Good morning, and welcome to Ionis First Quarter 2023 Financial Results Conference Call. As a reminder, this call is being recorded. I would now like to turn the call over to Wade Walke, Senior Vice President of Investor Relations, to start the call. Please go ahead.

Thank you. 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've also posted slides on our website that accompany today's call. With me this morning are Brett Monia, Chief Executive Officer; Richard Geary, Chief Development Officer; and Beth Hougen, Chief Financial Officer; Eric Swayze, Executive Vice President of Research; Eugene Schneider, Chief Clinical Development Officer; and Onaiza Cadoret, Chief Global Product Strategy and Operations Officer, will also join us for the Q&A portion of the call. I would like to draw your attention to Slide 3, which contains our forward-looking statement. During this call, we will be making forward-looking statements that 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, Wade. Good morning, everyone, and thanks for joining us today. This year is off to a strong start with several important achievements already, especially from our neurology franchise. Last week, the FDA granted QALSODY accelerated approval for the treatment of SOD1-ALS. This approval represents a major scientific breakthrough. QALSODY is the first and only approved treatment to target a genetic form of ALS. And with this approval, QALSODY joined SPINRAZA as our newest product to reach the market for patients with a devastating neurological disease. In addition to being a tremendous advance for the ALS community, this approval further validates our RNA-targeted therapeutic platform to treat neurological diseases that today includes 12 medicines in clinical development. We also just reported positive data from the Phase 3 NEURO-TTRansform study of eplontersen in patients with ATTR polyneuropathy. In this study, eplontersen was shown to halt neuropathy disease progression with approximately half of patients experiencing improvement in the co-primary efficacy endpoints, mNIS+7 and Norfolk Quality of Life. Eplontersen also demonstrated favorable safety and tolerability. Based on the totality of the data, we are confident in eplontersen's strong product profile and its potential to be an important treatment for the largely untapped hereditary ATTR polyneuropathy population. With these data, we and our partner, AstraZeneca, are working towards additional regulatory submissions in countries outside the U.S. This, of course, is in addition to our NDA, which is under review with a PDUFA date of December 22 of this year. And as Onaiza discussed during our webcast last week, we're working hand in hand with AstraZeneca to bring this important medicine to the market as quickly as possible. Our two other near-term commercial opportunities, olezarsen and donidalorsen are also progressing very well. With olezarsen, we remain on track for data from the Phase 3 BALANCE study in FCS in the second half of this year. And we're preparing for our first independent commercial launch in this rare disease indication. We also continue to make really good progress in our pivotal SHTG studies of olezarsen. With donidalorsen, we're on track to complete enrollment in the Phase 2 OASIS HAE study soon, keeping us on track for data in the first half of next year. Additionally, our robust late-stage pipeline continues to expand, now at seven programs advancing in nine separate indications with the initiation of Phase 3 development of bepirovirsen in chronic HBV. Our expanding late-stage pipeline sets us up for a steady and growing cadence of data readouts over the next few years, increasing the potential for a substantial number of new Ionis medicines to reach the market. And importantly, we remain on track to accomplish our key strategic goals across the business and achieve our 2023 financial guidance. With that, I'll turn the call over to Richard to discuss our recent pipeline progress and preview our upcoming key events. Next, Beth will review our first quarter financial results, and then I'll wrap up our prepared remarks before taking your questions. Over to you, Richard.

