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spk08: Good morning, and welcome to the IONIS Pharmaceuticals Third Quarter 2022 Financial Results Conference Call. As a reminder, this call is being recorded, and at this time, I would like to turn the conference over to Ms. Julie Tepper, Investor Relations, to lead off the call. Please go ahead, ma'am.
spk16: Thank you, Chuck. Before we begin, I encourage everyone to go to the Investors section of the IONIS website to view the press release and related financial tables we will be discussing today. including a reconciliation of GAAP to non-GAAP financials. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website that accompany today's call. With me this morning are Brett Monia, Chief Executive Officer, Richard Geary, Executive Vice President of Development, and Beth Haugen, Chief Financial Officer. And joining us for the Q&A portion of the call are Eric Swayze, Executive Vice President of Research, Eugene Schneider, Chief Clinical Development Officer, and Oneza Katare, Chief Global Product Strategy and Operations Officer. 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.
spk11: Thanks, Julie. Good morning, everybody, and thanks for joining us on today's call. This year has been catalyst rich and strategically important for IONIS, enabling us to conclude 2022 in a position setting us up for substantial growth. We're looking forward to potentially adding two new commercial products from our rich Bay Street pipeline to our portfolio next year. These are, of course, Eplon-Tersen for ATTR polyneuropathy and Tofersen for SAD-1 ALS. In addition, we've made excellent progress advancing our late and mid-stage pipeline. With eight positive key data readouts so far this year, Our rich phase three pipeline is poised to expand with two new phase three starts expected in the first half of next year. And based on all our pipeline progress, we're well positioned to continue delivering a steady cadence of phase three data readouts in 2023, 2024, 2025, and beyond. This year, we have also advanced our commitment to deliver transformative medicines to the market with our go-to-market commercial preparations for our near-term product opportunities at Blantersen, Olazarsen, and Donna Dolorsen. We have also made great progress expanding and diversifying our technology with the recent advancement of three new programs into IND-enabling development activities. These programs involve our first medicines incorporating Leica technology for enhanced delivery to muscle, and our mesophosphoramidate, or MSPA, backbone chemistry designed to improve both efficacy and durability. These advancements further enhance and expand our drug discovery capabilities for both our new programs and our follow-on programs. We've also taken additional steps to support our future growth. We recently began work on a new state-of-the-art manufacturing facility. facility will ensure we have the capacity we need to continue to successfully deliver our medicines to patients and continue to expand into new chemistries. We also recently capitalized on the record demand for life science real estate assets by monetizing several of our facilities through a sale leaseback transaction. This transaction further strengthens our balance sheet to support our plans for accelerated growth. With that, I'll turn the call over to Richard to discuss our recent key data readouts, pipeline updates, and preview our upcoming catalysts. Then Beth will review our third quarter financial results, the financial impacts of our recent real estate transactions, as well as review our full year financial guidance. And after Beth, I'll wrap up our prepared remarks before taking your questions. So now over to Richard.
spk07: Thank you, Brad. Well, our pipeline has certainly performed extremely well this year. We reported eight positive data readouts so far this year. As a result, we are looking forward to potentially having two new medicines on the market and expanding our rich phase three pipeline next year. Over the next few minutes, I will review our recent achievements and then preview our upcoming catalysts. Our next potential medicine to reach the market is Tofersen. our medicine for patients with SUD1 ALS. Tofersen is currently under priority review with the FDA, has the potential to become the first approved disease-modifying medicine for the treatment of a genetic form of ALS. Tofersen has a PDUFA date of April 25, 2023. In September, we presented positive Eplon-Tersen data from the Phase III NeuroT-Transform study in patients with ATTR polyneuropathy. at the International Symposium on Amyloidosis. In the eight-month interim analysis, zeplantersin achieved highly statistically significant and clinically meaningful change compared to historical placebo for its co-primary and key secondary efficacy endpoints, including demonstrating robust TTR reduction from baseline with improvements in neuropathy impairment and quality of life relative to baseline in a substantial portion of patients. With these very positive data, we in AstraZeneca look forward to filing for regulatory approval in patients with TTR polyneuropathy in the U.S. before the end of the year. Additionally, we are extremely pleased with the continued progress of CardioT Transform, the largest and longest study in patients with ATTR cardiomyopathy to date. Since we initiated CardioT Transform in late 2019, patients are being diagnosed much earlier in the course of their disease as a result of greater disease awareness and improved disease detection methods. This evolution in the ATTR-CM landscape is supported by new published and presented data from the scientific community. Based on these new findings, along with careful monitoring of patient demographics and blinded event breaks in our study, we've increased the target enrollment goal to 1400 patients. This increase will ensure our study fully reflects the entire population of patients, including patients with less severe disease. We believe this further increases our probability of delivering a highly positive study outcome that best positions at Blantersen to successfully compete