Good morning, and welcome to the Ionis Pharmaceuticals Third Quarter 2022 Financial Results Conference Call. As a reminder, this call is being recorded. And at this time, I would like to turn the conference over to Ms. Julie Tepper, Investor Relations, to lead off the call. Please go ahead, ma'am.

Thank you, Chuck. 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 that accompany today's call. With me this morning are Brett Monia, Chief Executive Officer; Richard Geary, Executive Vice President of Development; and Beth Hougen, Chief Financial Officer. And joining us for the Q&A portion of the call are Eric Swayze, Executive Vice President of Research; Eugene Schneider, Chief Clinical Development Officer; and Onaiza Cadoret, Chief Global Product Strategy and Operations Officer. I would like to draw your attention to Slide 3, which contains our forward-looking statements. During this call, we will be making forward-looking language 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. With that, I'll turn the call over to Brett.

Thanks, Julie. Good morning, everybody, and thanks for joining us on today's call. This year has been catalyst-rich and strategically important for Ionis, enabling us to conclude 2022 in a position of significant strength in setting us up for substantial growth. We're looking forward to potentially adding 2 new commercial products from our rich Phase III pipeline to our portfolio next year. These are, of course, eplontersen for ATTR polyneuropathy and tofersen for SOD1 ALS. In addition, we've made excellent progress advancing our late- and mid-stage pipeline. With 8 positive key data readouts so far this year, our rich Phase III pipeline is poised to expand the 2 new Phase III starts expected in the first half of next year. And based on all our pipeline progress, we're well positioned to continue delivering a steady cadence of Phase III data readouts in 2023, 2024, 2025 and beyond. This year, we have also advanced our commitment to deliver transformative medicines to the market with our go-to-market commercial preparations for our near-term product opportunities, eplontersen, olezarsen and donidalorsen. We have also made great progress expanding and diversifying our technology with the recent advancement of 3 new programs into IND-enabling development activities. These programs involve our first medicines incorporating LICA technology for enhanced delivery to muscle and our metal phosphoramidate, or MSPA backbone chemistry designed to improve both efficacy and durability. These advancements further enhance and expand our drug discovery capabilities, for both our new programs and our follow-on programs. We've also taken additional steps to support our future growth. We recently began work on a new state-of-the-art manufacturing facility. This facility will ensure we have the capacity we need to continue to successfully deliver our medicines to patients and continue to expand into new chemistries. We also recently capitalized on the record demand for life science real estate assets by monetizing several of our facilities through a sale-leaseback transaction. This transaction further strengthens our balance sheet to support our plans for accelerated growth. With that, I'll turn the call over to Richard to discuss our recent key data readouts pipeline updates and preview our upcoming catalysts. Then Beth will review our third quarter financial results, the financial impacts of our recent real estate transactions as well as review our full year financial guidance. And after that, I'll wrap up our prepared remarks before taking your questions. So now over to Richard.