Thank you, Brett. As Brett just mentioned, we have met a number of goals in key programs already this year. We believe that the positive data we reported from the NEURO-TTRansform study demonstrate eplontersen's potential to substantially improve outcomes in patients with ATTR polyneuropathy. Eplontersen met all co-primary and all secondary efficacy endpoints, demonstrating consistent benefit for ATTR polyneuropathy patients across a range of important neuropathy and quality of life measures. Eplontersen demonstrated robust and sustained reductions in serum TTR and significant improvements in measures of neuropathy and quality of life with a substantial number of patients demonstrating improvement at both week 35 and week 66. Eplontersen also showed statistically significant and clinically meaningful benefit across all four secondary endpoints and continue to demonstrate a favorable safety and tolerability profile. In addition to publishing results from this study, we're set to present additional data at upcoming medical conferences. We and our partner, AstraZeneca, remain on track for a potential approval in the U.S. in December and are preparing regulatory submissions in additional markets around the world for later this year and next year. The positive efficacy and safety results we've seen for the NEURO-TTRansform study give us even greater confidence for the performance of eplontersen in our ongoing CARDIO-TTRansform study in patients with ATTR cardiomyopathy. CARDIO-TTRansform is the longest and largest study in this indication to date, designed to demonstrate benefit in a broad set of patients that represents the current treatment landscape. We anticipate completing enrollment midyear. Our broad olezarsen development program for two indications, characterized by severely elevated triglycerides, FCS and severe HTG is also continuing to progress well. The Phase 3 BALANCE FCS study is fully enrolled, and we remain on track for data in the second half of this year. In our multi-study Phase 3 program designed to evaluate olezarsen in the broader SHTG indication is also continuing to progress. Additionally, our donidalorsen development program remains on track. We expect to fully enroll the Phase 2 OASIS HAE study shortly, which keeps us on schedule for data in the first half of next year. During the first quarter, we reported additional positive longer-term data from the donidalorsen Phase 2 open-label extension study in patients treated for one year, reinforcing its potential competitive profile which included rapid onset of action with clinically meaningful improvements in quality of life, durable attack protection and a continued favorable safety and tolerability profile. Our neurology franchise includes 12 medicines in development, including two in Phase 3 studies and eight in Phase 2. I would like to spend a couple of minutes highlighting two of these medicines that have important recent updates. As Brett mentioned, we are pleased that the FDA recently approved QALSODY, making it the first and only approved treatment to target a genetic form of ALS. This is a monumental breakthrough for the ALS community. QALSODY's approval was based on the reduction in plasma neurofilament light chain or NfL, a marker of neuronal damage that correlates with disease progression in ALS patients. The approval was supported by the 12-month integrated results from the Phase 3 VALOR study and the open-label extension. The integrated results showed patients who started treatment earlier experienced a slowing decline in measures of clinical function as well as respiratory and muscle strength. Additionally, QALSODY demonstrated a favorable safety profile. QALSODY is under review in the EU and additionally, the ongoing Phase 3 ATLAS study in presymptomatic SOD1-ALS patients is also progressing nicely. We are encouraged by the recent data Biogen presented at the ADPD Conference and published in Nature Medicine from the IONIS-MAPTRx Phase 1b study. Our MAPT medicine, also known as BIIB080 is our medicine aimed at reducing the production and aggregation of tau protein associated with disease progression in patients with Alzheimer's disease. Results in early AD patients treated for up to 100 weeks showed a rapid, substantial and sustained reduction in tau pathology as measured by both CSF levels and tau PET imaging. In fact, our MAPT drug is the first to demonstrate this magnitude of a reduction of tau pathology across important brain regions to date. Biogen is advancing the Phase 2 study in patients with early AD, which includes two different dose cohorts dosed every six months and one dose cohort dosed every three months. Our MAPT drug is just one example of advances we are making with our technology to potentially extend duration and reduce dosing frequency for CNS diseases and even more broadly. Our late-stage pipeline expanded this year to seven drugs advancing in a total of nine separate indications with the start of a pivotal program for the bepirovirsen in patients with chronic HBV. We expect our late-stage pipeline to expand further this year when Roche advances IONIS-FB-LRx into a Phase 3 study for IgA nephropathy. We recently took steps to further focus our R&D efforts and prioritize our pipeline with the discontinuation of two programs: cimdelirsen in acromegaly and sapablursen in beta-thalassemia. With both drugs, we saw evidence of good target engagement and favorable safety and tolerability, but efficacy results in the mid-stage studies did not meet our minimum target product profile to justify further development. We continue to advance the Phase 2 study of sapablursen for polycythemia vera and we plan to share data from this study as it becomes available. We remain on track for a number of key events, including regulatory decisions and late-stage pipeline achievements. These include U.S. eplontersen approval and Phase 3 data for olezarsen, our next potential medicine to launch after eplontersen. We will keep you updated on our progress on these events and more throughout the year. And with that, I'll turn the call over to Beth.

Thank you, Richard. Our first quarter financial results reflect our ability to generate meaningful revenue while making investments in key growth opportunities across our business. We earned revenues of $131 million for the first quarter, approximately half from our commercial products and half from numerous partnered programs. Our operating expenses and operating loss for the first quarter increased over the same period last year as we advanced our commercial readiness activities and advanced our pipeline, especially our late-stage programs. We ended March with substantial cash and investments of $2.3 billion, enabling us to continue making investments to create future growth opportunities. We earned $50 million in SPINRAZA royalty revenue based on global product sales of $443 million in the first quarter. Our SPINRAZA royalties reset annually and based on our revenue expectations, we anticipate reaching the highest royalty tier by mid-year. Additionally, we continued to record 100% of our SPINRAZA royalties as commercial revenue under our Royalty Pharma transaction. While SPINRAZA product sales were slightly lower in the first quarter compared to last year, we and Biogen continued to see signs of stabilization in Biogen's patient base. Importantly, Biogen remains focused on expanding into new markets and expanding existing markets, while also generating important efficacy data from its robust life cycle management program. Based on all these efforts, we and Biogen believe SPINRAZA can return to growth. We earned R&D revenue of $63 million in the first quarter for advancing numerous programs partnered with Biogen and AstraZeneca, among others. Already in the second quarter, we earned a $16 million milestone payment for QALSODY U.S. approval. Our non-GAAP operating expenses increased in the first quarter compared to the same period last year. As we advanced our robust pipeline, our study costs increased as most of our ongoing Phase 3 studies were either fully enrolled or approaching full enrollment, which resulted in higher R&D expenses. Additionally, as we continue to prepare to launch eplontersen, olezarsen and donidalorsen, our SG&A expenses also increased modestly year-over-year. We bolstered our working capital by adding $500 million from Royalty Pharma in exchange for a minority share of our SPINRAZA and potential pelacarsen royalties. As a result, we recorded a long-term liability, which we will reduce when we make payments to Royalty Pharma. Additionally, we will recognize imputed noncash interest expense, which for the first quarter of 2023 was $16 million. Looking ahead, we expect our revenues in Q2 to be modestly higher compared to Q1. We also anticipate that second half revenues will be weighted toward the back end of the year. We project operating expenses to increase slightly in Q2 and to gradually increase over the course of the remainder of this year. Consistent with our guidance, which includes expenses related to our capital-intensive Phase 3 studies, we estimate our full year R&D expenses will increase between 20% and 25% year-over-year, excluding the Metagenomi upfront payment we made last year. We also project our full year SG&A expenses to increase in the range of about $35 million year-over-year from our investments in our commercial preparations for eplontersen, olezarsen and donidalorsen. For the next few years, we are planning to continue to be in a period of investment as we advance our late-stage clinical programs, and prepare to independently commercialize our medicines. As a result, we project our operating expenses to grow modestly. Additionally, by keeping more programs for ourselves, we anticipate a greater proportion of commercial revenues compared to R&D revenue. And as we add increasing commercial revenues on top of our substantial and sustained base of R&D revenue, we project our commercial revenues to be the primary driver of future revenue growth. With our goal to continue to build our Ionis-owned pipeline, we expect our investments today and into the future to drive greater value for Ionis and our shareholders. And with that, I'll turn the call back over to Brett.

