Good morning. And welcome to the Ionis Pharmaceuticals Fourth Quarter and Full Year 2021 Financial Results Conference Call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Jennifer Capuzelo, Investor Relations, to lead off the call. Please begin.

Thank you, Anthony. Before we begin, I encourage everyone to go to the Investors section of the Ionis website to view the press release and related financial tables we will be discussing today, including a reconciliation of GAAP to non-GAAP financials. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website to accompany today's call. With me this morning are Brett Monia, Chief Executive Officer; Beth Hougen, Chief Financial Officer; and Richard Geary, Executive Vice President of Development. And joining us for Q&A are Eric Swayze, Executive Vice President of Research; and Onaiza Cadoret, Chief Product Strategy and Operations Officer. I would like to draw your attention to slide three, which contains our forward-looking statements. During this call, we will be making forward-looking language statements and are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail. And with that, I'll turn the call over to Brett.

Thanks, Jennifer. Good morning, everyone. And thanks for joining us for today's call. We made substantial progress last year toward achieving our vision of becoming a leading, fully integrated biotechnology company. We're building our commercial pipeline, advancing and expanding our technology and moving towards delivering an abundance of new medicines to the market, which together we expect will drive substantial future growth. At our Investor Day late last year, we introduced our go-to-market strategies for our near-term commercial opportunities eplontersen, olezarsen and donidalorsen. And through our strategic collaboration with AstraZeneca to jointly developing commercialized eplontersen, which we announced late last year, we bolstered our commercial organization and accelerated preparations for our near term product launches, while also positioning eplontersen to win in the competitive TTR amyloidosis market. The clinical development of eplontersen, olezarsen and donidalorsen also continued to progress well. The Phase III NEURO-TTRansform study of eplontersen in patients with TTR polyneuropathy completed enrollment in 2021 and remains on track for data around midyear, followed by regulatory filing by the end of the year, assuming positive data. And the Phase III CARDIO-TTRansform study in patients with TTR cardiomyopathy is also progressing well with data on track for 2024. We expanded our Phase III pipeline late last year when we initiated the core severe hypertriglyceridemia study for olezarsen. This was an important step as it expands the olezarsen Phase III program beyond FCS to potentially address the more than 3 million patients with severely elevated triglycerides. Importantly, with first mover advantage, we have the potential to deliver a first in class medicine to this broad patient population. We plan to report data from our olezarsen program in patients with FCS next year and in patients with severe hypertriglyceridemia in the following year in 2024. We also initiated the Phase III OASIS-HAE study of donidalorsen in patients with hereditary angioedema late last year, putting it on track for data also in 2024. Donidalorsen has demonstrated a potential best in class profile in studies to date. And given the continuing unmet medical need for more effective HAE prophylactic treatments, we see donidalorsen as a very compelling opportunity for Ionis. This year, we plan to report additional data from the Phase III study for donidalorsen and the ongoing open-label extension, further demonstrating donidalorsen's highly favorable profile based on studies to date. Now looking more broadly at our late and mid-stage programs beginning with programs from our leading cardiovascular disease franchise. The Phase III Lp(a) HORIZON study of pelacarsen continues to progress well. Novartis reached 50% enrollment last summer and the study remains on track for data in 2025. And coming up this year, we look forward to several Phase IIb data readouts, including three from our cardiovascular franchise. Beginning with data from the adhesion [ph] study of ION449, our PCSK9 LICA medicine with AstraZeneca in patients with dyslipidemia at ACC in April. Later this year, we expect data for fesomersen, our Factor XI LICA medicine with Bayer in patients with end-stage renal disease and Phase IIb data for IONIS-AGT-LRx in patients with treatment-resistant hypertension. Moving to our neurological disease franchise. We further strengthened our leadership position in SMA by advancing a follow-on program to SPINRAZA with Biogen for the treatment of SMA, which has the potential to reduce dosing treatments. We're also pleased that Biogen continues to actively engage with regulatory authorities, working towards a potential path forward for tofersen in patients with SOD1-ALS while continuing to evaluate the data from the Phase III VALOR study and the open-label extension. The other programs in our ALS franchise also continued to progress well, and this includes our C9 ALS program, which is on track for data in the first half of this year. We are also pleased that based on the findings from the GENERATION HD1 study, Roche has identified a path forward for tominersen in patients with Huntington's disease with plans to initiate a new Phase II study in younger patients with less disease burden. We look forward to additional updates from Roche later in the year. And in addition to the SPINRAZA follow-on, we made other important technology advancements throughout last year, including advancements in new microchemistries, and in the potential identification of a new backbone chemistry as we highlighted at our Investor Day in December. Importantly, we achieved all these pipeline and technology advances while strengthening our overall financial position and substantially exceeding our 2021 financial guidance. And looking ahead, we expect 2022 to be a busy year with a steady cadence of key catalysts that will keep moving us closer to our goal of becoming a leading, fully integrated biotechnology company. And with that, I'll turn the call over to Beth to review our 2021 financial results and our 2022 financial guidance. And Richard will discuss our recent key pipeline achievements and highlight pipeline catalysts for the year ahead. After Richard, I'll wrap up our prepared remarks before taking any of your questions. So now over to Beth.

