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spk07: Good morning, and welcome to the Ionis Pharmaceuticals first quarter 2022 financial results conference call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Ms. Julie Tepper, investor relations, to lead off the call. Please begin, ma'am.
spk19: Thank you, Chuck. Before we begin, I encourage everyone to go to the investor section of the Ionis website to view the press release and related financial tables we will be discussing today. including 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, Beth Haugen, Chief Financial Officer, and Eugene Schneider, Chief Clinical Development Officer. And joining us for the Q&A portion of the call are Eric Swayze, Executive Vice President of Research, and Anaza Kateri, Chief Product Strategy and Operations Officer. I would like to draw your attention to slide three, which contains our forward-looking statements. During this call, we will be making forward-looking language statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filing for additional detail. With that, I'll turn the call over to Brent.
spk09: Thanks, Julie. Good morning, everyone, and thanks for joining us on today's call. This year, we are already off to a very strong start. We continue making excellent progress in building our commercial organization, advancing and expanding our technology and moving towards delivering an abundance of new medicines to the market. This includes the great progress we're making with our near-term commercial opportunities, Eplon-Tersen, Olazarsen, and Donny-DeLorsen. The Phase III Neurotransform study of Eplon-Tersen in patients with PTR polyneuropathy remains on track for data mid-year. And working hand-in-hand with AstraZeneca, we're preparing for regulatory approval by the end of the year, assuming positive data. At the same time, we're also trying to be advancing our go-to-market preparations. We recently achieved our original enrollment goal in our CardioTransform study for patients with ATTR cardiomyopathy. And last week, we announced that we took a bold step by increasing the size and duration of our study. And in doing so, better positioning us to successfully compete in this dynamic market estimated to grow to well in excess of $10 billion. Based on these updates and our current brisk enrollment rate, we expect a modest shift in our timeline with data reading out shift, with data readout shifting from late 2024 to the first half of 2025. We also continue to advance our oligosarcin-based program in patients with high triglycerides. The BALAM study of patients with familial cardiomyocardemia syndrome, or FCS, remains on track for data next year. And the CORE study in patients with severe hypertriglyceridemia, SHTG, continues to progress with data expected in 2024. Severely elevated triglycerides is a key independent cardiovascular disease risk factor for which current standard of care therapies are in effect. With over 3 million patients in the U.S., severe hypertriglyceridemia, and our first mover advantage, we believe olizarcin represents a blockbuster opportunity for Ionis. Our Phase III OASIS HAE study with donavolarsin in patients with hereditary angioedema also continued to progress well, with data expected in 2024. We believe donavolarsin has been for HAE patients, and as a result, Donna Dolores represents a significant opportunity for us given the significant unmet medical need of these patients in this growing billion-dollar-plus market. We also made excellent progress across our rich mid-stage pipeline. AstraZeneca presented positive Phase IIb data in ACC in April from the antigen study of IM449, our PCSK9 medicine in patients who are at high risk for cardiovascular disease with hypercholesterolemia. The study managed primary and secondary endpoints, showed good safety and tolerability, and IM449 demonstrated a potential best-in-class profile. With more than 10 million patients in the U.S. who remain above their LDL-C goal, despite maximum statin and acetamide therapy, we believe IM449 could be a significant opportunity for us. Additionally, we reached full enrollment in the Phase IIb study of Ionis AGT-LRX in patients with treatment-resistant hypertension with data expected in the second half of this year. We're also evaluating Ionis AGT-LRX in a Phase II study in patients with chronic heart failure with reduced ejection fraction. These indications combined represent over 15 million patients in the U.S. alone. Despite advances in therapies, a significant need remains for more effective treatments to address treatment-resistant hypertension and heart failure. Looking ahead, we expect numerous additional catalysts highlighted by the phase 3 of Montursen data readout mid-year and our planned regulatory filing by year-end. We also expect three more phase 2B data readouts, several key study initiations, and updates on important technology advances. And with that, I'll turn the call over to Beth to review our first quarter financial results. Then Eugene will discuss our recent key pipeline updates and preview upcoming catalysts for the rest of the year. After Eugene, I'll wrap up our prepared remarks before taking your questions. Now over to Beth.
