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

The R&D Day 2021. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications, and we are very pleased that you've turned in to hear about progress across our portfolio. As you can see, we have a very exciting lineup of presentations scheduled during our time together, spanning the breadth of our pipeline, from our TTR franchise, to progress with zilebesiran as a potential treatment for hypertension, to our R&D efforts beyond the liver and what we have percolating in the next wave of our R&D engine before we close with an update on our progress towards P5x25. A few quick reminders before we dive in. This event is scheduled to run until 1:00 p.m. And we've incorporated a break into the agenda. We'll be hosting 2 live moderated Q&A sessions during the meeting. To ask a question, please type your question into the Q&A box on your screen. A replay of today's session will be available on the Investor page of our website later today. During the course of today's meeting, we'll be making forward-looking statements. For additional information, I encourage you to review the most recent SEC filings posted in the Investors section of our website. Finally, I'd like to thank our 2 external speakers Dr. Sadda and Dr. Cohen, for joining us today and share information about their disclosures here. With that, I'd like to turn it over to John. John?

Thank you, Christine. Good morning, everyone. It's so wonderful to be here today for our annual R&D meeting. Without a doubt, this is one of my favorite meetings every year. We've had over 15 R&D days since Alnylam was founded, and I've been at every single of them, and I'm really amazed to see all the progress that we've generated over all these years. In fact, it's fair to say that the progress has been nothing short of stunning, positioning Alnylam for an incredibly bright future ahead. Today, I'm going to give a brief introduction reflecting on some of Alnylam's past accomplishments and how it informs our future. RNAi therapeutics represent a rare opportunity to create a whole new class of medicines. By harnessing the endogenous RNAi pathway, synthetic small interfering RNAs can selectively target messenger RNAs that encode disease-causing proteins for disruption. By silencing the mRNA, RNAi therapeutics act upstream of small molecule drugs as well as monoclonal antibodies. RNAi therapeutics represent a reproducible and modular approach to design new medicines. If 15% to 20% of the genome is available for small molecule drugs and 25% to 30% of antibody -- for antibody therapeutics, 100% of the genome, in theory, is available for targeting with small interfering RNA-based medicines, representing a substantial expansion of our ability to fight human disease. Largely due to our pioneering efforts at Alnylam, RNAi therapeutics represent a clinically and commercially established approach. This is very, very far away from a science experiment. It is a proven approach, and I expect there will be dozens of RNAi therapeutic medicines in the future and perhaps over 100 over time, rivaling, if not, exceeding what we've seen historically with monoclonal antibody therapies over the years. These are the data that launched Alnylam. In 2001, worked by our founder, Thomas Tuschl, led to the discovery of synthetic small double-stranded RNA molecules that can mediate gene silencing in mammalian cells. Prior to this point, RNA interference is believed to be mediated by long, double-stranded RNA molecules and also were believed to be in operative in mammalian systems due to the evolution of the interferon response, the finding that a synthetic small interfering RNA molecule comprised of just 21 nucleotides in each strand could silence the lam and gene and HeLa cells was a remarkable finding, and it really shook the world. While at Millennium Pharmaceuticals, at the time, I received a phone call from my old friend, Phil Sharp, seeking Millennium thoughts on this new finding prior to the paper being published. My colleagues and I immediately saw the opportunity for RNAi as a potential tool for functional genomics, and we also imagined how this approach could be used for developing new medicines. But little did I know that a year later, I'd be joining a bold new endeavor as the founding CEO to develop RNAi therapeutics. The founding days of Alnylam back in 2002 were just like the start of every other biotech company. We had 5 scientific founders, including Tom Tuschl, Phil Sharp, but also Phil Zamore, Dave Bartell, and Paul Schimmel. Paul Schimmel wasn't involved in the early RNAi research, but Phil Sharp brought him into the fold due to his experience in founding successful biotech companies. Paul is also responsible for naming Alnylam, which was out of his love for his ant who is an Arabic scholar. In Arabic, the name Alnylam means string of pearls. The lead investors who put the first $2.5 million of capital to work where John Clark at Cardinal Partners and Chris Westfall at then at Polaris. Later that year, the syndicate grew to include Peter Barrett at Atlas and Bob Nelson at Arch. I joined in December of 2002 as the company's founding CEO. On a personal note, I just got remarried just a few months earlier. So 2002 was full of new beginnings for me personally. As we look back on the RNAi therapeutics and Alnylam journey, it is remarkable to think that it took about 3 decades from the first observation of RNAi in the petunia and 2 decades from the seminal findings of Fire and Melo until the first RNAi therapeutic made it to market. While some of you may see this as a long time, frankly, it's just the time it takes to bring cutting-edge early scientific discoveries to patients, especially if you're building a platform for sustainable innovation along the way. Some of the key scientific milestones, all by Alnylam scientists, are shown on this slide. It started in 2004 with the first-ever therapeutic gene silencing in a mammal in paper by suit check at all and then the development of LNPs for delivery in 2007, published in a paper by Zimmerman at all. And then GalNAc conjugates emerged in 2014 with further optimization in 2018. This is the scientific journey of pioneers who work tirelessly to bring RNAi therapeutics to patients around the world. And while our focus on delivery has been aimed at small interfering RNAs, it's both gratifying and rewarding to see how our science has contributed to the advancement of delivery for other modalities. For example, our scientist discovery of novel biodegradable lipids has been foundational for both the biotech Pfizer and Moderna efforts to deliver messenger RNA for COVID-19 vaccines. So many of you in the audience have already appreciated a part of Alnylam Science directly in your arms this past year, and I suspect that many of you, if not all of you, will also get more Alnylam Science in the form of booster shots that you get going forward. In our history, we also had multiple near-death moments, "Friedrich Micha, whatever doesn't kill you makes you stronger." And that's indeed the case for us at Alnylam. Indeed, it was the passion, the perseverance, the grid and the challenge accepted mentality of our people that got us through those dark moments. While much of the outside world had given up hope, internally, we continue to believe in the power of RNAi and it didn't take us long to bounce back from those adverse moments. Less than 1 year after pharma exited the RNAi space in 2010, we saw the first evidence of human RNAi in our TTR program. And then less than 1 year after discontinuing revusiran in 2016, we reported massively positive APOLLO Phase III data for patisiran. To paraphrase TS Elliot, RNAi therapeutics emerged with a bang, not with a whimper, and so a new class of medicines was born. These positive data readouts on the heels of those tough days confirmed to us what we had suspected all along, that RNAi therapeutics would soon become clinical reality and that we were going to help lots and lots of patients around the world. In so many ways, our progress and our journey have been charted in our 5-year goals. In early 2011, we launched Alnylam 5x15 to bring 5 RNAi therapeutics into the clinic by the end of 2015. We exceeded that goal by delivering 8 clinical programs by the end of 2015. Then in early 2015, we launched our Alnylam 2020 strategy to bring 3 or more RNAi therapeutics to the market by the end of 2020. We also exceeded that goal by bringing 4 programs to the market and also doing so on a global basis. We even did this after a Phase III setback. And now earlier this year, we launched our third 5-year goal installment with Alnylam P5x25. Evan will talk about this further at the end of the day's meeting, but I have no doubt that Alnylam will achieve, if not, exceed these very bold objectives, building a top 5 biopharma along the way. We're very proud to have brought 4 potentially transformative RNAi therapeutic medicines to patients around the world. Today, ONPATTRO, our first RNAi therapeutic ever approved, is the leading medicine for the treatment of the polyneuropathy in hereditary ATTR amyloidosis in adults, a progressive, debilitating disease that is generally fatal within 5 to 10 years of diagnosis. One year after ONPATTRO, we gained approval for GIVLAARI, the first-ever medicine approved for the treatment of acute hepatic porphyria, a devastating disease, often afflicting young women early in their adulthood. Most recently, we gained approvals for OXLUMO, our first pediatric RNAi therapeutic for the treatment of primary hyperoxaluria type 1, a disease that leads to end-stage renal failure and a need for dual liver kidney transplant in most patients. And then our partners at Novartis have advanced the first RNAi therapeutic for a prevalent disease, LEQVIO, which targets PCSK9 for the treatment of hypercholesterolemia and mixed dyslipidemias. For ONPATTRO, GIVLAARI and OXLUMO, where Alnylam is directly leading commercial efforts, we demonstrated excellence in commercialization and execution, adding to our heritage of excellence in R&D. I'm especially proud to the leadership we've shown market access of these medicines, paving the way for the entire industry's efforts around value-based agreements. Imagine that, Alnylam leading the dialogue on the value of innovation in addition to our championing the frontiers of medicine. Of course, we have so much to look forward to in our future with over a dozen programs in clinical development from Phase I to Phase IV, including vutrisiran, which is in registration, destined to become our fifth RNAi therapeutic to reach the market, pending its approval. Our clinical pipeline also includes life cycle studies on our TTR franchise programs with our APOLLO-B and our HELIOS-B trials that could significantly open up our ATTR amyloidosis opportunity pending positive results in the studies and also positive approvals. Earlier in the clinical pipeline, we are advancing programs for many prevalent chronic diseases where RNAi therapeutics can potentially impact millions of patients around the world. And at the same time, our organic product engine is poised to deliver sustainable innovation with 2 to 4 new INDs every year exiting 2025 with 4 or more INDs per year. What other biotech company is able to deliver sustainable innovation with a proven modality? I'm pretty sure you can count that number in less than one hand. I suspect there are many great things you're going to hear today about our future. As is often the case, we have some news to share with you. For example, you'll hear about a relatively near-term opportunity to expand our TTR franchise in Stargardt disease with a Phase III study starting just next year. You'll also hear about 2 new programs that I believe can be highly disruptive. First, our GEMINI CVR program that is aimed at reducing both LDL cholesterol and blood pressure as a single molecular entity whereby reducing these 2 high solidated risk factors could reduce cardiovascular morbidity and mortality and at-risk populations with tonic control of both risk factors and with a highly adherent vaccine-like medicine given once or twice per year. Second, you'll hear about a very new discovery from our U.K. Biobank collaboration that is a liver-expressed protein where loss of function human mutations are associated with lower visceral adiposity, and lower levels of atherogenic lipids and blood pressure that are together known to be associated with the clinical sequela of metabolic syndrome. This could be a PCSK9-like opportunity that is perfect for intervention with RNAi. Finally, you'll hear about very strong progress in extrahepatic delivery of RNAi therapeutics. This is a big part of our future. And based on data we'll share today, I am very confident that RNAi will find broad applicability across a wide range of cell types and tissues and thus broadly across human disease. Now as you know, this is my last R&D Day as Alnylam's CEO. I'm incredibly proud of what our scientists and clinicians have accomplished at Alnylam over all these years. Everything that we've accomplished has really come down to our people and our culture. These elements are both here to stay and are very much a big part of the legacy I leave behind as I begin a new personal chapter for myself. At the start of the new year, we'll have an amazing new leader, Yvonne Greenstreet, to take Alnylam forward in what is almost certainly going to be Alnylam's brightest days ahead. In the meanwhile, I am so grateful to all of you for your support and confidence over all these years. Now with that, let me turn the call over to Akshay Vaishnaw, our President of R&D; and somebody who, without a doubt, is the most remarkable colleague I have ever worked with. Akshay, take it away.

John, thank you for that generous comment and for describing the amazing 19-year journey, leading Alnylam from an in-vitro observation in 2001 to a mature platform sustainably delivering truly important drugs for patients. This figure showing RNAi and HeLa cells inspired of the founding of Alnylam. That observation led to a focused R&D strategy where we develop RNAi therapeutics to address genetically validated targets in high unmet need diseases. In turn, that led to the creation of transformative medicines. In fact, our advances in liver delivery have led to 4 approved products in the last 3 years alone, ONPATTRO, GIVLAARI and OXLUMO, which we've commercialized directly and Leqvio, partnered with Novartis. I want to now turn to how those drugs are helping patients and how life cycle approaches with each will hopefully help more patients still. The first of our approved products, patisiran, gave remarkable Phase III results showing the ability of the drug to improve outcomes, both in terms of neuropathy and quality of life in the inherited disorder hATTR-PN. Patisiran is now helping patients in many countries, although we believe there's much more we can do with an RNAi-mediated TTR silencing approach. First, building on the success of patisiran, we've been developing vutrisiran, a subcutaneous product injected Q3 monthly for hATTR-PN patients. Recently, we announced positive 18-month data for vutrisiran in the pivotal HELIOS-A study. Excited that the regulatory review of vutrisiran is on track with a PDUFA date of April 2022 and EMA approval anticipated for September 2022. Beyond HELIOS-A, we're also testing the hypothesis that TTR-lowering can safely help patients with hereditary or wild-type ATTR cardiomyopathy in the form of the APOLLO-B study for patisiran and HELIOS-B study for vutrisiran. Both studies completed enrollment in mid-2021, with the results expected for APOLLO-B in mid-'22. However, there's much more we can do. Recently, our research team have identified a relatively common inherited neuropathy, Stargardt disease, as an exciting new opportunity for vutrisiran. Stargardt disease is caused by an inherited defect in the retinal pigment epithelial cell or RPE cells. That genetic defect in the enzyme ABCA4 leads to a buildup of toxin, lipofuscin, with resulting macular damage and blindness in children and adults. Crucially, lipofuscin is between a derived, which is delivered to the eye by TTR. We believe that by reducing circulating TTR, we could reduce the buildup of toxic lipofuscin and potentially help patients with Stargardt disease. Following my presentation, you're going to hear much more detail about patisiran and vutrisiran and some of these very important opportunities in ATTR-related disorders and Stargardt disease. Earlier this year, we would like to present long-term data on our second product, givosiran, approved for the treatment of acute hepatic porphyrias in the U.S., EU and most recently in Japan. Here, you can see the transformative impact of givosiran with the majority of patients being rendered free of attacks and with evidence suggesting a gradual increase in efficacy over time. It was heartening to see this outcome at 30 months in AHP patients, where attacks can lead to hospitalization and be life-threatening. Since its approval in 2020, we've added to the data establishing lumasiran as an important new treatment for primary hyperoxaluria type 1 or PH1. On the left, you see the effect of lumasiran-mediated reductions in urine oxalate in very young patients, including babies. On the right, you see the most recent data showing plasma oxalate reductions in patients with severely impaired renal function, including some on dialysis. Both data sets will be impactful as they can guide prescribers on the use of lumasiran in patients across the full age and disease severity range. In the case of ILLUMINATE-C, the data will be part of supplemental filings to update the label in all relevant territories. As compared to PH1, recurrent kidney stone disease is a much larger indication where reducing urine oxalate could be helpful to patients. Patients with recurrent statins have high unmet medical need with episodes of severe pain, infection, hospitalization and sometimes renal damage. The triangle on the right shows the epidemiology of kidney stones in the U.S. alone. The numbers are truly remarkable in scale. In the middle of the triangle, you can see that about 4 million to 6 million patients have had recurrent kidney stones, 80% of whom have had recurrent calcium oxalate stones. As you see at the bottom, somewhere between 0.6 million and 2.5 million have had recurrent calcium oxalate stones associated with elevated urinary oxalate. Whilst these numbers are approximate, the potential for lumasiran could meaningfully impact a very large number of patients is clear. More than 50% of urine oxalate is endogenously produced and may be amenable to reduction by lumasiran. Importantly, stone formation occurs when the level of urine oxalate is supersaturating, giving us our therapeutic hypothesis that lowering oxalate may be beneficial. Accordingly, we expect to initiate a Phase II study by urine in patients with recurrent kidney stone disease, where the primary endpoint will be reduction in 24-hour urine oxalate. Next, let's discuss inclisiran, which is currently approved by the EMA and where we look forward to an FDA approval in the coming weeks. In Phase III, the product demonstrated a unique profile, specifically after initiation of treatment, subsequent 6 monthly administration, led to a time average reduction of 56% in LDL cholesterol, with safety similar to placebo. These inclisiran attributes of durability and cloud pharmacology within frequent injections are almost unique to RNAi therapeutics, and will be important as we expand the portfolio. Specifically, we think that in prevalent diseases, where about 50% of patients do not adhere to treatment, these features could be major advantages and help us reimagine the treatment of a number of major disorders, just some of which I will mention now. First to note, hypertension, a disease affecting 1.2 billion adults globally and which leads to a series of complications, making cardiovascular mortality, the #1 killer on the planet. There'll be much more on hypertension and our RNAi therapeutic for that disease, zilebesiran, from my colleague, Weinong Guo, later on. Next, consider HBV. Almost 300 million people are chronically infected with the hepatitis B virus and are at risk of cirrhosis or hepatoma. We're developing an RNAi therapeutic ALN-HBV02 with our partner, Vir. The drug is currently in Phase II, and my colleague, Pushkal Garg, is going to discuss the program, including some exciting new data recently by Vir showing the possibility of achieving a functional cure in this disease. Pushkal will also discuss how we're advancing multiple drugs against genetically validated targets, namely HSD17B13 and PNPLA3 in NASH. As shown here, in the U.S. alone, recent estimates suggest up to 2% of U.S. adults will suffer from fatty liver disease evolving through NASH to cirrhosis. So we have an incredible opportunity to help in this prevalent disease. In each of these settings, hypertension, HBV and NASH, our ability to potentially deliver potent, durable treatments with infrequent injection will be a crucial advantage. With that, let me now turn to how advances in our remarkable platform are driving sustainable innovation at Alnylam now and for many years to come. I'll discuss just 2 areas in detail with respect to our liver-directed RNAi therapeutics. Kevin Fitzgerald, our CSO, will discuss extrahepatic advances. Over the last 2 decades, systematic efforts using a suite of chemical modifications have allowed us to generate progressively more potent and specific sRNAs, going from partially modified SRNAs to SDC to the ESC generation of molecules. If we compare the impact of different chemistry on the same sequence, the earlier STCs in blue, the more recent advanced ESC in red, and we see equivalent knockdown. But where the advanced ESC maintains target suppression for almost a year, and that is despite more than 100-fold lower annualized exposure. The latest advance in the step-wise process of improvements in potency and safety, we call IKARIA. We've applied the IKARIA platform to a new TTR sequence, ALN-TTRsc04. On the left, you can see an in vitro RNA seq analysis of thousands of transcripts, where the only target to show suppression is TTR. This demonstrates the exquisite specificity for molecule. In the middle, you can see that in the nonhuman primate, comparing vutrisiran analog to sc04, which, despite the chemistry enhancement, given greater specificity, has not lost any potency or durability. Based on all our prior translational work, we can use the monkey data to model what will likely happen when we take sc04 to humans. So on the right, we predict that with the enhanced safety of sc04, a single 300-milligram dose would achieve more than 90% TTR knockdown with unparalleled durability of a year or more. We intend to bring ALN-TTRsc04 to the clinic in 2022. We look forward to using the IKARIA platform for future targets, which will yield other potentially annually dosed drugs. That point is important when we look at the unmet need in the cardiovascular space. Recall that in most chronic diseases, 50% of patients are not taking their medication within a year of prescription. So lack of adherence is a huge problem, and yet it appears intractable with current approaches. The other problem is that most patients at risk of cardiovascular disease are prescribed multiple medications for multiple risk factors, for example, high LDL and blood pressure. There have been attempts to study this in clinical trials. Clinical trials confirm that tackling both LDL and blood pressure is better than doing either alone or none. Just one example of this is the study shown here, where over 12,000 individuals at intermediate risk of cardiovascular disease were compared by treatment with different regimens. In the green curves, you can see clearly that the risk of stroke and heart attack is lowest if both LDL and blood pressure are tackled when patients are on rosuvastatin and candesartan-hydrochlorothiazide as compared to either alone or neither. And those results were seen despite fairly modest effects on the key parameters, LDL and blood pressure. So whilst tackling multiple risk factors in cardiovascular disease works in the clinical trial setting, we know in the real-world setting, humans don't reliably take their drugs. And that is if the appropriate risk factors were identified and treat in the first place. Net-net, neither the patients nor the health care system derive maximum benefit from the available medicines. At Alnylam, recent progress now allows us to think about a new way to treat patients at risk of cardiovascular disease. We call this the GEMINI platform. The goal would be to take 2 sRNAs with the most advanced chemistry and create a single subcutaneous injectable drug that can potently, durably, safely and conveniently silence 2 targets that put patients at risk. Of course, this kind of approach, once validated, has multiple applications in other therapeutic areas, including cardiometabolic, CNS, oncologic and virologic spaces. As you can see on the X-axis here, we've been working on the GEMINI platform for sometime. Compared to the top, about 5 years ago, to the bottom or most recent data, you can see how we can now take 2 siRNAs, for example, here addressing APOC3 and ANGPTL3, and the mixture of the 2 sRNAs at 3-milligram per kilogram each, that is the black curves versus the new GEMINI single construct at 6 mg per kg, the blue curves, gives identical knockdown characteristics for both targets in terms of potency and durability. We're rapidly developing the platform and are busy working on a single construct, GEMINI-CVR, against 2 highly validated targets in cardiovascular disease, ANGPTL3, which lowers the atherogenic lipids, LDL and triglycerides and angiotensinogen, which lowers blood pressure. Indeed, for the latter, our zilebesiran program, which knocks down angiotensinogen, has already shown durable effects in hypertension in a Phase I study, with a single injection showing up to 17 millimeters mercury drop in systolic blood pressure was 3 months or more. The construct we are building would take full advantage of all our platform advances such as IKARIA and GEMINI, and it's exciting to think about the resulting target product profile, namely, a drug that patients with abnormal lipids and high blood pressure can take as a single injection, potentially annually, to prevent major adverse cardiac outcomes. That's a vaccine-like approach to cardiovascular disease. We hope to have a development candidate in this program by 2023. We'll, therefore, have the potential to address unmet need in the cardiovascular space in a unique and powerful new way. A drug like Gemini CVR would mean that patients won't have to remember to take their daily pills, they can just get an annual shot. And that shot will address the multiple risk factors, putting them at risk of diseases like stroke and heart attack. Innovation at Alnylam not only relies on the type of platform advances I've just shared, but also on our ability to continue to find new genetically validated targets, thereby, driving further pipeline expansions to 2025 and beyond. I've shared this slide before, showing the value of genetically validated targets in our industry. Importantly, the likelihood of approval is doubled when a compound entering the clinic is against a genetically validated target. With the success of Alnylam 5x15 and Alnylam 2020 strategies, which John shared with you, we feel the discipline of this approach around careful target selection is important and reflected in our pipeline probability of success numbers, which I'll share with you later. Accordingly, however, we've continued to invest in major databases associated with rich genome and phenotypic data, including most notably, the U.K. and UCLA buybacks. Our collaboration with Regeneron is also invaluable in this regard as they share our passion for genetically validated targets. Over the last couple of years, these databases have begun to generate new targets for us. For example, using the U.K. Biobank, our research team asked a very simple question, what are the genetic determinants of serum urate? Now that's an important question because elevated urate causes gout, a very common disease. The answer they found was that the major determinant of serum urate was the enzyme, xanthine dehydrogenase, or XDH. Notably in the U.K. buyback, heterozygous loss of function of XDH significantly reduced serum urate and also the risk of gout. As shown here on the left, XDH, which is also known as xanthine oxydase, or XO, in the blue boxes, is integral to the puring metabolic pathway. Importantly, that pathway generates urate shown in the red oval. So we've generated a hypothesis that hepatic silencing of XDH will lower serum urate and helping gout. Although XDH is expressed in many tissues, in the mouse, liver-specific XDH knockout led to about a 50% reduction in plasma urate. So ALN and XDH is our candidate for gout. And in the NHP, we have shown a single subcutaneous dose substantially and durably reduces liver XDH by more than 90%. Based on our translational pharmacology experience, we know from the data on the right that in humans, ALN-XDH will likely be a Q3 or 6 monthly subcutaneous drug. Current gout therapies have significant limitations, such as inability to normalize serum urate levels, have significant side effects and because the medications or daily pills are associated with poor adherence. This leaves millions of people who are partially treated and at risk of gout flares affecting joints and even damage to other organs such as the kidney. We believe ALN-XDH, which we will file a CTA for very soon, has the potential to safely and conveniently lower serum urate. A second very dramatic example of a recent discovery our group made from the U.K. buyback concerns the metabolic syndrome. This syndrome is occurring at epidemic levels in the U.S. and Europe and increasingly around the world with changes in diamond exercise. In most major developed countries, more than 20% of adults have the disease. Until recently, no single molecule appear to account for the syndrome, which was thought to result from the complex interplay of many factors affecting the liver, abdominal fat and the pancreas. The end result is a cardiometabolic phenotype comprising: visceral obesity and atherogenic lipid profile with high triglycerides and low HDL; insulin resistance, which can result in diabetes and hypertension. Any 3 or more of those lead to a diagnosis of the metabolic syndrome. A prospective study we conducted in the U.K. Biobank on individuals who had up to 5 features of the metabolic syndrome at baseline showed that these features are powerful predictors of major adverse cardiac events like stroke and heart attacks. The red curve shows that if you had all 5 features at baseline, that in just over a decade, you had about a 20% chance of a MACE event. Our research team wanted to find genetic factors that influence features of the metabolic syndrome and started with the question of visceral obesity, which leads to an abnormal waist-to-hip circumference ratio. They discovered and will shortly publish a novel gene that we'll term gene X here that influences waist-to-hip characteristics. Specifically, heterozygous gene X loss of function is associated with the lower waist to hip ratio, which is healthier. Accordingly, we also found that gene X loss of function leads to an improved profile in atherogenic lipids, liver enzymes and blood pressure. Most importantly, loss of function also favored protection from diabetes and coronary artery disease. We're very excited because gene X is liver expressed and therefore, amenable to an RNA therapeutic approach. We predict that 90% knockdown of X will have broad effects on the metabolic syndrome phenotype, with significant potential to reduce the incidence of diabetes and coronary artery disease. We will apply all our platform learnings and are busy generating a development candidate for a Q6 monthly or annual subcu drug targeting gene X. We supplement our database searches for genetically validated targets was a study of the literature. This next target discovered in this fashion has the potential to address diabetes, fatty liver and obesity, 3 components of the metabolic syndrome. Fructose began entering the diet as an additive in the 1970s in the form of high fructose corn syrup. The graph shows the dramatic increase in fructose consumption and how between 1980 and 2000, it paralleled the epidemic rise in obesity. There are more pernicious effects of excessive calorie consumption in the form of fructose. Dietary fructose is transported straight to the liver, where it's essentially prediabetic by increasing glucose production and induces excess energy storage in the form of liver fat, causing hepatic steatosis, a precursor to NASH. Here is one of many studies showing the phenotypic effects of excess fructose intake in humans. Obese subjects consumed either glucose or fructose-sweeten beverages. And if you compare the right-hand side to the left in each of the following panels, and we see that fructose specifically increased visceral adiposity, circulating triglyceride levels and impaired glucose tolerance. In the hepatocyte, the first step in fructose metabolism is capitalized by the enzyme, ketohexokinase, or KHK, shown here in blue. Inherited deficiency of KHK, has ben known since the 1980s, causes the benign disorder fructose urea, but the failure to initiate fructose metabolism leads to its urine excretion. So KHK is a genetically validated target to prevent fructose uptake into the liver. Pfizer have a small molecule inhibitor of KHK, which has undergone 2 Phase II studies. In Study I, they showed dose-dependent improvement in liver fat and a number of other pro-inflammatory markers. In Study II, they again showed dose-dependent improvements in liver fat, but also improvement in HbA1c. Currently, however, this program is not active. KHK is expressed in the liver and gut, but we have found that RNAi-mediated knockdown of the enzyme in the rodent liver improves many major aspects of the metabolic syndrome phenotype. Again, we will apply all our platform learnings and are busy generating a development candidate for a Q6 monthly lead or annual subcutaneously administered drug targeting KHK. Beyond the liver programs I've discussed, we have many other equally compelling opportunities with over 25 preclinical programs in 4 distinct tissues. Those programs, all against genetically validated targets, will utilize the full scope of our platform advances to generate exciting differentiated product candidates that we will bring to the clinic with 2 to 4 INDs per annum. Looking beyond 2025. There are 2 factors that will allow us to sustainably deliver innovation in an ongoing fashion. These factors are validated targets and a validated platform. This diagram shows our workflow. At the top -- we know that sources like U.K. Biobank, or the genetic databases, the literature and various collaborations will continue to yield high-quality genetically validated targets similar to gene X that I described earlier. Using the platform, we can then build optimal product candidates for those targets, including extra hepatic targets, as Kevin Fitzgerald will later discuss. Candidates will then progress into the pipeline, such that in 2025, we aim to file 4 more INDs per annum. Ultimately, this combination of carefully selected targets and a powerful platform increases the probability of success at each stage of development, including ultimately the approval of transformative medicines. Finally, my comment about probability of success gets support from this bar chart summarizing our progress to date versus industry metrics. Most importantly, on the far right, you see that our cumulative probability of success from Phase I to III is 64.3% as compared to industry metrics that range between 5% to 10%. That multiple speaks to the power of our R&D strategy for patients, families, payers and health care systems as we deliver products that address high unmet needs with, as John described, a bang, not a whimper. And with that, I'll close and also thank my good friend and colleague, John Maraganore. John, thank you for inviting me to join Alnylam at the end of 2005. We've been on an incredible scientific odyssey. Thank you for your leadership. We will keep your legacy alive. We'll make it grow and we'll serve many more patients yet. Thank you. I'll now turn it over to John Vest, my colleague, who will update you on the progress of our TTR franchise.