and lead in this growing dynamic and global market. Importantly, based on our current rate of enrollment and the added power from additional patients, We remain on track to report data in the first half of 2025. Our broad olosarcin development program in FCS and severe high triglycerides is also progressing nicely. The phase three balance FCS study is fully enrolled. It's planned to read out mid next year. And our broad clinical program supporting the larger severe high triglycerides or SHTG indication also continues to progress well. Core, our pivotal, our first pivotal study in patients with SHTG remains on track for data in 24. Core two, our confirmatory pivotal study in the same population is now underway with data also expected in 2024. We recently initiated Essence, a supportive phase three study. Essence is designed to build out the safety database for the much larger SHTG indication. With first mover advantage, we remain very confident in the potential of olisarcin to be a substantial driver of future growth. Now, our Donna Delorsen OASIS Phase 3 program in patients with hereditary angioedema remains on track for data also in 2024. We will report new longer-term data from the Phase 2 OLE study this Sunday, November 13th, at the American College of Allergy, Asthma, and Immunology Annual Scientific Meeting. The goal of the OLE study is to reinforce Donna Doloresen's potential best-in-class profile by demonstrating long-term protection from HAE attacks, along with longer-term safety and tolerability in patients treated for one year. We look forward to sharing our OLE data with you on Sunday. Recently, we and our partners presented positive data from several of our mid-stage programs further advancing our rich pipelines. We recently presented positive and competitive phase two data from Ionis FBLRX in patients with IgA nephropathy at the American Society of Nephrology's Kidney Week. This study was designed to demonstrate clinical proof of concept for the potential to treat IgA nephropathy by targeting complement factor B and the alternative complement pathway. And of course, to evaluate safety and tolerability. Ionis FBLRX met the primary endpoint, demonstrating substantial and clinically meaningful reductions in 24-hour urinary protein in patients with IgA nephropathy with a mean reduction of 44%. Additionally, patients effectively maintained their EGFR throughout the study. And together with this, achieved a favorable safety and tolerability profile. Based on these positive data, Roche already announced their plan to advance Ionis FBLRX into phase three development by mid next year. Also at kidney week, Bayer reported positive phase two B study for Fezomersin, R factor 11 like a medicine for the treatment of thrombosis. The goals of the Rethink ESRD study were to demonstrate dose dependent substantial reductions in factor 11 levels and no increase in bleeding risk compared to placebo. in patients with end-stage renal disease. Safety and tolerability were also key outcomes. We were pleased that Fezomersen exceeded all of the goals of the study. Fezomersen achieved dose-dependent and sustained median reductions in steady-state factor XI levels that exceeded 85% at the top dose and with no imbalances in major bleeding or non-major bleeding compared to placebo. Additionally, incidences of dialysis circuit clotting and AV access thrombosis diminished significantly with decreasing Factor XI levels, both of which were exploratory efficacy endpoints. And Fezomersen demonstrated favorable safety and tolerability in this study. Despite these highly positive results, Bayer made the decision to only advance their small molecule Factor XI medicine to Phase III and therefore return Fezomersen to Ionis. While we understand Bayer's decision not to move a second factor 11 drug forward, we and our clinical advisors believe that these positive data support advancing Fezomersen into pivotal studies. Given the large potential addressable patient population and numerous potential indications to explore, we are focused on getting Fezomersen into the hands of the right partner to deliver it to the market as soon as possible. Turning now to the exciting tapiravircin data GSK reported at AASLD. Tapiravircin is a potentially transformative treatment for people living with chronic hepatitis B. HBV is responsible for approximately 900,000 deaths annually. The goal of the phase 2Bb clear study was to assess efficacy, safety, and tolerability in HBV patients treated with tapiravircin. This was an important study because it demonstrated for the first time that papiroversin alone or in combination with antiviral nucleotide or nucleoside inhibitors can deliver a sustained and substantial reduction in both viral DNA and HBV surface antigen, which together are key measures of efficacy. The results showed that 9% of patients on nucleoside nucleotide analog treatment 10% of patients on Vapiravircin alone achieved the primary outcome of viral DNA and HPV surface antigen below the lower limit of quantification at 24 weeks after Vapiravircin treatment. These data strongly support the potential for Vapiravircin to achieve functional cures in people suffering with chronic HPV infection. Based on these encouraging data, GSK is currently in discussions with regulators on the design of the Phase 3 studies with plans to initiate a robust Phase 3 program in the first half of next year. Well, it has been an eventful and catalyst-rich year, and we anticipate continuing the momentum with the remainder of the year and in the year ahead. We're looking forward to presenting our upcoming HAE data this coming Sunday, and we are on track to file the NDA for Eplon-Tersen by the end of the year. Next year, we're looking forward to more key catalysts, including the potential approval of Tofersen in the first half of the year, full 66-week data from the Neurotransform study of Eplon-Tersen, the potential FDA approval of Eplon-Tersen later in the year, Phase 3 data from olisarcin and FCS patients, along with the initiation of two new Phase 3 programs, among other important advances. With that, I will turn the call over to Beth.