spk03: Thank you, Brad. Our first quarter financial results clearly demonstrate a key element of our financial strength. That is our ability to consistently generate substantial revenue and cash from numerous diverse sources. Our revenues increased more than 25% year over year to more than $140 million, and were split approximately 50-50 between commercial and R&D revenues. Our operating expenses and net loss, both on a non-GAAP basis, were in line with our expectations. And we ended March with a healthy balance sheet, including cash and investments of $2.1 billion. These results keep us on track to meet our 2022 financial guidance. We earned $72 million in the first quarter in revenue from our marketed products, with the majority coming from Spinraza. Spinraza's global sales were $473 million, increasing more than 7% compared to last quarter. As a result, we earned $54 million in royalty records. Just as a reminder, our royalty rate resets at the beginning of each year. And as in prior years, we expect to quickly move through the royalty tiers and reach the highest tier by mid-year. Spinraza revenue increased in both the U.S. and ex-U.S. in the first quarter compared to the fourth quarter last year. In the U.S., new patient starts for Spinraza reached a two-year high while discontinues discontinuations continue to decrease. Outside the U.S., the increase in Spinraza revenue was driven by strong initial uptake in China. Baijin recently presented updates from the Ascend and Respond study in patients previously treated with competitive products. Baijin also presented new results from the Nurture presymptomatic study, which continues to show that patients receiving early and sustained Spinraza treatment Achieve and maintain motor milestones consistent with normal development. Based on these results and Spinraza's attractive profile, we continue to see a bright future for Spinraza. We earned R&D revenue of $70 million, which more than doubled compared to the same quarter last year. We earned R&D revenue from several different partners for advancing 15 programs. and revenue from our strategic collaboration with Biogen was the largest contributor. We earned $40 million in the first quarter from Biogen for advancing numerous neurological programs. Our R&D revenue also included $20 million in payments, cost-sharing payments from AstraZeneca for their 55% of first quarter development costs. We reported non-GAAP operating expenses of $173 million, which was a 9% increase compared to the same period last year. R&D expenses increased by more than 25% driven in large part by the six phase three studies we are currently conducting. Our R&D expenses also included increased spending for CMC and medical affairs activities to support our near-term commercial opportunity. SG&A expenses decreased year-over-year by about 40%. This was largely due to the substantial savings from the AXIA integration and SOVI transactions. These savings were offset in part by the investments we are making in our go-to-market preparation for Eplon-Turcin, Oluzarsan, and Donita-Lorison. Looking forward, we expect our revenues in Q2 to be similar to Q1. And we also anticipate that second half revenues will be more weighted toward the back end of the year. We project operating expenses to increase in Q2 and over the course of this year. Consistent with our guidance, we expect R&D expenses to increase between 25% and 30% this year compared to last year as our phase three studies continue to progress. We project our SG&A expenses to be in line with last year, even while we increase our investments in preparing to bring Athlon Tursons, Ola Zarsson, and Donita Lorson to the market. With $2.1 billion in cash and investments at the end of March, combined with our ability to generate substantial revenue from many diverse sources, we have the financial strength to underwrite the investments we are making to drive significant future growth. And with that, I'll turn the call over to Eugene.
spk11: Thank you, Beth. I'm pleased to report on the continued pipeline progress we made during the first quarter. Our phase three programs are progressing well. Most advanced is at one person, but data from the phase three neuro-transform study expected mid-year. And as Brad said, we're preparing to file for regulatory approval in the second half of this year, assuming positive data. Additionally, we're looking forward to presenting baseline characteristics from the neurotransform study at the Peripheral Nerve Society Congress later this month. Last week, we announced that we achieved our original enrollment goal ending up on person phase three cardiac transform study. We also announced an important amendment to our study. The amendment included expanding enrollment to approximately 1,000 patients from 750 patients. and extending the blinded dosing period to 140 weeks from 120. The Cardiotransform study is the largest study in patients with ATTR cardiomyopathy. It was designed to generate clinical evidence of up on-tours benefit when administered alone or in combination with stabilizers. This should enable physicians and payers to make the most informed decision. By increasing the size and duration of the study, our aim is to ensure a highly positive study outcome and to generate an even more robust data in a broad patient population to successfully compete in this growing and dynamic . The timing is right to implement these changes now because enrollment is occurring at a very high rate. We have accumulated a substantial amount of baseline demographic and clinical data. And our first patients are nearing entry into the open-label extension. Based on our current rate of enrollment, together with the updates to the study that I just outlined, we're projecting a modest shift to our timeline with data readout moving from late 2024 to first half of 2025. Our broad Alzheimer's development program also continues to advance and remains the leading program targeting APOC3 currently in clinical development. We designed the Olazarsen Development Program to fully realize the potential of this medicine, including moving it towards the market in two indications, FCS and severe hypertriglyceridemia. We have two ongoing phase three studies, the balanced FCS study, which is on track for data next year, and the core SHTG study, with data planned for 2024. In phase two, we demonstrated robust reductions in triglycerides and ApoC3 with monthly 50-milligram dose. And our two phase two studies, in addition to evaluating 50-milligram monthly dose, we're also assessing an 80-milligram monthly dose, which we expect to result in even greater triglyceride reductions. The Dunning-Dolorsen phase three OASIS-EGE study data in 2024. Earlier this year, we reported additional data from the Dolores and Phase II study demonstrating clinically