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spk02: Good morning and welcome to Iona's first quarter 2023 financial results conference call. All participants will be in a listen-only mode. Should you need assistance, please signal a conference specialist by pressing star then zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star then one on a touchtone phone. To withdraw your question, please press star then two. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Wade Walk, Senior Vice President of Investor Relations, to lead off the call. Please begin, sir.
spk08: Thank you. Before we begin, I encourage everyone to go to the Investor section of the IONIS website to view the press release and related financial tables we will be discussing today, including 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 Haugen, Chief Financial Officer. Eric Swayze, Executive Vice President of Research, Eugene Snyder, Chief Clinical Development Officer, and Oneza Katare, 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 three, 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.
spk14: 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 CALSATI accelerated approval for the treatment of SAG1 ALS. This approval represents a major scientific breakthrough. CALSATI is the first and only approved treatment to target a genetic form of ALS. And with this approval, CALSATI 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 Neurotransform study of Eplon-Tersen in patients with ATTR polyneuropathy. In this study, Eplon-Tersen was shown to halt neuropathy disease progression with approximately half of patients experiencing improvement. in the co-primary efficacy endpoints MNIST plus 7 and Norfolk quality of life. Eplon-Tersen also demonstrated favorable safety and tolerability. Based on the totality of the data, we are confident in Eplon-Tersen'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 22nd of this year. And as Oneza discussed during our webcast last week, we're working hand-in-hand with AstraZeneca to bring this important medicine to the market as quickly as possible. Our two other near-term commercial opportunities, Olazarsen and Donny Delorsen, are also progressing very well. With Olazarsen, we remain on track for data from the phase three 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 Olazarsen. With Donna Doloresen, we're on track to complete enrollment in the Phase 3 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 with seven programs advancing in nine separate indications with the initiation of phase redevelopment of the periversin in chronic HPV. 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.
spk11: Over to you, Richard. Thank you, Brett. As Brett just mentioned, we have met a number of goals in key programs already this year. We believe that the positive data we reported from the NeuroT Transform study demonstrate effluent person's potential to substantially improve outcomes in patients with ATTR polyneuropathy. Eplon-Tersen 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. Eplon-Tersen 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. Eplen-Tersen also showed statistically significant and clinically meaningful benefit across all four secondary endpoints 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 NeuroT Transform study give us even greater confidence for the performance of eplentersin in our ongoing CardioTransform study in patients with ATTR cardiomyopathy. CardioT Transform 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 mid-year. Our broad olisarcin development program for two indications characterized by severely elevated triglycerides, FCS, and severe HTG is also continuing to progress well. The phase three 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 three program designed to evaluate olisarcin and the broader SHTG indication is also continuing to progress. Additionally, our Donna Delorsen development program remains on track. We expect to fully enroll the phase three 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 Donna Delorsen Phase II open-label extension study in patients treated for one year, reinforcing its potential competitive profile, which included rapid onset of action with clinically meaningful improvements in quality of life, durable attack protection, and a continued favorable safety and tolerability profile. Our neurology franchise includes 12 medicines in development, including two in phase three studies and eight in phase two. I would like to spend a couple of minutes highlighting two of these medicines that had important recent updates. As Brett mentioned, we are pleased that the FDA recently approved CALSATI. making it the first and only approved treatment to target a genetic form of ALS. This is a monumental breakthrough for the ALS community. CalSati'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, CALSATI demonstrated a favorable safety profile. CALSATI is under review in the EU, and additionally, the ongoing phase three ATLAS study and presymptomatics.1 ALS study patients is also progressing nicely. We are encouraged by the recent data Biogen presented at the ADPD conference and published in Nature Medicine from the Ionis MAP-TRX Phase 1B study. Our MAP-T medicine, also known as BIB80, is our medicine aimed at reducing the production and aggregation of tau protein associated with disease progression in patients with Alzheimer's disease. Results in early AD, Patients treated for up to 100 weeks showed a rapid, substantial, and sustained reduction in tau pathology as measured by both CSF levels and tau PET imaging. In fact, our MAPT drug is the first to demonstrate this magnitude of a reduction of tau pathology across important brain regions today. Biogen is advancing the phase two study in patients with early AD. which includes two different dose cohorts dosed every six months and one dose cohort dosed every three months. Our MAPT drug is just one example of advances we are making with our technology to potentially extend duration and reduce dosing frequency for CNS diseases and even more broadly. Our late stage pipeline expanded this year to seven drugs, advancing in a total of nine separate indications with the start of a pivotal program for Bifirversin in patients with chronic HPV. We expect our late stage pipeline to expand further this year when Roche advances Ionis FBLRX into a phase three study for IgA nephropathy. We recently took steps to further focus our R&D efforts and prioritize our pipeline with the discontinuation of two programs, Simdiluricin in acromegaly and Sampabluricin 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 sapoblursin 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. Eplon-Tersen approval and Phase III data for olisarcin, our next potential medicine to launch after Eplon-Tersen. 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.
