Ionis Pharmaceuticals - Q1 2023
May 3, 2023
Transcript
Operator (participant)
Good morning, and welcome to Ionis 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 touch-tone 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 Walke, Senior Vice President of Investor Relations to lead off the call. Please begin, sir.
Wade Walke (SVP of Investor Relations)
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 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. With that, I'll turn the call over to Brett.
Brett Monia (CEO)
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. With this approval, QALSODY joins 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-Diabetic Neuropathy. 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 the PDUFA date of December 22nd of this year. As Onaiza discussed during our webcast last week, we're working hand-in-hand with AstraZeneca to bring this important medicine to the market as quickly as possible.
Our two other near-term commercial opportunities, olezarsen and donidalorsen, are also progressing very well. With olezarsen, we remain on track for data from the phase III Balance study in FCS in the second half of this year. 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. Our robust late-stage pipeline continues to expand, now at seven programs advancing in nine 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. 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 Geary (Chief Development Officer)
Thank you, Brett. As Brett just mentioned, we have met a number of goals in key programs already this year. We believe that the positive data we reported from the NEURO-TTRansform study demonstrate eplontersen's potential to substantially improve outcomes in patients with ATTR polyneuropathy. Eplontersen met all co-primary and all secondary efficacy endpoints, demonstrating consistent benefit for ATTR polyneuropathy patients across a range of important neuropathy and quality of life measures. Eplontersen demonstrated robust and sustained reductions in serum TTR and significant improvements in measures of neuropathy and quality of life with a substantial number of patients demonstrating improvement at both week 35 and week 66. Eplontersen also showed statistically significant and clinically meaningful benefit across all four secondary endpoints. 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 mid-year. Our broad olezarsen development program for two indications characterized by severely elevated triglycerides, FCS, and severe HTG, is also continuing to progress well.
The phase III BALANCE-FCS study is fully enrolled, and we remain on track for data in the second half of this year. 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 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 2 medicines in phase III studies and 8 medicines in phase II. 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 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 in presymptomatic SOD1-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-MAPTRx phase IB study. Our MAPT medicine, also known as BIIB080, is our medicine aimed at reducing the production and aggregation of tau protein associated with disease progression in patients with Alzheimer's disease. Results in early AD patients treated for up to 100 weeks showed a rapid, substantial, and sustained reduction in tau pathology, as measured by both CSF levels and tau PET imaging. In fact, our MAPT drug is the first to demonstrate this magnitude of a reduction of tau pathology across important brain regions to date.
Biogen is advancing the phase II study in patients with early AD, which includes two different dose cohorts dosed every six months, and dose 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 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 two programs, cimdelirsen in acromegaly and sapablursen in beta thalassemia.
With both drugs, we saw evidence of good target engagement and favorable safety and tolerability, but efficacy results in the mid-stage studies did not meet our minimum target product profile to justify further development. We continue to advance the phase II study of sapablursen for polycythemia vera. 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. With that, I'll turn the call over to Beth.
Beth Hougen (EVP, Finance and CFO)
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 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 earn $50 million in SPINRAZA royalty revenue based on global product sales of $443 million in the first quarter.
Our SPINRAZA royalties reset annually. 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 Pharma transaction. While SPINRAZA product sales were slightly lower in the first quarter compared to last year, we and Biogen continued to see signs of stabilization in Biogen's patient base. Importantly, Biogen remains focused on expanding into new markets and expanding existing markets while also generating important efficacy data from its robust lifecycle management program. Based on all these efforts, we and Biogen believe SPINRAZA can return to growth. We earned R&D revenue of $63 million in the first quarter for advancing numerous programs partnered with Biogen and AstraZeneca, among others. Already in the second quarter, we earned a $16 million milestone payment for QALSODY U.S. approval.
Our Non-GAAP operating expenses increased in the first quarter compared to the same period last year. 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. 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. We recorded a long-term liability, which we will reduce when we make payments to Royalty Pharma. 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 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 OpEx to grow modestly. Additionally, by keeping more programs for ourselves, we anticipate a greater proportion of commercial revenues compared to R&D revenues. 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. With that, I'll turn the call back over to Brett.
