Q1 2023 Ionis Pharmaceuticals Inc Earnings Call

Participants

Brett P. Monia; Founder, CEO & Director; Ionis Pharmaceuticals, Inc.

D. Wade Walke; SVP of IR; Ionis Pharmaceuticals, Inc.

Elizabeth L. Hougen; Executive VP of Finance & CFO; Ionis Pharmaceuticals, Inc.

Eric E. Swayze; EVP of Research; Ionis Pharmaceuticals, Inc.

Eugene Schneider; Executive VP & Chief Clinical Development Officer; Ionis Pharmaceuticals, Inc.

Onaiza Cadoret-Manier; Executive VP, Chief Global Product Strategy & Operations Officer; Ionis Pharmaceuticals, Inc.

Richard S. Geary; Executive VP & Chief Development Officer; Ionis Pharmaceuticals, Inc.

Brendan Mychal Smith; Associate; TD Cowen, Research Division

Huidong Wang; Research Analyst; Barclays Bank PLC, Research Division

I-Eh Jen; MD of Healthcare Research & Senior Biotechnology Analyst; Laidlaw & Company (UK) Ltd., Research Division

James Condulis; Research Analyst; Stifel, Nicolaus & Company, Incorporated, Research Division

Jessica Macomber Fye; Analyst; JPMorgan Chase & Co, Research Division

Joseph Robert Stringer; Senior Analyst; Needham & Company, LLC, Research Division

Konstantinos Biliouris; Director & Biotechnology Analyst; BMO Capital Markets Equity Research

Luca Issi; Research Analyst; RBC Capital Markets, Research Division

Michael Eric Ulz; Equity Analyst; Morgan Stanley, Research Division

Myles Robert Minter; Analyst; William Blair & Company L.L.C., Research Division

Tommie M. Reerink; Research Analyst; Goldman Sachs Group, Inc., Research Division

Yanan Zhu; Senior Equity Analyst; Wells Fargo Securities, LLC, Research Division

Presentation

Operator

Good morning, and welcome to Ionis First Quarter 2023 Financial Results Conference Call. (Operator Instructions) As a reminder, this call is being recorded.
At this time, I would like to turn the call over to Wade Walke, Senior Vice President of Investor Relations, to lead off the call. Please begin, sir.

D. Wade Walke

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 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.
And with that, I'll turn the call over to Brett.

Brett P. Monia

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 III 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 2 other near-term commercial opportunities, olezarsen and donidalorsen are also progressing very well. With olezarsen, we remain on track for data from the Phase III 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 III 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 7 programs advancing in 9 separate indications with the initiation of Phase III 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.

Richard S. Geary

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 4 secondary end points, and continued 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 from 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 2 indications, characterized by severely elevated triglycerides, FCS and severe HTG is also continuing to progress well. The Phase III BALANCE FCS study is fully enrolled, and we remain on track for data in the second half of this year. And our multi-study Phase III 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 III 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 II open-label extension study in patients treated for 1 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 2 in Phase III studies and 8 in Phase II. I would like to spend a couple of minutes highlighting 2 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 III 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 III ATLAS study and presymptomatic SOD1-ALS study. Patient is also progressing nicely.
We are encouraged by the recent data Biogen presented at the AD/PD 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 type of 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 II study in patients with early AD, which includes 2 different dose cohorts dosed every 6 months and 1 dose cohort dosed every 3 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 7 drugs advancing in a total of 9 separate indications with the start of a pivotal program for 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 III study for IgA nephropathy.
We recently took steps to further focus our R&D efforts and prioritize our pipeline with the discontinuation of 2 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 II 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 III 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.

Elizabeth L. Hougen

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, was 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 midyear. Additionally, we continued to record 100% of our SPINRAZA royalties as commercial revenue under our royalty pharma transaction.
With 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. And 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 III 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 III 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.

Brett P. Monia

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 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.

Question and Answer Session

Operator

(Operator Instructions) Our first question comes from Joseph Stringer with Needham & Company.

