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

Welcome, everyone, to Alnylam's R&D Day 2022. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications. We're pleased that you've tuned in to hear about progress across our portfolio. Turning to our agenda. You can see we have a very exciting lineup of presentations scheduled during our time together, starting with some strategic perspectives on how we are building our business and executing towards our R&D strategy to achieve our goals. We will then turn to deep dives on different elements of our pipeline spanning from our TTR franchise to progress with zilebesiran as a potential treatment for hypertension to our early and mid-stage pipeline before we close on perspective of what's percolating in the next wave of our R&D engine. A few quick reminders before we dive in. This event is scheduled to run until 12:30 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 Investors 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 external speaker, Dr. Sarswat for joining us today and share information about her disclosures here. With that, I'd like to turn it over to Yvonne. Yvonne?

Thank you, Christine, and good morning, everyone. It's a real pleasure to be here today for our Annual R&D Day meeting and very inspiring to see the progress from our platform and anticipate what's in store in the months and years ahead. Our R&D Day is a capstone event for a year in which we've been celebrating our 20th anniversary as a company, and we have a lot to celebrate. Since our filing in 2002, we have stayed focused on developing RNA interference as a new class of medicines and are proud today to have 5 RNAi therapeutics approved and helping patients around the globe. RNA therapeutics represents a rare opportunity to create a whole new class of medicines by harnessing a natural pathway to selectively target messenger RNAs that enco disease-causing proteins for destruction. By silencing mRNA, RNAi therapeutics act upstream of existing therapeutic classes like small molecules and monoclonal antibodies. We've established a modular and reproducible approach to designing new medicines, and with 100% of the human genome in theory available targeting for RNAi, it represents a potential opportunity to significantly expand the ability to fight human disease. Leveraging this, we truly believe Alnylam is poised to be a top-tier biotech in the near years to come. Take a step back for a moment, let's reflect on our journey to date. While Alnylam was founded in 2002, the experiment that catalyzes the journey took a place a decade early importunius. Fire Mellow describes this mechanism a few years later and in another few years Alnylam was born. Alnylam was a company that was created from the aspirations of people who believe they could harness a breakthrough discovery and biology to treat disease in a better way, having recognized the limitations of current therapeutic approaches. However, the early days saw a lot of skepticism from the outside. Science was too new. The techniques unproven and the technologies required not yet developed. But we believe we persisted we persevered and made progress and moved our platform along. Fast forward to today, -- we're thrilled to have been able to overcome those initial hurdles. But it's important to highlight that we retain the innovative and scientific expert that got us here and which will continue to drive a success for Alnylam for many years to come as we evolve to target tissues beyond the liver and move into prevalent indications alongside rare diseases, and you'll hear a lot about that today. With the maturing commercial organization and band reputting signs, we've successfully established Alnylam as a fully integrated biotech company with a profile that's rarely seen in our industry. As I mentioned earlier, we have 5 RNAi therapeutics that were approved in under 4 years, ONPATTRO, GIVLAARI, OXLUMO and AMVUTTRA, which we commercialize as Alnylam and Leqvio, which is being marketed by Novartis. And as of the third quarter of 2022, the 4 Alnylam therapies were helping over 3,270 patients around the world. The success has been made possible by the commercial organization that we've built over the past few years, which has enabled us to establish a foothold in key global markets. We currently have a presence in 23 markets directly and 24 markets through distributors. We've also established end-to-end manufacturing capabilities to support operations. And our global commercial presence will continue to grow as we advance the many exciting programs in our pipeline. These programs are in all stages in development and are addressing both rare and more common diseases. In addition, we'll continue to grow that pipeline with new targets and enhanced chemistries borne of this amazing underlying RNAi therapeutics platform that MA and Vasant will speak to in detail later this morning. Looking at our pipeline churn here, you can appreciate the diversity of opportunity across these programs. You'll hear about many of them today, including from Dion about as our Bizoran hypertension program, where we look forward to Phase II data next year. You'll also hear from John about our TTR franchise and the outlook there is we look to expand the ONPATTRO label following positive APOLLO B results and anticipate results from the vutrisiran HELIOS PED trial in early 2024. our guest key opinion leader, Dr. Sarswat will also highlight the unmet need facing patients with ATTR cardiomyopathy. We now will share updates on our earlier stage programs, including ALN-KHK, for metabolic liver disease and type 2 diabetes, ALN-HSD and ALNPNP for NASH and our first CNS program, ALN-APP, for Alzheimer's disease and cerebral amyloid angiopathy where we expect initial Phase I data early next year. You'll also hear about some strategic pipeline prioritization decisions that we've made. Actually, we'll talk through our rationale with regard to pausing development of cemdisiran in IgA nephropathy and discontinuing ALN-XDH and gout and ramasiran for recurrent renal stones. You know we have a history of charting our progress with bold 5-year goals. In early 2011, we launched Alnylam 515 to bring 5 RNAi therapy 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 market and doing so on a global basis. And in early 2021, we launched our third 5-year goal installment with our Alnylam piece [indiscernible] - and we're making really good progress in delivering on these goals and believe that Alnylam can become a top biotech company, developing and commercializing transformative medicines for rare and prevalent diseases for patients around the world, driven by a high-yielding pipeline of first and/or best-in-class product candidates from our organic product engine, all while delivering exceptional financial results. There are a few fundamental key growth drivers for the company, which are listed here. Us as a potential near-term expansion of our ATTR amyloidosis franchise where we aim to become the global leader in delivering impactful and highly differentiated medicines for patients with all forms of ATTR amyloidosis. The second key growth driver is our expansion beyond rare diseases into more prevalent indications. The pharmacological features of RNAi therapeutics are uniquely suited for the treatment of chronic prevalence diseases where durable effects enable infrequent dosing to maximize adherence and where client pharmacology creates the potential for improved efficacy and outcomes. The third growth driver comes from our sustainable innovation engine. As you know and we'll hear more about today, we continue to maintain our leadership in RNAi and push the boundaries of the technology, bringing forward new platform enhancements and novel therapeutic targets taking us beyond 2025. Ultimately, at Alnylam, we know that the secret source of our success over these past 20 years will continue to be the key to our success going forward, and that's our people and culture. This is foundational to realizing our vision of building a top-tier biotech company, and we're proud of what our commitment to this mission has achieved to date. And as seen here, we continue to be recognized across pharma and biotech and other industries for multiple elements of our culture, including our leadership in scientific innovation, diversity, equity and inclusion, social responsibility and first and foremost, a steadfast commitment to the patients we serve. With that, I'll turn it over to Akshay Vaishnaw, our President, to set the stage further for today's event. Thank you very much.

Thank you, Yvonne. Good morning to everybody, and let me also welcome all of you to our Annual R&D Day. I want to start with an overview of our strategy and what you can expect to see from my colleagues during the day that follows. Alnylam was founded in 2002 based on the discovery of RNAi in human cells by one of our founders, Tom Tuschl. The top left panel shows the RNI mediator silencing of a human gene lamin in this case, for the first time. Over the last 20 years, we've focused our R&D strategy to convert that in vitro observation into a reality for patients. This strategy has consistently had 3 components: the selection of a target organ, the presence of relevant genetically validated disease causing genes in that organ, and finally, an appropriate system to deliver RNAi therapeutics to the target tissue. In turn, that strategy, which began with addressing liver targets has to date led to the 5 approved RNAi therapeutics we have today. We continue to be guided by the strategy and look to expand beyond liver targets to other organs such as the brain eye, muscle and other tissues. Our R&D approach has been very productive. And today, in addition to the 5 approved RNAi therapeutics, we have a pipeline of 12 clinical development programs across 4 therapeutic areas with targeting multiple tissues, including the liver and the central nervous system. We also have a rich discovery engine and many interesting opportunities in preclinical development. ATTR amyloidosis represents our most advanced franchise. This is essentially a single disorder caused by the deposition of misfolded transthyretin or TTR resulting in systemic amyloidosis, most often affecting peripheral nerves or heart or often both. The disease can result from mutant or wild-type TTR, but we believe that all the manifestations can be addressed by lowering circulating TTR levels by an RNAi mechanism. The patisiran and vutrisiran Phase III studies, APOLLO and HELIOS-A, respectively, led to the regulatory approvals of ONPATTRO and AMVUTTRA. Importantly, not only did these studies demonstrate the impact of TTR lowering via our drugs on the peripheral neuropathy, but exploratory endpoints from these studies as well as findings from investigator-initiated studies also showed the potential for cardiac benefit. Earlier this year, we were thrilled that the encouraging exploratory cardiac findings from prior studies were validated by the positive findings for patisiran in ATTR cardiomyopathy patients in the APOLLO-B study. In this case, our 7 positive Phase III study in the last 5 years. My colleague, John West, is going to review all the latest data from our TTR portfolio and also discuss our enhanced confidence in HELIOS-B, where we are studying vutrisiran in ATTR cardiomyopathy patients. The development and approval of inclisiran by our partner Novartis has illustrated the power of infrequently administered RNAi therapeutics to achieve tonic control in a prevalent disease, namely hypercholesterolemia. Recently, it has also been exciting to see preliminary data from the inclisiran Phase III program showing translation of reductions in LDL cholesterol, shown on the left, to lower rates of major cardiac adverse events shown on the right. Even more importantly, the encouraging efficacy and safety results from the inclisiran clinical development program have inspired us to develop what we believe could be a transformative approach to another common disease, resulting cardiovascular morbidity and mortality, namely hypertension. Zilebesiran is our investigational RNAi therapeutic for hypertension. Clinical data from the Phase I study have shown the impact of a single dose of Zilebesiran on his target angiotensinogen shown on the left here. On the right, you see associated reductions in systolic blood pressure with over 20 millimeters reductions, which were sustained 24 weeks after drug administration. My colleague, Dion Zappe, will share the rationale for the development of Zilebesiran, 4 Phase I data encompassing the safety and efficacy of single and multiple doses, the interesting and important pharmacodynamic effects, which distinguish Zilebesiran from current oral RAS inhibitors and the progress with our Phase II studies, Cardio 1 and 2. Separately, our mid- and early-stage pipeline continues to progress, both with new data and new INDs. My colleague, when I Go, will discuss these additional opportunities with you, including, but not limited to, exciting data from multiple studies for LNHBV02 conducted by our partner, VIA. -- positive Phase I proof of macansmdata from our first NASH drug, ALN-HSD in conjunction with Regeneron. LN APP, our first CNS drug in development for Alzheimer's and cerebral amyloid angiopathy, which is currently in Phase I and where we expect to have initial data in early '23. And finally, LNKHK for type 2 diabetes where we're on track to file a CTA imminently. Our focused R&D strategy driven by the selection of genetically validated targets has led to an impressive probability of success rate or POS. As you can see on the right of this slide, currently, our cumulative POS from Phase I to III is a remarkable 62%, which is far greater than industry averages around 5% to 10%. In spite of this enviable historical POS rate, it's critical that we remain disciplined in making important data-driven pipeline decisions. Some current examples of this type of pipeline prioritization that we're sharing today include the following: -- for cemdisiran monotherapy earlier this year, we reported impressive Phase II IgA nephropathy data, showing well over 30% reduction in proteinuria. Whilst we find these data encouraging, Regeneron recently decided not to participate in further development of the cemdisiran monotherapy program. As a result, we will now take some time to consider options for the best path forward for cemdisiran in this indication. Our Phase I data with ALN-XDH in development for Gal are now available and shown an encouraging safety profile with some evidence of change in serum urate. However, the degree of serum urate lowering we have observed does not reveal a transformative potential for the drug in gout, and as such, we have decided to terminate the program. Finally, our Phase II study of lumasiran in patients with recurrent kidney stones has been ongoing this year. However, in the early screening phase of the trial with a significant number of patients screened, it became clear that the proportion with elevated urine oxalate is lower than originally thought. The hypothesis that reducing elevated during oxalate in recurrent kidney stone patients could be beneficial is an important one. But with the current screening data, we will terminate the Phase II study and assess whether a small trial with a single investigator is warranted. The pipeline prioritization decisions I just shared with you illustrate the importance of exercising discipline when it comes to building a robust and high-yielding pipeline. Another key factor in the further growth of our pipeline is our sustainable innovation engine. For example, as shown on the left here, my colleague, Aimee Deaton will discuss how we have made great progress with our genetics program under the umbrella of the Alnylam Genetic Center, where we have discovered multiple non targets in recent years and where she'll discuss an exciting new liver target today. As importantly, is leadership in our platform and delivery sciences. My colleague, Vasant Jadhav, will discuss platform advances such as Ikaria, GEMINI and Reversia. Respectively, these approaches, we believe, will allow us to achieve annual dosing, enable us to hit multiple targets simultaneously and also provide the flexibility to reverse an RNAI effect, if needed. The further advancement of our platform and reaching the full potential of RNAi therapeutics involves achieving delivery to new tissues as shown on the right here. Our experience and know-how developing conjugates for the liver and CNS is serving us well and accelerating our experimental progress in getting RNAi therapeutics to many new tissues such as muscle, adipose and the heart. [indiscernible] is going to discuss these important advances with you. Ultimately, our scientific leadership should drive leadership in the clinic. A good example of that is shown here via our TTR portfolio. Bottom left, we started with patisiran an IV Q3 weekly drug for hATTR-PN. -- with platform advances and the development of the GalNAc conjugate technology for liver delivery, we progressed to vutrisiran, a subcu quarterly administered drug for hATTR-PN, which also has the potential to be administered biannually and where his profile is very suitable for development of not just hATTR-PN, but also ATTR-CM. Finally, top right, one of our most recent platform developments, Ikaria, allows the use of chemical modifications to drive potentially to annual subcu administration with our drug, LNT Terra C4, which should enter Phase I at or around year-end. With our chemistry and delivery platforms, we aim to drive continued and concerted innovation with progressively better product profiles to meet the needs of patients, doctors and the entire health ecosystem. We feel confident we can efficiently and rapidly use similar approaches as shown here, for other targets and indications in the current and future Alnylam pipeline. Let me close by sharing our 2023 goals, which show that we have a very exciting year ahead. Beyond progress getting out approved drugs to more patients, we look forward to FDA approval of patisiran for ATTR-CM in late '23 pending regulatory review and 10 clinical readouts from proprietary and partner-led programs. Specifically, these proprietary readouts include a potential sNDA submission from vutrisiran in early 2023, pending data on a biannual dosing regimen. Top line results from the Phase I study of LNT TRCF in late '23. Top line results from CARDIO 1 and 2 studies of Zilebesiran, ALN-APP top line Phase I results in patients with early onset Alzheimer's disease in early '23 and top line Phase I results from our LNK program for type 2 diabetes in late '23. We also anticipate progress with our alliance programs, including additional Phase III hemophilia results for fitusiran pondered with Sanofi, HBV and HDV Phase II data for LN HBV02 partnered with Via and the initiation of the ALN PNP Phase I NASH study by Regeneron. In closing, I want to say that Alnylam's R&D strategy continues to flourish as we make advances with our suite of liver-directed programs, but the future looks even brighter as we await progress with our CNS efforts and leverage our significant scientific strengths to address new targets and tissues. With that, I'd like to thank you for your attention and hand it over to my colleague, John vest, to review the exciting progress and future growth potential of our TTR franchise. John?