Brett Monia (CEO)
Thank you, Beth. We anticipate continuing our positive momentum as we advance our key priorities with additional important regulatory and late-stage pipeline events still to come this year. We're well on our way to achieving our goal of delivering an abundance of new genetic medicines to the market. We just added QALSODY to our commercial portfolio. With a December PDUFA date, we could also add eplontersen late this year. 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.
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. With that, we'll now open it up for questions.
Operator (participant)
Thank you. We will now begin the question and answer session. To ask a question, you may press star then one 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 two. At this time, we will pause momentarily to assemble our roster. Our first question comes from Joseph Stringer with Needham & Company. Please go ahead.
Joseph Stringer (Senior Analyst)
Hi, thanks for taking our questions. Just wanted to get any additional color on the two program discontinuations. 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? Any additional color on that would be helpful. Thank you.
Brett Monia (CEO)
Sure, Joey. Happy to. 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 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. 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 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. We saw some reductions, but it wasn't good enough. Considering the richness of our pipeline, it just didn't clear the bar. We're moving on from acromegaly. Sapablursen is more interesting in my view. Sapablursen we're developing for multiple indications. The first was beta thalassemia intermedia. As a reminder, we showed that sapablursen targeting TIMP-6, GalNAc targeting strategy, showed 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 years ago.
We showed very significant elevations in hepcidin levels, which is what we're trying to achieve with, by targeting TIMP-6. 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, TIMP-6 is a pathway target. It's not a genetically validated target. Keep that in mind. We didn't see the biology translate from preclinical to clinical in that setting. With that said, it didn't meet the product profile. With that said, in parallel, we advanced into polycythemia vera, 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 TIMP-6 versus beta-thalassemia intermedia. 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 gonna bring the greatest value. That drug for acromegaly and that indication for sapablursen did not meet the bar.
Joseph Stringer (Senior Analyst)
Great. That's very helpful, and thank you for taking our question.
Brett Monia (CEO)
You're welcome.
Operator (participant)
The next question comes from Jessica Fye with JPMorgan. Please go ahead.
Jessica Fye (Managing Director, Equity Research Analyst – Biotechnology)
Great. Thanks for taking my question. Question on eplontersen. First, with the IRA changes to Part D, can you talk about how you think about the annual out-of-pocket cost 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? Also related to eplontersen, I'm curious what you'll be watching for when the Akrimetis ATTRACT data reads out this summer. Thanks.
Brett Monia (CEO)
Thank you, Jess. Great questions. Anas, you would take the IRA. Eugene, maybe you could talk a little bit about data readouts from competitor programs in CM.
Onaiza Cadoret-Manier (Chief Global Product Strategy and Operations Officer)
Sure. Hi, Jeff. You know, first of all, it's important to understand the payer mix as we're going into the marketplace. We're estimating about a third of the patients in polyneuropathy are Medicare. Two-thirds will be commercial, they will not be subjected to the Medicare Part B/D design you're talking about. They'll go through the normal, hopefully, you know, tier two, tier three 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 eplontersen for the third of the patients that go through it, their patient out-of-pocket costs starting in 2024 for all Medicare Part D recipients will be capped at $2,000.
As you know, currently, it goes until it gets to catastrophic care, it ranges in the $20,000s. It's gonna come down 10-fold for these patients, which is a huge positive change for patients in Medicare Part D. I would say that we still expect to provide access for these patients to the foundations for the disease, for TTR disease 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. The office costs have to be considered as well because, you know, 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. 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 at home is a really continues to be a really big driver of preference for eplontersen.
Brett Monia (CEO)
Eugene, what are you looking for? What's most interesting in the upcoming Akrimetis readout?
Eugene Schneider (EVP, Chief Clinical Development Officer)
Well, the most interesting thing to me would certainly be the effect that we see on outcomes in a modern trial. By modern, I mean the trial that really was conducted post tafamidis, sort of the last couple of years relative to what was seen in the past. I think the most interesting bit for me would be to see the background rate in placebo arm, not even the active arm, although, of course, we're all focused on also seeing the treatment effect. This is the study now has followed these patients over a number of years.
This is going to be the first readout, as I said, for the, for the population, which we believe is more reflective of what the current population of newly diagnosed patients may look like. Whether or not the patients indeed are more mild than what they were in the placebo group compared to the ATTRACT study. 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. That'll be interesting. Next question.
Operator (participant)
The next question comes from Yanan Zhu with Wells Fargo. Please go ahead.