Thank you, Brett. While our pipeline has certainly performed extremely well this year. We reported 8 positive data readouts so far this year. As a result, we are looking forward to potentially having 2 new medicines on the market and expanding our rich Phase III pipeline next year. Over the next few minutes, I will review our recent achievements and then preview our upcoming catalysts. Our next potential medicine to reach the market is tofersen. Our medicine for patients with SOD1-ALS. Tofersen is currently under priority review with the FDA, has the potential to become the first approved disease-modifying medicine for the treatment of a genetic form of ALS. Tofersen has a PDUFA date of April 25, 2023. In September, we presented positive eplontersen data from the Phase III neurotransfORM study in patients with ATTR polyneuropathy at the International Symposium on amyloidosis. In the 8-month interim analysis eplontersen achieved a highly statistically significant and clinically meaningful change compared to historical placebo for its co-primary and key secondary efficacy end points including demonstrating robust TTR reduction from baseline with the improvements in neuropathy impairment and quality of life relative to baseline in a substantial portion of patients. With these very positive data, we and AstraZeneca, look forward to filing for regulatory approval in patients with TTR polyneuropathy in the U.S. before the end of the year. Additionally, we are extremely pleased with the continued progress of CARDIO-TTRansform, the largest and longest study in patients with ATTR cardiomyopathy to date. Since we initiated CARDIO-TTRansform in late 2019, patients are being diagnosed much earlier in the course of their disease as a result of greater disease awareness and improved disease detection methods. This evolution in the ATTR-CM landscape is supported by new published and presented data from the scientific community. Based on these new findings, along with careful monitoring of patient demographics and blinded event rates in our study, we've increased target enrollment goal to 1,400 patients. This increase will ensure our study fully reflects the entire population of patients, including patients with less severe disease. We believe this further increases our probability of delivering a highly positive study outcome that best positions eplontersen to successfully compete and lead in this growing dynamic and global market. Importantly, based on our current rate of enrollment and the added power from additional patients, we remain on track to report data in the first half of 2025. Our broad olezarsen development program in FCS and severe high triglycerides is also progressing nicely. The Phase III BALANCE FCS study is fully enrolled as planned to read out mid next year. and our broad clinical program supporting the larger severe high triglycerides or SHTG, indication also continues to progress well. CORE, our pivotal -- our first pivotal study in patients with SHTG remains on track for data CORE 2, our confirmatory pivotal study in the same population is now underway with data also expected in 2024. We recently initiated ESSENCE a supportive Phase III study. ESSENCE is designed to build out the safety database for the much larger SHTG indication. With first-mover advantage, we remain very confident in the potential of olezarsen to be a substantial driver of future growth. Now our donidalorsen OASIS Phase III program in patients with hereditary angioedema remains on track for data also in 2024. We will report new longer-term data from the Phase II OLE study this Sunday, November 13 at the American College of Allergy, Asthma and Immunology Annual Scientific Meeting. The goal of the OLE study is to reinforce donidalorsen's potential best-in-class profile by demonstrating long-term protection from HAE attacks along with longer-term safety and tolerability in patients treated for 1 year. We look forward to sharing our OLE data with you on Sunday. Recently, we and our partners presented positive data from several of our mid-stage programs further advancing our rich pipeline. We recently presented positive and competitive Phase II data from IONIS-FB-LRx in patients with IgA nephropathy at the American Society of Nephrology's Kidney Week. This study was designed to demonstrate clinical proof of concept for the potential to treat IgA nephropathy by targeting complement factor B and the alternative complement pathway. And of course, to evaluate safety and tolerability. IONIS-FB-LRx met the primary end point demonstrating substantial and clinically meaningful reductions in 24-hour urinary protein in patients with IgA nephropathy with a mean reduction of 44%. Additionally, patients effectively maintain their EGFR throughout the study. And together with this, achieved a favorable safety and tolerability profile. Based on these positive data, Roche already announced their plan to advance IONIS-FB-LRx into Phase III development by mid next year. Also at Kidney Week, Bayer reported positive Phase IIb study for fesomersen or Factor XI LICA medicine for the treatment of thrombosis. The goals of the rethink ESRD study were to demonstrate dose-dependent and substantial reductions in Factor XI levels and no increase in bleeding risk compared to placebo in patients with end-stage renal disease. Safety and tolerability were also key outcomes. We were pleased that fesomersen exceeded all of the goals of the study. Fesomersen achieved dose-dependent and sustained median reductions in steady state Factor XI levels that exceeded 85% and at the top dose and with no imbalances in major bleeding or nonmajor bleeding compared to placebo. Additionally, incidences of dialysis circuit clotting and AV access thrombosis diminished significantly with decreasing Factor XI levels, both of which were exploratory efficacy endpoints and fesomersen demonstrated favorable safety and tolerability in the study. Despite these highly positive results, Bayer made the decision to only advance their small molecule Factor XI medicine to Phase III and and therefore, return fesomersen to Ionis. While we understand Bayer's decision not to move a second Factor XI drug forward, we and our clinical advisers believe that these positive data support advancing fesomersen into pivotal studies. Given the large potential addressable patient population and numerous potential indications to explore, we are focused on getting fesomersen into the hands of the right partner, to deliver it to the market as soon as possible. Turning now to the exciting bepirovirsen data GSK reported at AASLD. Bepirovirsen is a potentially transformative treatment for people living with chronic hepatitis B. HBV is responsible for approximately 900,000 deaths annually. The goal of the Phase IIb B CLEAR study was to assess efficacy, safety and tolerability in HBV patients treated with bepirovirsen. This was an important study because it demonstrated for the first time that the bepirovirsen alone or in combination with antiviral nucleotide or nucleoside inhibitors can deliver a sustained and substantial reduction in both viral DNA and HBV surface antigen, which together are key measures of advocacy. The results show that 9% of patients on nucleoside nucleotide analog treatment 1% of patients on bepirovirsen alone achieved the primary outcome of viral DNA and HBV surface antigen be the lower limit of quantification at 24 weeks after bepirovirsen treatment. These data strongly support the potential for bepirovirsen to achieve functional cures in people suffering with chronic HPV infection. Based on these encouraging data, GSK is currently in discussions with regulators on the design of the Phase III studies with plans to initiate a robust Phase III program in the first half of next year. Well, it has been an eventful and catalyst-rich year, and we anticipate continuing the momentum with the remainder of the year and in the year ahead. We're looking forward to presenting our upcoming HEE data this coming Sunday, and we are on track to file the NDA for eplontersen by the end of the year. Next year, we're looking forward to more key catalysts, including the potential approval of tofersen in the first half of the year, both 66-week data from the NEURO-TTRansform study of eplontersen the potential FDA approval of eplontersen later in the year, Phase III data from olosarsen and FCS patients, along with the initiation of 2 new Phase III programs among other important advances. With that, I will turn the call over to Beth.