Thank you, Beth. We anticipate continuing our positive momentum as we advance our key priorities with additional important regulatory and late-stage pipeline events still to come this year. We're well on our way to achieving our goal of delivering an abundance of new genetic medicines to the market. We just added QALSODY to our commercial portfolio. And with the December PDUFA date, we could also add eplontersen late this year. And with our rich late-stage pipeline, we're well positioned to bring additional medicines to the market on a steady cadence over the next several years. Additionally, with the progress we're making in all of our pre-commercial activities, our first planned launch of eplontersen with AstraZeneca in patients with ATTR polyneuropathy is in sight with our independent launches for olezarsen and donidalorsen also clearly in view. We continue to make innovative technological advancements for future medicines. And finally, our strong financial foundation enables us to invest in areas with the greatest potential to drive growth and drive value. We look forward to sharing our progress as we build on our recent achievements and accomplish our important objectives. And with that, we'll now open it up for questions.

Our first question comes from Joseph Stringer with Needham and Company. Please go ahead.

Hi all, thanks for taking our questions. Just wanted to get any additional color on the two program discontinuations. You mentioned, it didn't fit your target product profile. But just curious, was it sort of efficacy threshold they didn't meet or were there any safety signals there, any additional color on that would be helpful. Thank you.

Sure Joey, happy to. So, no safety issues at all. The safety profile for sapablursen and poly in beta-thalassemia intermedia and cimdelirsen and acromegaly were clean, pristine. It was all about efficacy. In both of these cases, these two drugs were being tested in a scenario for the first time. No one's ever targeted focusing first on acromegaly to your question. Growth hormone receptor in on hepatocytes to block IGF-1 production, as you know acromegaly is caused by excess GH growth hormone and our hypothesis was that if we block the receptor on hepatocytes, we can lower IGF-1 levels substantially that it could be a competitive treatment for acromegaly. We tested in refractory and we reported that data last year and this was the monotherapy data. It didn't meet our minimum target product profile for IGF1 reductions. And we saw some reductions, but it wasn't good enough and considering the richness of our pipeline, it just didn't clear the bar. So we're moving on from acromegaly. Sapablursen is more interesting in my view. Sapablursen we're developing for multiple indications. The first was beta-thalassemia intermedia. As a reminder, we show that sapablursen targeting TMPRSS6 GalNAc targeting strategy. So really quite remarkable signs of efficacy in - or target engagement, I should say, in our Phase 1 normal volunteer study, we reported that a couple of years ago. We showed very significant elevations hepciden levels which is what we're trying to achieve with - by targeting TMPRSS6 and expected, predicted changes in iron metabolism, exactly as we had predicted in normal volunteers. In polycythemia, I'm sorry, in beta-thalassemia intermedia, we didn't see those changes. As a reminder, TMPRSS6 is a pathway target, it's not a genetically validated target, keep that in mind. And we didn't see the biology translate from preclinical to clinical in that setting. With that said, so it didn't meet the product profile. With that said, in parallel, we advanced into polycythemia vera and - very pleased to say that we're very encouraged by some of the initial data we're seeing in PV. PV seems - the biology seems to be very different by target - with targeting TMPRSS6 versus beta-thalassemia intermedia. So it's all about biology. We're laser-focused on ensuring that the drugs that we invest in in our pipeline meet a minimum target product profile, so we can focus our attention on the drugs that are going to bring the greatest value and that drug for acromegaly and that indication for sapablursen did not meet the bar.

Well that's very helpful, and thank you for taking our question.

You're welcome.

The next question comes from Jessica Fye with JPMorgan. Please go-ahead.

Thank you for taking my question. I have a question about eplontersen. With the recent changes to Part D under the IRA, could you discuss the expected annual out-of-pocket costs for Medicare patients using eplontersen in 2024 and 2025? How do these costs compare to the out-of-pocket expenses for your competitor's product that is reimbursed through Part B? Additionally, what specific aspects will you be monitoring regarding the Acoramidis attribute data readout this summer? Thank you.

Thank you, Jess, great question. Onaiza, would you take the IRA, Eugene, maybe you could talk a little bit about data readouts from competitor programs in CM?