Thank you, Brett. I'm pleased to report we ended 2021 with non-GAAP net income of $116 million based on revenues of more than $800 million and non-GAAP operating expenses of $695 million. These results significantly exceeded our 2021 revised guidance. Further, we remain well capitalized with 2021 year-end cash and investments of $2.1 billion. A key element of our strong financial foundation is our ability to consistently generate substantial revenue from numerous diverse sources. In 2021, we earned more than $340 million in revenue from our marketed products with the majority coming from SPINRAZA. SPINRAZA's global sales were $1.9 billion for 2021, from which we earned more than $265 million in royalty revenue. SPINRAZA global sales were down 7% year-over-year, primarily due to increased competition in the U.S. However, we were encouraged that discontinuations decreased compared to Q3. And in the rest of the world, SPINRAZA sales increased year-over-year, primarily from an increase in sales volume, particularly in Latin America and certain other markets. Biogen is continuing to evaluate SPINRAZA in the ASCEND, DEVOTE and RESPOND studies. These post-marketing studies are an important element of Biogen's ongoing work to further inform SMA treatment and address the remaining unmet needs of SMA patients of all ages. With the substantial and growing body of evidence supporting SPINRAZA's proven profile, we continue to see a bright future for SPINRAZA. TEGSEDI and WAYLIVRA generated more than $55 million of revenue this year. As a reminder, we completed the transition of our commercial operations for these medicines to Sobi over the course of 2021. Therefore, our 2021 revenue was a mix of product sales and distribution fees based on product sales. We are pleased that both medicines continue to expand into new markets throughout 2021 through the efforts of our partners, Sobi and PTC. Last year, we earned R&D revenue of more than $465 million, representing nearly 60% of our total revenue. Most of our R&D revenue came from a number of different partners as together we advanced nearly 20 programs. The $200 million upfront payment we earned from our eplontersen collaboration with AstraZeneca was an important contributor to our total revenues. Revenue from our strategic collaboration with Biogen was also an important contributor to our total revenue. We earned more than $160 million from Biogen for advancing numerous neurological programs, including the $60 million license fee for our SMA follow-on medicine. We have a large and growing pipeline of programs advancing under our Biogen collaboration, all with the potential to generate substantial revenue and cash flows as they advance. We reported non-GAAP operating expenses of $695 million, which was a 9% increase compared with 2020. R&D expenses increased by 33%, driven in large part by the 6 Phase III studies we are currently conducting. As these programs continue to advance, we anticipate our R&D expenses will continue to increase. Last year, we also invested in internal and external technology advancement. Of note, we obtained exclusive rights to Bicycle Therapeutics innovative peptide technology. This, together with our internal efforts and other external partnerships, positions us to meaningfully expand our drug discovery capability and deliver many more transformational medicines to the market. Our SG&A expenses decreased by 37% compared with 2020, driven by the substantial savings we realized from the Akcea integration and Sobi transaction. And as planned, we are reinvesting these savings as I will describe next. Now turning to our 2022 financial guidance. We are projecting to earn more than $575 million in revenue, incur operating expenses in the range of $825 million to $850 million and end 2022 with a net loss of less than $275 million, all on a non-GAAP basis. Additionally, we are projecting to end 2022 with a healthy cash balance of approximately $1.7 billion. Our long history of financial responsibility has served us well. At a time when we need to increase our spending, we have the substantial financial resources to underwrite these investments necessary to achieve our goal of becoming a leading fully integrated biotech company. Our 2022 guidance reflects our continued ability to generate significant revenue and make those necessary investments to realize our goals while remaining well capitalized with a healthy cash balance. Importantly, our 2022 guidance demonstrates our commitment to advancing our near-term commercial opportunities, building our Ionis-owned pipeline and ensuring our platform remains a key competitive advantage. Before I go into more detail on each of the elements of our 2022 financial guidance, I would first like to spend a few minutes explaining how we will reflect the cautionary provisions of our eplontersen collaboration with AstraZeneca in our financials. Under our eplontersen agreement, AstraZeneca is responsible for 55% of the global Phase III program costs. Including internal and external costs as well as CMC cost, we are leading and conducting the ongoing global Phase III program. For that reason, we will recognize the 55% reimbursement we received from AstraZeneca as revenue in the same period we recognize the related development expenses. Our R&D expenses will continue to include the development expenses we are incurring for eplontersen. AstraZeneca is also responsible for a large majority of the U.S. medical affairs costs. Since we and AstraZeneca are sharing responsibility for medical affairs activities in the United States, our R&D expenses will include 100% of Ionis incurred medical affairs expenses net of any cost sharing payment we received from AstraZeneca. AstraZeneca is also responsible for a large majority of the U.S. commercial costs for eplontersen. Because we and AstraZeneca are also sharing responsibility for commercialization activities in the United States, our SG&A expenses will include 100% of Ionis' incurred eplontersen commercialization expenses net of any cost sharing payments we received from AstraZeneca. As a reminder, AstraZeneca is fully responsible for costs associated with bringing eplontersen to market outside the United States. Importantly, these cost-sharing payments provide us with substantial resources to scale our capabilities for the U.S. launch of eplontersen, in addition to our upcoming planned launches for olezarsen and donidalorsen. Beginning with our Q1 earnings, we plan to provide a table of our expenses and the cost sharing payments we receive from AstraZeneca each quarter. Now I would like to provide a bit more color on our 2022 financial guidance. We are projecting another year of generating revenue from multiple diverse sources. We have a substantial and sustainable base of commercial revenue with SPINRAZA royalties as the quarters show. We also have a substantial and sustainable base of revenue from our partnerships that we expect will contribute meaningfully to our 2022 revenue. Year-over-year, the composition of our R&D revenue from our partnerships may shift, but the sustainability of that revenue is constant. As we have always done, our R&D revenue is probabilized based primarily on the anticipated timing of the many different milestone payments we expect to achieve as we advance our partner program. Additionally, our R&D revenue will also include the reimbursement we will receive from AstraZeneca for eplontersen collaboration, as I mentioned a few moments ago. Importantly, through our multiple streams of revenue, we can fund a large portion of our operating expenses. This year, we will be advancing more late-stage development programs than ever before. This includes the 6 Phase III studies and two open-label extension studies we are currently conducting. We also plan to initiate new studies supporting our Phase III programs, including additional open-label extension studies. Our R&D expenses will include increased spend for CMC activities and medical affairs activities to support eplontersen, olezarsen and donidalorsen. While a large percentage of our R&D expense relates to our late-stage medicines, we also will invest in our early and mid-stage pipeline to position us to deliver an abundance of new marketed products going forward. And we expect to continue to expand and diversify our technology, ensuring we remain innovative and competitive. As a result of these investments, we expect our R&D expenses to increase approximately 25% to 30% this year compared to last year. We are also investing in our commercial readiness efforts to prepare to bring eplontersen, olezarsen and donidalorsen to the market. With the cost-sharing payments we will receive from AstraZeneca, along with realizing a full year of savings from our Sobi transaction and the integration of Akcea. We expect our SG&A expenses this year to be in line with last year. Our financial strength has been an enduring quality of Ionis for many years. With $2.1 billion of cash and a substantial and sustainable base of commercial and R&D revenue, our solid financial foundation enables us to invest as needed to drive significant future growth. In doing so, we expect to deliver substantial value for the patients who rely on us and our shareholders. And with that, I'll turn the call over to Richard.