Joseph Robert Stringer

Just wanted to get any additional color on the 2 program discontinuations. You mentioned it didn't fit your target product profile. But just curious, was it sort of efficacy threshold that didn't meet? Or were there any safety signals or any additional comment, that would be helpful.

Brett P. Monia

Sure, Joey. Happy to. So no safety issues at all. The safety profile for sapablursen in beta thalassemia intermedia and cimdelirsen in acromegaly, were clean pristine. It was all about efficacy. In both of these cases, these 2 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 on hepatocytes to block IGF-1 production.
As you know, acromegaly is caused by excessive GH, growth hormone and our hypothesis was that if we block the receptor on the hepatocyte, 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 IGF-1 reductions. And we saw some reductions, but wasn't good enough. And considering the richness of our pipeline, it just didn't clear the bar. So we're moving on for 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 showed that sapablursen targeting TMPRSS6 GalNAc targeting strategy. So really quite remarkable signs of efficacy in -- or target engagement, I should say, in our Phase I normal volunteer study. We reported that a couple of years ago. We showed a very significant elevations in hepcidin 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 and 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 I'm 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.

Operator

The next question comes from Jessica Fye with JPMorgan.

Jessica Macomber Fye

Question on eplontersen. First, with the IRA changes to Part D, can you talk about how you think about the annual out-of-pocket costs of eplontersen for Medicare patients in 2024 and 2025 and beyond. And how that compares to the out-of-pocket costs for your competitor product reimbursed through Part B? And then also related to eplontersen, I'm curious what you'll be watching for when the Acoramidis attribute data reads out this summer.

Brett P. Monia

Great question. And as you would take the IRA, Eugene, maybe you could talk a little bit about data readouts from competitor programs in CM?

Eugene Schneider

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 1/3 of the patients in polyneuropathy are Medicare, 2/3 will be commercial. So they will not be subjected to the Medicare Part B, D, design you're talking about. They'll go through the normal hopefully, Tier 2, Tier 3 co-pays, which will -- which we obviously will offer some level of co-pay relief with co-pay cards with most manufacturers do.
On specific, the Part D path for eplontersen for the 1/3 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 $2,000. As you know, currently, it goes into -- until it gets to catastrophic care, 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 is 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 coinsurance they would 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 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 a really far drive for many of these patients as well. And that ability to self-administer at home is really -- continues to be a really big driver of preference for eplontersen.

Brett P. Monia

Eugene, what are you looking for what's most interesting in the upcoming Acoramidis readout?

Eugene Schneider

Well, the most interesting thing to me would certainly be the effect that we see on outcomes in a modern trial. And by modern, I mean the trial that really was conducted post tafamidis sort of the -- within the last couple of years relative to what was seen in the past. And I think the most interesting bit for me would be to see the background rate in placebo arm, not even the active arm, although, of course, we're all focused on and also seeing the treatment effect. This is the study now was followed -- 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.

Brett P. Monia

So whether or not the patients indeed are more mild than what they were in the placebo group compared to the ATTRACT study. And it will also be interesting to see how a stabilizer looks up, it matches up to some of the early days we've seen with the silencer as well. That would be interesting.

Operator

The next question comes from Yanan Zhu with Wells Fargo.

Yanan Zhu

Congrats on the progress. Eplontersen, maybe 2 questions here. Maybe one, to follow up on what you're just talking about cardiomyopathy study. what to look out from the competitor study. I was wondering with your CARDIO-TTRansform study nearing completion of enrollment, could you provide an update on the mix of on tafamidis versus tafamidis naive patients in terms of proportions? And any update on the ongoing blinded event rate?
And also, 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 compared to different studies and anticipate the event rate with a relatively more than comparator? And lastly, on eplontersen polyneuropathy, wondering about your pricing strategy that you and AstraZeneca is -- I assume you're working on, whether it would be a parity strategy with competitor drugs or whether it could be a competitive price?