Yanan Zhu (Senior Analyst, Biotechnology Equity Research)
Hi. Thanks for taking the questions, and congrats on the progress. On eplontersen, maybe two questions here. Maybe one to follow up on what you're just talking about cardiomyopathy study, what to look out for from the competitor study. I was wondering, with your Cardio-Transform study nearing completion of enrollment, could you provide an update on a mix of on tafamidis versus tafamidis-naive patients in terms of proportions, and any update on the ongoing blinded event rate? 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 competitor.
Lastly, on eplontersen polyneuropathy, wondering about your pricing strategy that you and AstraZeneca I assume, working on, whether it would be a parity strategy with competitor drugs or whether it could be a.
Brett Monia (CEO)
Mm-hmm
Yanan Zhu (Senior Analyst, Biotechnology Equity Research)
... you know, a competitive price. Thank you.
Eugene Schneider (EVP, Chief Clinical Development Officer)
Thanks, Yanan. All great questions. 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 and detection and awareness of disease.
Brett Monia (CEO)
The second was to ensure that we had about a 50-50 well-balanced usage in the study of the tafamidis versus naive patients. Thirdly, to increase the percentage of patients that are variant versus wild type. Obviously, we're coming close to completing this study, and we're very confident in our decision to have upsized the study to around 1,400 patients, and we're gonna be wrapping up enrollment very soon. We're well on our way there, of course. 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. That's well in hand.
As far as the blinded event rates, we're monitoring those very carefully, and that too 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, you know, sicker, wouldn't have such a high percentage of mild disease. 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, I don't think we're gonna be rushing to do that.
As far as pricing strategy, Onaiza, would you like to comment on that?
Onaiza Cadoret-Manier (Chief Global Product Strategy and Operations Officer)
Yeah. You know, Manan, really simply, you know, we're gonna price accordingly to where we believe we're gonna get the best and strong access and coverage for our patients. That work is ongoing right now with AstraZeneca. In terms of your comment on Purity pricing, it's just a reminder that we're launching in multiple markets outside of the U.S., where we will be first. We will be setting the price in those markets as well. Those are both going into consideration. 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.
Yale Jen (Senior Managing Director, Senior Biotech Analyst)
Great. Very helpful. Thank you.
Brett Monia (CEO)
Thank you.
Operator (participant)
The next question comes from Mike Ulz with Morgan Stanley. Please go ahead.
Mike Ulz (Executive Director of Biotechnology Equity Research)
Yep. Hey, guys. Thanks for taking the question. Maybe just a quick follow-up on sapablursen, specifically in PV. I guess, do you anticipate any read-through to PV from the beta-thalassemia 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.
Brett Monia (CEO)
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 in a hepcidin production in a disease that's really caused by very low or non-existent hepcidin levels. 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 to. We think this bodes really well for other indications that we're thinking of for our sapablursen TIMP-6 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. Didn't happen. We were surprised. I really wish we knew the biology, what was going on there more. What I could 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. It's just there's something more complex about that patient population.
Richard Geary (Chief Development Officer)
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. In fact, the sensitivity in the PV patients, at least in the early look, seems to think we may be driving doses even lower.
Brett Monia (CEO)
Yeah.
Richard Geary (Chief Development Officer)
Big margins.
Brett Monia (CEO)
Yeah. We, a great point, Richard. 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. As Richard said, even though we pushed the dose, the safety was pristine. We came into another indication, we realized that we didn't need that dose. We're looking at the dose is gonna 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 gonna be a low dose treatment for indications we developed.
Mike Ulz (Executive Director of Biotechnology Equity Research)
Got it. Very helpful. Thank you.
Operator (participant)
The next question comes from Yale Jen with Laidlaw & Company. Please go ahead.
Yale Jen (Senior Managing Director, Senior Biotech Analyst)
Good morning, thanks for taking the question. My first question is regarding olezarsen in FCS. I know the data will be presented later this year. I'm just curious, what you have, 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 on other aspects of this drug. I have another follow-up.
Brett Monia (CEO)
Richard?
Richard Geary (Chief Development Officer)
Yeah. That's a great question, looking back at our not only previous but current experience with WAYLIVRA, we have really nice growth in the commercial space. I think what's really driving that are not only the significant triglyceride-lowering activity of, you know, this approach, APOC3 inhibition, but what appears to be a very strong connection to the downstream events of pancreatitis. Patients are feeling better, functioning better, all of these things drive, obviously, hopefully, commercial. That's the, that's the learning I think that we've gotten and the learnings that we have even today from our WAYLIVRA experience.