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 am very pleased for the opportunity today to update you on the programs and our plans to continue to expand the franchise. Additionally, Dr. Natacha Sarswat, in ATTR amyloidosis treating physician in clinical trialist has also joined us today to share thoughts on the unmet need in the patient population as well as her perspective on the future of treatment in the field. We now have 3 RNAi therapeutics in our TTR 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, for which we have recently announced positive Phase III results, but more on that later in the presentation. vutrisiran, an RNAi therapeutic, it gained its first approvals this year as AMVUTTRA utilizes ESC-GalNAc conjugate chemistry. It is also under further development in the ongoing HELIOS-A and HELIOS-B Phase III studies. 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 our other programs, this RNAi therapeutics specifically targets transitinmRNA. However, TTRSc04 utilizes our new Ikaria platform chemistry in its design, and we believe has the potential for once annual dosing in greater than 90% serum transthyretin reduction. Again, 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 TTR amyloidosis franchise and position us for sustainable market leadership. Collectively, as illustrated here, we intend to continue to build the TTR franchise over time, pending positive data readouts for the studies. I will be covering during the presentation and regulatory agency approvals we aim to have ONPATTRO, AMVUTTRA and ALN-TTRsc04 expand across the ATTR amyloidosis patient population over the coming years. Before we talk about specific studies or results, I'd like to briefly review the disease of TTR amyloidosis in our therapeutic hypothesis. TTR amyloidosis is a rare progressively debilitating disease caused by misfolded transthyretin 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 [indiscernible] diseases, the true prevalence is difficult to know, but we believe there are approximately 50,000 patients worldwide with the hereditary form of disease where the patient carries a TTR gene variant. Patients without a transthyretin variant can also accumulate misfolded transferation protein in tissues, often associated with advancing age, and this leads to wild-type ATTR amyloidosis. Prevalence 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 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 with an RNAi therapeutic to dramatically reduce the production of the disease-causing transthyretin protein in the liver will prevent continued amyloid deposition and potentially allow the body to remove existing deposits, ultimately halting or improving certain manifestations of the disease. Other treatment modality is attempt to interfere with the disease cascade at later points after the transfer in protein has been made and is circulating throughout the body. We strongly believe that suppressing the production of both 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've designed our TTR targeting RNAi therapeutics to do just that. This therapeutic hypothesis was first validated in the polyneuropathy of hereditary ATTR amyloidosis with the original APOLLO study. And as we'll discuss later in this presentation, we sought to validate this therapeutic hypothesis in patients with ATTR amyloidosis with cardiomyopathy and have now seen positive study results from our APOLLO-B Phase III trial. We would like to focus this presentation largely on our plans and efforts to expand RNAi therapeutics beyond polyneuropathy However, I would like to first take a briefly recap our exciting accomplishments in hereditary ATTR amyloidosis with polyneuropathy that unfolded over the course of 2022 as we are enormously proud of the progress that we made in bringing forward AMVUTTRA as a treatment option for these patients. To this end, we'll briefly take a look back at the HELIOS-A study of vutrisiran. As you may recall, 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 0.3 milligrams per kilogram once every 3 weeks, 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 in most secondary end points. The primary endpoint was the modified neuropathy impairment score plus 7 or mNIS+7. Quality of life is assessed by the Norfolk Quality of Life Questionnaire was a key secondary end point. Additional secondary endpoints assessed a wide range of important disease manifestations, including ambulatory function, nutritional status and disability. The study design included a primary analysis at month 9 and an additional analysis at month 18, with the full spectrum of clinical assessments were analyzed as secondary endpoints. The study is ongoing in a randomized treatment extension comparing the serum transparent in reduction of the 25-milligram quarterly regimen to the 50-milligram biannual regimen -- please note that our time line to share data for the treatment -- or from this treatment extension has shifted from the end of 2022 to early 2023 as we're awaiting the full data set. Here we're recapping key efficacy results from the study. The analysis for the primary endpoint was at month 9, the primary endpoint of mNIS+7 and the key secondary endpoint of Norfolk Quality of Life demonstrated a clinically and statistically significant improvement compared to the external placebo arm from the APOLLO study in this beneficial treatment effect persisted through month 18. -- indeed not shown but previously presented half the month 18 analysis, significant improvement with vutrisiran compared to external placebo was also observed for all other secondary endpoints, including ambulatory function assessed by the 10-year walk test, nutritional status assessed by modified body mass index and disability assessed by the rods instrument. Transthyretin reduction with vutrisiran was also confirmed to be noninferior to the within study patisiran arm based on prespecified criteria. Furthermore, an exploratory analysis of cardiac parameters, vutrisiran demonstrated favorable changes in NT-proBNP and certain echocardiographic parameters relative to external poll placebo. Importantly, as previously presented, vutrisiran also demonstrated an acceptable safety profile during the 18-month treatment period. These data from the HELIOS-A study have been the basis of our regulatory filings around the world, and we are absolutely thrilled that over the course of 2022, we have gained regulatory approval with AMVuTRa for hereditary ATTR amyloidosis patients with polyneuropathy in the U.S., Europe, the U.K., Japan and just earlier this month, Brazil as well to emphasize impressively approvals from 5 regulatory bodies have been secured in just the past 6 months. And of course, we intend to continue to expand the commercial AMVUTTRA footprint for hereditary ATTR amyloidosis with polyneuropathy in 2023 and beyond. Before we turn our attention to cardiomyopathy as a segue, I would like to highlight another notable study readout that occurred this year from our multicenter Phase IV observational study the Phase IV observational study evaluated the effectiveness of patisiran in patients with polyneuropathy of hereditary ATTR amyloidosis with a V122I or T60A variant, which are both variants that are frequently associated with cardiomyopathy manifestations of hereditary ATTR amyloidosis. The patient population was receiving commercial patisiran and was characterized in 1 of 3 cohorts, the prospective cohort where patients that are naive to patisiran at the time of enrollment, but intend to soon initiate therapy. The ambispective cohort where patients have been receiving commercially available patisiran for less than 12 months at the time of enrollment or the retrospective cohort, which includes patients who received commercially available patisiran for more than 12 months. The primary endpoint of the study was the proportion of patients with stable or improved polyneuropathy disability score, or PND score, at 12 months relative to baseline. A robust set of secondary endpoints was also evaluated, including Norfolk Quality of Life, Compass, modified body mass index, NT-proBNP in the Kansas City Cardiomyopathy Questionnaire. The study completed enrollment in June of 2021 with a total of 67 patients. These data were intended to complement the results of the APOLLO study as they further expand our understanding of the potential benefit of patisiran in hereditary ATTR amyloidosis patients with polyneuropathy due to these specific genetic variants where limited data or otherwise available. The study results demonstrated that patients with the V122I or T60A variant, which again are variants historically associated with cardiomyopathy also had evidence of polyneuropathy at baseline, as demonstrated by impaired quality of life, autonomic dysfunction and a wide range of ambulatory - a wide range of ambulatory dysfunction. The primary endpoint of the study was met, with 93.3% of patients demonstrating stabilization or improvement from baseline in polyneuropathy disability score after 12 months of patisiran treatment. As shown here, patients on patisiran treatment also demonstrated evidence of improvement from baseline in 2 key exploratory measures of quality of life. The Norfolk Quality of Life Questionnaire, which is typically used to assess quality of life in patients with polyneuropathy as well as the Kansas City Cardiomyopathy Questionnaire, which is typically used to assess health status and quality of life in patients with cardiomyopathy. Furthermore, patients on 12 months of patisiran treatment also demonstrated exploratory evidence of improvement from baseline in measures of autonomic symptoms as assessed by the COMPASS-31 instrument, including improvement in the orthostatic intolerance domain of the COMPASS-31, which reflects a particularly debilitating aspect of this disease for many patients. And as noted in the final bullet here, nutritional status as measured by modified body mass index also improved in patisiran-treated patients with an improvement from baseline observed at month 6 and maintained through month 12. Patisiran demonstrated an acceptable safety profile, consistent with the known profile of the drug, 11 patients were hospitalized during the study and 3 patients subsequently died. All hospitalizations and deaths were considered unrelated to patisiran. In summary, we're very pleased to be able to bring more data to the field describing the real-world patisiran experience in patients with V122I and T60A variants. Patients with these variants, which are historically associated with cardiomyopathy also experienced polyneuropathy at baseline. The primary endpoint of the study was met, and 93.3% of patients demonstrated stabilization or improvement from baseline in polyneuropathy disability score after 12 months of patisiran treatment. And importantly, patisiran demonstrated an acceptable safety profile. We will now move on to look forward and talk about our ongoing expansion into ATTR amyloidosis with cardiomyopathy and beyond. We feel extremely encouraged about the potential for vutrisiran and patisiran in ATTR amyloidosis with cardiomyopathy. While we now have data from APOLLO-B, we embarked on our cardiac program in the context of a sound foundation of evidence giving us confidence in the potential for RNAi therapeutics in the space. Thus, the results from our cardiac studies come in the context of a rich background of supportive evidence. As we have presented previously, the original APOLLO study of patisiran demonstrated exploratory evidence for improvement in cardiac biomarkers, echocardiographic parameters in ambulatory function with patisiran treatment compared to placebo. The significance of these improvements in cardiac assessments was supported by a 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 hospitalization over the course of this 18-month randomized controlled study. These initial data from the APOLLO study were complemented by data published by the National Amyloidosis Center in London 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 fraction in patients who received patisiran, the majority of whom also received iflunazol 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 has demonstrated compelling evidence of substantial amyloid regression. While these exploratory and post hoc while these exploratory and post-hoc analyses, we believe collectively demonstrate a consistency of findings across a wide spectrum of parameters and provide important context and confidence for the hypotheses we're pursuing in our cardiac studies. Indeed, with our ongoing studies in ATTR amyloidosis with cardiomyopathy, APOLLO-B with patisiran and HELIOS-B with vutrisiran. -- we are seeking to validate this hypothesis. The TTR reduction with an RNAi therapeutic will stabilize disease progression and result in clinically meaningful benefits and ultimately improved outcomes. APOLLO B has now read out, and we believe provides compelling data to support patisiran as a potential treatment option pending regulatory approval based on its important beneficial impact on how patients feel and function. HELIOS-B is our ongoing study of vutrisiran, which is designed to provide outcomes data. The study is fully enrolled and on track for top line readout in early 2024. -- we will discuss APOLLO-B and HELIOS-B further in the -- later on in the presentation, but I'd first like to turn the presentation over to Dr. Nitasha Sarswat, Assistant Professor of Medicine and Director of the cardiac amyloid program at the University of Chicago Hospitals for an update on the current state of ATTR amyloidosis.

Thank you, Dr. Vest. Today, I'm privileged to discuss with you the state of ATTR amyloidosis with cardiomyopathy. My disclosures, I am a consultant of Alnylam and my institution is receiving compensation for this presentation. I am also an investigator on the APOLLO-B and HELIOS-B studies, which are sponsored by Alnylam. So I'm going to start by discussing a very familiar case, and this is a type of patient that certainly I see all day long every day. Patient MD is a 76-year-old male who has been very active throughout his life who loves traveling, biking, traveling throughout Europe. Over the last few years, he had developed worsening [indiscernible] fatigue and didn't feel like he could keep up with his wife on a hike. He did have a history of spinal stenosis, bilateral carpal tunnel disease and actually had had a right carpal tunnel release about 8 years ago. He also has a history of atrial fibrillation, hypertension and some foot numbness. On exam, when I met him, he had an elevated jugular venous pressure of 8 centimeters suggesting volume overload, and irregularly regular heartbeat. His extremities were warm and well perfused, but he did have 1 plus edema bilaterally. He was noted to have a significantly elevated proBNP in troponin and an echocardiogram and cardiac MRI at the time of i met him that were both consistent with amyloidosis of the heart. When I met him in clinic, he had been reading on the Internet that amyloid was a death sentence. And certainly, we had a long discussion regarding the disease, the history of the disease, recent changes and some new hope on the horizon for a patient like him-- after this discussion, we proceeded with an AL rule out, which included an SBA PAP and light chains that were all normal. I sent him for PYP, technician PYP, which showed significant amyloid deposition. It was a grade 3 and did show a heart-to-lung ratio of 1.8 -- at that point, we also did genetics, specifically looking for a mutation in the TTR mutation, and they were negative as well. He returned to clinic for a discussion. And at that point, we had a long discussion regarding the idea that we had noninvasively now diagnosed cardiac TTR amyloidosis from our diagnostic algorithm and that he specifically had wild-type transthyretin cardiomyopathy. We had a review of medication options that were available to him and the data that we have thus far and really had a nice informed discussion. And this is common in practice for patients with wild-type TTR to review medication options and really review the options that we have to try to improve mortality, morbidity and how we can make them feel though. So that's going to launch us into this discussion. So the big things are how is -- how big is this population that's impacted by the disease that would potentially benefit from further treatments. What is the unmet need in terms of ATTR amyloidosis treatment, and we'll continue to come back to patient MD, who is a patient whose life is affected by discussions like we're having today. So first of all, why is heart failure so important? And heart failure, again, is the presenting symptom in the majority of these patients. Heart failure affects nearly 6.2 million Americans and is the primary diagnosis for a hospital discharge in about 1 million. a secondary diagnosis in about 2 million hospitalizations annually. And by 2030, more than 8 million people in the United States, we think 1 in every 33 will actually have heart failure. And this plays into really understanding the burden of the disease and just how common this disease is. Now what we see from heart failure is that this is truly an epidemic. The cases are rising and rising and this is not being mitigated and going away. But you get a sense of just how many people throughout the world are really going to be affected by heart failure as time goes. Now if we take all the patients of all those patients that have heart failure and why is this relevant to this particular conversation is that out of those people, slightly more than half of them actually have heart failure with preserved ejection fraction. And of those with heart failure with preserved ejection fraction, it's estimated that anywhere from 13% to 29% of those patients actually have cardiac amyloidosis. There was a recent study that [indiscernible] from Abu azadine, which looked at over 1,000 patients with an LV wall thickness of 12 millimeters, which is actually quite common. And what we found is that about 10% of men and 2.2% of women actually had TTR cardiomyopathy. Some other relevant data to understand the population. In a recent autopsy study, we found that 25% of patients greater than 80 actually had some level of TTR deposition in the heart. And of those, 2/3 had left ventricular involvement, and we saw significant cardiac involvement and anywhere from 8% to 16% of people greater than 80 years old. And while this is an autopsy study and certainly can have flaws that really just gives us a sense of just how many people actually have a level of amyloid deposition. Similarly, there was a recent study of patients undergoing TAVI for aortic stenosis. And they did a technetium PYP looking for amyloid deposition in these 150 patients. And in fact, 16% of them had evidence of true significant amyloid deposition. Similarly, when we look at the population of patients admitted in the hospital, which we talked about was a very growing number of patients, we see that heart failure with preserved ejection fraction in the hospital, about 13% of them actually probably have a level of TTR cardiac involvement. So again, just to hit home, this is affecting a large burden of patients, and this is not going away. Those numbers are just going to continue to increase. We think about 15,000 people or 5% at least of the estimated half prevalence have ATTR, though we may have milder deposition and many others. The Valley isoleucine mutation, which we see is the largest common mutation in the TTR gene in the United States has been found in 10% of African Americans over the age of 65 who have heart failure. We do know that the survival of these patients with wild-type TTR cardiomyopathy has also been observed as with worsening declining NYHA functional classes. And we know that patients who have worsening NYHA functional classes is an independent risk factor for adverse cardiovascular outcomes that include conduction disease, hospitalization and stroke. So where there is this population of significant heart failure with advanced symptoms, NYHA 3 to 4, and those are the people that are often untreated and that are going to have the worst outcomes. So let's talk about this unmet need of patients with TTR cardiac amyloidosis. So what are options? And when I talk about that patient MD that we had, what is this informed discussion I have. So our therapeutic approaches. The first thing we can do is actually stabilize the TTR tetramer. And we can do this in 1 of 3 potential ways. So the first is tafamidis, which is the approved -- the only FDA-approved treatment for wild type or hereditary amyloidosis in adults and reduces CV mortality and CV related hospitalizations. There is some data for diflunisal and we'll discuss this. And then we also have acoramidis, which is an investigational therapy for the potential treatment of cardiomyopathy and TTR amyloid, which has completed and enrolled -- completed a Phase III trial. The second options are reducing TTR production. So we have several opportunities here. So the first is patisiran, which right now is approved for the treatment of polyneuropathy of hereditary TTR amyloidosis and is an investigational therapy for the potential treatment of cardiomyopathy. Similarly, vutrisiran is now approved for the treatment of polyneuropathy for hereditary TTR amyloid, but is investigational for the potential treatment of cardiomyopathy -- we have inotersen, which is approved for the treatment of polyneuropathy or hereditary transthyretin-mediated amyloidosis in adults and aplonoterasin, which is an investigational therapy as well for the potential treatment of polyneuropathy, hereditary TTR and an investigational therapy for the potential treatment of cardiomyopathy of TTR amyloidosis. Other options may include there is some data for doxycycline and Tudco or torodeoxycholic acid and certainly, a very hopeful potential therapy going forward is CRISPR gene editing, though we're certainly trying to understand the role that this new technology can potentially have for our patients. So we talked about these therapeutic options. And what we see is that right now, there are these approved therapies for polyneuropathy, but very minimal approved therapies for cardiomyopathy. Well, why is that? When we look at the underlying pathophysiology of TTR amyloidosis. We understand that there's this tetramer that becomes unstable. And I always tell patients, it's like a 4-leaf clover that falls apart into one lease clovers. -- those one leave clovers develop misfolded proteins that come together to form amyloid fibrils. Those amyloid fibrils that can deposit in the heart, in the nerves and then the autonomic nervous system. So while the manifestations may be different, it's all the same underlying pathology in all one disease. And yet our treatments thus far have only targeted a fraction or a portion of the actual symptoms and manifestations of the disease. So let's just go back to our specific patient. What are his options right now? Again, he has wild-type transthyretin cardiomyopathy. -- is really only option at this point is a stabilizer. He cannot afford his tafamidis co-pay and does not qualify for any patient assistance. So again, there are these patients whose needs to remain unmet by these current treatments because of affordability and access. And then we have current TTR silencer therapies that are approved only for the hereditary neuropathy. Similarly, what about those patients that get stabilizers and don't respond and who continue to significantly progress despite therapy with a stabilizer. And then we also know that despite these therapies that are available, quality of life remains a significant issue and a lot of patients are very impacted on a day-to-day basis despite current therapy. So let's go through again what we have. So we know that tafamidis, again, which is approved for wild-type and hereditary cardiomyopathy showed in the ATTRACT trial showed a significant improvement in mortality. We see those curves start to separate and we know that the patients who were on tafamidis did better than those who were on placebo, but we also see that there's still a continued progression of disease despite therapy. When we look at the subgroup analysis from this ATTRACT study, we see that both hereditary and wild-type patients were benefited by tafamidis therapy. But when we look at NYHA classes, again, the healthier patients were the ones that benefited -- the Class III patients, there was a questionable benefit and the Class IV patients were excluded from the study. So what do we have to offer a patient who right now has Class III symptoms who may or may not benefit for tafamidis or who cannot get tafamidis?. So this is actually a study that we did looking at patients in a community heart failure, a community system that were diagnosed with TTR amyloid, and we looked at 107 patients with -- that were about 84 years old, the majority were men, and only 59% of them were actually on tafamidis. Those patients who were on tafamidis did better. The people that were not on tafamidis tended to be the patients that had resticker again, the NYHA 3s and 4s. And the most common reasons the patients were not on tafamidis were because of delays in obtaining the drug or financial barriers, which is 59% of the people and about 20% of people that were just too sick and had NYHA Class IV heart failure. The patient taking tafamidis had a higher survival, which is similar as we would expect with compared to people who are not getting it, similar to what we would expect with the ATTRACT trial and we see that there was a survival benefit. So what are other options for people who can't we can't get tafamidis. So diflunisal has been studied more retrospectively, not in a prospective randomized controlled trial diflunisal is essentially an NSAID, a nonsteroidal anti-inflammatory drug, which binds and stabilizes to the TTR tetramer, similar to tafamidis. But what we know is that we generally shy away from any medications in this class in our patients that have significant heart failure. This has been somewhat controversial and that's because of the potential adverse effects for with NSAIDs for patients with heart failure and others, which include GI bleeding, renal dysfunction, worsening fluid retention and hypertension. And we're still trying to understand the role of that diflunisal can play in our patient's lives. So what we see is that there are these patients who are Class III/IV who potentially cannot either get on tafamidis or will progress despite tafamidis and -- or who just don't benefit because they're already too sick. So just to review, the Class III and IV patients are the ones that are most significantly affected. They have a marked limitation of physical activity or cannot do normal physical activity and have symptoms even at rest. Well, certainly, we have other things to offer patients who have significantly advanced heart failure, and this is a big part of my career is trying to offer these other patients with heart failure options. However, none of those options unfortunately really apply to the amyloid population. So we have things like Verastem. We have cardiac modulation therapy. We have ENTRESTO. We have vericiguat. We have omecamtiv, all of which look very promising as therapies for advanced heart failure, none of which have been studied in amyloid and none of which are available to any of these patients or have a sense that they would help the underlying disease or help symptoms in any of our patients. So we're stuck. Similarly, for patients who don't have amyloid, we can offer things like LVAD therapy. Now again, LVADs are generally not helpful in our amyloid patients because what we see is that the LV cavity is very small and that by introducing an LVAD, where we're actually removing and pulling blood out of the alpicavity are actually worsening the patient symptoms. There are a select group of patients who with amyloid cardiomyopathy can actually have enough LDdilation to potentially withstand in ALVAD. But certainly, this is not a therapy we can count on and not something that we are commonly offering by any means to our amyloid population. Similarly, transplant. The Class III/IV patients with normal heart failure that we're often able to offer for transplant, we're in a tough situation. A good portion of our amyloid patients that are at the time of diagnosis have already aged out and were unable to offer this therapy. Similarly, when we talk about other manifestations of amyloids such as autonomic dysfunction and the neuropathy, those patients often we can't offer transplant to when they have a multisystemic disease -- so we know that there is this unmet need, where these patients with TTR cardiomyopathy cannot get the therapies they need to potentially make them live longer. And certainly, then there is the issue of quality of life. So a lot of these patients, despite therapy, continue to have shortness of breath, leg swelling fatigue and develop ataxia. They have conduction disorders and arrhythmias and autonomatiofibrilation, which leads to ablations, therapies, all sorts of things, WATCHMAN devices and things like that, which we don't have any current treatment for the underlying disease that we know would prevent atrial fibrillation or any of those symptoms. For our patients that have wild-type [indiscernible] that may have a component of neuropathy as well, we have nothing to offer. Patients can often develop even large fiber neuropathy, which can lead to wheel chair confinement. And then certainly, the autonomic dysfunction, arrhythmias orthostatic hypotension, gastrointestinal general and urinary disturbances. These type of symptoms are constantly plaguing our patients, and we have no targeted therapy for a lot of our wild-type cardiomyopathy patients or hereditary patients that don't have polyneuropathy. So let's go back to this patient. So he was unable to get tafamidis therapy, again, because of cost and access issues. He had a progression in the symptoms and actually had trouble making it through his daughter's wedding. He's now been on diflunisal therapy for 6 months, but has shown significant progression in his symptoms. He sends me messages frequently honestly, on almost a daily basis asking about the ability of new drugs that could potentially help him feel better. We really continue to need more options to help improve the quality of life and availability of medications to this group of patients. Thank you. And back to Dr. Vest.