Thanks, Akshay, and hello, everyone. My name is John Vest. I'm the Global Clinical Lead for our TTR franchise. And on behalf of the TTR team, I'm very pleased for the opportunity today to update you on the programs and our plans to continue to expand the franchise. I'll be covering a number of topics, including our recent HELIOS-A Phase III results, ongoing clinical development work in ATTR cardiomyopathy as well as our efforts in advancing ALN-TTRsc04. Then I'll end with an overview of an exciting new and near-term opportunity for vutrisiran in an ocular disorder called Stargardt disease. I'll begin with a brief background on the disease and an overview of the ATTR amyloidosis franchise. ATTR amyloidosis is a rare, progressively debilitating disease caused by misfolded TTR protein that accumulates as amyloid deposits in multiple tissues, including the heart, nerves and GI tract, typically resulting in polyneuropathy and cardiomyopathy. As with most rare diseases, the true prevalence is difficult to know, but we believe there are approximately 50,000 patients worldwide with the hereditary form of the disease where the patient carries a TTR gene variant. Patients without a transthyretin variant can also accumulate misfolded transthyretin protein and tissues, often associated with advancing age. This leads to wild-type ATTR amyloidosis. Prevalent estimates for this patient segment are significantly larger, perhaps 300,000 patients worldwide, though some estimates are much higher. Both the hereditary and wild-type forms of the disease may present with multisystem involvement and a high burden of disease that is often fatal. Our therapeutic hypothesis, which has remained consistent since we began working in this space over 10 years ago, hypothesizes that utilizing an RNAi therapeutic to dramatically reduce the production of the disease cause transthyretin protein in the liver will prevent continued amyloid deposition and potentially allow the body to remove existing deposits, ultimately halting or improving the manifestations of the disease. Other treatment modalities attempt to interfere with the disease cascade at later points, well after the transthyretin and protein has been made and is circulating throughout the body. We strongly believe that suppressing the production of both the variant and wild-type transthyretin protein in a highly potent and reversible manner, may prove to be the best approach to treating this disease. And we have designed our TTR targeting RNAi therapeutics to do just that. We now have 3 RNAi therapeutics in our ATTR amyloidosis franchise. On the left, you see ONPATTRO or patisiran, which was the first-ever approved RNAi therapeutic, with U.S. approval in August of 2018 for the treatment of the polyneuropathy of hereditary ATTR amyloidosis, based on the landmark, APOLLO Phase III study. Patisiran is also currently in further clinical development in our APOLLO-B Phase III study. Vutrisiran, an investigational RNAi therapeutic, utilizing ESC GalNAc conjugate chemistry, is in clinical development in multiple ongoing Phase III studies, including HELIOS-A and HELIOS-B. Vutrisiran has a very compelling product profile with subcutaneous administration of a 25-milligram dose once every 3 months. We are also evaluating a potential additional dosing regimen of 50 milligrams once every 6 months. And finally, ALN-TTRsc04 is the newest program within our franchise. Like other programs, this RNAi therapeutics specifically targets transthyretin mRNA. However, TTRSc04 utilizes our new IKARIA platform chemistry in its design, and we believe has the potential for once annual dosing and greater than 90% serum transthyretin reduction. More on this later in the presentation. Collectively, it is our belief that these 3 programs will support Alnylam's vision to be the leading ATTR amyloidosis franchise and position us for sustainable market leadership. Now let me turn to some recent news on vutrisiran. Last month, we were absolutely thrilled to share the positive top line results from the month 18 analysis of our HELIOS-A study. As a reminder, HELIOS-A is a study of vutrisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. 164 patients were randomized 3:1 to either vutrisiran 25 milligrams quarterly or patisiran, which served as a reference comparator. The study compared vutrisiran to the placebo arm of the APOLLO study is an external control for the primary and most secondary endpoints. The primary endpoint was the modified neuropathy impairment score plus 7 or mNIS+7, and secondary endpoints assessed a wide range of important disease manifestations, including quality of life, ambulatory function, nutritional status and disability. The study design included a primary analysis at month 9 and an additional analysis at month 18, where the full spectrum of clinical assessments were analyzed as secondary endpoints. The analysis from the primary endpoint was at month 9. The primary endpoint of mNIS+7 demonstrated a clinically and statistically significant improvement compared to the external placebo arm from the APOLLO study. The majority of vutrisiran-treated patients also demonstrated an improvement compared to baseline, which is in stark contrast to APOLLO placebo patients who, on average, demonstrated marked worsening. Significant improvement compared to APOLLO placebo was also observed in both of the month 9 secondary endpoints, Norfolk Quality of Life, in the 10-meter walk test as well as the exploratory cardiac biomarker NT-proBNP. Importantly, vutrisiran demonstrated an acceptable safety profile. Following on from these positive month 9 results, we have now completed the second planned analysis for the study, this one, at the month 18 time point. As we recently announced, top line results for the month 18 analysis were indeed positive. And as shown on this slide, vutrisiran demonstrated significant improvement compared to APOLLO placebo for all month 18 secondary endpoints, which included mNIS+7, Norfolk Quality of Life, 10-meter walk test, modified body mass index and rods. Overall, vutrisiran results and HELIOS-A are generally comparable with patisiran results with APOLLO, across the primary and all secondary endpoints. We also observed encouraging results on exploratory cardiac endpoints at 18 months, which included favorable changes in NT-proBNP and certain echocardiographic prams relative to external APOLLO placebo, and favorable change in cardiac technetium uptake relative to baseline in the majority of patients in the cohort, suggesting potential evidence for reduced cardiac amyloid burden with 18 months of vutrisiran treatment. Given these month 18 results, in the previously reported month 9 results, vutrisiran has now met the primary and all secondary endpoints in the HELIOS-A study. We look forward to reporting full 18-month results at a medical conference in early 2022. Importantly, with regard to TTR reduction, the month 18 analysis confirmed noninferiority of vutrisiran relative to the within study patisiran arm, as expected. In this figure, showing serum transthyretin reduction across the duration of the 18-month treatment period, with the vutrisiran-treated patients depicted in dark blue, and the within study patisiran arm shown in light blue. You can appreciate the remarkable consistency of the pharmacodynamic effect in reducing the disease-causing protein with both RNAi therapeutics. Of equal importance, vutrisiran continues to demonstrate an acceptable safety profile. During the 18-month treatment period, there were no drug-related discontinuations or deaths. There were 3 discontinuations due to adverse events in the vutrisiran arm. None were considered related to the study drug. These included 2 fatal events, both previously reported at month 9, 1 due COVID-19 and 1 due to iliac artery occlusion during a hospitalization for pneumonia in a patient with heart failure, and a single event of cardiac failure leading to discontinuation. There were 2 serious adverse events deemed drug-related, both previously reported at month 9, which included dyslipidemia and urinary tract infection. Treatment-emergent adverse events occurring in greater than or equal to 10% of patients receiving vutrisiran included fall, pain in extremity, diarrhea, peripheral edema, urinary tract infection, arthralgia and dizziness. With the exception of pain in the extremity and arthralgia, each of these events occurred at a similar or lower rate as compared with external placebo. Injection site reactions were reported in 5 patients or 4.1% of vutrisiran-treated patients all of which were mild and transient. And overall, there were no hepatic safety concerns. As we have previously announced, we are very excited about the potential opportunity for a biannual dosing regimen with vutrisiran, which could further differentiate vutrisiran from other products and provide yet another compelling option for patients. While we remain very confident in the 25-milligram once every 3-month dosing regimen, based on results of the Phase I single-dose study of vutrisiran in healthy volunteers shown in the left-hand panel, as well as pharmacodynamic modeling results shown in the right-hand panel, we believe that the pharmacodynamic profile of vutrisiran also supports even less frequent dosing. Such as a 50 milligrams once every 6 months regimen, which is expected to achieve serum TTR reduction that is similar to that achieved with patisiran in its clinical dose. And is anticipated to be comparable to vutrisiran 25 milligrams, every 3 months that steady state. Accordingly, we are now generating the clinical data to advance this additional 50-milligram biannual dosing schedule for vutrisiran. Specifically, the open-label extension period of the HELIOS-A study now includes a randomized treatment extension where patients from the HELIOS-A study will be randomized to receive vutrisiran at a dose of either 25 milligrams every 3 months or 50 milligrams biannually. These data, which are intended to demonstrate the safety and efficacy of the 50-milligram biannual regimen, are expected in late 2022. We believe that advancing this alternative regimen has the potential to further reduce the burden of care and provide additional optionality for patients and physicians. We'll now move on to talk about our ongoing expansion into ATTR amyloidosis with cardiomyopathy. We feel extremely encouraged about the potential for vutrisiran and patisiran in ATTR amyloidosis with cardiomyopathy. As we have presented previously, the APOLLO study of patisiran demonstrated exploratory evidence for improvement in cardiac biomarkers, echocardiographic parameters and ambulatory function with patisiran treatment compared to placebo. The significance of these improvements in cardiac assessments was supported by post hoc analysis of safety data from the APOLLO study, which, as shown on the left, demonstrated a roughly 50% reduction in the composite rate of all-cause mortality and hospitalizations over the course of this 18-month randomized controlled study. These initial data from the APOLLO study have now been complemented by data published by Julian Gillmore and colleagues at the National Amyloidosis Center from 32 patients with hereditary ATTR amyloidosis with cardiomyopathy. At 1 year, there was evidence of a reduction in cardiac amyloid burden assessed by extracellular volume for action in patients who received patisiran, and a majority of whom also received diflunisal compared to retrospectively matched control patients who received no disease-modifying therapy. The patisiran-treated patients also demonstrated substantial improvements in 6-minute walk test and NT-proBNP compared to the control group. Overall, the authors described these data is demonstrating "compelling evidence of substantial amyloid reduction -- amyloid regression." It's important to note that patisiran is not currently indicated for the treatment of ATTR cardiomyopathy and vutrisiran is not yet approved for any indication. These are exploratory and post hoc analyses, and thus need to be confirmed in ongoing trials. Overall, we believe that there's a consistency of findings across a wide spectrum of parameters that all support the hypothesis we're pursuing in the ongoing APOLLO-B and HELIOS-B studies in patients with ATTR amyloidosis with cardiomyopathy. The APOLLO-B study of patisiran was designed to enroll approximately 300 patients with ATTR amyloidosis, either wild type or hereditary, with cardiomyopathy and symptomatic heart failure. Patients were randomized 1:1 to patisiran or placebo. The primary endpoint is the change versus baseline in 6-minute walk test at 12 months. The 6-minute walk test is a recognized measure of clinical benefit in heart failure, and we identified this as an endpoint that could allow us to bring patisiran and the potential benefits of this therapy to this population as rapidly as possible. We will, of course, first look at a variety of secondary endpoints, including outcomes of death and hospitalization as well as exploratory endpoints, such as cardiac biomarkers and cardiac imaging. We are extremely pleased with the progress on the study, which completed enrollment this past May, and we expect to report top line results in mid-2022. HELIOS-B is our ongoing Phase III cardiac outcome study with vutrisiran. The study was designed to enroll approximately 600 patients and is a randomized placebo-controlled trial. Like APOLLO-B, all patients will have confirmed hereditary or wild-type ATTR amyloidosis with cardiomyopathy and symptomatic heart failure. Patients are randomized 1:1 to vutrisiran 25 milligrams quarterly or placebo. The primary endpoint is a composite of mortality and CV events to be analyzed when the final patient completes month 30. There is also a robust package of secondary endpoints that will allow us to fully elucidate the treatment effect. Enrollment in HELIOS-B was completed this past August, much earlier than originally expected, and we anticipate top line results on the 30-month endpoint in early 2024. The study includes an optional interim analysis, providing the potential for an earlier data readout. We will be engaging with regulators to align on the details of a potential approach for this optional interim analysis. Importantly, the analysis would be staged such that results from APOLLO-B can inform our final strategy and allow us to achieve the optimal balance between speed and the desired label expansion for vutrisiran in ATTR amyloidosis with cardiomyopathy. Therefore, we expect that we will only be in a position to share further information on our thinking after the APOLLO-B study data are available in mid-2022. We'll now shift gears to touch on our plans to continue advancing innovation with ALN-TTRsc04. ALN-TTRsc04 is the newest addition to our ATTR amyloidosis franchise. This new siRNA targeting transthyretin was generated using our IKARIA platform. Preclinical development suggests exquisite specificity for the intended target in nonhuman primate studies have demonstrated remarkable potency. Collectively, we believe the profile of TTRsc04 could support an annual dosing regimen with greater than 90% transthyretin reduction. In advancing the IKARIA platform, we are very excited about the plans to rapidly develop ALN-TTRsc04, in order to continue our commitment to innovation in the treatment of ATTR amyloidosis, with the potential for an annual subcutaneous dosing regimen with potent and reversible effects. Importantly, there are no third-party royalty obligations associated with this program. We also anticipate patent protection, covering us from a loss of exclusivity extending beyond 2040. As we think about the path forward for TTRsc04, we would note our demonstrated track record for rapidly advancing innovation in ATTR amyloidosis, such as advancing vutrisiran from first-in-human readout to positive Phase III results in HELIOS-A in approximately 3 years. In driving forward this exciting program with TTRsc04, we expect to file an IND application in late 2022. I'm particularly excited about this next section of the program, as we are announcing today a promising new opportunity for vutrisiran for the treatment of Stargardt disease. As you will hear, this is a major opportunity for us to expand the program and to potentially treat a devastating inherent ophthalmologic disease affecting the retina, which is an important cause of blindness, affecting both children and adults, where we feel vutrisiran has the potential to be an effective treatment in a disease with high unmet need. To further discuss Stargardt disease, I am very pleased to introduce Dr. SriniVas Sadda. Dr. Sadda is a Professor of Ophthalmology at UCLA and Director of Artificial Intelligence and Imaging Research at the Doheny Eye Institute. He received his M.D. from Johns Hopkins University, where he completed an ophthalmology residency and neuro-ophthalmology and medical retina fellowships at the Wilmer Eye Institute. Dr. Sadda has more than 600 peer-reviewed publications and 13 book chapters, and has given over 400 presentations worldwide.