meaningful and sustained improvements in quality of life in patients with HIV. Coming up later this year, we plan to report data from the ongoing Phase II open-label extension study, including data from the monthly and bimonthly dose group. In June, Biogen plans to present new integrated Toperson data from VALOR and the ongoing NOAA leak in patients with SADL1 ALS who were treated for up to one year. Additionally, Biogen remains engaged with regulators to identify potential BAP or Toperson. We also have a rich mid-stage pipeline that we expect to continue to deliver. Here are some of the recent highlights. We're pleased with the positive case-to-be data from the Etesian study for ION449 or PCSK9-like medicine in patients who are at high risk of cardiovascular disease with hypercholesterolemia. The study methods, primary and secondary endpoints, ION449 demonstrated dose-dependent reductions in mean LDL cholesterol levels by up to 79% and PCSK9 levels by up to 94%. The positive results from the ETGEN study give us confidence that IOM449 could change the current standard of care for patients affected by hypercholesterolemia who have cardiovascular disease. Additionally, the Solana Phase 2B study of IOM449 designed to confirm potential Phase 3 deaths is ongoing. We believe that AstraZeneca will make a decision on further development later this year based on the ETGEN and Solana study results. We also recently completed enrollment in our Phase II D study of Ionis AGT-LRX, our medicine to treat patients with treatment-resistant hypertension, keeping us on track for data in the second half of this year. We're also advancing Ionis AGT-LRX in a Phase II study in patients with chronic heart failure with reduced ejection fraction, which we expect to read out next year. In addition to the programs I already mentioned, we expect several more data readouts in our hepatitis B drug and Bayer to report data from our base-to-B study of hesomersin or Factor XI Leica medicine in patients with end-stage renal disease. As I just summarized, we have a number of important mid- and late-stage programs progressing. As the year unfolds, we're looking forward to a steady cadence of data rebounds.
spk09: And with that, we'll turn the call back over to Fred to close this portion of the call. Thank you, Eugene. We're off to an excellent start this year. We continue to execute on our three strategic priorities that I believe will drive substantial growth for Ionis, building the Ionis commercial pipeline, including rapidly advancing our three near-term commercial opportunities at Blantersen, Olisarsen, and Donniforsen toward the market, and making great progress in building on our commercial organization for these important medicines. technology, including advancing our follow-on medicine, Spinraza, that we announced earlier this year, as well as making other important technology advances. We look forward to sharing further details on these advancements later this year. And our third strategic priority, delivering an abundance of new medicines to the market in the near term and the longer term, starting with our planned launch of Epon Additionally, we're well capitalized with the resources we need to continue executing on all our priorities. With up to seven key data readouts expected from our mid and late stage pipeline before year end, the remainder of 2022 looks to be highly productive and eventful. And with that, I'll now open up the call for questions. Operator?
spk07: Thank you. We will now begin the question and answer session. To ask a question, you may press star then 1 on your touchtone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then 2. And at this time, we'll pause momentarily to assemble our roster. And the first question will come from Yanen Zhu with Wells Fargo. Please go ahead.
spk17: Hi. Thanks for taking my questions and congrats. the progress in the quarter. So I hope you could elaborate a little bit more on the protocol change to the CardioTransform study, putting things into context a little bit more for us. I think you probably have been monitoring the cardiovascular event rate And you probably also are looking at the overall patient mix in terms of disease severity, tefamidus use, and all that. So what have the observation been during those monitoring, and how did that lead to the decision to expand the study? And also, lastly, just curious, have you also looked at the six-minute walk data And how does that compare with some of the data that we have seen from other companies? Thank you.
spk09: Thank you for the question. Appreciate it. And I'll address it and ask Eugene to expand on it. So, you know, as we've been saying for quite some time now, we have been right from the onset of this study from the get-go. monitoring the enrollment and the demographics for this study. Demographics that relate to, for example, you know, the severity of how sick the patients are, New York Health Class Association 1, 2, 3, for example. How much defaminous usage is in the study versus naive patients, the balance between hereditary and wild type patients. Those are the primary things that we're looking at. And all along, we were projecting that we would possibly make adjustments to the study to ensure that the study readout was as successful as possible in a really big market, in a growingly competitive market. And that's exactly what we did. There were no fire alarms that went off or anything like that. We're doing something and pulling the trigger on something that we were planning to potentially do all along. It's really less about event rate. It's relatively early on in the study. Those events really start accumulating in the second half of a cardiovascular outcome trial. Sure, we're looking at events, but it's really driven by the demographics and the type and the patient populations that we want to have in our study that really ensures for a successful, a highly successful of making sure we have the right patients in the study. And then the last thing I'll say before asking Eugene if he has anything he might expand on is the fact that this is the right time to do that in this study. This is the perfect time. We're early on in the study. We are well positioned to be able to make that decision without having a significant, really a significant impact on the study timing. It's a modest delay. And the expense and the investments are small. Measure that up against a, you know, the upside that this provides in allowing us to have a very positive outcome, you know, is very, very important, very significant. Enrollment is going very fast. We're very strong, so this is the right time to do the study. There's no point making an adjustment like this waiting to study. This is the time to do it, and it's all for good reasons. Yep. Eugene, anything to add to that?