Thank you, Dr. Sarswat that really was a fantastic overview, which really highlights the remaining unmet clinical need and the overarching need for additional treatment options for this patient population. With that context, I'll now turn back to further discuss our ongoing studies in ATTR amyloidosis with cardiomyopathy, starting with APOLLO-B. By way of reminder, the APOLLO-B study of patisiran enrolled 360 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 study was designed to demonstrate the impact of patisiran on functional status with the primary end point in the change from baseline in 6-minute walk test at 12 months and health status and quality of life with the first secondary endpoint being the Kansas City cardiomyopathy questionnaire -- these are both recognized measures of clinical benefit in heart failure. And in the context of the existing unmet need, we identified these as endpoints that can allow us to bring patisiran and the potential benefits of this therapy to this patient population as swiftly as possible. While the study was not designed to demonstrate a treatment effect on outcomes of death and hospitalization, these were also included in the secondary endpoints. And the study also included a robust package of important exploratory endpoints, such as cardiac biomarkers and cardiac imaging. We were absolutely thrilled to announce in scientific meetings several months ago, the positive results of this study, and we are further pleased to announce last week that we have now submitted a supplemental application to the FDA for patisiran as a potential treatment of the cardiomyopathy of ATTR amyloidosis.. Here, we are looking at the baseline demographics between the 2 treatment arms. The study enrolled patients who are representative of the worldwide population of patients with ATTR amyloidosis with cardiomyopathy, including a broad spectrum of disease severity and a wide range of TTR genotypes and other disease manifestations. The treatment arms were well balanced, and disease characteristics on the 2 arms were largely overlapping and overall, were clinically comparable at the start of the double-blind period, thus supporting the effectiveness of randomization and the validity of comparisons between the treatment groups. -- characteristics were also consistent between patients receiving tafamidis at baseline and those patients not receiving tafamidis at baseline. Consistent with the known pharmacodynamic profile of patisiran, patisiran resulted in rapid and sustained reduction of the disease-causing transthyretin protein with a mean reduction of 86.8%. It should be noted that data not shown here but previously shared at the HFSA meeting, comparable serum TTR reduction with patisiran was observed irrespective of baseline tafamidis treatment. Patisiran met the primary endpoint of the study, demonstrating statistically and clinically significant benefit in functional capacity assessed by the 6-minute walk test compared to placebo at 12 months. As expected, based on the recognized natural history of ATTR amyloidosis, Patients in the placebo group showed a steady decline in functional capacity with a median change from baseline in 6-minute walk test distance at month 12 of negative 21.35 meters. In contrast, a much smaller decline of negative 8.15 meters was observed in the patisiran group. This observed change from baseline in the patisiran group over 12 months is comparable to the age-related decline expected in healthy adults of approximately 5 to 6 meters per year, thus indicating relative stability of disease progression in patisiran-treated patients. The study also met the first secondary endpoint, which was the Kansas City Cardiomyopathy Questionnaire overall summary score, which is an important measure of health status and quality of life. a pattern similar to that observed with a 6-minute block test was observed for the KCCQ. Over the double-blind period, patients in the placebo group showed a steady decline in KCCQ with a mean change from baseline of negative 3.396 points. In contrast, an improvement of 0.478 points was observed in the patisiran group, indicating relative stability in health status and quality of life over 12 months in patisiran-treated patients. Thus, a clinically meaningful and statistically significant change in KCCQ at month 12 was demonstrated with patisiran compared to placebo. With an [indiscernible] difference of 3.7 points and a p-value of $0.0397 million. The treatment benefit was consistent across all KCCQOS domains, which include physical limitations, total symptoms, quality of life and social limitation as well as nearly all the questions within each of these domains. These results provide important insights into how placebo-treated patients manifested ongoing disease progression and how patisiran treated patients experienced preservation of health and quality of life over the 12 months of treatment. This study was not powered to show a treatment difference in composite endpoints that assess morbidity and mortality for the 12-month double-line period. And the study did not achieve statistical significance for outcomes. However, certain favorable trends were observed. Specifically, the stratified win ratio of 1.27 for patisiran versus placebo, with a p-value of 0.057 for the composite endpoint of all-cause mortality, frequency of CV events and change from baseline in the 6-minute walk test at month 12 suggests a trend toward benefit of patisiran compared to placebo. Additionally, as shown on this slide, a prespecified analysis of all caused mortality during the double-blind period numerically favored patisiran. In the overall population, all-cause deaths were observed in 10 or 5.6% of placebo-treated patients compared to 4 or 2.2% of patisiran-treated patients. As specified in the statistical analysis plan, this analysis treated heart transplants as deaths and did not include that due to COVID-19. Consistent results were observed in both patients on baseline tafamidis and in patients not on baseline tafamidis. Here, we are showing the exploratory results for the cardiac biomarkers, NT-proBNP and troponin I, which reflect cardiac stress and heart failure severity in myocardial damage, respectively. These are clinically important biomarkers that are routinely monitored in clinical practice and are incorporated and recognized ATTR amyloidosis disease staging systems and an expert consensus for defining disease progression. Furthermore, NT-proBNP levels, an increase in levels are recognized as product agnostic of outcomes in ATTR amyloidosis. Over the double-blind period, the placebo group showed a steady increase or worsening in the levels of both of these biomarkers. Of note, the substantial rise in these biomarkers in the placebo arm by month 12 was in line with published expert consensus criteria by Garcia Papia at all for disease progression, i.e., a 30% increase in either NT-proBNP or troponin I, while in market contrast, the patisiran group demonstrated relative stability, resulting in a nominally statistically significant beneficial treatment effect for both biomarkers at month 12. As alluded to on the previous slide, these biomarkers, along with ATTR disease stage, which is based on NT-proBNP and EGFR, have been incorporated into published expert consensus criteria for defining disease progression. Based on these published criteria, the post-hoc exploratory analysis was done on APOLLO-B biomarker data to determine the proportion of patients who did not meet criteria for disease progression. As shown in the left-hand column, the criteria for NT-proBNP, troponin I and ATTR disease stage, indicating no progression were an NT-proBNP change of less than 30% or a change of less than 300 nanograms per liter, Troponin I change of less than 30% and no increase in ATTR disease stage. As shown in the forest plot compared to placebo, patisiran patients were significantly less likely to experience disease progression based on the composite of these 3 criteria or by any of the individual criteria. Indeed, patisiran patients were approximately twice as likely as placebo patients to not experience disease progression. We believe these data underscore the relevance of the demonstrated treatment effect of patisiran on cardiac biomarkers and further support the primary results of the study. It is also notable that in a separate analysis of change over time in NYHA class, worsening occurred more frequently in the placebo group, 24.1% versus the patisiran group at 13.6% at month 12. A further note, patisiran treatment also resulted in a benefit or trend towards benefit in change from baseline of most echocardiographic parameters, reflective of cardiac structure and function compared with placebo at month 12. -- of particular note were the nominally significant beneficial effects compared to placebo in global longitudinal strain, which is reflective of systolic function and in LV mass. LV mass increased in the placebo arm, which is potentially consistent with ongoing amyloid deposition. The magnitude of the increase is similar to that reported in a recent natural history study by Chaco [indiscernible]. We were also very excited about the exploratory results from a planned cohort of patients with technetium Syntigraphy imaging, which is a noninvasive assessment of cardiac amyloid involvement. An analysis of technetium centigraphy, parageni-grading is a visual assessment of technetium uptake in the myocardium compared to bones, which is widely used to make the diagnosis of ATTR amyloidosis. -- and 100% of evaluable cyntigraphy patients in the patisiran arm, per genie grade was reduced or demonstrated no change from baseline at month 12 with 37.8% of patients in the patisiran arm demonstrating a reduction from baseline of greater than or equal 21 parogenia grade, including 3 patients who were educed by greater than or equal to 2 pair genie grades at month 12. And no patient in the patisiran arm increased from baseline in [indiscernible]grade at month 12. In contrast, among evaluable patients in the placebo arm, no patients had a [indiscernible] grade that was reduced from baseline at month 12. Importantly, in the double-blind period of APOLLO-B, patisiran demonstrated an acceptable safety profile that is consistent with the known profile of patisiran from other studies and post-marketing experience. AEs were mostly mild or moderate. AEs have served more commonly in the patisiran arm included infusion-related reactions, arthralgia and muscle spasms. SAEs, severe AEs and AEs leading to discontinuation or balanced between the treatment arms. It should specifically be noted that there were no cardiac safety concerns. And indeed, patisiran demonstrated fewer events within standardized metro queries, exploring potential cardiac safety issues, including cardiac arrhythmias and cardiac failure compared to placebo. So as you can see, in summary, we're very pleased that the totality of the data coming out of APOLLO B, we feel the study validated the therapeutic hypothesis that RNAi therapeutics targeting transthyretin like patisiran have the potential to positively impact measures of ATTR amyloidosis with cardiomyopathy. We feel the results show a favorable benefit risk profile across multiple clinically important measures, including functional capacity, quality of life, biomarkers and imaging assessments. Thus, the APOLLO-B study demonstrated the potential benefit of patisiran treatment in patients with the cardiomyopathy of ATTR amyloidosis, and it did so in just 12 months. As most of you are likely aware, in parallel with the APOLLO-B study of patisiran, our Phase III cardiac outcome study with vutrisiran, HELIOS-B, is ongoing. The study, which was designed to enroll approximately 600 patients is a randomized, placebo-controlled trial. Like APOLLO-B, all patients have confirmed hereditary or wild-type ATTR amyloidosis with cardiomyopathy at baseline 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 cardiovascular 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 in August of 2021, much earlier than originally expected, and we anticipate top line results from the 30-month endpoint in early 2024. We recently announced that we would not be proceeding with the optional interim analysis in the HELIOS-B study given the relatively short time line to the full study readout, allowing the study to run to completion will help us to generate the strong as possible data package and positioned putrisiran to be a highly compelling and differentiated product among other treatments in this space. 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 TTR amyloidosis franchise. This new investigational sRNA targeting transthyretin was generated using our [indiscernible] platform. Preclinical development suggests exquisite specificity for the intended target in nonhuman primate studies, which have demonstrated remarkable potency. Collectively, we believe the profile of TTRsc04 could support an annual dosing regimen with greater than 90% serum transfer and reduction. In advancing the Ikaria platform, we're very excited about 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 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. We are preparing for an initial Phase I study of TTRSC04 in healthy volunteers, which we plan to initiate at or around year-end of 2022. Phase I top line data would then be anticipated in late 2023. 2022 was a landmark year for our TTR franchise with the approval of AMVUTTRA in major markets around the world for the treatment of hereditary ATTR amyloidosis with polyneuropathy and the readout of APOLLO-B in ATTR amyloidosis with cardiomyopathy. With that said, there are numerous significant and impactful goals and milestones ahead for the TTR franchise, including initiation of a Phase I study of ALN-TTRSC04 at or around year-end of 2022. With the readout of vutrisiran, biannual dosing data now expected in early 2023. We also have the goal of submission of a supplemental new drug application for vutrisiran biannual dosing regimen in early 2023. The goal of achieving patisiran approval from the U.S. Food and Drug Administration in late 2023 for the treatment of the cardiomyopathy of ATTR amyloidosis. Continuing global launches of AMVUTTRA and hereditary [indiscernible] amyloidosis for polyneuropathy, reporting top line ALN-TTRSC04 Phase I study results in late 2023 and importantly, rigorous execution of the ongoing HELIOS-B Phase III study with top line data in early 2024. We could not be more excited about the accomplishments to date, and we look forward with great anticipation to bringing further innovative therapies to patients in the years to come. With that, I thank you for your attention and would like to hand the presentation over to Dion Zappe who will review the latest progress with our Zilebesiran program, Dion?