Well, thank you, Beth. We certainly achieved many pipeline advancements in 2021, with several key pipeline updates taking place even since our last call. We now have six medicines in our rich Phase III pipeline for eight indications, including our three near term commercial opportunities, eplontersen, olezarsen and donidalorsen, which alone, address five separate indications. As both Brett and Beth mentioned, we're jointly developing and preparing to commercialize eplontersen with AstraZeneca. Under our collaboration, we are continuing to lead and oversee the global Phase III studies, which continue to progress well and remain on track. We were pleased that eplontersen was granted orphan drug designation by the FDA, underscoring the significant unmet need that remains for patients with TTR amyloidosis. This sets us up nicely for our planned data readout of the Phase III NEURO-TTRansform study, in patients with TTR polyneuropathy and planned filing for regulatory approval in the second half of this year assuming positive data. For olezarsen, we have a broad development program designed to fully realize its potential to address a range of patients at risk for triglyceride-driven disease, who today have limited treatment options. The BALANCE FCS study, our first Phase III study of olezarsen remains on track for data next year. And recently, we initiated a second Phase III study of olezarsen, our core study, in patients with severe hypertriglyceridemia with triglycerides over 500-milligram per deciliter. Severe high triglycerides represent a substantial opportunity with more than 3 million patients in the U.S. alone. Data from the Phase II study of olezarsen in patients with moderate hypertriglyceridemia at high risk or with established cardiovascular disease were also recently published in the European Heart Journal. The data showed that treatment with olezarsen resulted in substantially reduced APOC3, triglycerides and atherogenic lipoproteins. Importantly, more than 90% of those treated with the monthly 50-milligram dose achieved fasting triglyceride levels within the normal range. As a reminder, in addition to 50-milligram monthly, we are also evaluating an 80-milligram monthly dose in both our core and balanced Phase III studies, which we expect to provide even greater triglyceride reduction. We've also made significant progress with our donidalorsen development program for the treatment of hereditary angioedema. We initiated the Phase III OASIS-HAE study of donidalorsen with data expected in 2024 We also presented positive Phase II results at the ACAAI Annual Meeting, demonstrating rapid and sustained reductions in HAE attacks with mean reductions of up to 97%, with a favorable safety and tolerability profile, leading us to believe that donidalorsen could be a best-in-class prophylactic treatment for patients with HAE. Now to review our recent progress from our leading cardiovascular and neurological disease franchise, starting with cardio. At AHA in November, our partner AstraZeneca presented new data from a multiple ascending dose study of ION449, targeting PCSK9 in patients with dyslipidemia on stable statin therapy. In the study, ION449 demonstrated robust and sustained reductions in PCSK9 and LDL-C with mean PCSK9 reductions of up to 95% and LDL-C reductions of up to 73% and favorable safety and tolerability. Coming up at ACC in April, we look forward to data from Phase IIb adhesion study of ION449 in patients with dyslipidemia. We expect safety and efficacy data from adhesion, which was conducted in a similar patient population, dyslipidemia patients on moderate or high-intensity statin therapy to be highly consistent with the previously reported MAD study and to continue to support the potential for this medicine to be best-in-class for LDL-C reduction. We also had several recent achievements in our leading neurological disease franchise. Early this year, we announced the advancement of ION306, our follow-on treatment to SPINRAZA, further enhancing our leadership position in SMA. This significant technology advancement is based on novel Ionis chemistry that includes enhanced potency and duration of action. And based on our preclinical data, we believe ION306 offers the potential to substantially extend dosing intervals. We also recently initiated a Phase I/II study in patients with Angelman syndrome, a rare genetic neuromuscular disease that presents in early childhood, resulting in profound developmental delays and frequent and severe seizures. We and Biogen remain encouraged by the data from the Phase III VALOR study of tofersen in patients with SOD1-ALS which showed signs of reduced disease progression across multiple secondary and exploratory endpoints. Biogen continues to analyze results from the Phase III study and collect new data from the ongoing open-label extension study. And importantly, Biogen remains actively engaged with regulators to determine the next steps for this medicine. And in addition, the ATLAS presymptomatic study continues to enroll patients. We're also pleased that Roche has identified a potential path forward for tominersen. Findings from the post-hoc analysis of the Phase III GENERATION HD1 study saw that tominersen may benefit younger adult Huntington's disease patients with less disease burden. Based on these findings, Roche plans to initiate a new Phase II study in this patient population. We're encouraged by this important step for tominersen and look forward to seeing additional data from the post-hoc analysis and learning more about the design of the Phase II study from Roche later this year. Now turning to 2022. This year, we have a deep pipeline of mid- and late-stage medicines with at least 9 mid- and late-stage data readouts highlighted by eplontersen. We are planning for the Phase III data from the NEURO-TTRansform study mid-year. Our joint Ionis and AstraZeneca team are working diligently and collaboratively to prepare a file for regulatory approval in the second half of this year. And of course, the teams are already preparing for the commercial launch of eplontersen. We also have the potential to further expand our rich Phase III pipeline as we look forward to 4 Phase IIb data readouts this year alone. As I just mentioned, we look forward to Phase IIb data from our PCSK9 drug, ION449, at ACC in April. We expect GSK to report data from the Phase IIb B-Clear study of bepirovirsen in patients with chronic hepatitis B. We also expect Bayer to report data from the Phase IIb Rethink [ph] ESRD study of fesomersen in patients with end-stage renal disease, and we're planning to report data from our Phase IIb study of IONIS-AGT-LRx in patients with treatment-resistant hypertension. In addition to our 4 Phase IIb data readouts, we also expect data from multiple Phase II studies this year, including IONIS-C9 data in patients with C9 ALS and donidalorsen data, including additional results from Phase II study and later data from the OLE or open-label extension study. We are also planning to initiate several key studies this year focused on our cardiovascular and neurology franchises to further advance and expand our rich pipeline. Further, we anticipate making additional technology advancements, which we hope to share with you later this year. And with that, I'll turn the call back over to Brett to close this portion of the call.

