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.
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, Elizabeth L. Hougen, Chief Financial Officer, and Eugene Schneider, Chief Clinical Development Officer. Joining us for the Q&A portion of the call are Eric E. Swayze, Executive Vice President of Research, and Onaiza Cadoret-Manier, Chief 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 Monia.
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 continued 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, Eplontersen, olezarsen, and Donidalorsen. The phase III NEURO-TTRansform study of Eplontersen in patients with TTR polyneuropathy remains on track for data mid-year. Working hand in hand with AstraZeneca, we're preparing to file for regulatory approval by the end of the year, assuming positive data. At the same time, we're also jointly advancing our go-to-market preparations. We recently achieved our original enrollment goal in our CARDIO-TTRansform study for patients with ATTR cardiomyopathy.
Last week, we announced that we took a bold step by increasing the size and duration of our study. In doing so, we expect to generate even more robust data, 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 readout shifting from late 2024 to the first half of 2025. We also continue to advance our olezarsen phase III program in patients with high triglycerides. The BALANCE study of patients with familial chylomicronemia syndrome, or FCS, remains on track for data next year. 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 ineffective. With over 3 million patients in the U.S., severe hypertriglyceridemia and our first-mover advantage, we believe olezarsen represents a blockbuster opportunity for Ionis. Our phase III OASIS-HAE study with Donidalorsen in patients with hereditary angioedema also continued to progress well with data expected in 2024. We believe Donidalorsen has the potential to be a best-in-class prophylactic treatment for HAE patients. As a result, Donidalorsen 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 ETESIAN study of ION449, our PCSK9 medicine in patients who are at high risk for cardiovascular disease with hypercholesterolemia. The study met primary and secondary endpoints, showed good safety and tolerability, and ION449 demonstrated a potential best-in-class profile. With more than 10 million patients in the U.S. remaining above their LDL-C goal despite maximum statin and ezetimibe therapy, we believe ION449 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 III Eplontersen data read out mid-year and our planned regulatory filing by year-end. We also expect three more phase IIb data read out several key study initiations and updates on important technology advances. With that, I'll turn the call over to Beth to review our first quarter financial results. Eugene will discuss our recent key pipeline updates and preview upcoming catalysts through the rest of the year. After Eugene, I'll wrap up our prepared remarks before taking your questions. Now over to Beth.
Thank you, Brett. 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. 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 revenues. Just as a reminder, our royalty rate resets at the beginning of each year. 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 discontinuations continued to decrease. Outside the U.S., the increase in Spinraza revenue was driven by strong initial uptake in China. Biogen recently presented updates from the ASCEND and RESPONSE studies in patients previously treated with competitive products. Biogen 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 Eplontersen's first quarter development costs. We reported non-GAAP operating expenses of $173 million, which was a 9% increase compared with the same period last year. R&D expenses increased by more than 25%, driven in large part by the six phase III 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 opportunities. SG&A expenses decreased year-over-year by about 40%. This was largely due to the substantial savings from the Akcea integration and Sobi transactions. These savings were offset in part by the investments we are making in our go-to-market preparation for Eplontersen, olezarsen, and Donidalorsen. 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 III 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 Eplontersen, olezarsen, and Donidalorsen 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. With that, I'll turn the call over to Eugene.
Thank you, Beth. I'm pleased to report on the continued pipeline progress we made during the first quarter. Our phase III programs are progressing well. Most advanced is Eplontersen, with data from the phase III NEURO-TTRansform study expected mid-year. As Brett 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 NEURO-TTRansform study at the Peripheral Nerve Society Annual Meeting later this month. Last week, we announced that we achieved our original enrollment goal in the Eplontersen phase III CARDIO-TTRansform 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 CARDIO-TTRansform study is the largest study in patients with ATTR cardiomyopathy. It was designed to generate clinical evidence of Eplontersen's benefit when administered alone or in combination with stabilizers. This should enable physicians and payers to make the most informed decisions. 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 market. 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 read out moving from late 2024 to first half of 2025. Our broad olezarsen development program also continues to advance and remains the leading program targeting APOC3 currently in clinical development. We designed the olezarsen 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 III studies. The Balance-FCS study, which is on track for data next year, and the CORE SHTG study with data planned for 2024. In phase II, we demonstrated robust reductions in triglycerides and APOC3 with monthly 50-milligram dose.