Thank you, Richard. This morning, I'll provide a summary of our third quarter results, discuss our recent real estate transactions and then touch on our full year guidance. We earned revenues of $160 million and $435 million for the third quarter and year-to-date, respectively, and approximately 20% increase over last year. Our revenue continues to be derived from numerous diverse sources with approximately half from our marketed products and the balance from numerous partner programs. Our operating expenses for the quarter and year-to-date reflect our continuing investments in advancing our rich pipeline and commercial readiness activities. Notably, we continue to maintain our healthy balance sheet with cash and investments staying steady at approximately $2 billion through the end of Q3. SPINRAZA's global sales were $431 million for the third quarter and $1.3 billion year-to-date. As a result, we earned $62 million and $175 million in royalty revenue for the corresponding period. In the U.S., SPINRAZA sales continued to stabilize in the third quarter. Additionally, we continue to see positive trends in discontinuation rates. We expect to see the same dynamics play out in markets outside the U.S., which we see as a path for SPINRAZA to return to growth. SPINRAZA's potential to return to growth is further supported by Biogen's continued geographic expansion and their robust life cycle management program. This includes the work Biogen is undertaking to further characterize the remaining unmet medical need of patients with SMA with their ASCEND, RESPOND and DEVOTE studies. We earned R&D revenue of $87 million in the third quarter and $212 million year-to-date, both of which increased substantially compared to the same period last year. Year-to-date, we earned $85 million from Biogen for advancing neurological disease programs under our strategic collaboration. We also earned $63 million from Roche for licensing and advancing IONIS-FB-LRx and $55 million in cost sharing payments from AstraZeneca for their portion of eplontersen's development costs. Our non-GAAP operating expenses increased in the third quarter and year-to-date compared to last year and were in line with expectations. The increase was driven by higher R&D expenses from advancing the 6 Phase III studies we are currently conducting with eplontersen comprising our largest investment. Our R&D expenses also included increased spending for CMC and medical affairs activities to support our near-term commercial opportunities. SG&A expenses increased in the third quarter compared to last year as we ramped up our go-to-market preparation. Year-to-date, SG&A expenses were below the same period last year continuing to reflect the substantial savings we realized from the Akcea integration and Sobi transactions. As Brett mentioned, we recently took 2 important steps to support our future growth. We entered into a long-term lease to construct a state-of-the-art manufacturing facility, significantly increasing our capacity to bring our medicines to the market and to expand into new chemistry. We will oversee the design and construction of the facility, ensuring it will incorporate advanced sustainability and environmental protection features. For example, we expect that approximately 50% of the new facilities power requirements will come from renewable energy sources. We anticipate completing this project in 2025. Based on our early design work, we expect it to cost us approximately $350 million. We also entered into a sale-leaseback transaction, which took advantage of the record demand for high-quality life science real estate assets. This transaction bolstered our cash balance with approximately $240 million in net proceeds, plus funding to expand our R&D campus. It also enables us to retain control over the operation of our facilities. We used a portion of the proceeds to pay off our existing mortgage on these properties. In doing so, we reduced our long-term debt. By putting this cash to work, we believe we can generate substantially more value advancing our growth initiatives, including expanding and advancing our pipeline and technology, preparing for multiple product launches and building our new manufacturing facility. Our Q3 results keep us on track to meet our 2022 revenue, operating expense and net loss guidance. We continue to expect revenues of more than $575 million with commercial and R&D revenue roughly split 50-50. As our Phase III studies continue to progress, we expect our R&D expenses to increase between 25% and 30% this year compared to last year. We project our SG&A expenses to be in line with last year, even while we increased our investments in preparing to bring our near-term opportunities to the market. In total, we expect our non-GAAP operating expense to come in at the lower end of our guidance, which is between $825 million and $850 million. And since our recent sale leaseback transaction was not contemplated in our guidance, we are increasing our 2022 cash guidance from $1.7 billion to $2 billion. Looking to the future beyond 2022, we expect our strong financial foundation to continue to serve us well. And as we continue to invest in advancing our strategic priorities, we are poised to deliver significant future growth. And with that, I'll turn the call back over to Brett.