Thanks, Richard. With at least 9 data readouts planned including Phase III data for eplontersen and a potential regulatory filing, we have an eventful and catalyst-rich year ahead. We remain focused on achieving our goal of becoming a leading fully integrated biotechnology company. To that end, our plans this year are focused on our 3 strategic priorities: building the Ionis commercial pipeline and advancing our 3 near-term commercial opportunities, eplontersen, olezarsen and donidalorsen; continuing to build on the substantial progress we made last year by expanding and diversifying our technology; and thirdly, delivering an abundance of new medicines to the market in the near term and longer term, highlighted this year by the Phase III readout for eplontersen and hereditary TTR polyneuropathy and the potential filing for approval. These 3 strategic priorities are central to my commitment to drive substantial growth for Ionis. As we have reviewed this morning, we have made great progress across our business in support of this commitment with even more exciting progress planned for this year. Before closing, I want to take a moment to speak about Rare Disease Day, which is Monday, February 28, and it's important to Ionis. There are approximately 7,000 rare diseases that affect more than 300 million people around the world. On Rare Disease Day, actually, every day, the Ionis team honors the determination, resilience and resolve of these patients and their loved ones who are working tirelessly and with a sense of urgency to discover, develop and deliver life-transforming treatments. And with that, I'll now open the call up for questions. Anthony?

[Operator Instructions] Our first question comes from Gary Nachman with BMO Capital Markets. You may now go ahead.

Hi, guys. Thanks for taking my questions. First, the follow-on product Biogen license for SMA, describe it a bit more. How similar is it to SPINRAZA in terms of mechanism? And what have you been able to do to potentially extend the dosing intervals for it, and when do you think Biogen might enter the clinic with it? And then the second question is just talk about some of the progress you've been making on the commercial side, preparing for eplontersen. How collaborative has the process been so far with AstraZeneca? And any sense of how big the sales forces will be for both you and AstraZeneca to capitalize on the PN opportunity and then prepare for the cardiomyopathy as well? Thanks.

Great questions, Gary. I'm going to ask Eric Swayze, Head of Research, can talk a little bit about the mechanism and the chemistry and the questions related to the SMA follow-on. And Onaiza Cadoret to talk a little bit about how the AZ co-development, co-commercialization partnership is going, which is going great. But Eric, why don't you kick it off?

Yes, sure. Thanks, Brett. So the follow-on, BIIB115, or ION306, it uses the same mechanism as SPINRAZA. So it is a splicing modulation mechanism that promotes synthesis of SMN protein, just like SPINRAZA. And the objective of the program was to improve potency and extend the dosing interval, and the follow-on does both of those things. We use a different backbone chemistry, which we haven't disclosed exactly what's in the molecule, but it's a new backbone chemistry that works particularly well in the slicing modulation mechanism. And it gives an improvement in potency of the molecule and extends the dosing frequency. So we've got great preclinical data on the compound and hope to really be able to extend the dosing regimen from SPINRAZA. And you asked about clinical trial starts. Biogen is working on their clinical program, but hasn't given guidance on when they're going to start there.

And just to add to that, thanks, Derek. The drug is ready for clinical development. So it's cleared tox studies and it's ready to go. They're just putting the final touches on clinical trial design and regulatory discussions. But stay tuned for that. As Eric said, they haven't disclosed timing for the start of that study. Onaiza, would you like to please talk a little bit about how the co-commercialization partnership is going with AstraZeneca in eplontersen? Onaiza Cadoret-Manier: Sure. Happy to, Brett. Thanks, Gary, for the question. The collaboration is just going swimmingly well. AstraZeneca and Ionis are just really great partners. I think having been on a lot of co-promotes in the past, I think we're approaching this in absolutely the right way. We're leveraging each other's capabilities where there is strength and differentiation. So in that sense, the mindset of within which we're entering this is just a fabulous start. More tactically to your question, Ionis will be certainly leading the areas where they have great expertise in the marketplace. We know amyloidosis really well. We've been in the marketplace with investigators and KOLs for a decade when you think about it. And we're really going to be leveraging that strength all the way through to field medical as well. So we're leading a lot of the medical research capabilities and having a field medical research team to launch eplontersen. We're also going to be leaning on our just great strength in rare diseases, patient services and patient support and planning that collaboratively and leading that effort as well. So that gives you a bit of color on the types of activities that Ionis will be leading. We will obviously rely on the broad strength in heart failure for - that AstraZeneca brings and just a great cardiovascular presence that they have in a variety of other ways. As to your question, size of teams, just not been established yet, we just have more work to do on that front. So happy to share that as we work along that path with AZ. And then lastly, I would say we are certainly taking the capabilities that we're building for eplontersen in this co-commercialization effort to really have an eye towards and a line of sight towards what we will be leveraging for olezarsen and donidalorsen, our next launches, which will be Ionis-only launches next [ph] month.