spk04: Thank you, Richard. This morning, I'll provide a summary of our third quarter results, discuss our recent real estate transactions, and then touch on our full year guidance. We earned revenues of $160 million and $435 million for the third quarter and year-to-date respectively, an approximately 20% increase over last year. Our revenue continues to be derived from numerous diverse sources with approximately half from our marketed products and the balance from numerous partner programs. Our operating expenses for the quarter and year-to-date reflect our continuing investments in advancing our rich pipeline and commercial readiness activities. Notably, we continued to maintain our healthy balance sheet with cash and investments staying steady at approximately $2 billion through the end of Q3. Spinraza's global sales were $431 million for the third quarter and $1.3 billion year to date. As a result, we earned $62 million and $175 million in royalty revenue for the corresponding period. In the U.S., Spinraza sales continued to stabilize in the third quarter. Additionally, we continued to see positive trends in discontinuation rates. We expect to see the same dynamics play out in markets outside the U.S., which we see as a path for Spinraza to return to growth. Spinraza's potential to return to growth is further supported by Biogen's continued geographic expansion and their robust lifecycle management program. This includes the work Biogen is undertaking to further characterize the remaining unmet medical need of patients with SMA with their ascend, respond, and devote studies. We earned R&D revenue of $87 million in the third quarter and $212 million year to date. both of which increased substantially compared to the same periods last year. Year to date, we earned $85 million from Biogen for advancing neurological disease programs under our strategic collaboration. We also earned $63 million from Roche for licensing and advancing Ionis FB-LRX, and $55 million in cost-sharing payments from AstraZeneca for their portion of F1-Tersen's development costs. Our non-GAAP operating expenses increased in the third quarter and year to date compared to last year and were in line with expectations. The increase was driven by higher R&D expenses from advancing the six phase three studies we are currently conducting, with Eplen-Turcin comprising our largest investment. Our R&D expenses also included increased spending for CMC and medical affairs activities to support our near-term commercial opportunities. SG&A expenses increased in the third quarter compared to last year as we ramped up our go-to-market preparations. Year-to-date SG&A expenses were below the same period last year, continuing to reflect the substantial savings we realized from the AXIA integration and SOVI transactions. As Brett mentioned, we recently took two important steps to support our future growth. We entered into a long-term lease to construct a state-of-the-art manufacturing facility, significantly increasing our capacity to bring our medicines to the market and to expand into new chemistry. We will oversee the design and construction of the facility, ensuring it will incorporate advanced sustainability and environmental protection features. For example, we expect that approximately 50% of the new facility's power requirements will come from renewable energy sources. We anticipate completing this project in 2025. Based on our early design work, we expect it to cost us approximately $350 million. We also entered into a sale-leaseback transaction, which took advantage of the record demand for high-quality life science real estate assets. This transaction bolstered our cash balance with approximately $240 million in net proceeds, plus funding to expand our R&D campus. It also enabled us to retain control over the operation of our facilities. We used a portion of the proceeds to pay off our existing mortgage on these properties. In doing so, we reduced our long-term debt. By putting this cash to work, we believe we can generate substantially more value advancing our growth initiatives, including expanding and advancing our pipeline and technology, preparing for multiple product launches, and building our new manufacturing facility. Our Q3 results keep us on track to meet our 2022 revenue, operating expense, and net loss guidance. We continue to expect revenues of more than $575 million, with commercial and R&D revenue roughly split 50-50. As our phase three studies continue to progress, we expect our R&D expenses to increase between 25% and 30% this year compared to last year. We project our SG&A expenses to be in line with last year, even while we increase our investments in preparing to bring our near-term opportunities to the market. In total, we expect our non-GAAP operating expenses to come in at the lower end of our guidance, which is between $825 million and $850 million. And since our recent sale leaseback transaction was not contemplated in our guidance, we are increasing our 2022 cash guidance from $1.7 billion to $2 billion. Looking to the future beyond 2022, we expect our strong financial foundation to continue to serve us well. And as we continue to invest in advancing our strategic priorities, we are poised to deliver significant future growth. And with that, I'll turn the call back over to Brett.
spk11: Thanks, Beth. To summarize this morning, we made great progress this year in advancing our key priorities to grow our commercial pipeline, to deliver an abundance of new transformational medicines to the market, and expand and diversify our technology. We're on track to file the up on person NDA by the end of this year. And with Topherson currently under priority review with the FDA, we're positioned to add these two new medicines to our commercial portfolio next year, assuming approval. Our late stage pipeline continues to advance and expand, setting itself to extend our phase three data readouts next year and for many, many years to come. We've made important advances to expand and diversify our technology with more advancements still to come, and we've taken additional steps to support our growth. Importantly, we have the resources to continue executing on our priorities to drive substantial value for all stakeholders. This has been a great year for Iona so far, and I think next year and the years to come are going to be even better. We're looking forward to sharing more on our progress in the coming months. With that, I'll now open the call up for questions. Operator, if you could open up the queue, please.
