modifying based on the totality of data, demonstrated benefit across both major disease manifestations, cardiomyopathy and hereditary polyneuropathy and achieved all of this within the infrequent quarterly dosing regimen. Importantly, vutrisiran has demonstrated an encouraging safety profile. And I just want to pause on this topic of safety for a moment. I'd like to note that our experience with vutrisiran in the HELIOS-B study adds to our now extensive experience, demonstrating the safety of TTR lowering with RNAi therapeutics across multiple products in our platform including ONPATTRO and AMVUTTRA. In both long-term clinical trials with patisiran, we've had patients on study for over 7 years and extensive real-world experience with both ONPATTRO and AMVUTTRA. Collectively, we believe that based on that profile, AMVUTTRA has the potential to be the first-line standard of care for both cardiomyopathy and hereditary polyneuropathy. And I'd just like to finally note that we're very pleased to update you about our steady progress and headway with our regulatory filings, now been completed in the U.S., Europe, Japan and Brazil. And we are on track and looking forward with great anticipation to our March 23 PDUFA date for the U.S. FDA. That's just a few short weeks away. I want to now shift gears and talk about nucresiran, which again underscores Alnylam's continued commitment to innovation for patients. ONPATTRO and AMVUTTRA have established a market-leading profile in hereditary ATTR polyneuropathy. And as I've just highlighted in the previous slides, we believe that AMVUTTRA has the potential to establish the same market leadership in ATTR cardiomyopathy. And now with the evolution of nucresiran, we believe we can bring even further innovation for patients and drive category leadership through the 2040s and beyond. So what are we trying to achieve in this next chapter? I've highlighted some key imperatives for the program on this slide. First, as shown on the left-hand panel, we believe nucresiran will establish a next-generation profile with the potential to improve patient outcomes. The profile of this drug will include deeper, faster knockdown of over 90% with low interpatient variability and we'll achieve this with an infrequent dosing regimen. We're announcing today that we will be taking forward a 300-milligram twice annual subcu dosing regimen. And second, as shown in the right-hand panel, we aim to proceed with an innovative development program that anticipates future category dynamics that will both yield a robust data set to inform healthcare providers and access decision-makers which we'll achieve with ATTR cardiomyopathy in an outcome study and make every effort to get this therapy to patients as quickly as possible with hereditary polyneuropathy as a potential fast to market strategy. So I want to start by recapping what we feel is a remarkable emerging profile for nucresiran. As shown here, we're recapping data from the ongoing Phase I single ascending dose study that was shared at the AHA Congress last fall. This is in healthy volunteers. As shown, following a single dose of nucresiran 300 milligrams or higher, we see rapid knockdown in serum transthyretin with mean reductions of greater than 90% by day 15. This knockdown of transthyretin was also deep with mean reductions of greater than 96% by day 29, and the knockdown was sustained with mean reductions of greater than 92% maintained through day 180. Very importantly, there was low interpatient variability, meaning that the vast majority of patients are achieving these levels of TTR reduction that we're seeking. So again, based on these data, we're bringing forward a regimen of 300 milligrams twice annually, subcutaneous into our Phase III programs. We believe that this regimen provides the optimal combination of rapid, deep and sustained TTR reduction and patient convenience and has the potential to establish a durable market-leading profile. So I want to take a minute here just to highlight the innovation that this emerging profile of nucresiran represents. In just over 6 years since the approval of ONPATTRO, we've gone from 17 intravenous infusions annually to achieve approximately 85% reduction of subcutaneous to 4 subcutaneous injections annually, again, to achieve about 85% transthyretin reduction and now just 2 subcutaneous injections annually with the potential to achieve up to 95% TTR reduction. We believe that this remarkable innovation has the potential to benefit patients on several dimensions. First, this represents a profound leap forward for patient experience with only 2 convenient injections per year which is, of course, substantially differentiated from profiles that require monthly injections, taking a pill every day or even taking pills multiple times every day. And as I noted on a previous slide, we've seen the infrequent dosing results in outstanding adherence to treatment. Indeed with vutrisiran in hereditary polyneuropathy, we've seen adherence rates of about 95%. This is really important. We know that these therapies only work if patients are taking them. And finally, the deeper TTR reduction that we believe we can achieve with nucresiran has the potential to lead to even further improvement in patient outcomes. I'll discuss this last point in the coming slides. So there's growing consensus in the TTR amyloid field that on a population level, deeper knockdown could result in better outcomes. This concept is in part derived from the experience in other forms of amyloidosis like AL amyloidosis and AA amyloidosis, which like TTR amyloidosis result from aggregation of amyloid fibrils that deposit in tissues -- various tissues of the body and lead to organ dysfunction. And it's become perfectly clear in data that's been collected in these other forms of amyloidosis over decades that maximal knockdown, the deeper the knockdown is, the better the outcomes for patients. And indeed, data from our own RNAi therapeutics in ATTR amyloidosis lead to the same conclusion. I'm showing here model data -- modeling based on data from the APOLLO study of patisiran, where greater reduction of transthyretin resulted in greater improvement in neurologic function. So if all of this in mind and considering emerging data from the HELIOS-B study, we feel very encouraged in the potential for nucresiran in the upcoming Phase III program. Now before turning to the details of the study design, I'd like to highlight several of the key considerations, sort of high-level considerations we took forward in designing this Phase III program. The first is that outcomes benefit will drive a durable market-leading profile in the competitive environment. The data we intend to generate will be impactful for patients, prescribers and payers. We considered a broad range of study designs, but ultimately felt it was clear that for ATTR-CM, outcomes will be necessary to maximize the potential for the franchise. The second is the combination therapy of silencers and stabilizers will become increasingly more common after the tafamidis loss of exclusivity anticipated in 2028. Accordingly, we want a data package that will inform us of nucresiran as a monotherapy or in combination with a stabilizer. Notably, we're very encouraged by the potential for this given that the HELIOS-B data set strongly support the opportunity here. Remember, we observed consistent results across all endpoints in patients who are on baseline tafamidis. This included a 42% reduction in all-cause mortality compared to placebo in the patients who are on this baseline tafamidis subgroup. And finally, patients will be continued -- will continue to be identified earlier and with milder disease. This is owing to increased disease awareness and improved diagnostics. We believe this dynamic is going to enrich the nucresiran Phase III population for patients with the greatest opportunity to benefit based on both data from HELIOS-B, where we saw outsized benefit in those patients with milder disease on the study as well as data from other previous Phase III studies. So with this concept -- these concepts in mind, we're pleased to share our plans for the TRITON CM Phase III study of nucresiran in ATTR cardiomyopathy. TRITON CM will be a randomized, double-blind, event-driven outcomes study. The population will include ATTR cardiomyopathy patients with either hereditary or wild-type disease with a medical history of symptomatic heart failure, New York Heart Association Class 1 through 3 and background stabilizer therapy will be allowed in all patients on the study, and we anticipate that this will be a majority of the patients on the study who will be taking stabilizers. Approximately 1,200 patients will be randomized either nucresiran 300-milligram subcu twice annually or placebo. And the primary endpoint will be a composite of all-cause mortality and CV events. This primary analysis will be event-driven and will occur a minimum of 24 months after the last patient enrolled. Following completion of the double-blind period, all patients will be eligible to go on to an open-label extension where they will receive nucresiran. We are thrilled about the potential for this study to thoroughly characterize the profile of nucresiran. And we'll give the potential for a durable market-leading profile. Now with the TRITON CM study I just described, we hope to launch in cardiomyopathy around 2030. But while we feel this is critical, excuse me, to a durable market-leading profile, we, of course, want to bring nucresiran to patients as quickly as possible. and we see a potential opportunity to achieve this in hereditary polyneuropathy. Thus, in addition to our Phase III study in cardiomyopathy, we're also pleased to announce our intention to study nucresiran in hereditary polyneuropathy in parallel in the TRITON PN Phase III study. With TRITON PN, we anticipate that we could launch in hereditary polyneuropathy several years in advance of our assumed launch in cardiomyopathy. While we are not yet prepared to disclose full details of the PN study, we will target to start by the end of 2025. We're currently exploring efficient designs and consultation with global regulators and we look forward to sharing more on this in due course. So in closing, Alnylam is deeply committed to advancing state-of-the-art in TTR amyloidosis. We aim to achieve this through continued evidence generation across multiple platforms, including real-world evidence, investigator-initiated studies and collaborations and, of course, ongoing post hoc analysis from the HELIOS-B study. Furthermore, as I've outlined, new research and discovery will be a cornerstone with the Phase III program of our next-generation silencer nucresiran. And finally, our robust and ongoing commitment to clinical and patient community support, including sponsorships, fellowship program support, global hereditary ATTR genetic testing and compassionate use and extended drug provision. With that, I want to thank everyone for their attention, and I'm now going to pass the program over to Simon Fox, my colleague, who will provide us with an update on the very exciting zilebesiran program.

Thanks, John. Thank you. So good morning, everyone. Simon Fox, I'm the Vice President and Program Lead for the zilebesiran program. So as Pushkal mentioned, earlier in his presentation, zilebesiran is a key near- to midterm growth driver for Alnylam. And today, it's my pleasure to provide you with an update for the zilebesiran program, which includes how we currently see the unmet need in hypertension. And the associated opportunity to serve patients with zilebesiran. I'll also summarize the previously reported positive Phase II data from KARDIA-1 and KARDIA-2 and provide a status update for our third Phase II study, KARDIA-3. And we're very excited to share for the first time the key design elements of our planned pivotal Phase III cardiovascular outcomes trial as well as what our focus will be once we initiate the trial in the second half of this year. Now it's become well known that even today, with numerous classes of oral antihypertensive medications. There are tens of millions of patients with uncontrolled hypertension. Of the 219 million patients with hypertension across the 7 major markets, 77 million also have high cardiovascular risk. And up to 62 million of these patients have uncontrolled hypertension. For these patients with uncontrolled hypertension, achieving just a 5-millimeter of mercury reduction in systolic blood pressure could result in clinically meaningful reductions in cardiovascular risk. So who are the patients that could benefit the most from achieving better blood pressure control? Patients with uncontrolled hypertension with high cardiovascular risk have the greatest unmet need. These patients can either have a history of ASCVD or would be a high risk of ASCVD. And many of these patients have either 1 or more of the major comorbidities such as diabetes, chronic kidney disease or heart failure, which put these patients at the greatest risk of having major adverse cardiovascular events. Now the challenge is today that many of these patients, even if treated have inconsistent blood pressure control, and it's due to a number of factors, 1 of those being excessive blood pressure variability. And this is why we believe the therapeutic hypothesis of zilebesiran could potentially transform the treatment of hypertension. Now blood pressure does not remain steady, but instead fluctuates continually within a 24-hour period, day-to-day month-to-month. And furthermore, these fluctuations are not random and tend to remain consistent in patients with hypertension. The traditional correlation between baseline blood pressure and outcomes has the potential to underestimate the true risk of elevated blood pressure due to the amount of variability in blood pressure that can occur in any given patient. On the left of this slide, you will see a chart from a study of a large cohort of U.S. veterans, almost 3 million patients with and without hypertension, who have 8 or more outpatient blood pressure readings over a 2-year period, and these patients were observed for up to 8 years to assess the relationship between systolic blood pressure variability and cardio and renal outcomes. Now systolic blood pressure variability was measured using the standard deviation of all of the systolic blood pressure values in an individual patient. As you can see, as the standard deviation quartiles rose, indicating patients and groups with higher systolic blood pressure variability, there was a sharp increase in the risk of all-cause mortality, coronary heart disease, stroke and end-stage renal disease. Now the findings of this study are quite alarming because if you look, the patients with the highest blood pressure variability are between 6x to 10x more likely to develop coronary heart disease, stroke or end-stage renal disease. And we believe with the therapeutic hypothesis of zilebesiran, which is to target continuous control of blood pressure to achieve a good magnitude of blood pressure control during the 24-hour period, blood pressure control throughout the nighttime to maintain nocturnal dipping as well as the ability to reduce excessive blood pressure variability during the 24-hour period and over the long term, all with the added benefit of infrequent dosing to improve adherence, we can potentially reduce cardiovascular and renal risk. Now as a reminder, we've designed a comprehensive clinical development plan to bring to life the therapeutic hypothesis of zilebesiran. By exploring the power of continuous control and blood pressure and its potential to improve outcomes. Our Phase I results were published in the New England Journal of Medicine in July of 2023. And we have now completed 2 Phase II studies. Data from our first Phase II study, KARDIA-1 were presented as a late breaker at the AHA in 2023 and then published in JAMA at the beginning of 2024. And data from our second Phase II study, KARDIA-2, were presented as a late breaker at ACC in 2024. Now our most recent achievement is the completion of enrollment of our Phase II study, KARDIA-3. And we plan to present data in the second half of this year, and I'll provide more details for the rationale for this study shortly. And of course, for our pivotal Phase III, we are planning to initiate a global cardiovascular outcomes trial in the second half of this year. And as I mentioned before, I'll be sharing new information and more specifics about this trial later in the presentation. So over the past 2 years, we've actually made fantastic progress with the zilebesiran program, generating positive data from 2 Phase II studies. The KARDIA-1 study here studying zilebesiran as a monotherapy highlighted the transformative potential of zilebesiran. We were -- it was demonstrated with clear evidence of the ability to achieve continuous blood pressure control with approximately a 15-millimeter of mercury reduction in systolic blood pressure at month 3 and month 6 after a single dose of zilebesiran. In addition, single doses of zilebesiran maintain blood pressure reductions throughout the daytime, the nighttime over the 24-hour period at month 6. And we also observed that zilebesiran was generally well tolerated with low incidence of adverse events and injection site reactions. Adverse events of special interest such as hyperkalemia, hypertension were mild, moderate in severity and transient, and the majority did not require therapeutic interventions. We also saw evidence of continuous control of blood pressure in KARDIA-2, whereas zilebesiran was added to background standard of care in patients with uncontrolled hypertension, achieving additional clinically significant reductions in systolic blood pressure of up to 12 millimeters of mercury in systolic blood pressure out to month 3. And for a key secondary endpoint in KARDIA-2, we looked at time-adjusted average in blood pressure at month 6, which is the measure of cumulative blood pressure divided by the time interval providing a weighted average of all scheduled changes from baseline throughout the entire time interval. And I mentioned previously that variability in blood pressure, which is a key marker in inconsistent blood pressure control is associated with an increase in cardiovascular risk. And what we are observing here is that zilebesiran results in more consistent, continuous control of blood pressure. Again, zilebesiran was generally well tolerated. Adverse events were an increase in mild hyperkalemia, hypertension and EGFR decline, mostly nonserious and resolved without intervention. Now our ongoing Phase II study, KARDIA-3, is a randomized, double-blind combination study in patients with high CV risk. The study enrolled adult patients with uncontrolled hypertension who are either at high risk of cardiovascular disease or had established cardiovascular disease. And we also enrolled patients with chronic kidney disease. Patients coming into the study had to be on stable doses of at least 2 background antihypertensives, angiotensin converting enzyme inhibitors and angiotensin receptor blockers were allowed at appropriate therapeutic doses. I'm pleased to say enrollment went exceptionally well, both cohorts enrolled in 3 to 4 months ahead of schedule and putting us in a great position at the beginning of this year to expedite and inform the next stage of development. So the rationale for this study is to understand the efficacy and safety of zilebesiran in the potential target patient population for Phase III. KARDIA-3 will confirm the dose selection for Phase III and we'll also use data from KARDIA-3 to better inform the inclusion and exclusion criteria as well as informing power and sample size for Phase III. As mentioned, we plan to present data for KARDIA-3 in the second half of this year. Again, we are very excited to be planning the initiation of a large global cardiovascular outcomes trial before the end of the year. Now planning for the trial with our partners at Roche is well underway, and we've already engaged with regulators to seek advice on the specifics of the trial design. The conversations have been extremely informative, and we look to finalize the design once we see KARDIA-3 data. The trial will be a global multicenter trial, and it's estimated that we will recruit patients from sites in over 30 different countries. Currently, we are planning for a sample size of up to 11,000 patients. The patients to be enrolled will be a KARDIA-3 like population, as mentioned previously, uncontrolled hypertension on a background of 2 more antihypertensives, with either established CVD or at high risk of developing CVD. It will be an event-driven trial with the primary composite endpoint of 4-point MACE, which is nonfatal myocardial infarction, nonfatal stroke, cardiovascular death and hospitalization for heart failure or urgent visits for heart failure. The trial will have a minimum follow-up of 2 years with an estimated duration of 4.5 years. As Pushkal mentioned, we've evolved our clinical research and operational capabilities to design and deliver the trial. We've already established a very strong collaborative relationship with our global partner, Roche, and we've now established strategic partnerships with the world-renowned Duke Clinical Research Institute and the global CRO PPD to execute the trial. So what's next as we move closer to initiating the Phase III cardiovascular outcomes trial. Our immediate focus operationally will be to initiate and expedite the enrollment of the cardiovascular outcomes trial through our clinical operations and medical affairs capabilities. Once we -- once the trial initiate, the medical affairs teams will be delivering medical education and scientific engagement. Organizationally, we will be looking to shape our go-to-market strategies as well as developing an understanding of the organizational capabilities and resources to commercialize zilebesiran successfully. We'll also be continuing to develop the Reversir, which will further demonstrate the capabilities of our RNAi platform. And we've also made a key strategic choice to evolve our manufacturing capabilities to reduce COGS, given zilebesiran is targeting a prevalent disease, such as hypertension, coupled with our aspirations to commercialize zilebesiran globally. And finally, the team at Alnylam and Roche are already assessing the potential to develop zilebesiran for additional indications such as heart failure and chronic kidney disease. And to conclude, Alnylam and Roche fully believe in the potential value zilebesiran has to offer. And how we unlock this is by generating the most robust data to optimize zilebesiran's value proposition. Generating cardiovascular outcomes data will ensure favorable guideline positioning and demonstrate value to healthcare systems. We believe for HCPs that cardiovascular outcomes data, coupled with the ability to achieve continuous control of blood pressure with infrequent dosing will potentially drive rapid uptake and differentiate zilebesiran. And finally, generating data will also drive confidence and preference amongst patients. And now I will pass to Julia Shirvan, who will provide an update for the mivelsiran program.