Thanks, Beth. As summarized this morning, we made great progress this year in advancing our key priorities to grow our commercial pipeline, to deliver an abundance of new transformational medicines to the market and expand and diversify our technology. We're on track to file the eplontersen NDA by the end of this year. And with toferson currently under priority review with the FDA, we're positioned to add these 2 new medicines to our commercial portfolio next year, assuming approval. Our late-stage pipeline continues to advance and expand setting itself to extend our Phase III data readouts next year and for many, many years to come. We've made important advances to expand and diversify our technology with more advancements still to come, and we've taken additional steps to support our growth. Importantly, we have the resources to continue executing on our priorities to drive substantial value for all stakeholders. This has been a great year for Ionis so far, and I think next year and the years to come are going to be even better. We're looking forward to sharing more on our progress in the coming months. With that, I'll now open the call up for questions. Operator, if you could open up the queue, please.

[Operator Instructions]. And the first question will come from Gary Nachman with BMO Capital Markets.

So first on eplontersen, just explain a little bit more the rationale for further expanding the cardiomyopathy study. What you were seeing in terms of having too many earlier-stage patients? Did you consider extending the duration of the study at all beyond what you did previously? And just how you're confident that the time line won't change in terms of getting those data? So that's one. And then just on the first in NDA was extended 3 months, just to explain why if the FDA asked for any additional information. And if you guys are still anticipating a panel and how you and Biogen are preparing for that, what you think the -- might be discussed if there is a panel?

Good thing, Gary. Maybe I'll take a stab at the tofersen question, and then I'll turn it over to Eugene to discuss the rationale reasoning behind the eplontersen protocol cardiomyopathy vertical. And so for eplontersen, yes, there was an extension of the time line for the NDA PDUFA date to April 25, 3-month delay, a major amendment, primarily because the FDA has communicated that they just need more time to review all the data. It's really not a request for any substantial or significant additional data they needed to do the review. It was really a bandwidth issue principally. They have a lot going on in the neuro division, especially this past fall for similar indications, and we suspect, although not definitive that, that probably caused them to have to take more time to review the data set. We're very much looking forward to the data readout, the decision, the outcome from the review by the FDA. No -- nothing new on the position by the FDA on ADCOM. We haven't heard anything new. We're still assuming that they're planning to have an ad com at some point, and we're very much looking forward to that as well. Eugene, why don't you take us through the rationale and also the importance of the amendment change to the cardiomyopathy Phase III trial for TTR?

Sure, Brett. Thanks for the question. So as Richard already mentioned in his remarks, it is clear to us and to many of the advisers we've been talking to that the population with ATTR cardiomyopathy has changed substantially over the past several years. And as you recall, the primary source for us to power the study, the original study that we started back in 2019 was the ATTRACT data set, which the study that Pfizer conducted but a few years back. And the more data became available to us internally as well as externally, importantly, quite a few publications have now endorsed the application population has changed in a meaningful way. Specifically, they come to a definitive diagnosis earlier than they used to. And as a result of that, and that's a factor of greater disease awareness, there are diagnostic measures. And that results in the patient journey being relatively different to what it used to be. So when ATTRACT was conducted, patients came to attention late in their clinical presentation and have multiple early events that were -- again, as I said, were used for the original powering study. So as we assimilate all of the data externally and internally coming from our study, it became clear that the study was not powered properly based on those updated assumptions, and we needed to resize the study accordingly. Of course, the question about duration is an important one, and we've looked at that as well. We've considered against it, extending the duration even further because that would substantially delay the timing of the readout. And we felt that, again, the upsizing of the study alone was sufficient to ensure that it's properly powered without taking a significant penalty time.

And thanks, Eugene. I'll just add. And of course, we also have patients in the open-label extension of the Phase III CARDIO-TTRansform study, who have now completed the 140 weeks, so we wouldn't want to lose those patients. So we can accomplish the same objective, the same goal by increasing the sample size, which we did. And we think that this is a strategic important move to the study to really help ensure for the most successful outcome possible for CARDIO-TTRansform.

Okay. That's very helpful. And just to confirm, you don't need to increase the number of sites and I guess, enrollment has been going quite well. Maybe just comment on that.

Yes, right, adding 400 patients not changing the timing for the readout means that we're well ahead in enrollment. So enrollments going very well, and we're not needing to open up new sites or the study the same existing sites, and we're just moving ahead rapidly to get to the 1,400 number.

The next question will come from Yanan Zhu with Wells Fargo.

Congrats on the progress in the quarter. I have a follow-up on CARDIO-TTRansform study and also a question on Lp(a). For CARDIO-TTRansform, how does the changing demographics change your powering assumption in terms of event rate in the control arm and the effect size? And what proportion of antifamidis patients did you assume in your powering assumption? For Lp(a), how do you and your partner, Novartis view the data for eplontersen presented at the AHA meeting where they showed up to 100% Lp(a) reduction, how does that affect your outlook for tenacarcen?