Brett Monia (CEO)
Yeah. I'll just add to that, Richard, that olezarsen is a more potent molecule, and we expect even deeper reductions in APOC3 and triglycerides than we saw with the early generation WAYLIVRA. Of course, with a pristine safety profile like we're seeing for all of our licas to date. The other thing is that we're gonna be paying attention to is, in addition to patients just feeling better, reductions potentially, you know, and strong trends, hopefully, in pancreatitis event reductions. You know, with WAYLIVRA, we saw reductions in liver fat. That's important too, and we'll be looking at that as well because, again, we're seeing greater reductions in APOC3, and we're gonna wanna replicate that. You had another question, Yale?
Yale Jen (Senior Managing Director, Senior Biotech Analyst)
Yes. Just in terms of tafamidis and PV. First of all, is the data will be reported later this year? Secondly, that in terms of optimism, if it's a positive optimism for, you know, a pivotal study, what do you think the approvable endpoint will be used or contemplated? Thanks.
Brett Monia (CEO)
Maybe Eugene, you can talk a little bit about what an approvable endpoint would be for PV. We don't know if we're gonna 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 gonna have to really figure out the dose and look at what the profile is. I'll leave it at that. Eugene, what do you look at that?
Eugene Schneider (EVP, Chief Clinical Development Officer)
Yeah. It's a good question. There's a number of things we're gonna 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 the kinda the main clinically significant endpoint. 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. 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 Monia (CEO)
Onaiza, you wanna add to that?
Onaiza Cadoret-Manier (Chief Global Product Strategy and Operations Officer)
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. 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. We do believe that both things are gonna be really important.
Yale Jen (Senior Managing Director, Senior Biotech Analyst)
Okay. Maybe just one more here.
Brett Monia (CEO)
Thank you, Yale.
Yale Jen (Senior Managing Director, Senior Biotech Analyst)
Which is that, you're seeking for first line or second line impact? Sorry.
Onaiza Cadoret-Manier (Chief Global Product Strategy and Operations Officer)
I think that's gonna be a bit of. I think it would be first line if there were no payers involved. 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 as too restrictive. There may be a step through in this.
Yale Jen (Senior Managing Director, Senior Biotech Analyst)
Okay, great. Thanks a lot. Appreciate it, and congrats.
Operator (participant)
The next question comes from Yaron Werber with TD Cowen. Please go ahead.
Speaker 19
Hi, guys. This is Brendan on 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 donidalorsen sales maybe starting in 2025? 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.
Brett Monia (CEO)
Yeah. The first question, the second question I'll ask Onaiza to address. The first question is easy to 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 (Chief Global Product Strategy and Operations Officer)
Yeah. We, 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. The 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 early data, which is also in testing, reading out really well, as an important point, our duration of activity and our rapid onset. All of those are really important, best-in-class profile features. Of course, our Q1 monthly, you know, beats kind of what standard of care is right now in the marketplace, which is Q2 weeks.
Brett Monia (CEO)
Thanks, Onaiza. Next.
Operator (participant)
The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.
Speaker 17
Thanks for taking our question, congrats on the progress. This is Tommy on for Salveen Richter. Now that we've seen positive data from two phase III Alzheimer's studies, how are you thinking about the ABD and any read-through? 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? Thank you.
Brett Monia (CEO)
Sure. Eric, you want to comment on what we're doing in dementia and how the recent successes stack?
Eric Swayze (EVP, Research)
Sure. Well, I think so certainly for AD patients, positive data is fantastic to see. Clearly, there are obviously different mechanisms, right? 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. 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. 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, BIIB080. 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 importantly, dosing intervals of two different doses of the drug to see if it really makes a difference. Lowering that tau pathology can make a difference in clinical outcomes. 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 Monia (CEO)
Yeah. 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, you know, we have several programs, a rich program in programs in dementia, that are coming behind tau. So stay tuned for those in the, in the, in the future. Our whole bet is not on just tau, although we're very excited about it, as is Biogen. Tommy, can you repeat your second question? I'm sorry.
Speaker 17
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? We've seen some headwinds here with other programs.