spk11: That was really, really well characterized. I would only also add that this change also gives us, maximizes our ability to look at important subgroups within the study, which is also going to be critical for informing practice patterns and providing a meaningful data set for stakeholders when the study reads out.
spk17: That's super helpful. Thank you for that answer. If I may ask about the mid-year aplomb person polyneuropathy data readout, would you be able to share any color on what stage are you currently in, in terms of locking the database, data analysis, and all that, and any additional color around what time could we potentially see the data? Thank you.
spk09: Yeah, so as we've been saying, Jan, and we're right on track to achieve, we've been saying mid-year this year, we're expecting the top-line data from the up-on-tours polyneuropathy-based study, and we're really not providing much more color than that. What I can add to that is that, In parallel with, you know, the study coming to completion, we're preparing for the filing, regulatory filing, as we said, and our prepared remarks. And we're also planning to, for the launch. And maybe I could ask the name to maybe provide some color on the preparations we're doing on preparing for the launch with our partner, AstraZeneca.
spk15: Yeah, sure. Diane, and, you know, launch preparation, you know, it takes a lot of effort across a lot of team members, and I'm pleased to say, you know, the teams just had actually a pretty robust launch readiness meeting last week with AstraZeneca and their offices in the East Coast, and we had really everybody from clinical to CMC and obviously the marketing teams as well as the customer-facing teams and medical affairs to kind of think through the overall launch preparedness. They are in great shape. It's a collaboration that is really building on each other's strengths. You know, our knowledge of amyloidosis and being in the market for about a decade and rare disease along with kind of the broad reach and expertise is really a really great complementary collaboration made in heaven, I would say. So we're in really good shape, and I would say well ahead of the curve for getting this product launched next year, assuming everything all goes well, and we're expecting to file by the end of the year as well. So teams are ready to go.
spk17: Thank you. Thank you. That's great to hear.
spk07: The next question will come from Yaron Werber with Cowen. Please go ahead.
spk18: Hi. This is Brendan on for Yaron. Congrats on the quarter, guys, and thanks for taking the questions. Just a couple quick ones from us. First, in treatment-resistant hypertension, can you maybe just remind us what the Phase 2 readout is going to look like there, maybe in terms of the number of patients and what kind of data we can expect? And really, in that same program, I guess, as you're looking ahead to a potential Phase 3, is there like a threshold or what are you really looking for in terms of efficacy or target engagement there that would give you confidence to move forward with the drug? Excuse me. Thanks very much.
spk08: Eugene, would you like to take that?
spk11: Sure. Yeah, so the phase two current data is in patients with treatment-resistant hypertension. We're hoping basically to see consistent effects with what the earlier smaller study had demonstrated, which range in the order of 10 to 15 millimeter mercury. But again, in a larger study, of course, with greater variability, what we're hoping to see, of course, are highly statistically significant changes. The study is appropriately sized for this type of exploration. It's in 150, approximately 150 patients. So really there's, that's all I could tell you at this point.
spk09: And if I can just expand on that a little bit. Thanks, Eugene. Just a reminder, Brendan, we have a pre-comprehensive program ongoing for AGT right now. In addition to that readout for the Phase IIb study later this year in refractory hypertension, we have an ongoing study with that drug in patients with heart failure. We're looking for that to read out next year. And then coming up behind our lead drug is a new molecule, our Gen 2.5 AGT molecule that completed phase one very successfully, and now we're planning to start phase two. And sometime next year, we plan to look at all the data, the lead molecule, the follow-on molecule, heart failure, refractory hypertension, and we will make a decision on what's the best molecule confirmation of the proof of concept we already achieved in refractory hypertension in a bigger patient population. And also with good safety, of course. And when I say safety, I mean on-target safety. We need to be very, you know, aware of the fact that the vision of this pathway, the RAS pathway in the kidney, you know, can cause kidney issues. And we haven't seen it in our phase two studies. which targets the liver, not the kidney, but we need to confirm that. And once we look at all the safety and the efficacy of the study, we'll make a call on the next step for potentially for phase three.
spk18: All right, great. Thanks so much.
spk07: Thanks, Brandon. The next question will come from Luca Issy with RBC. Please go ahead.
spk05: Well, great. Thanks so much for taking my question. Congrats on all the progress here. So maybe on TTR polinuropathy, I think the primary endpoint is actually at nine months. Will that be sufficient for filing both in the U.S. and in the EU? Or will you need to weigh the 18-month data point to file in the EU, similar to what has happened to Alnylin? And then maybe on PCSK9, I think pretty impressive knockdown. However, we did see four patients at the high dose experiencing some ALT elevations, two of them, I think, discontinued the drug. So, wondering how you're thinking about that in the context of Inclisiran. At least I'm not aware of that signal. And then finally, any update on the pulmonar franchise post the ENAC discontinuation? Thanks so much, guys.