Thank you, Simon. It's my pleasure to turn everyone's attention right now to a different organ, the brain, as I discussed, Alnylam's transformative work in neuroscience. I will give a brief overview of our Neurologic pipeline and a focused update on the mivelsiran program. Alnylam leads the field in targeting the CNS with RNAi therapeutics Currently, we have 3 assets in clinic summarized in the blue tables. We additionally have more assets that are approaching the clinic and all of our programs target severe diseases with high unmet need. Our programs for CAA, Huntington's and SOD1-ALS, all dosed their first patients last year, which are important milestones. These programs will continue to advance in accordance with R&D strategic principles, which include prioritizing high conviction targets and pursuing best-in-class opportunities. This platform utilizes the C16 conjugate that's depicted in the diagram to the right. This is an Alnylam innovation that optimize delivery of the siRNA to the central nervous system. Mivelsiran is the first asset in clinic, and it is an RNAi therapeutic designed to reduce amyloid production. This diagram demonstrates its upstream mechanism. Mivelsiran works at the source of amyloid production. It targets the mRNA for APP. APP stands for amyloid-beta precursor protein. And as the name implies, it is a precursor for all forms of amyloid beta peptides. These include the intracellular forms represented above the blue line in the diagram and the extracellular forms presented below it. By lowering all the substrates available for amyloid deposits, mivelsiran may not only decrease new amyloid deposition, but also promote natural clearance of amyloid already in the brain. By targeting the amyloid pathway, mivelsiran may benefit both Alzheimer's disease and cerebral amyloid angiopathy. These are 2 severe neurological diseases that are driven by amyloid accumulation. The pathogenic role of amyloid in these diseases is highlighted by the fact that both include subpopulations defined by genetic variants in the APP gene. In Alzheimer's disease, amyloid deposits in the cortex, represented by the blue image. This pathology leads to cognitive decline in Alzheimer's disease is the most common form of dementia, it carries an incredibly high burden of morbidity and mortality for patients. And despite years of research, there is a high unmet need for therapies that offer patients improved efficacy and safety. We think that mivelsiran can close this gap because of its differentiated mechanism. For example, as I've just explained, it targets all forms of pathogenic amyloid before deposits form. In contrast, the monoclonal antibodies that were recently approved only target the extracellular amyloid after it's deposited. Monoclonal antibodies also carry a risk of ARIA. And due to increased risk of bleeding, their use is not indicated for patients with CAA. So turning our attention to CAA. In this disease, amyloid accumulates in the small blood vessels represented in the red image. This pathology leads to cerebral bleeds. And CAA is a major cause of intracerebral hemorrhage, which is the most severe form of stroke. And although patients with CAA have the highest risk of recurrent ICH, they have no options for disease-modifying therapies to date. Alnylam has active trials ongoing for both Alzheimer's disease and cerebral amyloid angiopathy, which I'll review today, beginning with the Phase I study and early onset Alzheimer's disease. We recently passed an amendment that expanded the scope and duration of our open-label multi-dose extension. Specifically, we doubled the duration of dosing in this extension. Therefore, we're able to follow key exploratory endpoints through 36 months. These endpoints include amyloid PET, CSF biomarkers and cognitive scales. This enhancement increases our ability to detect the treatment effect of mivelsiran in this study. Today, I will present new data from the 100-milligram SAD cohort as well as the 50-milligram MAD cohort. And of note, we have dose escalation ongoing in our study. Beginning with the single-dose data. The graph here demonstrates that mivelsiran has achieved potent, durable and dose-dependent reduction of APP in the CSF. The bottom black line is from the 100-milligram cohort that I just mentioned. And the data demonstrate that 10 months after a single dose of mivelsiran, patients are still experiencing greater than 60% reduction of APP in the CSF. This robust target engagement may benefit patients by increasing the time between doses and decreasing the cumulative exposure to drug for patients. Our multi-dose data demonstrate that second doses further reduced APP in the CSF. This graph shows in the blue line the single-dose data for the 50-milligram cohort. And in the red line, the multi-dose data for the 50-milligram cohort. We're presenting these data for the first time through 12 months in the multi-dose extension. And as you can see, at that time, at 12 months, patients have nearly 75% reduction of APP in the CSF. This substantial reduction is particularly noteworthy because the 50-milligram cohort is our lowest dose in the multi-dose extension. You can also infer from this graph that we have patients in the multi-dose extension who are now entering their second year, which represents important progress for the study. Now those data suggest that Alnylam has the best-in-class opportunity in clinical pharmacology. These data that I'm about to discuss suggests that Alnylam has a best-in-class opportunity for clinical safety. Other CNS-targeted mortalities have been limited by inflammatory side effects. Even after multiple doses of mivelsiran, we are not seeing immune responses in our data. Three relevant variables are presented in the graph here, CSF white blood cell count, CSF total protein and CSF neurofilament light. In each graph, what's plotted are the mean values for all of our cohorts. This includes placebo and all of our dose levels, including the 50-milligram cohort in red. What you're observing is expected variability for these cohorts. In contrast, if we were seeing immune responses, you would see high elevations that are sustained. And we are not seeing an immune response in any of our cohorts after all of our dose administrations. And so these are very reassuring CSF profiles. As a Phase I study is ongoing, we are going to work towards a Phase II study in AD for later this year. This work will be guided by the R&D strategic principles as everything in the pipeline is. These include following compelling human genetics, best-in-class opportunities and clear path to clinical proof of concept. As we design this study, we will discuss populations that include those genetically defined, those that are sporadic, those that are presymptomatic, symptomatic and then early and late stages of the disease. In the enhanced Phase I study design I just mentioned, it will be generating data to help inform the decisions we need to make there. Our CAA program already has a Phase II study underway. It's called cAPPricorn-1. As background, CAA is a severe progressive cerebrovascular disease with high unmet need. Endocerebral hemorrhage is a life-threatening sequela of CAA. And CAA is the second most common cause of ICH after hypertension. The risk of a recurrent life threatening ICH is 3x higher when the initial event was due to CAA. In addition to ICH dementia is a serious clinical sequela of CAA. As I mentioned before, though, the recently approved monoclonal antibodies are not indicated for patients with CAA. This is of note because CAA and Alzheimer's disease are frequently comorbid in patients. But CAA can independently contribute to dementia as well. And studies have found that advanced CAA pathology corresponds to faster clinical decline for cognition, irrespective of copathologies. Given this clinical course, CAA is a major driver of morbidity and mortality. Our cAPPricorn-1 study is designed to investigate both the hemorrhagic and the non-hemorrhagic manifestations of CAA. The primary analysis will focus on the 24 months double-blind period. At the end of that time, all patients will have the opportunity to enter an open-label extension for an additional 18 months. The vast majority of patients in this study will have sporadic CAA, but a small cohort is open for those with a genetically defined Dutch-type CAA. Enrollment in the study began this summer and is ongoing in North America, Europe and Australia. The preclinical data supporting the CAA study is compelling and was recently presented at the International Stroke Conference. I'll go through 2 slides worth of data. They come from a rodent model of CAA, and the treated animals had a single dose of an APP lowering siRNA. In this slide, the images on the left use a neon green stain to identify vascular amyloid. The control animal on the left has a substantial staining because it has numerous amyloid deposits as expected. So treated animal on the right has much less staining because it has less amyloid accumulation. The graph on the right demonstrates that on average, the reduction in the vascular area occupied by amyloid for the treated animals is greater than 80%. In addition to the significant reduction in amyloid beta accumulation, we also saw that the number and size of cerebral microbleeds decreased in our treated animals. The images you're looking at on the left have control animals on the top and treated animals on the bottom. The blue stain is used to identify blood. And as expected, there's multiple bleeds in the control animals. In contrast, the treated animals, in some cases, show no bleeds. The graph on the right demonstrates that on average, the reduction in the number and size of bleeds is approximately 60% for these treated animals. These data once again suggests that our mechanism may not only prevent the accumulation of new amyloid, but also help promote the clearance of existing amyloid deposits. In so doing mivelsiran may preserve vascular health and prevent bleeding events in CAA. In conclusion, mivelsiran lead a transformative gene targeting platform that we've built at Alnylam. Mivelsiran studies have 2 ongoing studies for severe neurological diseases, Alzheimer's disease and CAA. The interim data coming from our Phase I EOAD study suggests that Alnylam has best-in-class opportunities for both clinical pharmacology and clinical safety. We've demonstrated robust reduction of APP in the CSF that is well tolerated over a range of doses, and this target engagement supports infrequent dosing and low lifetime exposures to the drug. Not only mivelsiran, but all of our clinical assets made important strides last year. As I mentioned, our programs in CAA, Huntington's and SOD1-ALS, all dosed their first patients, and our programs will continue to advance according to the R&D principles. And now I'll hand it over to my colleague, Kevin Sloan, who will talk about the Huntington's program.

Thanks, Julia, and good morning, everyone. I'm excited to tell you about 1 of our newer clinical programs for Huntington's. Huntington's disease is a progressive and fatal neurodegenerative disorder. It's autosomal dominant, with more than 100,000 symptomatic individuals worldwide and many more presymptomatic or undiagnosed. It's a truly devastating disease. Physical and mental abilities deteriorate during prime working years. And as we heard from Melissa earlier, it's been described as having ALS, Parkinson's and Alzheimer's combined. No disease-modifying therapies exist. Huntington lowering is the primary therapeutic strategy being pursued in clinic, but it's been hampered by technical and platform limitations. So a key question is whether Huntington lowering can provide clinical benefit to patients while remaining well tolerated. ALN-HTT02 is an investigational therapeutic that we're developing for Huntington's that we believe is the right tool to answer this question. It leverages the same C16-siRNA delivery platform as mivelsiran, which Julia just told us about. Our vision is that ALN-HTT02 will slow or halt disease progression to improve the quality of life for patients and become a best-in-class disease-modifying therapeutic. There are several key points of differentiation. First, a more inclusive exon 1 targeting strategy, which I'll tell you more about today. Second, the potential to fully explore deep and widespread Huntington lowering. And third, the safety and durability of the C16-siRNA delivery platform, which should enable infrequent dosing regimens in clinic and lower lifetime drug exposures compared to what's been typical for antisense platforms. We're particularly excited about this program as we believe there may be an opportunity to move directly from our ongoing Phase I study into a Phase II/III registrational study and if the drug is effective, there may be potential for accelerated approval in this space. So Huntington's disease is caused by a CAG repeat expansion in the first exon of the Huntington gene. We've known about the root cause of this disease for over 25 years. The genetic mutation leads to a toxic, broadly disruptive gain of function that's characterized by somatic instability, protein aggregation and widespread neurodegeneration. Now research has shown that the mutant Huntington allele can give rise to both a full-length mutant Huntington protein shown on the right, as well as a shorter splice isoform called HTT1a, which consists of just the first exon with the expanded CAG repeat shown on the left. Both the full-length mutant Huntington and the shorter HTT1a proteins have been implicated in protein aggregation and disease pathology. We believe that targeting exon 1 is important as it allows us to silence expression of both full-length mutant Huntington protein and the shorter HTT1a-isoform. And a growing body of data has implicated the shorter 1A protein is a key link between CAG repeat expansion and disease pathology. We know that somatic instability can lead to expansion of CAG repeats over time in individual patients. And expanded CAG repeats have been found to drive aberrant splicing to produce the shorter 1a protein. And in preclinical models, longer CAG repeats correlate with increasing expression of the 1a protein. That shorter 1a protein is highly aggregation prone and highly toxic in mouse models. And it's been suggested as a potential initiator of protein aggregation with fragments of full-length Huntington potentially contributing after an initial seeding event. Several labs have recently shown that Huntington lowering approaches that include the shorter 1a protein can prevent protein aggregation and other hunting phenotypes, while approaches that only lowered the full-length Huntington is much less effective. In sum, the HTT1a protein may play a key role in initiating and accelerating the disease process. ALN-HTT02 targets a conserved sequence within exon 1. It's designed to reduce expression of all Huntington protein species, including the shorter 1a isoform implicating disease pathology. Now the exon 1 sequence space is limited. So we took our time to fully explore the universe of sequences and modifications to arrive at our development candidate, fully optimizing for potency and selectivity. And by reducing all forms of mutant Huntington, we believe that ALN-HTT02 has the potential to limit toxic gain of function activities and alter the course of disease progression. It's now my pleasure to introduce Dr. Sarah Tabrizi to tell us more about Huntington's disease. Dr. Tabrizi is Director of the Huntington's Disease Center at the University College of London. In addition to seeing patients, she leads an internationally recognized translational research team and has served as a PI or adviser on numerous drug development efforts. She's received many accolades over her career. But notably, she's an elected fellow of the U.K. Royal Society, and a member of the U.S. National Academy of Medicine. After her talk, I'll come back up and share a bit of preclinical data and update on our Phase I study.