spk05: 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, with approximately half from our commercial products and half from numerous partner programs. Our operating expenses and operating loss for the first quarter increased over the same period last year as we advanced our commercial readiness activities and advanced our pipeline, especially our late-stage programs. We ended March with substantial cash and investments of $2.3 billion, enabling us to continue making investments to create future growth opportunities. We earned $50 million in Spinraza royalty revenue based on global product sales of $443 million in the first quarter. Our Spinraza royalties reset annually. And based on our revenue expectations, we anticipate reaching the highest royalty tier by mid-year. Additionally, we continue to record 100% of our Spinraza royalties as commercial revenue under our royalty farmer transaction. While Spinraza product sales were slightly lower in the first quarter compared to last year, we in 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 lifecycle management program. Based on all these efforts, we in 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 CALSATI US 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 three studies were either fully enrolled or approaching full enrollment, which resulted in higher R&D expenses. Additionally, as we continued to prepare to launch F1 Turson, Olazarsson, and Donny DeLorsen, 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 Pella Carson 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 non-cash 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 three studies, We estimate our full-year R&D expenses will increase between 20% and 25% year-over-year, excluding the metagenomic 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 Appalancherson, Olazarsen, and Donny Delorsen. 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 revenues. 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.
spk14: Thank you, Beth. We anticipate continuing our positive momentum as we advance our key priorities with additional important regulatory and late-stage pipeline events still to come this year. We're well on our way to achieving our goal of delivering an abundance of new genetic medicines to the market. We just added CalSade to our commercial portfolio, and with a December PDUFA date, we could also add Eplon-Tersen 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 Eplon-Tersen with AstraZeneca in patients with ATTR polyneuropathy is in sight, with our independent launches for Olizarsen and Donny-Tolorsen 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.
spk02: Thank you. We will now begin the question and answer session. To ask a question, you may press star then 1 on your touchtone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star then 2. At this time, we will pause momentarily to assemble our roster. Our first question comes from Joseph Stringer with Needham and Company. Please go ahead.
spk09: Hi. Thanks for taking our questions. Just wanted to get any additional color on the two program discontinuations. You mentioned it didn't fit your target product profile, but just curious, was it sort of efficacy threshold that didn't meet, or were there any of any additional color on that would be helpful. Thank you.
spk14: Sure, Joey. Happy to. So, no safety issues at all. The safety profile for sapoblursin in beta thalassemia intermedia and simbolircin in acromegaly were clean, pristine. It was all about efficacy. In both of these cases, these two drugs were being tested in a scenario for the first time, no one's ever targeted, focusing first on acromegaly to your question, growth hormone receptor 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, you know, substantially, that it could be a competitive treatment for acromegaly. We tested it 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 it wasn't good enough. And considering the richness of our pipeline, it just didn't clear the bar. So we're moving on from acromegaly. Sapa-Blurcin is more interesting in my view. Sapa-Blurcin we're developing for multiple indications. The first was beta thalassemia intermedia. As a reminder, we showed that Sapa-Blurcin targeting TMPR6, GALNAC targeting strategy showed really quite remarkable of efficacy in, or target engagement, I should say, in our phase one normal volunteer study. We reported that a couple years ago. We showed very significant elevations in hepcidin levels, which is what we're trying to achieve with, by targeting TMPR6. 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, TMPR6 is a pathway, pathway target. It's not a genetically validated target. Keep that in mind. And we didn't see the biology translate from preclinical to clinical in that setting. With that said, so it didn't meet the product profile. With that said, in parallel, we advanced into polycythemia varum. I'm very pleased to say that we're very encouraged by some of the initial data we're seeing in PB. PB seems, the biology seems to be very different by target, with targeting TMPR6 versus beta thalassemia intermediate. 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 are the tension on the drugs that are going to bring the greatest value. And that drug for acromegaly and that indication for sapoplairsin did not meet the bar.