spk09: Thanks, Luca. You squeezed a lot in there. I'm happy to... on 449, our PCSK9 drug was presented to ACC. You know, there's such an enormous need for more effective LDL lowering drugs for patients at high risk for cardiovascular disease and continued hypercholesterolemia despite being on statins, azetamide, despite being on monoclonal antibodies for PCSK9, but despite being on Inquisiran. This molecule looks to be the most potent, efficacious PCSK9-lowering drug, LDL-C-lowering drug, of any that has come out to date. And that is why AstraZeneca is so enthusiastic about this program. It could be a real game-changer for the millions of people suffering from hypercholesterolemia and CBD. The Phase IIb incision study was a dose-ranging study. And we achieved reductions of LDL-C greater than well over 70%. And HFK9 in the 90% range had doses where there were no signals on ALTs. It was a 50 mg monthly dose in that study. And 90 mg dose where we saw, I think, four patients with mild ALT elevations. A couple of things worth noting. One is that they're mild. Two is that two of the patients continue dosing and ALP turns baseline or towards baseline. So, you know, this isn't all a toxicity. It's an ALP observation in a very small number of patients at 90. But more importantly, about the phase three dose, the phase three doses are going to be in the range of 50 or so. in that range because that's what we're achieving, our LDL targets there. And there's an ongoing study called Solano that AC is conducting to further confirm the phase three dose. And that study's looking very good, and they're preparing for phase three development. So the drug looks very good, very safe, and we haven't seen any bumps in the road. With respect to Clisiran, I prefer not to comment competition, except what I already said. There's a need for more effective LDLs. See lowering agents. Patients are not getting to their target. And so a drug like Ion449 is needed in this patient community.
spk08: You want to talk about pulmonary a little bit, Eric?
spk10: Sure. So what we're doing in pulmonary is taking a hard look at some of our chemical class. And the hope there is we can find some molecules that overcome some of the clinical issues we saw with inflammatory effects and not even primates. And here we're thinking of some of the new backbone chemistries that we've talked about that allow us to tinker with the properties of the molecule and reduce the baseline potential for inflammatory effects. And we've seen really good data on some of these compounds across multiple programs and are working hard to try get some data in the relevant species in the not too distant future to both advance some new chemistries and also potentially move them into some pulmonary diseases where we think there's lots of potential applications with lots of unmet medical needs.
spk09: And we're making solid progress in the areas It's going to be reactivated soon on the development side. I didn't answer your question about polyneuropathy. I apologize. I kind of went out of order. So we're planning to file the MDA this year on epinephrine and polyneuropathy. I should point out that you mentioned 18-month data. Remember, our full data set completes 15 months, not 18, in the neurotransform study. But what you're highlighting is the fact But XUS, European regulators, have set a higher bar for approval, and they have signaled that they would like to see the full data set. With that said, we have a rule about XUS filing, and we're keeping that option open. But we're focused right now on the NDA.
spk07: Super helpful. Thanks so much, guys. Got it. The next question will come from Jessica Fye with J.P. Morgan. Please go ahead.
spk02: Hey guys, good afternoon. Thanks for taking my questions. I wanted to follow up on a prior question about the changes to CardioTransform. You talked about them being driven by patient demographics. Are you changing any of the inclusion or exclusion criteria and or the regions you'll focus on for further recruitment in addition to just increasing the sample size and treatment duration?
spk11: Thanks for your question, Jessica. So no, we're keeping eligibility criteria the same. We are, however, looking into sort of geographies with fairly specific intention of, again, as Brad said, ensuring that the population we enroll is number one representative of sort of the current landscape of patients with ATTR, the full landscape, but also importantly enables us to make some inferences For drug attacks, an importance of groups of patients.
spk09: And that could involve prioritizing certain geographies and territories, to your second point.
spk02: Okay. So I guess it's related.
spk09: I should say it will involve that. It will involve that.
spk02: Yeah. Because I think in the past you've talked about your expectation for maybe a 50-50 split between patients who are on background tofamilis and those who are not. even though you're not limiting background depamitis. So is that still your expectation, that that'll be the mix?
spk09: With what we've said, Jess, is we want the naive versus depamitis usage to be very well balanced. So, you know, 50-50 would be perfect, but, you know, we're looking for a well-balanced naive versus depamitis usage.
spk02: Okay. And I guess the last one on this topic, Were these changes to CardioTransform prompted by a recommendation from the DSMB, or were they made without DSMB input? And has there been an interim analysis in the trial at this point?
spk09: There's been no interim analysis. We still have an option to conduct an interim analysis after the patient's, you know, at the appropriate time, but we have done no interim analysis at this stage. This was driven entirely by IONIS. This has nothing to do with a safety oversight committee or even AstraZeneca. We put this forward, as I said earlier in the call. It's always an option. This was always part of the plan, not to necessarily do it. potentially to it, and we're now triggering that option that we have, and we're in an excellent position time-wise and enrollment-wise to be able to trigger this today. Of course, we engage AstraZeneca, and they fully support the decision, and we're working, you know, hand-in-hand with them on implementing that. But no, this is entirely driven by IONIS.