Thank you, Dr. Vest. As was mentioned, I'm Vas Sadda. I'm a Professor of Ophthalmology at UCLA. I've been very involved in Stargardt disease trials, and so I'm very pleased to be here today to discuss Stargardt disease. So Stargardt disease actually is a very important topic for discussion because it's actually quite common. It's prevalence in the United States. It's 1 -- it's rated to be between 1 in 8,000 to 10,000. It was first described actually over a century ago by Karl Stargardt in Berlin, hence the name. But one of the interesting things about Stargardt is it's actually found around the world. It's one of the few diseases where, really, you can see it in every single country and there's no racial or gender predilection. It is the most common cause of juvenile macular dystrophy in the U.S., and therefore, it's an important cause of vision loss in younger individuals. So to understand Stargardt disease, some people call it the Stargardt macular dystrophy, I think it's pretty important to define, well, what's the macula? And why is it important? And I know that, for this audience, not everyone may be familiar with the enemy of the eye. So it's worth mentioning that when you think about your eye, when we're talking about the macula. We're really talking about the back part of the eye. In fact, the macula is the center part of the retina as opposed to the front part of the eye, which consists of the focusing elements of the eye that focus the light onto the retina. And ultimately, information that's focused on to the retina gets to the brain via the optic nerve. So one of the analogies I like to use on explaining the eyes to my own patients is that it's very similar to the camera and envision the retina as a film of the camera. And it contains all of the light sensitive cells. And the macula, again, is the very central part of that retina that we use for central or straight-ahead vision. So let's dive a bit more into detail in terms of the macula because I think that's important to emphasize that the macula is special, and it's special because it's the highest resolution part of our retina. So again, our central vision, as you can easily tell, has got much higher resolution than a peripheral vision. If you try to hold your hand in front of your face, and you can see the lines, but hold your hand out to the side, you can tell your hands there. But you can't see all the lines on your hand because the resolution is not the same. And it really relates to the density of the light-sensitive cells that are in the retina. And so even though we often explain that the retina and the macula, which is the center of the retina, is like the film of a camera, and it's very thin like the film, in itself, of course, is quite complex. It's composed of many layers of cells, including the light-sensitive cells that are at the very bottom of the retina in this image. And then these cells transmit their information to these cells in the inner retina. So when you're talking about macular diseases, we really focus on them, and they're very important to us because these diseases affect the central vision. And so because our central vision is our sharpest vision, it impacts many of our activities, including reading, driving, watching television. And in fact, once the vision and the center declines to 2,200 or worse in the better eye, we consider that to be evidence of legal blindness. So Stargardt disease, unfortunately, is a disease that affects the macula. And so when your eye doctor looks inside your eye, and because the eye is, at least, the center, is translucent, we can actually see inside. So we can actually see, in this case, the film of the camera, so we can see an image like on your left, which is an image of a normal retina and you can see the retinal blood vessels and the like. And in the very center there is the macula, you don't have to be a retina specialist to see that there's something wrong in the image on the right. And in fact, there is evidence of disease with some yellowish sort of dots as well as a central kind of area where you don't see the pigmentation as well. And this is evidence of a patient with Stargardt disease. And you can imagine, if you have an area of damage to the center, what you might notice, well, if you're looking at a grid and we commonly use these kinds of grids, enough ophthalmology clinical practice, you might see missing areas in grid or if you're trying to look at someone, you really can't make out their faces. And so this is -- can be pretty visually disabling. So it's an important problem that we have to contend with. So as I mentioned earlier, Stargardt is the most common inherited macular dystrophy and in most cases, are inherent in autosome or recessive fashion. And the interesting thing about this disease is that 90% of the cases are actually attributable to a specific gene, a gene we call ABCA4. And this is a gene that's -- that they are commonly mutations out there in many, many individuals. And so sometimes, you can have patients who -- obviously, you get one gene from your mother, one from your father. And you can have patients who have very different mutations in the 2 different ABCA4 genes that they get from their 2 parents, and that's something we call a compound heterozygote. I mentioned that mainly because I want to emphasize that there can be a lot of variability in the disease depending on the mutation. Well, what does this ABCA4 gene do? I mean it's on the chromosome 1. It's a very large gene. It's probably one of the reasons why you can have so many different mutations or call heterogeneity. In fact, there's more than 490 different disease-causing mutations that have already been identified. In terms of what the gene actually does, it expresses a protein that's important for transporting various molecules. And the way the retina works is that there's a lot of communication between the light-sensitive cells in the retina, which we call rods and cones, and a supporting layer of cells below the retina called the retinal pigment epithelium, or RPE. I mean not critical for this presentation, except as much to understand that cycling of materials between different cells in the retina is very important. So if you have a problem in a protein, in this case, ABCA4, that's responsible for that kind of transport, that could be an issue. And in particular, ABCA4 is important for transportation is something we call all-trans-retinal, which is a vitamin A metabolite. And it turns out this is very important for vision. It's very central to the functionality of those rods and cones in terms of their ability to receive a photon of light and transform it into electrical or chemical signal that can then get to our brain. So without the proper function of ABCA4, you get toxic vitamin A metabolites to start to accumulate. And they accumulate this material that we call lipofuscin and particularly. They accumulate in the cell that I mentioned earlier called the retinal pigment epithelial cell, which you can imagine is kind of a support cell for the rods and cones. And this function of this retinal pigmothilial, or RPE cell, this can ultimately lead to loss of the light-sensitive cells or the photoceptors and then loss of vision. So that's how patients with Stargardt disease ultimately lose vision. So you can envision this as some kind of a trash buildup type of a problem. And so these patients can present very early on. There's actually quite a bit of variability because I mentioned that you can have a variety of different mutations in this large gene. So there are some patients who present very early in their teens or 20s, but there are even situations where you could have adults that present with Stargardt disease, and that can be due to milder mutations in the gene. And so those patients can actually be confused with an entirely different condition called age-related macular generation. But ultimately, over time, these patients do lose vision, and so they drop down to 2,200 even worse vision over time. Initially, patients can have a relatively normal appearing retina, as you see in this illustration. But over time, they start to develop abnormalities. Again, you don't have to be a retina specialist to recognize there's something wrong. You can see these little yellowish deposits that are apparent in this image, we call Flex, or sometimes people have said they look like fish-like or fish-like tails, and they call them, disciform Flex. But the point is that's a very helpful finding in terms of recognizing the disease. And then over time, eventually, you can actually lose cells in this very center of the retina. You can maybe appreciate in the very center of this image that it kind of has a sort of almost metallic-like appearance sometimes people call that beaten bronze. I don't know if that looks like beaten bronze because I've never beaten bronze, but maybe you can perceive that. In this case, it's kind of subtle, and we have other tools that could help us really see where is it that the patient is losing cells from this condition. As I said, it's really the loss of those light-sensitive cells. It's key. And again, just like I showed you in those color images of the eye, how easy it is to tell apart Stargardts from a normal eye. You can also see it's very easy on other imaging technologies that we have in ophthalmology. We have a huge advantage in ophthalmology in our ability to take pictures of the retina, and we can actually see the layers of the retina in detail. So it's a technology called OCT. Think of it kind of like a CT scan for the eye, except it involves light. There's no radiation here. And all that you're seeing there, all those little stripes are sort of the layers of the retina, similar to the microscopic image I show on the left. And again, you don't have to be a retina expert to see that there's something wrong in the Stargardt's case, which is the lower right. And there, you can see that there is clearly evidence of missing bands in the outer part of the retina. And of course, losing those light-sensitive cells is something that progresses throughout the course of the disease, and that leads to progressive central visual dysfunction that really impairs our ability to do a number of tests from recognizing faces, as I mentioned, to reading, driving, watching television, a lot of things that are really important to us in life. So in terms of visualizing these areas where the cells are being lost, we have another type of tool. I don't want to get too much into the weeds on how we diagnose the condition, but I wanted to highlight something we call fundus autofluorescence. And this is an imaging strategy that takes advantage of the fact that lipofuscin, which is that accumulation of toxic vitamin A metabolites, that actually -- it turns out has an interesting property that when you shine light into the eye, the light bounces back in a fluorescent sort of fashion. And so initially, you have accumulation of these toxic vitamin A metabolites. And you can see those are these little bright spots in the image. But over time, the cells that accumulate them die as I mentioned. Then you can see this black spot in the center. So it's very easy for us when we explain it to patients. They can see, oh my goodness, I have this black hole in the middle of my vision. That really is the loss of those of light-sensitive cells. And it's also how we track and follow the disease over time. And this is just another example showing how much better and easier it is to see using the fundosotoflorescence image on the right to see those areas of missing cells. And in addition, even though the macula is the main part of the disease that -- in terms of the area of the retina, the disease effect, it's important to recognize that you can have abnormalities that extend throughout the retina. Here again, you can appreciate, in a much wider angle view of the retina, how extensive the abnormalities can be in an eye with Stargardt disease. This is just one more example to kind of illustrate the variability from patient to patient. Again, this all relates to the type of mutation that these patients can have. So some patients are going to have relatively localized disease some patients can have very, very extensive disease, all depending on the mutation. And you can imagine patients who have more extensive disease, in the kinds of patients who may be progressing faster. So in terms of how we ultimately make the diagnosis before we used to get all of these types of imaging tests and figure this out and make sure it was Stargardt and not some other condition, now genetic testing is widely available. We have mechanisms to obtain this free of cost for patients. And really, once we suspect, based on examining the patient, that they may have Stargardt, the easiest thing is to just to get a genetic test and see, do they have a mutation in ABCA4 or not? Okay, let's turn from sort of diagnosing the condition, what the disease looks like to how do we treat it? And that's really the big problem, of course, with Stargardt is that unfortunately, there is none. So this is a huge area of unmet need for. So what do we do currently in the absence of a treatment? Well, there are certain things that we can do that we suggest to a patient. One, is photo protection. We know that bright light exposure, especially blue light can be harmful for a number of inherited retina diseases, especially diseases where you're accumulating toxic vitamin A metabolite. So this is potentially helpful. And obviously, in a condition like this, we'd want to avoid any supplemental vitamin A because people oftentimes take a variety of different vitamins and the like. And this would be a no-no for a patient with Stargardt. And the other biggest aspect in terms of how we currently approach the disease, of course, is in terms of visual rehabilitation, visual aids. These are quite important. And they're fortunately, are good services, low-vision services where we can send the patient to, to get help with magnifiers and other things to try to at least use the vision they do have a little bit better. So again, this is an area of unmet need. And so not surprisingly, it's an area where there is activity in terms of trying to find a potential treatment for these patients. And I've listed kind of some general areas of focus. One of the really big and, I think, topics and I think what's most relevant also here to the Alnylam program is really in this concept of visual cycle modulation. I highlighted how accumulation of toxic vitamin A metabolites is so central to disease. So if you could potentially interfere with this process, you could potentially prevent the accumulation of these types of toxic materials in the patient's eye, and that could potentially save their photoreceptors from dying. So that's obviously not surprisingly a very important focus. There are other areas that one potentially could target with other mechanisms of neuroprotection or potentially gene therapy, although gene therapy can be a big challenge in this particular disease because the ABCA4 gene is very large. So it's hard to package it into the viral vector. And of course, in very late-stage disease when a patient has already lost vision, then stem cells, artificial vision strategies may be relevant. But again, so far, no treatment available for these patients. So we're very anxious to find a treatment strategy for these patients. And so it's very exciting to see potential strategies that might -- to target the fundamental pathophysiology of the disease, in terms of this accumulation of toxic vitamin A metabolites. So we've been very involved, as I've mentioned, in trying to help in this space and trying to find therapeutics for patients with Stargardt. And one of the important things, which I think has really set the stage for doing effective trials in this disease is having good natural history data. And that's what the Stargardt program, which is funded by the foundation for Blindness. You can see my picture here as well because we have analyzed all of the images for patients collected in this study. And that really helped us define -- and again, I'm not going to go through all the tables, but this is just one of many, many papers that we've published, have this helped us understand what the rate of change is in terms of vision as well as change in terms of sensitivity, on visual field testing as well as the change in terms of the progression of the atrophy. You can see examples like this where you see enlargement of the autofluorescence or loss of the photoreceptors, on OCT testing. We have good data now on how the disease progresses over time. And understanding this variability and the rate of progression has made it much more feasible to design adequately powered clinical trials to test novel therapeutics. And we have these endpoints now that are acceptable for regulatory agencies. We just need agents that will work to stop this disease progression. It's just an example, you can see, again, this is the kind of stuff we show our patients. You can witness the progression and the enlargement of that dark area. And that's what we're hoping with therapeutics that we can prevent that progression and preserve vision for patients. And so we have very good tools now, I think, to track the progression and we're very ready for these types of clinical trials. And we've shown, again, in these clinical trials commonly, what happens is these images are sent to centralized centers. That's an area of focus for me, personally. And we're able to have human assessors measure the extent of the disease. So we're able to track the progression reliably, whether it's on autofluorescence, imaging, as shown here, or even on OCT, where we can show the progression and loss of the retinal layers over time. And hopefully, prevention with appropriate therapeutic strategies. So to summarize, Stargardt disease is clearly the most common inherited macular disease, and it's seen worldwide. And the critical thing is a loss central vision in these individuals. And the age of onset and the rapidity of the progression is really ultimately dependent on the severity and the impact of the genetic mutation. And as I said, nearly all the patients, 90% of them, are due to mutations in that ABCA4 gene. There's currently no treatment. So this represents an area of significant unmet need. And then at the same time, we have extensive natural history data now. So we're very well-suited to conduct and designing an interventional clinical trial to address this. And I'm excited about the possibility of, for example, interfering with the vitamin A-related issues, in particular, of given the underlying pathophysiology of this condition. With that, I will stop there. Thank you very much for your attention, and I'll turn things back over to Dr. Vest.

Thanks so much, Dr. Sadda for that fantastic overview. It is really difficult to follow such a comprehensive description of the disease. But as you have just heard, Stargardt is a rare inherited disease caused by accumulation of toxic vitamin A metabolites in the retina, which leads to central vision loss and is an important inherited cause of blindness in children, and almost all people affected by this disease are legally blind as adults. So a truly devastating disorder that we estimate impacts about 1 in 8,000 people. Notably, as you just heard from Dr. Sadda, this is an area of extremely high unmet need as there are currently no approved treatments. Transthyretin, which is produced in the liver, and is, of course, the protein responsible for ATTR amyloidosis, is highly relevant to Stargardt disease as well given its role in the transport of vitamin A. More specifically, in serum, transthyretin forms a complex with retinal binding protein, or RBP4, the primary carrier of vitamin A. And this complex collectively allows for delivery of vitamin A to extrahepatic tissues, including the eye. In healthy individuals, vitamin A enters the visual cycle and through the proper function of the ABCA4 protein and appropriate balances maintained such that toxic vitamin A metabolites do not accumulate in the retina. In Stargardt disease patients, however, there is an inherited defect in ABCA4. Thus, the ABCA4 protein cannot properly remove the toxic vitamin A metabolites and they accumulate in the retina is lipofuscin. This accumulation triggers degeneration of macular rods and cones, leading to central vision loss and eventually, blindness in most patients. With this pathophysiology in mind, one can imagine that interfering with vitamin A delivery to the eye could be an effective therapeutic approach. Indeed, published preclinical data in a mouse model of Stargardt disease support this concept. As shown in the far left panel, treatment of Stargardt mice with an antagonist of retinal binding protein results in substantial reductions in circulating RBP4, the primary carrier of vitamin A, as expected. This, in turn, reduces accumulation of toxic vitamin A metabolites that drive disease, which is reflected in panel B, is a decrease in a lipofuscin fluorophore in the retina. In the right-hand panel, this is further demonstrated visually with autofluorescence in retinal sections, deposit lipofuscin, which is, in essence, an accumulation of toxic vitamin A metabolites, fluoresces break green in the retina of untreated Stargardt mice. However, in mice treated with RBP4 antagonist, this accumulation of lipofuscin has been mitigated with the retina appearing similar to that of healthy control mice. While these data in Stargardt mice are shown with a small molecule antagonist of RBP4, RNAi-mediated TTR knockdown in humans is also known to decrease retinal binding protein, which, in turn, results decrease in serum vitamin A levels. This correlation between transthyretin and serum vitamin A levels is illustrated on the right-hand panel of this slid,e, showing data from HELIOS-A. Accordingly, as we reduce transthyretin with vutrisiran, it is expected pharmacology that there will be a similar reduction in serum vitamin A levels. Indeed, this has demonstrated in data from the HELIOS-A month 18 analysis in the left hand panel, where you can see a robust and sustained reduction in serum vitamin A over the 18-month treatment period in both the vutrisiran and patisiran arms, consistent with the expected PD effect of these drugs. Taken together, this provides a sound therapeutic hypothesis for vutrisiran as a potential treatment for Stargardt disease. TTR knockdown will reduce RBP4-mediated vitamin A delivery to the eye, prevent lipofuscin accumulation and macular damage, which is anticipated to halt progression of vision loss. We believe that Stargardt disease represents a substantial opportunity for vutrisiran to expand beyond ATTR amyloidosis for the treatment of an entirely new disease area of high unmet medical need. Importantly, we feel that Alnylam is particularly well-positioned to advance this opportunity given our expertise with vutrisiran. There are currently no approved therapies in this indication. And to our knowledge, there is no one taking an approach of transthyretin reduction in this space. It should be noted that transthyretin stabilizers would not be expected to work based on the pathophysiology of the disease. Importantly, we believe we have the potential to move forward rapidly and directly to a pivotal trial. And indeed, we are anticipating the start of the Phase III study in Stargardt disease in late 2022, just about 1 year from now. Now pulling it all together, you can see how we intend to build the ATTR amyloidosis franchise over time, pending positive data readouts and regulatory reviews for the various studies I've just outlined, we aim to have ONPATTRO, vutrisiran and ALN-TTRsc04 expand across the ATTR amyloidosis patient population over the coming years. Additionally, we could not be more excited about the potential to further expand vutrisiran into the Stargardt disease space, as we've announced today. With that, I would like to thank everyone for their attention, and I will now hand the program over to Weinong Guo to discuss zilebesiran in hypertension.