Sure. Hi, Jess. So first of all, it's important to understand the payer mix, as we're going into the marketplace. So we're estimating about a third of the patients in polyneuropathy or Medicare, two-thirds will be commercial. So they will not be subjected to a Medicare Part B, D design, you're talking about. They'll go through the normal hopefully Tier 2, Tier 3 co-pays which will obviously offer some level of co-pay relief with co-pay cards as most manufacturers do. On specifically the - on Part-D path for eplontersen for the third of the patients that go through it, their patient out-of-pocket costs starting in 2024 for all Medicare Part-D recipients will be capped at $2000, as you know, currently it goes into - until it gets to catastrophic layer, it ranges in the 20,000. So it's going to come down tenfold for these patients, which is a huge positive change for patients in Medicare Part-D. And then, I would say that we still expect to provide access for these patients to the foundations for the disease - for TTR diseases as it's currently being used for first-generation silencers as well for stabilizers. In terms of the Part B, I think that's a very different dynamic in terms of what is happening for those patients, they still have to think about, depending on their coverage, what level of co-insurance, they'll be paying if they don't have supplemental, then that could be actually really high for them. And then the office costs have to be considered as well because you really have some dynamics there in terms of increasing the number of staff you have on-board for those particular offices to make sure they have the ability to administer patients that are coming in. And then, I'd just characterize our benefit of self-administration at-home, it really reduces the burden on both the patient as well as the physician, particularly if you're not close to our center of excellence. It's really far drive for many of these patients as well, and that ability to self-administer at home really continues to be a really big driver of preference for eplontersen.

Eugene, what you're looking for - what's most interesting in the upcoming Acoramidis readout.

Well, the most interesting thing to me would certainly be the fact that we see on outcomes in a modern trial and by modern, I mean, the trial that really was conducted post tafamidis sort of within the last couple of years relative to what was seen in the past. I think the most interesting bit for me would be to see the background rate and placebo arm, not even the active arm. Although, of course, we're all focused on are also seeing the treatment effect. This study now has followed these patients over a number of years. So this is going to be the first readout. As I said, for the population, which we believe is more reflective of what the current population of newly-diagnosed patients may look like.

So. Whether or not the patients need are more mild than what they were in placebo group compared to the ATTRACT study, and it will also be interesting to see how a stabilizer looks up - matches up to some of the early data we've seen with the silencer as well. That will be interesting. Next question.

The next question comes from Yanan Zhu with Wells Fargo. Please go-ahead.

Hi, thanks for taking the questions, and congrats on the progress. Eplontersen maybe two questions here, maybe one to follow-up on what you're just talking about cardiomyopathy study. What to look out for from the competitor study? I was wondering with your CARDIO-TTRansform study nearing completion of enrollment, could you provide an update on a mix of tafamidis versus tafamidis naive patients in terms of proportions and any update on the ongoing blinded event rate? Additionally, would we be able to learn about the baseline characteristics of these patients once you complete enrollment before you read-out the data, so that we could, as you suggested, look at - compare different studies and anticipate the event rate with relatively more than the comparator? And lastly on eplontersen polyneuropathy, wondering about your pricing strategy that you and AstraZeneca is - I assume, working on, whether it would be a parity strategy with competitive drugs or whether it could be a competitive price? Thank you.

Thanks, Yanan. All great questions. So we - when we upsized the study, the CARDIO-TTRansform study, we had several objectives that we sought to achieve. One was to ensure that we have the size of the study to support the powering that was necessary for a patient population that has become more mild due to earlier diagnosis and detection and awareness of disease. The second was to ensure that we had about a 50/50 well-balanced usage in the study of tafamidis versus naive patients. And then, thirdly, to increase the percentage of patients that are variant versus wild-type. Obviously, we're coming close to completing this study and we're very confident in our decision to have upsized the study to around 1,400 patients and we're going to be ramping-up enrollment very soon. So we're well on our way there, of course, but we're also very pleased that our objectives for a good balance between tafamidis and naive as well as increasing the percentage of variant patients in the CM study is we're achieving it. We're well on our way to achieving all of our goals there. So that's well in-hand. As far as the blinded event rates. We're monitoring those very carefully and that too is doing - is performing very well as we had hoped it would when we upsized the study and prioritize sites when we upsized the study, where we think patients would be sicker. Wouldn't has such a high percentage of mild disease. So that's working very well too. We're seeing - what we want to see in the blinded event rates. With respect to publishing demographics. I don't have that plan in front of me. I don't think - it's a very competitive space. We'll publish or present that data at the right time, but I don't think we're going to be rushing to do that. And as far as the pricing strategy, Onaiza, would you like to comment on that?

Yes, Yanan really simply, we're going to price according to where we believe we're going to get the best and strong access and coverage for our patient. And that work is ongoing right now with AstraZeneca. In terms of your comment on parity pricing, it's just a reminder that we're launching in multiple markets outside of the U.S., where we will be first. So we will be setting the price in those markets as well. So those are both going into consideration. And again, the goal is to get access for these 40,000 patients both mixed phenotype, as well as in polyneuropathy and make sure we have products and coverage.

Great, very helpful. Thank you.

Thank you.