Thank you, John. Hello, I'm Dion Zappe, Executive Director of Clinical Development at Alnylam. I lead the clinical research team in the development of Zilebesiran, an investigational and innovative RNI interference therapeutic for the treatment of hypertension. I'm very excited today to give you an overview of our ongoing Phase II program with our 2 cardio studies, focusing on the management of hypertension. As you'll hear in this presentation, we believe Zilebesiran has the potential to drastically change the way hypertension is currently managed by addressing one of the biggest challenges with current treatments, inconsistent and ineffective blood pressure lowering primarily due to medication non-adherence. It is well recognized that hypertension is a highly prevalent disease with over 200 million people with primary hypertension in just the 7 major markets. Hypertension poses substantial risk for cardiovascular morbidity and mortality, if not effectively treated. Despite the widespread availability of treatments to manage the disease, more than 70% of hypertensive patients are not at their target blood pressure goal. Factors for poor control of hypertension include lack of intensification of therapy and poor adherence to treatment with which both contribute to the low blood pressure control rates, and as a result, a heightened risk for cardiovascular disease. Despite the widespread availability of numerous oral antihypertensives across a number of different drug classes, these once-a-day therapies cannot adequately address the unmet need of medication nonadherence in hypertension. Indeed, improving the management of hypertension includes more than blood pressure lowering. It is done with the hope of further reducing cardiovascular risk and end organ damage. To do this, you need to achieve a magnitude of blood pressure reduction to reach a target blood pressure, which is the quantity of blood pressure control, but you also need to reduce blood pressure consistently throughout the 24-hour period, including nighttime blood pressure and over the long term, that is blood pressure variability. And we call this the quality of blood pressure control. So tonic blood pressure control should then include a treatment that targets not only the quantity of blood pressure lowering but also the quality of blood pressure lowering to reduce blood pressure variability over time and within the 24-hour period to address the key unmet need in hypertension management. We believe zilebesiran, a novel investigator RNI therapeutic can address the unmet need and hypertension. zilebesiran is a [indiscernible] conjugated small interfering RNA targeting the hepatic production of angiotensinogen, or AGT, the most upstream product of the renin-angiotensin system or RAS. The RAS is one of the key regulatory systems underlying blood pressure control. In essential hypertension, it is this system, which is typically dysfunctional with the reninangiotensin system being inappropriately elevated. Silencing the messenger RNA that would encode for AGT or angiotensinogen, it's the most upstream precursor for the RAS, therefore, blocking the production of angiotensin 2 essentially removes the key factor needed to activate the Renanagetes system. It is this approach that differentiates it from oral RAS blockers. These drugs suffer from poor adherence and the possibility of RAS escape limiting their efficacy. In clinical trials, zilebesiran is being dosed infrequently via subcutaneous injection with prolonged duration of pharmacologic action. This durability of effect could potentially provide both improved medication adherence and consistent durable blood pressure control. The clinical development of zilebesiran began over 3 years ago. Of course, this began with our Phase I study, a multicenter trial designed to evaluate safety, tolerability, the pharmacokinetic pharmacodic effects of subcutaneous administration of zilebesiran in patients with mild to moderate hypertension. The study was conducted in 4 parts. Today, I'll review the results from these various parts, and we believe these provide the initial indication of zilebesiran clinical profile and its potential to address the unmet need in hypertension. It's worth noting that some results from Parts 1, 3 and 4, included in this presentation have been previously presented. Results from Part 2 are being presented today for the first time as well as some biomarker data from Part 1. So let me now review results from Part 1, a randomized, placebo-controlled, single-ascending dose study aimed at establishing single-dose proof-of-concept. In part 1, treated or untreated hypertensive patients received either a single dose of zilbesiran across 7 doses with 8 patients per cohort or placebo with 4 patients per cohort. So this study was conducted in an outpatient setting, allowing patients usual daily activity and dietary sodium intake. The study evaluated the safety and efficacy of zilebesiran after a single dose, specifically to assess its long-term effects on angiotensinogen, blood pressure, safety and as mentioned, to establish the single dose proof of concept. The dose-ranging study with zilebesiran confirmed what we had anticipated, a dose-dependent effect with target engagement clearly achieved. zilebesiran administration demonstrated a reduction of greater than 90% in serum angiotensinogen from baseline with single doses of zilebesiran from 100 to 800 milligrams from week 3 and sustained up to 12 weeks. All patients who received a single dose of zilebesiran-800 milligrams maintained greater than 90% reduction in serum angiotensinogen levels through wood24 or 6 months. This effective and sustained inhibition of angiotensinogen is critical to zilebesiran's ability to chronically inhibit the renaNago1en system and its proposed durability of effect, something standard oral RAS blockers have never been able to achieve. Thinking in more detail about the mechanism of action of zilebesiran in comparison to standard oral RAS blockers and their effects on the renin-angiotensin-aldosterone system cascade, you will see some important differences. If you look at current agents on the market, such as angiotensin receptor blockers, they act on downstream mediators of the RAS, specifically angiotensin 2 receptors or AT1 receptors to lower blood pressure. However, by acting on downstream mediators, there are counter regulatory rises in Renin and also increases in angiotensin 2 as depicted here with the ARBs Increases in Renin associated with ARB treatment lead to increases in angiotensin 2 levels higher than pretreatment, which can overcome blockade of the angiotensin receptor causing loss of blood pressure lowering effect. This is further compounded by the requirement of oral therapies to be dosed daily leading to medication adherence concerns, which can lead to variable blood pressure lowering. Thus, the possibility for escape from the effects of current oral RAS blockade can result in a modest blood pressure lower in response. It is evident then in our view that there are a number of potential mechanistic disadvantages with angiotensin receptor blockers and broader oral RAS blockers. First off, short duration of action, which facilitates variable blood pressure reductions and the potential for incomplete RAS inhibition. Daily dose administration, which carries the potential for low treatment adherence and this RAS escape phenomenon with subsequent loss of antihypertensive response to potentially avoid these disadvantages and get optimal blood pressure control, we believe it may be more effective to dampen the whole renin-angiotensin industrial system pathway by acting further upstream, that is by silencing liver-derived angiotensinogen. Angiotensinogen is the primary substrate and the sole precursor of all angiotensin peptides, including the generation of angiotensin-2. Thus by silencing angiotensinogen, you can effectively shut down the involvement of the RAS in hypertension. So what effect does zilebesiran have on the reninangiotensin-aldosterone system? Well, the increase in renin depicted here with zilebesiran treatment is caused by the silencing of AGT, which is Reninsubstrate. This increase in Reno is not expected to lead to Rascape as the silencing of AGT works to deplete levels of angiotensin 2, whereas angiotensin 2 levels increase with ARBs and in some cases, high enough to even overcome the receptor blockade. In summary, our RNI approach with zilebesiran potentially confers a number of mechanistic advantages, including liver-specific AGT silencing, prolonged duration of action, consistent and durable blood pressure response, infrequent dose administration, that is injection every 3 or 6 months. and thus the potential for improved adherence with more effective RAS inhibition potentially avoiding the escape from an associated with oral RAS blockers. So how does zilebesiran affect the RAS biomarkers? If we are right with this new data, which has never been previously presented, we should see a differential effect of zilebesiran on the RAS biomarkers. On the left-hand side, the graph shows increases in plasma renin. Now as mentioned before, a dose-related rise in plasma renin is a response to the effectiveness of the angiotensinogen silencing. This is indeed what we saw in Part 1 of our Phase I study, sustained increases in plasma renin at weeks 12 and 24. These increases in plasma renin concentration were associated with the reduction in angiotensin2 and aldosterone, as shown on the graph on the right-hand side. The changes in the RAS biomarkers associated with angiotensinogen silencing demonstrate the potential ability of zilebesiran to affect more complete inhibition of the renanagatensasome and thus avoid the RAS escape, which is associated with oral RAS blockers. With this kind of control on the RAS cascade, one would expect excellent quantitative and qualitative effects on blood pressure control. And this is what we saw with the single dose effects of zilebesiran . As shown in the left graph, the reduction in systolic blood pressure with zilebesiran-treated patients was consistent and stable at all time points over the entire 24 hours at week 6 with clear effect at both daytime and nighttime blood pressure. Although the data is not shown here, the reductions in daytime and nighttime systolic blood pressure were sustained even to later time points, weeks 12 and 24. And Thus, a single dose of zilbesiran demonstrated effective blood pressure control throughout the 24-hour period, highlighting its persistent effect on the quality of the blood pressure lowering. The graph on the right demonstrates the sustained effect of zilbesiran on the quantity of blood pressure lowering. That is reductions in mean 24 hour systolic blood pressure of greater than 10 millimeter mercury were achieved at week 12 across 3 dose groups of zilebesiran, 200, 400 and 800 milligrams with clinically meaningful reductions in blood pressure being maintained out to week 24. Most interesting after a single dose of zilebesiran 800 milligrams, a mean 24 hour systolic blood pressure reduction of greater than 20 millimeter mercury was observed at week 24. It's also important to note that 6 out of the 8 patients in this group achieved this reduction in systolic blood pressure greater than 20 millimeters of mercury at week 24 without the use of add-on and diapetensivs. So in summary, for part 1, effective RAS inhibition with zilebesiran translated into qualitative and quantitative aspects of blood pressure control by resulting in 24-hour blood pressure lowering, which was sustained with a single dose out to 6 months of treatment. Moving on to Part 2, our Phase I study. We conducted a proof-of-concept study to test multiple doses of zilebesiran in obese hypertensive patients. Data from this part of the study have not been previously presented. In Part 2, there's a cohort of 12 obese hypertensive patients, they were randomized 2:1 to receive zilebesiran at 800 milligrams at baseline and at day 85 or week 12, however they received the ARB [indiscernible] at 150 milligrams a day, which is the standard anti-hypertensive dose. The study evaluated the effects of multiple dosing of 800 milligrams zilebesiran in obese patients every 85 days or 3 months in a head-to-head comparison with 150 milligrams of herbisartin daily. The change from baseline blood pressure was measured by 24-hour ambulatory blood pressure monitoring, and this occurred at week 6, 8, 12 and out to 24 weeks. Other evaluations looked at the impact of zilebesiran on body weight, body composition and metabolic parameters by testing the hypothesis that changes in angiotensinogen levels may drive some metabolic effects. As you saw the exciting effects of single dose zilebesiran blood pressure line, we are very eager to investigate the level of blood pressure reduction with multiple doses of zilebesiran . We observed reductions in mean 24-hour systolic blood pressure for zilebesiran 800 milligrams at weeks 8, 12 and 24, and we observed reductions of up to 27 millimeter mercury in systolic blood pressure in comparison to the blood pressure lowering observed in patients undergoing treatment with the ARB irbesartan. As we investigated this in part 2, we are delighted to find that if anything, the blood pressure lowering effect was maintained but also quantitatively, it looked better in this small sample size and also numerically different from the standard of care ARB irbesartan. We did not, however, observe any changes in body weight, body composition or changes in metabolic parameters with zilebesiran after 24 weeks of treatment. As we discussed earlier, the biomarker data observed with zilebesiran was consistent, and it is quite contrasted with the oral ARB [indiscernible], where you see the signs of reninactivation driving increases in angiotensin-2 to overcome the receptor blockade. Looking at the bar chart on this slide, we observed consistent increases in plasma renin and reductions in angiotensin 2 and aldosterone out to 24 weeks in response to 800 milligrams of zilebesiran . For [indiscernible], we saw increases in plasma renin concentration, but also saw increases in angiotensin-2 and aldosterone, quite different than what you get with effective angiotensinogen inhibition. These biomarker results with multiple dose of zilebesiran are similar to Part 1 of the single dose data and provide preliminary evidence that supports the potential for zilebesiran to lead to effective and sustained RAS inhibition, thus avoiding RAS escape. Moving on to Part 3 of our Phase I study, which was designed with a focus on evaluating the safety of zilebesiran , specifically the study was designed to observe the effects of salt restriction with an aim to inform the safety and tolerability of volume depletion and responses [indiscernible] treatment. In order to assess the safety effects during a 2-week period of controlled salt intake, a single subcutaneous injection of zilebesiran at a maximum dose of 800 milligrams was evaluated. A cohort of 12 patients were randomized 2:1 to receive zilebesiran 800 milligrams or placebo. Changes in 24-hour systolic blood pressure responds to a low salt diet followed by a high-salt diet were measured before and after zilebesiran dosing over a 2-week period. So how did Salt affect the blood pressure response. The first part of the study was a control to observe changes in blood pressure response to a low-salt diet, followed by a high SALT period. As expected, there was an average reduction of 9 millimeter mercury in 24-hour systolic blood pressure at day minus 15, following a low-salt diet. Blood pressure then increased back to baseline at day minus 8 upon switching to a high salt diet in all patients. Thus, in this study, the hypertensive patients demonstrated a sensitivity to the effects of salt on blood pressure. Approximately 6 weeks after a single injection of zilebesiran, the blood pressure responds to the same low salvediet, followed by a high salt period were observed. In patients given zilebesiran, the change in 24-hour systolic by pressure, we're much more profound following a low-salt diet. For patients receiving zalbisiran, there was an approximately 19 millimeter mercury reduction in systolic blood pressure complained to placebo, which saw a reduction of 10 millimeter marker. Subsequently, a high-salt diet attenuated the blood pressure lowering effect of zilebesiran with values returning to baseline levels. These data demonstrated that variations in salting can influence the blood pressure lowering response to zilebesiran. From a safety perspective, there were no serious adverse events or adverse events in Part 3 leading to study withdrawal and no patients required intervention for low blood pressure, including during the low-salt diet, -- in addition, no clinically significant elevations in liver enzymes, serum cotinine or serum potassium were reported in the zilebesiran group. As a whole, these data demonstrate that something as simple as a high-salt diet may be sufficient to reduce the blood pressure lowering effect of zilebesiran. The clinical significance of these findings could be in instances in which we'd want to modify the antihypertensive response of zilebesiran. These data indicate that using standard measures such as increasing salt and water intake could potentially limit the antihypertensive response. As discussed, because of these effects in the rare or uncommon cases where you may want to see so reverse the antihypertensive effect such as if a patient is hemodynamically unstable, current conventional means, in theory, could be adequate. But in order to further explore the capabilities of the Alnylam R&I platform, we have developed the reverse of technology that could reverse the effect of a treatment like zilebesiran. This topic will be addressed later today by my colleague, Vasant. Now turning to Part 4, the last part of our Phase I study. We were interested in exploring the safety, tolerability and additivity of adding the RAS blocker herbicide at its maximum antihypertensive dose of 300 milligrams to zilebesiran. This type of therapeutic regimen that is combining 2 RAS agents is currently discouraged in managing hypertension. But in this Phase I study, we wanted to see the safety effects of adding the ARB herbisartin to zilebesiran, a novel anti-hypertensive that also affects the RAS but in a unique way. In Part 4, 16 hypertensive patients received open-label treatment with zilebesiran 800 milligrams subcutaneous on day 1. After 6 weeks of zilebesiran treatment, patients whose mean 24-hour systolic blood pressure remained at or above 120 millimeters of mercury proceeded to receive [indiscernible]. There were 10 patients who did this. While those whose mean 24-hour systolic blood pressure was less than 120 millimeters of mercury, remained on zilebesiran-only, and there were 6 patients in this group. In those patients who remain on zilebesiran-only, they had large reductions in systolic blood pressure, approximately 22 millions of mercury at week 6 or day 41, and this was maintained through to at least day 56 or week 8. And those patients who received add-on irbesartan of 300 milligrams a day for the next 2 weeks, that is from day 43 to day 57 and -- they experienced roughly an additional 6 millimeter mercury reduction insist all with blood pressure on top of the approximate 8-millimeter mercury delivered by zilebesiran through day 41 or week 6. Encouragingly, there were additional blood pressure reductions, but it was not associated with any significant elevations in serum cratinine or potassium. Additionally, there were no serious adverse events or adverse events of hypotension or low blood pressure that required intervention -- since our Phase I study was also focused on evaluating the tolerability and safety effects of zilebesiran in hypertensive patients. It's important to summarize our findings from these 4 parts of our Phase I program. In Part 1, single-dose zilebesiran was well tolerated, and there were no treatment-related serious adverse events. All adverse events were mild, they're moderate in severity, and they resolved without intervention. No patients required intervention for low blood pressure, and there were no cases of elevations in liver enzymes, serum cotinine or potassium during the study. In Part 2, multiple doses of zilebesiran at the maximum dose of 800 milligrams were generally well tolerated, and there were no treatment-related serious adverse events. All adverse events were mild or moderate in severity and they resolved without intervention. No patient required intervention for low blood pressure, there are no elevations in liver enzymes, serum cratinine or potassium during this study. In Part 3, in response to salt restrictions, zilebesiran was well tolerated with no treatment-related serious adverse events, and there were no patients required intervention for low blood pressure. In Part 4, the addition of irbesartan to zilebesiran were generally well tolerated and led to further reductions in systolic blood pressure with no adverse events of concern for hypotensive events, and there were no clinically significant changes in serum cratinine or potassium and there were no treatment-related serious adverse events. Overall, these data from our Phase I study provide initial indication of zilebesiran's potential clinical profile. That is angiotensinogen inhibition leads to more effective inhibition of the reninangiotensisystem as demonstrated by improvements on the quality and quantity of blood pressure lowering with effective 24-hour blood pressure control that sustained out to 6 months of treatment. These findings support continued development of zilebesiran and leads us to our Phase II cardia program. We initiated a Phase II clinical program in 2021 to further interrogate zilebesiran and its potential profile in hypertension. This clinical program includes 2 studies: Cardia 1 a monotherapy Phase II study in 375 hypertensive patients designed to evaluate the efficacy and safety of zilebesiran as a monotherapy in patients with mild to moderate hypertension. This trial is exploring both quarterly and biannual dosing regimens. Our second Phase II study is CARdIA-2, which is a combination study in 630 patients that's designed to evaluate the efficacy and safety of zilebesiran as concommitment therapy in hypertensive patients whose blood pressure is uncontrolled despite receiving standard anhipertensive therapy. More specifically, Cardia 1 is a double-blind placebo study to evaluate the effects of zelbesiran in patients with mild to moderate hypertension. The study is designed to identify the dose or doses of zilebesiran to take into Phase III by evaluating the effectiveness at 3 and 6 months using quarterly and biannual dosing. The study was initiated in mid-2021, and we are very pleased to announce that enrollment in Cardio 1 is now expected to be completed at or around year-end 2022, earlier than previously expected, with top line results in mid-2023. Cardia2 is our double-blind, placebo-controlled study in patients with blood pressure, not adequately controlled on standard of care antihypertensive therapies. This study is focused on evaluating the efficacy and safety of zilebesiran 600-milligram at its max dose when added to each of the 3 most common classes of antihypertensives, the angiotensin receptor blocker omesarten, the calcium cane blocker amlodipine and the diuretic indapamide in patients despite receiving one of these therapies, but whose blood pressure is still uncontrolled. The primary endpoint of the study is to evaluate zilebesiran after 3 months of therapy on the additive blood pressure lowering effect. Additional secondary endpoints will evaluate the 6-month effects of zilebesiran and whether blood pressure was controlled without the need for add-on antihypertensive therapy. The study will also assess the safety and tolerability of zilebesiran as additive therapy to standard of care antihypertensive. The study will enroll 630 patients that randomized to zilebesiran or placebo who remain hypertensive after completing 4-week run-in on protocol-specified background antihypertensive medication. Enrollment completion is now expected to be in early 2023 with top line results expected by or at year-end 2023. In summary, there continues to be significant unmet need for the treatment of hypertension in patients with uncontrolled blood pressure. And we think this can potentially be addressed by Zilebesiran. Data from our Phase I study support the therapeutic hypothesis that zilebesiran may allow for patients to achieve tonic blood pressure control. That is durable 24-hour blood pressure control, sustained blood pressure lowering throughout the day and night time, and this happens day after day for up to 6 months. We also have some new exciting data that highlights the persistent effect of zilebesiran to inhibit angiotensinogen and decrease vasoactive RAS biomarkers through week 24, suggesting more complete RAS inhibition in contrast to oral RAS blockers. Accordingly, we believe zilebesiran has a potential to become a new class of anti-hypertensive treatment for patients with a history of poorly controlled hypertension. We are currently testing the further blood pressure lowering efficacy of zilebesiran in our cardia Phase II program as we have 2 ongoing studies, and we're excited about how these 2 trials are progressing with top line results expected in mid-2023 for Cardia 1 and year-end 2023 for Cardia2. This concludes my presentation today. But as you can see, we have a lot to look forward to with the zilebesiran hypertension program in 2023. Thank you for your time and attention. We'll now move on to our first question-and-answer session of the day.