Thank you, John Vest. Hello, everyone. I'm Weinong Guo, Senior VP of Clinical Development at Alnylam. Today, I will provide you a program update on zilebesiran, including the latest data from the ongoing Phase I study in hypertensive patients that were just presented at the American Heart Association scientific session last week. I will also provide an overview of the ongoing Phase II KARDIA studies of zilebesiran. Both studies have been recently launched. Zilebesiran represents an opportunity to reimagine the treatment of hypertension, a highly prevalent disease that has been lacking significant innovation for the last decade. As we all know, hypertension is the most common modifiable risk factor for cardiorenal adverse events, such as stroke, coronary arterial disease, myocardial infarction and kidney failure. There is an increasing prevalence of hypertension diagnosis and uncontrolled hypertension at high risk in the U.S. and the world, representing a global health crisis. In addition, hypertension management is further challenged by poor medication adherence with the current standard of care oral medications, which contribute to greater than 70% of hypertensive patients having uncontrolled blood pressure in the U.S. despite the treatment leading to substantial risk of CV mortality and mobilities. Here, we believe our RNAi therapeutic, which can be administered subcutaneously at infrequent dosing intervals that provides tonic blood pressure control may offer a paradigm shift in managing this global health crisis. Let me hone in first on the challenge of medication treatment adherence. On the left is a depiction of the various barriers to adherence, from a prescription being written all the way to a patient taking their medication correctly and consistently over an extended period of time. Though these data are not specific to antihypertensive medications, the general trend also holds for hypertension management. Several of the potential features of zilebesiran, such as infrequent dosing, with durable actions and the ability to reduce daily pill count could help improve patient adherence. In addition to the improvement of treatment adherence, we think that chronic blood pressure control offered by RNAi therapeutic may also reduce the cardiorenal adverse events. In this framework from Professor [ Korio ], there are 3 components of blood pressure control: the 24-hour blood pressure level, nocturnal blood pressure dipping and blood pressure variability, such as the unwanted morning blood pressure surge. The quantity of blood pressure reduction is important. But ideally, that reduction is consistently maintained throughout the 24-hour period and doesn't wane during the night, which is a challenge with many oral medications that have peak to trough effect every day. Restoring normal nocturnal dipping and avoid exaggerated morning blood pressure surge are more the qualitative aspect of the blood pressure control, which will also have an impact on cardiovascular risks. Achieving the objectives on both the quantity and the quality of blood pressure control will reduce the risk of target organ damage and prevent cardiorenal adverse risk events. Zilebesiran is a GalNAc conjugated sRNAi targeting the hepatic production of angiotensinogen, or AGT, that is the most upstream regulator of the renin angiotension system, RAS. This is a well-categorized system underlying blood pressure control. This results in liver-specific life silencing of AGT without an impact on local RAS activities, such as in the kidney. As with other RNAi therapeutics from Alnylam, zilebesiran can be dosed infrequently by subcutaneous injection with prolonged duration of pharmacological action. This durability of effect can provide both improved medication adherence and consistent and durable blood pressure control. The clinical development of zilebesiran for hypertension started about 2.5 years ago. It is currently in Phase II clinical development for hypertension, with 3 ongoing clinical trials. The first-in-man study of zilebesiran started in 2019 in patients with mild to moderate hypertension and has been ongoing since. I will first talk about 3 aspects of this Phase I study before turning into the ongoing Phase II studies a little bit later. This Phase I trial is a multicenter study designed to evaluate the safety, tolerability and PK/PD effect of subcutaneous administration of both single ascending and multiple dose of zilebesiran in patients with mild to moderate hypertension. The study has incorporated multiple parts, each with a difficult objective, as depicted on this slide. Today, I will share with you the latest set of new data from the proof-of-concept portion Part A and safety, tolerability in the low-salt diet and co-administration with [indiscernible] in Part B and E, respectively. The top line results of these parts of the study were presented at AHA Virtual Scientific Sessions last weekend. As for the Part D, this part is still ongoing to evaluate the metabolic effects of multiple dose of zilebesiran in obese hypertension patients, and it has recently completed patient enrollment. We look forward to sharing the data from Part D some time next year. The design of Part A is detailed on this slide. It is a randomized, placebo-controlled, single ascending dose study to evaluate the safety, tolerability and PK/PD of a single-dose zilebesiran via subcutaneous administration. The dose range from 10 up to 800 milligrams across a total of 7 cohorts of patients with mild to moderate hypertension. For each cohort, 12 patients were randomized 2:1 ratio to zilebesiran versus placebo. The patients were qualified based on ambulatory blood pressure monitoring, ABPM, with mean 24-hour systolic blood pressure when 30-millimeter mercury or above for either treatment-naive patients or treated patients who have their daily oral anti-hypertension meds washed out. The change from baseline in mean 24-hour systolic and diastolic blood pressure were exploratory endpoints for this study. The safety and tolerability of single doses of zilebesiran were evaluated for 12 weeks following the dosing. These results were presented earlier this year at the ESH ISH Annual Congress. A total of 84 hypertensive patients were randomized to participate in this study. The baseline demographic and clinical chataracteristics, not shown here, were typical of an essential hypertension population and balanced through different zilebesiran dose cohorts. The trial enrolled 22 black patients, about 1/4 of the trial participants. Single dose of zilebesiran, up to 800-milligram, was safe and generally well tolerated without treatment-related serious adverse events or adverse events leading to study withdrawal. Injection site reaction was mild and transient and only occurred about 9% of zilebesiran-treated patients. Now let's look at the results of serum AGT knockdown in Part A, which was a pharmacodynamic part of the study assessments. The results of the serum AGT knockdown through week 24 following a single dose administration of zilebesiran are summarized on this slide. As reported previously, dose-dependent reduction in serum AGT were observed from week 3, with 90% or greater reduction in serum AGT from baseline by a single dose of zilebesiran 100-milligram or above. These reductions were sustained through week 12. While the low dose, as you can see from the slide, shows some recovery of serum AGT levels from week 12 and onwards, it is important to note that all patients who received a single dose of zilebesiran, 800-milligram maintained greater than 90% reduction in serum AGT throughout the week 24. This data allows us to model the repeated dosing of zilebesiran and to investigate quarterly and biannual dosing in our Phase II study, which I will discuss in more details in a few minutes. This slide shows the waterfall plot of individual patient blood pressure response assessed by changes from baseline to week 8 in the mean 24-hour systolic blood pressure. Data from all placebo-treated and zilebesiran-treated patients with greater than 100-milligram dose are depicted here. As evident from the different patterns of individual BP response, compared to placebo, single doses of zilebesiran at 100-milligram dose or above provides -- that provides greater than 90% AGT knockdown were associated with reduction in blood pressure at week 8. With this first glimpse of blood pressure results in mind, using the waterfall plot at week 8, let's now investigate more closely the blood pressure effect of zilebesiran over the follow-up period of 24 weeks, and also the daytime and nighttime blood pressure response. This slide summarize changes from baseline in mean 24 systolic and diastolic pressure at weeks 8, 12 and week 24. Our mean 24-hour systolic blood pressure reduction, 10-millimeter mercury or higher, was achieved at week 8 across zilebesiran-dosed groups and clinically meaningful reduction in blood pressure were maintained through week 24. Notably, after a single dose of 800 milligrams zilebesiran, a mean 24-hour systolic blood pressure reduction, 20-millimeter mercury or greater was observed at week 24. Of these 8 patients on this dosing group, 6 achieved a 24-hour systolic blood pressure reduction, 20-millimeter mercury or greater at week 24 without receiving oral add-on antihypertensive medications. The 24-hour blood pressure monitoring allows additional analysis of daytime and nighttime blood pressure in our study. The results on reduction from baseline in daytime and nighttime blood pressure at week 8 are illustrated in the bar graph here, showing consistent daytime and nighttime blood pressure reduction over 24 hours following a single dose of zilebesiran at 800-milligram dose. Similar findings were also observed for week 12 and week 24, but data are not shown here. These findings is quite extraordinary, suggests early evidence of chronic blood pressure control with zilebesiran, a unique property of our angiotensinogen targeting RNAi therapeutic that is distinctly different from the commonly used standard of care oral agent. As shown on the left plot, the reduction in systolic blood pressure over the 24-hour time in zilebesiran-treated patients was consistent and stable at all time points over the entire 24 hours, even weeks after a single dose. This is in contrast to the blood pressure plot on the right, showing that Losartan, one of the most commonly used angiotensin receptor blocker, ARB, in the U.S., is associated with market variation of blood pressure reduction over the 24-hour dosing period, in particular, the second half of dosing period during the night and early morning. Such peak and trough blood pressure variabilities, as noted with arrows placed at the peak and trough time points for Losartan, are typical and expected with most daily oral antihypertensive medications. And one can imagine such variation in blood pressure control could be further exacerbated when there is no adherence with the oral antihypertensive therapies. To summarize the key findings on Part A, here in the slide showing that a single dose of zilebesiran subcutaneous administration was well tolerated in patients with mild to moderate hypertension with no treatment-related SAE or AEs leading to study withdrawal. Durable reduction in serum AGT, 90% or greater, were sustained for 24 weeks after a single dose of zilebesiran 800 milligram. Zilebesiran led to 10-millimeter mercury greater reduction in 24-hour mean systolic blood pressure at week 8 across all doses of 200, 400 and 800 milligrams zilebesiran, with a clinical meaningful blood pressure reduction maintained through week 24. Zilebesiran produced consistent blood pressure reduction during both daytime and nighttime, showing early evidence of chronic blood pressure control at all time points over a 24-hour period that is sustained during the entire dosing intervals. This data supports further evaluation of both quarterly and biannual dose administration of zilebesiran in hypertension. Now for the next part of my presentation, I'm going to go over the top line results from Parts B and E of the ongoing Phase I study. These are the latest data we presented at AHA virtual scientific session a week ago. Part B is a randomized placebo-controlled single-dose study with controlled soft intake. The purpose of this study is to assess the safety, tolerability of zilebesiran under volume depletion due to sodium loss induced by 7-day low-salt diet. This is an important evaluation of the safety, tolerability of long-acting RNAi therapeutics, such as zilebesiran. A cohort of 12 hypertensive patients were randomized 2:1 ratio to receive a single dose of 800-milligram zilebesiran or placebo. There was a controlled salt intake sub protocol for 2 weeks: 1 week of a low-salt diet site followed by 1 week of high-salt diet. These were performed pre-dose at week minus 3 to minus 1; and again, post-dose at week 6 and week 8 after single dose administration of zilebesiran or placebo, as illustrated in the study design diagram here. Zilebesiran was safe and well tolerated in Part B of the study. There was no SAEs or AEs leading to the study withdrawal. No patient required intervention for low blood pressure, including during the low-salt diet period. In addition, no clinically significant elevation is seen in creatinin, ALT, serum potassium in zilebesiran group were reported. The 24-hour ambulatory blood pressure monitoring at various time points was performed before and after dosing in this study to further quantify the blood pressure effects of zilebesiran under a low and high salt diet, with the changes in mean 24-hour systolic and diastolic blood pressure over the course of dietary [indiscernible] depicted on the right. At pre-dose, a reduction in 24-hour systolic and diastolic blood pressure was observed for all patients following a low salt diet for 7 days. Blood pressure increased upon switching to high salt diet for another 7 days. These changes in blood pressure are consistent with the role of sodium intake for blood pressure regulation. At the post-dose phase, blood pressure changes were more profound following the low salt diet for patients receiving zilebesiran compared to placebo. The high salt diet moderated this blood-pressure lowering effect of zilebesiran, showing an increase in blood pressure from the nadir of low-salt diet, which is similarly to that manifested by the high-salt diet during the pre-dose phase. These results from Part B supports the safety and tolerability of zilebesiran under volume depletion, when at its peak effect, was greater than 90% AGT knockdown. Let me walk you through the final new set of the data from Part E of this study. Part E is an open-label, single-dose study to evaluate the safety, tolerability of zilebesiran with co-administration of IRB, and irbesartan and angiotensin receptor broker. The study design is illustrated in this diagram. A total of 16 patients with mild to moderate hypertension entered the study and received a single dose of 800 milligrams zilebesiran on day 1. Based on the ABPM assessment on day 41, roughly around week 6, patients with a mean 24-hour systolic blood pressure of 120-millimeter mercury or below would be followed up through week 12 without additional intervention. Whereas those patients with a mean 24-hour systolic blood pressure 120-millimeter mercury greater would receive 300 irbesartan once daily as add-on treatment for 2 weeks. ABPM was performed again in all patients on day 57, roughly week 8. There were 6 patients in total receiving only the single dose of zilebesiran and 10 patients who received co-administration of zilebesiran plus irbesartan, per study design. Here is a high-level summary of the Part E results showing that irbesartan further reduced ambulatory blood pressure without clinically significant changes in creatinine or potassium. Let me walk you through these data step by step. First, a single dose of 800 milligrams zilebesiran produced 13.1 over 7.4 millimeter mercury reduction from baseline in the mean 24-hour systolic and diastolic blood pressure at week 6. According to the ABPM assessment on day 41, patients then entered 2 separate legs for the second half of the study based on their blood pressure response, as I explained to you on the prior slides. For the 6 patients who received only a single dose of 800-milligram zilebesiran from day 1, throughout the entire study period, there was a 22-millimeter mercury reduction in the mean 24 hours systolic blood pressure over the first 6 weeks, which was sustained through week 8 without additional intervention. For the other 10 patients who received a single dose of 800-milligram zilebesiran at day 1, there was about 8-millimeter mercury reduction from baseline in mean 24-hour systolic blood pressure at week 6 and the addition of irbesartan once daily for 2 weeks at dose of 300 milligrams produced an additional 6.4 millimeter mercury reduction. The changes in the mean 24-hour diastolic blood pressure follow the same pattern as for the systolic blood pressure for both groups of patients. Lastly, no clinically significant elevation in serum creatinine or potassium were observed in either patient cohort during the entire 12-week study period. The overall conclusion of Part B and E is summarized on this slide. Subcutaneous administration of zilebesiran 800-milligram was safe and well tolerated in patients with mild to moderate hypertension with no SAE, AEs of hypertension or low BP requiring intervention reported during the low-salt diet or co-administration with an ARB. High-salt diet moderated blood pressure-lowering effect of zilebesiran, which provides early evidence that this standard intervention could be effective to treat potential hypertensive adverse events if they were to occur. Addition of irbesartan to zilebesiran further reduced the blood pressure without clinically significant changes in creatinine or potassium. These data supports the investigation of zilebesiran for treating hypertension in patients with uncontrolled blood pressure despite the standard of care antihypertensive therapies in the Phase II clinical program. Thanks a lot for your attention and time to this point. Now let me switch the gear and I'd like to present a brief overview of the ongoing Phase II program that has 2 dedicated efficacy safety blood pressure studies of zilebesiran in different hypertension patient population. Alnylam has recently initiated 2 multicenter randomized placebo-controlled Phase II efficacy safety studies of zilebesiran. The first one is a dose-filing monotherapy study known as KARDIA-1. And the second is a combination study known as KARDIA-2 in those patients with uncontrolled blood pressure despite using a single standard of care antihypertensive aid. The rationale supporting the selection of zilebesiran dose regimen in the Phase II program is further described here. The blood pressure efforts of -- effect of different dose regimen of zilebesiran administered at either quarterly or biannual dosing intervals have been modeled based on the correlation between serum AGT knockdown and blood pressure response obtained in the Phase I study. Dose-dependent reduction in the mean 24-hour systolic blood pressure can be expected over the range of biannual dosing of 150 to 600 milligrams zilebesiran, with 600-milligram dose expected to provide 90% or greater serum AGT knockdown and also 10-millimeter mercury greater reduction in mean 24-hour systolic blood pressure at month 12. With the same annual dose, the quarterly regimen of 300-milligram on the other hand, is also going to -- expected to achieve similar range of blood pressure reduction at month 12. As such, these 4 dose regimens of quarterly and biannually dosing of zilebesiran are being taken into a dose-finding Phase II monotherapy study. Data from this study will allow us to further refine our pharmacodynamic modeling to help determine Phase III doses, should the data support continued development of zilebesiran. The study design of KARDIA-1 is captured on this slide. It is a multicenter, randomized, double-blind and placebo-controlled dose finding study of quarterly and biannual dosing of zilebesiran in patients with mild to moderate hypertension. The study was initiated earlier this year and aims to randomize approximately 375 patients in the U.S. and Europe. The changes from baseline in the mean 24-hour systolic blood pressure at month 3 and month 6 are the primary and key secondary efficacy endpoints. This study also incorporates time-adjusted blood pressure changes through month 6 and over the long term, assessed by office and home blood pressure monitoring to delineate the relationship of different dose regimens of zilebesiran with the area and the curve, AUC, of blood pressure changes over time that could be indicative of the risk burden for hypertension. These planned time-adjusted analysis of blood pressure changes over either 24 hours or longitudinal follow-up over weeks and months are believed to more accurately categorize the chronic blood pressure control with zilebesiran that has been demonstrated earlier in the Phase I study. In addition, we also recently initiated the second Phase II study, KARDIA-2, to evaluate the efficacy and safety of zilebesiran 600-milligram dosing at Q6M in patients not adequately controlled on a single class of background antihypertensive medication. The trial design is illustrated on this slide, which aims to enroll approximately 800 hypertensive patients to enter the run-in period of the study. After a 4-week run-in period, approximately 630 patients with uncontrolled blood pressure, despite protocol-specified background antihypertensiive treatment of olmesartan, amlodipine and indapamide will be randomized to receive either zilebesiran or placebo. Changes from baseline in the mean 24-hour systolic blood pressure assessed by ABPM at month 3 and 6 are the primary and key secondary efficacy endpoints. Both KARDIA-1 and KARDIA-2 studies are being conducted in the U.S. and Europe. We anticipate that 6 months top line results of the KARDIA-1 trial will be available in late next year. This is my final slide to conclude today's program update on zilebesiran. We believe the significant unmet medical need for treating uncontrolled hypertension could be addressed by zilebesiran, which provide both chronic blood pressure control as well as infrequent dosing benefit, aiming to significantly improve patient adherence. Current data of the ongoing Phase I study, which I gave to you the overview here, in patients with mild to moderate hypertension, supports continued development of zilebesiran. We have demonstrated encouraging safety and tolerability profiles. Zilebesiran achieved 10-millimeter mercury or greater persistent reduction in 24-hour systolic blood pressure at week 8 at single dose 100-milligram or above, with clinical meaningful blood pressure reduction maintained through week 24. This delivery of action is supportive of once-quarterly and biannual dosing. Alnylam has initiated the cardio Phase II clinical program, which consists of 2 randomized trials: KARDIA-1 monotherapy study of zilebesiran is open and actively enrolling patients in U.S. and Europe. KARDIA-2 add-on study of zilebesiran as a concomitant therapy with standard-care antihypertensive agents has just been initiated. Thanks a lot for your time and attention. We can now go into our first Q&A session. Thank you.

Great. Well, thanks, Weinong, and thanks to all of our speakers this morning for all the great presentations and thanks to all the people in the audience. I'm Pushkal Garg, the Chief Medical Officer at Alnylam, and I'll be moderating the next 30 minutes of Q&A. So we have all the speakers from this morning's session. We also are joined by Rena Denoncourt, who's Vice President and Program Leader for our TTR franchise here at Alnylam. So welcome, Rena, for joining us. So we're getting a lot of questions. And please, if you do have questions, send them in. But I will start going down and then will sort of sprinkle some of these questions to all of our speakers. So the first question that comes, Akshay, I think, is probably directed towards you. There was a lot of -- a number of questions about this GEMINI-CVR program that you announced as sort of the next advance or a major advance in the platform. And I think people just want to understand. A number of different questions coming out. How are we thinking about clinical applications of this? Is there more that we can talk about with regard to this program? When do we see it going into the clinic?

Yes. Thanks, Pushkal. Clearly a very exciting program and a logical development of our platform and all the advances we've been making. So if you bring the idea by carrier, once-annual dosing, along with the ability to multiplex sRNAs and hit 2 targets simultaneously, then at last, new therapeutic area opens up the terms of cardiometabolic disease, and that's just to start with the liver. Of course, we'd apply that approach with other organs as well. And with respect to liver targets and specifically cardiometabolic, we've got animal data of 2 lipid-related targets not found simultaneously. We're, of course, very interested in targeting the 2 common factors that drive cardiovascular disease in terms of hypolipidemia and hypertension. And so the initial construct we're building is very much focused on atherogenic lipids with 1 sRNA, the target being anti-PDL3 genetically validated and high blood pressure with zilebesiran-like molecule linked to it. And we're making great progress. All the platform advance being applied. Development candidate, hopefully, in the '23 time frame or so. And then we can file [ CPR MND ]. And of course, the Phase I program will provide proof-of-concept there. And broadly speaking, this is a drug that certainly should, once developed, if it's safe and effective, be given to patients at risk of cardiovascular disease. They already have had some form of major adverse cardiac outcome. But ultimately, let's face it, it would be exciting to think of this as a vaccine-like approach to prevent cardiovascular disease in anybody that approach middle age and have abnormal parameters like lipid blood pressure. So...

Can I just jump in here? I mean, I think it's really important to emphasize that this is an opportunity to really rethink medicine with a drug like this. I mean a single vaccine-like approach to reduce cardiovascular risk can have enormous public health impact. Enormous public health impact. And I'm just extremely excited about how we can chronically control both of these risk factors and really, in at-risk populations, provide patients with a potential way of managing their risk for cardiovascular morbidity and mortality. We just have a dramatic impact in terms of public health. And very, very exciting.

I think, John, you would even say at a global scale, right? I mean something like this.

Yes. Absolutely.

Yes. No. Thank you both. I think it's very exciting. Maybe I'll switch a little bit. We've gotten a number of questions around Stargardt disease and the announcement about expanding the TTR franchise into Stargardt disease. And maybe the first question to you, Dr. Sadda, the people really appreciate a great overview of the disease, but it'd be helpful to understand what you think about the therapeutic hypothesis of TTR silencing and reducing vitamin A in that approach and the potential for that to have an impact on this disease.

Yes. Thanks for that question. I think that the -- that, that therapeutic hypothesis is very sound in terms of what we understand about the disease pathophysiology. We know that the primary problem when you have the mutations that these patients have is the accumulation of vitamin A, which leads to the development of toxic metabolites of vitamin A, and that ultimately leads to cell death. So if you have a strategy that can substantially reduce this, that has great potential. And that's sort of been seen in preclinical models. We don't have a perfect animal model of Stargardt disease because, as I mentioned in my presentation, humans have actually done human primates really we're the only animals if you will, that have macula for these very specialized central parts of the retina. So there's some aspects you can't evaluate. But you can see that interference with this type of silencing or this type of approach can reduce the accumulation of those metabolites over time. So you would anticipate that, that would have a therapeutic benefit. So I think the approach seems very reasonable to me.

That's great. And maybe following on from that, maybe it's a question for you to start and then John Vest to follow. Do we have any understanding about what degree of TTR or vitamin A reduction we might want to see to test the therapeutic hypothesis. And then John, maybe you can comment some -- I'll come back to you about what we've been seeing in our clinical program so far.

Yes. I think that it's clear that you'd want to have a substantial reduction in this process. Same time, obviously, you don't want to have 100% reduction because we do still need vitamin A for vision. So you want to reduce the accumulation of the toxic metabolites. And I think -- and actually, in terms of treating these patients, you'd like to see some reversals. So you really want to have a significant slowing to give the cells that have accumulated these toxic or these retinoids time to clear. And so I think that, that seems like something you can achieve with the types of reduction this kind of RNAi silencing approach could yield. But you're probably looking at trying to get down to a range more than 70%, I suspect. Again, that's the kind of thing that you're going to evaluate in the appropriate preclinical as well as early phase trials.

Yes. And then John -- thank you, Dr. Sadda. And then John, a question that came in, I think, on a related point that I think you're probably best poised to answer is, what degree of vitamin A lowering might we expect? And some questions of didn't we give vitamin A supplementation to some of our amyloidosis trials and how will that be managed? What do we expect to see in the Stargardt disease?