The next question comes from Mike Ulz with Morgan Stanley. Please go ahead.

Yes, hey guys, thanks for taking the question. Maybe just a quick follow-up on sapablursen specifically in PV. I guess, do you anticipate any read-through to PV from the beta cell study? It sounds like you don't based on some biology, but maybe you could just explain why the biology may be different in those two different indications? Thanks.

We thought - thanks, it's a very good question. We thought that there could be some read-through from beta-thal to PV because in both our objectives for both studies was to elevate hepcidin production in a disease that's really caused by very low or nonexistent hepcidin levels. But we didn't see the read-through. We're not seeing the read-through. We're seeing very encouraging early signs in polycythemia vera that the biology in beta-thalassemia intermedia just does not translate. And we think that this bodes really well for other indications that we're thinking of for our sapablursen TMPRSS6 drug. I wish, I had an answer for why the biology is different; we don't. What was really surprising was the preclinical data in beta-thalassemia intermedia which we published on extensively in a model that we thought were predictive. Beta-thalassemia intermedia had all the right signs and profile, so those animal models were very strongly similar to the human condition. It didn't happen. So we were surprised, but I really wish we knew what was going on with the biology more. What I can tell you is that, in beta-thal, we did not get the hepcidin increases that we expected to get, that we got in normal volunteers and we're seeing elsewhere, so it's just something more complex about that patient population.

I completely agree, Brett that there is no read-through on the efficacy, but on the safety, I would say, it's reading through very nicely and that means, we're not seeing any safety issues, and in fact, the sensitivity on the PV patients at least in the early look is saying, we may be driving doses even lower and so big margins.

Yes, great point, Richard. And if I could expand on that, the - we really pushed the dose in beta-thal and just - and we treated a long-time because we expected to see effects in beta-thal. And as Richard said, even though we pushed the dose, the safety was pristine. And we came into another indication, we realized that we didn't need that dose. So we're looking at, so the dose is going to be lower than what we pushed in beta-thal and that just further gives us confidence in why we chose this target and why we pursued it for various indications. It looks like, it's going to be a low-dose treatment for indications we develop.

Got it, very helpful. Thank you.

The next question comes from Yale Jen with Laidlaw and Company. Please go ahead.

Good morning, and thank you for the question. My first inquiry is about olezarsen in SHTG. The data will be shared later this year. I'm curious about what insights you have gained from the experience with WAYLIVRA that may enhance the commercial outlook and other aspects of this drug. I also have a follow-up question.

Rich.

Yes, yes, that's a great question. And looking back at our - not only previous but current experience with WAYLIVRA, we have really nice growth in the commercial space and I think what's really driving that are not only the significant triglyceride lowering activity of this approach ApoC-III inhibition. But what appears to be a very strong connection to the downstream events of pancreatitis. And so patients are feeling better, functioning better and so all of these things drive obviously, hopefully commercial. So that's the learning, I think, that we've got and learnings that we have even today from our WAYLIVRA experience.

Yes, and I'll just add to that, Richard, that olezarsen is a more potent molecule, and we expect even deeper reductions in ApoC-III and triglycerides than we saw with the early generation WAYLIVRA. Of course, with this - with the pristine safety profile like we're seeing for our all of our lipids today. And the other thing is that we're going to be paying attention to is - in addition to patients feeling better, potential strong trends hopefully in pancreatitis event reductions, with WAYLIVRA we saw reductions in liver fat. And that's important too and we'll be looking at that as well because again, we're seeing greater reductions in ApoC-III and we're going to be very - we're going to replicate that. And then you had another question, Yale.

Yes, yes, in terms of sapablursen and PV. First of all, is the data will be reported later this year and secondly, the outlook, if it's a positive outlook for the pivotal study, what do you think the approvable endpoint will be used or contemplated? And thanks.

So maybe Eugene, you help a little bit about what an approvable endpoint would be for PV. We don't know if we're going to have sufficient data this year, Yale to report on the PV. We're getting dose-ranging. I wouldn't rule it out, but I'm not. We certainly are not promising it at this point. We just really have to figure out the dose and cyclical with the profile, and so I'll leave it at that. And Eugene, what do you look at that?

It's a good question. There are a number of things we're going to explore in early - in proof-of-concept studies. Obviously, the goal is to maintain these patient's hematocrit level within the range that doesn't require phlebotomy. That's the kind of the main clinically significant endpoint, but there's a number of other exploratory endpoints where we're examining these patients, experiencing pretty low-quality of life-related to their PV symptoms such as fatigue and we're obviously going to explore the impact of improving their hematocrit control and being phlebotomy free, but also whether this impact translates into them actually experiencing better quality of life.

Beth, you want to add to that?

Yes, I'll just add that it's a really attractive commercial opportunity. There is a significant addressable population, both in the U.S. as well as outside of the U.S. and in addition to what Eugene said in terms of reducing phlebotomy or phlebotomy free, there is also a significant portion of this market at high-risk for thrombotic events. So we do believe that both things are going to be really important events.

Maybe just - which is that, is it - you're seeking for first-line or second-line impacts? Sorry.

I think that's going to be a bit of - I think it would be first-line if there were no payers involved. But because there are payers involved, we do think and we're doing some work on this that they may have to step through some of the generic, certainly not too restrictive, but there may be a step through in this.