Brett Monia (CEO)
Yep. Yep. Onaiza?
Onaiza Cadoret-Manier (Chief Global Product Strategy and Operations Officer)
Yeah. You know what? 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 product's 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 state and unmet need, and then price accordingly to that. We have done some really good work if you're talking about olezarsen in the broader prevalent SHTG market. 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.
We really do believe we have very compelling value proposition to price in that, in that more, CV premium range.
Brett Monia (CEO)
Thanks, Tommy. Thanks, Onasa.
Operator (participant)
The next question comes from Paul Matteis with Stifel. Please go ahead.
Speaker 18
Hi, this is James on for Paul. Thanks for taking our question. Maybe just a kind of broader high-level question. You know, assuming olezarsen hits in SHTG and donidalorsen hits in HAE, what do you think Ionis looks like in 2025, 2026? You know, specifically with respect to what your, you know, sales force 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.
Brett Monia (CEO)
Well, I'll just start. I'll ask Onasa 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 olezarsen and donidalorsen. We're expecting, you know, a half dozen or so new drugs on the market in that timeframe, James. You know, that includes, of course, wholly owned and drugs we commercialize as well as our partner, and we're pretty confident in that. Onasa, you want to talk a little bit about the growth?
Onaiza Cadoret-Manier (Chief Global Product Strategy and Operations Officer)
Yeah. It looks really exciting. I mean, we have two cross-functional teams planning for both launches. 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? 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. We'll see lots of synergy there. 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.
For olezarsen, we know it's a large opportunity, but we're really honing in on two specialties, which is cardiology and endocrinology. 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. We're working on the sizing of that team. 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 sized well.
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.
Speaker 18
Thank you.
Brett Monia (CEO)
Thanks, James.
Operator (participant)
The next question comes from Kostas Biliouris with BMO Capital Markets. Please go ahead.
Kostas Biliouris (Director, Biotech Equity Analyst)
Hello, everyone. Thanks for taking our questions. 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? Then I have a follow up.
Brett Monia (CEO)
Well, I'll start, and I'll ask Onaiza if she wants to expand or not. You know, 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, you know, the safety, the off-target potential, on, you know, to potentially permanently 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? If it's not, can you redose? There's a whole 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 by, from patients about editing their DNA, to be blunt, at an early, at such an early age, when they're thinking about building families and those sorts of things. 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 target identification in drug development that we're trying to address those types of concerns as we bring our molecules forward.
It's still early days, we believe in our investment in DNA editing, we don't think HAE is gonna be the right place for this approach. What do you think, Onasa?
Onaiza Cadoret-Manier (Chief Global Product Strategy and Operations Officer)
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, in their lifespan and not knowing what the long-term consequences are are major. 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 gonna fulfill that. We have a great product, and, you know, again, it is, I think it's gonna be fully satisfied by the time they get there.
Brett Monia (CEO)
You had a second question, Kostas?
Kostas Biliouris (Director, Biotech Equity Analyst)
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 two different populations? I would assume that the drug will be exactly the same in terms of dosing and all these. Thank you.
Onaiza Cadoret-Manier (Chief Global Product Strategy and Operations Officer)
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. 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. You know, stay tuned. We're thinking through a lot of, like, different strategic ways to get at it. You should know if you're, you know, 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, it'll be in the cardiovascular kind of premium pricing range that you see for more prevalent disease.
Kostas Biliouris (Director, Biotech Equity Analyst)
Thank you very much. Very helpful.
Brett Monia (CEO)
Thank you.
Operator (participant)
The next question comes from Gena Wang with Barclays. Please go ahead.
Gena Wang (Managing Director, Biotech Equity Research)
Thank you. Three very quick questions. One more question regarding the HAE program. You already described quite a lot of the 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? Lastly, very quickly on commercial readiness for eplontersen. Is AstraZeneca taking full charge, and what is the marketing strategy giving Amvuttra already in the market?
Brett Monia (CEO)
Thanks, Gena. That was quite thorough. This is three very different topics, but very good questions. I'll let Onaiza handle the HAE two-month dosing and the commercial readiness for eplontersen. I'll take the Angelman just as a quick answer. We, 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. There are no concerns for the Angelman program. Onaiza, bimonthly dosing HAE and-
Onaiza Cadoret-Manier (Chief Global Product Strategy and Operations Officer)
Yep.