In our two phase III 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 Donidalorsen phase III OASIS-HAE study is also progressing and remains on track for data in 2024. Earlier this year, we reported additional data from the Donidalorsen phase II study demonstrating clinically meaningful and sustained improvements in quality of life in patients with HAE. 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 groups. In June, Biogen plans to present new integrated tofersen data from VALOR and the ongoing OLE in patients with SOD1 ALS who were treated for up to one year. Additionally, Biogen remains engaged with regulators to identify a potential path forward tofersen.
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 phase IIb data from the ETESIAN study for ION449, our PCSK9-like medicine in patients who are at high risk of cardiovascular disease with hypercholesterolemia. The study met its 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 ETESIAN study give us confidence that ION449 could change the current standard of care for patients affected by hypercholesterolemia who have cardiovascular disease. Additionally, the SOLANO phase IIb study of ION449, designed to confirm potential phase III dose, is ongoing. We believe that AstraZeneca will make a decision on further development later this year based on the ETESIAN and SOLANO study results.
We also recently completed enrollment in our phase IIb 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 this year, including GSK to report data from the phase IIb study in our hepatitis B drug and Bayer to report data from our phase IIb study of fesomersen or Factor XI LICA 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 readouts.
With that, we'll turn the call back over to Brett Monia to close this portion of the call.
Thanks, 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, Eplontersen, olezarsen, and Donidalorsen toward the market, and making great progress in building out our commercial organization for these important medicines. We're also continuing to build on the substantial progress we made last year in expanding and diversifying our technology, including advancing our follow-on medicine to Spinraza that we announced earlier this year, as well as making other important technology advancements. Look forward to sharing further details on these advancements later this year.
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 Eplontersen for patients with ATTR polyneuropathy as early as late next year. 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. With that, I'll now open up the call for questions. Operator?
Thank you. We will now begin the question-and-answer session. To ask a question, you may press star then one on your touchtone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. At this time, we'll pause momentarily to assemble our roster. The first question will come from Yanan Zhu with Wells Fargo. Please go ahead.
Hi, thanks for taking my question, and congrats on the progress in the quarter. I hope you could elaborate a little bit more on the protocol change to the CARDIO-TTRansform study, putting things into context a little bit more for us. I think you probably have have been monitoring the cardiovascular event rate, and that you probably also are looking at the patient, overall patient mix, in terms of disease severity, Tafamidis use and all that. What have the observation been during those monitoring, and how does that lead to the decision to expand the study? 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.
Thanks, Yanan, for the question. Appreciate it. I'll, you know, address it and ask Eugene to expand on it. You know, as we've been saying for quite some time now, we have been at 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 Heart Association one, two, three, for example. How much tafamidis 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.
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 and a growingly competitive market. 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, Yanan. 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, highly successful outcome.
We're not looking at six-minute walk tests. That has nothing to do with this decision. This is all about making sure we have the right patients in the study. The last thing I'll say before asking Eugene if he has anything he'd like to 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. The expense and the investments are small.
You measure that up against, you know, the upside that this provides in allowing us to have a very positive outcome, you know, is very important, very significant. Enrollment is going very fast. It's very strong, so this is the right time to do the study. There's no point in making an adjustment like this late in the study. This is the time to do it, and it's all for good reasons. Yep. Eugene, anything to add to that?
No, it's really well characterized. I would only also add. 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.
That's super helpful. Thank you for that, answer. If I may ask about the mid-year Eplontersen polyneuropathy data readout, can you would you be able to share any color on what stage are you currently in terms of, you know, locking the database, data analysis and all that? Any additional color on around what time could we see, potentially see the data? Thank you.
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 Eplontersen polyneuropathy-based study. 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 a completion, we're preparing for the filing, regulatory filing, as we said in our prepared remarks. We're also planning for the launch. Maybe I can ask Onaiza to maybe provide some color on the preparations we're doing on preparing for the launch with our partner, AstraZeneca.