Okay, great, thanks a lot. I appreciate and congrats.

The next question comes from Yaron Werber with TD Cowen. Please go ahead.

Hi guys, this is Brendan on for Yaron. Thanks for taking the question. Just a couple of quick ones from us, really on HAE here. Can you just remind us, are you prepared to file in the U.S. next year as the data hits in the first half? So we could potentially see $1 billion in sales maybe starting in 2025. And then Onaiza, just wondering if you have any new or additional feedback from some of these HA physicians on how you think the drug may fit into the existing paradigm and maybe where you're seeing kind of the high unmet need and lowest-hanging fruit that you think you could most quickly move into an HAE launch. Thanks.

Yes. The first question - the second question, I'll ask Onaiza to address. The first question is easy answer. We're expecting data readout early next year, filing next year, launch in '25. We are very much getting ready to do that.

Yes. We are - where the teams are working very diligently on and launch preparations over here. We continue to do research in the marketplace and our best-in-class profile holds true on a couple of very important parameters that will be important for switch and/or uptake in new patients. But our data in terms of the mean reduction in HAE attacks is really by far the most compelling point for physicians and for patients that really want to have virtually as many zero attacks as they can, right, in a given year. We also have really strong quality-of-life data that emerged. If you took a look at our OLE data, which is also in testing, reading out really well as an important point, a duration of activity and our rapid onset. So all of those are really important best-in-class profile features. Then, of course, our Q1 monthly, kind of what standard-of-care is right now in the marketplace, which is Q2 weeks.

Thanks, Onaiza. Next.

The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.

Thank you for taking our question, and congratulations on the progress. This is Tommie filling in for Salveen. With the positive data from two Phase 3 Alzheimer's studies, how are you approaching ABD and any implications? Additionally, regarding the Cardio portfolio, as you move these programs into larger markets, how do you consider reimbursement access dynamics or models for longer-acting treatments in contexts where oral treatments may already exist? Thank you.

Sure. Eric, you wanted to comment on what we're doing in dementia and how the recent successes sway?

Well. I think, so certainly for AD patients, positive data is fantastic to see. And so clearly, there are obviously different mechanisms, right. So the therapies with positive data and the one from Lilly, this morning was an amyloid reducing antibody, which is affecting one of the pathologies involved in Alzheimer's disease. The other key pathology is the accumulation of tau, and that's what BIIB080 addresses. So we think they're - we're nicely positioned to be the first drug that can really test the tau hypothesis in Alzheimer's disease and lower pathogenic tau accumulations, and that's the data that was shown by Biogen from the open-label extension at the recent AD/PD meeting whereby tau PET, where you can actually visualize the accumulation of pathogenic tau inside the brain. We were able to reduce that with the MAPT drug of BIIB080, and that generated lots of enthusiasm and it has prompted Biogen to take that forward into a pretty large Phase 2b study, where they're looking at six month dosing, in form of dose - importantly dosing intervals of two different doses of the drug to see if it really makes a difference and lowering that tau pathology can make a difference in the clinical outcomes. So certainly, I think that you can make the fact that improvements have been seen with other drugs is encouraging and we look forward to testing the tau hypothesis. I think it's a great program.

Yes. The intracellular tau hypothesis, which hasn't been tested before. And we have a great-looking drug in BIIB080. The other thing is just to expand on that a bit more. We have several programs, a rich program in dementia, programs in dementia that are coming behind tau. So stay-tuned for those in the future. It's not our whole bet, is not on just tau, although we're very excited about it as is Biogen. And then, Tommie, could you repeat your second question? I'm sorry.

Right. It was on some of the Cardio programs in general on more prevalent markets, how do you think about reimbursement and access for longer-acting treatments whereas oral may already be available, because we've seen some headwinds here with other programs?

Yes, Onaiza.

Yes, it's a really good question. I mean, I go back to kind of basics on this. So I think you have to really think about what the continued unmet need is in the marketplace and what your products bringing in terms of its profile to deliver on that. We take that combination and say, okay, what's the value proposition we're bringing to this particular disease stated unmet need and then price accordingly to that. So we have done some really good work, if you're talking about olezarsen in the broader prevalent SHTG market and we do see really good pricing potential in the kind of higher premium cardiovascular product ranges, which again our triglyceride reduction is like 3x the magnitude of what the world's are right now. So we really do believe we have a very compelling value proposition to price in that or CV premium range.

Thanks, Tommie. Thanks, Onaiza.

The next question comes from Paul Matteis with Stifel. Please go ahead.

Hi, this is James on for Paul. Thanks for taking our question. Maybe just a kind of broader high-level question. Assuming olezarsen hits in SHTG and donidalorsen hits in HAE. What do you think Ionis looks like in 2025, 2026, specifically with respect to what your salesforce could look like and what type of synergy there would be between those two assets if at all, any thoughts there would be great? Thanks.

Well, I'll just start, I'll ask Onaiza to address her sort of vision for the build of our commercial organization. It's something we're working on in preparing for launches in the near-term with olezarsen and donidalorsen. But we're expecting half-dozen or so new drugs on the market in that timeframe, James. And that includes, of course, wholly-owned and drugs we commercialized as well as our partner, and we're pretty confident in that. But Onaiza, you're going to talk a little bit about the growth.