Thank you for inviting me to come and talk to you about Huntington's disease. I am based at UCL in London, I'm the Director of the UCL Huntington's Disease Center and based at the UCL Queens Square Institute of Neurology, where I'm Chairman of the Department of Neurodegeneration and also a physician at the National Hospital for Neurology and Neurosurgery. I've worked in Huntington's disease for over 30 years, and I'm going to give you an update on what we know about the disease now. Huntington's disease is a devastating inherited disorder. It's the world's most common genetic dementia. We have no treatments and it affects people in the prime of life. On the right is a lady, age 38, and this is her 13 years later with end-stage disease. This is a lady from Lake Maracaibo in Venezuela. Huntington's disease is caused by a CAG repeat expansion in the first exon, which codes for a protein mutant Huntington, which causes disease through what's known as a toxic gain of function. But what we understand now is there are new mechanisms of pathogenesis that have become apparent over the last 5 years. Before we go to this, I want to show you a video of this lady, Kim, who I look after. She has early-stage Huntington's disease. She's got widespread career for movements. She's got dystonic and twisting movements of her trunk. She also has early dementia and neuropsychiatric symptoms. Huntington's disease also affects children. It's young boy I looked after, he's actually 21 in this video. He died a few years later. He developed the disease when he was 13. Behind me is his mom, her husband died of Huntington's disease in her 30s and [ Amar's ] sister also died of Huntington's disease. It's a devastating disorder of families. There is a huge unmet need. It's a rare disorder, but it's 1 of the common rare disorders and a recent paper in Nature Medicine with worldwide incidents was put at 1 in 4,109 individuals, much more common than previously thought. It has orphan disease designation. We have a critical path regulatory science committee that helps facilitate discussions with regulators early in particular the FDA. And it has a huge health economic burden. It costs hundreds of millions of dollars worldwide. So the molecular base of Huntington's disease, it's 2 steps. Step 1 is the CAG repeat expansion, and we know that CAG repeat expansion undergoes expansion throughout life in the brain in particular. This is called somatic CAG repeat expansion and you can have repeats of up to several hundreds. You can see here in the striatum of postmortem brain, there is a repeat of 700 repeats. Genetic modifiers in DNA damage repair pathways, that have been found in the last 10 years have all been shown to act on somatic CAG repeat expansion. And now we know that somatic CAG repeat expansion in the brain drives the age at disease onset and rate of progression in Huntington's disease. So it's the rate driver. It gives rise to the toxicity driver, which is step 2. The Huntington gene is transcribed to full length Huntington mRNA, which undergoes proteolytic cleavage of the Huntington protein and this N-terminal proteolytic fragments of the protein are toxic. But also, we now know that with increasing CAG repeat expansion, another Huntington mRNA species is produced through alternative splicing. This is the Huntington Ia mRNA that's produced as the repeat gets longer. This produces a highly toxic aggregate prone Huntington exon 1 protein. And it is this species that is thought to be the toxic key species in Huntington's disease. This is from a review I did a few years ago, giving an overview of therapies in development. It's a simplistic diagram, but it really covers those targeting DNA, which are in preclinical development like CRISPR and DNA repair modulators, small molecules targeting splicing of mRNA, antisense oligonucleotides and RNA interference approaches. So Huntington lowering as a therapeutic. There are over 50 preclinical mouse model studies of Huntington's lowering therapies in different HD mouse models. There is overwhelming evidence that lowering mutant Huntington through a number of different approaches reverses symptomatology in mice and reverses neuropathology. So this overwhelming preclinical evidence that lowering mutant Huntington is beneficial. And why is targeting toxic exon 1 so important? There were 2 studies that are now -- have been submitted for publication, but that were presented at a meeting at HDF in Boston last year. One was from Jeff Carroll from Washington University, where he had tested an exon 1 ASO in HD mice, and he found that the exon 1 treated mice had the best transcriptional rescue, which is a key early pathogenic event in Huntington's disease ever observed in an interventional study. Geo Bates at UCL had done a similar study with the Huntington full-length sRNA and then an sRNA targeting the exon 1 fragment. This is immunohistochemistry at 6 months and 10 months of the mice and collectively targeting the Huntington Ia transcript had a much more pronounced effect on Huntington aggregation. You can clearly see a difference and transcriptional dysregulation than the full length Huntington. And these data have really very important implications for Huntington lowering and they support strategies that also lower the toxic exon 1 protein. Last year, a number of companies, PTC, Wave, uniQure and Skyhawk all announced updates to their early clinical programs in Huntington's disease Huntington-lowering. This is a table of the summary of clinical studies so far. This tominersen, the Roche ASO, the Generation HD1 study was stopped, but the Generation HD2 study is ongoing. And you can see here in the top row, tominersen had a 55% reduction in mutant Huntington but had a peak neurofilament in generation HD-1 of 30% and as we know, that trial was stopped early. Wave 1&2 and Branaplam were both stopped for different reasons. PTC518, it was a 12-month study so far, had 43% lowering of CSF mutant Huntington and no increase in neurofilament. The Wave is allele selective with a treatment duration of 4 months. They had 35% mutant Huntington lowering but a 60% peak NFL looks like it is caused by the Huntington -- mutant Huntington targeting ASO. UniQure is targeting exon 1. It's a gene therapy targeting the striatum. They announced a potentially promising early clinical data in a small cohort recently, including some suggestion of lowering of CSF neurofilament. There was an increase at peak NFL, but that was surgery related. And here at the bottom, we have Alnylam, it's exon 1 targeting and the trial has started, and we will learn more as it progresses. So why do I think the Alnylam approach is important? Well, it's exon 1 targeting, which is critical in my view. It has a broad CNS distribution, including both the stratum and cortex, which we have to target. There is the potential for infrequent dosing and a potential and emerging safety profile of the C16 platform through their APP program, which is more advanced in the clinic. Our hope for Huntington's disease is to treat people with Huntington's disease before clinical symptoms. And we have the opportunity to do that because we can identify people through a 100% sensitive and specific genetic test before they have symptoms or signs of the disease. And that gives us what we call this golden window of opportunity to intervene decades before onset to prevent further neurodegeneration. And with that goal in mind, I chaired a working group to develop a new staging system for Huntington's disease to help us allow to do earlier stage trial. The challenge we had is the clinical diagnosis is a late event in the course of the disease. You can see here 3 brain scans. On the left is a control, a person with HD in the middle who's years before their symptom diagnosis and on the right, a diagnosed patient of motor onset diagnosis. And you can see very clearly around the striatum that in the control individuals, the brain is healthy. But you can see in a person who's been diagnosed with Huntington's disease, they've lost a lot of their striatum and cortical volume. And that's very obvious on these brain scans. The challenge is that the clinical diagnosis of motor diagnosis is a really late event in the course of the disease, and that was making early stage and prevention trials impossible. Disease-related signs and symptoms occurring early were not accounted for. And the current trial endpoints, particularly the total functional capacity all show movement in late-stage disease. So what is the HD Integrated Staging System? It started with a biological research definition. So Huntington's disease is defined as the presence of a CAG expansion in exon 1 of the Huntington gene of 40 or more repeats. And the HD integrated staging system was developed by a consortium over a number of years, and it really resembles the cancer staging system. It's over 4 stages, Stage 0 to Stage 3. Stage 0 is the presence of the Huntington gene. The time line is from birth to death. Stage 0 is you're born with the Huntington's disease expansion mutation, but at Stage 0, there is absolutely nothing to find of any evidence of disease. Stage 1 is when there is a detectable biomarker that we know is associated with pathogenesis. And the landmarks for that is a change in putamen or caudate volume of the striatum that is out with the fifth percentile of controls, and then that's Stage 1. Stage 2 is the presence of an early clinical sign or symptom, very early change in the total motor score or in a cognitive test single-digit modality. And Stage 3 is functional change and is divided into mild, moderate and severe. All of the clinical trials in the past have been done in Stage 3, where there's already functional impairment and it's late in the course of the disease. So the HD Integrating Staging System represents the entire course of Huntington's disease. Stage 0, Stage 1 and most of Stage 2 are the old premanifest, presymptomatic prodromal. You can see here with the dotted arrow, that's the motor diagnosis, clinical diagnosis. And you can see that's late in the stage course of the disease. All trials now are really focusing on Stage 2 and very early Stage 3, which is much earlier than previous trials. And we're building the framework to be able to do Stage 0 in 1 trials. We're developing biomarkers as a path to earlier-stage trials. Change in caudate and putamen volume can be measured over time from the earliest time points; change in CSF neurofilament and Proenkephalin levels. Proenkephalin is a marker for medium spiny neurons in the striatum. And for example, in Stage 0 and 1, a prevention trial with a 50% treatment effect requires relatively small sample sizes for a 3-year prevention trial. And actually, later in the disease with the Stage 2, the numbers are even smaller and the biomarkers changed more significantly. So my vision is a world in which Huntington's disease is no longer something families have to worry about. And that's what us, myself, the community are all working towards. I'd like to thank you for listening, thank my lab and who's all in blue, all my collaborators, my funders, and I'm happy to take any questions.

Thanks to Sarah. She'll be back to join us for Q&A in a bit. I'll now share data from 2 preclinical studies in nonhuman primates. First, is a single-dose PK/PD study, where we observed widespread target engagement across the CNS, including the cortex, hippocampus, caudate and putamen. You can see dose-dependent lowering of Huntington protein with robust lowering 3 months after a single dose in the top graph and some recovery, but sustained lowering 6 months after a single dose in the bottom graph. This profile is consistent with our past experience, and we believe it will support infrequent dosing regimens on the order of 6-month intervals or better in clinic. The safety profile was very encouraging in this study with no in-life abnormalities and no elevations in CSF, NFL or total protein. Next is a multiple dose GLP toxicology study, where we've pushed the exposure quite far. With a cumulative exposure at the highest dose of 240 milligrams over 6 months. We did this to establish a wide safety margin but also to explore the safety of deep Huntington lowering in healthy primates. Even after very deep Huntington lowering beyond 90%, we saw a very encouraging safety profile with no in-life abnormalities no adverse CSF parameter changes and no microscopic findings after a thorough histopathology workup. So to date, ALN-HTT02 has been evaluated in 4 independent primate studies. Across all of them, we've seen a favorable safety profile, supporting continued development. Last year, we initiated a Phase Ib study of ALN-HTT02 in adult patients with Huntington's. This is a placebo-controlled, single-ascending dose study to evaluate safety, tolerability and PK/PD and to help establish dosing regimens for a future Phase II/III study. The study is being conducted in HD-ISS Stage 2 and early stage III patients, and participants who received placebo are eligible to receive a dose of active study drug after 6 months. We partnered closely with the Huntington's community on the design and the protocol was reviewed and accepted by the Enroll-HD Clinical Trial Committee and endorsed by the EHDN Executive Committee. The study is initiating in the U.K., Canada and Germany and initial participants were dosed late last year. I'm happy to say that things are proceeding quite well, and we expect to share a substantial progress update at a Medical Congress next year. In summary, our C16-siRNA platform offers a new approach for Huntington lowering in the CNS with broad distribution, infrequent dosing and an encouraging safety profile. ALN-HTT02 is an investigational RNAi therapeutic designed to durably lower all forms of mutant Huntington, including the shorter HTT1a isoform, which we believe may be important to fully realize the potential of Huntington lowering. Wild-type Huntington lowering in the CNS appears well tolerated in nonhuman primates after intrathecal dosing with our molecule. And a Phase I study of ALN-HTT is ongoing in people with Huntington's disease. And we anticipate being able to tune or optimize the depth and duration of Huntington lowering through clinical dosing regimens to maximize efficacy while preserving safety. Looking ahead, we're making significant progress towards building a neuroscience pipeline. We achieved the first human translation of RNAi in the CNS and the encouraging clinical profile of mivelsiran has unlocked our ability to tackle many serious neurodegenerative diseases. Together with Regeneron, we now have 3 molecules in active clinical studies, all leveraging the same C16-siRNA delivery platform, mivelsiran for cerebral amyloid angiopathy in Alzheimer's, ALN-HTT02 for Huntington's and ALN-SOD for ALS. We have additional molecules in CTA-enabling development that are rapidly approaching the clinic, including one targeting tau for Alzheimer's and another targeting alpha-synuclein for Parkinson's. Beyond that, our research team is actively pursuing many additional targets and working to evolve the delivery platform with new approaches, including systemic brain shuttles, which you'll hear more about later today. Our partnership with Regeneron is supporting rapid growth of the Neuroscience platform, and we look forward to sharing more updates on our CNS efforts in the future. Thank you. I think we're going to take a short break. And then we'll regroup for a Q&A session moderated by Pushkal. [Break]

Awesome. All right. Well, look, welcome back for Q&A. We've got about 30 minutes. I am joined up here by John Vest, Simon Fox, Julia Shirvan and Kevin Sloan. And then on the video monitor, we're very lucky to have Dr. Tabrizi, who's joined us from Palm Springs, where she's at the CHDI Conference. So she's going to be with us for this 30-minute session. So one, we should definitely take advantage of Dr. Tabrizi joining us this morning. So please, if you have questions, there's going to be 2 circulating mics. Raise them, and then I will triage them between Dr. Tabrizi, myself and the people, the speakers. And then the second housekeeping point that I just want to emphasize, I'm sure many of you have questions about the potential upcoming launch of AMVUTTRA. Unfortunately, Tolga has developed laryngitis. Jeff has developed laryngitis. And so we will not be answering any questions about that. We've had opportunities in the past. We will have many opportunities in the future -- on future calls. So we really want to focus on the R&D Day presentations for this morning. And then a reminder, we'll have a second set in a couple of hours to talk about the second set of topics of the agenda. All right. So with that, Gena has got the first one.

Gena Wang from Barclays. So I have 2 questions. One is regarding the nucresiran Phase III trial design. So you -- now you come up with a 2-arm study and you allow a stabilizer. So is there a cap? And do you allow for both tafamidis and acoramidis? And also, you do use event-driven. So what is the event you are powering for? And based on the HELIOS-B, what is your assumption, how long the follow-up the event could happen? And my second question, very quick, Huntington program. So it's a very exciting. And you did show 90% knocking down in the nonhuman primates and show no adverse events. So what we learned from all the others, we know that -- and given you are knocking down both wild-type and mutant version, what we understand is the optimal knockdown is 50%. So what is your latest thoughts regarding what is your goal when you entering clinical study?