spk08: Will do. We will now begin the question and answer session. To ask a question, you may press star then 1 on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. And to withdraw your question, please press star then 2. And at this time, we'll pause momentarily to assemble our roster.
spk05: And the first question will come from Gary Natchman with BMO Capital Markets.
spk08: Please go ahead.
spk02: Hi, good morning. So first on up on Tersen, just explain a little bit more of the rationale for further expanding the cardiomyopathy study. What you were seeing in terms of having too many earlier stage patients, did you consider extending the duration of the study at all beyond what you did previously or and just how you're confident that the timeline won't change in terms of getting those data. So that's one. And then just on the first in NDA, it was extended three months, just to explain why, you know, if the FDA asked for any additional information and if you guys are still anticipating a panel and how you and Biogen are preparing for that, what you think might be discussed if there is a panel. Thank you.
spk11: Sure thing, Gary. Maybe I'll take a stab at the Tofersen question, and then I'll turn it over to Eugene to discuss the rationale reasoning behind the Epron-Tersen protocol, cardiomyopathy protocol amendment. So for Tofersen, yeah, there was an extension of the timeline for the NDEA PDUPA date to April 25th, three-month delay, major amendment. primarily because the FDA has communicated that they just need more time to review all the data. It's really not a request for any substantial or significant additional data that they needed to do the review. It was really a bandwidth issue principally. You know, they have a lot going on in the neuro division, especially this past fall for similar indications. And we suspect, although not definitive, that that probably caused them to have to take more time to review the data set. We're very much looking forward to the data readout, the decision, the outcome from the review by the FDA. Nothing new on the position by the FDA on a adcom. We haven't heard anything new. We're still assuming that they're planning to have an adcom at some point, and we're very much looking forward to that as well. Eugene, why don't you take us through the rationale and also, you know, the importance of the amendment, Sure, Brett.
spk10: Thanks for the question. So, as Richard already mentioned in his remarks, it is clear to us and to many of the advisors we've been talking to that the population with EDTR cardiomyopathy has changed substantially over the past several years. And as you recall, the primary source for us power the study the original study that we started back in 2019 was the attract data set which um the study that pfizer conducted quite a few years back and and the more um data became available to us internally as well as externally importantly um quite a few publications Specifically, they come to a definitive diagnosis earlier than they used to, and as a result of that, and that's a factor of greater disease awareness, better diagnostic measures, and that results in the patient journey being relatively different to what it used to be. when a tract was conducted, patients came to attention late in their clinical presentation and had multiple early events that were, again, as I said, were used for the original towering study. So, as we assimilated all of the data externally and internally coming from our study, it became clear that the study was not powered properly based on those elevated assumptions, and we needed to resize the study accordingly. Of course, the question about duration is an important one, and we've looked at that as well. We've considered against it, extending the duration even further because that would substantially delay the timing of the readout, and we felt that, again, the upsizing of the study alone was sufficient to ensure that it's properly powered.
spk05: without taking a significant penalty of time.
spk11: And thanks, Eugene. I'll just add, and of course, we also have patients in the open-label extension of the phase three CardioTransform study who have now completed the 140 weeks. So we wouldn't want to lose those patients. So we can accomplish the same objective, the same goal by increasing the sample size, which we did. And we think that this is a strategic, strategic important move. to the study to really help ensure for the most successful outcome possible for cardio transfer.
spk02: Okay. That's right, Helen. Just to confirm, you don't need to increase the number of sites, and I guess enrollment has been going quite well. Maybe just comment on that. Thank you.
spk11: Yeah, right. You know, adding 400 patients and not changing the timing for the readout means that we're well ahead in enrollment. So enrollment's going very well, and we're not needing to open up new sites the same existing sites, and we're just moving ahead rapidly to get to the 1,400 number.
spk05: Okay, great. Thanks.
spk08: The next question will come from Yanen Zhu with Wells Fargo. Please go ahead.
spk14: Hi. Thanks for taking my questions, and congrats on the progress in the quarter. I have a follow-up on CardioTransform study. and also a question on LP little a. For CardioTransform, how does the changing demographics change your powering assumption in terms of event rate in the control arm and effect size? And what proportion of ontophamidus patients did you assume in your powering assumption? For LP little a, how do you and your partner Novartis view the data for Opacerin presented at the AHA meeting where they showed up to 100% LP little a reduction. How does that affect your outlook for Pellicarson? Thank you.
spk11: Thanks, Yanen. Two great questions. I'll ask Eugene to share what he can share about powering assumptions and so on, and then Richard to talk about Pellicarson. Sure.
spk10: Thanks again for your question. So related to our original assumptions, you may recall we did what we thought was responsible and conservative thing to do, which was assuming that all of our placebo patients will be on the background of . So we took the essentially the arm event rate in our original calculations. As I just said, even Even that rate turns out to be overly quite a bit different from what we're seeing in what's being published recently to be the case in patients in general in today's care. So even that rate was overly high relative to the population available today. We haven't really changed any of our other moves No, the treatment, the true treatment effect is not known, and we're not prepared to change any of our assumptions, nor have we commented on what specifically we used other than to say that we used what our advisors said would be considered clinically meaningful for them.