Yes, it looks really exciting. I mean we have two cross-functional teams planning for both launches and they're not overlapping. I would just say that, you know, behind the scenes of all the commercial infrastructure that you need, there are a lot of synergies right. So what we're building for even for eplontersen with our patient services and hubs and where we have our field medical team, we're thinking about how we bring them forward to our next independent launches and then all the systems that go behind it as well, and we'll see lots of synergy there. But where we will see differences is obviously in our sales teams eventually for these two products and they will be different, they're different call points. And for olezarsen, we know it's a large opportunity, but we're really honing in on two specialties, which is Cardiology and Endocrinology, and these are very severely elevated triglycerides - so this is not a place where a lot of PCPs or GPs are actually prescribing, they're referring out to those specialties. So we're working on the sizing of that team. And then for donidalorsen, it's allergists and very, very concentrated, 50% of the docs actually prescribe 80% of the prescriptions, and you can bench it really easily to where the - our market leader Takeda is and they have about fifty-fifty reps or so that are going after that opportunity and very well concentrated in size. Well, so it is different, but there are really good ways that we're thinking about ensuring that the teams get the focus that they need and are calling on the right docs with the most efficient model.

Thank you.

Thanks, James.

The next question comes from Kostas Biliouris with BMO Capital Markets. Please go ahead.

Hello, everyone. Thanks for taking my questions and congrats on the progress. A couple of questions from us. The first one on HAE, given the relatively small size of the market there, how are you thinking about the competitive gene editing therapies or gene therapies, which if they are really one and done, they can swing the market size even further? And then I have a follow-up.

Well, I'll start and I'll ask Onaiza, she wants to expand on that. But HAE patient population, well, first, let me start here. DNA editing is still very early on. There's a lot to prove with respect to all aspects of the pharmacology. That includes the safety, the off-target potential to potentially, permanently edit DNA in a non-preferred manner, as well as the durability, is it really one and done. We've never done gene therapy. We'll have a thing truly be one and done as well. And in case if it's not, can you re-dose. There's all so much to learn here for DNA editing. The second thing is when you start getting into these younger patient populations which HAE largely is, this is a disease that's getting diagnosed earlier and earlier. The interest, there's real concerns by - from patients about editing their DNA to be blunt - at an early - at such an early age, when they're thinking about building families and those sorts of things. So there's a lot of headwind on DNA editing thing specifically for HAE. As you know, Kostas, we are investing in DNA editing. We have a different strategy for target identification in drug development. Well we're trying to address those types of concerns as we bring our molecules forward. It's still early days, but we believe in our investment in DNA editing. But we don't think HAE is going to be the right place for this approach. What do you think Onaiza?

No, I think, you summarized it well. I would say, in addition to kind of the long-term safety that still needs to be demonstrated, this patient population's appetite for actually taking a DNA edit so early in their life span and not knowing what the long-term consequences are a major concern. And then, I'll add in a third. I think the third one is, what will be the continuing remaining unmet need in HAE, because we are really going to fulfill that. We have a great product and again, it's - I think it's going be fully satisfied by the time they enter.

Then you had a second question Kostas?

Yes, and the second quick one on olezarsen, how are you thinking about the pricing, because you're potentially launching in two different markets, where the size of the targeted population is different. How are you thinking about pricing there in these two different populations? And I would assume that the drug will be exactly the same in terms of dosing and all these? Thank you.

Yes, it's a good question. We know that we have a rare disease population with FCS and then a more prevalent broader with SHTG, so we don't expect a rare disease pricing obviously for the broader population. We are working through the pricing strategy in terms of what our launch pricing will be but stay-tuned. We're thinking through a lot of different strategic ways to get at it, but you should know if you're looking at the broader population that we don't expect that obviously to be in rare disease pricing range at all. Again, as I said earlier, it will be in the cardiovascular kind of premium pricing range that you see from more prevalent diseases.

Thank you very much, very helpful.

Thank you.

The next question comes from Gena Wang with Barclays. Please go-ahead.

Thank you. Three very quick questions. One more question regarding the HAE program. You already described quite a lot of clinical profile you're looking for. Do you also consider once every two months dosing as a to-go choice to become more competitive? My second question, quick question is regarding the Angelman program, what is the expected timing for data update and what kind of safety signals you have seen so far? And lastly, very quickly, on commercial readiness for eplontersen. Is AstraZeneca taking full charge and what is the marketing strategy given and future already in a market.

Thanks, Gena. That was quite thorough. This is three very different topics. So very good questions, so I'll let Onaiza handle the HAE two-month dosing and the commercial readiness for eplontersen. Because the - but I'll take the Angelman just it's a quick answer. We - there's no - nothing new to report on timing. The enrollment is going well. And the study has been - is going very well and we're very pleased with the safety profile that we're seeing to date. No, there are no concerns for the Angelman's program. Onaiza, bimonthly dosing HAE and commercial readiness.