spk07: Please, that's very helpful.
spk09: And thank you for taking our question.
spk07: You're welcome.
spk02: The next question comes from Jessica with JP Morgan. Please go ahead.
spk03: Great. Thanks for taking my question. Questions on eplontersin. First, with the IRA changes to Part D, can you talk about how you think about the annual out-of-pocket costs of Eplen-Turcin 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 Eplen-Turcin, I'm curious what you'll be watching for when the agrametis attribute data reads out this summer. Thanks.
spk14: Thank you, Jess. Great questions. And as you would take the IRA, Eugene, maybe you could talk a little bit about data readouts from competitor programs in CM. Sure.
spk04: Sure. Hi, Jess. So, you know, first of all, it's important to understand the payer mix as we're going into the marketplace. So, we're estimating about a third of the patients in polyneuropathy are Medicare. Two-thirds will be commercial, so they will not be subjected to the Medicare Part BD design you're talking about. They'll go through the normal, hopefully, you know, Tier 2, Tier 3 copays, which we obviously will offer some level of copay relief with copay cards, as most manufacturers do. On specifically the Part D path for Eplon-Turcin, for the third of the patients that go through it. Their patient out-of-pocket costs starting in 2024 for all Medicare Part D recipients will be capped at $2,000. As you know, currently it goes into, until it gets to catastrophic care, it's, you know, 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, you know, we still expect to provide, you know, 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, you know, 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 know, you really have some, 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, you know, 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 a center of excellence. It's a really far drive for many of these patients as well. And that ability to self-administer as home is a really, continues to be a really big driver of preference for a blunt person.
spk14: Eugene, what are you looking for, what's most interesting in the upcoming acaramidus readout?
spk13: Well, the most interesting thing I think 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-tifamidis, 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 also seeing the treatment effect. This study now has followed these patients over a number of years, so this is going to be the first readout, as I said, for the population, which we believe is more reflective of what the current population of newly diagnosed patients may look like.
spk14: 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'll also be interesting to see how a stabilizer, you know, looks up and matches up to some of the early data we've seen with the silencer as well.
spk07: That'll be interesting. Next question.
spk02: The next question comes from with Wells Fargo. Please go ahead.
spk16: Hi. Thanks for taking the questions and congrats on the progress. Maybe two questions here. Maybe one to follow up on what you're just talking about, about cardiomyopsy study, what to look out for from the competitor study. I was wondering with your CardioTransform study nearing completion of enrollment. Could you provide an update on a mix of on tefamidus versus tefamidus 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, you know, look at, compare different studies and anticipate the event rate with a relatively modern comparator. And lastly, I have one person, polyneuropathy, wondering about your pricing strategy that you and AstraZeneca is, I assume, working on, whether it would be a parity strategy with competitor drugs or whether it could be a competitive price. Thank you.
spk14: Thank you, Ann, and all great questions. So when we upsized the study, the CardioTransform 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 and detection and awareness of disease. The second was to ensure that we had about a 50-50 well-balanced usage in the study of tefamidus versus naive patients. And then thirdly, to increase the percentage of patients that are variant versus wild type. Obviously, we're coming close to completing the study, and we're very confident 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 tefamidus 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. As far as the blinded event rates, we're monitoring those very carefully. And that, too, is doing it, is performing very well as we had hoped it would when we upsized the study and prioritized sites when we upsized the study where we think patients would be, you know, 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, you know, 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, Oneza, would you like to comment on that?
spk04: Yeah, you know, Yanen, really simply, you know, we're going to price according 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. 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.
spk06: Great. Very helpful. Thank you. Thank you.
spk02: The next question comes from Mike Oles with Morgan Stanley. Please go ahead.
spk17: Yep. Hey, guys, thanks for taking the question. Maybe just a quick follow-up on cepablircin, 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 two different indications. Thanks.
spk14: We thought, thanks, it's a very good question. We thought that there could be some read-through from beta-thal to PV because our objectives for both studies was to elevate in a 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 saprobluris and TMPR6 drug. I wish I had an answer for why the biology is different. We don't. What was really surprising, was the preclinical data in beta thalassemia intermedia, which we published on extensively in models that we thought were predictive of beta thalassemia intermedia. I mean, they had all the right signs and, you know, profiles of those animal models was very strongly similar to the human condition. It 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.
spk11: 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.