spk11: Thank you, Gene. And I'll just add, you know, we're focused on the CardioTransform study, of course, But, you know, this change in demographics for TTR cardiomyopathy we think applies to all contemporary studies evaluating investigational medicine. And we're in a very strategic position and made a very strategic move to ensure for a very successful outcome in this study. So we think this is a very important move, and it gives us even greater confidence in a successful outcome. Hello, Carson. Richard?
spk07: Yeah. So speaking directly to the question, how does it – change our view on Pelagarsen, doesn't change it at all. And just to take you back to a remembrance of phase two for Pelagarsen, the dose that we took into phase three achieved taking 98 plus percent of the patients to goal. And the goal is to get below that threshold of 50 milligrams. It's not to get to zero. So it's a little bit different than LDL. It's a different way of thinking. Lower is not better. But getting below that threshold is the goal. And so we're going into phase three with a product that gets nearly 100% of the patients to where they need to be out of risk. And we're well ahead of the competition. There's competition. And that just... gives us all the urgency that we've had all along to get this thing to the market as quickly as possible.
spk11: Yeah. And thanks, Richard. Probably worth noting too, that the epidemiology data is substantial, continues to grow, really enforcing the conclusion, reinforcing the conclusion that that threshold is where you need to be below that threshold where you need to be to get out of harm's way. As Richard said, Pella Carson delivers on that based on the, very significant, large phase two study, which we were studying the same patient population, the same phase three dose, but also there's now emerging data, published data, indicating that if you go too low on LP little a, it can also, you know, cause some problems. There are publications now out there that says if you go very low on LP little a, that you can actually have an increased risk for diabetes. go that low. And all it does is bring further risk. I also want to add this. This study is fully enrolled. This study is well on its way to reading out. This study gets reviewed by oversight committees, independent oversight committees regularly. That drives risk down, right? Competitors are going from a small phase two study to a large phase three outcome trial, okay? That brings risk. We like our risk profile today, fully enrolled, on our way to readout, well ahead of the competition, and getting virtually all the patients into the safe zone for LP little a level. So I hope that answers your question, Yanni.
spk14: Yes, yes. Thank you for all the help for color, and congrats again on the progress of this quarter. Thank you, sir.
spk08: The next question will come from Miles Minter with William Blair. Please go ahead.
spk17: Hey, just a quick question on Fezomersen. Just with your new partner, considering you did show that the data in ASRD with dialysis and it looks to be hitting everything that you set out to demonstrate, what sort of indications would you encourage a new sponsor to chase with that asset versus the oral inhibitor competitors that look to be going for a more acute setting? Thanks, Myles.
spk11: You know, as I think we've been very transparent with over the last, you know, I think really last year, we were hoping Bayer was going to take Fez immersion forward based on positive phase 2, really positive phase 2b data, which ended up being very positive. But we were also anticipating preparing for the eventual potential return because Bayer had three independent modalities being developed for targeting factor XI, their own homegrown small molecule, in-licensed monoclonal antibody, and in-licensed Phezomiracin. As I said, as you know, the, some of the small molecule data has been presented already at ESC. You know, a lot of aspects look good. I think it's a bit of a mixed bag. We're very pleased with the Phase IIb data for Phezomiracin, and the antibody data isn't out yet. So they made the decision to go forward with one drug forward. And, you know, Bayer was focused on end-stage renal disease as a potential population for mesomericin. We believe that that's too limited. We believe that a once-a-month, highly effective factor XI inhibitor that achieves knockdown of factor XI beyond 85% could be used for any prophylactic treatment to prevent thrombosis. atrial fibrillation, secondary stroke prevention, end-stage renal dialysis, so on. So we think that this has the potential to be used broadly. And that's what we're going to be looking for in a partner, a partner that can bring, as Richard said in his statements, to bring it to the market as quickly as possible, but also to really maximize the opportunity as a thromboplasmic
spk17: Okay cool and then a quick one on cardio TTR transform study just with the 400 patients that you're going to additionally enroll are they going to be equally balanced across the patient subgroups like wild type versus hereditary to feminist experience versus naive or are they specific subpopulations as you've seen the demographics of the thousand patients currently that you might want to bolster with the addition of these 400 patients coming into the trial? Thanks.
spk10: Yeah, thanks for your question, Miles, Eugene. So, clearly, the opportunity here is to be fairly intentional with the remaining portion of the population that we're enrolling. Because we're in a position where all sites are open, we have an ability to be kind of more targeted in the types of patients that are being brought in, and that's what we're doing. As you said, of course, if you look at the, epidemiology data, the risk is different for certain types of patients with regard to outcomes, and that's what we're trying to maximize here. Of course, bringing in more hereditary patients, fewer patients who are on tefamidus
spk17: Okay, thanks for the questions.