For HAE, our competitive profile is so strong that we actually don't really need the two-month dosing as a way to differentiate in the marketplace. We'll wait for the Phase-3 data, but certainly, it's an option for us to make that available for physicians and for patients if need be but it will all be data dependent on Phase-3. For eplontersen commercial readiness, lots of work going on, as you can imagine, we're right in that L minus X months of window over here and we're going at it in a very strong way. We do believe that this is a market where there is a lot of growth because of the number of patients who haven't been identified, diagnosed or treated yet, and we're planning for that approach in terms, really understanding where the centers of excellence currently are and where they could be in the future and really trying to hit both. It's an and versus an or us and we have the ability to do that with the scale of AstraZeneca. And then I would say that the clinical data in and of itself speaks for itself. So it has a really nice strong profile. And then lastly I’ll add it is important to note that even though we're coming in second in the U.S., that's not necessarily the order of entry that you should expect outside of the U.S. in many, many markets as well, of course the - some European markets will be second but there are a lot of European markets, Eastern Europe and China and Japan, where we expect to be first.

Thanks, Gena.

The next question comes from Luca Issi with RBC. Please go-ahead.

Thank you for taking my questions. I have two quick ones. Brett, can you discuss how your relationship with Biogen has changed with the new leadership team in place? It seems that Viehbacher is focused on cost containment, and with the ending of your collaboration on ataxin 3, I'm curious if the standards for advancing partner molecules have increased due to this cost focus. Any insights would be appreciated. Also, regarding ApoC-III, could you remind us of your commercial plan outside the U.S.? Will you be partnering the rights, using a distributor like SOD1, or having your own sales force? Any details would be helpful. Thank you.

Great. Second question for Onaiza. On the first one, Luca, thank you for the questions. Our relationship with Biogen is as strong as it has ever been, it's a great relationship. We're very pleased by the fact that Biogen is prioritizing very highly while working with us programs like the BIIB080 tau program that Eric commented on before, it's a really exciting program to them, very important. It's getting all the resources you can imagine that it's needed, as they are the Angelman's program as well. We just - they did a great job in bringing QALSODY through the finish line, in on to the market and it's already launched. So they are totally ready to launch that drug. And several of the other mid stage and research programs are progressing and going very well. Absolutely, Biogen, I'm not saying anything that's not - hasn't been in the public, they are focusing their efforts on programs that they think are going to bring the greatest value to their company. And we are a large part of that pipeline. So who we - we are a top priority for them. Relationship is growing very well. As far as the ataxin 3, and you know, a bit of a - kind of like a ultra-rare disease, if you will. Clearly was a portfolio prioritization exercise. That was communicated directly to me as was the reason behind the drug being returned to Ionis, that's not surprising. As it's probably not - if we know it's not in their sweet-spot, where the areas that they want to focus on. We are evaluating what to do with that program today whether to keep it or to repartner it. We have a rich neuro pipeline, it’s growing, that’s wholly-owned by Ionis and we’ll emphasize this pipeline going-forward and we will expand on it as well, so this also goes well for Ionis to build-out our wholly-owned pipeline in drugs that we’re interested in commercializing come back from Biogen, but the relationship is going strong and where absolutely have no concerns about any programs that are returned to Ionis because for the - most of them, we love to have them back and if we don't keep them ourselves, we will seek to repartner. ApoC-III ex-U.S. commercialization, that’s a quite interesting question, and something we have been talking about.

Thanks, Luca. I’d say listen, first of all, we’re getting very ready for launch readiness in the U.S. for both indications for FCS and for severe hypertriglyceridemia. Our plans - current plans OUS is to look for a partner. The type of partnership is where you're going for has not yet been determined, but it's important to note, like we're going to look for a really good quality partner that can reach as many patients as possible in a swift manner and that's going to be a really important criteria.

We're still working on that - Luca. So stay tuned. Thanks. And I think we have time for one last question before wrapping up.

Yes. Our last question for today comes from Myles Minter with William Blair. Please go ahead.

Thanks for sneaking me in. Again on olezarsen, just wanted your updated thoughts on the potential need if any for a cardiovascular outcome study in severe hypertriglyceridemia. Maybe not so much for regulatory approval, but certainly for reimbursement just given the comments that it seems like you're trying to take a slight premium pricing range for that product relative to the standard of care.

Yes. Since it's focused on reimbursement, I'll ask Onaiza to take that as well.

Yes, it's a good question. We actually tested our hypothesis pretty early in the program and we continue to for all sorts of payers, as you can imagine. The 500 plus population that has - it's severely elevated has a clear regulatory path, as you said, without a CVOT study. And given the unmet need and the fact that this is really a different population and we're looking for different risks for many of these patients, which is acute pancreatitis risk, this is not a place where even payers are wanting or expecting a CVOT from a reimbursement perspective. So, it's going in right in-line with where the unmet need is and the value proposition of what we bring, again the 3x magnitude of what's currently available for triglyceride reduction for these severely elevated trig patients with high-risk for acute pancreatitis, is where the payer focus is, so in there without the cardiovascular studies.

Thanks, Myles. And thanks everybody for joining us on our call today. Looking ahead, we plan to continue our momentum by delivering additional key updates, progress against our objectives on the commercial front, the pipeline and on our technology. And we're going to provide updates throughout the second half of the year. We look - very much looking forward to it. So with that, we'll close and thank you again and have a great day, everybody.

The conference has now concluded. Thank you for attending today's presentation. You may all now disconnect.