Yes. Thanks, Pushkal. Both terrific questions. And certainly, as we showed in the presentation, we have observed robust and sustained vitamin A reduction on our current studies. What we know, and those were, as you point out, on top of vitamin A supplementation, we know from earlier work in our TTR programs that we would anticipate, in the absence of vitamin A supplementation, essentially a one-to-one reduction in vitamin A relative to the reduction we're seeing in transthyretin. So you can imagine then that we would project, in the absence of vitamin A supplementation, based on the data we've seen, we would have 80% plus reduction we would anticipate. And the question around by vitamin A supplementation, what would we do on the Stargardt trial? That's a good one. Obviously, we need to put the details around those trial designs, but we would anticipate likely not using vitamin A supplementation. But we think that really what we want to do is hit the sweet spot, as Vas has pointed out, we would not imagine that we'd be completely eliminating vitamin A. We would just be substantially reducing it. So we believe that we'll be able to get that spot where we're able to impact the pathophysiology of the disease without running into the major issues of -- around vitamin A deficiency.

Thanks, John. That's really helpful. John M, this is probably a question for you that's come in. So more on -- a little bit more on the business front, but people noted that the Novo acquisition of the intended acquisition of Dicerna that was announced yesterday. What are the implications of that to Alnylam? And then maybe, the follow-on, is there's been rumors out there about Alnylam being a potential target given the interest in RNAi. Maybe you could comment on your take on all of that.

Yes. Back at JPMorgan in 2010, I predicted that we were entering the RNA decade. And I think I was right, between the advances of RNA interference and mRNA. And obviously, we've really entered an amazing period of time where RNA therapeutics and RNA interference, in our case, really has come of age and there's a lot of enthusiasm and excitement about that. So in terms of the Novo acquisition, I think it really reflects the very strong interest from the broader biopharmaceutical industry in RNAi-based medicines and RNAi-based approaches. Obviously, regarding the question about Alnylam, we can't comment on and don't comment on rumors whatsoever. Again, our focus is really on building a remarkable company. We have a terrific 5-year plan with our Alnylam P5x25 strategy, which we believe allows us to have line of sight to building a top 5 biopharma company within the industry, obviously, delivering significant value for our shareholders. But obviously, on any type of discussion like this, we always have a fiduciary duty as a Board that we would also have to consider. And I think I'll just leave it at that, Pushkal.

Sounds good, John. Thank you. Actually, a question that's for you, I'll read it verbatim. GenX looks incredible. Visceral adiposity is a huge unmet need. Can you talk a little bit more? I think the question that followed on was really about when will we disclose more about what that target exactly is? And what are our plans to advance that into the clinic? What more can we tell -- speak to about GenX.

Yes. I mean just as a preferencing comment, I think these genetic databases that fortunately we have access to and we're increasing that all the time, were just proving so rich. And to find a target like this, a hepatokine that would be amenable to RNAi therapeutics that alters all the major aspects potentially of metabolic syndrome is just, just very exciting. We have been really combining the paper now. We'll submit it quite shortly actually, I think in the coming weeks. It will become clear upon the publication what the target is. And in parallel to that, of course, we've begun to work on building a development candidate, again, a carrier-like platform being applied. So it could be a once every 6, once every 12 month therapeutic. We could have the DC in hand by '23 or so. And gaining taking the clinic in Phase I, there will be lots of data point to demonstrate the proof-of-concept there which would inspire to take it rapidly into late development. So I think this is a really, really incredibly exciting target and our reach is fine so far in the U.K. Biobank. And there'll be others that come, I'm sure.

Thanks, Akshay Weinong some questions around zilebesiran that I'll maybe direct to you. So there's a question about appreciating this low-salt challenge that was done with zilebesiran. And what I want to understand a little bit more is sort of is this a test of pharmacology? And particularly, were there any hypotensive episodes there? And how do we -- in that particular challenge for patients? And how low did the blood pressures go?

Thanks, Pushkal, and this is a great question. As we know, salt intake is -- can regulate the blood pressure. And the reason we take this study to investigate zilebesiran and the low salt is very conscious about this is supposed to be a long-acting antihypertensive therapy, and we want to make sure, before we go to relatively large size of population in Phase II, we ensure the efficacy and safety under the low salt, which is usually a typical battery of the experiment to mimic the volume depletion. So the results, as I presented, show that quite tolerated the zilebesiran at the peak of the pharmacodynamic effect. And the blood pressure, we did not experience any -- no blood pressure that require the intervention, no AEs of the hypotension. In terms of the actual blood pressure measured by the 24-hour ambulatory monitoring, blood pressure monitoring, no patients on zilebesiran during the low-salt period goes below mean 24-hour systolic or diastolic of 110 over 70-millimeter mercury. So I think data was quite reassuring for us to go forward to the Phase II.

That's fantastic. And then the other question that's come up around zilebesiran is, you talked about the Phase II studies that are kicking off. But can you talk a little bit about when we might start a registrational program? And particularly will we need outcomes to register this product.

Yes. Thank you, Pushkal. As you all know, blood pressure lowering is a validated efficacy endpoint accepted by the health authority around the world, and it is predictive of the clinical benefits in CV outcomes. So our plan is to confirm the efficacy and safety in the Phase II. And as you know, the KARDIA-1 results is likely to report out end of this year. And after that, we will certainly proceed to the Phase III blood-pressure programs. And that will be likely in the '23, '24 horizon.

Great. That's fantastic. Thanks, Weinong. Some more questions coming in on Stargardt disease. Maybe Dr. Sadda, I'll ask you, start with you, which is just can you speak a little bit about the prevalence of Stargardt disease and what proportion of patients with that disease might be amenable to a TTR silencing approach?

Yes. So great question. And it is a very common problem in the sense of an inherited retinal disease, that with the estimated prevalence is 1 in 8,000. And actually, unlike many conditions, it's not particularly prevalent in one country versus another. We see Stargardt all over the world, and it may speak to when this mutation occurs sort of human evolution based on its worldwide sort of prevalence. So it's relatively common for an inherited -- in a generation. We say it's the most common, in fact, form of inherited macular dystrophy. And so in terms of the patients who will be amenable, obviously, ultimately, these things, in part, are determined based on the safety profile of these types of things. But you can imagine that once a patient is symptomatic or maybe even just before they're symptomatic, that might be a good time to intervene. And then even after they've developed the symptoms and even a recent atrophy, one can imagine that interference could help slow progression of the atrophy. So you would anticipate -- and I would estimate, essentially half of the patients out there with Stargardt would be -- will be good candidates for this type of an approach.

That's great. That's wonderful to hear. Maybe another question was -- and maybe Dr. Sadda or John, you want to speak, John Ves, you want to speak to this. The question was, would it stabilize? So or there are TTR stabilizers out there. And would that be in a potential therapeutic approach? Or can you expand on why it might not be an appropriate therapeutic approach? John Vest, do you want to -- Akshay, do you want to speak to that?

Yes. Maybe I'll start. And John, you can jump in to the side, obviously.

Sure.

I think the idea of the stabilizers, it's not particularly well supported by the science, I think. Because remember, the stabilized -- well, let's go back to what TTR actually does. TTR is a tetrameric protein that then carries retinal binding protein, which then has a hydrophobic groove to carry the vitamin A. And what the stabilizers do is actually stabilize that complex and prevent it falling apart, which is what happens both in mutant settings as well as in wild-type settings. And that's the reason for its use in ATTR-related disorders like cardiomyopathy. Now in this disease, Stargardt, we're trying to prevent the supply of vitamin A to the eye via the TTR/RBP access. And so stabilizing it with its metromer is not going to particularly support that Herculean hypothesis. So John Ves, I don't know if you have anything to add. I don't think you can create a strong hypothesis with a drug like tafamidis, for example, in this ocular setting. Whereas our approach, and we've already demonstrated this, that systemic administration of vutrisiran lowest RBP, lowest vitamin A, does seem to have a strong therapeutic [indiscernible].

Yes. Yes. I think what you're saying, net-net -- oh John, were you going to add something? John Ves?

No, no. I was just going to say I really think that covers it. It just doesn't fit with the therapeutic hypothesis. We believe that we need to reduce the transthyretin in order to prevent this complex with RBP 4 that's critical for the delivery of vitamin A. It's really going to take reducing the TTR and stabilizing it. It just doesn't fit with the therapeutic hypothesis as we've labeled out.

Yes, I think even more simplistically, you guys are both saying is really you have to lower vitamin A, and a stabilizer doesn't lower vitamin A. So I think -- so that's very helpful. Maybe Rena, a question to you, commenting on really what is a pretty growing and expanding TTR franchise. First, hereditary to wild type, going from PN to CM, and now to this ocular disease, this retinal disease. Can you comment a little bit about how we're building out our TTR franchise? And particularly, what are the pricing implications of going across this range of diseases? How will we manage that?

Sure. We're really excited to get vutrisiran and to evaluate vutrisiran as a potential therapeutic for Stargardt disease and expanding the footprint of vutrisiran to more patients with significant unmet medical need, right? We do not anticipate -- on the pricing side, we do not anticipate any challenges of expanding vutrisiran in that regard vis-a-vis the rest of our TTR franchise as a whole. So we'll continue to pursue it in accordance with our patient access philosophy and all of our Alnylam products priced in accordance with that approach, and we will move forward in that direction.

Awesome. Thanks. Let's see here. So there's a -- so there's a question that came in. Maybe, Akshay, I'll direct this to you, that Merck showed some data this weekend at AHA on an oral PCSK9 inhibitor and previously target those thought to be undruggable. What do you think -- what's your take on that? And what are the potential implications for something like inclisiran, which is just starting to get launched or waiting for the FDA approval soon? So what's the implications around that?

Sure. No, interesting new data. It's a peptide-based drug that seems to be orally administered that reduces PCSK9 and LDL cholesterol levels. So I think for patients, it's always important to keep innovating and keep developing new therapeutics. It will be interesting to see how it progresses. A couple of comments on the data that whilst, clearly, sort of interim data in Phase I, the drug requires coadministration sodium caprylate to permeabilize the gut wall and allow the uptake of this peptide-based drug. Now I think it's widely appreciated that those kinds of permeation enhances often lead to GI side effects. So it will be interesting to see, as the drug is developed further, how well tolerated it is. And then more broadly, I would say that, yes, even if it gets through development, ultimately makes it, what is the problem in the cardiovascular space when it comes to lipids? More than half the patients just don't take the oral medicines, and people drop their statins within a year, a majority of patients do, once prescribed. So having another oral agent is good, but if patients don't take their drugs, they can't get the benefits. And this is why inclisiran, I think, is so exciting because once every 6 months administered by the physician or a pharmacist, the collaboration between Novartis and the National Health Service in the U.K., where the whole health care system is now motivated and driven to prescribe it once patients go into their health care setting [indiscernible]. That's kind of the future of medicine, given these kinds of compliance issues we have. So those are my perspectives.

Yes. I think that latter point is when I think -- I'd love to expand on. I think we're really sitting on an exciting opportunity with this long-lasting pharmacology and these richness of CV metabolic targets, right, to really think about fundamentally changing the way these diseases are managed by physicians, by patients and through health care systems. When we talk about the GEMINI program, when we talk about angiotensinogen, we talk about NASH targets, we talk about GenX, I think there's a real opportunity for us to really reimagine the way these very prevalent diseases are changed or can be managed, and particularly address this not only long lasting and durable pharmacology and getting to the proximal cause of disease, but also adherence, which continues to just be a real problem with these diseases. So it's a really exciting opportunity that we have here. Go ahead, please.

Maybe [indiscernible]. I know you and I, and John and I and others, we've discussed this, is we comment on this vaccine-like approach. And for me, there's an interesting analogy, right? But if you look at the last century and the nature of infectious disease, many factors impacted the reduction in infectious diseases over time, nutrition, antibiotics, gene, et cetera. But ultimately, vaccines have had a major impact on infectious diseases and the whole world has benefited. And with respect to cardiovascular and cutting anabolic disorders, we have really globally not seen that kind of downturn in those diseases. In fact, we've seen things go the other way in the U.S. Instance of stroke is going up because of hypertension. And at a population level, in Western countries globally, everywhere, we need basically something that is a vaccine-like approach so patients get the benefits of the science. And clearly, relying on oral meds alone is not cutting it. And so that's why this concept of a once-every-6-months, every-12-month approach with whether it's in inclisiran or the GEMINI-CVR construct, with [indiscernible] these are really innovative and futuristic ways to think about more closer delivery of health care to patients in this century. John, I don't know -- you're passionate about it.

Yes, John...

I look and...

You got it. You got it totally.

For once, I've silenced you, John.

Yes, it's settled.

We have time for 2 more questions. So one about the -- maybe John Vest and Rena, this is for you. Maybe we'll start with John, and then Rena, you can add. We're expecting some data for Acoramidis from Rich Bio as a stabilizer. So maybe, John, if you could just describe a little bit what the data that we're expecting. And then Rena, if you can talk about any implications for us as well, that would be really helpful.

Yes. Thanks, Pushkal. We're certainly, along with I'm sure everyone on this call, anxiously awaiting that data readout and to see what impact they've had on a 6-minute walk test. And look, this is another potential therapeutic option for patients. And we always think that options for patients are great. And certainly, in a disease like ATTR amyloidosis, the disease awareness alone really is something that benefits us all. If it's good for patients, it's good for us. What would the results be? We don't know. We certainly don't particularly, when we think about the data from 20 milligrams versus 80 milligrams of tafamidis, it's unclear to us whether the concept of a super stabilizer will show a greater benefit than what we've seen with tafamidis. It could, even if just due to differences in patient populations between the trials, et cetera. But we'll have to wait and see what the data looks like. We certainly, as you know, believe strongly in our therapeutic hypothesis and our approach. And we are highly confident in how we'll perform, but we'll await the results of the data. Rena, I don't know, do you want to add?

Yes, I think you covered it largely on the Acoramidis side. I think just to add that basically our APOLLO-B study will be reading out in the middle of next year. And certainly, we are very excited to see that data and the continuation of the story of patisiran in the expansion of ATTR amyloidosis with cardiomyopathy as well.

Yes. Thank you, both. It's going to be an action-packed '22. I know Yvonne is going to cover some of those catalysts and data readouts next -- for next year. So we'll be coming to that in a few moments or later in the afternoon. I think that's going to close our Q&A session. Maybe before I totally close it down, I just want to take professional prerogative and just acknowledge and thank John. You sort of did a real tour de force of your leadership over Alnylam for the last 2 decades. And I just want to say, both on a personal basis and a professional basis, just thank you for your remarkable vision and leadership of Alnylam over the last 2 decades. Your legacy of advancing a whole new class of medicines is, I think, really unparalleled in the industry. And the impact on patients, I think, is going to be seen for decades to come. So thank you on behalf of everyone at Alnylam, and we're going to look to continue your mission. With that, I'm going to close down the Q&A session, and we're going to take a break and resume at 11:10. Thanks, everybody. [Break]

Hi, everyone. I'm Kevin Fitzgerald, Chief Scientific Officer at Alnylam Pharmaceuticals. I have the pleasure of introducing our next guest speaker, Dr. Sharon Cohen. Dr. Cohen is a behavioral neurologist and the Medical Director of the Toronto Memory Program, a community-based facility, which she established in 1996, for the purpose of enhancing diagnosis and treatment of Alzheimer's disease and related neurological disorders. Dr. Cohen has over 28 years of experience in clinical research and has been a site PI for over 150 trials. Her clinical and research site are among the most active in Canada. Additionally, Dr. Cohen represents Canada on a number of international advisory boards and steering committees and has served as a consultant to a range of government and patient advocacy organizations. With that, let me welcome Dr. Cohen to the podium. Dr. Cohen?