Thanks, Onaiza.

Okay. Very helpful. Thanks, guys.

Thanks, Gary.

Our next question comes from Jessica Fye with JPMorgan. You may now go ahead.

Hey, guys. Good – I guess now, afternoon. Thanks for taking my question. I had a couple - it looks like you're going to have two updates this year for the HAE program: one in the first half, one in the second half. Can you elaborate on what types of data we should expect you to share in each of those two updates? And then second, what do you see as the benchmark for differentiated LDL lowering with ION449? Like what constitutes a meaningful difference relative to inclisiran?

Sure thing. Thanks, Jess. So for donidalorsen, the updates that are coming for in AHE, in the first half of this year, as you said, we're planning an update at a medical meeting. And there, you're going to see more data from the Phase II controlled study, data like quality of life, for example, and other data from deeper investigations into the results of that study. Also - and then in the second half of the year, we're planning to present at a medical meeting open-label extension data to demonstrate not only to go beyond the robustness of the Phase II study to demonstrate the durability of the protection that these patients have received in the long-term tolerability and safety, which we think will further support our position that this is a best-in-class molecule. And I would also look for a third update, which is a publication. We're planning to publish the Phase II data in a journal sometime hopefully soon. There will be a further update on that. With respect to ION449 differentiation, it's really straightforward. There's a need for better drugs that lower PCSK9 and LDL-C better than current drugs that are out there, whether they are monoclonal antibodies or other drugs, siRNA, to get patients that are - have a risk of cardiovascular disease despite these treatments. So it's a better lowering agent. It's a better PCSK9 inhibitor and consequently, a better LDL-C lowering effect from the better potency and efficacy we see. And that's based on the Phase I data that, in patients with - on statins with high cholesterol that Richard talked about in his talk earlier, but also the Phase IIb data that will present the APCs. It really does look like a best-in-class molecule. And of course, the more you lower LDL-C, the greater part of vascular risk reduction is achieved. So that's really the key differentiator there.

Thank you.

Our next question comes from Joseph Stringer with Needham & Co. You may now go ahead.

Hi, good afternoon. Thanks for taking our question. Just on one of the Phase IIb readouts with the AGT program and hypertension, just given the competitive landscape in different modalities, what are you looking for in terms of clinically meaningful changes in blood pressure? And again, what would constitute sort of a competitive profile in this indication? Thank you.

Richard, do you want to take that?

Yes, happy to take that. Thanks. So great question. What we expect to see with this molecule is robust systolic reduction in blood pressure. Really anything more than 5 is something you would like to see in blood pressure lowering. But for these patients who are resistant to lowering and they're on multiple medications for their blood pressure lowering, getting them to essentially a lower blood pressure and control. And we're thinking around 10 millimeters of mercury reduction in systolic would be a real winner. And best-in-class to be able to add on to medications that are not bringing these patients to control. We're excited about it, and the trial is going well, and we expect it will read out this year.

Great. Thanks for taking our question.

Our next question comes from Paul Matteis with Stifel. You may now go ahead.

Hi, there. Thanks for taking our questions. This is Alex on for Paul. Just one on the upcoming C9 readout in the first half, you know, curious if you could talk a little bit more about biomarkers beyond target engagement that we might see. I guess I'm curious if you expect to disclose in the NFL data? And if so, do we know anything about NFL natural history in this population? I know it's a little bit less known here than the [phased out one]. So curious if you could elaborate more? Thanks.

Yeah. Sure thing, Alex. So we're excited by the fact that study is wrapping up and Biogen is going to dispose the C9 Phase II data and potentially next steps as well for that program. That study is, of course, focused on selecting a dose potentially for future study, potentially a Phase III study in C9-ALS. So aside from safety and tolerability, of course, which is very important for a first in patient study, very important is to select a dose based on target engagement C9 peptide reductions in those patients and to correlate those reductions with what we - how that translates to reductions in the relevant regions of the CNS, the spinal cord brainstem based on preclinical data. We will certainly be looking as a secondary/tertiary endpoints characterizing all of the classic endpoints that you would expect to see, but that's really not the main focus of the study. That would include NFL certainly, that would include vital capacity, that would include ALS functional rating scale, but that's really not the objective. The objective is to select the dose to achieve the productions and targets that we want to achieve with the safety and tolerability to position it for potentially a Phase III study.

All right. Thank you.

Our next question comes from Josh Schimmer with Evercore ISI. You may now go ahead.

Thanks for taking the question. First, for the next gen and MsPA backbone technology, when can we expect this to be in the clinic? And how do you plan to prioritize targets? Do you expect you'll be revisiting validated targets such as TTR with a third-generation product? Or is it going to be deployed more for novel target and novel tissues? And then separately or relatedly, there's been a fair amount of evolution in your portfolio, including some of the neuro data sets in ALS and Huntington's. How are you now thinking about which programs you're likely to advance the commercialization on your own? I think that for that strategy, at least historically, you've been in CNS focused and heavy. Is that still the case?