Thanks, Yan. And two great questions. I'll ask Eugene to share what he can share about powering assumptions and so on. And then Richard to talk about cars.

Sure. Thanks, Yanan, for your question. So related to our original assumptions, you may recall, we -- we did what we thought was responsible and conservative thing to do, which was assuming that all of our placebo patients will be on the background of Kavita. So we took the -- essentially the tafamidis arm event rate in our original or calculations. As I just said, even given that rate turns out to be overly -- quite a bit different from what we're seeing and what's been published recently to be the case in patients in general in today's care. So even that rate was overly high relative to the population available today. We haven't really changed any of our other assumptions on the treatment effect. As you know, the treatment -- the true treatment effect is not known and we're not prepared to change any of our assumptions, nor have we commented on what specifically we use other than to say that we use what our advisers said would be considered clinically meaningful for them.

Thanks, Eugene. And I'll just add, we're focused on the CARDIO-TTRansform study, of course, and -- but this change in demographics for TTR cardiomyopathy, we think applies to all contemporary studies evaluating investigational medicines. And we're in a very strategic position and made a very strategic move to ensure for a very successful outcome in the study. So we think this is a very important move and it gives us even greater confidence in a successful outcome. Pelacarsen, Richard?

Yes. So speaking directly to the question, how does it change our view on belocarsen doesn't change it at all. And just to take you back to a remembrance of Phase II for pelacarsen, -- the dose that we took into Phase III achieved taking 98-plus percent of the patients the goal. And the goal is to get below that threshold of 50 milligrams. It's not to get to 0. So just -- it's a little bit different than LDL. It's a different way of thinking, lower is not better, but getting below that threshold is the goal. And so we're going into Phase III with product that gets nearly 100% of the patients to where they need to be out of risk, and we're well ahead of the competition. There's competition and that just gives us all the urgency that we've had all along to get this thing to the market as quickly as possible.

Yes. And thanks, Richard. It's probably worth noting, too, that the epidemiology data is substantial, continues to grow, really enforcing the conclusion -- reinforcing the conclusion that, that threshold is where you need to be below that threshold need to be to get out of harm's way. As Richard said, melecarson delivers on that based on a very significant large Phase II study, which we are suing the same patient population, the same Phase III dose, but also there's now emerging data, published data indicating that if you go too low on Lp(a), you can also close some problems. There are publications now out there that says if you go very low on Lp(a), that you can actually have an increased risk for diabetes. That's associated, not causal, not proven, but there's no need to go that low. And all it does is bring further risk. I also want to add this. The study is fully enrolled. This study is well on its way to reading out. This study gets reviewed by oversight committees, independent oversight committees regularly. That drives risk down, right? -- competitors are going from a small Phase II study to a large Phase III outcome trial. Okay, that brings risk. We like our risk profile today, fully enrolled on our way to read out well ahead of the competition and getting virtually all the patients into the safe zone for Lp(a) levels. So I hope that answers your question, Yan.

Yes. Yes. Congrats again on the progress this quarter.

The next question will come from Myles Minter with William Blair.

Just a quick question on fesomersen. Just with your new partner considering you did show that the data in ESRD with dialysis, and it looks to be hitting everything that you set out to demonstrate, what sort of indications would you encourage a new sponsor to chase with that asset versus the oral inhibitor competitors that look to be going for a more acute setting.

Thanks, Myles. As I think we've been very transparent with over the last, I think, really last year. We were hoping Bayer was going to take this immersion forward based on positive Phase II really positive Phase IIb data, which ended up being very positive. But we're also anticipating preparing for the eventual potential return because there had 3 independent modalities being developed for targeting Factor XI, their own homegrown small molecule, in-licensed monoclonal antibody and in-licensed fesomersen. As I said, as you know, the -- some of the small molecule data has been presented already at ESC. A lot of aspects look good. I think it's a bit of a mixed bag. We're very pleased with the Phase IIb data for fesomersen and the antibody data is now yet. So they made they need a decision to go forward with 1 drug forward. And Bayer was focused on end-stage renal disease as a potential population for fesomersen. We believe that that's too limited. We believe that a once-a-month highly effective Factor XII inhibitor that achieves knockdown of Factor XI beyond 85% could be used for any prophylactic treatment to prevent thrombosis, metro fibrillation, secondary stroke prevention, end-stage renal dialysis and so on. So we think that this is -- has the potential to be used broadly. And that's what we're going to be looking for in a partner, a partner that can bring, as Richard said in his statements to bring to the market as quickly as possible, but also to really maximize the opportunity as a thromboprophylactic treatment for thrombosis.