Okay. Thanks, Gena. So let's -- so I think there are 2 questions there. Maybe John, the first is for you. If you can just talk a little bit about the background stabilizer use that's allowed in the upcoming study as well as some of the powering assumptions in terms of an event-driven trial. And then maybe the second question, I'll turn it to you, Dr. Tabrizi, I don't know if you heard that. The question that came up was just what have we learned from other trials in terms of what level of knockdown we may seek to achieve in Huntington's disease, both with mutant wild-type and the exon 1 fragment that you spoke about to see a beneficial effect in this disease, right? But maybe first, John.

Yes. Thanks for the question. So let me start with the stabilizer piece. And I think the question was, is there going to be a cap? And I believe would we allow any stabilizer. So there is no cap. We will allow anybody to come on to the study that's taking a stabilizer that will -- can include either tafamidis or acoramidis. So both will be allowed. And as I said, we anticipate that will be a majority of patients on the study who will be on the stabilizer. The next question was about the event-driven aspect of the trial and the powering. So yes, we are doing this as an event-driven trial. And the primary endpoint, as I indicated, will be a composite of all-cause mortality and CV events. And as always, we power in the number of events that we were powering for that composite. So that includes both of those components.

Thank you, John. And then maybe Dr. Tabrizi, if you want to speak a little bit about targets for lowering Huntington protein and the exon 1 fragment. And Kevin, if you have anything to add after that, please do.

Thank you. Sorry, I can't be with you. I met a Huntington's Therapeutics meeting in Palm Springs, and I was doing the keynote last night. So sorry, I'm joining on Zoom. So it's a good question. I don't think yet from any of the clinical trials to date, we know exactly the dose that's safe in humans. What we know preclinical animal models is that Huntington lowering up to 50% to 70% is well tolerated in numerous different animal models. And in humans, I think the -- we still don't know. So the tominersen failure with the generation HD-1 was not thought to be due to wild-type Huntington lowering. It was thought to be due to the pro-inflammatory effect of the antisense oligonucleotide with very high doses. And the very high doses we used because they wanted to try and maximize deep brain penetration to the strike and where we absolutely have to treat in Huntington's disease. And I think there's 2 pieces of data that's come out of Huntington lowering trials in humans recently, which suggest that adults are able to tolerate wild-type Huntington lowering to a degree. The first is the PTC data that was -- had public announcement last year. And they have about 45% lowering in CSF, which means in brain per parenchyma, it's probably about 70% -- 60% to 70%. And because the CSF is a diluent of the brain parenchyma and over 1 year, albeit in a small cohort, there was absolutely no adverse signs associated with potential wild-type Huntington lowering. And in fact, the CSF neurofilament, which is a key marker of neuronal injury did not move. And the other study that I think is targeting exon 1 and total Huntington is the uniQure study, again, a gene therapy. But over 2 years, it now really begins to see that there is some evidence of really statistically significant clinical improvement in a very small cohort. This is 10 to 20 individuals. And CSF neurofilament going below the subject's baseline, which is good news. It means we're saving neurons. So I think there's more evidence now that we can tolerate more Huntington lowering. And I think the beauty of the Alnylam program is unlike other oligonucleotides like antisense oligonucleotides, where you have to really ramp up the dose given intrathecally to getting up to the striatum. The Alnylam molecule is very potent. So much lower doses can be used to get deep brain penetration. And I think the nonhuman primate data very clearly shows very nice deep brain penetration. And in fact, the best deep brain penetration I've seen in NHPs for any oligonucleotide.

Great. Wonderful. Let's go to another question and we will -- although Gena's stuck in, we'll try and do 1 question per person so we can get as many people to have questions.

Salveen Victor Goldman Sachs. With regard to your updated analysis on mortality through 42 months for your ATTR CM program. Can you just put in context for us the relative risk reduction on monotherapy arm, which was greater than what we saw in the overall arm?

Thanks, Salveen. So John, the question is for you. Can you just put a little context around we see is close to 40% lowering of mortality and why we're seeing that in the monotherapy arm over time.

Yes. Look, we're certainly thrilled with the results. And as I tried to highlight during the presentation, I think they're important for a couple of reasons. First and foremost is that they corroborate the analysis, the primary -- the analysis is done at the primary analysis, everything is entirely consistent. I think that's probably the most important message. Yes, we are encouraged that with longer follow-up, not only do we see -- does this add to the robustness of the results and that consistency. But the point estimates were a little bit larger. And as you point out, we saw upwards of 39% reduction in that monotherapy arm. Very encouraging to us. It's a suggestion that the treatment effect may be growing over time, but I really think very, very importantly is this consistency that we see every cut of the data.

Kostas Biliouris here, BMO Capital Markets. A question from me on nucresiran. Given that you have a stronger knockdown now and the number of patients is larger than HELIOS-B, would you expect an earlier separation between the placebo and active cares for all-cause mortality, we have seen that the 2 separate approximately at 18 months for time to all-cause mortality. So would you expect this effect to come earlier here? And the second part of the question is whether you expect to potentially see a significant difference between the combination, stabilizer and silencer versus -- I mean, a combination effect, statistically significant combination effect given the larger number of patients here versus HELIOS-B.

All right. So John, maybe it's for you. What do you think about separation of curves over time in a larger study? And then second of all is just what you expect to see in terms of the combination effect and what we understand about that already from HELIOS-B.

Yes. Both great questions. Let's start with the curve separation. What's important here with this emerging profile, as I highlighted, is that we are seeing deeper knockdown upwards of 95% with low interpatient variability, meaning that we expect, based on what we're seeing emerging for the vast majority of patients to reach the TTR reduction targets that we're aiming for. And we do believe based on all of the data in the field, including other forms of amyloidosis that this has the potential to lead to a greater treatment effect. Whether the curve separate earlier or not, that would be highly speculative for me to say it's possible. Of course, we need to do the study, and we'll see what the results are. But we are really encouraged by the potential with this profile. What was the second half of the question? Combination -- yes, sorry. So as I said in the response to the first question, there's not a cap. We expect that it will be a majority of the patients who are on combination therapy in this study. And we are designing that as I laid out 1 of the principles that we had when we went through the study designs that we want a data package that's going to inform use of the drug either as monotherapy or in combination with stabilizer.

Maybe just one thing I can add, Kostas to the point around the curve separation look there's probably a couple of things just to think about, right? So we know that this drug acts pretty quickly in terms of causing rapid knockdown or TTR. So there's an app, and you've seen John presented this actually a rapid onset of various physiologic effects, whether it's on biomarkers or echocardiographic parameters, et cetera. So we know there's -- so there is probably an aspect where curve separation is just going to be an aspect of having enough events over time, right? If you've got 1 or 2 events over time, you're not going to see curve separation. So this larger sample size may help with that, but also we are seeing in the world that patients are getting diagnosed earlier, and that's going to affect, right? And that's why I think you don't see the clinical community that concerned about this phenomenon. I think the main thing is what is the effect size? And are we seeing it. But certainly, with a larger study, we may be able to certainly -- those dynamics may evolve.

Jess Fye, JPMorgan. I have one multipart question on zilebesiran. I guess, part one, what do physicians tell you would represent a clinically meaningful MACE benefit in the CVOT. Two, when thinking about the potential MACE benefit in the CVOT, I think one slide you showed had the relative risk reduction on various types of events that's associated with every 5-millimeter of mercury improvement in blood pressure, and I think the CV events benefit was 10%, so not to oversimplify it, but does that mean that if you show a 10-millimeter mercury benefit on top of multiple background agents in KARDIA-3, and that's maintained in the CVOT then we could think about that trial delivering a 20% benefit on cardiovascular events? Or with tonic control, do you think zilebesiran could outperform those historic relationships between pressure improvement and risk reduction? And then part 3, you mentioned KARDIA-3 could inform the inclusion, exclusion criteria for the CVOT. So what specifically would you be looking to refine there? And would you consider limiting the proportion of patients on background ARBs?

All right. Simon, I think that one is squarely for you.

What was the first question? Yes, sure. I mean you saw on the slide, right, 5 millimeters of mercury systolic blood pressure reduction is classed as clinically meaningful, and it does result in a 10% relative risk reduction, it's now well known that 10 millimeters of mercury systolic blood pressure reduction would translate into a 20% relative risk reduction. But as I mentioned, this is the traditional view, the correlation between baseline blood pressure and outcomes. And we know that given the fact that the amount of variability that can happen with blood pressure in any given patient that this probably underestimates the true risk associated with baseline or high or elevated blood pressure. So yes, I mean, look, we believe with the therapeutic hypothesis of zilebesiran, where we're affecting both the quantity of blood pressure control and the quantity. So the ability to control excessive variability in blood pressure during the 24-hour period and over the long term, we would hope to see a disproportional benefit in favor of zilebesiran compared to the comparator, which is going to be placebo in the [indiscernible]. So even if you saw just a 5-millimeter mercury reduction, you probably also have the benefit of visit-to-visit variability being reduced with zilebesiran because it's always there with infrequent dosing. Yes. So the rationale is for the -- obviously, to understand the efficacy and safety of zilebesiran in a high CV risk population uncontrolled of minimum of 2 background therapies. So we're looking obviously for the -- not only the magnitude of effect at a point in time, whether that's month 3 or month 6. We'll also be looking at parameters for the duration of effect as well, looking at quality metrics of blood pressure control. We will be -- we call it -- we're going to call it a multi assessment -- multi-analysis assessment of all of the data to really inform efficacy and safety. And from the safety standpoint, we need to know the safety on top of 2 background meds or 3, and we'll also have varying doses as well of ACEs and ARBs in the study. You'll see that we -- I mentioned ARBs and ACEs are included, but included the therapeutic doses -- appropriate therapeutic doses as well.

Great. Thanks, Simon.

Ritu Baral, TD Cowen. I also have one question with multiple parts. So going back to Gena's question on background therapy and powering, which you didn't answer. Not just stabilizers, but the increasing use of SGLT2s, the increasing, I guess, the earlier stage diagnosis -- how is this impacting the potential power of Triton and your expectations? Is it even possible to have a monotherapy group if you're going to be completing the trial around the time of genericization of stabilizers. Can you help us frame at least directionally how we should be thinking of Triton Power versus HELIOS B power -- and then I have a follow-up on the primary endpoint.

Yes. So let me start, and then John, maybe you can build on that. I mean, look, I think those are all great questions. We've got the richest data set out there to understand these things because we do actually have patients on background SGLT2s. We have patients who've had diuretic intensification. And so our full expectation is the patients are going to be treated with good standard of care around the world. And so we've powered the study appropriately and conservatively around the primary endpoint, as John spoke about, to account for those parameters. And so maybe, John, I can turn it over to you, but that's part of the calculus in terms of how we thought about this. We are expecting that patients are being diagnosed earlier. That's why this is an event-driven trial. We'll be able to monitor those events over time. We're counting on background medications, et cetera to be used fairly broadly. So maybe, John, you can speak a little bit about how we might generate monotherapy data in particular in this study, recognizing that many patients will be on stabilizers.

Yes. Yes. So this is going to be obviously a global study with a really wide footprint. And we're going to see around the world, the time frame that it's going to take for different reasons of the world to have access to silencers, for example, is going to range and even access to stabilizers varies a great deal around the world. So we're confident in our ability to bring this in. And as we said, the majority of the patients will be on stabilizers, but we believe we'll have a meaningful number of patients on monotherapy as well. And even in areas where there is access to stabilizers, there's this going to be an opportunity for patients to have the potential to be on combination therapy, which would be important as well.

And on the [ TRITON ]primary endpoint, not a question for Tolga, who lost his voice. But how should we be thinking about that primary endpoint of TRITON being informed by your payer discussions, your commercial experience for AMVUTTRA in this population. Very little detail was given, but is there anything you can tell us now about what's important for his team and for doctors?

Yes, look, I think as we launch, you'll certainly see more details around the study design, but I think at the high level, absolutely, we're working with, this is a franchise we want to build a durable franchise for -- into the 2040s, and so as we've come to this development plan with our commercial medical business colleagues, everyone around the table, this is where we've landed. And that's why you've heard us talk about, a, doing an outcome study to generate an outcomes, focused on mortality and hospitalization as part of the primary endpoint. There's been discussions about, hey, why don't you do a biomarker study with TTR lowering, et cetera. So we're really leaning in, we want to show that this 95% knockdown will twice your dosing, is going to lead to a best-in-class profile and generate a label accordingly that's going to show those benefits with concordance around the components of that end point. And then we have coupled with that, this fast-to-market strategy with hATTR-PN that John talked about to actually pull that time for the initial approval in. So that's how we're thinking about all of this. And certainly, well aligned. We're really committed to building a durable franchise here.

Tazeen Ahmad, Bank of America. I have a couple of questions on Huntington’. So can you give us a sense of when the next data update will be from Alnylam on that program? And then perhaps just to reference some of the points that were made on the presentation. uniQure does have an accelerated path granted to approval. And if we assume at least one or more of the other companies that were listed is also able to get accelerated approval. Do you think that raises the bar in terms of what needs to be shown for future therapies? And what, in particular, do you think FDA would need in order to feel comfortable provided an accelerated path for your program in terms of differentiation?

Thanks, Tazeen. So Kevin, maybe you can start and just talk about pending data, the status of the current trial and what's happening there? And then maybe Professor Tabrizi, you can talk a little bit because you're involved in some of the discussions with regulators, FDA and others. And Kevin, you can certainly build. But on what's sort of the emerging viewpoint in the regulators around accelerated approval for this devastating disease and what we're learning from other companies in the field. So Kevin, do you want to start?

Yes, happy to. It's a good question. I think we're still very early. The Phase I study just started. And I think I highlighted in the presentation, we spent a lot of time really characterizing the molecule and nonhuman primate studies, taking our time to make sure we understood the molecule we had because there's been so much confusion in the field about the safety of Huntingtin lowering and how much Huntingtin lowering is appropriate. And we think that's really been mired in the types of hammers being used to hit these nails and a lot of dose-limiting toxicities, not just with antisense molecules, but also with some of the small molecule splice modulators in the space. So we're working through the Phase I. We're enrolling effectively. There's lots of enthusiasm in the field from physicians and from patients to get in. We'll be working through this single ascending dose cohorts throughout this year. What we really want to show is not just target engagement, but target engagement and safety in the Phase I with prolonged Huntingtin lowering in patients. And so our first real substantial update, we're hoping to provide next year at the Huntingtin's EHDN International Congress most likely or a relevant medical meeting that's at that appropriate time. Well, it really will show target engagement, PK/PD profile and the safety and then hopefully be able to talk more about our plans for next steps.

Great. And Dr. Tabrizi, maybe just what would you be excited to see coming out of this program? What would make you feel good about the data that was coming out of the program? And then two, maybe comment on the regulatory landscape that's out there in terms of accelerated approval and what the regulators are looking for.