Hello, everyone. Welcome back, and thank you for joining us for the second part of our R&D Day. My name is Weinong Guo. I'm currently leading the clinical research group responsible for all of the non-TTDR programs [indiscernible] at Alnylam. This morning, you have heard about the progress Alnylam has made across the ATTR amyloidosis and hypertension programs. In the next 20 minutes, I will walk you through a number of very exciting earlier and mid-stage NAI programs that are anticipated to drive the future organic growth of our organization by addressing high unmet medical needs in new disease areas for Alnylam. As we think about the excellent progress we have made in the late-stage pipeline, we continue to build the pipeline towards P25 525 and beyond. In this regard, we will be expanding our pipeline of liver indications. We will also be expanding across rare specialty and prevent diseases. And we will include programs targeting gene expressed in new tissues as well. So the pipeline you see here begins to reflect those elements. I'd like now to spend some time diving deeper into some of these programs. I will walk you through the 4 key areas of our pipeline that we believe holds significant potential, starting with assets that are wholly owned and then covering programs being advanced with or by our partners. This will include programs against genetically validated targets in the liver as well as other tissues. So the 4 key areas of the pipeline that I will cover in this presentation are type 2 diabetes program, central nervous system programs, NASH programs and partner-led programs. Let me first start with our AI NKHK programs, which represents our first RNAi therapeutics to address the unmet medical needs in type 2 diabetes and potentially other metabolic diseases. As we know, fructose intake and metabolism contribute to metabolic syndrome. This is of increasing importance because as shown in the left part on this slide, dietary Fructose supplementation is believed to contribute to the growing pandemic of obesity. Obesity and associated fatty liver are 2 profound risk factors resulting in insulin resistance and the development of type 2 diabetes. On the right shows the metabolic pathways of how fructose intake can produce many of the key features for the metabolic syndrome. Kito HEXO kinase or KHK, also known as fructokinase is the first enzyme in this pathway, so therefore, constitute an important therapeutic target for addressing the kinds of effects shown on the left. It is important to note that loss of function variants in the KHK gene caused essential Fructose, capitalized by increased urinary fructose excretion. However, overall is a symptomatic benign and usually does not require treatment. This piece of human genetic data provides preliminary safety support for silencing KHK with an RNAi therapeutic approach. An important way to test the hypothesis highlighted on the previous slide is to look at the high fat diet-fed rodent model, where additional fructose or glucose intake creates the arrangement of glucose hemostasis. Preclinical data supporting the therapeutic hypothesis are shown here on this slide, with ALN-KHK, a Garnet conjugated sRNA designed to specifically suppress the hepatic expression of ketoaxolkinase. Let's first look at what happens when you knock down the KHK. As shown on the left part of this slide, the effect of ALN-KHK in human primates has clearly demonstrated dose-dependent and profound KHK protein knockdown at day 29 following a single subcutaneous injection. On the right, shown the rodent model of high fed diet plus fructose or glucose-induced metabolic disorders. Knockdown with sRNA led to improved in-[indiscernible] sensitivity demonstrated by the reduced area under the curve of glucose levels in response to the glucose tolerance test. Taken together, these animal experiments established the preclinical proof of KHK silencing in improving insulin sensitivity. Alnylam is on track to file the CTA for ALN KHK by the year-end and initiate the Phase I study in early 2023. -- this randomized double-blind trial will be a fused in human single ascending dose in healthy of these subjects. We expect top line results in late 2023. This will be then followed by a multiple dose proof-of-concept study in obese patients with type 2 diabetes. If the study described here is positive, there is a potential to continue the development of ALN-KHK in type 2 diabetes and also the opportunity to expand development to other metabolic disorders, including fatty liver disease. I will now turn the section to our CMS portfolio. We have been building on the recent preclinical success of our CMS platforms with C16 conjugate aiming to unlock a significant range of opportunities for IMI Therapeutics in the CMS space. Today, I'm not going to talk about [indiscernible], which is in IND-enabling studies for amyotropic netrosclerosis, nor our program for Huntington's disease, where we are working towards a development candidate. I will be discussing ALN-APP, our first-ever CMS target SINA product currently in clinical investigation. This program entered the clinic early this year, which exemplifies the potential of our platforms to treat CNS diseases. Earlier this morning, you heard the progression by John Vest on the success of our AINI approach in treating ATTR amyloidosis and building on the success of our AINI platform for other types of amyloidosis, ALN-APP is designed to reduce protein production of amyloid precursor protein, APP, that is upstream of amnodogenic process. With ALN-APP, our therapeutic hypothesis is that by allowing APP protein production in the CMS with RNAi, we can reduce both the intracellular and extracellular aggregation of FPP degradation products such as amyloid beta and thereby heart or improve the clinical manifestation of Alzheimer's disease and other chronic and debilitating amyloid driven disorders. As my colleague in research will share with you in the next presentation, we have made tremendous progress with delivery of our drugs to the CNS. We have shown how we can achieve broad biodistribution, reaching deep brand structure and where single intra-sea [indiscernible] injections provide up to 9 months of silencing of a target. Specifically, intrathecal administration of ALN-APP in nonhuman primates successfully produced profound and durable APP reduction over 6 months, assumed by APP offer and APP beta levels reduction in cerebral spiral fluid. Importantly, as shown on the right, interest into dosing of SINA targeting APP resulting in meaningful APP MI reduction across multiple deep brand and spine regions of nonhuman primates. Taken together, these PD data highlights here provide evidence for effective and sustained suppression of APP mRNA and the CSFI biomarkers when ALN-APP is successfully delivered into the intrathecal compartment and then to the brain when administered by Lunda IT injection in nonhuman primates. Note, a key differentiator for our program would be the ability to reduce both intracellular and extracellular accumulation of the various protein species that come from APP degradation. This is possible by silencing the amyloid precursor protein production within the Neuro. On this slide, we are pleased to show that an IAI therapeutic targeting APP suppresses intracellular aggregates in neurons produced by induced PSC cells derived from Alzheimer's patients. So between these last 2 slides, you have preclinical data that supports ability to suppress both extracellular and intercellular accumulations of APP degradation products -- the amyloid precursor protein is best known for its connection to Alzheimer's disease. The most common calls are dementia worldwide affecting 5 million in the U.S. and approximately 30 million people worldwide. Targeting APP with IMAI therapeutics is a novel approach in Alzheimer's disease, which acts upstream of this pathological process. This approach is designed to reduce APP protein at its sources, reducing both intracellular and extracellular drivers to disease pathology and all APP cleavage products, including all species of amyloid beta. As such, we believe the targeting APP at IMAI-level has the potential to provide a more comprehensive intracellular and extracellular impact to the disease pathology, our preclinical data on the previous 2 slides indeed support this hypothesis. In addition to the opportunity for ALN-APP to address Alzheimer's disease, we believe that lowering this target may also have therapeutic applications in another disease called cerebral amyloid angiopathy or CAA. While Alzheimer's disease is characterized by the accumulation of amyloid flex in the prorate of the brain as well as the intraneuronal accumulation of power tenders and newer degeneration, CAA is a disease while amyloid deposits in the vasculature of the brand, which can increase the risk for hemorrhage strokes, hemorrhagic strokes. In fact, CAA is the second most common cause of intracerebral haemorrhage after hypertension. It is a disease with high unmet medical need. And today, there are no specific treatments available to treat CAA and very little activity currently in clinical development. The therapeutic hypothesis for CAA is simple by reducing the production of APP and thereby reducing Abeta-40 and all other amyloid species, we aim to interfere with the progression of amyloid deposits in the vessels and potentially enable natural clearance of the existing deposits and thereby address some of the vascular damage that occur during the disease. We have begun this journey of development with ALN-APP with our Phase I randomized double-blind study in patients with early onset Alzheimer's disease. This study is designed in 2 parts, a single ascending dose part A, followed by a multiple dose Part B. The primary endpoint of the study is safety and tolerability of AIM-APP. We also hope to begin to characterize the pharmacology of our CMS conjugates and assess the level of target knockdown we can achieve as well as the duration of such effect. We are currently enrolling patients in Part A and are progressing through the dose escalation portion of the study. We expect to share some of the preliminary data from this study in early next year. We expect the results of this Phase I study will help inform our next steps in the clinical development of ALN -APP. If successful, these results will derisk further development in Alzheimer's disease. In addition, this study will also provide us useful insights into the pharmacology of ALN-APP and enable the initiation of development as a potential treatment for CAA. In this way, we aim to explore both potential opportunities and leverage the emerging data and evolving landscape in these indications to inform our late-stage development plan in the CNS space. The success of ALN-APP program will potentially derisk other programs and future targets for our rich CMS portfolio. Now turning to our NASH program. Our genetic colleagues at both Alnylam and Regeneron have identified a number of targets implicated in NASH, which includes HSD17B13, PNPLA3 and CDI. We are now building an industry-leading portfolio of programs for NASH against these genetically validated targets. Today, I'm going to discuss with you exciting proof-of-concept data we reported early this year for the first of those NASH programs that is ALN-HSD. Nonalcoholic state hepatitis, NASH, is a highly prevalent chronic liver disease in which inflammation and liver cell injury are caused by accumulation of hepatic fat. NASH is the subset of a group of conditions called nonalcoholic fatty liver disease NAFLD that can lead to progressive fibrosis, sorosis and hepatocellular carcinoma. Comobility always include obesity, metabolic syndrome and type 2 diabetes. Approximately 5% of adult that is 60 million people in the U.S. live with NASH and the prevalence increasing due to rising rates of obesity and type 2 diabetes. There are currently no approved medical treatment for NASH, highlighting the significant unmet medical need in this space. Genome-wide associated study have identified loss of function variants in the HSD17 beta 13 gene, which reduce the risk of chronic liver disease and progression from statosis to statohepatitis. On the other hand, gain of function variance is in the PMPLA/3G that increased risk and the strongest protection and increased risk in individuals, homozygous for each of these 2 variants. These genetic validation data have motivated us to develop IMAI therapeutic targeting HSD17B13 and PNPLA3 in collaboration with our partner, Regeneron. ALN-HSD is a gale conjugated sRNA intended to mimic the genetic loss of HSC17-beta13 function to hard or reduce capacity injury, fibrosis and inflammation that occurs in NASH. We carried out a Phase I study of ALN-HSD, which is a randomly which is a randomized, double-blind, placebo-controlled, multicenter single-ascending dose and multi-dose studies to evaluate the safety, tolerability, PK and peeing effects of AirNSD in [indiscernible] adult subjects as well as in adult patients with NASH. The part-A enrolled healthy adult subjects to receive a single ascending dose of ALN-HSD from 25 milligram all the way up to 800 milligrams. Part A of this study has been completed. For Part B, it enrolled patients with NASH to receive 2 doses of 25, 200 or 400 milligrams of ALNHSD or placebo via quarterly subcutaneous injections. Sunderwent Pal, liver biopsy at baseline and Mango month 12, depending on the cohorts. Patients in all cohorts of the Part B have completed at least 6 months on this Phase I study. ALNFC has exhibited an encouraging safety and tolerability profile to date. The most common treatment-emergent adverse events is KC subjects treated with ALNHSD with injection site reactions in 5 patients out of 44 healthy subjects. All injection site reaction was mild in severity, no treatment-related serious SAEs have been reported in either healthy volunteers in Part A or patients with NASH in Part B to date. The sum of the dynamic effect of ARNHSD was assessed by hepatic HSD levels at month 6. These data were reported by press release early this year but are being shown here in graphic forms for the first time. As you can see on the left, ALN-HSD, dose dependently suppressed liver HSD MIA levels, 2 quarterly dose of ALN-HSD 25 milligram, 200 milligram and 400 milligram resulting in a median reduction in HSD MAA levels of 40%, 71% and 78%, respectively, compared to the observed 5% increase in placebo group. It is noted that 1 patient in 400-milligram dose group with the second dose at VnV as shown in this red dot data point here, but still achieve approximately 55% knockdown 6 months after the single dose of 400-milligram ALN-HSD. There is a positive trend in lowering the liver enzyme as shown on the right chart and the improvement in the biopsy-derived nearfield activity score over 6 months in patients receiving ALN-HSD relative to the placebo. Although this study was not powered to achieve statistical significance on these exploratory endpoints. We are planning to present these exciting PD safety and exploratory efficacy data at the medical conference next year. The data we have seen by topping a genetically validated target like HSP give us a lot of excitement. Our next generic targets, genetically validated target in NASH is PNPLA3. This is a lipid droplet associate protein predominantly expressed in the liver. Numerous GWAS reports have shown that [indiscernible] PNPLA3 risk allele variant is associated with hepatic stetosis, inflammation, fibrosis and syrosis. Some of the reasons these are -- we are excited about the potential for ALNPMP are illustrated here. Public data shown on the left part, are from a preclinical NASH model, which use of an antisense oligonucleotide to lower PNPLA3 resulted in improvement in the number of histology parameters, including stetosis, inflammation and fibrosis. On the right, you can see that we have already identified a number of highly potent and durable SIMsA, both in rodents and nonhuman primates. Importantly, as these 2 targets I highlight here, HSD and PNPLA3 address different aspects of the pathology of the NASH. They may be well suited to be used in combination to treat this disorder. This is certainly we are evaluating with our colleagues in Regeneron, and we look forward to share more data of these exciting programs in the future. Our partner Regeneron will now be advancing the ALN-HSD program from Phase II onwards, they have also recently filed ALNPNPand plan to initiate a Phase I study in early next year. Finally, I would like to quickly share with you some highlights of 3 partnership-led programs in which Alnylam retains substantial economics and contribute to the future growth and value creation. These programs include ALN-HBV02, also now known as VIR-2218 for chronic hep2 infection, fitusiran for hemophilia A and B with or without inhibitors and [indiscernible] combo regimen for myasthenia gravis and proximal nonhematolobin urea. Chronic HBV infection remains an urgent global public health challenge associated with significant morbidity and mortality. -- approximately 290 million people around the world are living with HBV. And approximately 900,000 of those die from associated complications each year. These patients are significantly underserved by existing therapies with low functional cure rates, lifelong daily therapies and poor tolerability. Our partner VIR Technology is evaluating a combination regimen of VIR-2218 and VIR-3434 as a potential functional cure for HBV. As you know, VIR-22 is an investigational subcutaneously administered RNAi therapeutic targeting HPV that was discovered by Alnylam scientists whereas VRS 13 14 is an investigation of subcutaneous administered antibody designed to block the entry of HBV virus into the hepatocytes. In the recent AASLD Congress in November in Washington, D.C., the top line results of Phase II MAC study were presented demonstrating that VIR-2218 and VR-34. So the 4 combination regimens achieved mean surface antigen reduction, 2.5 log or greater in all cohorts. And also, we have reported absolute service energy level less than 10 units per milliliter achieved in most participants over a 20-week of treatments. Patents of response demonstrates additive surface entity reduction from the complementary modes of the action of these 2 agents, -- all AEs were mild to moderate in severity. There were no AEs leading to treatment discontinuation. We are very excited about these Phase II study results that suggest a transformative potential of the combo regimen for the functional cure of chronic HPV infection. There are several additional Phase II readouts expected from VIR during the course of next year. Importantly, Alnylam has an opt-in right prior to Phase III development .as for fitusiran, this is a first-in-class RNAi therapeutic targeting antithrombin discovered by Alnylam. Sanofi is conducting multiple Phase III studies designed for patients with hemophilia A or B, with or without inhibitors. As depicted on this slide, 3 Phase III studies were conducted in adults and adolescents with all trials demonstrating statistically significant reduction in bleeding and the median annualized bleeding rate of 0 in fitusiran-treated patients across the spectrum of hemophilia patient study. Not shown on this slide, fitusiran prophylaxis also significantly improved health-related quality of life in these treated patients. The most common treatment-emergent AEs of special interest for fitusiran with liver enzyme innovation greater than threefold of the upper limit of normal. However, the mass majority of these LFT elevation returns to normal and did not result study discontinuation. There were a small number of suspected or confirmed combo embolic events in the fitusiran arm across the 3 studies. Additional Phase III studies where lower doses are expected in late 2023 with an NDA submission expected in 2024. Finally, multiple ongoing studies with cemdisiran and RNAi therapeutic targets targeting complement C5 discovered by Alnylam and pozelimab an antibody against C5 discovered by Regeneron are being conducted by our partner, Regeneron, to evaluate the role of this combination therapy with potent inhibition in C5 in 2 complemental mediated disease, by senior gravis and PNH. So in summary, -- we see multiple opportunities to advance our innovative RNAi therapeutics against hepatic and extrahepatic targets to address diseases of high unmet medical need, such as the ones I have shown you here today. Importantly, we continue to focus on genetically validated targets, which increase the probability of success. We have an increasing focus on specialty and large market opportunities, which is enabled by emerging safety profiles of our technology platform and the pharmacological profile of our molecules, which offer the potential for dealable tonic control of target gene expression with infrequent dosing. I would like to thank you very much for your attention, and we'll now turn it over to my colleague, Aimee Deaton . Thank you.