Okay. Cool. And then a quick one on CARDIO-TTRansform study. Just with the 400 patients that you're going to additionally enroll, are they going to be equally balanced across the patient subgroups like wild-type versus hereditary, tafamidis experience versus naive? Or are those specific subpopulations as you've seen the demographics of the 1,000 patients currently that you might want to bolster with the addition of these 400 patients coming into the trial?

Yes. Thanks for your question, Myles. This is Eugene. So clearly, the opportunity here is to be fairly intentional with the remaining portion of the population that we're enrolling because we're in a position where all sites are open, we have an ability to be kind of more targeted in the types of patients that are being brought in and that's what we're doing. As you said, of course, if you look at the epidemiology data, the risk is different for certain types of patients with regard to outcomes and that's what we're trying to maximize here, of course, bringing in more hereditary patients, fewer patients who are on tafamidis therapy and obviously patients at later stages of their cardiomyopathic compression is going to be a priority, and that's what we're trying to do with the remainder of enrolled population.

The next question will come from Jessica Fye with JPMorgan.

Can you give us an update on the Angelman program? What's that stand? And when can we expect an update?

So unfortunately, Jess, we don't have a whole lot new to provide. We're enrolling the study. As you know, it's an open-label extension study. And we're looking forward to completing the studies as rapidly as possible. We're not really planning to share any data, right, Eugene? On like anecdotal observational data as we go forward. We want to get the study completed. It's dose ranging. And it's intended to set us up for a Phase III start as quickly as possible.

Absolutely. And it's also a partner program. So because of the open-label nature and the fact that it's really in early stages of dose escalation. We're not really commenting on the timing other than to say it's going according to the plan.

Going according to plan, it's enrolling well, and we're just moving along.

The next question will come from Luca Issi with RBC.

Great. This is Lisa on for Luca. This question is for Brett. Just a bigger picture. I know you've talked in the past about broadening your reach to technologies beyond antisense legonuclotides. So I was wondering if you can comment what your latest thinking is there.

Sure. Lisa, thanks for the question. So we -- as I mentioned in my prepared remarks today, we're making great progress in advancing our technology in many different ways. We've now moved with a partner a new program using a new LICA targeting muscle. Can't talk more about the target or the indication at this point because it's a highly competitive area, but we're looking forward to providing an update maybe next year. That has a potential to open up new diseases for Ionis as well as partners targeting the muscle. We've also now brought forward a new backbone chemistry called MsPA. We brought into development now supporting toxicology studies for 2 CNS targets using that backbone. That backbone is intended to do to increase efficacy, potency as well as durability, so less frequent dosing. And we expect that to translate the book CNS as well as systemic applications. So stay tuned for that. They're both a broad indications. We're one with a partner, one Ionis wholly owned, we expect to keep that one ourselves as well. As far as other approaches, as I've been saying now for quite some time, we are -- we will continue as we've been now for the last couple of years, evaluating SI strategies as well as ASO strategies, and our philosophy is let the best drug win based on preclinical data, bringing them to the clinic. We're expecting to move our first SI into development Nalin tox at probably early next year, not early this year. And there are specific applications where we see advantages for SI. There are specific advantages or areas where we see advantages for ASOs. And we're going to be multi-modal here. As far as new platforms go, we're in sort of seeking evaluation phase right now about diversifying our platform capabilities. And I really can't say much more about it than that, Lisa, except stay tuned. We hope to be able to make some progress in the future about some of our thoughts, ideas in that area.

The next question will come from Gena Wang with Barclays.

I just have one regarding the HAE update this Sunday. So you already see pretty impressive early efficacy. So with this only data should we expect further improvement in attack reduction given the longer follow-up? And also which data point will be more important regarding percentage of patients attack-free versus percentage of a reduction in attacks?

I'll start at the beginning on like Onaiza to talk from a commercial standpoint, maybe what is since we're planning to launch this drug ourselves what is most important to patients and the prescribers for prophylactic for HAE. So I can't get ahead of the presentation on Sunday. That wouldn't be fair. But we're expecting -- our plan is to show -- I mean it's hard to get better than the Phase II data, right? I mean these patients were essentially attack-free once we got to steady state after 5 weeks after 1 dose. I mean it's hard to get better. What we're really looking to do is what to show is whether that unprecedented efficacy is actually sustained for a year, right, as well as compliance as well as the long-term tolerability. So those go hand in hand from an approval standpoint, as you know, Gena, tolerability as well as sustained efficacy. So that's really -- I don't think we can go beyond. I mean, maybe but it's really one of these and to the patients or percentage points, I should say, because you can't get much better than the efficacy we showed in Phase II. What are you thinking? Is it from what's most important to patients?