spk14: Yeah, a great point, Richard, and if I could expand on your expanding on me. You know, we 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 chose this target and why we pursued it for various indications. It looks like it's going to be a low-dose treatment for indications we develop.
spk17: Got it. Very helpful. Thank you.
spk02: The next question comes from Yael Jen with Laidlaw and Company. Please go ahead.
spk19: Good morning, and thanks for taking the question. My first question is regarding Zops and FTS. I know the data will be presented later this year. I'm just curious what you guys have learned from the prior experience from ReliverArt and in terms of the future sort of steps that will... further sort of improve the commercial outlook on other aspects of this drug? Then I have another follow-up.
spk08: Richard?
spk11: Yeah, that's a great question. And looking back at our not only previous but current experience with Rayway Libra, 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, APOC3 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 the learnings that we have even today from our whey Libra experience.
spk14: Yeah. And I'll just add to that, Richard, that olivarcin is a more potent molecule and we expect even deeper reductions in A plus C3 and triglycerides than we saw with the early generation whey Libra. of course, with a pristine safety profile like we're seeing for all of our Likas today. And the other thing is that we're going to be paying attention to is in addition to patients just feeling better, reductions potentially, you know, strong trends hopefully in pancreatitis event reductions. You know, with whey liver, 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 A plus C3. And we're going to be very, we're going to want to replicate that. And then you had another question, Yale?
spk19: Yes. Just in terms of sufferers and PV. First of all, is the data will be reported later this year? And secondly, that in terms of optimist, if it's a positive optimist for you know, a pivotal study, what do you think the approvable endpoint will be used or contemplated? And thanks.
spk14: So maybe Eugene needs to talk 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. We're, again, in dose ranging. I wouldn't rule it out, but 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, what do you look at?
spk13: It's a good question. There's a number of things we're going to explore 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 of the main clinically significant endpoint, but there's a number of other exploratory endpoints where 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. You want to add to that?
spk04: Yeah, I'll just add that it's a really attractive commercial opportunity. There's 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, you know, 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.
spk19: Maybe just one more here, which is that, is this, you're seeking for first line or second line? Yeah, thanks. All right.
spk04: 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 too restrictive, but there might be a step through in this.
spk07: Okay, great. Thanks a lot. I appreciate it and congrats.
spk02: The next question comes from Yaron Verber with TD Cowen. Please go ahead.
spk15: Hi, guys. This is Brendan for Yaron. Thanks for taking the question. Just a couple quick ones from us, really on HAE here. Can you just remind us, are you prepared to file in the U.S. next year if the data hits in the first half so we could potentially see zoning dilution 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. Thanks.
spk14: Yeah. The first question, the second question I'll ask, and these are 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.
spk04: Yeah, 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 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, our 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, you know, beats kind of what standard of care is right now in the marketplace, which is Q2 weeks.
spk07: Next.
spk02: The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.
spk01: Thanks for taking our question. Congrats on the progress. This is Tommy on for Salveen. So now that we've seen positive data from two phase three Alzheimer's studies, how are you thinking about the ABD 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 and these indications where oral treatments may already be available? Thank you.
spk14: Sure. Eric, you want to comment on what we're doing in dementia and how the recent successes? Sure.
spk13: Well, I think so certainly for AD patients, positive data is fantastic to see, and so Clearly, they're obviously different mechanisms, right? So the therapies with positive data and the one from Lily 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 Bib80 addresses. So we think 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 ADPD 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, BIM-80. 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 six-month dosing and four-month dose, and importantly, dosing intervals of two different doses of the drug to see if it really makes a difference. And lowering that tau pathology can make a difference in 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.
spk14: I think it's a great program. The intracellular tau hypothesis, which hasn't been tested before. And we have a great-looking drug in . The other thing is, just to expand on that a bit more, you know, we have several programs, rich programs 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, Tommy, can you repeat your second question? I'm sorry.
spk01: 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?
spk14: Yep, yep. Oneza?
spk04: Yeah, you know, 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, what's the value proposition we're bringing, you know, to this particular disease stated unmet need and then price accordingly to that. So, I, we have done some really good work if you're talking about a Lazarsin in the broader prevalent SHTG market and we do see really good pricing potential in the, 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 very compelling value proposition to price in that more CV premium range.
spk07: Thanks, Tommy. Thanks, Anaysa.
spk02: The next question comes from Paul Mattes with Stifel. Please go ahead.