Thank you, Weinong. Hello. I'm Aimee Deaton, Associate Director of Human Genetics. And I'm going to talk to you today about some of our work using genetics to find exciting new therapeutic targets. After that, Vasant Jadhav will speak to you about some of our recent innovations in our platform. So why use genetics to help find drug targets? Well, we know that drug development is a high rate of failure with the vast majority of drugs that go into development failing to get regulatory approval, primarily for reasons of efficacy and safety. Why is this? Well, one reason is that animal and cell-based models traditionally used in drug discovery, do not fully recapitulate human biology and physiology. But we can overcome this challenge by using natural genetic variation in humans to inform drug discovery. It's been shown that targets with genetic validation are twice as likely to lead to approved drugs. And by this, we mean that mutations in the gene coding the drug target lead to a phenotype that matches the desired effect of the drug. -- evidence coming from rare protein coding variants such as those captured by exome sequencing, have the greatest effect on probability of success. In fact, if you look at Alnylam's historical probability of success, you can see that it's many times higher than industry standards. And this is in part due to our focus on genetically validated targets on genetic disease. Because we do want to continue the success, we made a significant commitment to genetics. First, through our involvement with the UK Biobank, a cohort of 500,000 people with rich health-related information. We were part of the consortium that exome sequence participants and are now part of a group performing proteomic profiling on a subset of the cohort. Several highly impactable findings have come out of our work in U.K. Biobank. This includes the association of prevalent U.S. TTR mutation V122I with the polyneuropathy manifestations of hATTR amyloidosis. It also includes the association of Innovia loss of function with abdominal obesity, which we introduced last year as GenX and on which I'll elaborate today. We also have found a new target, which we're calling GeneY for type 2 diabetes. We continue to access new genetic data sources, and we're finding industry members of our future health, which is collecting genetic and health information on 5 million people. So this is 10x as many people as in U.K. Biobank. And you can just imagine the scale of the targets that we'll be able to make using this data set. In addition to our internal data, we collaborate with Regeneron Genetic Center. They have access to additional cohorts and data from health systems. They discovered HSD17B13 as a target for NASH, which you've just heard Weinong talk about and may provide an independent validation of our finding for [indiscernible]. In addition to these data sources, we have a strategic eye focused on what new data sources we can access in the future. At last year's R&D Day, we introduced Inivine as GenX. We were really excited by the finding that loss of function and inivine associated with lower waist to hip ratio. We found this using our U.K. Biobank exome data, and we replicated it using data from the T2D genes consortium. And this finding was recently published in the Journal Nature Communications. Strikingly, carriers of loss of function variants in Innovent E, who have on average a 50% decrease in InnoventE have a really favorable metabolic profile. This includes lower triglycerides, lower alanine transaminase levels, suggesting better liver health and lower fasting glucose. They also have fewer metabolic syndrome traits than noncarriers. For the reason studying the genetics of waist to hip ratio is important, is that directly reflects abdominal fat and [indiscernible] effects risk for type 2 diabetes and heart disease. Consistent with best carriers of Innovent-e loss-of-function variants have fewer cases of coronary heart disease and type 2 diabetes. And this is true for other waist to hip ratio lowering genes in our study with disease protection being proportional to the effect on waist to hip ratio. Another reason [indiscernible] is such a compelling target for us is that it's exclusively expressed in the liver, making it an ideal target for our platform. [indiscernible] encodes active in E, a secreted protein, which we believe binds to receptors on adipose tissue. While efforts to characterize the receptors and signaling pathway are ongoing, we can silence inovin-e using RNAi and directly impact the causal gene prior to discerning these details. Through doing this, we may impact cardiometabolic disease in a way that's mechanistically distinct from current therapies. So we were inspired by our finding for Innovent-e to look for targets to address unmet need and other common diseases. And we focused on type 2 diabetes. This is because half of type 2 diabetes patients fail to reach target HbA1c on current treatments with low rates of compliance for many therapies. Many of these patients progressed are requiring supplemental incident. T2D is a multifactorial disease, but we believe we can influence key aspects of disease through the liver. Because of this, we focused on identifying liver-expressed modulators of incident signaling whose silencing might improve type 2 diabetes. And we did this by searching for a genetic variance that reduce type 2 diabetes risk. We identified Gen-Y, encoding a negative regulator of insulin signaling. And this gene harbors a damaging missense variant that reduces risk of type 2 diabetes as well as HbA1c levels. To test the impact of GNY on insulin sensitivity, we silence GenY in the livers of obese mice. We saw a blunting of the hyperglycemic response in these mice as measured by glucose tolerance test, and we saw improved insulin sensitivity. You can see that the SI RNA-treated mice, shown in blue here have glucose and insulin tolerance comparable to [indiscernible] animals. Strikingly, this was achieved without any increase in body weight. In fact, we might be seeing a trend towards decreased body weight in the siRNA-treated animals. Additional compelling observations in these treated mice included enhanced insulin sensitivity in extrahepatic tissues, reduced liver fat and reduced HOMA-IR. Alnylam has been a pioneer in using genetics to identify therapeutic targets. And we are continuing to invest in genetics to identify new targets and continue our run of clinical success. The genetics of inoven-e make it a compelling target for cardiometabolic disease, and we're aiming to have a development candidate for inoven-e in 2023.I Using genetics, we identified a new target geneY for type 2 diabetes and consistent with the genetics, hepatic silencing of Gen-Y improves insulin sensitivity in obese mice. So I've talked to you today about new liver targets identified through human genetics. I'm now going to hand off to my colleague, Vasant jadhav, who's going to talk to you about some exciting innovations in our platform. And this includes delivery to new tissues where there are additional genetically validated targets that we can silence to address unmet medical need. So over to you, Vasant.

Thank you, Aimee. Hi, everyone. My name is Vasant Jadhav, I lead our RNAi platform technology efforts. I'm thrilled to share with you the platform advances as a source of sustainable innovation at Alnylam Aimee talked about the first source of this sustainable innovation, where we learn from the natures experiments to gain clues for novel targets of therapeutic interest. The other 2 sources are the first one, platform designs and the second one, extrahepatic delivery expansion. Both benefit from our long track record of industry-leading RNAi platform. Our sRNA designs include Ikaria platform that enables robust and specific target knockdown. -- based on all our previous advances with annual dosing potential. Gemini is our approach of combining 2 sRNAs as a single chemical entity. And finally, the reverse here oligos that provide tailored control of RNAi for [indiscernible] . The next source of innovation is delivery to extrapetic tissues of interest. These targeted delivery approaches are benefiting from lessons learned from our YanlagEssani delivery platform. Let's begin with advances in the platform designs and dig deeper into that. As I mentioned earlier, Ikaria platform provides the potential for robust knockdown with annual dosing potential. The data shared here is for TTRSC04. As my colleague, John Vest shared earlier, TTR SCO4 for CTA has been submitted. As shown in the data here, the RNS analysis shows exquisite specificity for TTR knockdown. NHP data in the middle graph shows high level of potency and our modeling data suggests or it predicts potential for once a year dosing in humans with greater than 90% TTR protein reduction. Now making such molecules is a norm for us. These advances are also utilized for our Gemini platform. Gemini or in other words, base RNAi platform combines 2 sRNAs via a proprietary linker to obtain a single chemical entity. This will be particularly useful in indications involving role of multiple genes from same or different pathways. For example, elevated blood pressure and higher cholesterol are the top 2 leading risk factors for cardiovascular disease. Now what are the potential benefits of GEMINI or bIs-RNAi design? We believe by combining 2 sRNAs in 1 molecule, it potentially simplifies clinical development path compared to 2 entities or the combo. It also ensures uptake of both sRNAs in same cells across tissue types and provides controlled [indiscernible] reductions in the 2 targets. So let's see how well this design is working. And again, based on our deep expertise in Sri designs and delivery, we now have a Gemini Gala construct that includes a proprietary linker along with subcutaneous reduction of 2 different liver targets. The data shown here is in NHP, where Gemini platform shows potent and durable activity comparable to the mixture of 2 parent [indiscernible]. Now we can take the lessons learned from here and also apply them for CNS Gemini design. Obviously, in that case, a different ligand for delivery would be needed. So in CNS indications, there are multiple genes implicated in Alzheimer's disease, in ALS, in Parkinson's disease and others. As shown in the data here, GEMINI C16 design is providing excellent RNAi activity in rat CNS when dosed by intrathecal dosing. The activity of GEMINI C16 is comparable to that of mixture of 2 [indiscernible] . Now one of the defining features of our SNA designs is their remarkable durability that allows very infrequent dosing. While long-acting agents are very desirable for compliance and other reasons, there may be cases where the ability to reverse a long-acting agent would be designable. The concept of antidotes of reversal agents is not a new one, and it is widely used in the medical practice with a few examples shown in the table on the left here. In this regard, we have previously reported reverse your platform, the name Reversion comes from combining the words, reversing its RNA activity. This approach is [indiscernible] sequence-based utilizes same GalNAc ligand for delivery and is amenable for a subcutaneous route for dosing. We have done several proof of concept studies, designing and administering reverser agents targeted to some of our long-acting molecules. One example I showed here is the reversal of zilebsiran-RNAi activity. zilebesiran is our investigational compound for blood pressure lowering. In this NHP study, zilebesiran was given at 3 mg per kg dose and the blue line indicates robust reduction of circulating AGT protein. Then dosing of the reversia at 22 days results in a rapid rebound of serum AGT levels within days with long-acting pharmacology of zilesiran be, Reverser offers an option for the rapid reversal of the drug effect as shown by this data. Now moving to the next source of platform innovation, and that is extrahepatic delivery expansion. RNAi therapeutics approach in CNS diseases is very appealing as there are no current therapies for neurodegenerative diseases. And there are a number of genetically validated CNS targets. We believe this provides significant opportunity for RNAi therapeutics in CNS space. Earlier this year, we published our work on C16 conjugate platform in the Journal of Nature Biotechnology. This paper was selected by prestigious oligolitlutide therapeutics society as the paper of the year in basic research category. This is our second year in a row for such an award last year. It was awarded to our conjugate durability work published in the Journal of nucleic acids Research. For C16 platform, we conducted exhaustive optimization of [indiscernible] its position and included SIA modifications like vinyl phosphonate a stable phospatimic to improve the potency. So how do these C16S [indiscernible] show activity across CNS regions? And here is the data utilizing Murfish technology that allows special resolution of target mRNA knocked on within tissues. After a single ICV injection in mice, our scientists evaluated the target knockdown by Murfish and the data speaks for itself. The control on left shows ubiquitous expression of target mRNA. And with the C16 SNA treatment, we see robust knockdown across brain regions of these mice. This is very clearly exciting as Brain is a complex organ, and this data shows it is feasible to achieve knockdown by C16 sRNAs across all regions of the CNS. Based on the C16 SRA conjugate technology, we have designed a sanamolecule targeting amyloid precursor protein. With a single IT dose in NHP, we observed robust and durable knockdown as shown here. My colleague Weinong Guo earlier talked about the ongoing ALN-APP Phase I study, and we expect the initial data in early 2023. -- in the C16 sRNA conjugate publication that I mentioned earlier, we also showed functional benefit in the mouse model of Alzheimer's disease by APBC16-sRN. Now we show another example with C16 sRNAs, this time, targeting alpha-synuclein demonstrating benefit in the mouse model of Parkinson's disease. We designed the C16 SRAs targeting SNCA and evaluated them in collaboration with our partner, Regeneron. These homozygous transgenic mines overexpress 853 alpha-synclein and show phenotype of the Parkinson's disease. We conducted the study in prevention as well as therapeutic paradigm as described on this slide with the experimental details. Remarkably, the data shows administration of SNCA SRS, the C16 SRAs prevent of [indiscernible] aggregation and spread in preventive as well as therapeutic dosing paradigm. In addition, in the behavioral test shown on right, SNCs is prevent motor deficits by reducing the number of falls. This is the second example of C16 SR needs, showing functional benefit in the mouse model of CNS disease. Now beyond liver and CNS, we know that RDI machinery is present in all biological tissues, and we have optimized the sRNA design for in vivo delivery based on all our experiences for liver delivery. So now it is really about delivering these highly modified sanes to the tissues and the cell types within those tissues where lowering the targets of interest could have benefit in various disease states. We are doing this by broadening the range of ligands and receptors. The left panel shows potency improvements of our [indiscernible] SRNA, targeted delivery conjugates over time in mice. Learnings from these efforts serve as a blueprint to expedite the extrahepatic delivery efforts. Ideally, we're looking for something like a Gana ligand that is small in size, provides support and knockdown and works by subcutaneous delivery and importantly, also has CMC benefits for development. To support these efforts, we have expanded our core capabilities for ligand receptor characterization. In addition to that, ligand Discovery internally as well as externally through collaborations like PeptiDream, where we continue to make progress in finding peptide-based ligands against multiple receptors of our interest. Now let's go through some of the examples of data in 4 different issues and to begin with CNS. As we discussed earlier, C16 conjugates show robust activity in CNS after intrathecal dosing. We now report a ligan that appears about threefold better than C16 for activity in NHP by intrathecal dosing. It is very important for us to keep improving the potency to reduce the dose lower and lower, and this is just another example of our continued innovation. The next example is for delivery to skeletal muscle. Here, we identified another ligand for now calling it as ligand B. We are seeing dose-dependent and potent knockdown in mouse skeletal muscle at doses as low as 1 milligram per kilogram, while minimal activity is seen in liver even at the higher doses. Importantly, these conjugates are also amenable for subcutaneous dosing. As expected from our SNA designs, the durability looks good in skeletal muscle. The next example is for hard delivery. Here, we use ligands atonic conjugate that is unable to multiple routes of administration, including IV, intramuscular subcutaneous intraperitoneal, all of them showing robust knockdown. The middle panel shows dose-dependent knockdown in liver -- sorry, in heart after IV dosing. We have taken these conjugates further in nonhuman primates showing knockdown in heart. And finally, delivering to the adipose tissue. Here, we are using ligandD conjugate that shows robust knockdown in various adipose depots in nonhuman primates. The immunohistochemistry and the in-situ hybridization assays were used to show test article that is SRNA exposure and importantly, robust mRNA knockdown. These conjugates are also amenable to subcu or IV dosing as assessed by the mRNA and protein levels. So in summary, we think that all these delivery advances open door to many potential therapeutic opportunities across range of tissues beyond liver and CNS. Once we made the critical advances in liver delivery, this led to 5 drug approvals in 4 years, showing our proven ability to rapidly capitalize on the scientific advances, our CNS journey has started with ALN-APP. Now we are evaluating other tissues of interest where delivery is looking promising, and there are many targets with therapeutic cautionaries. In summary, our multiple sources of sustainable innovation, including, as Aimee talked about, the human genetics efforts SRNA designs. -- including Ikaria, Gemini, Reverser and delivery beyond liver, including CNS, mustskeletal muscle, adipose tissue and examples like that, we believe this should continue to drive our organic engine for robust pipeline growth for years to come. With that, I would like to thank you for your attention. And now we will move to the Q&A session. Thank you.

Here with all of you. There we go. It looks like it just came up... all right. So good morning, everybody. My name is Pushkal Garg. I'm the Chief Medical Officer at Alnylam. And it's great to see thanks, Dion, for your presentation and Dr. Sarswat and John Vest. We've got a great panel, and we wanted to now get into some questions. We've got a great attendance at R&D Day today, and a lot of questions have come in. So maybe just more formally, I want to welcome Dr. Nitasha Sarswat, from the University of Chicago. Rena Denoncourt is our Vice President and TTR franchise lead. We have John Vest, who is the overall TTR clinical franchise lead and Dion Zappe, who is the clinical lead for our zilebesiran program in hypertension. So I'm just going to start going through some of the questions that have come in. So maybe I'll first start John, with you. There have been a number of questions and comments, just congratulating on the submission of the APOLLO-B sNDA application and questions about what are the next steps? When will we hear back about whether the file has been accepted? And will this be a standard or priority review? So what's the course for that application?

Yes. Thanks so much, Pushkal, and thanks for the question. We are absolutely thrilled to have announced that we have submitted the file to the FDA. Typically, we would expect to hear back from the FDA within 60 to 74 days with regard to the application. And then we would expect that this will be a standard review, which would then mean we would expect an approval late next year in late 2023, of course, pending the FDA's review and decision on the filing.

Fantastic. That's really helpful. We've also gotten some questions, John, about whether there would be an AdCom for this application. Anything you can comment on that?

Look, the question with regard to AdCom that's always going to be at the discretion of the FDA. So I don't think there's anything further that we can comment on there, that will be a decision for the FDA.

Great. So another question that's come in is we talked early on. Akshay mentioned the fact that the that Regeneron has opted to not move forward with the SemdSuran-iGAN program. They've opted out of that. And I wanted to -- and questions about what is the impact of that on the combination programs that are going on, Regeneron is advancing programs with in both myasthenia gravis and PNH. And I can take that one, which is that there's really no impact on that at all. Those programs are still going forward. We're very excited about the potential of zilebesiran [indiscernible] combination in those diseases and the potential to address real unmet need for patients with those. And so those programs are continuing on without change. I also want to just reiterate that there was questions about what was the reason about their opting out. And again, for them, this was really a private portfolio prioritization decision. And I really can't comment beyond that. This was not related to safety or efficacy. The efficacy that we've seen has been quite compelling with about a 37% reduction in proteinuria, an encouraging safety profile. So we really see an opportunity for this medicine. But in light of Regeneron's recent decision, we need to just take a step back and consider future options and how we'll develop this medicine going forward. And we'll keep everyone posted as we have updates on that. There was a question that -- a couple of questions that have come in around the AMVUTTRA biannual dosing regimen. We announced today that there's going to be a delay in the top line results coming out of that. And then really questions about how do we think about the opportunity there relative to the quarterly AMVUTTRA regimen that's already been approved. Maybe Rena, I could turn to you? And can you just talk a little bit about the reasons for the delay? And then what are we seeing so far as we talked about actually the Amvutras now starting to be launched. It's been approved in 5 territories. What are we seeing there? And then what are the implications and what are the -- what's the thinking around the biannual regimen and the opportunity that, that presents.