So thank you. So a number of things I think I personally think are very exciting about this program. I think it's really important to target exon 1. The meeting I'm attending here, there are numerous presentations on the critical importance of targeting exon 1. And the uniQure and the Alnylam program are the only programs targeting exon 1. And the uniQure program has had some favorable discussions with the FDA. It's the cell and gene therapy group. And really the meeting and the discussions that ensued and I was privy to that conversations were that the FDA and also the neurology arm, know how much devastation Huntington's disease causes. And recently, a large number of patients and families met with the FDA on the neurology arm and really got across the devastation of this disease. And then I was invited on the 16th of July to meet with the FDA, present some of my new data that was recently published in Nature Medicine. And there was a very helpful discourse about the path to getting drugs more quickly to patients with HD. They acknowledged the huge unmet need. They acknowledged we had no treatments. They acknowledged the complexity and we had a 4-hour discussion on biomarkers, surrogate biomarkers and what they would want to see to get an accelerated approval. So I think in this study, after the Phase I and runs into the Phase II, if we get evidence that were caudate and putamen volumes, very well-established biomarkers. We changed and slowed deterioration. We may see a change in CSF neurofilament, which means we're saving neurons and that's well established in the neurodegeneration field. And I think in the cohorts that are planned to be studied, over a period of time of 12 to 18 months, we may see slowing of clinical progression. And I think targeting Exon 1 should give a bigger effect than targeting total Huntington without targeting exon 1.

Thank you, Dr. Tabrizi.

Julian Pino, Stifel. Quick question on mivelsiran. How are you all thinking about whether or not you're going to be targeting genetic subsets of Alzheimer's given the less favorable risk-benefit profile for ApoE4 patients, is that a priority for you? And then also, what are your thoughts on tau as a target? And how closely are you monitoring Biogen's ongoing Phase II study in Alzheimer's? And how could that potentially inform your clinical development?

Great. So I think these are for Julia, who joined us from Biogen some years ago. So.

Sure. Thanks for that question. Starting at the beginning, as I mentioned during the presentation, we are working towards the Phase II at the end of this year, and we will be evaluating different populations that include genetically defined populations. As we want to do in all of our CNS programs, we're looking for populations that have high unmet need that match well with the biology of our mechanism. And so that's what's going to drive our decision making as we move forward. And so towards the end of the year, we should have more of an update on that program for you. In terms of tau, Kevin did mention that we have an IND-enabling tau program. And so we're really in AD for the long run, and we're looking at different mechanisms, and we're looking at how -- what the right target is, how you should target it and when you should intervene with that target in the population. And so all of this information will inform our decisions. As you said, Biogen does have an advanced program. It's a very competitive space at Alzheimer's disease. And it represents in part that we haven't figured it out yet. We don't know exactly what to target, how to target, and when and that's something we want to be part of the solution for.

Yes. I think the only thing I would add to what Julia said, which is, look, we're in a unique position, I think, both based on the platform. But as you'll hear a little bit later, how we think about combinations as well in these diseases, right? So we have a number of assets that potentially can be used singly or in combination, for genetic subsets or broader subsets of patients. And so I think that's really the unique opportunity that we have here at Alnylam to affect these diseases.

I just add on tau. I mean I think we and others believe strongly that how you target really matters with something like tau and APP probably, right? -- where the genetic targeting approach when we get the intracellular and extracellular components are probably really important. And for tau, the failures of the antibodies are really largely due to the extracellular targeting approach that's happened there. So it's a crowded space, absolutely. We are all watching for clinical proof of concept linking tau lowering with slowing cognitive decline. Just thinking about how is there's a universe of tauopathies that could be addressed with the tau-lowering strategy. So if you see a direct benefit in slowing cognitive line, sure, all in taking partial -- part of that population, it's going to be subsets where you treat when very critical. If that doesn't pan out, there's still a lot of avenues, I think, in primary apathies and smaller rare disease plays like PSP and other areas that we could explore as well. So we're trying to keep our options open, really understand what we have. And again, we expect to have a differentiating profile with the C16 siRNA platform, long durability, low exposures infrequent dosing, which we think will allow us to differentiate from antisense molecules in this space.

Leland Gershell from Oppenheimer. Also a question from us on mivelsiran, wanted to about potential safety and how may be differentiated. We've seen with the anti-amyloid antibodies, there is risk albeitm low, but intracranial bleeding and edema, triple edema. Just wondering if the mechanism with suppressing the generation of amyloid versus attacking it with an antibody could actually be an advantage with respect to safety, given MLA deposition in arteries and that potentially causing the side effects.

Sure. And thanks for that question. So yes, we have a differentiated mechanism that worth of the source of amyloid production and the differentiation about not targeting the extracellular amyloid does make us think that mechanistically, we have -- we don't have an increased risk of ARIA. And in fact, that's what we're seeing. We aren't seeing increased risk of ARIA in our population. And in fact, I showed the preclinical data today from our rodent studies where the animals were treated with an APP lowering siRNA, and actually, they reduced bleeding in those animals. And so we feel confident about being able to differentiate on that safety end point.

Great. Is that it, or do we -- what was that? Okay. So I want to thank you all. Dr. Tabrizi, I really want to thank you, your presentation was very well received earlier, and thanks for joining us early in the morning from California and squeezing us in. It really meant a big difference. So thank you for that. And I'll thank all my colleagues, and I'm going to turn it over now to Kevin Fitzgerald, who's going to be opening up the second part of the morning. Thank you all.

Good morning. Can you believe that's only about half of the content. So I'm Kevin Fitzgerald. I'm Chief Scientific Officer. I've been with Alnylam for almost 20 years. Before that, I actually worked on RNAi a little bit earlier. So I have a long history of experience in RNAi. And I have to say that in all of those years, I've never been more excited about the potential for RNAi therapeutics and where it's headed. And also for where Alnylam is headed. And the potential of this technology to really impact medicine going forward for millions of patients. I'm going to remind you that Alnylam really drove the first phase of the RNAi revolution from its founding. And really, the basic fundamental science that we had to solve was how do you take these very large double-stranded molecules of 14,000 molecular weight. And how do you turn them into drugs, right? And part of that was to stabilize the hell out of the molecules, but also then to work on delivery, delivery and delivery. And if you look at the delivery systems that are out there that have been all the way to products, you have lipid nanoparticles that we developed, that became ONPATTRO as the mechanism of delivery for that drug. We developed GalNAc as an innovation that's now part of a lot of the drugs that have been approved. And now we've innovated C16 in the brain. And we will continue to innovate in the delivery space, and you'll see that later today of the progress that we continue to make. And that's led to a number of products, as you all know. And I want you to think about RNAi as a generational technology. And what do I mean by that? If you think about the generation of therapeutics over the years, you have small molecules that started with antibiotics. And then you had the advents of -- it took a lot of years, but then antibodies, right? Antibodies as a therapeutic class, they didn't just show up overnight. They took a while to develop where you had a few products here and there. And then the technology evolved in that innovation curve and then suddenly have an explosion of products. And then even there, the innovation doesn't stop where you go from an antibody that targets one thing to now we have bispecific and even upcoming trispecific antibodies, you see a very similar thing starting to happen in the RNAi space. right? And I'll talk a little bit about combinations of some of that innovation. But if you look now at the pipeline of emerging RNAi therapeutics, there's now about 140 of these things coming through. And in various phases, some of them now in registration. A lot of that driven by the GalNAc technology, but now new delivery technologies are starting to emerge. And Alnylam is positioned to continue to innovate and lead in this field. And I'll tell you a few reasons why. One, we've got the largest database. We've been screening RNAis for almost 20 years. So we're now using AI to interrogate those sequences in that database to really find the molecules that are not only have exclusive specificity but also drive safety, right? We have a very large database continue to work in that space. And that changes a little bit across tissue. We also can go very rapidly from idea to clinic. Now we're beyond the stage where we're just going to take an idea and put it in the clinic just to be first, right? There will be cases where we choose to be second or third good example is Huntington. We had a full-length molecule that was not an exon 1. We could have driven it in the clinic and said, "Oh, we're in clinic first." It's not what we're doing, right? We're going to be data-driven, and we waited in order to be able to find a molecule within that exon 1 sequence. And we think that's the best approach for this disease based on the current science. In addition, if you think about -- we've got 20 years of clinical experience. We've got experience with regulators. We've got experience designing trials and designing trials for long-acting molecules is actually not easy, right? And so that experience bodes well as we design trials. And we've been able to show consistently that we can get things across the finish line. We publish our work, right? I don't underestimate what this is. We publish New England Journal of Medicine. These are peer-reviewed papers in Nature so and so. So when we say that we've solved something scientifically, you can believe it because in general, it's peer review. Right? And it's reproducible. Next, state-of-the-art manufacturing. We'll talk a little bit about we innovate across the board. And you'll hear today something in innovation in manufacturing that I think is really worth paying attention to, especially as we start to get into common disease, where you're going to have to have drug for millions of people. And Vasant will talk about that. And we have brought intellectual property. We have intellectual property on a lot of the molecules that are in other people's pipelines. We have intellectual property around delivery. And so last year, we spoke about 2-2-5. And 2-2-5 was an ambitious goal where we said by 2025, and I checked, it's 2025, but it was by the end of 2025, we would have 2 new tissues with INDs. We would have 2 new Alnylam-led programs in the CNS and we have 5 new liver programs. And these were not just numbers. These were high-quality programs. So that meant that we had to have almost double the number of ideas in order to take these in. So how are we doing? So in 2024, we filed with our -- between us and our partners, we filed 8 INDs. We also promised that we would double the pipeline so we would have 15 total programs with partners. So we're more than halfway there. And so I'm excited today. There are 4 Alnylam-led programs here. So we've got plasminogen, which we announced for the first time today. So a very exciting program that we think will work across multiple bleeding disorders. So we think it's a universal hemostatic agent and the genetic suggests that it doesn't have a risk of thrombosis, which is key. So Paul will come on and talk a little bit about more about -- and Anna will talk more about that program. We announced GRB14, again, identified through our human genetics efforts. This is a target that we believe will be the first insulin sensitizing agent in over 30 years that doesn't give you weight gain or fatty liver, right? At least our preclinical data is very strong on this target and you'll hear about that today. We moved to REVERSIR, which is a new technology where if you're going to have a long-acting molecule, sometimes you may want to have an agent that could reverse it, right? So that's a new technology that we now moved into clinic. And you heard about the Huntington's program where we target exon 1. In addition, our partners have taken 3 liver targets into the clinic and 1 additional CNS target. And those programs, we have a strong financial interest in. In addition, we dosed our first patient in hepatocellular carcinoma program. This is our beta-catenin program. This is driven by a lipid nanoparticle. And there, we're looking for patients that actually have activated beta-catenin mutations. So we're selecting subsets, and that's a fairly large portion of HCC, but we're selecting those patients for activating mutations. Nine development candidates. So these are the programs. These are drugs that will be in clinic in 2025 and some in 2026. And so it shows that we have ramped up our ability to make development candidates. We've automated the heck out of things. And so we can drive things very quickly when we choose to. So looking ahead, we're going to stick to what we know best. We're going to have genetically validated targets. We've got bigger and bigger databases. The databases are getting better. We have our own proprietary tools to go in and access that data and actually analyze it. And so I think that shows up in some of our publications, where we've been the first to find some genes INHBE being a good one of those, where we found the gene, we were able to publish on it before some of our competitors that have bigger databases and other things. We're going to have early biomarker. We -- like biomarkers in Phase I. We want to have early proof of mechanism or proof -- and confidence that we're getting the doses right in clinic because we think that, that allows us to have a higher probability of success. If we're going to fail, we want to fail early, right? So we want to fail and no, and we're not going to be shy about pulling things out of clinic, if we don't think they're going to be transformational drugs. We're looking for drugs that have the potential to halt or reverse serious disease, and we're looking to be best-in-class. So we also talked about our ambition. So we're very ambitious and we want to unlock every major tissue by 2030. It's an ambitious goal, what do I mean by major tissue. We're going through the different tissues and I'll talk about combinations of tissues in a minute to look for the ones where we think there are 4 or 5, at least good targets that are going to transform people's lives if we inhibit them with RNAi. So we're going to pick them off one at a time based on where we think the unmet need is and where the targets are. The good news with RNAi as it works in every organ in the human body. In fact, it seems to work in every cell in the human body. So it's an engineering problem, like we've solved before in order to deliver these molecules where they need to go to get them to work. So liver really is just the beginning. We're going to start to pick these off. You'll hear later from Vasant. We're making good progress already. But keeping in mind that when we want a delivery system, ideally, we would like something that's subcutaneously delivered, long-acting, less than 3 mgs per kg, so it could be a single injection and where we can scale it. So I mean manufacturing is an issue. Some of the things that we've talked about in the past, you'll hear about the manufacturing innovation we've made that will actually allow us to make larger molecules for some of the combination things that I'll talk about. And so let's talk a little bit about the future and combinations. So if you look at where we started, it's not surprising that if you have a new technology, we've gone after essentially monogenic disease. So TTR, mutant TTR is toxic, it comes out of the liver that causes disease. You inhibit it, makes sense, you might fix the disease. PH1 or porphyria, these are monogenic diseases. So one gene mutation causes those diseases. We're able to figure out a part of the pathway or you inhibit something else and you help fix the disease. HDL and cholesterol PCSK9 is again, a single target. But as you start to move towards common diseases, there's actually -- more of them are actually multigenic, so they got more than one gene that's behind that disease. So that's where you'd really like to have combination therapy and the ability to go after multiple targets at the same time. Not only that, a lot of the diseases involve multiple organs, right? So not only do you want to have multiple targets, but then you also want to be able to go after selectively multiple organs. So if you think about where the state of the state is sort of last year, you've got single genes going single RNAi targeting a gene going into the brain, you've got one going into the liver. An interesting application that we have with our partners at Regeneron is being able to combine an RNAi called CEMDISIRAN that target C5 with their antibody called -- I can't say it, poze. That's what they call it. And what you find there is a very interesting thing. So antibodies target proteins. Well, if there's a lot less protein around, then the antibody PK actually changes. And if you can target intracellular and extracellular at the same time, you can be more efficacious. And so we really believe that, that combination of the antibody plus an siRNA is better than either of them alone. So you're going to start to see that in the field is that you can combine things. On the RNAi side, which you can start to see is that right now, you can have an SI that we can now drive to multiple tissues. So if you want to, you can have multiple ligands that will take a single SI and take it into 2 different tissues at the same time. We're starting to work on that very selectively. So you're going to be able to pick and choose what tissues you want to go to. In addition, you're now going to be able to have what I call sort of a -- we've talked about GEMINI before, but now you can have a GEMINI where it goes into the plasma, one, 1/2 of it goes to one organ and one 1/2 of it goes to another organ, right? So if you start to think about the possibilities now, it gets more complex, but it also gets much more exciting about where we can go and the types of things that we can attack. So we've been driving the RNAi revolution, and we're going to continue to do that in the future. We have a sustainable engine. So we're well on track for our 2-2-5 initiative. Our pace of innovation and drug discovery is rapid and it's accelerating. And we -- of the size now where we have the resources that we can put back in and we can do things like we can scale and we can automate, we can do things faster. We can do things bigger, and we're going to do that. We have high-quality programs based on human genetics, 20 years of clinical development experience. You heard about our emerging CNS portfolio. Sandeep is going to come on next, and he'll talk about our strategy in CV metabolic space. We'll then have Anna come on and talk a little bit about our plasminogen program. And then Paul will come on and talk a little bit about exciting new program in the ocular space that we're working on. And then finally, Vasant will come on and anchor the day with all of the amazing things that we're doing on the delivery side that are going to enable the combinations that I talked about that are going to enable our goal of getting to every major tissue by 2030. So with that, I'm going to hand it over to Sandeep, who's going to come on and talk about our metabolic strategy.