Brett P. Monia

Thanks, Yanan, all great questions. So when we upsized the study, the CARDIO-TTRansform study, we had several objectives that we sought to achieve. One was to ensure that we had 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 in 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 varying versus wild type.
Obviously, we're coming close to completing the 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 wrapping 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 have 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 -- this is a very competitive space. We will 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 pricing strategy, Onaiza, would you like to comment on that?

Onaiza Cadoret-Manier

Yes. Yanan, really simply, we're going to price accordingly to where we believe we're going to get the best and strong access and coverage for our patients. And that work is ongoing right now with AstraZeneca. And 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 broad access and coverage.

Operator

Next question comes from Mike Ulz with Morgan Stanley.

Michael Eric Ulz

Maybe just a quick follow-up on sapablursen, specifically in PV. I guess, do you anticipate any read-through to PV from the beta-thal 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 2 different indications?

Brett P. Monia

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 isn't reading through. And we think that this bodes really well for other indications that we're thinking of for our sapablursen and 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 have published on extensively in models that we thought were predictive of beta-thalassemia intermedia. I mean they had all the right signs and profiles of those animal models was very strongly similar to the human condition didn't happen. So we were surprised, but I really wish we knew the biology of what was going on there 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 there's something more complex about that patient population.

Richard S. Geary

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

Brett P. Monia

Yes. We -- a great point, Richard. And if I could expand on your expanding on me. We've really pushed the dose in beta-thal 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 shows 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.

Operator

The next question comes from Yale Jen with Laidlaw & Company.

I-Eh Jen

My first question is regarding olezarsen in FCS. I know the data will be presented later this year. I'm just curious what you guys have learned from the prior experience from WAYLIVRA and in terms of the future sort of steps that will further sort of improve the commercial outlook and other aspects of this drug? Then I have another follow-up.

Brett P. Monia

Rich?

Richard S. Geary

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, APOCIII 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 gotten and learnings that we have even today from our WAYLIVRA experience.

Brett P. Monia

Yes. And I'll just add to that, Richard, that olezarsen is a more potent molecule and we expect even deeper reductions in APOCIII and triglycerides that we saw with the early generation WAYLIVRA, of course, with a pristine safety profile like we're seeing for our -- all of our [like us] to date. And the other thing is that we're going to be paying attention to is, in addition to patients just feeling better, reductions potentially 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 APOCIII and we're going to be very -- we're going to want to replicate that. And then you had another question, Yale?

I-Eh Jen

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

Brett P. Monia

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 the sufficient data this year, Yale, to report on the PV, again, in dose ranging. I wouldn't rule it out, but I'm not -- we certainly are not promising it at this point. We're just going to have to really figure out the dose and look at what the profile is. So I'll leave it at that. And Eugene, where do you look at?

Eugene Schneider

It's a good question. There's a number of things we're going to explore in early in proof-of-concept studies. Obviously, the goal is to maintain these patients hematocrit level within the range that doesn't require phlebotomy. That's kind of the main clinically significant endpoint. But there's a number of other exploratory endpoints. We're examining these patients experience 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.

Brett P. Monia

Onaiza, do you want to add to that?

Onaiza Cadoret-Manier

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's also a significant portion of this market that's at high risk for thrombotic events. So we do believe that both things are going to be really important.

I-Eh Jen

Maybe (inaudible) which is -- is this strictly for first line or second line index. Sorry.

Onaiza Cadoret-Manier

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 generics certainly not -- that was too restrictive, but there may be a step too in this.

Operator

The next question comes from Yaron Werber with TD Cowen.

Brendan Mychal Smith

This is Brendan on for Yaron. Just a couple of quick ones from us, really on HAE here. Can you just remind me, are you prepared to file in the U.S. next year if the data hits in the first half, so we could potentially see donidalorsen sales maybe starting in 2025. And then honestly, just wondering if you have any new or additional feedback from some of these HAE physicians on how you think the drug maybe fit into the existing paradigm and maybe where you're seeing kind of the highest unmet need and lowest hanging fruit that you think you could most quickly move into in an HAE launch?