Thank you, Kevin, for that kind introduction. I'm Sharon Cohen, neurologist, and I'm very happy to be here to talk to you about Alzheimer's disease and cerebral amyloid angiopathy. As far as my disclosures, I am a consultant and Steering Committee member to many companies involved in Alzheimer's care and development of products. And I am involved in pharmacologic research in Alzheimer's disease with many companies, but receive no personal fees for this work. As far as my objectives today, I'd like to provide some insights regarding Alzheimer's disease, and I will often refer to it as AD as well as cerebral amyloid angiopathy, CAA. And I'd like specifically to give some insights about the clinical presentation of these diseases, the etiology, and I'll touch on pathophysiology and genetics, current treatment options, unmet need and future directions. This is a huge topic this conglomeration of bullets. And so this will be a rather overview style presentation. So the world held -- sorry, World Health Organization, in 2012, already declared Alzheimer's disease and urgent health care priority, not just because of its frequency and the rising numbers, but because of the severity of the disease and the cost. So this is an irreversible, fatal neurodegenerative disease. It is the commonest cause of dementia in seniors, but does not only affect seniors. There are 50 million cases worldwide, and this will triple to 150 million by 2050. The cost of care are enormous, both personal cost to patients and families and societal cost to our health care system and government and really exceed the cost of cancer care and heart disease combined. Many people don't realize that. And there is no prevention or cure. There are modest symptom treatments and very limited disease-modifying treatments at the moment. So this is an ongoing major unmet need of our time. Alzheimer's disease has a long clinical continuum. It also has a biological continuum. But starting with the clinical features, this is a disease that typically starts with mild memory symptoms or other cognitive complaints. But over time, this mild forgetfulness becomes very severe, such that people don't know who's in their family, whether they're married, where they were born. And functional decline goes along with and follows cognitive decline, all aspects of reasoning thinking and being able to interact with the environment are affected high-level activities such as driving and banking, later lower level activities of personal self-care, toileting, feeding or lost. And this occurs gradually over many years. It is relentless. Neuropsychiatric symptoms such as agitation, delusions, wandering, sleep wake reversal, these are common features. They are more variable than the relentless cognitive decline that contribute substantially to the disability of the disease for both patients and families and the cost of the disease. Three stages of Alzheimer's disease are generally recognized as far as the clinical continuum; the preclinical stage, at which brain pathology is building up, however, an individual is still seemingly normal and cognitively well. Over time, as enough of the brain is injured, there's a tipping point where memory or other cognitive deficits are evident and can be demonstrated on testing. This is the mild cognitive impairment stage of disease, but the impairment is mild enough that people are able to compensate. They are able still to be independent, living in the community and going about their day-to-day activities. As more disease progresses as the brain changes, are more significant in Alzheimer's disease over time, one enters the dementia phase of the disease, meaning that one is no longer able to be independent in day-to-day functioning, so loss of driver's license, loss of ability to look after one's home, to bank, to care for children, to shop and eventually, basic activities, again, are lost the ability to feed oneself, to toilet, to address oneself. There are typical presentations of Alzheimer's disease, the amnestic type of disease is the most common and later life 65 years and older, most common. But non-amnestic variants are well recognized. So there may be a predominance of language loss or a loss of visual perceptual ability rather than the classic memory changes that start the disease. And individuals can be under the age of 65. So a young onset version of Alzheimer's disease is very well recognized. There can be pure Alzheimer's pathology, but often, especially in seniors, there are comorbidities, atherosclerotic, cerebrovascular disease being very common in the elderly. So in a younger population, you may see more of the pure Alzheimer's pathology. Here's a picture of the Alzheimer's disease continuum, which shows you the time frame. This is a very long disease, with about a 20-year preclinical stage where changes are going on in the brain, and we'll talk about those in a moment, but people are still cognitively well. Then the MCI stage of the disease, where cognition is impaired, but people are still functioning and that lasts on average 5 years. That seamlessly moves into the dementia stage, often broken down into mild, moderate, severe and end-stage dementia, which goes on for another 10 years. So you have about a 30-year plus disease. Throughout this disease, abnormalities are accumulating. Amyloid plaque is developing in the parenchyma of the brain outside of cells. And tau tangles are developing within the cells, these little dash black areas and then the plaques smudgy brown areas. This is not the only pathology, and this is not the first pathology, but this -- these are the hallmark pathologies that Dr. Alois Alzheimer first described in 1906 when he reported the first patient ever with Alzheimer's disease. The brain is shrinking as a result of neurons being lost progressively due to injury from amyloid injury from tau. And so you see millions of neurons dropping out, and that's why you get a brain that is about 1/3 the size of the normal brain. And in this cartoon, you can see an empty cavity, which is in a healthy brand where the hippocampus lives. So that vital tissue that's so important for encoding and retrieving memory is basically lost at late-stage Alzheimer's disease. Now for anybody who thinks this is just a disease in which caregivers suffer, all you have to do is watch some of these movies like "The Father" in 2020 and others where you see the tremendous burden in the suffering of individuals with the disease themselves and not just their families. This is a disease of personal frustration and despair. A disease where there's stigma, loneliness, loss of self, loss of dignity and autonomy over a very long period of time. One's owned biography is no longer known to oneself, one is unable to make even the most basic decisions about what one might want to do in their day and psychiatric symptoms add to the disability. Families suffer along with the affected individual. The distress of seeing someone relentlessly decline without the power to do anything for them is devastating. Relationships are disrupted, where children are looking after parents, grandparents, sisters are looking after siblings and the stress of juggling with work and caregiving can be overwhelming for a large proportion of the workforce since this disease and caregiving, therefore, is very common. The financial burden is excessive for many. And emotional, physical health and sleep deprivation problems arise in caregivers and there are greater hospitalizations, more falls, and more musculoskeletal injuries, back injuries, due to caregiving for Alzheimer's disease. So what is the etiology of this disease? Well, the majority of cases are sporadic and only about 1% of all cases of Alzheimer's disease. Now that's 1% of 50 million cases. So a lot of people have an inherited cost for the disease. The pathobiology is complex, but we understand a chronologic cascade more or less. With the amyloid precursor protein, a long transmembrane protein on neurons being cleaved by enzymes and forming daughter proteins, one of them being Aß42, and it is this Aß42 that accumulates early on in Alzheimer's disease and forms plaques as in the electron microscope image that I showed you earlier. So APP-derived A beta protein. Now A beta protein doesn't just exist as plaque. There are many species, soluble species that start aggregating into dimers and trimers and oligomers, fibrils and then plaque. And there are various theories about which is the most toxic, which should be targeted in clinical trials for a therapeutic effect. And there are cases that many of these different species have different negative impact on neuronal health and on the brain. And they're also intracellular fragments. So we're talking about these -- the species that are cleaved from APP and go into the brain parenchyma. But within the cell, there are also fragments derived from APP that may drive pathology within the cell. What we do know is that once amyloid accumulates to a certain threshold, we start seeing tau become abnormal. And tau is essential in maintaining the structure and function of brain cells. And when tau becomes hyperphosphorylated, it can no longer maintain the integrity of neurons and neurons die. And still further, tau seeds spread from 1 cell to another, and infect, if you will, healthy cells, and therefore, we get a seeding of tau pathology across regional networks of neurons. There are additional pathologies in Alzheimer's disease. Immune dysfunction and neuroinflammation are those talked about frequently, and there are others. And the timing of these pathologies, something they are late phenomenon, something they are actually very early or act throughout that is still to be worked out. So what is the role of genetics in Alzheimer's disease? Well, we know that deterministic gene mutations, and there are many on the amyloid precursor protein gene, also on the presenilin-1 and presenilin-2 genes that directly cause autosomal dominant Alzheimer's disease with near full penetrants. All of these mutations have a common pathway they either increase the production of A beta or the ratio of Aß42 to Aß40. So they drive greater amounts of Aß42 in the brain. In those who have autosomal dominant Alzheimer's disease, the age of onset of symptoms, it's typically under age 65. It can be as young as ones 30s or 40s. In another inherited disease, Trisomy 21 or Down's syndrome, we also have evidence of the APP gene having a role in Alzheimer's disease. And here in Trisomy 21, you have an extra copy of chromosome 21, causing down syndrome. And the APP gene lives on chromosome 21, and this extra copy causes throughout the lifespan of the individual with Down's syndrome over production of A beta and Alzheimer's disease. So virtually all individuals with Down's syndrome, if they live into midlife, will develop Alzheimer's disease. Now in the sporadic form of Alzheimer's disease, which is the commonest form, genetics still plays an important role. It's just much more complicated to figure out, but there are multiple risk genes that have been identified, at least 30, and there are some protective genes as well. These risk genes can be divided into high risk, medium and low risk, but one could have a large number of low-risk genes that could tip on into developing Alzheimer's disease. The apoE gene and specifically the apoE4 allele confers the highest risk of developing Alzheimer's disease of these risk genes. And interestingly, a few years ago, a protective mutation on the APP gene, it's called the Icelandic mutation, actually reduces the production of A beta throughout the lifespan by about 30% and, in turn, reduces the risk of developing Alzheimer's disease. Turning for a minute to young onset Alzheimer's, which I said is much more common in the autosomal dominant form, but can occur without an inherited gene mutation being found. This comprises about 8% of those with Alzheimer's disease. So symptoms begin in one's 40s, 50s or under the age of 65, while people are still, perhaps, building their careers, looking after children at home, paying off a mortgage, so time of great responsibility and growth in one's life professionally and personally. And what you see is, in these folks, even greater burden. They have a harder time getting diagnosed. Nobody believes that a young person actually has Alzheimer's disease. They all get called anxious and stressed out and mid-life crisis, whatever, very few services available for the nonseasoned years with Alzheimer's disease, greater financial impact on the patient and their families and additional hours of caregiving to look after these folks greater rates of depression and severe psychiatric distress in patients and families. So what about medications? We've been working on this for a long time, and we're hoping for breakthroughs. The existing Alzheimer's medications for the last 20 years have been symptomatic treatments. 2 classes of medications, which modulate neurotransmitters have been developed and have been available around the world Cholinesterase inhibitors and a glutamate modulator and therefore all told. And as I say, these have been around for 20 years with no new medicines until 1 that I will talk about on the next slide. What these symptomatic treatments do is they act very downstream of APP, of amyloid and tau. They're acting on the loss of neurotransmitter because brain cells have dropped out. There isn't enough acetylcholine being made and transmitted. So with the cholinesterase inhibitors, if you can prevent the breakdown of acetylcholine, you'll have more available to cells. The idea is good. There is a cholinergic hypothesis for Alzheimer's disease that arose in the 70s and these drugs came about 20 years later to the market in the '90s. And yes, they do modestly increase the -- or modulate the levels of neurotransmitters at the synapse, side effects limit their usefulness in terms of the dose that we can achieve and the benefit to symptoms is very modest. As I said, we're not addressing the key underlying more proximal pathologies or not slowing disease. Individuals on these drugs will continue to progress, and none of these drugs have been approved for mild cognitive impairment stage, where has to progress to the dementia stage before ones accesses these medications. In June of this year, the FDA approved the first-ever disease-modifying drug for Alzheimer's disease, aducanumab, and it was given accelerated approval based on robust amyloid lowering felt reasonably likely to yield clinical benefit. A confirmatory trial is required and is in the planning stages. And since this FDA approval of aducanumab, 3 other anti-amyloid antibodies have received breakthrough therapy designation by the FDA and may well be approved within the next few years, giving patients and families more options for treatment. And while many of us are very excited to see the field moving forward and to have treatment options and a drug now based on underlying key pathology of the disease, at best, what we're seeing is that we may get a slowing of 20%, perhaps 30% of clinical disease in individuals on these anti-A beta monoclonal antibodies. So disease will continue to progress, but hopefully more slowly. Is that valuable? Yes, I think so. Is that the end game? Absolutely not. We need to halt this disease or reverse it more definitively. So fortunately, the Alzheimer's pipeline is replete with over 100 drugs and so -- at different phases of development. You can see the concentric circle is going from the outer circle Phase I drugs in the middle Phase II and then Phase III drugs. So each of the little shapes represents a unique compound under development. And although this slide is from earlier this year coming 2021, it is already out of date because some drugs have already dropped out and new drugs have come into Phase I. And we need this pipeline to be diverse and as large as possible. And this is a complicated disease, and it's been very challenging to treat. When you look at all the little shapes in red, these are drugs tackling amyloid in one way shape or form. Many of them are monoclonal antibodies, not all of them. Those in blue are tackling tau, many, but not all from the standpoint of removing extracellular tau through monoclonal antibodies. And those little shapes in yellow are drugs tackling either the immune system or inflammation. There're other colors and other mechanisms there. I won't go into those. But very few of these drugs, if any, are targeting the genetic aspect of Alzheimer's disease or the intracellular APP portion of the Alzheimer's pathophysiology story. I'm going to turn in the last segment to cerebral amyloid angiopathy. This is a cerebrovascular disease. It's caused by deposition of amyloid beta, Aß40. And this is also derived from the parent molecule amyloid precursor protein and Aß40 in CAA is accumulating in cerebral blood vessels. Unlike with other forms of systemic amyloidosis, this is not a systemic disease. This is particular to the cerebral vasculature, doesn't affect the heart or other visceral organs. In the brain, in this disease, all layers of blood vessels are injured and the blood vessels lose elasticity. They develop micro aneurysms, their walls are weak, they leak and they rupture. And what happens when that goes on? Well, you get hemorrhage, you can get small hemorrhage or you can get massive hemorrhage. And so here, we're talking about stroke. The stroke tends to occur in the lobes of the brain. -- often in the center of a lobe of the brain, tending to be more in the posterior back part of the brain than the front but can happen in any part. And so an individual may be in the middle of doing something very normal. Suddenly, they have a devastating headache they may become paralyzed on 1 side, lose their speech, lose their vision. Any host of neurologic deficits arising suddenly, they may lose consciousness because of the enormous pressure of blood spurting into the brain, into the intracranial cavity. They may have a seizure, they may die immediately. This is a devastating sudden acute event. And of course, hemorrhage or stroke is also a disease of survivors where people may not die but be left with very serious permanent deficits like paralysis. And in addition to low bar hemorrhage, we may have what's called convex subarachnoid hemorrhage, so subarachnoid hemorrhage, on the surface of the brain, and this may present as a mini stroke, a warning stroke and is often the harbinger of a more major lobar hemorrhage. And we see microbleeds, and we often pick these up as asymptomatic bleeds on a scan. But the more little microbleeds you accumulate the greater risk for a macro bleed, for a stroke, for dementia and shorter survival. Here, you see 2 different lobar hemorrhages on your left in the posterior part of the brain, this white area on a CAT scan. And in the frontal part on the right, the image on the right, you see it's actually reverse to how you're looking at it. So you see on the right, a large left frontal hemorrhage. What I want you to notice is also that the hemorrhage takes up so much space in the brain and the brain is deformed and pushed to one side or the other. So the black fluid filled space, the ventricles are deformed, and likely the brain is actually herniating downwards into the spinal cord. And this -- these patients are likely losing consciousness, they've tremendous headache at the onset, if they had time to feel that, losing consciousness and the brain here herniating down into the spinal canal because it's got no other place to go. Here's an autopsy rendition of a lobar hemorrhage. Again, a major bleed here and this person obviously did not survive. And here, you see microbleeds on an MRI scan. And on your left, these little black punctate areas, there are a whole bunch of them. You can maybe count 30 of them. But if you look at a different type of sequencing on the MRI scan, you can see there's actually hundreds of these little microbleeds. It looks like Swiss cheese with lots of little holes in the brain. So cerebral amyloid angiopathy has sporadic and inherited types. It sounds familiar, sounds like the Alzheimer's story. The sporadic type is common. It probably exists in about 20% of the elderly, maybe more. And it presents in seniors as hemorrhagic stroke and is probably the second cause, most common cause of hemorrhagic stroke after hypertensive stroke. There are hereditary forms, the Dutch type is the most common, but there are many. And the majority of these inherited forms are due to mutations, again, in the amyloid precursor protein gene. These are autosomal-dominantly inherited mutations. They increase the production and deposition of Aß40 in blood vessels, and they cause stroke and dementia that begin in midlife in one's 50s in these hereditary forms and death usually ensues within 10 years or earlier. This is a devastating type of disease, both the sporadic and inherited, but the inherited version, shorter lifespan, more devastating strokes, and often a dementia associated with the disease. The current treatment consists of supportive care for stroke. There is no specific treatment at the moment for CAA. So in summary, Alzheimer's disease and CAA are both devastating brain diseases with distinct abnormalities that arise downstream of amyloid precursor protein cleavage. APP is a genetically validated target as evidenced by multiple gene mutations that directly cause AD and CAA. AD is a slowly progressing dementing illness in which Aß42 accumulates in brain parenchyma, whereas CAA is a cerebrovascular disease with Aß40 accumulation in vessel loss leading to brain hemorrhage with or without dementia. Both have a common sporadic form with late life onset as well as inherited forms with younger age of onset. Current Alzheimer's disease treatments are largely symptomatic and only modestly effective and way downstream of key pathology. Newer disease-modifying treatments for Alzheimer's disease with anti-amyloid monoclonal antibodies will alone be insufficient to prevent cure or stabilize the disease, and therefore, a major unmet need will remain. No specific therapies are currently available for CAA and upstream approaches with the potential to block proximal mechanisms such as APP metabolism are of high interest as they may address a broad cascade of intracellular and extracellular pathological processes. Thank you so much for your interest and your attention, and I'll hand it back to Kevin.

Thank you, Dr. Cohen, for providing your perspective on the Alzheimer's and the CAA space. Let me now take a few minutes to walk you through our efforts around advancing RNAi therapeutics beyond the liver. As many of you are aware, Alnylam's platform has proven to be modular, robust and durable within the liver as evidenced on the left by the Leqvio ORION data shown here. Our platform profile, specifically the PK/PD characteristics, has generally been consistent across all the tissues we've studied to date. This is largely, I think, thanks to the well conserved siRNA AGO 2 pathway, and mechanism underlying the naturally occurring RNAi within the body. This dynamic creates an opportunity for our platform to advance beyond the liver, broadening the scope of RNAi therapeutics to include such tissues as a central nervous system, the eyes, the lung, and as you'll see later in this presentation, other tissues. Now as we've described in the past, we're applying a conjugate-based approach with our platform. And it's pretty clear with the RNAi mechanism being conserved in all tissues that the challenge will be finding the right delivery solutions for each different tissue or combination of tissues. Now ligands come in different shapes and sizes ranging from small molecules like GalNAc, which we helped innovate, or C16, which I'll talk about a little bit later, or slightly larger ligands such as stabilized peptides to relatively large ligands such as antibodies. Now each of these have different properties, possible advantages and disadvantages. While we have traditionally focused on small molecules such as GalNAc due to the ease of synthesis, the scaling, relatively short circulation half-lives, we do think that, in some cases, other ligands such as peptides or antibodies will be of high value. We plan to utilize each of these technologies depending on the disease and their tissue we're attempting to get into. We have and will also continue to lever partnerships to help advance our extrahepatic discovery and development efforts. With Regeneron, we enacted a landmark alliance focused on central nervous system and ocular RNAi therapeutics. This partnership leverages our expertise and excellence in RNAi therapeutics in combination with Regeneron's tremendous capabilities in human genetics and, of course, their world-class antibody expertise. Additionally, this past July, we announced a partnership with PeptiDream focused on the discovery and development of peptide siRNA conjugates aimed at further advancing our extrahepatic delivery efforts. This partnership was attractive as it provides an avenue to potentially develop ligands for receptors of our choice across a range of tissues. We've been working with several types of peptide ligands and have initial data that suggests that this approach is very promising for certain tissue types outside of the liver. Within the central nervous system, we are working to build the best-in-class oligonucleotide delivery platform through the use of our IKARIA CNS conjugate platform. I've included the term IKARIA here as this represents potent, safe and long-duration molecules, as you've seen in our liver work, which we think will apply to tissues beyond the liver, including the central nervous system and the eye. Ligands will, of course, change, but the properties linked to potent silencing remain the same. In preclinical studies, our C16 small molecule ligand, for instance, has enabled widespread biodistribution in the central nervous system with robust and durable knockdown. This supports a potentially favorable benefit risk profile for our CNS-directed RNAi therapeutics. For many of the targets in the central nervous system that are of interest, for example, we'll talk about APP and SOD1 and others today, very broad distribution to many areas of the spine and brain as well as different cell types is desired. To enable such broad delivery, we screened a host of lipid ligands ranging in size and the position of attachment to the siRNA for the degree of knockdown, the duration of action and their safety in preclinical models. Like our IKARIA platform in the liver, we have made backbone modifications to improve the metabolic stability of the central nervous system directed SIs. We've also included vinylphosphonate modifications in certain of our siRNAs to improve potency via enhanced risk loading. We found this to be very helpful in certain tissues where the N-phosphorylation appears to be less efficient yet required for risk loading. This will further facilitate our critical RNAi mechanism of action. The data in the figure bottom left shows that different levels of knockdown observed across a number of CNS-directed conjugates. In this experiment, rats received a single intrathecal dose, 0.9 mgs of SOD1 targeting siRNA. This was a [indiscernible] duplex that was conjugated to either C10, C12, C14, C16, C18 lipid ligands. And of course, we tested many others. On day 14, you can see that across a number of regions of the spinal cord and brain, the C16 conjugated siRNA yielded the highest degree of knockdown. The data on the bottom right are from a separate experiment comparing the influence within these modifications, this time focusing in C16 of a vinylphosphonate modification at day 28 post and IT injection. Looking at the data in the red box on the left side of the chart, it's evident that the C16 conjugate, with a vinylphosphonate, results in more robust knockdown across the spinal cord and brain. It is also clear we were seeing limited knockdown in other tissues such as the liver or the kidney with our C16 conjugate as intended. Similar to our liver-directed molecules, we have observed potent and dose-dependent knockdown across a number of cell types in the spinal cord and brain of rat models with our C16 conjugated SIs. This includes CNS regions such as the thoracic spinal cord, the cerebellum and the frontal cortex. We've also seen silencing deeper in the brain in places such as the striatum. Looking at the bottom of the slide, one can see the extensive biodistribution of our molecules across different cell types and regions. This is visualized in purple through the use of an antibody directed against our siRNA, which reveals uptake in activity in the cortex and the neurons as well as astrocytes and microglia. Net-net, these data serve to support the potential of our C16 conjugate platform, and more broadly, our central nervous system pipeline. As many are aware, our lead CNS program under our alliance with Regeneron is ALN-APP. This program leverages our IKARIA CNS platform and is targeted toward amyloid precursor protein for the potential treatment of Alzheimer's disease. Now Alzheimer's disease is the most common dementia worldwide, affecting roughly 5 million patients in the U.S. and 30 million patients globally. Of course, the number of patients affected by this disease grows as the general population continues to age. I'm sure many of us know someone who's been impacted by this terrible disease, whether they're patients, whether they're caregivers and this toll of this disease is really felt by all. This disease is characterized by a progressive loss of cognition, which essentially impairs a variety of mental functions, including memory, and the life expectancy for those diagnosed after the age of 65 is short, 4 to 8 years. Early onset in genetic forms of Alzheimer's, of course, impact patients' lives even earlier. Unfortunately, there's been limited progress to date on disease-modifying therapies. So patients and caregivers and the broader health care system continues to bear the brunt of this important and growing disease. From a development perspective, targeting APP has numerous benefits. They're genetically validated targets. Mutations that increase APP production or that alter APP processing are causative genetically in the onset of Alzheimer's disease. Further, mutations leading to a decrease in APP processing have shown themselves to be protective. The availability of biomarkers for Phase I evaluation is clear. You can measure things such as APP alpha and beta levels, you can measure downstream engagement in fluid markers such as tau levels or phosphorylated tau or something called neurofilament light chain. And we consider this to be very important as you're trying to develop a new therapy. You also have a definable path to approval with multiple populations to develop APP and with clear, very high unmet medical need. Expanding on APP, it's an 87 kilodalton membrane-associated protein produced in a variety of tissues, with the highest expression seen in the central nervous system. APP is processed via serial cleavage by a number of proteases, which ultimately yields a variety of peptides, including the amyloid beta peptide. Amyloid beta readily aggregates and clumps up into the extra cellular space of the brain creating the characteristic plaques of Alzheimer's disease. However, there is another form of amyloid beta that is produced from APP that is known to clump into the blood vessels of brain that's also toxic causing disease known as cerebral amyloid angiopathy or CAA with the blood vessel walls begin to weaken and they eventually leak leading to cerebral bleeds, hemorrhages and even strokes. Thus APP serves as a potential viable target for two several distinct diseases with some overlap that is Alzheimer's as well as CAA, which we will talk about more in a bit and then there's some overlap where some of the Alzheimer's disease patients also have CAA. By targeting APP for silencing, we are lowering its production upstream of the pathogenic process thought to be implicated in Alzheimer's disease. This serves as the basis of our therapeutic hypothesis with ALN-APP, that is, lowering APP production at its source will reduce both intracellular as well as extracellular drivers of the disease pathology. And that includes all APP cleavage products, not just Aß40 and Aß42, but all of the other cleavage products that come off of this very large APP protein. By removing the substrate of amyloid deposition, we believe this will enable a natural clearance of amyloid and have a clinical impact on Alzheimer's and CAA. Our approach is novel and distinct from those -- from existing therapies or existing trials such as anti-amyloid antibodies where marketed -- that are marketed or in clinical development that work only to lower some forms of extracellular amyloid beta. Other cell autonomous intracellular APP products thought to be disease contributors are not impacted by these therapies. Additionally, compared to BACE inhibitors, our approach with ALN-APP lowers all APP fragments not those just produced by beta secretase. Indeed, there continues to be growing literature around the role of not only intracellular APP, but also intracellular tau, all of these intracellular proteins or so-called cell autonomous effects in the progression of Alzheimer's disease. The work here sheds some light on what's going on inside neurons within the context of Alzheimer's. Looking to the left, we can see published data that shows that these are patient cells that have mutations in APP and PSEN1 that these are the known mutations that cause Alzheimer's disease. And in these cell lines that cause -- and also in these brands that cause enlargement of Rab5 early endosomes. Studies have shown this enlargement is one of the earliest manifestations of Alzheimer's. APP beta C terminal fragments are thought to drive this effect, and, thus, by silencing APP, the upstream substrate for these fragments inside the cell, we should see a reduction in Rab5 early endosome size. Looking at the images and quantitated on the far right, we can indeed see that this is the case. These cells treated with ALN-APP versus a control siRNA showed a clear reduction in endosome size subsequent to the APP lowering. Here we can see lowering of both alpha and beta forms of APP in the CSF of nonhuman primates up to 6 months after a single intrathecal injection of ALN-APP. These data demonstrate clear on-target engagement, but perhaps more notably support the potential for biannual or maybe even annual dosing, which is an attractive profile given the burden associated with intrathecal administration. As we think about ALN-APP's clinical development path, we can see significant opportunity in both Alzheimer's disease, and as I previously mentioned, CAA. We plan to run our Phase I study in the early onset Alzheimer's population potentially expanding development into HCAA, sporadic CAA, AD, ADAD or broader CAA in Alzheimer's disease. More on our designs in a bit. Thus, with 1 target, we have the ability to pursue different disease processes with different development strategies. And this provides us with a significant level of strategic opportunity. Of course, this is all underpinned by APP's pathological role across the range of these disorders. Let me elaborate just a little bit more on CAA. So CAA is underdiagnosed. It's an underdiagnosed cause of stroke and dementia. It's the second most common risk factor for intracerebral hemorrhage, ICH, after hypertension. This is not an overly uncommon condition with greater than 20% of the general elderly population exhibiting a moderate to severe CAA pathology. Diagnosis is typically accomplished through neuro imaging, which has been increasing with a rising disease awareness. However, CAA continues to be underdiagnosed, with only a small fraction of patients formally diagnosed today. Underlying clues of CAA include hemorrhages and microbleeds, which can be seen via neuro imaging. As it stands now, there are no therapies directed towards CAA. Similar to Alzheimer's disease, APP, as a target, carries significant benefits within the context of CAA. Again, it's a genetically validated target. Mutations that alter APP cleavage are known to be a cause of hereditary CAA. This is particularly evident in the Dutch type CAA, a genetically well-defined ultra-orphan population. Biomarkers are, again, available in Phase I, similar to Alzheimer's disease, and the CSF could be used to measure target engagement. For disease progression, measures of vascular reactivities such as bold FMRI could be used to -- given the vascular nature of the disease. Definable path to approval with high unmet need helps further development, while the availability of biomarkers could facilitate clinical trial design in conjunction with a genetically-defined population. This all sums up to a significant opportunity for ALN-APP complementary to the opportunity in broader Alzheimer's disease. Looking at the images on this slide, we can see clear size of target engagement in hippocampus of a rat HCA model. This visualization is enabled by antibodies, which detect both a neuronal signal in red to identify the neurons as well as human APP, which is the signal in green. On the bottom, you can see that cells treated with a single IT dose, 0.9 milligrams, again, of APP targeted siRNA results in the depletion of APP. On the top in our control, it's clear that APP has a mass within and around the cells depicted. Turning to the safety of CNF's directed siRNA conjugates. So we conducted a number of safety studies. We've had no test article-related changes that were observed in the rats and other nonhuman primate preclinical studies of ALN-APP. This includes a 6-month platform pharmacodynamic studies as well as platform early non-GLP tox studies in rats, as well as non-GLP studies in nonhuman primates. Importantly, GLP toxicity studies in both rats and nonhuman primates have been successfully completed, thus enabling the ALN-APP soon-to-be CTA filing. Circling back on my comments earlier, we plan to initiate a global Phase I study in early onset Alzheimer's patients. Our CTA will be filed in late 2021, with first patient dosed early next year. We are initially evaluating ALN-APP in an early onset Alzheimer's disease population as the role of APP production in these early ages makes them well suited mechanistically for an ALN-APP targeted siRNA. In the same vein, because this population is younger, they lack some of the comorbidities seen with the older patients, creating a comparatively homogeneous population. Part A will be placebo-controlled and will comprise of a single ascending dose ranging from 25 milligrams to 600 milligrams. Lower doses of 25 and 75 milligrams will be randomized 4 to 2, while the higher doses will be randomized 6 to 2, and optional higher dose cohorts may be included as well. Part B will not be placebo controlled and will include a multi-dose regimen evaluating Q3 monthly or Q6 monthly dosing. Two additional multi-dose cohorts may be included here as well. The primary endpoint for this trial will, of course, be safety and tolerability. PK and PD will be measured by measuring A beta -- alpha and beta fragments of APP, their secondary endpoints, and we'll also have a host of exploratory endpoints looking at biomarkers and neuroimaging. In summary, ALN-APP will be the first RNAi therapeutic delivered to the CNS. It's also the first therapeutic in general that targets APP messenger RNA, the sole precursor of all of the APP cleavage products, including amyloid beta with potential opportunities in both Alzheimer's disease and CAA. Further, ALN-APP is the first therapeutic overall that prevents the synthesis of other potential drivers of disease beyond amyloid beta. These include the beta and C terminal fragments. And perhaps most importantly, APP is the first that will comprehensively lower both intracellular and extracellular amyloid proteins. The first support our confidence in ALN-APP and the opportunity it may potentially provide in both Alzheimer's disease and CAA. Continuing along our CNS pipeline, let me now discuss our efforts in Huntington's disease. As you know, Huntington's is a CNS disorder characterized by progressive motor, cognitive and psychiatric decline. It is a genetically inherited disease that afflicts roughly 30,000 patients in the U.S. alone, with a disease duration of 15 to 20 years. The disease burden is quite severe. More specifically, Huntington's is an autosomal dominant gain of function disease caused by a trinucleotide repeat expansion in exon 1 of HTT gene. By targeting HTT for RNAi-mediated silencing, we believe we can reduce RNA and protein-induced neuronal toxicity, potentially halting the disease progression. But as you know, Huntington's is a very complex low side, with data continuing to emerge about the best strategy for tackling this disease. We've been evaluating 3 potential strategies, targeting full-length HTT, targeting exon 1 and targeting intron 1. As you can see in the right-hand panel, we've developed a very impressive molecule targeting a full-length HTT. As you can see on the right, after a single IT dose in nonhuman primates, we have greater than 90% lowering of HTT and this correlates quite well with drug concentration across the CNS. Given the complicated nature around the full length and the data around that lowering to date, we're in the process of developing similarly potent molecules for exon 1 and intron 1, with the goal to be able to compare the safety and efficacy of the different approaches in order to be sure to take the best one forward. In addition today, we are also announcing our third central nervous system program, ALN-SOD for SOD1-specific ALS. SOD1-specific ALS is a fatal neurodegenerative disease characterized by motor neuron loss in the brain and the spinal cord. This leads to a progressive loss of functional capabilities, including walking, speech and breathing. SOD1 is a genetically validated target with over 180 mutations described and mutant SOD1 is known to be a toxic gain of function that can misfold and mislocalize, which can ultimately lead to neuronal toxicity. By targeting SOD1 for RNAi-mediated knockdown, we hope to reduce the production of the mutant and toxic SOD1, thereby reducing neuronal toxicity and halting disease progression. Through the application of our RNAi platform, we see room for differentiation relative to other studied modalities such as antisense oligos. Today, we're delighted to share that along with our partners at Regeneron, we've nominated a SOD1 development candidate. Here, you can see robust lowering of SOD1 protein in nonhuman primate CSF 3 months out after a single IT dose of ALN-SOD. We plan to move this development candidate forward towards an IND. So changing subjects a little bit here and turning now to some of our work in the ocular space, along with our partners at Regeneron. We continue to make progress both on delivery, but also on identifying unique targets for diseases with high unmet medical need. First, I'm going to turn and focus on glaucoma. So glaucoma is a leading cause of irreversible vision loss worldwide. One of the major drivers of this loss is progressive nerve damage caused by rising intraocular pressure, also known as IOP. Our partners at Regeneron have been working very hard in the eye space for many years and have developed several different models of IOP. They've identified several new targets which have been now validated with siRNA knockdown in these models. Shown here is one example of a rodent model where IOP rises over time. The purple line is compared to a wild-type mouse in the black line. What you can see here is that a single dose of an siRNA is able to consistently reverse IOP for more than 5 months after a single dose from this model. This shows that our ocular platform behaves very similarly to our other platforms giving us substantial potent and durable knockdown in the eye space. Turning quickly to other tissues of interest. I don't have time today to go into the details, but suffice it to say that we continue to work on ligand receptor pairs to access other tissues and have seen robust effects in animal models, as illustrated by one graph here. Our data showing robust silencing after a single dose of a conjugated siRNA in tissues such as the heart, the adipose and the skeletal muscle. These data continue to demonstrate the potential of RNAi therapeutics across a range of tissues, underscoring its modular and reproducible nature. Finally, I want to turn to oncology for just a moment, and we continue to believe that RNAi therapeutics as a modality will play a future role in the treatment of cancer. The ability to silence individual undruggable targets are important with combinations of targets, perhaps with our GEMINI platform, will enable future targets of tumors of the immune system in oncology in innovative ways. Our starting place in oncology, and it shouldn't be a surprise, is hepatocellular carcinoma or HCC. Liver is a tissue we know well and where we have multiple ways to deliver large amounts of siRNA and get high drug exposure. Our first target in this space is the Wnt/beta-catenin pathway, and we have preclinical data shown below indicating that we can show significant tumor regression in HCC liver models. In addition to HCC, we are also considering other rare types of liver cancer, such as FLC, which is known to be driven by a gene fusion event, where specific targeting of the fusion transcript could be possible. Importantly, our efforts in oncology provide additional fuel for our organic pipeline engine and represent another manner through which we can make a difference in patients' lives. So in summary, we continue to make outstanding progress in the extrahepatic space, where the RNAi mechanism is active in all the tissues that we have studied to date. Importantly, the PK/PD properties of our molecules in liver and what we've learned there appears to be conserved throughout other tissues. That is molecules are potent and they're very long acting. We plan to progress our CNS pipeline by filing ALN-APP for early-onset Alzheimer's disease shortly, and that will be followed by ALN-SOD for ALS. We continue to evaluate molecules and strategies in the Huntington space. In addition, in the ocular space, we continue to make progress with our partners at Regeneron, who've identified several interesting targets that have shown durable lowering of IOP in different animal models. Finally, we continue to execute on our strategy to identify novel ligand receptor pairs across other tissues of interest, including skeletal muscle, heart muscle, adipose, tumor and others. And with that, I'll turn it over to Pushkal.