Thank you, Kevin. I'm Sandeep Menon. I'm the Chief Development Officer here at Alnylam. It's my pleasure to share our strategy in metabolic diseases today. As you've heard throughout the day that our key R&D principles are to develop best-in-class medicines to address diseases with high morbidity and mortality and potentially halt or reverse diseases. And as always, we are pursuing high conviction targets with strong biology and human genetics. That is our basic validation that we always do. Now we believe continued innovation is warranted in obesity and in diabetes. And our platform, along with our R&D strategy is very well positioned to bring forward the next generation innovation especially in obesity and in diabetes. Now in obesity, we are addressing the unmet needs that is not addressed by incretins. I've listed a few targets here, and we will be talking about that in the next few minutes or so. And then for diabetes, we are addressing the primary driver of type 2 diabetes, which is insulin resistance. And I also talk about target GRB14 in the next few minutes as well. Now we all acknowledge that the first wave of innovation has been dominated by incretins. And the market is expected to grow exponentially in the coming years. However, there is a significant unmet need that is evolving based on the unmet need that is left by the incretins. Nearly half of the patients discontinued the treatment due to tolerability issues. The treatments are not durable. 60% of the weight loss is regained within the first 1 year. And most of that weight regained is the fat regain that leads to the weight increase. So that is also because of the suboptimal tolerability, because of the suboptimal tolerability, the patients are not able to continue the treatments. And hence, there is an issue with the durability of weight loss. Now finally, there is a lot of room to improve in the body composition. From 15% to 60% of the reduction in lean mass happens because the patients lose lean mass, which will never be regained. And this is a huge problem for the elderly. Now when we look at the unmet need, most of the things that we are seeing here is the quality of weight loss. And the things that have been addressed by incretins is the quantity of weight loss. And we believe there will be a shift in the treatment paradigm, which will be from a quantity of weight loss to a quality of weight loss. Now the ongoing innovations, however, seem to mostly be dominated by next-generation incretins. And its combinations, which we believe will still not be able to address the unmet needs that is left on the table by the incretins. And here is where Alnylam will have a differentiated strategy. We are taking a differentiated strategy, and we are targeting the Inhibin/Activin pathway with the aim to achieve safe and sustained weight loss. And we have our reasons to believe, our reasons to believe are strong genetics backed by a very strong biology, exclusive tissue selectivity and long-acting because of the flexibility of our platform. Now we also have strong preclinical data that is evolving for monotherapy for combinations, namely with the combinations of novel siRNA, which targets multiple targets and multiple tissues at the same time as Kevin was alluding to, and also combination with low-dose incretin, almost incretin sparing approach. Because of all of these components, we think we have our reasons to believe that we will be able to bring durable weight loss, which is the quantity of weight loss and improve the quality of weight loss by preserving muscle mass, improved body composition, improve the tolerability, which is not addressed by incretins and finally, reduce the discontinuation rate. Now how are we going to do this? We are going to target the ligand receptor combination, which is the Inhibin/Activin pathway Inhibin E is a target in the liver. ACVR1C is a target in the adipose, and this pathway is implicated in regulating and blocking the lipolysis. So Alnylam, I just want to remind everybody has discovered this target, and we have studied this pathway pretty deeply. And hence, we are going to be very thoughtful on how we want to take this into the clinic. So our monotherapy data here is showing deep and durable knockdown. It is in NHP. The first target is the ACVR1c, which is in the NHP adipose. And the second 1 is Inhibin E, which is the knockdown in the liver for NHPs. So both of them show deep and durable knockdown. And we also see fat loss, lean mass preservation and wait regain attenuation. And I'm not showing that data here. But all in all, what we are seeing is deep knockdown and because of high potency and specificity, there are a lot of reasons to believe that this could be a game changer for patients in terms of when we are bringing this to the clinic. Now I'm going to share more emerging data, which is on the background of a very low dose of incretin. This is the data in high fat diet mice. It suggests greater fat loss, lean mass preservation and much slower weight regain after the cessation of semaglutide treatment. So you can see here that in the graph, the left-hand side that is labeled as fat loss, the blue and the purple line represents the siRNAs. And you can see that there is a greater fat loss compared to semaglutide and lower fat regain after semaglutide treatment is stopped. We have similar trends for lean mass preservation and attenuation of weight regain based on this combination. So this is our data with a combination of 2 siRNAs, targeting 2 different targets in 2 different issues. Again, this is a high-fat diet mice. And you can see again on the left side here, we see enhanced and sustained weight loss similar to a high-dose semaglutide and low-weight regain. The yellow line is the combination of ACVR1c with gene X, which is 1 of the targets in another tissue, which you are targeting. While on the right side, we see fat loss, which is greater than 45%, we also see increased lean mass and weight gain prevention post incretin treatment. So imagine if you can see a similar data in the patient, this will be a game changer in terms of the obesity patient management and treatment management in the clinic. So we plan to progress ACVR1C in the clinic in 2025, and this will be our first adipose target getting into the clinic this year. I'll shift gears now to type 2 diabetes, which is also a large market with a very significant unmet need with about 45% of the patients not on target, they are not controlled, very poor glycemic control. There is an issue with the comorbidity management with about 40% of the patients with at least 3 co-morbidities and there is an issue with treatment adherence as well for the oral antidiabetics. Now what we want to do here is we want to bring in the first insulin sensitizer in over 3 decades. So we have that flexibility to do that because we can do novel combinations with the standard of care, novel combinations with the 2 siRNAs in different tissues and targets. And it's going to be long-acting, which will help in the patient and the treatment adherence. Now, I want to take a step back, why is Alnylam targeting insulin resistance. Insulin resistance is one of the primary drivers and the target for type 2 diabetes. It can manifest 10 to 15 years before the type 2 diabetes actually is diagnosed. Hence, targeting insulin resistance is critical to manage type 2 diabetes. The current insulin sensitizers, however, is very, very limited by its use because of its side effects and adverse effects, mostly, it is weight gain that happens in this insulin sensitizer. So we are specifically targeting GRB14. GRB14 is a liver target, and it is a negative regulator of insulin sensitization -- sorry, the insulin receptor signaling. Blocking GRB14 leads to reduced hepatic production and increased glycogen storage, thereby increasing insulin sensitivity. So GRB14, just to remind everyone, is genetically validated and is a target, which lowers the risk of type 2 diabetes and the risk of comorbidities like NASH. So our emerging profile here is validated by preclinical data in preclinical models. And our preclinical data shows that we have got very effective HbA1c lowering, it is weight neutral, it is long acting, and it has the potential to give us the insulin sensitization, which is the true insulin sensitizer, which is the muscle sensitization as well. This is our data, preclinical data that we have on the -- on GRB14. As you can see, it achieves very deep and durable knockdown of 90% knockdown in NHPs just based on single dose. It is an OB-OB mice, which is a good model for human translation. It normalizes HbA1c. It improves insulin sensitivity, and this all happens without any weight gain. Based on this data and strong human genetics and the biology, we are set to enter the clinic in the next few weeks. We will have our first in-human study in healthy obese patients with primary objective of safety and tolerability. And we will then soon switch to our Phase II study, which will be an obese type 2 diabetics, which will be on a background of standard of care, and we plan to get our proof of concept soon. I just want to remind everyone that metabolism is not new to Alnylam. We already have got 3 programs in -- with our partners and 2 of them are already in the clinic. The third one is already on its way to be in the clinic in the first quarter of 2025. In conclusion, I just want to reiterate that though incretins are rapidly emerging as the first line of choice for diabetes and obesity, the unmet need still persists. And Alnylam RNAi therapeutics offer a very differentiated approach in managing metabolic diseases, especially diabetes and obesity. Our approach of high-confidence targets, validated human genetics, supplemented by strong biology and our platform, which offers differentiated approach for extended durability and flexibility of multiple types of combination positions us very well to deliver innovations for metabolic diseases. So we are very excited about our metabolic franchise now. multiple programs are advancing into the clinical development in 2025. So stay tuned for more in the coming months. With that, I'll transition to my colleague, Paul Nioi, who will share updates on the next wave -- I need to practice on the clicker. Next wave of RNAi therapeutics. Thank you.

Thank you, Sandeep.

Okay. Good morning, everybody. I'm Paul Nioi, SVP of Research at Alnylam. I head the discovery research team. And I'm going to be joined in a moment by my colleague, Anna Borodovsky, who's a VP in the discovery team. So you just heard from Sandeep about some of the really exciting early programs that we have going on in the metabolic space. What Anna and I are going to do is give you a broader view into the early pipeline at Alnylam and talk about some of the exciting programs that are either in the clinic now in Phase I or will be in the clinic by the end of this year. You've seen this figure before, but it illustrates the sustainable innovation engine that we have at Alnylam. We've talked about our ability to deliver our siRNAs to different tissues. Vasant is going to expand upon that in a moment. No one can design siRNAs like Alnylam. We have been in the game for 20-plus years. When it comes to potency, when it comes to specificity, Alnylam really truly is the leader. However, we need to find the right targets, of course. And we've invested significantly in human genetics, so we can point our platform at high-value targets with a high probability of translation into the clinic. And all of this has really fueled our 2-2-5 strategy. And remember, this was the end of 2023, we told you we were going to file 2 new INDs for new tissues, 2 new Alnylam-led INDs for CNS programs and 5 new Alnylam proprietary INDs for liver, so-called 2-2-5 strategy, all by the end of this year. As you'll see in a moment, we are very, very much on target with those goals. But I want to double-click on the genetics piece for just a moment because this truly is a differentiator for Alnylam amongst our genetic medicine technology peers. If you think about it, if you discover your drug target from a human being and you know that there's a correlation between a genotype and a phenotype, it makes sense that, that is much more likely to translate into the clinic versus something that you've discovered in a mouse or something that you've discovered in the cell line. All of our targets have a strong human genetic foundation. We actually have access to data from over 1 million people now where we have their genotype and we have access to their medical records. So we've really invested over the last few years in this. By 2030, we're actually aiming to have data from 6 million individuals. So really fueling our ability to identify the right targets for amazing platform. But it's not just the data, we've built an amazing team at Alnylam that really gives us the analytical horsepower to be able to analyze that data and gain the insights we need to identify the targets. So all of this is really what's fueled 2-2-5. And as you see from the table here, all the targets -- this, by the way, is what we showed you at the end of 2023 in terms of the menu of options for 2-2-5. All of the targets on the left have a strong genetic story behind them, all of them. You can see in the middle column that we're now targeting multiple tissues. We have programs in liver. We have programs in adipose. We have programs in skeletal muscle. And of course, we have programs in the central nervous system. There's also a range of different indications that you can see on the slide here, some of which there's tremendous unmet need, and there's a tremendous business opportunity for Alnylam. The middle column shows you what we told you we were going to do when we presented to you at the end of 2023. And you can see we've achieved every single one of the goals that we laid out for you, all of them. The progress and the stage of each program is shown in the right-hand column. And you can see several of these programs have now transitioned into the clinic. A number of other programs are now in IND-enabling studies and will be going into the clinic this year. One comment on this slide, though, is, this is a menu of options, right? It just shows the productivity of our research engine, and it gives us things to pick from. And really, if you put a strategic lens on this and think about what are the right opportunities for Alnylam, what makes sense for Alnylam, where should we go with our technology, this really gives us a list of options that we can choose to pursue or not. We're going to talk about a couple of programs, though, that we're particularly excited about. Anna is going to come up in a second and talk to you about the plasminogen program, which is now in Phase I for the treatment of bleeding disorders. And then I'm going to come back up in a moment and talk about Gene G, which is a novel target we're very excited about for the treatment of dry AMD. So with that, I will hand over to Anna.

Thank you, Paul. I'm very excited to introduce to you ALN-6400, our investigational drug for the treatment of bleeding disorders. Bleeding disorders affect more than 3 million people in the United States alone. And patients who suffer from these diseases have a profound impact on their quality of life and also experience life-threatening complications. Majority of bleeding disorders lack treatment, and where treatment does exist, it is often burdensome and increases the risk of thrombosis. The pathway of hemostasis lies at the center of the pathogenesis of bleeding disorders. This pathway is initiated upon vessel injury and through the action of clotting factors and the recruitment of platelets leads to the formation of a blood clot that seals the injury. The blood clot is then eventually dissolved by the action of the fibrinolysis pathway. By modulating fibrinolysis, we believe that it is possible to develop a universal hemostatic agent that can address unmet needs in bleeding disorders. ALN-6400 is an siRNA targeting plasminogen or PLG. PLG is secreted by the liver. And once it is activated to plasmin, drives fibrinolysis, the breakdown of the fibrin mesh that holds together blood clots. We believe that by lowering PLG with ALN-6400, we will slow down the process of fibrinolysis, thereby stabilizing clots and preventing bleeding. There is clinical precedent for this type of an approach from the use of tranexamic acid or TXA, which is a small molecule inhibitor of plasminogen activation. This particular drug is used off-label to treat bleeding disorders. However, it has a high pill burden and has a variable effect on fibrinolysis due to its short half-life and is not well suited to prophylactic use in bleeding disorders. ALN-6400 has the potential to be a universal hemostatic agent that opens the door to a pipeline and a product-type approach in the multiple bleeding disorders. We have done extensive analysis of the UK Biobank to support both the targeting of PLG and its safety. Circulating PLG protein levels are -- high levels are associated with GI and nose bleeding as well as a higher rate of heavy menstrual bleeding. Conversely, individuals that carry loss of function variants in plasminogen have a reduced rate of these types of bleeding, but importantly, do not show an increased risk of thrombosis. Additionally, individuals with a homozygous deficiency of plasminogen also do not experience an increased risk of thrombosis. We have compared the risk of thrombosis as it relates to levels of plasminogen to that of known thrombophilic factors. And we find that decreasing circulating levels of plasminogen are not associated with an increased risk of a thrombotic event. ALN-6400 is a GalNAc-conjugated siRNA targeting plasminogen, which utilizes our clinically validated GalNAc-conjugate platform. It has demonstrated greater than 90% reduction of circulating PLG in nonhuman primates, and we have not seen any evidence for increased thrombosis in preclinical studies with this molecule, including in GLP tox studies. We have generated a lot of evidence around the impact of plasminogen lowering with ALN-6400 on the fibrinolysis pathway. I just have a couple of examples here. We can show inhibition of fibrinolysis in NHP plasma in a lysis timer assay here on the left side of the graph as compared to treatment of NHP plasma with TXA. We can also demonstrate reduction in plasmin generation in NHP plasma. And when female NHPs are treated with plasminogen-silencing siRNA, we observe a reduction in menstrual bleeding, which demonstrates an impact on mucosal bleeding with PLG silencing. We have now taken ALN-6400 into a Phase I study in healthy volunteers, which is currently enrolling. This study uses an innovative design that includes a run-in period where volunteers are given a short dose -- course of treatment with TXA to benchmark the antifibrinolytic effect in an ex vivo assay that I will describe to you shortly. After a washout period, volunteers are then randomized to ALN-6400 or placebo to evaluate safety and tolerability. Let me give you a primer on how we use this ex vivo ROTEM assay to evaluate fibrinolysis. If we first look at TXA and the graph here shows the expected PK profile of TXA when it is given as it is normally would be 3 times a day. As you can see, the levels of TXA vary quite widely throughout the day. And for a large proportion of the time, are actually below the red line on this graph, which represents the level of TXA needed for a robust antifibrinolytic effect. During the run-in period of our trial, we collect samples at steady-state trough and peak of TXA and then evaluate them ex vivo in the ROTEM assay. This assay evaluates the extent of clot formation in -- I'll say there where you actually include tissue plasminogen activator, where the amplitude of the shape corresponds to the extent of clot formation. Initially, you have clot formation and followed by lysis over time. If we now look at what happens with TXA treatment. At baseline, we observed rapid clot formation followed by lysis. And then once individuals are given TXA, you see kind of an extension of the shape, which represents the delayed fibrinolysis in this ex vivo assay. Note that the 2 time points we have for TXA here, you have quite a bit of variability in the extent of antifibrinolytic effect observed. I will now share some initial proof of mechanism data with ALN-6400 from the first cohort of our trial that was obtained just 4 months after the filing of the CTA. These graphs up here represent time points from a healthy volunteer dosed with placebo evaluated in the same ex vivo assay that I just described. At all of these time points, we see consistent clot formation and lysis. Now if we look at an individual treated with ALN-6400, at baseline, you see a similar type of clot formation and lysis as in a person treated with placebo. However, at time points post the administration of ALN-6400, we see the antifibrinolytic effect as represented by a more extended shape of the graph. And this effect is very consistent at the days 29 and 43, especially in contrast to what we had seen with TXA on the previous slide. We are progressing within the cohorts of this study, and we plan to initiate a Phase II study in a bleeding disorder in the second half of 2025. I will now hand it back over to Paul to continue the presentation.