spk18: Hi, this is James on for Paul. Thanks for taking our question. Maybe just a kind of broader high-level question. You know, assuming Olazarsson hits in SHTG and Donald DeLoreson hits in HAE, what do you think IONIS looks like in 2025, 2026? You know, specifically with respect to what your, you know, Salesforce could look like and what type of synergy there would be between, you know, for those two assets, if at all. Any thoughts there would be great. Thanks.
spk14: Well, I'll just start. I'll ask Vanessa to address her sort of vision for the build of our commercial organization, something we're obviously working on and preparing for launches in the near term with Olazarsen and Donny Doloresen. But we're expecting, you know, a half dozen or so new drugs on the market in that timeframe. James, and, you know, that includes, of course, wholly owned and drugs we commercialize as well as our partner, and we're pretty confident in that. But, Anaisa, you want to talk a little bit about the growth?
spk04: Yeah, it looks really exciting. I mean, we have two cross-functional teams planning for both launches, and they're not overlapping. I will just say that, you know, behind the scenes of all the commercial infrastructure that you need, there are a lot of synergies, right? So what we're building for even for Eplon-Turson with our patient services and hubs and where we have our field medical team, we're thinking about how we bring them forward to our next independent launches. And then all the systems that go behind it as well. And we'll see lots of synergy there. But where we will see differences is obviously in our sales teams eventually for these two products, and they will be different. They're different call points. And for olosarcin, we know it's a large opportunity, but we're really honing in on two specialties, which is cardiology and endocrinology. And these are very severely elevated triglycerides, so this is not a place where a lot of PCPs or GPs are are actually prescribing, they're referring out to those specialties. So we're working on the sizing of that team. And then for Donna DeLorsen, it's allergist 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, Kakeda, is and they have about 50 reps or so that are going after that opportunity. and very well concentrated and sized well. So it is different, but they're really good ways that we're thinking about, you know, ensuring that the teams get the focus that they need and are calling on the right docs with the most efficient model.
spk07: Thank you. Thanks, James.
spk02: The next question comes from Costos Bilioris with BMO Capital Markets. Please go ahead.
spk21: Hello, everyone. Thanks for taking our questions and congrats on the progress. A couple of questions from us. The first one on AJE. Given the relatively small size of the market there, how are you thinking about the competitive gene editing therapies or gene therapies, which if they are really one and done, they can shrink the market size even further? And then I have a follow up.
spk14: Well, I'll start, and I'll ask Onesa if she wants to expand or not. But, you know, HA 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, you know, the safety, the off-target potential on, you know, to potentially permanently develop to edit DNA in an unplanned manner, in a non-preferred manner, as well as the durability. Is it really one and done? We've heard that for gene therapy. Will DNA editing truly be one 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, you know, 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, you know, there's real concerns from patients about editing their DNA, to be blunt, at such an early age when they're thinking about building families and those sorts of things. So there's a lot of headwind on DNA editing specifically for HAE. As you know, Costas, we are investing in DNA editing. We have a different strategy for target identification in drug development. 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, Vanessa?
spk04: No, I think you summarized it well. I would say, you know, 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 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, you know, again, I think it's going to be fully satisfied by the time they get there.
spk14: And then you had a second question, Kyle?
spk21: Yeah, and a second quick one on all this I've said. 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 two different populations? And I would assume that the drug would be exactly the same in terms of dosing and all these. Thank you.
spk04: Yeah. Yeah, it's a good question. You know, we know that we have a rare disease population with FCS and then a more prevalent broader with SHTG. So we don't expect the rare disease pricing, you know, obviously for the broader population. We are working through the pricing strategy in terms of what our launch pricing will be, but, you know, stay tuned. We're thinking through a lot of, like, different strategic ways to get at it, but you should know if you're, you know, looking at the broader population that we don't expect that, obviously, to be in rare disease pricing range at all. Again, as I said earlier, it will be in the cardiovascular kind of premium pricing range that you see for more prevalent diseases.
spk07: Thank you very much. Very helpful.
spk02: The next question comes from Jenna Wong with Barclays. Please go ahead. Thank you.
spk20: Three very quick questions. One more question regarding the HAE program. You already described quite a lot of clinical profile you're looking for. Do you also consider once every two months dosing as a to-go choice to become more competitive? My second question, quick question, is regarding the Enderman program. What is the expected timing for data update, and what kind of safety signals you have seen so far? Lastly, very quickly, commercial readiness for Eplon-Tersen. Is AstraZeneca taking full charge, and what is the marketing strategy giving Ambutro already in the market?