Thanks, Kevin, and hello, everybody. I'm Pushkal Garg, Chief Medical Officer at Alnylam. And I'm delighted to be here with you today to speak about our early to mid-stage liver-directed programs, which we believe are well poised to address important unmet needs for patients and drive future growth for the company. As I hope you've seen from all of today's presentations, the unique profile of Alnylam's RNAi therapeutics with potent and specific target knockdown, durable silencing that permits convenient, infrequent dosing, and a rapidly growing patient experience and well-understood safety profile, has enabled us to build an unparalleled pipeline of medicines to address both rare and prevalent diseases. Now in this presentation, I want to update you on some of our earlier liver-directed programs. You've already heard from others about zilebesiran for hypertension, but we have several other early to mid-stage programs that can address diseases with high unmet need. So over the next few minutes, I'm going to discuss several exciting clinical and preclinical programs that we are pursuing to address complement-mediated disorders, hepatitis B, NASH and gout. Let me start first with cemdisiran, which is in development for complement-mediated diseases. C5 is a key component of the terminal complement pathway and is a genetically and clinically validated target. Importantly, cemdisiran as a monotherapy has already been shown to be a very potent and durable inhibitor of C5. As demonstrated in our Phase I/II study, single doses of 600 milligrams led to mean maximal C5 knockdown of 98% with potent inhibition lasting for over a year. We now know that there are multiple debilitating diseases that are complement-mediated and which may be addressable by cemdisiran. We're pursuing a dual strategy for cemdisiran development in collaboration with our partners at Regeneron. First, we're evaluating cemdisiran as a monotherapy for IgA nephropathy and other inflammatory renal disorders. In these diseases, submaximal complement inhibition may be effective. IgA nephropathy is the most common glomerular disease in the world, and it's caused by immune complex deposition and complement activation at the glomerulus. And importantly, 30% to 40% of patients with IgA nephropathy end up in chronic renal failure, and there are no definitive therapies other than renal transplantation. Secondly, we're also developing cemdisiran in combination with an anti-C5 antibody, pozelimab, for diseases that will require highly potent inhibition of C5. Here, our colleagues at Regeneron are taking the lead, as we work to develop a best-in-class, highly potent, C5 inhibitor regimen for PNH, myasthenia gravis and other diseases. We have a Phase II study of cemdisiran in IgA nephropathy that's already underway. The study includes 30 patients with IgA nephropathy who are being randomized 2:1 to cemdisiran versus placebo with an endpoint of proteinuria reduction at 32 weeks. The study is fully enrolled. And as we recently updated, we expect initial data in early 2022. Now for other diseases, we and our Regeneron colleagues are developing cemdisiran in combination with their anti-C5 monoclonal antibody, pozelimab. Now this regimen offers an even more potent level of complement inhibition. Importantly, we already have human data for such a combination from the Phase I/II study of cemdisiran with eculizumab, another C5 antibody in PNH. There, we saw that the combination led to a multi-log increase in potency relative to the antibody alone with lower peak to trough fluctuations. In addition, the regimen prolonged the functional half-life of the antibody resulting in a convenient, less frequent dosing regimen. Our Regeneron colleagues have recently conducted a Phase I study of the combination of cemdisiran and pozelimab and plan to present those data at ASH in December. They've also begun studies with a combination in PNH and myasthenia gravis. In PNH, they've embarked on several Phase II studies, both in de novo and switch patients. And they just recently announced the initiation of a Phase III study in MG. We're really excited about the initiation of these studies and the continuing advancement of the cemdisiran pozelimab combo regimen, which has the potential to be best-in-class. The next program I'd like to talk about is HBV02 or VIR-2218, which is in development for hepatitis B infection by our colleagues at Vir. Now HBV, as you may know, is one of the most prevalent diseases in the world. It affects an estimated 290 million people worldwide and is an important cause of cirrhosis, liver failure and death. VIR-2218 is an siRNA that targets a conserved region in the X gene of the virus. It's an ESC+ molecule optimized for both potency and specificity. VIR-2218 can silence all 4 major transcripts of the virus that overlap this region and should suppress HB surface antigen from both integrated and covalently closed circular DNA. 2218 is currently being evaluated in a Phase II study in patients where we've already seen some exciting results that were just presented at the recent AASLD meeting. In that study, 2218 as a monotherapy exhibited dose-dependent knockdown of HB surface antigen with an approximate 1.5 log reduction seen with doses of 200 milligrams monthly. In the same study, 2218 was given in conjunction with PEG interferon given for 12, 24 or 48 weeks. Interestingly, co-administration with PEG interferon led to larger reductions in circulating HB surface antigen with 2 to 2.5 log reductions observed in both e-antigen positive and negative patients. Now this slide shows the same data, but focused on achieved levels of HB surface antigen in the monotherapy and combination therapy regimens. The combination regimens resulted in substantial reductions in HB surface antigen. In fact, 3 patients had undetectable levels of HB surface antigen, and 2 of the 3 experienced anti-HBs seroconversion. This is an incredibly exciting result because it suggests the potential for functional cure of hepatitis B by a combination of VIR-2218 and PEG interferon. Based on these encouraging data, Vir is now expanding the development program and developing 2218 as a foundational therapy for hepatitis B infection. We are, of course, working closely with our colleagues at Vir to support the development program and enthusiastically awaiting the results as Alnylam has opt-in rights to this program prior to Phase III. Let me turn now to our RNAi programs for NASH. Our lead program is ALN-HSD, which is in the clinic, but we also have a preclinical program for NASH, ALN-PNP, which has a complementary mechanism of action. NASH or nonalcoholic steatohepatitis represents a subset of disease under the umbrella term of nonalcoholic fatty liver disease. NASH patients have fat accumulation in the liver accompanied by the presence of liver cell injury and inflammation. NASH affects approximately 16 million adults in the United States alone. And once NASH develops, it can lead to fibrosis, cirrhosis and hepatocellular carcinoma. And unfortunately, there are no specific therapies for NASH. While weight loss can be effective, it's very difficult to achieve and maintain. As part of our strategy, we're pursuing 2 targets for NASH, which address complementary aspects of the pathophysiology of this disease. Our lead program, ALN-HSD, targets HSD17B13 or HSD for short. HSD is involved in the inflammation and injury of NASH and other liver diseases. We also have an earlier program targeting PNPLA3 or PNP. This protein is involved in the steatosis that marks nonalcoholic fatty liver disease and NASH. This slide highlights some preclinical data on ALN-HSD from nonhuman primates. These 2 graphs show highly potent and durable knockdown of the HSD transcript and protein in the NHP liver by single doses of this siRNA. Moreover, the preclinical safety profile was very encouraging as well. Based on these data, we initiated a Phase I study with 2 parts. Part A evaluated single doses of ALN-HSD in healthy volunteers. The primary objective of Part A is to assess safety and tolerability. As HSD is not a circulating protein, we can't measure protein knockdown directly. However, we will be assessing HSD levels in urine and plasma exosomes. Part B is evaluating multiple doses of ALN-HSD in NASH patients. In this part of the study, we'll be collecting liver biopsies to directly measure HSD knockdown as well as potential histologic changes in the liver. I'm pleased to share with you today the safety and tolerability profile that's emerging from Part A of the Phase I study of ALN-HSD. Overall, we studied ALN-HSD in 44 healthy volunteers, and it was well tolerated. Specifically, there were no AEs related to study drug, nor any deaths or AEs leading to study discontinuation. There was a single treatment-emergent SAE, a case of tonsillitis considered unrelated on the study drug that went on to resolve. There were no clinically significant LFT elevations, and there was a low incidence of mild transient injection site reactions. Overall, the safety profile is encouraging and supports further development of this siRNA. Now looking forward, our next milestone for this program is to enter Part B and to hopefully share data indicating human proof-of-concept sometime in 2022. Finally, let me close this section on NASH by showing some preclinical data on another program, ALN-PNP. On the left, you can see published data from a preclinical NASH model in which use of an antisense oligonucleotide to lower PNP resulted in improvements in a number of histologic parameters, including steatosis, inflammation and fibrosis. On the right, you can see that we've already identified a number of highly potent and durable siRNAs, both in rodents and nonhuman primates. Importantly, as these 2 targets, HSD and PNP, address different aspects of the pathophysiology of NASH, they may be well suited to be used in combination to treat this disease. That's certainly something we'll be evaluating with our colleagues at Regeneron. We look forward to sharing more about this exciting program in the months to come. Finally, let me now turn to an exciting preclinical program, ALN-XDH for gout. We will be filing a CTA for this program by the end of this year and starting a Phase I study in early 2022. Gout is the most common inflammatory arthritis globally, affecting 14 million to 18 million people in the U.S., EU 5 countries and Japan. It's caused by an accumulation of uric acid crystals in the joints, leading to pain, edema, buildup of tophi and joint destruction. In some patients, the elevated urate levels contribute to chronic urate nephropathy as well. Importantly, we know that urate lowering therapy is essential to control this disease. And it's in that context that we believe that an siRNA targeting xanthine dehydrogenase or XDH may offer potent and durable urate lowering and thereby improve disease control. XDH represents a clinically validated target as it's the target for 2 approved therapies for gout already, allopurinol and febuxostat. An important question is whether hepatic silencing alone, using a liver-directed siRNA, will be effective. And in fact, the preclinical data on the right from a liver-specific XDH knockout mouse model show that hepatic silencing has the potential to be quite effective. In these published data, use of a liver-specific knockout of XDH reduced the transcript by 95% and reduced plasma uric acid by 50%. Thus, these data are quite encouraging about the potential for liver-directed RNAi therapeutic targeting XDH to reduce uric acid levels and gout flares. We're in the process of finalizing the design of our first-in-human study for ALN-XDH and plan to file the CTA by the end of this year. However, today, I can share the high-level design of the study with you. We're planning to conduct a seamless Phase I/II study in healthy volunteers and gout patients. Part A will evaluate single ascending doses of ALN-XDH in healthy volunteers. The key objectives of Part A will be safety and tolerability, uric acid lowering, PK and xanthine oxidase activity. Part B will evaluate multiple doses of ALN-XDH in patients with gout and elevated levels of uric acid. The key objectives of Part B will be safety and tolerability, uric acid lowering, the occurrence of gout flares and xanthine oxidase activity. We'll provide more details of the study design after the protocol has been finalized. To sum up, we are excited about the potential to use an RNAi therapeutic, ALN-XDH, to treat a highly prevalent disease like gout. Despite the availability of treatments, there remains a tremendous amount of unmet need in this disease because current therapies have substantial limitations, primarily due to safety and tolerability concerns. As a result, the majority of patients cannot adhere to prescribed therapy and do not reach target uric acid levels. For instance, it's been reported that fewer than 50% of patients with uric acid goals on allopurinol. Thus, ALN-XDH may address unmet needs for gout patients with potent urate lowering, infrequent dosing with tonic control, acceptable safety and tolerability and a reduction in gout flares. So in summary, we see multiple opportunities to advance meaningful RNAi therapeutics against liver targets to address diseases of high unmet need, such as the one I've shown here today. Importantly, we continue to focus on genetically validated targets, which increase the probability of success. And as you also note, we have an increasing focus on specialty and large market opportunities, which is enabled by the emerging safety profile of our platform and the pharmacologic profile of our molecules, which offer the potential for durable tonic control of disease-causing genes. Thanks very much for your attention, and I look forward to updating you on these programs in the months to come. I'll now turn it over to Yvonne, our incoming CEO.