Yes. I would say to both physicians and to patients, Gena, efficacy is, first and foremost, we tested and hierarchy in order of efficacy, just to kind of glean like what's most important and the 0 attack rate is the #1 efficacy measure. Then followed by mean attack reduction and then followed by how much you're actually withdrawing them off of the acute treatment. So those are -- that's the order of hierarchy, but 0 attack rates basically the name of the game here. And as Brett said, we -- in our Phase IIs, as you've already seen, showed the mean kind of a max clinical efficacy of 97% 0 attack rates that we achieved in weeks 5 to 17. So as quickly as after your first dose. Also important to note that in this marketplace, we also just completed some market research to say, okay, well, where are the patients at currently with Takhzyro being the market leader and the #1 prophylastic agent that is used out there, again, with a pretty significant 0 attack rate. We're still seeing patients have reported. On average, there are about 3 HAE attacks happening in a year and in -- and that's pretty substantial still. So we do believe that we're going to really fulfill this unmet need that still exists in the marketplace.

The next question will come from Joseph Stringer with Needham & Company.

A quick one on the GSK partnered HBV program, the pelacarsen. Just wondering if you could talk about the differentiation of your approach from, say, competitor approaches that are using dual or even triple combo therapy, some of which are RNA inhibitory knockdown based?

Great question, Joe. Thanks. I'm going to ask Eric to comment on that.

Yes, sure. Really, I think the the key differentiator is that the pelacarsen as a single agent was able to do things that the other approaches really haven't been able to accomplish. And that was evidenced by the BCA results, both showing around a 30% HBS antigen lulu detection level at the end of treatment and then maintaining that for about 10% of the patients at 24 weeks post study, and this highlights for the potential of that drug to achieve the ever-elusive functional cure in HBV, where patients are being able to remove from therapy. I think GSK is doing a great job with this program and thinking about combination approaches. They have to be together study ongoing right now, which is adding interfering on top of that. And I think some of the competitive studies you're referring to are using HPV RNA lowering agents in combination with interferon and showed some S antigen loss, but that was at the end of study not after removal of treatment. So I think the field is moving forward. It's actually -- great to talk about HBV functional cures and having the buzz around it at the recent meeting that that's happening. And I think it's good for patients. And ultimately, we and GSK think that BEP will be a foundation for treatment of HBV, including combinations involving BPI that will hopefully increase the rate of patients that can remain therapy free.

Yes. I think that's something I just want to emphasize, that Eric just closed on is that the 9%, 10% functional or undetectable levels 24 weeks after completing dosing. So off all drugs, 24 weeks later, undetectable in about 10% of patients, whether monotherapy or on NUCs really is unprecedented and is the foundation to build from that alone, we believe, is an approvable mark, benchmark. That's a marketing, that's marketable and end point or achievement and is beginning. Once we get into combination treatments and selecting subpopulations, we know that the undetectable levels were even greater in patients that had less HPV burden coming into the study in the 20% to 30% range, right? So all this is just beginning. It's still really impressive. But as we go, and GSK is going to be taking a comprehensive approach, Phase III approach to looking at various combinations, immunotherapy interferon combinations and so on to maximize the value of BEP for HBV patients.

The next question will come from Paul Matteis with Stifel.

This is James on for Paul. Maybe just one on olezarsen. It looks like it could potentially be Ionis' first kind of independent drug launch and I guess, one, is that how you're thinking about it today to launch it yourself? And if so, would the investment there look like? And then maybe just separately, quickly, be great to just get your thoughts on what you would want to see efficacy and safety wise to have confidence in a competitive drug profile there.

Sure. Onaiza, you want to take that?

Sure. Yes, that is a very correct assumption that this will be the first on self-commercialization outside of a cocoa F1 Tillerson being the first one. And we are looking at 2 indications, as you know. The first one is in FCS and then the second one in severe hypertriglyceridemia. Severe hypertriglyceridemia is a large patient population in the U.S. with close to 3 million patients available for treatment over here with elevated TG. This is the investment that's required is actually going to be pretty focused, I would say, it would seem on the face of it because of a large patient population you're going to go out and have to call on GPs and stuff. But we've done a fair amount of work to see where the referral patterns are for these patients, and they're coming into a couple of specialties. So we're going to be actually very targeted there. And we're also going to employ just really more innovative tools such as omnichannel and just a lot of AI to identify where the patients are from predictive analytics to be able to manage our investment to get to this large patient population. So we are working very actively in terms of preparing as these trials are all in Phase IIIs right now, the 2 CORE trials, which are the pivotal and confirmatory trials and then the ESSENCE, which is a safety trial that just got initiated as well. As to what's the competitive profile, listen, the standard of care are fibrates and niacin and Vascepa and their triglycide reductions were in the 20% to 30% range. So we're doing -- we expect to do about 2.5x to 3x more of that. We have a real good confidence that we'll get there based on our Phase IIs which, as a reminder, the Phase IIs were substantial, but we're not in these really high elevated sHTG. They were in the 500-milligram range. And in that, we already showed a 62% placebo corrected TG lowering. So if you take a look at what we expect in the severe hypertriglyceride range, we expect that it's going to be higher. And as a reminder, we are also studying 2 doses, both the 50 milligrams and the 80 milligrams in our original Phase IIs were at the 50 milligrams. So we have a very competitive profile. And a reminder, we are well ahead of the competition, and we have a first mover advantage over here by a substantial margin. So we'll get to really prepare the market, shape the market and price the market.