spk14: Thanks, Gina. That was Quite thorough. This is three very different topics, but very good questions. So I'll let Oneza handle the HAE two-month dosing and the commercial readiness for Eplon-Tersen. But I'll take the angel one just as a quick answer. There's 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. There are no concerns for the Angelman's program. Oneza, bimonthly dosing, HAE, and lunch readiness?
spk04: You know, for HAE, our competitive profile is so strong that we actually don't really need the two-month dosing as a way to differentiate in the marketplace. We'll wait for the phase three data, but certainly, you know, it's an option for us to make that available for physicians and for patients if need be, but it'll all be data dependent on these three. For Eplon tourism commercial readiness, lots of work going on. As you can imagine, we're right in that, you know, 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's 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 the centers of excellence currently are and where they could be in the future and really trying to hit both. It's an and versus an or for us, and we have the ability to do that with the scale of AstraZeneca.
spk13: Okay.
spk04: And then I would say, you know, 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.
spk07: Thanks, Gina.
spk02: The next question comes from Luca SC with RBC. Please go ahead.
spk10: Oh, great. Thanks so much for taking my questions. I have two 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 V. Bakker is pretty focused on actually containing costs, and obviously we've seen them discontinue your collaboration with Taxin-3. So just wondering if the bar for progressing partner molecule is now higher given they're focused on cost. Again, any call there will be much appreciated. And then maybe on APOC3, circling back to the prior question, can you remind us what's your commercial plan, XUS, for APOC3? Will you partner the rights? Will you use a distributor like Sobe? Will you have your own sales force on the ground? Again, any caller, much appreciated. Thanks so much.
spk14: Great. Second question for Onesa. On the first one, Luca, thank you for the questions. Our... Our relationship with Biogen is as strong as it has ever been. It's a great relationship. You know, we're very pleased by the fact that Biogen is prioritizing very highly while working with us programs like the BIB 80 Tau program that Eric commented on before. 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, you know, they did a great job in bringing CalSati 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 tax in three and, you know, a bit of a kind of like a ultra rare disease, if you will, clearly was a portfolio prioritization exercise. That was communicated directly to me as the reason behind the drug program being returned to Ionis. That's not surprising, as we know it's not in their sweet spot where the areas that they want to focus on. We are evaluating what to do with that program today, whether to keep it or to repartner it. We have a rich neural 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 of drugs that we're interested in commercializing and come back from Biogen. But the relationship is growing strong, and we absolutely have no concerns about any programs that are returned to IONIS because for the most of them, we'd love to have them back. And if we don't keep them ourselves, we'll seek to repartner. APOC3 XUS commercialization, that's an interesting question.
spk04: Yeah, it is.
spk14: It's something we haven't been talking about much.
spk04: 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 SCS and for severe hypertriglyceridemia. Our plans, current plans, OUS, is to look for a partner. The type of partnership is where you're going for has not yet been determined, but it's important to note, like, we are 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 crisis.
spk14: We're still working on that. Stay tuned. Thanks. And I think we have time for one last question before wrapping up.
spk02: Yes. Our last question for today comes from Miles Minter with William Blair. Please go ahead.
spk12: Thanks for sneaking me in. Again, on Olasasin, just wanted your updated thoughts on the potential need, if any, for a cardiovascular outcome study in severe hypertriglyceridemia. You know, maybe not so much for regulatory approval, but certainly for reimbursement, just given the comments that it seems like you're trying to take a slight premium pricing range for that product relative to the oral.
spk14: Yep. Since it's focused on reimbursement, I'll ask Gonesa to take that as well.
spk04: Yeah, that'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, it's severely elevated, has a clear regulatory path, as you said, without a CVOT study. And given the unmet need and the fact that this is really a different population, And we're looking for different risks for many of these patients, such as acute pancreatitis risk. This is not a place where even payers are wanting or expecting a CVOT from a reimbursement perspective. So, you know, it's going in and 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 these severely elevated trich patients with, you know, high risk for acute pancreatitis is where the payer focus is. So in there without the cardiovascular studies offering.
spk14: Thanks, Miles, and thanks everybody for joining us on our call today. Looking ahead, we plan to continue our momentum by delivering additional key updates, progress against our objectives on the commercial front, the pipeline, and on our technology. And we're going to provide updates throughout the second half of the year, 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.
spk02: The conference is now concluded. Thank you for attending today's presentation. You may all now disconnect.
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