Brett P. Monia

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

Onaiza Cadoret-Manier

Yes. We're -- the teams are working very diligently on 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 the -- 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, duration of activity. and our rapid onset. So all of those are really important best-in-class profile features. And of course, our Q1 monthly beats kind of what standard of care is right now in the marketplace, which is 2 weeks.

Operator

The next question comes from Salveen Richter with Goldman Sachs.

Tommie M. Reerink

Congrats on the progress. This is Tommie on for Salveen. So now that we've seen positive data from 2 Phase III Alzheimer's studies. How are you thinking about the [AD] and any read-through and more broadly, on the cardio portfolio, as you start to advance these programs in larger markets, how do you go through the process of thinking about reimbursement access dynamics or models here for longer-acting treatments in these indications where oral treatments may already be available?

Brett P. Monia

Eric, you want to comment on what we're doing in dementia and how the recent success is?

Eric E. Swayze

I mean 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 there -- 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, where by 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 IIb study where they're looking at 6-month dosing in form of those -- importantly, dosing intervals of 2 different doses of the drug to see if it really makes a difference and lowering that tau pathology can make a difference in 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.

Brett P. Monia

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, can you repeat your second question? I'm sorry.

Tommie M. Reerink

Right. It was on some of the cardio programs and generally 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.

Brett P. Monia

Onaiza?

Onaiza Cadoret-Manier

Yes. It's a really good question. I mean I go back to kind of basics on this, 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, with the value proposition we're bringing to this particular disease state is 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 orals are right now. So we really do believe we have a very compelling value proposition to price in that CV premium range.

Operator

The next question comes from Paul Matteis with Stifel.

James Condulis

This is James on for Paul. 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 sales force could look like and what type of synergy there would be between -- for those 2 assets, if at all? Any thoughts there would be great.

Brett P. Monia

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

Onaiza Cadoret-Manier

Yes, it looks really exciting. I mean we have 2 cross-functional teams planning for both launches and they're not overlapping. I will just say that 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 2 products, and they will be different. There are different call points. And for olezarsen, we know it's a large opportunity, but we're really honing in on 2 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 it's very, very concentrated 50% of the docs actually prescribe 80% of the prescriptions and you can bench it really easily to where the market leader Takeda is, and they have about 50 reps or so that are going after that opportunity. and very well concentrated and sizable. So it is different, but they're 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.

Operator

The next question comes from Konstantinos Biliouris with BMO Capital Markets.

Konstantinos Biliouris

Congrats on the progress. A couple of questions from us. The first one on AD. 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 won and done, they can shrink the market size even further? And then I have a follow-up.

Brett P. Monia

Well, I'll start, and I'll ask Onaiza if she wants to expand or not 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 an unplanned manner in a non-preferred manner as well as the durability. Is it really won and done.
We've heard that for gene therapy. DNA editing truly be won and done as well. And if it's not, can you redose. There's 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 from patients about editing their DNA, to be blunt at an early -- at such an early age when you're thinking about building families and those sorts of things.
So there's a lot of headwind on DNA editing specifically for HAE. As you know, Kostas, we are investing in DNA editing. We have a different strategy for targeted identification and drug development that 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?

Onaiza Cadoret-Manier

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 is appetite for actually taking a DNA edit so early in their lifespan and not knowing what the long-term consequences are major. And then I'll add in a third. I think the third one is what will be the continued remaining unmet need in HAE because we are really going to fulfill that. We have a great product. And again, it is -- I think it's going to be fully satisfied by the time being, get there.

Brett P. Monia

And then you had a second question, Kostas?

Konstantinos Biliouris

Yes. And the second quick one on olezarsen. How are you thinking about the pricing because you are potentially launching into different markets where the size of the targeted population is different. How are you thinking about pricing there in these 2 different populations? And I would assume that the drug will be exactly the same in terms of dosing and all these.