spk02: Okay, great. Thank you.
spk07: Thank you. The next question will come from Paul Mateus with Stifel. Please go ahead.
spk12: Hey, thanks for taking our questions. This is Alex on for Paul. Just one Eplon-Tersen polyneuropathy question and then one neuro question. So for Eplon-Tersen, can you remind us, is there a pre-specified cardiac subgroup within the polyneuropathy study? And if so, do you expect to have any exploratory biomarker imaging data either at this readout or the full readout? And then on neuro, Given that Biogen announced that their pipeline prioritization, have you thought at all about reacquiring any rights to your neuro programs in collaboration with Biogen? Thanks. You know, I think the first one, the cardio subgroups in the neuro. Yeah. Thanks for your question.
spk11: So, yes, there will be an analysis, a look at specific subgroup, predefined look in the cardiac subgroup of polyneuropathy. Neurotransform study. It's, again, just to remind you, it's not exactly the same population to Cardiotransform. These patients don't have symptomatic heart failure. They're largely polyneuropathy patients with mixed phenotype and having some evidence of cardiac disease. I think that's an important distinction. But yes, there will be an important subgroup . Yeah, now it's a, let me just take a step back. We have a very strong partnership and relationship with Biogen that spans 10 plus years now.
spk09: And, you know, started with Spinraza and grown and got stronger and stronger over the years. Their relationships are strong at all levels. in the partnership. We've gone through management changes before at the top with Biogen and without a bump in the road, without any setbacks or anything like that. I actually think that the Ionis pipeline of drugs that we're working on with Biogen have become, will become an even higher priority than Biogen. I don't think they're going to be willing to give those up easily. You know, they're going to be turning the page they're going to be looking at the drugs like MAPT, the follow-up, and everything else that we're working on with them. I think these will continue to be very high, higher priorities with Biogen. With that said, we're very pleased with our neural pipeline of drugs that, you know, that we are growing here at Ionis, that whole known Ionis neurology pipeline. And one example of that is we're, very much looking forward to starting our studies in prions in the second half of this year as one of our lead programs, not our only program, but one of the key programs that we've highlighted as a key study initiation this year. So, no, I don't think we're going to be requiring assets from Biogen as a result.
spk12: Thanks, and just one clarification. Do you expect any of the cardiac data at the top line midyear or not until later? Thanks. No, so the top line will be data on the full population.
spk11: All of the subgroups will be reported at a later time.
spk07: The next question will come from Gary Nachman with BMO Capital Markets. Please go ahead.
spk16: Hi, thanks. So, first, just another follow-up on Eplon-Tersen and adding more patients to the cardiomyopathy study. So, why didn't you wait until the PN data before making the decision since the data are coming soon? And it sounds like, you know, we will have some cardio data in there. for some of the patients, and it potentially could have been informative to your decision. So that's one. And then also for Beth, the 20 million that you got from AZ for Eplon-Turistan development costs, is that the kind of number we should expect on a quarterly basis, or is there some upfront loading in there? And then lastly, just what are the next steps for 449, the PCSK9 program? Do you have an idea? what types of dyslipidemic patients you'll target in the next phase based on the phase 2b data that read out? Thank you.
spk11: I think the answer is sure. I'll take the first question. So related to timing of this amendment, as Brad said, again, we've been, We've been mulling this over for quite some time, and the timing was one of the key considerations, and we felt that the timing now was really kind of ideal for implementing a change such as this one. Why not wait until neurotransform? Well, firstly, it's just a very different patient population that we enrolled in neurotransform, so we just don't see how this would inform us whatsoever with regard to cardiac transform. Secondly, the cardiac transform changes are really driven by their intentional desires for particular sort of balance in the population characteristics that Brad had outlined.
spk03: Sure. So on the 20 million, the way to think about that is it's the 55% of our, FULLY LOADED EPLON TURSON BROAD PHASE THREE DEVELOPMENT EXPENSES IN THE FIRST QUARTER. SO WHEN I SAY FULLY LOADED, THAT MEANS EXTERNAL EXPENSES, INTERNAL FTE EXPENSES, AND CMC EXPENSES. SO THAT 20 MILLION IS ESSENTIALLY 55% OF WHAT WE INCURRED IN THAT PHASE THREE PROGRAM IN THE FIRST QUARTER. SO AS WE CONTINUE TO SEE THOSE EXPENSES GROW, over the course of the remainder of the time, particularly with the cardiomyopathy study. And as we get closer to that data readout and to launching the drug, those expenses in that broad phase three program are going to continue to grow. And so the 55% that AstraZeneca is responsible for will also grow. And you'll see that each quarter. And it's true that it's the same amount Let me say this differently. The development expenses and the 55% of revenue are for the same quarter. So there's no offset. There's no loading. There's no lag in that. They're aligned. So as expenses grow each quarter, so will the 55% of revenue under the Appalachian Joint Collaboration Revenue Line.