spk05: Thanks, Miles.
spk08: The next question will come from Jessica Fye with J.P. Morgan. Please go ahead.
spk12: Hey there. Good afternoon. Thanks for taking my question. Can you give us an update on the AngelLyn program? Where does it stand, and when can we expect an update? Thank you.
spk05: So, unfortunately, Jess, we don't have a whole lot new to provide.
spk11: We're enrolling the study. As you know, it's an open label extension study. And, you know, we're looking forward to completing the studies as rapidly as possible. We're not really planning to share any data, right, Eugene, on, you know, like, you know, on anecdotal observational data as we go forward. We want to get the study completed. It's dose ranging. And it's intended to set us up for a phase three start as quickly as possible.
spk10: Yeah, absolutely. And it's also a partner program. timing other than to say it's going according to the plan.
spk05: It's going according to plan, it's enrolling well, and, you know, we're just moving along.
spk13: Thank you.
spk05: All right. Thanks, Jess.
spk08: The next question will come from Luca Issy with RBC. Please go ahead.
spk15: Oh, great. Thanks for taking our questions. This is Lisa on for Luca. This question is for Brett, just a bigger picture. I know you've talked in the past about broadening your reach to technologies beyond antisense oligonucleotides. So I was wondering if you can comment what your latest thinking is there. Thanks.
spk11: Sure. Lisa, thanks for the question. So we, as I mentioned in my prepared remarks today, we're making great progress in advancing our technology in many different ways. We've now moved with a partner a new program using a new Leica targeting muscle. Can't talk more about the target or the indication at this point because it's a highly competitive area, but we're looking forward to providing an update maybe next year. That has the potential to open up new diseases for Ionis as well as for partners and going after targets in the muscle. We've also now brought forward a new backbone chemistry called MSPA. We brought into development now supporting toxicology studies for two CNS targets using that backbone. That backbone is intended to increase efficacy, potency, as well as durability, so less frequent dosing. And we expect that to translate to both CNS as well as systemic applications. So stay tuned for that. They're both for broad indications. One with a partner, one I own is wholly owned. We expect to keep that one ourselves as well. As far as other approaches, as I've been saying now for quite some time, we will continue as we've been now for the last couple of years evaluating SI strategies as well as ASO strategies. And our philosophy is let the best drug win. They have some preclinical data, bring it to the clinic. We're expecting to move our first SI into development, IND enabling tox studies, probably early next year, not early this year. And there are specific applications where we see advantages for SI, and there are specific advantages or areas where we see advantages for ASOs. And, you know, we're going to be multimodal here. As far as new platforms go, we're in sort of seeking evaluation phase right now about diversifying our platform capabilities. And I really can't say much more about it than that, Lisa, except stay tuned. We hope to be able to make some progress in the future about some of our thoughts, ideas in that area.
spk16: Excellent. Thanks for taking our questions.
spk08: Thank you, Lisa. The next question will come from Gina Nguyen with Barclays. Please go ahead.
spk13: Thank you for taking my questions. I just have one regarding the HAE update this Sunday. So you already showed pretty impressive early efficacy. So with this early data, should we expect further improvement in attack reduction given the longer follow-up? And also, which data point will be more important regarding percentage of patient attack free versus percentage of a reduction in attacks?
spk11: I'll start at the beginning, but then I'd like Anais to talk from a commercial standpoint, maybe what she views since we're planning to launch this drug ourselves, what is most important to patients and the prescribers for prophylactic for HAE. So, can't get ahead of the presentation on Sunday. That wouldn't be fair. We're expecting, you know, our plan is to show, I mean, it's hard to get better than the phase two data, right? I mean, these patients were essentially attack free once we got to steady state after five weeks, after one dose. I mean, it's hard to get better. What we're really looking to do is to show is whether that unprecedented efficacy is actually sustained for a year, right? As well as compliance, as well as the long-term tolerability. So- Those go hand in hand from an approval standpoint, as you know, Gina, tolerability as well as sustained efficacy. So that's really, I don't think we can go beyond, I mean, maybe, but it's really onesies and twosies of patients or percentage points, I should say, because you can't get much better than the efficacy we showed in phase two. What do you think, Anaisa, from what's most important to patients?
spk03: Yeah, I would say to both physicians and to patients, Gina, that, you know, efficacy is first and foremost. We tested a hierarchy, an order of efficacy, just to kind of glean like what's most important. And the zero attack rate is the number one efficacy measure. then followed by mean attack reduction, and then followed by how much you're actually withdrawing them off of the acute treatment. So those are, that's the order of hierarchy, but zero attack rates is basically the name of the game here. And as Brett said, we, in our phase two, as you've already seen, showed a mean kind of, a max clinical efficacy of 97% zero attack rates that we achieved in weeks five to 17, so as quickly as after your first dose. Also important to know that in this marketplace, we also just completed some market research to say, okay, well, where are the patients at currently with Texairo being the market leader and the number one prophylactic agent that is used out there, again, with a pretty significant zero attack rate. We're still seeing patients have reported On average, there are about three HAE attacks happening in a year, and that's pretty substantial still. So we do believe that we're going to really fulfill this unmet need that still exists in the marketplace.