Onaiza Cadoret-Manier

Yes. Yes, it's a good question. We know that we have a rare disease population with FCS and then more prevalent, broader with SHTG. So we don't expect the 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 like 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 the rare disease pricing range at all. Again, as I said earlier, we'll be in the cardiovascular kind of premium pricing range that you see for more prevalent.

Operator

The next question comes from Gena Wang with Barclays.

Huidong Wang

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 2 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 giving future already in the market?

Brett P. Monia

Thanks, Gena. That was quite thorough. These are 3 very different topics, a very good question. So I'll let Onaiza handle the HAE 2-month dosing and the commercial readiness for eplontersen, because the -- but I'll take the Angelman, as a quick answer. There's no -- nothing new to report on timing. The enrollment is going well. And the study 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 readiness?

Onaiza Cadoret-Manier

For HAE, our competitive profile is so strong that we actually don't really need the 2-month dosing as a way to differentiate in the marketplace. We'll wait for the Phase III 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 III.
For eplontersen commercial readiness, lots of work going on, as you can imagine, we're right in that L minus X months of a 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 of really understanding where 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 for 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.

Operator

Next question comes from Luca Issi with RBC.

Luca Issi

I have 2 quick ones. Maybe, Brett, big picture. Can you just talk about how your relationship with Biogen has evolved now that there's a new leadership team in place sounds like (inaudible) is pretty focused on actually containing costs. And obviously, we've seen them discontinuing your collaboration with ataxin 3. So just wondering if the bar for progressing 1/4 molecule is now higher given their focus on cost. Again, any color there would be much appreciated.
And then maybe on APOCIII, circling back on the prior question, can you remind us what your commercial plan ex U.S. for APOCIII? Would you partner the right? Will you use a distributor like (inaudible)? Will you have your own sales force on the ground? Again, any color is much appreciated.

Brett P. Monia

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, a really exciting program to them very important. It's getting all the resources. You can imagine that is needed as they are the Angelman's program as well. We just -- they did a great job in bringing QALSODY through the finish line and onto the market, and it's already launched. So they're 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're 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 we are a top priority for them. Relationship is growing very well.
As far as the ataxin-3 and a bit of a kind of like an ultra-rare disease, if you will, clearly was a portfolio prioritization exercise that was communicated directly to me as the -- was the reason behind the drug being returned, program being returned to Ionis. That's not surprising. As it's probably not -- we know it's not in their sweet spot, or in the areas that they want to focus on. We are evaluating what to do with that program today, whether to keep it or to re-partner it. We have a rich neuro pipeline that's growing that's wholly owned by Ionis, and we will emphasize this pipeline going forward, and we will expand on it as well.
So this also bodes well for Ionis to build out our wholly owned pipeline drugs that we're interested in commercializing come back from Biogen. But the relationship is going strong and we absolutely have no concerns about any programs that are returned to Ionis because for the most of them would love to have them back. And if we don't keep them ourselves, we'll seek to re-partner. APOCIII ex-U.S. commercialization, that's a quite interesting question. It is something we have been talking about.

Onaiza Cadoret-Manier

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, O-U.S. 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 frame.

Brett P. Monia

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

Operator

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

Myles Robert Minter

Again, on olezarsen. I 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 are trying to seek a slight premium pricing range for that product relative to (inaudible)?

Brett P. Monia

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

Onaiza Cadoret-Manier

Yes. It's a good question. We actually tested that hypothesis pretty early in the program, and we continue to for all sorts of payers, as you can imagine. The 500-plus population it has, is severely elevated. It 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 right in line with where the unmet need is and the value proposition of what we bring, again, this 3x magnitude of what's currently available for triglyceride reduction for the severely elevated trig patients with high risk for acute pancreatitis is where the payer focus is. So in there without the cardiovascular study.

Brett P. Monia

Thanks, Myles, and thanks, everybody, for joining us on our call today. Looking ahead and 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, and we're very much looking forward to it. So with that, we'll close. And thank you again, and have a great day, everybody.

Operator

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