Brett Monia (CEO)
Launch readiness.
Onaiza Cadoret-Manier (Chief Global Product Strategy and Operations Officer)
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 III 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 as well. For eplontersen 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. 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.
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. I would say, you know, that the clinical data in and of itself speaks for itself. It has a really nice, strong profile. 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.
Some European markets will be second. There are a lot of European markets, Eastern Europe and China and Japan, where we expect to be first.
Brett Monia (CEO)
Thanks, Gena.
Operator (participant)
The next question comes from Luca Issi with RBC. Please go ahead.
Luca Issi (Senior Biotechnology Research Analyst)
Great. Thanks so much. 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 Viehbacher is pretty focused on actually containing costs. Obviously, we've seen them discontinue your collaboration with Ataxin-3. Just wondering if the bar for progressing partner molecule is now higher given their focus on cost. Again, any call there will be much appreciated. Maybe on APOC3, circling back to the prior question, can you remind us what's your commercial plan ex U.S. for APOC3? Will you partner the rights? Will you use a distributor like Sobi? Will you have your own sales force on the ground? Again, any color, much appreciated. Thanks so much.
Brett Monia (CEO)
Great, second question for Onasa. 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. You know, 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. Really exciting program to them, very important. It's getting all the resources you can imagine that is needed, as they are the Angelman program as well. We just. You know, they did a great job in bringing QALSODY through the finish line and onto the market, and it's already launched. They're totally ready to launch that drug.
Several of the other mid-stage and research programs are progressing and going very well. Absolutely, Biogen, I'm not saying anything that hasn't been in the public. They're focusing their efforts on programs that they think are gonna bring the greatest value to their company. 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, 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 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, where the areas that they wanna focus on. We are evaluating what to do with that program today, whether to keep it or to repartner it. We have a rich neuro pipeline that's growing, that's wholly owned by Ionis, and we will emphasize this pipeline growing forward, and we will expand on it as well. This also bodes well for Ionis to build out our wholly owned pipeline. If drugs that we're interested in commercializing come back from Biogen. 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, we love to have them back. If we don't keep them ourselves, we'll seek to repartner.
APOC3 ex-U.S. commercialization, that's a quite interesting question, Oneza.
Onaiza Cadoret-Manier (Chief Global Product Strategy and Operations Officer)
Yeah.
Brett Monia (CEO)
Something we haven't been talking about much.
Onaiza Cadoret-Manier (Chief Global Product Strategy and Operations Officer)
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, our plans, current plans OUS is to look for a partner. The type of partnership is where you're going for has not yet been determined, but it's important to note like we're gonna look for a really good quality partner that can reach as many patients as possible in a swift manner, and that's gonna be a really important criteria.
Brett Monia (CEO)
We're still working on it.
Luca Issi (Senior Biotechnology Research Analyst)
Thanks so much.
Brett Monia (CEO)
Stay tuned. Thanks. I think we have time for one last question before wrapping up.
Operator (participant)
Yes. Our last question for today comes from Myles Minter with William Blair. Please go ahead.
Myles Minter (Partner, Biotech Equity Research Analyst)
Thanks for sneaking me in. Again on olezarsen, just wanted your updated thoughts on the potential need, if any, for a cardiovascular outcome study in severe hypertriglyceridemia. 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 seek a slight premium pricing range for that product, relative to your-
Brett Monia (CEO)
Yep.
Myles Minter (Partner, Biotech Equity Research Analyst)
Thanks.
Brett Monia (CEO)
Since it's focused on reimbursement, I'll ask Oneza to take that as well.
Onaiza Cadoret-Manier (Chief Global Product Strategy and Operations Officer)
Yeah. 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, has a clear regulatory path, as you said, without a CVOT study. 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. you know, it's going right in line with where the unmet need is and the value proposition of what we bring.
This 3x magnitude of what's currently available for triglyceride reduction for these severely elevated trig patients with, you know, high risk for acute pancreatitis is where the payer focus is. In there without a cardiovascular study is not the right way.
Brett Monia (CEO)
Thanks, Myles, 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. We're gonna provide updates throughout the second half of the year. We're very much looking forward to it. With that, we'll close and thank you again and have a great day, everybody.
Operator (participant)
The conference is now concluded. Thank you for attending today's presentation. You may all now disconnect.