Eric, take the MsPA backbone.

Yeah. I'll take MsPA one but not the commercial. So the MsPA backbone is currently in consideration for every new drug we're making. So we haven't given exact timing on when it would enter in the clinic. It depends a little bit on how it performs with all the other chemistries we have. But we're actively competing it with every modality and every chemical technology we have at our disposal to make the best possible drug. And that's again - and that's in all therapeutic areas and all platforms.

And if I could just expand on that a little bit, Eric. So this chemistry, we also expect [Technical Difficulty] other chemistry. And we're looking to allow us to open up tissues that we may have had control within the past as they are presented at Investor Day last year. We believe we have a molecule that can greatly reduce pro-inflammatory effects in tissues where that can be a for example, pulmonary. We're hoping that, that could be a path forward there. We're not committing to that yet, but certainly, that's a possibility. We also like the durability that this chemistry gives us, which really allows us to dose very frequently, at least based on preclinical data so far using subcu route. So it's offering a lot, a lot of different aspects of the overall profile. And yes, we're planning to move it in - first molecule into development this year, but that means initiated tox studies in clinical development thereafter. With regard to the portfolio in neuro, wholly-owned pipeline, of course, we have our Phase III FUS-ALS study that's progressing nicely, and we're rolling that study. We're planning to bring that to the market ourselves. Really - and then we have two other drugs in development right now that are wholly owned by Ionis as well. One, is our GFAP study in Alexander's disease, which is in a Phase II/III study. And then thirdly, a drug a study that we're planning to initiate this year in first - in carriers and patients is in Prion disease. And we're really looking forward to the second half of this year to talk more about that program. And we think it's a very exciting program. We think we have a very novel path forward for potential approval from a regulatory standpoint. I think we have a great drug based on our preclinical data. Behind that is a rich pipeline of neuro drugs, targets which we haven't disclosed yet, but it's growing. And we do believe that following our near-term commercial opportunities, you've heard about eplontersen, olezarsen and donidalorsen, we're really looking towards our neuro pipeline as being the follow-on of real movers for our commercial pipeline in the future, and we're going to talk more about that this year.

Our next question comes from Yanan Zhu with Wells Fargo. You may now go ahead.

Thank you. And congrats on the progress. I have a question regarding eplontersen study in cardiomyopathy, certainly looking forward to the midyear polyneuropathy data. But if we look a little further ahead for the cardiomyopathy opportunity, I think one of the features of the trial's design is that there's no cap for patients on tafamidis. And therefore, it may be a more real-world mix of patients in contrast to a competitor's trial. So the question I have is, wouldn't the increased proportion of tafamidis patients in both arms, would that affect the delta between the two arms. And do you have a statistical measure to address that? And if there are hierarchical testing that may allow you to look at tafamidis patients versus patients who are not - in those two subgroups separately. And if you may also elaborate, how does this trial design allow you to have a better claim in a marketplace. I think you highlighted that, but could you elaborate how - exactly how that could support a differentiated plane? Thank you.

Thank you, Yanan. Richard, maybe you can address the first part on the cardiomyopathy design and the usage of - and the management of tafamidis, uses in the study and how the study is powered at a high level. And then, Onaiza, you talk a little bit about why this is relevant in a real-world setting, why we're so enthusiastic about the trial design. Richard?

Yeah. So the trial design is one that we're really excited about because it does allow us to actually benefit from a real world experience and the expectation of the world that we're going to enter upon approval, if all goes well. And so the study, which is larger than any of the other cardiomyopathy studies in this indication allows for tafamidis use. It's actually powered - and this may not be well understood, but the study was powered based on the assumption that everyone in the control group was on tafamidis, so already benefiting from a tafamidis background. In reality, we've selected countries that have tafamidis available like the United States and other countries that do not. So it will be a mix, which will allow us to do a statistical analysis not only looking at those on tafamidis, but also looking at naive patients that are not on tafamidis. So it provides a broad spectrum look and a real nice benefit in terms of the design of the study. So that's the design and the reason that we're excited about it. I'll pass it over to Onaiza to speak to why this is so important. Onaiza Cadoret-Manier: Yeah. Thank you, Richard. So I would say our customers are very excited about the design as well. I think we're skating to where the puck will be in the future, and we know particularly in large geographies, such as the U.S., there will be a lot of patients who will be on tafamidis because the patients are getting diagnosed and they're treating, which is all great. So we have the ability with the largest clinical trial now to generate the evidence and data for both sets of patients. There will be patients who will be naive to stabilizers and there will be patients who will be on stabilizers. And the ability to actually come in and give physicians a data set on how to evaluate a patient who's currently on background tafamidis and what that incremental then benefit looks like in cardiovascular risk reduction above that will be extremely important. And they will be requiring that data to make that decision for the patients on tafamidis. So we will have the data, the evidence. And as all things go in terms of our ability to get these from a label perspective, we certainly are working towards the very likely outcome that we will be able to have that and put those into claim, as you had asked. So these will be the two generated claims that we're looking forward to. I'll also add, this is also great data, not just for health care professionals, but also for patients because they want to know, if I add on another treatment, what does that look like? If I'm not in any treatment, is eplontersen the best treatment to go on? So we will have those data sets for them. And very importantly, you always have to check on reimbursement and access, and we - we've done that for our US payers to really see if there were a combination used, how they would actually think about reimbursing that. And very fortunately, and a very patient mindset because these patients are very sick. They came at it at the same pace and said we would cover both stabilizers and silencers together as long as you have the data and evidence to generate that, and physicians were actually making that choice. So we do see from all three perspectives, this real-world evidence and clinical trial is going to be very, very stable [ph] as we launch in cardiomyopathy.