Sure, sure. Let me start with the exciting AMVUTTRA progress that we've had since the commercial launch. So we are very pleased with what we've seen in the first few months of launch in the U.S., particularly. There have been an average of start forms that have increased significantly since what we had previously seen with ONPATTRO. So in the ONPATTRO world, historically, there were about 30 start forms per month on average. And since the approval of AMVUTTRA, we're seeing that tick up to about 60 start forms per month average that we've reported in Q3. Now those start forms are coming from new to Alnylam patients as well as ONPATTRO switches which I think really conveys the attractiveness of the totality of the Amvutra product profile across efficacy, safety and the mode and frequency of administration. So Q3M is off to a strong start. Now certainly, the Q6M regimen or the biannual dosing regimen, we do consider that to be a nice to have, and that's why we're evaluating it in the HELIOS-A randomized treatment extension right now, as we've discussed. So we are looking forward to sharing that data with you in 2023, early 2023. And again, it was an aggressive goal to achieve by year-end 2022. So we're just around the corner with looking forward to further shed light on those results in 2023.

Fantastic. Thanks, Rena. Dr. Sarswat, some questions coming in for you, a lot of appreciation for how you've sort of framed out the unmet need. Can you talk a little bit -- one of the things that I think people were looking to hear is you highlighted the unmet need. In light of that unmet need and what you're seeing from the APOLLO-B data, what are your impressions? Do you -- can you maybe comment a little bit about what you've seen in the data, whether you see this as a potential treatment option for patients and what strikes you in the data?

Absolutely. So we talked about the unmet need largely being that there's still a good portion of patients that feel inhibited in that their quality of life is still not what they want it to be. despite stabilizer therapy, there are still a good number of patients that either can't afford or can't get on stabilizer therapy or just continue to progress. We know from the ATTRACT data that there are still a good number of patients that will continue to progress. And with that progression and longer life comes worsening morbidity. So certainly, there is a niche here for patients to improve their quality of life. I think the APOLLO-B data is meaningful and that 6-minute walk test, quality of life testing was impressive, and that is something that I discuss with patients on a daily basis and run through the data. I think one of the most striking things that I've seen in the APOLLO data was also a suggestion that perhaps there's a level of myocardial regression of amyloid deposition that we see in the ECHO data and certainly, the biomarker data is also very impressive. I think the most striking though, however, is really that imaging data that has even caused me to rethink how I follow a lot of these patients and what parameters we should be following going forward.

That's great. Really helpful. John, there were some questions because you presented some new data in terms of clinical progression, looking at a couple of different measures. Can you just elaborate a little bit more on what was found there? And then maybe Dr. Sarswat can talk a little bit about does she use those types of measures in following her patients in clinical practice.

Yes. Thanks, Pushkal. We are really excited about this data, and we're very pleased for it to begin with to see that there's starting to be consensus and publications around what defines progression in these patients and this linked to biomarkers. And when we look at this, I'm very pleased to see that along any of the metrics that are followed, whether it's NT-proBNP, troponin ATTR disease stage or a composite of all of the above that it appears that there is less progression by these increasingly accepted and now published criteria, there's suggestion of less progression in the patisiran treated patients compared to placebo. So for us, this really -- we were very, very pleased about the overall biomarker data with NTP in troponin, but these additional analyses, we think, really underscore the clinical importance of those findings and of the primary results of study.

Great. And Dr. Sarswat, can you comment a little bit, I guess, maybe 2 parts. How do you follow progression in patients? You said that there are some patients who are, for example, stabilized or nonresponders or other patients who may be progressing with their disease. And do you use measures like BNP or troponin or disease stage or NYHA class to follow those patients.

Absolutely. So that's exactly what we follow. We have a pretty set clinic algorithm where we're essentially following biomarkers on these patients, NT-proBNP and troponin as well as eGFR depending on which staging system you look at. We're following all of those things every 3 months in patients. We're assessing quality of life and New York Heart Association. We're not obviously doing KCCQ on every single one every 3 months, but that is a big part of what factors into the discussion that we have in clinic. Similarly, from an imaging perspective, I've always felt that cardiac MRI will offer us the best way to follow amyloid deposition. But as you guys pointed out in APOLLO-B data, right, again, the LVAD, the stroke volume, I think, are things that we should be focusing on, whether it's by Echo or MRI should be following going forward in addition to T1, T2 ECBs on MRI, LV mass on Echo. I think all of those are important parameters. And those certainly fit into our serial measurements for -- in our algorithm. Obviously, when we talk about what constitutes disease progression, there is a level of what's happening with biomarkers and imaging, but certainly, there's just a patient that's sitting there in front of you, telling you something is different. Something's gotten worse. I can't keep up with my grandkids, the way I could 6 months ago, something's changed. And that means more than anything.

Really helpful. It looks like there's just a whole host of different measures that you can be following in these patients. And so that's -- that's great to hear. Maybe we'll turn over Dion to you some questions coming in on the hypertension program. You presented some new biomarker data on Renin and ANG2 and Aldo. Maybe the question -- the first question has come in is the understanding that elevated renin levels are a potential driver of RAS escape. And I think you showed some data showing higher elevations in renin levels. Can you just comment on whether that's a cause for concern with zilebesiran?

Yes. Thank you, Pushkal. So as I -- as you mentioned in my presentation, with zilebiseran, you get very effective inhibition of angiotensinogen. And we know that if you can inhibit angiotensinogen to a very significant amount, and we showed with up to 800 milligrams, greater than 99% reduction in angiotensinogen levels. And what that does is it actually changes the way the reninangiotensystem is regulated rather than being an renin dependent rate limiting step, you actually change it. So angiotensinogen becomes rate limiting. So effective reductions in angiotensinogen results in effective reductions in angiotensin II. And as a result, you see increases in Renin. But in contrast to oral RAS blockers, where that increase in Reno is observed, particularly with angiotensin receptor blockers. And if it gets to high enough levels, it can overcome the RAS blockade, whereas that's not the case with zilebesiran. So very interesting to contrast the 2 effects.

That's really helpful. And can you comment a little bit about how common is RAS escape with conventional ACEs and ARBs. Is that a common phenomenon? Do you see patients who aren't responding to those agents? Is that -- maybe you could give a little context around that?

Yes. And one of the interesting things with angiotensin receptor blockers and ACE inhibitors has been that the -- these are well-established agents and the management of hypertensive, they are effective in reducing blood pressure. But there's also been a desire in the last 20 years to improve on the blood pressure lowering effect of these agents. And it was always thought that more complete inhibition of the reninangiotensinsystem would derive more benefits on blood pressure lowering. But we've seen that, that hasn't really worked in terms of showing really much additional reductions in blood pressure, but we've seen some added safety concerns. So what we're doing with zilebesiran is we're really interested in looking at this unique way or novel way of interrupting the reninangioten system and perhaps by exploring it as an add-on as we've shown in our Phase I study, where we had additional reduction of blood pressure and really further evaluating that in our Phase II study to see if we can see added benefits on blood pressure lowering without a safety concern. And I think that will be the real test for us to see if there's added benefit with zilebesiran on top of standard oral RAS escape.

Fantastic. That's really, really helpful. John, questions come in around there's awareness that Ionis has increased the size of some of the eplitersen clinical trials in cardiomyopathy. Can you just comment on a question that's come in is around HELIOS-B? How are we feeling in terms of the sizing and powering of our study, do we feel confident about that? Are there plans to increase the size, for example, of our study...

Yes. Thanks, Pushkal. Look, we remain very confident in what we're seeing on Helios B and very confident in the design, the size and the powering of the study. So we do not have any intention at this point of time to make any changes.

Great. Very, very helpful. Maybe another question for you and Rena, just what are the plans in terms of the APOLLO B, maybe I can turn this to Rena, 18-month data in the open-label extension, I guess, patients are crossing over, and there's questions around will we -- what are the plans for putting those data out in the public domain. And then I guess, John, maybe for you, is that something that we'll be providing to the FDA? Or how will that happen? What's the management of that in the context of the ongoing review of the application.

Sure. I'll start, and then happy to turn it over to John. So certainly, consistent with typical Alnylam practice, we do intend to bring these data forward. The 18-month data are right around the corner, and we would be mapping out what our 2023 Congress and presentation plan looks like right now and fully intend to share that with you in due time. John?

Yes. Thanks. And with regard to what we would plan to share with the FDA, what the standard practice is, is to provide safety data at day 120, and we will certainly be doing that.

Great. That's helpful. So Dr. Sarswat, a question for you. You talked in your presentation about sort of the growing burden of heart failure, and you talked about sort of increased numbers of patients. Can you comment on -- and maybe I guess more specifically for ATTR, are you starting to see patients being diagnosed in earlier stages of disease? And is that part of why we're seeing this growth? And what are the implications of that with regard to when do you think with the available therapies, we should be treating these patients and how early?

Absolutely. I think I've seen a huge paradigm shift. I feel like I've been in the amyloid field for a little over 10 years and what a difference it has made. Not a single week goes by that a resident or follow is not calling me with new cases. They are thinking about it. They're attuned to it. Everybody has a much higher index of suspicion. When you go to cardiology conferences, it's a hot topic. People are interested in the research behind this and what is happening. So absolutely, there is certainly earlier diagnosis that's occurring and just more widespread diagnosis. And I think that's not just at academic institutions, that's in the community as well. I think not only industry and academia, everybody has done a wonderful job really trying to hit at education, and it's made a difference. I think it certainly makes a difference. I think the patients that we're catching earlier and getting on treatment earlier are more likely to respond. They are the people that after a year or 2 of treatment are looking at an [indiscernible], -- are you sure you got the diagnosis, right? It just feels so good. And everything I read says that I'm supposed to be getting a lot -- supposed to be getting a lot worse. And I feel so good. There are definitely those -- that category of patients as well. And I think what we don't understand certainly is who are those nonresponders and who are the responders? Are there certain clues that can give us on who will respond and who will need more therapy. We don't know that yet. But absolutely, I do think the earlier we catch people, the more treatable and I think our threshold for treating should be a very low one because the consequences of not doing so are potentially very disastrous for that patient.

Very, very helpful, very helpful. Maybe another question for you, Dr. Sarswat is given what you just said and in light of what you're seeing in terms of the clinical data from APOLLO-B on ONPATTRO, the questions are coming in, where -- from your clinical experience, where do you see assuming it was approved, potentially using a drug like ONPATTRO for the patients when you describe the unmet need and the range of patients that you see in your clinical practice, how might you use this or employ this in the treatment of your patients and where in the armamentarium?

Sure. So I mean I think this is still a discussion that we have every day. The patient that I talked about in the presentation, there are a lot of very intelligent patients who are looking for a discussion with their physician. And it's walking through the data that we have and presenting it and saying, this is what we know so far. We know that this is a changing landscape. But what we know so far is that there is potential for regression. There is certainly a sense of improvement in quality of life and biomarkers. And if things are not going in the right direction or even people that are still continuing to do well to be able to attack the disease at a different level, knowing the downside of not potentially adding therapies? Is this something that you would be willing to take on. I think as the therapies become easier and easier for patients, for instance, for vutrisiran versus patisiran, right, just in their lifestyle and being able to actually be able to get the drug in the convenience of their life, things will get easier and easier for the patients and they're more likely to want to be on these drugs as well. There are lots of patients that will just defer to us and say, if you think this is the right thing to do, I will do it regardless of anything else, and then there are patients that want to know the data that actually will want to see APOLLO-B data that I will show them the actual data. I will show them what I know. And everyone is different, but I think there is still that need there. in those discussions. And it fits in the armamentarium, as you said, for people, wild-type patients who cannot get on any therapy, wild-type patients who are progressing or maybe even those that aren't that just want to be able to have another way of attacking the disease, hereditary patients who don't have a neuropathy or don't have other indications right now for SAR as they are any therapy.

Super helpful. Dion, questions come in around zilebesiran. Can you talk a little bit -- I guess people are asking you just long-acting blood pressure lowering medicine. And what happens if there are hypotensive events after someone who started therapy? And maybe you could talk a little bit out what the clinical experience has been with regard to hypertension in the Phase I that you've reported out on? And then what are the plans and how can that be addressed if someone did have a hypotensive event on zilebesiran...

Right... Perfect. Yes. In our Phase I study, it's important to remember here that we did not see any cases of hypotensive related episodes. But it's also important to note that in our ongoing Phase II studies, if a patient does experience a hypotensive event. We have certain protocol in place. And the first one is to reduce any background oral antihypertensive medication. So that's the first strategy. It's also important to note that in our preclinical program, we demonstrated that with SI RNA inhibition of angiotensinogen, you can reverse the effects the [indiscernible] effects by using standard measures. -- such as salt loading and pressures and so forth. And we also demonstrated in our Phase I study that in a high salt intake can also limit the antihypertensive response to zilebesiran. So we feel very confident that using standard clinical measures in clinical practice, if a patient does have experience a hypotensive events. There are certain things that can be done to limit the anti-hybrid in of a hypotensive response to zilebsiran. But there may be some clinical conditions where acutely, we need to reverse the effects of zilebesiran. And as I mentioned in my presentation, we are going to have later today a discussion about the development of a reversal agent for zilebesiran. So right now, it's in preclinical development. We have plans to have discussions with health authorities on what would be a successful clinical development plan for this reversal agents, but we do have plans for that in place.

Thanks, Dion. Very helpful. A question came in around our -- the Akshay announced the ALN-XDH program hadn't met our expectations, and we'll be stopping that program. And the reasoning to elaborate a little bit more about that. So let me take that one. I think this was a very interesting program. There's a tremendous amount of unmet need in gout where patients progress, and we have the opportunity with RNAi to target xanthene dehydrogenase. But an important biological question that we had going into the study was to what extent will hepatic silencing alone with the GalNAc conjugated siRNA be sufficient to produce enough uric acid lowering to be important for patients with gout. And that was something that was difficult to assess in preclinical models because of some of the limitations that are inherent in preclinical models of gout. And so what -- we did actually a very efficient, small Phase I single ascending dose study in healthy volunteers. And through that, while the drug was safe and well tolerated, and we did see some evidence of pharmacologic activity, the magnitude of uric acid lowering that we see here is not suggestive that this will be a transformative medicine for patients to get with gout. And that's really what we're focused on here at Alnylam is to bring forward transformative medicines. And so based on this single ascending dose experience, we're able to make a decision, data-driven decision, that we shouldn't advance that program forward. And that's really the substance of what went into the decision-making here. So we won't be advancing that program further and focusing our resources on other programs where we think we can make a bigger impact on patient health.. Maybe... Question that came up is around -- if you could talk a little bit about Dion in terms of what are we looking for in terms of treatment effects. You talked about Cardio-2, which is a combination study. What are we thinking about in terms of what would be clinically meaningful treatment effects as additive therapy on top of the various background medicines that you talked about?

Yes. So remember, in our Phase I study, we showed very effective reductions in blood pressure with angiotensinogen for doses from 200 to 800 milligrams. And so in that Phase I study, a reduction of systolic blood pressure of 10 millimeters of mercury or more, we thought was clinically meaningful with up to 20 millimeters of mercury reduction in blood pressure to the 800 milligrams. So in Cardia2, where we're looking at the additive effects of zilebesiran on top of standard of care, -- so the first one, where we add zilebesiran to the common diuretic indapamide we're expecting to see reductions properly around 10 millimeter mercury or more with the calcium channel blocker amlodipine, we're expecting to see additional reductions in blood pressure of at least 8 millimeters of mercury. And with the add-on to Omesa in the angio tens receptor blocker, we'd be interested in seeing reductions of 5 to 6 millimeters of mercury additional. So again, it's a different effect for different types of classes of antihypertensives we're really looking to see what's the added blood pressure lowering efficacy to zilebesiran on top of the standard of care at the business crisis. So again, we'll hopefully see the results at or around end of the year next year. And that's really going to help shape our Phase III clinical program where we go, what types of patients we propose to use in our Phase III program to really assess the clinical benefit of zilebesiran, particularly in patients that have uncontrolled hypertension.

Great. Great. Rena, a question came in for you. How do you anticipate the pricing of ONPATTRO to be impacted by the potential launch in cardiomyopathy, assuming a positive FDA review.

Sure. Certainly an important question. And I think exactly what you are alluding to, we need to take this step by step. First, let's -- as we announced last week, we did complete the submission of the SNDA with the FDA. So the next step will be to get that, as John mapped out, accepted and then an approval later in 2023. So pending all that goes smoothly, we would then have the label. And that would be important for kind of further refining and shaping our pricing approach. So I don't think we want to go into too much detail on specific pricing, but I will make a connection here to our access efforts. And I think access is really important as we heard as a key unmet need in the space from Dr. Sarswat's talk, right? So what we've seen with ONPATTRO in the AMVUTTRA in the polyneuropathy space has really been significant progress in aligning our access strategy, things like our value-based agreement strategy and really having broad access for patients with the hereditary ATTR amyloidosis with polyneuropathy and gaining strong access for both our ONPATTRO and AMVUTTRA products to date. We think that really serves as a strong foundation for what we're building for the future with ONPATTRO in the cardiomyopathy space potentially and then, of course, [indiscernible]-- so I think those proactive efforts for access will be really important over the course of the coming year as well.

Fantastic. That's really helpful. We're getting down to the last just few minutes of the Q&A. So we'll just have maybe 1 or 2 more questions. Maybe one, John, can you just talk a little bit about next steps with regard to TTRSc04? -- question came in about really interesting. What do you see in terms of will we be able to take that program directly from Phase I into Phase III? Will it go into PN and CM? What's the thinking about how we can develop that and how quickly we can develop it.

Yes. Thanks, Pushkal. Look, we are really very, very excited about the potential for TTRsC04. We are anticipating getting started on that Phase I study in the immediate future and really looking forward to that and having results -- top line results that we could share by the end of next year. With regard to the clinical development plan, how we're going to move that forward, that's certainly something that's still -- we're still under discussion and considering, and we'll certainly share that in due course. And I think with regard to moving things forward rapidly, I would just point to our track record with how we've been able to move things forward with vutrisiran and other compounds in our pipeline, but we'll certainly look forward to sharing those clinical development plans as they become available.