Thanks, Pushkal, and hello, everyone. What a remarkable lineup of presentations we've had this morning. As you're all aware, this is John's last R&D Day as Alnylam's founding CEO. And I think it's quite clear from everything we've seen today that we owe a debt of gratitude to his leadership over the past 19 years to usher in RNAi therapeutics as an entirely new class of medicines with potential to have a transformative impact for patients. I'm honored to be taking the baton after the new year, and we'll continue to execute on our near- and long-term goals towards becoming a top biotech company with a self-sustainable innovative platform. And to that end, I'll be concluding today's program with a high-level strategic outlook before wrapping things up with another Q&A session. Starting with the near term. We announced this morning our new set of annual goals for 2022. I won't go through these line by line. But you can see that we have another busy year ahead marked by key milestones that include 5 commercial products on the market generating revenue, currently ONPATTRO, GIVLAARI, OXLUMO, Leqvio and next year, one new product launch with vutrisiran, assuming successful review and approval by the April PDUFA date. One Phase III readout with patisiran in the APOLLO-B study, and assuming that study is positive, one sNDA filing for patisiran in ATTR cardiomyopathy. Five Phase III programs as well as 5 ongoing Phase II programs and 2 to 4 new INDs. But as we move forward with these activities, 2022 is going to be a year full of exciting catalysts. For starters, it will be an important year for our TTR franchise as we present full 18-month results from the HELIOS-A Phase III study of vutrisiran and await FDA approval, as mentioned earlier, both in the early part of the year. Mid-2022, we expect APOLLO-B results for patisiran, which, if positive, could pave the way for potential label expansion for ONPATTRO to include both hereditary and wild-type ATTR amyloidosis with cardiomyopathy. And later in the year, we expect data on the biannual dosing regimen of vutrisiran, which could further differentiate this important medicine. Another very important milestone next year will be initial clinical results from the Phase I study of ALN-APP. This will be the first clinical readout of an RNAi therapeutic targeting a gene expressed in the CNS. Therefore, if results are positive, they could be significantly derisking not just for the ALN-APP program, but for our entire CNS portfolio and broader extrahepatic delivery efforts as well. 2022 also promises to deliver a series of clinical readouts in prevalent diseases, including top line results from the KARDIA-1 Phase II study of zilebesiran in hypertension, data from Part B of the Phase I study of ALN-HSD in NASH patients and initial clinical data with ALN-XDH for the treatment of gout. So lots to look forward to throughout next year. Moving beyond 2022, we are pleased with the progress of the 5-year vision we laid out at the beginning of this year, Alnylam P5x25. This bold strategy was co-created by John and myself to establish Alnylam as a leading biotech company with transformative medicines in both rare and common diseases for patients around the world and a robust and high-yielding pipeline of first and/or best-in-class product candidates from our organic product engine while delivering exceptional financial performance. As the name suggests, and as you see outlined here, this strategy revolves around 5 key pillars or Ps with specific goals that we expect to achieve by 2025. Let's dive into each one a little more to help clarify this important road map. Starting with patients, always our North Star at Alnylam. The goal we have set for ourselves in this regard is over 0.5 million patients on Alnylam commercial products globally by the end of 2025. An important element of our progress towards this goal is the expansion of our pipeline from rare to prevalent diseases, which you've heard quite a bit about today. Leqvio partnered with Novartis represents the first RNAi therapeutic in a prevalent indication and will contribute significantly to this goal. We're really excited about the potential here, especially in light of the innovative arrangement that Novartis has negotiated with the NHS in England. This is a first of its kind population health management approach to address elevated LDL cholesterol in approximately 300,000 eligible patients with atherosclerotic cardiovascular disease across England. As a reminder, U.S. approval is expected soon with a PDUFA date of January 1, 2022. Furthermore, assuming we meet the required clinical and regulatory milestones, the potential expansion of our TTR franchise to include the full spectrum of disease, hereditary and wild type, polyneuropathy and cardiomyopathy, will also be a notable contributor to our patient goal. The next P we have is for products. Specifically, we aim to have 6 or more marketed products in rare and prevalent diseases by the end of 2025. With 4 already being commercialized, vutrisiran on track to be the fifth, with a PDUFA date next April, and fitusiran and cemdisiran, both currently in Phase III programs, we believe this goal is well within our reach. This doesn't even include anticipated label expansions for both patisiran and vutrisiran in ATTR cardiomyopathy. The third P to discuss is pipeline. Here, by the end of 2025, we expect to have more than 20 clinical programs ongoing with 10 or more in late stages and 4 or more INDs per year. Akshay did a brilliant job earlier highlighting the plethora of opportunities we have with RNAi therapeutics and our ability to self sustainably grow our pipeline and enhance our platform, which will all continue to accelerate in the years to come. The final 2 Ps relate to outstanding financial performance. First, we plan to meet or exceed a 40% revenue compound annual growth rate through year-end 2025. To achieve this, we expect steady and continued growth from our existing commercial portfolio as well as the successful launch of vutrisiran and including expansion of the TTR franchise to include the broader patient population. The last goal in our P5x25 vision is profitability. And as we've talked about in recent years, we understand the importance of balancing our steady revenue growth with our pipeline investments. And through those disciplined operations, we expect to achieve sustainable non-GAAP profitability between now and the end of 2025. This slide may be a familiar one to you all by now and dates back to when we declared that 2019 would be our peak non-GAAP operating loss year, which remains true. The chart again represents sell-side consensus, so don't get caught up trying to pinpoint when the line crosses zero. We haven't committed to a specific year for profitability, but we're confident that we'll get there. Finally, I want to wrap up by discussing a sixth P that is not formally included in our P5x25 goals, but will be absolutely critical to our success in achieving them, and that's our people. As they say, culture eats strategy for breakfast. And we're so proud of everything Alnylam has achieved on that front, thanks to the amazing employees that are fully committed to our mission. We continue to receive industry awards, including being named a top employer by Science Magazine for 3 years in a row, being named one of The Boston Globe's top places to work for 6 years in a row, and many, many more. I've been at Alnylam for 5 years now, and I couldn't agree more with these accolades. Across the organization, my colleagues push the traditional boundaries of biotech to advance science, innovate new treatments addressing unmet needs, navigate the regulatory processes, launch and commercialize products, and everything else that goes into operating a top-tier biopharma company. And that's why I'm so humbled to be taking over as CEO next year. Alnylam is firing on all cylinders, and I'm fully committed to the strategic vision that we've highlighted for the company. I also share the optimism you all have that we will make that vision a reality. And as I hope you can appreciate from what you've heard today, Alnylam's future is looking brighter than ever, and we're just getting started. With that, let me welcome back our speakers and turn it over to Pushkal to moderate our second and final Q&A session for the day. Thank you.

Well, welcome, everybody. This is Akshay Vaishnaw. I'm going to moderate this second panel. So welcome back to Dr. Cohen and my colleagues, Yvonne Greenstreet, Kevin Fitzgerald and Pushkal Garg. So Yvonne, maybe we'd just go straight to you. As you said, the enormous sort of breadth of opportunities, and there's a question here about that. Going forward, how do you see us balancing this richness of opportunities versus the goal of profitability?

Actually, that's a great question. And that's exactly what we've set out to do with the P5x25 strategy, where we're going to drive top line growth underpinned by disciplined investments and achieve non-GAAP profitability within the period. And critically, we're also going to drive continued delivery of our pipeline and platform. What's unusual about Alnylam is our low attrition. And actually, you touched on this in your presentation where you emphasized that our greater than 60% success rate going from Phase I to Phase III. So just to emphasize that investments in our product engine deliver, in my view, an impressive return.

Terrific. A lot of interest in the CNS program. So maybe I'll just turn to some questions relating to that. Dr. Cohen, there's a question here asking about the prevalence of CAA. I think people are probably not as familiar with how common that disease is. Are there some rough numbers to guide people?

Yes. So most of the numbers for CAA because it is underrecognized and underdiagnosed, most of the prevalence numbers come from autopsies. And in the elderly, it is seen in cerebrovascular pathology at, I would say, greater than 40% of cases in the elderly. In individuals with Alzheimer's disease, CAA actually accompanies Alzheimer's disease in 80% of brains. So it is very common. But of course, when somebody appears well and then suddenly has a stroke or intracranial hemorrhage, that may be attributed to hypertension or other things and CAA may be underrecognized.

Great. So essentially a very common disease. And you also answered another question I want to add about, do the 2 coexist sometimes. So do you think a therapy like ALN-APP could tackle both elements of the disease if the 2 coexisted?

Absolutely. I think that's one of the exciting potentials for this therapy. We know that in Alzheimer's disease, Abeta42 is the main toxic protein that accumulates in the parenchyma of the brain and also intracellularly. We'll probably talk about that a little bit later. But Abeta40 is also accumulating in Alzheimer's disease in blood vessels and leads to microbleeds and sometimes lobar hemorrhage. And then there are individuals who just have CAA and not AD. So being able with one compound to lower the offending initial protein, the amyloid precursor protein, which gives rise to Abeta40 and 42, is very exciting.

Great. So I think from our perspective, the therapeutic hypothesis is indeed very exciting for ALN-APP. But there's a question here about the Abeta landscape is complicated. There have been a lot of failures over the years attempting to drug Abeta. So why should we still be excited about APP, I think, is the first of the question given all those Abeta failures or setbacks?

Yes. It really has been a very challenging ride tackling Abeta and understanding how best to do that. So I think the genetic data has been clear that cleavage of amyloid precursor protein and increased amounts of Abeta peptide is an important early aspect in the pathogenesis of Alzheimer's disease and leads to downstream other pathobiological changes, including tau hyperphosphorylation. However, when Abeta is formed, it takes many forms. It can be soluble initially and then form oligomers and protofibrils and plaque. Some of the monoclonal antibodies and other approaches have targeted specific subspecies. So when you look at some of the monoclonal anti-Abeta antibodies, they target soluble monomers. Others target plaque and then still others target a range of aggregated soluble and insoluble amyloid. And we just don't know which is the best to target. There's evidence that all of these species have different neuropathological effects on the brain. If you can go further upstream and target all of them by silencing the amyloid precursor protein or reducing the amount of that precursor protein, then you don't have to struggle with which of the subspecies of Abeta are the most toxic. And you also have the opportunity to do something about the intracellular fragments of APP.

Yes. And in fact, there's a question about the data that Kevin shared on the intracellular or intraneuronal aspects. And the BACE inhibitors, which have been previously evaluated in this space, didn't really do too well. And so they act intracellularly, of course. Why does the ALN-APP have a shot then when the BACE inhibitors have essentially failed, Dr. Cohen?

The BACE inhibitors were very challenging. The BACE inhibitors, so BACE enzyme has many substrates, not just APP. And so it includes many other proteins and the specificity, selectivity of BACE inhibitors to cleave only what we want in the amyloid precursor protein was lacking for the most part in these programs. And there were off-target effects. So the BACE programs failed in Alzheimer's disease largely because of toxicity. We saw worsening rather than benefit. And we didn't have a clean enough system here. So if you can reduce the amount of APP substrate and allow BACE enzyme to cleave its other physiologic substrates, then I think we have a much better shot.

Great. Just to follow the theme, Kevin, there's another question here saying the part about the intraneuronal APP and the different toxicities, you went through quite quickly, there was a slide. Can you recap the intraneuronal toxicities of APP products and Abeta?

Sure. There's just really an enormous amount of growing information about the role of intracellular deposition of products coming off of APP and AbP. For instance, Abeta42 itself has been shown to aggregate intracellularly, but other C-terminal fragments that people don't generally talk about like C99 or C31 have been shown to also aggregate. Obviously, in the data that we showed, you could see that trafficking, endosomal trafficking even early on in those patient cells was disrupted, and that was readily sort of changed by silencing all of APP.

Got it. We'll come back to maybe...

I'd just add one thing. There's also some evidence that intracellular fragments of C-terminally cleaved APP or Abeta itself can produce cytokines within the neuron and trigger the immune response that has been so complicated and curious in Alzheimer's disease because this is a disease where neuroinflammation and the problem with the innate immune system exists and to focus just on immune reactivity to extracellular Abeta plaques is probably misplaced. And we are seeing disruption of the immune mechanisms within the neuron with accumulation of intracellular fragments of Abeta.

Recently, there was a publication on intracellular tau as well, which will be related.

Yes. Well, a lot of additional questions on CNS. So we'll come back to that, but maybe just to go to you, Pushkal, questions on the mid- and early-stage pipeline. With respect to the HBV program and Vir, the question is, when does Alnylam have the opt-in and what data will you see before Alnylam chooses to opt in or not?

Sure. Thanks, Akshay. Look, as I outlined in the earlier presentation, Vir has taken a really exciting approach to advancing ALN-HBV or VIR-2218, which is really thinking about this siRNA approach as potentially a foundational therapy that can be used to achieve what has been the holy grail in hepatitis B, which is a functional cure. This is obviously a chronic disease affecting hundreds of millions of people around the world that progresses to liver damage, fibrosis, cirrhosis and death. And so the ability to achieve functional cure, which is really preventing the replication of the virus, suppressing the tolerogen HB surface antigen and causing seroconversion for patients off of drug is really the holy grail. And so they've shown some very exciting data. They're looking at this molecule in combination with a number of other agents. The data that we just shared with -- that they've shared with PEG interferon really starts to show some inklings about the ability of that combination to bring down HB surface antigen to almost undetectable levels and even that they achieve seroconversion in 2 patients. So we'll be looking in the coming months and over time at the accumulating data both in terms of safety and tolerability, in terms of patients, who actually can achieve reductions of HB surface antigen to very, very low levels, seroconversion and then using all that, the totality of that data to make our decisions and the various regimens around opt-in. Our rights are really to make that decision going into before Phase III. And so that will be the marker. There's not a specific time frame set out for that, but it will be before Phase III that we have that choice to opt in.

Great. There's another question, Pushkal, on the HSD now. What do we think of the emerging Arrowhead data with their HSD molecule and what are the implications for our program?

Yes. So as I outlined, HSD is a very exciting target that may have an important role in the pathogenesis of NASH. We have our own program that's in Phase I and moving very well. It's partnered with Regeneron. The data that I think the question is referring to is some recent data that were presented on 5 patients by Arrowhead that has also a program in NASH. So those data suggest that in the small number of patients, 5 patients, and there wasn't a placebo group, that there may have been some benefits seen with regard to transaminase reductions to liver fat and liver fibrosis. Now again, it's a small data set, no control group. But if those were validated, they really do support the therapeutic hypothesis that we are advancing with our own program, very exciting. We are really excited about the program we have. As I said, it's in Phase I moving fast. It's our program and using our ESC+ platform. So it has very high specificity and potency. And then the other part I would just mention is, when we think about a disease like NASH, we really think about this as a very complex disease that's probably going to require a variety of agents to target that. And so we're particularly excited that we're collaborating with Regeneron and in addition to a target like HSD, we're advancing a target like PNPLA3. And the combination of those approaches may actually yield better outcomes for patients. And finally, I would just note that the target HSD was really identified by our partners at Regeneron. And so we are quite confident with them and with us that we have a strong patent estate for HSD. So I'll leave it at that.

Yvonne, before I go back to CNS because we have some more questions there. There's a question here that, as you take the helm in January, how you think about business development? And how will Alnylam think about emerging technologies? And I imagine people have gene editing and other things like that in mind.

Well, look, we have so much potential to deliver out of RNAi platform. As we've seen today, I mean, there's so much opportunity ahead of us, and we're going to continue to prosecute that opportunity and make sure that we can bring transformative medicines to patients. So lots of focus on within what we currently have in our hands. Having said that, yes, I did some BD before looking forward to taking on the CEO role in January. And we'll continue to monitor the external environment as we always have done. And we're not going to be complacent. But I do want to underscore that we have a lot to deliver on our own. I think as John was saying, we've got a lot of wood to chop. And I think some of these technologies, whilst they're exciting, there's still some ways to go in terms of really demonstrating safety, durability, thinking about some of the development challenges where there are pre-existing therapeutics, thinking about some of the market access challenges with these one-and-done strategies. So it's an exciting field. There's some ways to go, and we will continue to watch developments very closely.

Very good. Going back to ALN-APP now, Dr. Cohen. There's a question here that you talked about autosomal dominant and inherited forms of disease in part of your presentation. Is that the same as early-onset Alzheimer's disease? So in the trial, the Phase I trial that Kevin described, will we be enrolling the inherited forms or is early onset a different syndrome?

So early onset is defined as onset of Alzheimer's symptoms before the age of 65. So it's agnostic as to the cause. All of the APP mutations that are known that directly cause Alzheimer's as well as the presenilin-1 and presenilin-2 mutations, the majority of those cause disease with early onset. So the younger you target an age or a cohort for clinical trial population in Alzheimer's disease, the more you will enroll people who have the autosomal dominant gene mutations for that disease. However, early-onset Alzheimer's disease can also happen. Young age of onset of symptoms can also occur without an identified gene mutation. Regardless of whether you have young onset Alzheimer's disease because of a sporadic cause that we can't identify or a gene mutation, the overproduction of amyloid-beta is the core pathology. And so targeting APP has an advantage in these young folks because they are overproducing amyloid precursor protein and you avoid some of the mixed pathology that you see in an older Alzheimer's cohort, where you have Lewy body disease, coexisting cerebrovascular disease, a commonly coexisting factor, and some other proteinopathies coexisting, so you are not really interrogating pure Alzheimer's disease.

Very good. There's a question here that what will be important and exciting about the ALN-APP data as they emerge. I guess you should all answer it. Dr. Cohen, maybe you can start and then Kevin, Pushkal, you should tell us what you'll be looking for in the Phase I. Let's start with Dr. Cohen.

Thank you. I am so excited about going very proximally in this disease and for a number of reasons. One, I described before, do we target plaque-bound amyloid, do we target the soluble oligomers? It's been so confusing and the monoclonal antibodies that we have while exciting are not going to appreciably slow the disease. I mean, I think they'll provide some disease slowing, but then there's still tau and tau is intraneuronal. And we know that amyloid has to reach a certain threshold before tau starts becoming a problem. And so it's got to be that the intraneuronal portion of Abeta is a key driver of pathophysiologic changes in Alzheimer's disease with the therapy. We're talking about here tackling APP. We are covering amyloid very proximally not worrying about all the subspecies and which one is more important. And we are targeting intracellular pathology, intraneuronal pathology, including tau and inflammation. To me, that's very exciting. And if we can do this safely, then perhaps that will put a limit on how much combination therapy. Our field is talking heavily about we'll need an anti-amyloid, we'll need an anti-tau, we'll need an anti-inflammation drug. Maybe if we go proximally enough, one therapy can be a very substantial benefit to this population.

Yes. Thank you, Dr. Cohen. Pushkal, what will you be looking for in the Phase I data?

Yes. Look, I think Dr. Cohen said it really wonderfully. I think we're terribly excited about this opportunity. First, as Kevin's laid out, this is really our first foray into the CNS. And so I think this from a platform perspective really opens up the opportunity for us to evaluate delivering siRNAs into the CNS space, and there's a whole range of diseases that we can potentially target. Being able to have our inaugural program going after such a prevalent debilitating set of diseases like Alzheimer's disease and CAA, I think, is an incredible privilege. And so that Phase I program will be launching shortly. And first and foremost, we're going to want to look at safety and tolerability as we advance the platform into the CNS. So that will be an important readout, just as Dr. Cohen has outlined. But we'll also be able to measure a number of target engagement biomarkers. We'll be looking at APP alpha and beta in the CNS. We'll be able to look at peripheral blood markers. We would look at NFL, a tau. And we'll also be doing some imaging biomarkers. There'll be a whole constellation of assessments that we can do to really understand how we're hitting the target and potentially impacting the disease. And I think those will then guide us in terms of potentially moving forward then in parallel after this Phase I study into parallel development, both in Alzheimer's disease more broadly as well as in CAA. And so we're really excited about the data that should be coming next year and beyond.

Great. Just to move us along, Kevin. There are quite a few questions on how do we feel about our Huntington's program and the SOD1 program after the unfortunate setbacks for patients were the Ionis HTT program with Roche unfortunately failed and the recent SOD1 data in ALS also, they missed the mark. So why are we excited about an RNAi-based approach against these targets?

Yes. I mean, first, let me just say that those were some devastating days for the patient communities and the caregivers, right? Those are 2 very serious and devastating diseases. So the unmet need there continues to be high. And if you look across both of those diseases, with the approaches that were taken with the antisense oligos, for instance, I think there are a couple of things. In Huntington's disease, as you see, we have a development candidate for the full-length approach. However, there continues to be biology there that we're unraveling around whether that's the best approach or targeting exon 1 or intron 1 because it's a very complicated transcript where you get mutant -- repeat proteins coming off both the C-terminal as well as the full-length protein. And there's some discussion around whether wild-type Huntington is necessary for function. So we continue to make progress there. There's some biology questions we're trying to answer in parallel to developing very strong and potent molecules, as you could see with our Huntington's program, over 80, 90, 95-plus percent of knockdown of that transcript throughout a large portion of the brain. With SOD1, again, that program, there were some interesting things in that program that were announced around sort of changes in neurofilament light chain. But one of the aspects of that program is that there appeared to be some dose-limiting toxicity where they weren't really able to get more than, I think it was somewhere between 26% and 38% lowering. And that may just not have been enough. And what we're looking to do here is similar into the liver is to take advantage of our ability to make highly potent molecules that last a very long time to be able to perhaps take that protein down 60%, 70%, 80% across the regions where it's necessary.

Great. Thank you, Kevin. Well, we've got a lot more questions. Unfortunately, we don't have time for. So thanks for everyone's attention. But one last question, Yvonne, to you. What's the most exciting thing in the pipeline? I know John has had this question many times. But what do you regard as the incoming CEO as the most exciting opportunity?

That's actually the most difficult question on the panel. It's hard to choose. It's always hard to choose your favorite child. And my goodness, we've grown quite a large family here. But taking a step back, what I would say is that I think what is so unique about Alnylam is the sustainability. If you look at the totality of what we're doing is the sustainability of our innovation engine that's going to allow us to continue to bring transformative medicine to patients for decades to come, for rare diseases, for prevalent diseases within the liver, extrahepatic. Kevin spoke about some of the opportunities in CNS. So I am just so excited about the journey that we have ahead of us. But in closing, I would be remiss if I didn't also personally offer my thanks to John for his leadership over the remarkable journey that Alnylam has had through 19 years of endeavor. All of us stand on the shoulders of giants. And John is one of those giants. So thank you, John. Thank you for your leadership. I'm so glad that you're going to be on the Scientific Advisory Board so you'll be intimately involved with helping us to continue to be bold with our science and deliver the promise of what we have in our hands. And I'd also like to thank everybody that has hopefully enjoyed spending the last several hours with us today. Thank you very much, indeed.

Thank you all. Bye-bye.

Thank you.