Got it. Thank you for the very detail color. Appreciate it.

Thank you, Yanan.

Our next question comes from Jason Gerberry with Bank of America. You may now go ahead.

Hey, guys. Thank you for taking my questions. I guess just thinking ahead this year to the eplontersen update, if you can speak to how you guys are thinking about the safety differentiation relative to TEGSEDI and just to have a more competitive product in the market. Is it, really - is there one of the two black box warnings and REMS monitoring components, either renal or thrombocytopenia that is more important? Or is it really the key to sort of develop a product with a profile that distances itself from both of those safety considerations? And as we think about sort of TEGSEDI so far commercially, I think you talked a lot on these calls, but just what proportion of patients are currently contraindicated for TEGSEDI? If you could just speak to the underlying kind of market share and volume trends which are hard to tease out because of the revenue reporting changes, that would be helpful? Thanks.

Sure, Jason. Yes, we agree it's a rich year for our pipeline, our catalysts, a lot of catalysts coming up this year, including eplontersen Phase III readout by mid-year for polyneuropathy. We don't expect any safety issues for eplontersen in the polyneuropathy readout at all. I mean - and that's based on blinded data that's been continuously evaluated by our safety oversight committee and moving this drug forward each time it's been reviewed, and our LICA platform overall. So to us, which is more important? The need for renal monitoring - to move away from renal monitoring or platelet monitoring that's occurring with TEGSEDI for eplontersen is not really that relevant because we don't expect any monitoring beyond what's normal for any drug to reach the market today. So we don't expect any platelet signals or renal signals, and that's the assumption going forward. And as far as patients that are not eligible for TEGSEDI, I would have to go back and look at that and maybe we can follow back with Jennifer. But TEGSEDI is approved for patients with hereditary TTR amyloidosis and symptoms of polyneuropathy, period. So all our patients are eligible for TEGSEDI provided that they are tested first for certain renal and platelet parameters, and they're above a certain threshold, which I don't have that number exactly in front of me, but all patients are eligible for the drug except that small population. But eplontersen is where our focus is, Eplontersen has demonstrated TTR reductions in our Phase I study that are highly competitive, not superior to what we've seen out there today. We think this has a potential as a best in class product for TTR amyloidosis - hereditary TTR amyloidosis with polyneuropathy as we do for eplontersen in cardiomyopathy.

Our next question comes from Myles Minter with William Blair. You may now go ahead.

Hi. This is Sarah on for Myles. Thanks for taking the questions. Just to kind of follow up on our question a bit, can you comment on kind of the trajectory of the TEGSEDI franchise moving forward?

Beth?

Sure, happy to. So as I mentioned in our prepared remarks, TEGSEDI - sales of TEGSEDI continued to expand into new countries last year, and we're pleased with the work that Sobi and PTC are doing. Obviously, I can't get ahead of what each of them have disclosed publicly, but we would expect to see continued support from Sobi and PTC in their respective areas for TEGSEDI going forward. And then in terms of revenue, of course, this is our first full year of revenue from TEGSEDI based on a distribution model. So you would expect to see our revenues actually decline year-over-year, decrease year-over-year because last year was a mix of product sales and distribution fees. So this year, you would expect to see that decrease. However, we also had substantial expense savings when we moved to the distribution model with the Sobi transaction for TEGSEDI and WAYLIVRA for that matter. So our overall P&L impact from that change is actually quite positive. And as I've said before, we're reinvesting those savings into our commercial opportunities, into the neuro pipeline, into the rest of our mid-stage pipeline, our technology, commercial capabilities, all of the things that we think are absolutely essential to build Ionis into the leading fully integrated biotech company.

Got it. Thank you.

Thanks, Sarah.

Our next question comes from Luca Issi with RBC. You may now go ahead.

Great. Thanks so much for taking my question. Maybe circling back on a prior question for TTR polyneuropathy. Maybe to ask the question a little more directly, a great partnership with AstraZeneca, obviously, but a fairly competitive market. So maybe, Onaiza, how are you thinking about the market share split long term between you and Alnylam? Given that, obviously, they're ahead and they may be in a position to dose less frequently. And then maybe second question on AGT. Can you just remind us the rationale for going after heart failure? Again, one of your competitors are going after just hypertension, but you have a trial for heart failure with reduced ejection fraction. So we'd love it if you can remind us the rationale there. And then maybe lastly, it sounds like you're going to have some data with GSK for Hepatitis B. Wondering if you can give us some color on that one. I forget if that trial is monotherapy or combination with nukes or combination with CAPS inhibitors. So any color there would be great. Thanks so much.

Onaiza? Onaiza Cadoret-Manier: Thanks, Luca. Since he already directed the question to me. Yeah, so for eplontersen in polyneuropathy, particularly as the first launch, you want to think about this as a systemic disease and that we will be in hereditary ATTR. So we will be looking at both the mixed phenotype as well as the pure polyneuropathy patients. So think about it as a large market, only 10% to 15% of those patients have been diagnosed and treated. So it's a big market for multiple players to share. We have - are expecting very strong data in terms of efficacy with both mNIS+7 and our Norfolk Quality of Life. Brett just went through what we expect on the safety profile. And then after those things are done, then you have to look at what's next in terms of hierarchy that's important to the market, be it physicians and patients. And here, I would say our product presentation of self-administration at home is a very key driver of choice. So we do believe that, that's going to be a really important feature of the products as well that will, in addition to efficacy and safety, be really important. And I'll say in our new normal of kind of COVID, it's actually a great deal even more important, where more virtual visits are being done by physicians and there's just a preference to that. So giving patients the control of self-administration at home continues to be a really big benefit. And we think that the monthly is certainly a very important kind of consideration, but it really didn't show up very, very strongly when we tested this in terms of monthly versus quarterly. Honestly, it was the self-administration that was driving more of the choice than in-office administration. So I wanted to give you that color. And you can calculate shares based on that and just think about what the product really offers. And hopefully, you'll get to be able to model that. But I wanted to make sure you have that perspective as well.