spk13: Thank you very much.
spk08: The next question will come from Joseph Stringer with Needham & Company. Please go ahead.
spk06: Hi. Thanks for taking our questions. A quick one on the GSK-partnered. HBV program, the Puraversen. Just wondering if you could talk about the differentiation of your approach from, say, competitor approaches that are using dual or even triple combo therapy, some of which are RNA inhibitory knockdown based.
spk11: Great question, Joey. Thanks. I'm going to ask Eric to comment on that.
spk07: Yeah, sure.
spk09: Really, I think the The key differentiator is that the Piravircin as a single agent was able to do things that the other approaches really haven't been able to accomplish. And that was evidenced by the B-CLEAR results both showing around a 30% HPS antigen below the limit detection level at the end of treatment. maintaining that for about 10% of the patients at 24 weeks post-study. And this highlights for the potential of that drug to achieve the ever-elusive functional cure in HPV where patients are being able to remove from therapy. I think, you know, GSK is doing a great job with this program and thinking about combination approaches. They have the Be Together study ongoing right now, which is adding interferon on top of that. And I think some of the competitive studies you're referring to are using HBV RNA lowering agents in combination with interferon and showed some S antigen loss, but that was at the end of study, not after removal of treatment. So I think the field is moving forward. It's actually great to talk about HBV functional cures and having the buzz around it at the recent meeting that that's happening, and I think it's good for patients. We in GSK think that BEPI will be a foundation for treatment of HPV, including combinations involving BEPI that will hopefully increase the rate of patients that can remain therapy free.
spk11: Yeah, I think that's something I just want to emphasize that Eric just closed on is that the 9-10% functional or undetectable levels 24 weeks after completing dosing, so off all drugs, 24 weeks later, detectable in about 10% of patients, whether monotherapy or on nukes, really is unprecedented and is the foundation to build from that alone, we believe is an approvable benchmark. That's a marketing, that's a marketable endpoint or achievement. And it's the beginning. Once we get into combination treatments and selecting subpopulations. We know that the undetectable levels were even greater in patients that had less HPV burden coming into the study in the 20-30% range, right? So, you know, all this is just the beginning. It's still really impressive, but off we go. And GSK is going to be taking a comprehensive approach, phase three approach, looking at various combinations, immunotherapy, interferon combinations, and so on.
spk05: to maximize the value of BEPI for HPV patients. Great. Thanks for taking that question.
spk08: Thanks, Joey. The next question will come from Paul Matthias with Stifel. Please go ahead.
spk19: This is James on for Paul. Thanks for taking our question. Maybe just one on olizarcin. It looks like it could potentially be Ionis' first kind of independent drug launch and I guess one, is that how you're thinking about it today, to launch it yourself? And if so, what would the investment there look like? And then maybe just separately, quickly, it'd be great to just get your thoughts on what you'd want to see efficacy and safety-wise to have confidence in a competitive drug profile there. Thanks so much. Sure. Anazy, you want to take that?
spk03: Sure. Yes, that is a very correct assumption that this will be the first Ionis self-commercialization outside of a COCO, F1-tyrosine being the first one. And we are looking at two indications, as you know. The first one is in FCS, and then the second one in severe hypertriglyceridemia. Severe hypertriglyceridemia is a large patient population in the U.S. close to 3 million patients available for treatment over here with elevated SHTGs. This is the investment that's required is actually going to be pretty focused, I would say. It would seem on the face of it, because of a large patient population, you're going to go out and, you know, have to call on GPs and stuff. But we've done, you know, a fair amount of work to see where the referral patterns are for these patients, and they're coming into a couple of specialties. So we're going to be actually very targeted there. And we're also going to employ just, you know, really good, more innovative tools such as Omnichannel and just a lot of AI to identify where the patients are from predictive analytics to be able to manage our investments to get to this large patient population. So we are... working very actively in terms of preparing as these trials are all in phase 3's right now, the two core trials, which are the pivotal and confirmatory trials, and then the essence, which is safety trial that just got initiated as well. As to what's a competitive profile, listen, the standard of care Our fibrates and niacin and vasepa and their triglyceride reductions were in the 20 to 30% range. So we're doing, we expect to do about two and a half to three X more of that. We have real good confidence that we'll get there based on our phase twos, which as a reminder, the phase twos were substantial, but we're not in these really high elevated SHTGs. They were in the 200 to 500 range. And in that, we already showed a 62% placebo-corrected TG lowering. So, if you take a look at what we expect in the severe hypertriglyceride range, we expect that it's going to be higher. And as a reminder, we are also studying two doses, both the 50 milligram and the 80. And our original phase twos were at the 50. So, we have a very competitive profile. And a reminder, we are well ahead the competition, and we have a first mover advantage over here by a substantial margin. So we'll get to really prepare the market, shape the market, and price the market.