spk09: And Mary, regarding PCSK9, if you think about it like this, it's the same patient population that was treated in adhesion. That's why that study is so important. It's actually the same by patient population. Patients that have cardiovascular disease, so they've had an event in their life, have high LDL cholesterol on moderate to maximum doses of statins and Zetia. That can't get to their LDL target.
spk16: population. Okay, great. And when is that study going to start? I may have missed it. I jumped on late.
spk09: No problem. The actual study start hasn't been disclosed, but what has been is that AstraZeneca will make a decision on phase three development in the second half of the year. Remember, there's a study ongoing. The reason for that is there's a study ongoing. to confirm the base three dose. And so that not necessarily the same dose that was in the teach, right? They're looking to really solidify the base three dose in Solano. That study is wrapping up. It's really coming to a completion. And that's the basis of the delay in making that decision.
spk16: Okay, great. Thank you.
spk07: Yeah. The next question will come from Manny Ferruher with SVB Securities. Please go ahead.
spk04: Thanks for taking my question. Not to be an entirely dead horse, but I want to talk a little about the commercial opportunity and strategy around your approach to TGR cardiomyopathy. There's a clear avenue for you guys to have the closest thing to a true add-on label for combination therapy on top of a stabilizer. How do you think about pricing strategy should you be approved with a label that has data that supports that use? And how do we think about the pricing opportunity prior to and then after to FAMNA's genericization in the U.S. versus EU markets?
spk08: Manisha, would you like to take that?
spk15: Sure. Hi, Mani. How are you? So yeah, great thinking over here in terms of the Eplen-Turcin strategy. I'll kind of start off with I think the amendment that we filed here is just to really accelerate our leadership position in ATTR from early to late stage disease. We're looking at about 300,000 patients in cardiomyopathy. The data set that we're going to get, as Eugene said, is really important for all all players, including payers as well as clinicians. So as we've gone out in the marketplace and, you know, really tested out the target product profile, it is extremely important to generate data that's on top of defamitis as well as naive because we're going to have, you know, in this very dynamic market, a set of patients that are going to be either naive to therapy or a lot, particularly in the U.S., treated on tefamidus. And they're going to look for what is your clinical evidence for these patients and how do I actually treat them if they're already on tefamidus and how do I treat them if they're naive. And we will have both data sets to be able to do that. The payer strategy and what we've learned from payers thus far is that they view this patient population differently. as a very sick patient population, you know, in terminal disease, and they are not going to manage this actively to say what a physician should do if you're already on another standard of care or you're in combination to that. If the physician requires a combination therapy, that's what they're looking to approve and not necessarily have a step through in this situation, which is one of the questions obviously we had. So we're expecting actually a relatively open environment from a payer perspective. Obviously, they all go through prior odds, but nothing onerous in terms of, you know, huge requirements and or steps through therapies as well. So we'll price accordingly to where the clinical value proposition is coming out, which is going to be a very robust set of clinical evidence.
spk04: Great. That's really helpful. Thank you.
spk07: Thanks, Ben. The next question will come from Joseph Stringer with Needleman Company. Please go ahead.
spk06: Hi. Thanks for taking our question. A quick one from us on Cyndalersen and Acromegaly, the Phase II readout, excuse me, second half of this year, monotherapy. What reduction in IGF-1 or perhaps a percent of patients that have normalized IGF-1 would you be looking for or that would give you confidence in this program going forward? Thank you.
spk11: Sure. So really the remaining need here is being able to achieve normalization of IGF-1, and that's really the bar that we set for this drug, both in a monotherapy setting as well in the add-on setting. So outside of that, I can't really speculate what the threshold in terms of responder rate that would get us really, really excited. We're obviously planning for very positive readouts in terms of IGF-1 normalization.
spk15: Yeah, I would just add here that both sets of data on monotherapy and in addition to SSAs are going to be really important here from a market perspective as well. And we'll have both sets of data. And people are still seeing good breakthrough attacks over here, so I do think that IGF normalization is a key goal, but having sets of data as monotherapy as well as in combination will be very important.
spk07: The next question will come from Salveen Richter with Goldman Sachs. Please go ahead.
spk14: Hey, thanks. This is Matt for Salveen. Just going back to 449, could you guys discuss your thoughts on market strategy or pricing? And then separately, could you give us an update on your ALS programs? In particular, when should we expect Phase 1-2 data for 541? Thanks a lot.
spk09: So for 541, that's our 8-axis-2 drug. in sporadic or non-genetic ALS. Biogen is running that study, and they've disclosed timing, but I would, you know, look towards next year for that data readout. And, of course, you know, we're very much looking forward to that. And that could go to phase three based on, you know, if the results are positive. Oneza, would you like to talk a little bit you know, commercial opportunity, and I don't know if you really touch on pricing much for DCSK9, but why don't you go for it?