Great. And maybe I can take the heart failure question for angiotensinogen. So first of all, angiotensinogen has shown some real benefit in some of the preclinical models for heart failure, and we moved into this heart failure initial study to look at the safety of shutting down or reducing angiotensinogen production in these patients. One of the issues in heart failure is you have to be very careful because of the renal issues as well as the possible benefit on the cardiac side, actual RAS inhibition or the ability to utilize those medications has been very limited in these patients. And so they aren't getting the - what they need in terms of control, both on blood pressure as well as their heart failure side effects. And so - what we see with angiotensinogen is the opportunity to treat at the top of the RAS pathway with angiotensinogen without hitting the kidney. And so we're looking at safety as a primary as well as, of course, the lowering of angiotensinogen and control of blood pressure. So we're excited about the study. We're excited about that as a possible indication for angiotensinogen and we'll learn more as we complete these early studies.

Thanks, Richard. Eric, do you want to comment on the HPV trial design plus nukes, what we might expect from that readout?

Sure. So that's basically it. So they've got the bepirovirsen drug on top of standard of care, which is nucleoside inhibitors of the Sunrise [ph] and alone and the idea is in Phase II, to see if we can get reduction of the S-antigen protein and subsequent immunoclearance of the viral infection and trying to achieve what we call a functional cure, where the system can overcome the S-antigen, which is causing - kind of inhibiting the immune system's ability to cope with the virus and clear it. So that's the goal. And in some corporate clinical data that suggest that it might be possible, and hopefully, it will be borne out in the Phase II study.

Thanks, Eric.

Thanks so much.

Thank you.

Our next question comes from I-Eh Jen with Laidlaw & Co. You may now go ahead. I-Eh Jen: Thanks for squeezing me for the questions. I've got two quick ones. The first one is that given that you have the AstraZeneca co-commercialization agreement, should we anticipate in terms of adding sales force, sales rep to your commercial structure teams will be something maybe starting in 2024 or later? And the second one is just on the previous question in terms of eplontersen in PN, besides the self-administrative advantage, is there any other sort of theoretical benefit you can think of competing - comparing to the eplontersen [ph] at this moment? Thanks.

Onaiza? Onaiza Cadoret-Manier: Yeah, I'd be happy to. So for AstraZeneca, in the collaboration, we're still working out how we're going to divide up some of the customer-facing resources. But for your modeling purposes, I would just suggest that - we have - are likely going into this that we're going to be doing more of the non-sales customer-facing resources. So the larger part of the salespeople that will be required will be handled by AstraZeneca, and we will be handling more of the field medical as nurse case managers and those types of customer-facing resources. So hopefully, that will help you calibrate in terms of size for that. And then I think for the differentiation, it's always - it's a trifecta, right? You have to look at it from all the things that you offer to the physician, the patient and the payer. And we really are very, very confident in the product profile, both for polyneuropathy and for cardiomyopathy in terms of what this is going to offer in efficacy and safety, in ease of administration, tolerability and obviously, the at-home dosing, as I just explained earlier as well. But it's really the whole package together that will drive the differentiation that - but we are very excited about both the polyneuropathy launch and then the cardiomyopathy with the differences in terms of our real-world evidence trial that will really help us characterize the two sets of populations for tafamidis and or alone on naive tafamidis as well.

Our next question comes from Yaron Weber with Cowen. You may now go ahead.

Hi. This is Brendan on for Yaron. Thanks for taking the question as well. First, honestly, I just wanted to follow up on one of the earlier questions about the hep B infection readout in H2. Given the data we've seen in the last couple of years from competitors, really just want to see where you think the bar is at this point in terms of antigen reduction. And then actually, in acromegaly, I also wanted to see how enrollment here has been going, given some of the difficulties in the combo study last year. And I guess how you're all thinking about potential next to the program, and I guess that drug moving forward with - based on everything you know so far. Thanks so much.

You're welcome. Eric, why don't you take the first one? I'll touch on acro.

Sure. I mean the bar is probably more than just antigen reduction per se. The objective, as said earlier, is to reduce S-antigen enough and then combine that with the ability of the immune system to create what they call a functional clearing of the virus. And so I don't think just S-antigen reduction alone is enough. And in our Phase IIa trial that we reported on, published recently in major [ph] medicine somewhere, there, we actually showed evidence that, that could, in fact, happen and had some really impressive clearances of viral infection in patients. And so that's what we're hoping to - what GSK is hoping to show in the larger Phase IIb study.

And for the acromegaly Phase II monotherapy study, we're very confident this study will read out as planned this year. Enrollment is actually ahead of schedule and going very well and looking forward to that readout. So no concerns, no red flags there whatsoever. And I also want to remind you that we also have an update on the open-label extension from the acromegaly study that we had data come out last year on in patients that are resistant to somatostatin analogue. So we're going to have additional data beyond the monotherapy. But we're very confident, the enrollment has gone great in the monotherapy study, and we're looking forward to that readout.

And I think that pretty much wraps up the questions where we are now. So I'd like to thank everyone who joined us and participated on the call today. We'd like - look forward to providing further updates on our progress throughout the year and until then, thank you again. And have a great day.

The conference has now concluded. You may now disconnect. Thank you.