Thank you, Anna. Okay. So now turning to ophthalmology. I want to tell you about a target that we're very excited about, Gene G, and a potential therapeutic that we're very excited about ALN-Gene G, which would be a subcutaneously administered treatment for dry AMD. And as you may know, dry AMD is a disease that affects literally millions of individuals around the world and within the United States. There's a huge amount of unmet need. And that's illustrated even further on this slide. Actually, within the U.S., there are 10 million individuals who are diagnosed with some stage of age-related macular degeneration. About 4.25 million of those people are in the early stages of the disease, and there's about the same number in what's called the intermediate stage of the disease, which, by the way, there's no treatment for. And then there's about 1.5 million individuals divided equally between what's called the wet and the dry forms of AMD, this is the later stage of the disease. Dry AMD is the topic for today, and that's characterized by the progressive loss of vision. And that's driven by the progressive death of photoreceptors in the eye. So of course, without photoreceptors in the eye, you can't see, and those cells actually die in dry AMD. There's a number of risk factors, including your genetics, it's comorbid with things like heart disease and obesity. And while there are effective treatments for wet AMD, there are no approved therapies that improve vision in dry AMD. So there's tremendous unmet need here. A little bit more on the pathophysiology of the disease. So in the left-hand figure, you can see an image of a normal healthy fundus in the eye. The middle panel shows you what happens in the intermediate stage of AMD. So the green arrow is pointing to what's called drusen. This is like a fatty-like substance that accumulates in the eye. And these patients might report blurring of vision. They might have issues with dark adaptation. And there's actually no therapies that are approved for this condition. Remember, I told you there's 4.25 million patients diagnosed with this in the United States. The disease can then progress to either the wet form of AMD. This is where the new blood vessels invade the eye. The blood vessels can be leaky. It's treated effectively with anti-VEGF antibodies or it can progress to dry AMD. And this is where you get this growing patch of atrophy. This is where the photoreceptors are literally dying within that part of the eye, and those patches of atrophy correspond to loss of vision in that part of the eye. Now there are 2 therapies that have relatively recently been approved that inhibit a couple of different complement proteins, but neither of them has been shown to improve vision in these patients. And you only see a very subtle slowing of the growth of that patch of atrophy within the eye. There's some rare side effects that have been reported. And of course, these are all intravitreally administered. This is where ALN-Gene G comes in where we think we have the potential to really fill the gaps that I've just laid out for you in this disease. And the reason that we're so bullish about it is because of the human genetics that underlie our discovery of Gene G. So our genetics team actually found this gene. I will say this is truly a differentiated target. No one else is working on this. This is something that came out of our own in-house genetics efforts. It's not a me-too program. It's not something else that's in someone else's pipeline, something that only Alnylam is focused on at the moment. The table here shows you some of the genetics. So we found individuals that are heterozygous loss of function for Gene G. They lack one copy of the gene. And you can see in the table here that they have a lifetime risk of developing either wet or dry AMD, that's about half what you see in the general population. So a really, really significant reduction in risk. And the fact that it impacts dry and wet AMD tells you that there's a potential here to go upstream and treat the intermediate form of the disease. We also see significant odds ratios for both individually the dry and wet form of the disease. And importantly, in these same individuals that we have the genetics and the medical records from, we have OCT scans of a subset of them of their eye. So this is like a CT scan of the eye where you can get more detailed structural information. And we actually find in people that lack one copy of this gene that the photoreceptor layer is thicker and that indicates more cells and healthier cells. So that gives us confidence that we can impact vision in these patients. The other thing here that's really amazing, I mean, the liver is just incredible in terms of the number of things that's involved in and it continues to surprise us. But this is a gene that is exclusively expressed in the liver. It's a secreted protein, but it's only expressed in the liver. So we can go after this with our GalNAc platform, which, as we've talked about, we have a ton of experience with. So you can think about a therapy that is subcutaneously administered, not intravitreal, and is given infrequently on the order of once every 3 to once every 6 months. Summarize the therapeutic hypothesis on the left, we are going to silence Gene G with ALN-Gene G, stop it from being secreted, stop it from traveling to the eye where it plays a role in photoreceptor cell death. In the right-hand side, you can see an example of a couple of our siRNAs that target Gene G in the nonhuman primate. We get deep durable silencing of the target. We are on track to file our IND for this program this year, actually. So this is going to be part of our 2-2-5 strategy. So very excited to bring this into the clinic and to patients. And I want to just finish before I hand over to Vasant with a little primer. Everything that I've talked about and that you've heard today is very much focused on 2-2-5. But I want you to walk away from here feeling that we have a lot of very exciting targets that we're working on that are going to fuel our pipeline beyond 2025. So we're thinking about INDs for '26, '27, '28, and our genetics investments really continue to bear fruit. And here's a couple of examples of novel findings that we've made and that we're working on siRNAs for. So on the left, we have a new liver target that we're going to call target A, where we found individuals that are heterozygous loss of function for this gene, and they have a decrease in their LDL cholesterol level on the order of about 30 milligrams per deciliter, which is very similar to what you see for individuals that lack one copy of PCSK9. It's a big effect. When we knock this target down in nonhuman primates and compare that with a PCSK9 siRNA, we can lower LDL levels to a similar extent. But importantly, we know this is completely independent of PCSK9. It's a novel mechanism. It's not going through PCSK9. So that opens up some interesting opportunities for us to think about. We've also found a target in skeletal muscle, where individuals that lack target B are stronger. They have an increased grip strength. They have increased muscle mass. They have increased basal metabolic rate. This is not myostatin. This is a completely different pathway and target, again, something exciting for us to explore. And then on the right-hand side, another example of an adipose target where we have individuals that lack one copy of target C. They've got less abdominal fat, lower risk of type 2 diabetes, and we've seen really nice translation of those findings into rodents. So not to say that we're going to pursue all of these, but this is just to give you an example that we're able to make these types of discoveries, gain these insights from our genetics efforts, and then we couple that with the amazing progress that we have made in our platform and in our ability to target different tissues, which is a nice segue now for me to hand over to Vasant, who is, I think, going to blow you away with some of the really amazing progress we've made on the platform side. Vasant?

All right. Thank you, Paul. Hi, everyone. My name is Vasant Jadhav. I'm the Chief Technology Officer at Alnylam. I've been at Alnylam from last 11 years. And before that, I was at Sirna/Merck for about 12 years or so. So pretty much all my professional life and career is in the field of RNAi therapeutics. And the sentiment that Kevin expressed earlier on the future of RNAi and the impact it will have on patients, I can't agree any more with that one. I mean, this is an exciting time despite all these 23 years in the field. One can say that RNAi currently is at the stage where antibodies were in early 2000, and you know what antibodies have done now. I mean they are a major class of medicine. So let's bring this home now with the technology, the foundational technology that built Alnylam. So we continue to define the leading edge of RNAi therapeutics by expanding the delivery to multiple tissues, and we do that by having best-in-class delivery solutions. If we are not first-in-class, we intend to be best-in-class. And we continue to fine-tune our siRNAs designs. And as Paul mentioned, nobody makes siRNAs better than Alnylam, but we make them, we fine-tune them all the time. And today, I'm very excited to share with what we call revolution in manufacturing with the oligonucleotides. In the presentation today, we're also reiterating our ambition, all major tissues with therapeutic targets by 2030. And we want to go after this by having the solutions that are CTA enabling one every year. We want to go one by one, one by one for all of these tissues. So for the presentation today, we'll have 5 different tissues. We'll go one by one with all of these ones and also the combination data with a couple of them. Let's begin with the CNS and that one with overcoming blood-brain barrier. Now my colleagues shared with you the data earlier on the C16-siRNA platform and the translation of that in humans. Very exciting data. When you look at just the C16 putting on the siRNA, there's a whole lot that goes in coming up with that kind of design. We have looked at so many different constructs, and that's where we settle on. So it's very satisfying to see a construct like that translating in humans with the doses as low as 50 milligrams, multi-dose, giving about 70% knockdown, and that gives us the confidence to expand our pipeline. Very excited about the Huntington's program and the other programs that we are following up with the C16. It's an intrathecal dosing. And we believe it will be pretty appropriate for many disease indications. But now think about systemic dosing. If we can overcome blood-brain barrier, then it will allow us more conventional route of dosing. It will expand indication opportunities and potentially we will have more homogeneous distribution that what you get with the intrathecal dosing. But overcoming BBB, it is there for a reason, and it is easier said than done. We have been at this one for a long time. And this requires a unique approach, approach of transcytosis. So last year, we shared our early data in this space, and we were giving an siRNA conjugate that was given at 5 mg per kg, 4x. So the accumulative dose of 20 milligrams per kilogram. And that was giving us modest activity. So this was last year's R&D Day. I'm pleased to share with you today the data on what we have now with a new construct that is giving us an activity at 0.1 mg per kg. That is 200x lower dose than what we had last year to get that level of knockdown. And we're also seeing improved knockdown happening as we increase the dose, and these doses are still pretty low, 1 mg per kg. Now very importantly, in the oligonucleotide field, you want to see the translation in the nonhuman primates, and we just got this data as well. And I'm very happy to share that with 1 mg per kg dose given 3 times, we are seeing very good activity in nonhuman primate in different regions of the brain. So clearly, a big advance, and we are very proud of this effort, and we'll be doing everything to move this in development as fast as we can. Now tissue #2 for the delivery update, the adipose tissue. Last year, we talked about the advances we had in this delivery space using a platform target. And now we're sharing with you the data for the program, the ACVR1c program that you heard about earlier. So CTA enabling or the data with this development candidate showing deep knockdown happening across all the depots of the adipose and very importantly, matching the criteria that we set out for best-in-class profile of subcu dosing, dose less than 3 mg per kg and efficient manufacturing so that we can scale up, we can work with these molecules much more efficiently. The CTA for this year. Tissue #3, skeletal muscle, very important tissue. And as you know, I mean, there is clinical data in this space by others. But that data is also with TfR1-based antibodies. And with that approach, does have very high load of the antibody. When you think about 1 mg per kg of siRNA, that is 10 milligrams per kilogram of the antibody. For nanobody, it might be a little less, but still very high and it's IV dosing or the IV infusion. When we set out for this, we were looking for best-in-class solution, and we wanted to have a solution that is across the different ligands and we can look at. So we have put together small molecules, peptides, antibodies, all different kind of things last year, and we have come up with a small molecule-based delivery approach that gives us the activity that we're looking for. Again, all those parameters of subcu dosing, less than 3 mg per kg and efficient manufacturing, the data shown here is for our development candidate that will be moving into the CTS stage this year. And the data on the right is showing the activity at the mRNA level. Tissue #4. This is a new one. There are 2 new tissues that we'll be talking about today, and this is data in heart. We now have a targeted delivery that shows robust activity in heart at the doses as low as 2 mg per kg, very low dose. And this activity appears to be more specific for heart. As you see on the right side that in the skeletal muscle, the activity is modest. We're very proud of this, the data and the innovation by our team here. And finally, tissue #5, kidney, one of the hardest tissues in the oligonucleotide space. And what I've seen in my 23 years of this field, this is the tissue where paradoxically, delivery or putting an oligo in kidney is not that hard. ASOs, siRNAs do end up in kidney, but the trouble is they don't do much. There is no functional delivery. There is no knockdown. And the complexity, the anatomy and the cell types of the kidney doesn't help. But we have figured it out to a point now we have activity with our siRNA conjugates at the doses of 0.5 mg per kg and looking very promising in mouse. Again, with the data that I showed in heart and kidney, so look out for further advances in this space as we move them along. Now after sharing with you the data on these individual tissues, let's talk about the multi-tissue targeting that Kevin talked about earlier, multi-organ targeting, the polygenic diseases, how can we go after these kind of things? So you obviously need a technology for that one. So earlier, we had talked about the GEMINI platform where you have 2 siRNAs in a single construct. We've shown activity in liver. The data shown here is for CNS. So if you want to make a GEMINI platform, we can do it for liver, CNS, you name it, as long as the delivery system is there. Now we are sharing with you the concept of dual targeting, a single siRNA that is targeted 2 different tissues of choice, not by default, but of choice, targeted delivery. So let's go through the data. So the first one is just the control. So as expected, no activity. Then you have liver-targeting molecule showing activity in liver. You have skeletal muscle-targeting molecule showing activity in skeletal muscle. And now you have dual-targeting molecule at the same dose, having the activity in both tissues. We believe the approach like this will really expand the scope of RNAi therapeutics by going into different tissues and looking at the different targets. So with that one, now I will move into briefly on to the siRNA design space and manufacturing. As Paul mentioned, we are pretty good at designing our siRNAs, but we just don't stop there. We continue to fine-tune. One example here is a phosphate mimic. This is a modification that we use for most of our extrahepatic delivery conjugates. And we currently use vinylphosphonate. What we have found is now a new phosphate mimic that looks as good or even better than vinylphosphonate. We also continue to fine-tune our ESC+ design. Yes, remember, ESC+ design is our design with the specificity, the exquisite specificity where you have 20,000 genes that can be dysregulated or impacted with siRNAs, and we have only on-target activity for the one that we care about. And that kind of specificity is very important to us. This is how we design our molecules, and we continue to make improvements on this one. So here is an example of a refined ESC+ where, even if there is a residual NfL signal that was seen with one of the molecules, we have reduced that with this kind of design with a tweak within our ESC+ molecule. And finally, our designs work in most of the sequences, but there are some odd sequences that the standard designs don't work, but those are the ones where we also add a few additional tweaks by which we can bring back the activity with these molecules. Now let's move to the manufacturing part. Now it's very interesting for this kind of presentation that I am giving with all the details on the siRNAs designs and delivery, the manufacturing part comes in. But this is the beauty of Alnylam. The innovation comes from all parts. And so very proud of the efforts that our QoQ team has done on this one. So the current state of siRNA manufacturing is with solid-phase synthesis. And the solid-phase synthesis, when you're making a 23-nucleotide siRNA, every step has many, many different steps. And this process works pretty well. It's been working for a very long time, and has supported our current pipeline and supporting the approved therapies. It's well suited for the low-demand, shorter development time programs. But as we go into bigger and broader indications, we're not looking at just kilograms of material, we're looking at tons. That's not feasible with solid-phase synthesis. So a new technology is absolutely needed, and this is where enters enzymatic ligation. So what is enzymatic ligation? Well, it's the process by which you take short synthetic blockmers and you stitch them together, you ligate them together to make a full duplex, really uniquely suited for the duplex structure of the molecules. And by doing this, you can really minimize all the purification, the chromatographic purification that are needed for different stages or the different steps of the solid phase synthesis because this one is happening at once. And we have the chromatograph here showing the purity of these molecules. We have the POC with 90% to 95% pure drug substance. Very importantly. You don't need chromatographic purification. And what does that mean? And the number of solvents and all that you have to use for solid-phase synthesis is huge. All of that is minimized. And that's what we mean by having this environmental impact on sustainability, that the use of solvents and the facilities needed for the solid-phase synthesis versus what you can get with enzymatic ligation and still improve the scale. And it's a highly reproducible method. Another important point about this advance is it will expand our capabilities. When we think about GEMINI platform with 2 siRNAs together from 23 plus 23, 46 nucleotide by solid-phase synthesis, that's a tough task. But those are the kind of things that we should be able to make much more easily -- easy for me to say, with the enzymatic ligation method. So with that one, I hope you get the sense that we have been driving and we continue to drive the leading edge of RNAi therapeutics. We intend -- we are marching towards the delivery to all major tissues with therapeutic targets by 2030. We'll be very methodical about this one. We go after the tissues where, as Kevin was mentioning, the targets are there. You don't want to come up with a solution and then look for the problems. We'll be focused on best-in-class delivery solutions. We, today, reported progress on 5 different tissues, 2 of them new ones, 2 CTAs going in, very excited about the data I shared with you about multi-tissue targeting. And we continue to fine-tune our siRNA designs and to improve their potency and specificity. And as I mentioned in just last minute or so, the enzymatic ligation, we believe, is a revolution in the manufacturing, and we are leading this part of revolution as well. With that, I will stop, and I will ask my colleagues to join here, maybe getting help with the chairs. Otherwise, bring your own chair.