Yeah, sure. Yanan Zhu 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 out in their offices in the East Coast. We had really everybody from clinical to CMC and obviously the marketing teams as well as the customer-facing teams and medical affairs to kinda 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 their broad reach and expertise is really a really great complementary collaboration made in heaven, I would say. 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. Teams are ready to go.
Thanks.
Thank you. Thank you. That's great to hear.
The next question will come from Yaron Werber with Cowen. Please go ahead.
Hi, this is Brendan on for Yaron Werber. Congrats on the quarter, guys. 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 II readout's gonna look like there, maybe in terms of number of patients and what kind of data we can expect? Really in that same program, I guess, as you're looking ahead to a potential phase III, 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.
Eugene, would you like to take that?
The Phase II data, 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 10-15 mm Hg. 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 approximately 150 patients. Really, that's all I could tell you at this point.
If I could just expand on that a little bit. Thanks, Eugene. Just a reminder, Brendan, we have a pretty 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. Coming up behind our lead drug is a new molecule, our Gen 2.5 AGT molecule that completed phase I very successfully and now we're planning to start phase II.
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 and what's the next step for phase III. You know, what we're looking to see is what Eugene said, confirmation of the proof of concept we already achieved in refractory hypertension in a bigger patient population and also with good safety, of course. When I say safety, I mean on target safety. We need to be very, you know, aware of the fact that inhibition of this pathway, the RAS pathway in the kidney, you know, can cause kidney issues. We haven't seen it in our phase II studies. We don't expect to see it.
It's like which targets the liver, not the kidney, but we need to confirm that. Once we look at all the safety and the efficacy in the study, we'll make a call on the next step for potentially for phase III.
All right. Great. Thanks so much.
Thanks, Brendan.
The next question will come from Luca Issi with RBC. Please go ahead.
Well, great. Thanks so much for taking my question. Congrats on all the progress here. Maybe on TTR polyneuropathy, I think the primary endpoint is actually at nine months. Will that be sufficient for filing both in the U.S. and in the E.U., or will you need to wait the 18-month data point to file in the E.U., similar to what has happened to Alnylam? 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, had discontinued the drug. Wondering how you're thinking about that in the context of inclisiran. At least I'm not aware of that signal. Finally, any update on the pulmonary franchise post the ENACT discontinuation? Thanks so much, guys.
Thanks, Luca. You've squeezed a lot in there. Happy to do our best in addressing all three of those questions. Yeah, we're very excited, very pleased with the data readout on ion four four nine, our PCSK9 drug that 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, ezetimibe, despite being on monoclonal antibodies for PCSK9, despite being on inclisiran. This molecule looks to be the most potent efficacious PCSK9 lowering drug, LDL-C lowering drug of any that's been that has come out to date. 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 CVD. The phase IIb INCEPTION study was a dose-ranging study, and we achieved reductions of LDL-C greater than well over 70% and PCSK9 in the 90% range at doses where there were no signals on ALTs. That was at the 50 mg monthly dose in that study. 90 mg dose where we saw, I think, four patients with mild ALT elevations. A couple of things worth noting. One is that they were mild. Two is that two of the patients continued dosing, and the ALT returned to baseline or towards baseline. You know, this isn't all a toxicity.
It's an ALT observation in a very small number of patients at 90. But more importantly, it's not the phase III dose. The phase III doses are gonna be in the range of 50 or so, in that range because that's what we're achieving our LDL targets there. There's an ongoing study called SOLANO that AZ is conducting to further confirm the phase III dose, and that study is looking very good, and they're preparing for phase III development. The drug looks very good, very safe, and we haven't seen any bumps in the road. With respect to inclisiran, I prefer not to comment on competition except what I already said. There's a need for more effective LDL-C lowering agents. Patients are not getting to their target. A drug like ION449 is needed in this patient community. You wanna talk about pulmonary a little bit, Eric?
Sure. What we're doing in pulmonary is taking a hard look at some of our chemical class. The hope there is we can find some molecules that overcome some of the preclinical issues we saw with inflammatory effects in non-human primates. 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. We've seen really good data on some of these compounds across multiple programs and are working hard to try and 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. There's lots of unmet medical needs.