Great. Thank you, John. Well, folks, I think this is really at the end of the time that we have for Q&A this morning in this first session. So I'm really -- I want to thank John, Rena, Dr. Sarswat, Dion, for all of your input and the interesting discussion. We're going to take a break everybody until 11:05, and then we'll resume with Part 2 of R&D Day, where there will be an update on our early and mid-stage programs as well as our platform efforts, and then a second Q&A panel after that. So we're going to break until 1105 and I hope you'll all come back and join us for the second half of R&D Day. Thank you.

Good afternoon. Welcome, everybody, to the Q&A. So I'm Kevin Fitzgerald. I'm our Chief Scientific Officer. I'm here were Dr. [indiscernible], our President, Weinong Guo, our Senior VP of Clinical Research, Aimee Deaton, our Associate Director of Human Genetics and Vasant Jadhav, our Senior VP of Technology. So I hope you all are as excited about the presentations in the previous session as we are really, as we continue to extend and harness this revolution in biology for human medicine called RNAi therapeutics. And not only maximizing what we can do in the liver as you've seen time and time again, but now also extending that into organs such as the central nervous system, skeletal muscle in terms of adipose tissue and others. So with that, we're going to jump into a bunch of questions coming. And I'm going to start a little bit around there are a lot of questions around APP. And so I'll start off with a question to Akshay sort of around what data can we expect from the Phase I and APP in early 2023. And really, kind of what level of knockdown would you consider significant and why?

Sure. Thanks, Kevin. Hello to everybody, and thanks for joining us on our R&D Day. Let me answer the second part, maybe Weinong, you can help us with the data expected from the APP Phase I study early '23. I think the question of the degree of knockdown obviously is a very interesting, important one. One area that gives us good insight is looking at individuals with price Me2 the individuals that delivered Down syndrome, and they now have a triplication of eclobasone resulting in 3 [indiscernible] of the APP local, so a 50% increase -- and that turns out to be a very powerful genetic association with a couple of [indiscernible] Alzheimer's in a premature age. And so that gives us some clue that about 50% reduction, we should be consistent with maintaining safety, we believe, based on all our animal work would be a good target to import the therapeutic benefit. So about 50% is what would be interesting to see. Beyond that, in terms of the expectations of Phase I or data we can expect in the first quarter, but Weinong, do you want to pick up on that?

Sure. Thanks, Akshay. So as I presented, we are currently launching a Phase I study being conducted in U.S., U.K. and Canada, and we are nicely progressing the single ascending dose cohort. And we expect that -- some of the emerging data will be available for -- from that multi single ascending dose cohort in early 2023. So stay tuned, we will report those data out with regard to the nicely progressing to the as per study protocol. Thank you.

All right. So sort of riffing on APP a little bit more. So one of the questions is around mechanism. So obviously, there are AP beta AMOLED targeting antibodies out there. Actually, Weinong why don't you want to comment a little bit about sort of the differences mechanistically we expect to see as well as the current landscape out there with the antibodies in this disease.

Yes, I'll start and Weinong please do join in. I think in the first instance, the recent news about lucanumab from Biogen is very important and exciting, it's the validation of the AGP hypothesis that is being so troubled. And finally, we're seeing that extra cellar reduction of APP is associated with multiple benefit in patients. So let's see what happens to that drug, hopefully, it will get approved and it will start helping patients. I think separately, what we're interested in addition is the ability to [indiscernible] aproximately at the message level and so reduce APP-related fragments, both intracellularly and extracellular. And there's a wealth of information now that's accumulated on the neurotoxic effects of intracellular APP fragment. And Weinong might have showed in one of these slides, [indiscernible] neurons from presenilin mutated patients who have Alzheimer's how we reduce the commotion, we wrap [indiscernible] endosomes, which are hallmark of intraneural on first [indiscernible]. So I think the antibody news is exciting. We hope to do more by reducing not just the extracellular deposits, but the intra-cellular effects of toxic [indiscernible] from APT and looking forward to the Phase I data in early '23.

Just one follow-up. -- anything?

Yes. Yes, I think actually, you explained very well. I just want to add that APP sit on the very upstream of the Amlogenic process. So we expect to see silencing a number of variety of the amyloid privilege products, both intracellularly and extracellularly. And we think targeting this genetic target will offer us a well-differentiated profile versus so many of the other monoclonal antibody currently in clinical investigation. So stay tuned and with the data come out and happy to report and share...

Thank you. A little bit further Weinong so. So if you think about silencing of APP, is there such a thing as going too low and where are we targeting similar to a question before. But also, can you talk a little bit about this disease called CAA and why we think that silencing APP could be beneficial in those patients?

Yes. Good question. Thanks, Kevin. And for the CAA, as we know, this is just a different phenotypic of the increased amyloidosis. And particularly, as I shared in my presentation, these are the amyloid deposits in the vasculature of the brain. And as we said, I presented, there is a high minimum need. There's a lot of much of the clinical development currently ongoing. And we are very eager to looking at how the C16 congregate through the Intrasecadministration of ALN-APP demonstrated in the early asset of Alzheimer's disease. And we -- if we clear that a gating mechanism, then we certainly is very much looking into the potential conduct proof-of-concept or additional studies in the CAA doing some expansion programs, building on the scientific rationale.

Thank you, Weinong. So... I mean Go ahead, Akshay.

Yes. No, I was just going to add, Kevin. I always see this wonderful analogy to work with TTR and ATTR-related disorders that you have this one protein, the petuletic fragments of which mediate the severe neurodegenerative phenotype, Alzheimer's, and we hope they are out there. And using the same mechanism with the same growth, we also hope to help this very other phenotype, the renal amyloid angiopathy, which causes hemorrhages and ultimately rather our strength. So I just think it's a really powerful opportunity for 2 major neurological disorders. And again, we all expect about the data that we'll be hope to see in early '23.

Thank you, Akshay. So final 2 questions around this particular topic. One, I'm going to put this over to Vasant. A couple of questions came in around a -- our duration of action and how it differentiates from antisense oligos and the other things and the others in the field. And b, have we thought and are we working on perhaps trying to get away from intrathecal dosing and get across the broad brain barrier?

Yes, that's a great question. Thank you, Kevin. So historically, I mean the data that we took for the sRNAs and the antisense oligos for liver targets, we do clearly see the benefit with RNAi technology or with our sRNAs in terms of the durability of effect, and we have published this work. And that's the reason we can do every quarterly or in case of inclisiran is every 6 months. And now with Ikaria, we believe we'll be going every 1-year injection, that's the kind of potential. To our knowledge, I mean, we are not really seeing the anise oligos that go beyond weekly or monthly kind of dosing regimen. So we believe that benefit will continue to remain with the sRNAs -- can you remind me the second part?

The second part was around blood-brain barrier work.

Yes. So I mean I can take that one quickly and obviously, getting across go ahead. I was going to say getting across the. barrier was always the goal. Sorry, we have a little bit of a delay. And so I think we continue to work in that area to make sure that if there's a true breakthrough in that area that we're all over it. And right now, we're very confident with very infrequent IT dosing that we'll be able to treat a lot of the a lot of these diseases. So I'm going to --a little bit in -- go ahead, Vasant.

No, I would just exactly was going to add that same point that we are pleased with what we have seen with the C16 sRNAs. I mean we saw the data in NHP right? it is for months and months with a single injection. We're seeing potent and very long-lasting activities. So with that kind of approach, making it very infrequent potential for very infrequent IT dosing, that still is a great option.

Great. So I'm going to turn now to HSD and presented a little bit of the data today. And maybe Weinong, can you talk a little bit about the program? And then maybe Akshay, you want to join in around questions around why do we opt out of that program? How does that program relate to PNPLA3, which is another program in that space? And how do we think about those targets? So maybe start with Weinong and Akshay, you can jump in.

Sure. Thanks, Kevin. As I presented, we have obtained quite positive. I think to us, is a proof of concept in the first Phase I studies with ArinHSD shows a dose-dependent knockdown of the HSD-level with a liver biopsy, well tolerated. That's a primary objective of the study we conducted, and we are very pleased to see some preliminary liver enzyme data showing a nice reduction as well as the pathology, a nice trend, although the study is not particularly powered for those endpoints. And we are looking forward to share most of these data through the -- the next year presented at a major scientific congress. In terms of next steps, Regeneron is leading the HSD program. And very soon, a Phase II study will be launched to further evaluate the efficacy in the NASH patients -- so Akshay, do you have anything additional to add on about the [indiscernible] Of the out...

Yes. Let me just pick up on that Weinong Kevin. So I think we're obviously delighted with the Phase I data. I think it's probably, I don't know, over -- we're double digits in terms of number of proofs of concepts we've achieved in early results. So it's really an exciting result. It's a full validation of the selection of the target they [indiscernible] from the original genetics at Regeneron. And the data fall exactly in line with the expectation of the due to roll of the target in the pathogenesis of NASH. So not only do we see target reduction, but we also see improvements in transaminases and most importantly, improved trends in the mental score. And as we obviously the [indiscernible] but the other NASH progression from the [indiscernible] . So that's exciting. Whilst we're excited about the day, I'm very confident about the future of that program in the [indiscernible] Regeneron, I think we're in the wealth of riches and we have really a full portfolio, and we're going to continue to make the best decision we can to focus our resources on the highest value opportunities where we can deliver the best products for patients. So we're also going to continue to support Regeneron with HFC. We're going to be very actively involved in the rest of the NASH portfolio that we work on with the PMP 5 and other targets. But there's plenty here for us to contribute and help with that or help patients and also help build value for our line...

Thanks Akshay . So just staying with HSD for PNP for one second, I'm going to turn over question over to Aimee. So Aimee, a question came in about sort of the genetics of PNPLA3 and ASD and is there any potential overlap between the 2? And are they -- or could they potentially be used together?

Yes. I think that's a really interesting idea. And the idea of a combination approach is supported by genetic showing that the risk reduction conferred by the protective allele of HSD is greater in carriers of the PNPLA3 I148M Leo. As you know, Regeneron is advancing those programs. So it will be up to them to entertain this possibility, but it's definitely an interesting one.

Thank you, Aimee. So moving on from HSD, a lot of questions here from people about REVERSER or and in particular around how do we think of the need for reverser the development? What would a Phase I look like? Maybe I'll start with Weinong-- and Akshay, you can certainly talk about.

Yes. Great questions. And we are, as a clinician, a drug developer, I'm very pleased to see that we now have the technology to develop a reverser that may be warranted in certain clinical circumstances. As you heard earlier from Dr. Dion's presentation, particularly focused on Zilebesiran. And Vasant showed you some of the nice data of the AGT reverse with our reverser in nonhuman primate, we think in probably the first potential clinical scenario are those particularly situations when you need a reverse here in the clinical settings that can reverse the hypotensive or other effects imposed by the [indiscernible]. So I think we are currently, we are looking into the clinical candidate development candidates and hopefully bring it to the clinical development in the near future. And difficult to talk about the earlier programs, clinical devent plans at this point, but happy to share in the future opportunities...

Yes. Let me just build on that, Weinong. I think the interesting thing about our technology is that we have the flexibility to have reverse like approaches if needed. So that's just the power of our platform, and I saw one slide very nicely illustrated that. Most importantly, so far the safety for zilebesiran has been outstanding. When Phase 2 continues to go well. In the Phase I study, we saw how even in salt and water depleted patients, you didn't see an exaggeration of the high cotensive effects and patients tolerate it is obvious on as well. Dion discussed how, in any situation, there's lowering of blood pressure with zilebesiran, if you want to increase blood pressure. I think talking to our experts and look at the mechanism of action, just giving saline would probably do the trick actually, in most cases, it looks like -- now having said that, as with other classes of medicines, most reasonably 10 and 10 inhibitor, novel astiagulants where the reversal agents. I think it's wise to have something like this in our back pocket. And let's see if we -- ultimately, we'll need to develop it fully. There's certainly no requirement that's being made to us as yet and clinically with the progress of program, we're very comfortable. But certainly, it's a wonderful example of what our technology can do if needed...

All right. So we're moving on from reverser here. I want to talk a little bit about the HBV program, and there were some questions about sort of the degree of knockdown and what is a functional cure mean? I don't know maybe, Akshay, you can weigh on on that one.

Yes. I mean, with -- I mean the FDA actually has issued guidance documents on drug development, [indiscernible] functional cure with respect to at [indiscernible], I mean you basically have to become undetectable and then you have to maintain that undetectable status half treatment for 6 months or longer. So that's in the guidance, and we are fortunate to have that. It's a readily measurable biomarkers, as you saw with the date of Weinong showed.And I'm sure the Phase II data start coming in later this year across multiple trials our colleagues at Vir, who leads this opportunity, we'll share more, not just another data for the service development and how the data guiding them...

Anything to add Weinong?

No. I think that's perfect. Yes. exciting...

I agree very exciting and certainly a lot of unmet medical need. I'm going to move on to a couple of newer targets, questions have come in. Very exciting to reveal GenX from last year being InhibiteAnd now we have Gen-Y. So a couple of questions for Aimee. One, if you think about Inhibite,what are we looking at in terms of -- and thinking about it in terms of indication? And then a question a little bit around Gene-y, sort of the same question and how are we thinking that these agents will differentiate in the cardiovascular metabolic space.

Thanks, Kevin. Good questions. In terms of innovent E, we're considering multiple indications in cardiometabolic disease. And I think a major differentiator for Innovent E is a distinct mechanism from current therapies. -- we believe it will decrease abdominal fat and improve insulin sensitivity with additional potential benefits on lipids and blood pressure. So we see this really as a likely complement to targets for cardiometabolic disorders. In terms of Innovent E- sorry, in terms of gene-y , we know that type 2 diabetes is one of the largest global diseases. So it's clear that there's still a huge unmet need in that space that I showed you figures, which demonstrate that almost half of patients are not achieving target HbA1c, many go on to require supplemental insulin. And the mechanism of Gene-y is that it's going to improve insulin sensitivity, which is really central to glucose control. And we have this preliminary evidence showing that this is achieved without weight gain, which could be an issue with insulin. So we're continuing to evaluate the effect of gene-y silencing in preclinical models, but I think we'll be just really excited to expand the treatment options available for diabetes patients because there's a clear unmet need in that space.

So Weinong you have any comment on that space again and how we're thinking about it overall.

Yes. I think in terms of the type 2 diabetes market, and it is a gigantic with millions of patients with type 2 diabetes, although there is various variety of the [indiscernible]. But as Aimee commented, more than 50% of the patients are lack of glucose control with HVAC above 7%. And also very similar to the hypertension these patients are also suffered from the low adherence and compliance. So we think with the SINA approach with tonic control of some of the target gene expressions, we feel there is a unmet need we can address through those normal targets and potentially use in combination with the current standard of care.

Great. So anything to add there, Akshay? Or shall you for the next couple of questions. We're coming close on time.

No. I mean I would just add that inhuman-e looks to be a very exciting target. And I think, Aimee, your paper this year illustrated very nicely with human data, the reduction in the improvement in glucose menopaces in these individuals [indiscernible] the improvement in the lipid profile, the improvement in blood pressures and all of that suggesting and with larger [indiscernible], I'm sure this issue will elaborate further at all of that adding up to reductions in major cardiovascular events so forth. And so I think it's a really, really exciting target and one that -- in contrast to current approaches like the GLP1 agonist, which can reduce body mass by using both Adipose tissue and Masterman, here's an opportunity to reduce added patissier loan and exit these beneficial [indiscernible]. I find it fascinating target and one that could really create a very differentiated in both product profile for a large number of patients.

Thanks, Akshay. I'll also answer the one final question on that. There was a question about whether this is -- whether inhibit-e is Alnylam fully owned or whether it's partnered with Regeneron. And the answer is that this is a fully owned Alnylam program. We have a certain number of programs within Regeneron, but we also developed a bunch of our programs outside of that relationship. So I'm going to turn very quickly to some question around news that's out there now or around I think this morning, there was a company that showed some delivery to muscle with an RNAi approach. And so I'm going to turn this one over to Vasant to talk a little bit about what we think about our approach to delivering the muscle in our early data. And really, what are the characteristics that we're looking for in a delivery solution.

Yes. Thank you, Kevin. Yes, I believe, I believe, released some of this data, this morning today or recently. I mean, we look at this one as a positive news. It just shows how robust and validated the RNAi technology is that you can go into these different issues. Now we believe this data is with the antibody SRA conjugates. In our case, -- we are not limiting ourselves to the ligands are specific. We're going all the way from small molecules to psychic peptides to nanobodies to antibodies. And we'll try to find the best possible molecule for safety, for efficacy for CMC in terms of its development and for commercial considerations. So with all that together, we'll try to find the best solution that gives us the potency and the safety to reach to the muscle tissue of the targets of interest and improve upon what is reported.

Thanks, Vasant. So it looks like we're out of time. So I want to thank everybody. And with that, I'm going to turn it over to Akshay to close.

Yes. Thanks, Kevin. And in closing, I just want to say I hope everyone has enjoyed this wonderful morning of science and medicine. We've talked about our TTR franchise with tremendous progress with Apollo-b this year and much more to look forward to with the submission of the sNDA and of course, HELIOS-b fully enrolled. Zilebesiran had a very interesting new data on had a very elegant sort of discussion about the differentiation that zilebesiran offers patients who have truly transformative that drug could be a major global disorder. We've discussed the earlier the mid-stage pipeline, which continue to fuel our growth as well as the powerful advances from the platform that AV and Vasant discussed. And I think you can rely on us to continue our journey to new targets and tissues, not just for the liver and the central nervous system. But important genetically valid targets in tissues like muscle and at adequate tissue, lung, kidney, and we're actively working on all of those. And I think some very provocative data both as on today. So 2023 looks very bright. There's a full year of work ahead of us. We look forward to achieving those goals. Thank you for your attention today, and happy holidays. Bye-bye, everybody.

Happy holidays.