All right. We're running a little over time, but we'll start to take questions.

Great. Gary Nachman at Raymond James. So for 1C, for that program that's moving into the clinic this year for weight loss, when looking at muscle preservation specifically, will it be targeting older sarcopenic obese patients? Or could it be applicable for all patients on GLP-1s potentially? Will you be thinking of just combination treatment or monotherapy as well? And when you go into the Phase I, will you be looking at the DEXA scan measurement or function as well? And then just for metabolic in general, can you do this alone? Or would it make more sense to partner these programs?

Yes. So we'll start out with the first part of that, I guess I'll turn to Sandeep, talk a little bit about older patients and sarcopenia. And the second part of that question was mono versus combo. So we'll start with those 2.

So the first part of the question is what are we thinking in the clinical development plan. We are keeping it very, very flexible as you see this -- you've seen the data that there is a real need in terms of the lean mass improvement for an overall population. So you start with a broader population and then we may go into special populations as well in the future. But starting, yes, we are going to start with a broader population when we are getting into the clinic. And as we evolve, we will be looking at select populations that can be helped with this therapy. The second question was on the combination or monotherapy. Obviously, we are starting with the monotherapy. And as we evolve, we will be getting into -- with combinations, especially with the low-dose incretins as we evolve into the Phase II study. But for now, we will be starting with the monotherapy. And we are measuring the things that you mentioned. We will be measuring a few things that will help us guide the next phase of the development.

And I think the last part of the question was around partnership. And like we're at a stage where certainly, in this kind of disease, you see that we're doing outcome trials. We can run large trials if we choose, I think. But we're always open to the fact that if it were the right partner and the right partnership, that's something that we might consider. So...

Will Pickering from Bernstein. For the geographic atrophy candidate, how do you expect the product profile to compare to the pozelimab, cemdisiran combo that Regeneron recently took into Phase III? And presumably, the safety will be a lot better, but specifically, if you could talk about the efficacy. And can you just clarify, does Regeneron have any rights to participate in that program?

Sure. So I'll turn it to Paul. I'd say initially, just to say the last part of that question first. So this is an Alnylam proprietary target. So...

So yes, as Kevin said, this is a liver target. So it's something we're working on. In terms of the -- if you really think about the genetics that I showed you, we've never seen anything that looks like this in terms of the protection that we're seeing from the disease. So we're very confident that this has the potential to really be kind of a best-in-class product for the treatment of dry AMD. Of course, the proof is in the pudding once we get into the clinic. But certainly, the genetics tell a very strong story that we'll be able to go upstream into the intermediate part of AMD, but also potentially have a positive impact on vision in those patients.

Greg Harrison, Scotiabank. So in a broad sense, how do you think about developing products for indications with large populations like hypertension or AMD that would be attractive to and have strong uptake in patients with maybe lower motivation or urgency to treat their disease relative to some of these more rare disease patients with more imminent threats? And how do you give these products the best chance of broader adoption?

So I'll start with that, and maybe I'll go to Sandeep. I think one of the beauties that we like about RNAi is drugs don't work if you don't take them, right? And the ability to dose these things every 6 months or potentially annually, I think really can change the standard of care. Now people are going to have to adjust, right, anytime you're trying to change the standard of care, it takes time. But I do really think that -- and we're doing a lot of those trials to show that this area under the curve in a lot of these diseases, the lower LDL cholesterol you have over time, the better off you are. We think in a lot of these other diseases, it's very similar. So I think the data will drive adoption over time. I don't know if you want to add.

No, you covered it very well, right? If you look at obesity 6 years back or 7 years back, it was -- it's the same question people would have asked basically about the risk factor, show me the data that it is going to take -- it's cardioprotective or renal protective. So it's a similar stage we are in, but we have got a lot of data for hypertension that can cause a huge CV risk. And then Paul shared the data on AMD, it is a huge risk as we age. So this is going to be an evolving paradigm. At the same time, because of what we have seen in obesity, there is more trend in terms of adoption of these kinds of therapies for prevalent diseases.

Great. Lisa Walter here for Luca Issi at RBC Capital Markets. Maybe just a big picture question here. What's the latest on Reversir as an antidote to potentially revert the pharmacology of your drugs? For TTR, it feels like the more knockdown, the better. But as you kind of move into things like hypertension or bleeding disorders or diabetes, maybe there's a need to be a little bit more cautious about the risk of hypotension or thrombosis or hypoglycemia, all of which are basically your drug is just doing too much of a good thing. So how should we think about that? Just any color here would be appreciated.

Sure. So we're -- I'll start and then maybe Sandeep can chime in as well. So we like the ability in certain cases to have a Reversir. I think most of our targets are genetically validated, right? And so that gives us some confidence on the safety side that going low is okay in a lot of those indications. And then I don't know if you want to comment a little bit from a clinical perspective.

Yes. So from a clinical perspective, Reversir is just developed just in case of an ultra-rare case because we have seen data in maybe more than 1,000 patients or 1,500 patients or so. We have got K1, we have got K2 and the K3. And a lot of patients have got this therapy for a long duration of time, and we have hardly seen hypotension as a side effect. So we are basically keeping this as more of a backup option in a very rare case just in case people need it. So we have data to back that we don't need -- we may not need that ever.

This is Joohwan Kim on for Whitney Ijem at Canaccord Genuity. Thinking on the manufacturing side, how quickly do you anticipate being able to shift to enzymatic ligation? And thinking through regulatory requirements, can you talk about some of maybe the rate-limiting steps agencies may require and how we should be thinking about COGS there versus the solid phase?

Sure. So I'll start and then Vasant can chime in. So we're moving pretty rapidly with it because we think it's exciting. And obviously, you have to make batches and do the things that you need to do in order to satisfy regulators, but we're very confident that we can move pretty quickly with it, and we think it's a substantial benefit on COGS.

Yes. I mean, just to add, we can match the profile of solid-phase synthesis. So it's at ones that we are very excited about. We're not at this stage now to say what would be the impact on cost and other things, but we'll be moving it forward as quickly as we can.

Eliana Merle from UBS. In terms of your obesity pipeline, you have a number of targets that you've discussed. Can you tell us a little bit how you're thinking about the prioritization between the different targets, priorities in terms of combination approaches? And then just a question following up on Huntington's. Do you have an assay that can measure the exon 1 fragment, specifically as you're thinking about the clinical importance, which I know is highlighted earlier this morning.

So I'm going to start with Sandeep.

Yes. For obesity, the way we are thinking about it, and we have shared throughout the day that we are looking for best-in-class medicines that we want to bring in. So we are going to keep our basics, and we are going to just follow our basics in terms of strong genetics backed with biology and get the right combinations for the right tissue and targets. So that is how we are trying to prioritize. For now, we are looking at ACVR1C, which is going to get into the clinic. And as we have shared before, some of these pathways, we have studied very, very deeply, and we are very thoughtful in terms of how we are thinking to take this into the clinic, specifically to address the unmet needs that has not been addressed by the incretins or the new combinations which are being tested, which is mostly all incretins. So we are trying to be very differentiated and thoughtful in terms of how we want to bring these targets into the clinic.

Yes. And I'll just add that the incretin pathway has been studied, but not necessarily always well studied, right? And if you think about even ACVR1C, it is the receptor for Inhibin E, but it's also the receptor for a couple of other ligands, right? And so we're actively -- have a lot of ongoing research in that space to figure out what is the best combination, both from a safety and an efficacy profile for the things that we want to take in. Some of that we'll have to learn in clinic, obviously, but some of that we would love to learn earlier.

Myles Minter from William Blair. Just on the blood-brain barrier ligand, is the way to think about it that you're developing a single ligand for the best brain delivery that you can get across superficial and deep brain structures? Are you going to create a library of compounds that, let's say, for Huntington's, you selectively want to target putamen caudate over other areas of the brain versus in Alzheimer's, you want something for the hippocampus, prefrontal cortex, that sort of thing. Yes, is it a single ligand to solve all brain delivery? Or is it a library of ligands that you're looking at?

Yes. So I think it's a great question. Let's go step by step. The first goal is to overcome the BBB, right? I mean that would be the key thing. And after that, you engineer the other cell type specificity. For now, it is overcoming the BBB will be the first step. I think, Chris, on this side.

Just another question with respect to the enzyme ligation. I believe that's with Codexis, the other companies. But just curious if you're going to owe any royalties or future obligations should you use that technology or if you basically pay for the enzyme out right and effectively it's just paying a mark on the catalyst?

I'm not sure I understood the question.

Well, I don't think -- I mean, I have not heard about any IP restrictions with enzymatic ligation for us.

I mean we discovered it and published on it early on. So it's Alnylam.

It's wholly owned? It's not with partners?

Correct.

Jess Fye, JPMorgan. Just following up on Myles' question on the BBB technology. For the preclinical nonhuman primate data you showed, what receptor are you leveraging to get across the BBB in that example? And what was the target of the drug used to demonstrate proof of concept?

Well, I mean, we didn't say it for the reason.

We're not going to disclose at this point. Again, we're choosing very carefully when and where we disclose things at this point, given that there's a lot of competition in the field. And as you probably have noticed with our targets, we're now -- we used to disclose a target as soon as we discovered it, and now we're disclosing targets as they're in the clinic, right? And so we're just going to hold some of that close to the vest.

[indiscernible] .

I'm not going to comment.

Okay. Gena Wang from Barclays. Hopefully, my question, you can answer a little bit more. This is regarding the Gene G for AMD. I know, I'm pretty sure you will do a lot of patent around the genes. I don't know at what point you will share the data with us? And also, have you done the knockout mice model for the Gene G? And what is the phenotype there?

Do you want to start, Paul?

Yes. So just -- so I understand the question you're asking when are we going to reveal what the target is? Yes. I mean, as Kevin said a moment ago, we're being more cautious these days about when we disclose targets. So most likely, once we're actually in the clinic and as you saw with the example with plasminogen, then we'll be in a place to talk about it further. With regard to your second question, which is, I think if I understood you correctly, a knockout mouse of Gene G and what the phenotype is. Actually, there are knockout animals. There's some species differences, I would say, between the sort of preservation of that gene amongst rodents, primates, humans, which make it a little bit challenging. But it's fairly unremarkable in terms of -- there's no sort of adverse findings. Maybe to add to that, in humans, I showed you that we have individuals that lack one copy of Gene G in our data set. Other than the protection that we see from AMD, we don't see anything else going on that would give us any cause for concern in humans.

And then generally put a lot of weight on the human genetics versus the mouse models. All right. I think we're out of time. So thank you all. I hope you enjoyed the day as much as we did, and see you all soon.

Thank you all. We are going to [indiscernible] on behalf of all my colleagues at Alnylam for joining us to hear about [indiscernible] RNAi therapeutics. And a couple of housekeeping points. One [indiscernible] second. So we really appreciate your feedback today as well. So please take [indiscernible] . Next slide, I just want to really come back to where it all started. As you've seen from our pipeline goals, 2025 is really, really consequential year for Alnylam with many important milestones in the R&D organization and broadly in the company. Okay. Thank you. Sorry about that. And in particular, we expect to deliver on our P5x25 goals and end the year with 6 commercial products, including the label expansion and launch for vutrisiran in ATTR-CM, KARDIA-2 results, 3 Phase III starts, 4 more new INDs and well on the path of sustainable non-GAAP profitability. So it's going to be a big year. Next slide, please. But beyond 2025, I hope you'll all see as we do, the enormous long-term potential we have at Alnylam. We've had a lot of success to date, but we believe that we can apply this generational technology, RNAi interference with state-of-the-art delivery to treat a very, very vast number of diseases and a lot of patients around the world. So stay tuned. We have the vision, we have the experience, we have the capabilities. And hopefully, today, you saw we have a plan, and the best is yet to come. Thank you all very, very much.