spk15: Yeah, sure. Really large market, you know, about 11 to 16 million patients, so a very large population that's still uncontrolled on maximal tolerated statins. The guidelines are really getting aggressive here because of the cardiovascular risk for these patients, particularly secondary patients. prevention and they're leading to about 70 milligrams per deciliter in the US and 55 actually milligrams per deciliter outside of the US. So really good momentum I would say in terms of aggressive guidelines to treat which I think will help this entire market growth substantially. Etizien showed you some tremendous LDL-C reduction, which is well above what the MABs have shown and also well above what Inclisiran has shown in this area. So just to put into context, we're looking at about the 50% range for Lecvio, about the 60s for the MABs, and we're looking at in the 70s for our PCSK9, which is going to be a really substantial improvement in LDL lowering and we expect with all the modeling this will also translate into really good MACE reduction as well. That positioning is what will drive the value proposition and kind of the pricing strategy and also which level of area that we actually want to go into in terms of the reimbursement schemes as well. So it's really well positioned to do well, but the efficacy profile, the best in class efficacy is what's going to kind of drive the go-to-market strategy for this agent.
spk07: The next question will come from Miles Minter with William Bleer. Please go ahead.
spk13: Just in your prepared remarks on 449, you did say AstraZeneca is going to make a formal decision on the phase three in the second half, but the commentary on the call today seems to be like that's well and truly going ahead. So Brett, can you just clarify what prepping for phase three development actually means? Is that just getting these phase two trials done? Or have you seen a protocol? And then Beth, can you talk to the milestone structure, if anything, on that deal, if a phase three is started up in the second half? And my last one is just on the muscle like a program. Are you planning to take a single asset into IND enabling studies there? I know you have multiple collaborations and programs there. Or would you take multiple programs into the IND top studies? Thanks. Thanks, Myles.
spk09: Yeah, this is, AstraZeneca is not planning to start phase three development from, you know, from a stop position after the ongoing slots data reach out. They're very much preparing for phase three now. That includes making the drug, getting the drug ready, and then that's on display. The protocol, sure, protocol's being developed, and they're preparing for an end of phase two meeting. So, you know, and we're working very closely motion. All that is happening. We're really just waiting on finalizing protocols and getting ready for regulatory interactions. You know, obviously we've had regulatory, they've had regulatory interactions previously, but now this is the end of phase two interaction for that and getting drug ready. So yeah, all those wheels are in motion. And as far as the economics of that.
spk03: Sure. So we've already or earned a substantial amount of revenue from this program. So now as we look forward to the next step, there aren't any milestones associated with phase three, but there are, you know, a substantial amount of milestones for sort of common regulatory type events. And then a very significant amount of commercial milestones that add to our tiered royalties that go up into the teams.
spk10: Muscle lichen. Eric. Yeah, sure. So what we've stated was we're having an objective to advance one muscle lichen into development this year. As you know, we have lots of programs. We have to start one first before we get to many, I think. There's lots of great opportunities there. We have lots of preclinical programs, and we plan to be aggressive in picking off the best clinical opportunities and where there's the most unmet need and moving those programs forward.
spk09: Yeah. I mean, we're, just to put a fine point on that, Miles, Eric, under pressure to move several muscle-like to development because the data's really looking great. I also want to remind you that we have our own muscle-like programs. I own this whole young. We also are working on neuromuscular diseases with Biogen. And we also have an excellent partnership with AstraZeneca in cardiovascular disease, aka cardiac. So we have a lot of, you know, balls here. And things are moving forward, but, you know, what will be first is less important than
spk07: Fair enough, thanks for getting to all of this. You got it. The next question will come from Yeo Jin with Laid Law and Company. Please go ahead.
spk01: Thanks for taking the questions and congrats on the progress. Just two quick ones. The first one, just want to clarify that in terms of the cardio transform trials, does that include any patient with a mixed phenotype, in other words, with the polyneuropathy patients or simply purely all in cardiopsy?
spk11: Yeah, no, it very much includes some patients that have mixed phenotype. We are certainly aware of how significant of an overlap there is between the two sort of edges of the spectrum, if you will, that used to be considered very separate diseases. organ systems. So yeah, we are looking at neurological endpoints appropriate for the patient population.
spk09: And you know, Yale, it's an interesting question. There's more and more attention in this field being paid to neuropathy symptoms that patients with wild-type cardiomyopathy have. So it's a very relevant question. It's something we are paying very part of your transform study, like Eugene said. So thanks for the question, Yale. Unfortunately, we're over time, so we're going to have to close the call. I really do want to thank everybody for joining today and participating on the call. We're making great progress at IONIS. We're very happy about the first quarter, and we're very excited about the rest of the year ahead. And we look forward to providing additional updates throughout the rest So then thanks very much and everybody
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