spk05: Very helpful. Thank you. Thank you.
spk08: The next question will come from Salveen Richter with Goldman Sachs. Please go ahead.
spk01: Thanks for taking our question. This is Tommy on for Salveen. Our question is on epilontursin and polyneuropathy. Could you envision sharing detailed functional data over time such as MNIST plus seven trajectories at one, one and a half, two years so that people can see the benefit that you're getting on these measures over time? Thank you.
spk05: Yeah, so thanks for your question.
spk10: We are anticipating providing a pretty thorough and wholesome update on all of the co-primaries and key secondary endpoints once we look at our primary endpoint week 66 data next year, around mid-next year. As we said, until that point, the key results have been disclosed, but we're obviously not able to share additional details. But once the week 66 data become available, study results will be shared more broadly and more exhaustively.
spk11: Yes, Tommy, we expect to present that, have that data by mid-year next year, and we'll also prepare a publication, presentation, so on. We're very much looking forward to sharing the full data set, the Week 66 data at that time, when we have it, when we have the data.
spk05: Thank you.
spk08: The next question will come from Jeroen Werber with Cowen. Please go ahead.
spk20: Hi, this is Brendan for Jeroen. Thanks for taking the question. Just quick ones from us. First on for Acromegaly. I know you guys have so many things advancing. We can't always get to all of them here. But just wanted to see what the latest thinking is for timing and presentation of that data and maybe whether you're targeting a medical meeting for the release or not. Um, and then just quickly wanted to see if there are any new updates on the Huntington's program with Roche, um, either on the timing or just the overall clinical plan with Toma nursing there. Thanks.
spk11: Um, so for the, our acromegaly program, uh, uh, we're still planning to review the data, um, the phase two data of the monotherapy data this year, right, Richard? And, um, I don't know if we're going to have the opportunity to present the data because the year's rapidly coming to a close. Certainly a medical meeting is out of the question. We'll see what we can do. It's a relatively small phase two study. Probably not going to be able to get that data out until next year. But we're going to, we'll try to get it out as quickly as we can. For Huntington's, Roche has done a pretty good job of sharing a lot of data on the post-hoc analysis recently. It's, it's post-hoc, but it's compelling that patients with less, less disease burden, we're doing better. And we're doing better with less frequent dosing of some of the nursing. And they've also laid out their trial design, right? Their phase two trial design in pretty detail. It's a big study. There's, as I recall, I'm looking at Eugene and Richard, there's three cohorts, about 120 patients per cohort, two doses, one placebo. Is that right?
spk07: Yeah, that's about right.
spk11: Yeah. So it's a big, it's a big study.
spk05: They haven't given timing on exact first patient dose, but it's not far out there. All right, great. Thanks very much, guys.
spk08: The next question will come from Yeo Jin with Laidlaw and Company. Please go ahead.
spk18: Great. Thanks for taking the questions. For GSK as well as the Roche, even they are advancing the program forward to phase three study, Do we anticipate any milestone payments to the company later this year or early next year?
spk11: You were asking about the GSK HPV program, Yale?
spk18: Yes, as well as the FTE for Roche.
spk11: Oh, the FTE and the property.
spk04: Yeah. Yeah. So on the milestones, I think with the license fee and milestones we've already earned in the second and third quarter this year, we will be looking forward to regulatory approval milestones for that drug going forward, and then potentially milestones as the geographic atrophy study continues to advance with that same drug with the Ionis FB-LRX.
spk18: Okay, that's very helpful. Maybe one more question here, which is for the AGT, for the treatment-resistant hypertension. You will have a data readout. Could we get a little bit more color, what to expect later this year? And thanks.
spk11: Yeah, thank you, Yael. We have three studies in progress, right? We have the refractory hypertension with Gen 2 Glyca molecule. We also have the heart failure study with the Gen 2 glyca molecule, which is still in process. Both studies are in process. And we have the Gen 2.5 in hypertension patients. We're probably going to present the data. We're going to pull all the data together and probably have a presentation in some form or another or announcement probably early next year. We really want to look at the full data set for both indications as well as both drugs. The next question that we're going to get once we present this data, if we do it in pieces, is will be what are the next steps, right? And we don't know what the next steps will be until we look at all the data from two drugs and two indications. So, we'll certainly have completed at least one of those studies this year, but we'll probably wait until all the studies are complete before getting the data out there. Yeah. Okay, great. Thank you. Thanks, everybody. Yeah, we're going to have to close it out. Thank you. Thanks everybody for joining us, participating in today's call. We're really pleased with the quarterly results. We're very much looking forward to the rest of the year as well as moving into next year as well and continuing to provide you with updates on the progress we're making. Thanks again and have a great day.
spk08: The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.
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