The next question will come from Salveen Richter with Goldman Sachs.

This is Tommy on for Salveen. Our question is on tornado -- could you envision sharing detailed functional data over time, such as mNIS+7 trajectories at 1, 1.5, 2 years so that people can see the benefit that you're getting on these measures over time?

Yes. So thanks for your question. We are anticipating providing a pretty thorough and wholesome update on all of the co-primaries and key secondary end points once we look at our primary endpoint, week 66 data next year around mid next year. As we said until that point, the key results have been disclosed, but we're obviously not able to share additional details. But once the week 66 data become available, the study results will be shared more broadly and more exhaust.

I mean we expect to present that -- have that data by midyear next year. And we'll also prepare publication presentation. So we're very much looking forward to sharing the full data set the week 66 data at that time when we have it, when we have the data.

The next question will come from Yaron Werber with Cowen.

This is Brendan on for Yaron. Just a quick one from us. First on Sindelarson for acromegaly. I know you guys have so many things advance thing we can get to all of them here. But just wanted to see what the latest thinking is for timing and presentation of that data and maybe whether you're targeting a medical meeting for the release or not? And then just quickly, I want to just see if there are any new updates on the Huntington's program with Roche, either on the timing or just the overall clinical plan with tominersen there?

So for the -- our acromegaly program, we're still planning to review the data, the Phase II data, the monotherapy data this year, right, Richard? And I don't know if we're going to have the opportunity to present the data because the year is rapidly coming to a close. Certainly, medical meeting is out of the question. We'll see what we could do. It's a relatively small Phase II study. Probably not going to be able to get that data out until next year. But we're going to -- we'll try to get it out as quickly as we can. For Huntington's, Roche has done a pretty good job of sharing a lot of data on the post-hoc analysis recently. It's post hoc, but it's compelling that patients with less disease burden, we're doing better. And we're doing better with less frequent dosing of tominersen. And they've also laid out their trial design, right? Their Phase II trial design in pretty detailed. It's a big study, as I recall, I'm looking at Eugene, Richard, there's 3 cohorts, about 120 patients per cohort, 2 doses, 1 placebo. Is that right?

Yes, right.

Yes. So it's a big study. They haven't given timing on exact first patient dosed but it's not far out there.

The next question will come from Yale Jen with Laidlaw & Company.

For GSK as well as the road, given they are advancing the program forward to pivotal Phase III study, do we anticipate any milestone payment to be able to the company later this year or early next year?

You were asking about the GSK HBV program, Yale?

Yes, as well as the FTE for the -- for Roche?

It's the FP and the property.

Yes. Yes. So on the milestones, I think with the license fee and milestones we've already earned in the second and third quarter of this year, we will be looking forward to regulatory approval milestones for that drug going forward. And then potentially milestones as the the geographic atrophy study continues to advance with that same drug with the IONIS-FB-LRx.

Okay. That's very helpful. Maybe one more question here, which is for the HGT for the treatment-resistant hypertension. You will have a data readout. Could we give a little bit more color what to expect later this year?

Yes. Thanks, Yale. We have three studies in progress, right? We have the refractory hypertension with Gen 2 like a molecule. We also have the heart failure study with the Gen 2 lycomolecule, which is still in process, both studies are in process. And we have the Gen 2.5 in hypertension patients. We're probably going to present the data. We're going to pull all the data together and probably have a presentation in some form or another or announcement probably early next year. We really want to look at the full data set for both indications as well as both drugs because the next question that we're going to get once we present this data, if we do it in pieces, it will be what are the next steps, right? And we don't know what the next steps will be until we look at all the data from 2 drugs and 2 indications. So we'll certainly have completed at least one of those studies this year, but we'll probably with all the studies are complete for getting the data out there. Yes, we're going to have to close it out. Thank you. Thanks, everybody, for your -- for joining us participating in today's call. We're really really pleased with the quarterly results. We're very much looking forward to the rest of the year as well as moving into next year as well and continuing to provide you with updates on the progress we're making. Thanks again, and have a great day.

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