We're making solid progress in the areas that Eric said, Luca. We're encouraged. We're very encouraged that the pulmonary program's gonna be reactivated soon on the development side. I didn't answer your question about polyneuropathy. I apologize. I kind of went out of order. We're planning to file the NDA this year on Eplontersen for polyneuropathy. I should point out that you mentioned 18-month data. Remember our full data set completed 15 months, not 18 in the NEURO-TTRansform study. What you're highlighting is the fact that ex-US 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 haven't ruled out ex-US filing, and we're keeping that option open. We're focused right now on the NDA.
Super helpful. Thanks so much, guys.
Got it.
The next question will come from Jessica Fye with JP Morgan. Please go ahead.
Hey, guys. Good afternoon. Thanks for taking my questions. I wanted to follow up on a prior question about the changes to CARDIO-TTRansform. 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?
Thanks for your question, Jessica. No, we're keeping eligibility criteria the same. We are, however, looking into sort of geographies with fairly specific intention of, again, as Brett 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 effect in important subgroups of patients. And, and that could involve-
Okay. Okay.
Jess, that could involve prioritizing certain geographies and territories. To your second point.
Okay. I guess related.
Well, I should say it will involve that. It will involve that, Jess.
Yeah. 'Cause I think in the past you've talked about your expectation for maybe a 50/50 split between patients who are on background tafamidis and those who are not, even though you're not limiting background tafamidis. Is that still your expectation that that'll be the mix?
What we've said, Jessica, is we want, well, the naive versus tafamidis usage to be very well balanced. You know, 50/50 would be perfect, but, you know, we're looking for a well-balanced naive versus tafamidis usage.
Okay. I guess last one on this topic. Were these changes to CARDIO-TTRansform prompted by a recommendation from the DSMB, or were they made without DSMB input? Has there been an interim analysis in the trial at this point?
There's been no interim analysis. We still have an option to conduct an interim analysis after patients have met with complete enrollment 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. This is always an option. This was always part of the plan, not to necessarily do it, but to potentially do it. We're in excellent position time-wise and enrolling-wise to be able to trigger this today. Of course, we engaged AstraZeneca, and they fully supported the decision. We're working, you know, hand in hand with them on implementing it now. No, this was entirely driven by Ionis.
Okay. Great. Thank you.
Thank you.
The next question will come from Paul Matteis with Stifel. Please go ahead.
Hey, thanks for taking our questions. This is Alexander for Paul. Just one Eplontersen polyneuropathy question and then one neuro question. For Eplontersen, 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 their pipeline prioritization, have you thought at all about reacquiring any rights to your neuro programs in collaboration with Biogen? Thanks.
You wanna take the first one, the cardio subgroups and neuro?
Yeah. Thanks for your question. Yes, there will be an analysis, a look at specific subgroup, predefined look, in the cardiac subgroup in a polyneuropathy study, NEURO-TTRansform study. It's again, just to remind you, it's not exactly the same population to CARDIO-TTRansform. 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. Yes, there will be an important subgroup analyzed.
Let me just take a step back for Biogen. We have a very strong partnership and relationship with Biogen that spans 10+ years now. You know, started Spinraza, and it's grown and got stronger and stronger over the years. The 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 will become an even higher priority for Biogen. I don't think they're gonna be willing to give those up easily.
You know, they're gonna be turning the page, and they're gonna be looking at the drugs like MAPT, the follow on with Spinraza, and everything else that we're working on with them. I think these will continue to be very high, but I think these might be even higher priorities with Biogen. With that said, we're very pleased with our neuro pipeline of drugs, that you know that we are growing here at Ionis, that wholly owned Ionis neurology pipeline. One example of that is we're very much looking forward to starting our studies in prion disease 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 for this year. No, I don't think we're gonna be reacquiring assets from Biogen as a result of the change in management that they announced yesterday.
Great. Thanks. Just one clarification. Do you expect any of the cardiac data at the top line mid-year or not until later? Thanks.
No. The top line will be data on the full population. All of the subgroups will be reported at a later time point.
The next question will come from Gary Nachman with BMO Capital Markets. Please go ahead.
Hi. Thanks. First, just another follow-up on Eplontersen and adding more patients to the cardiomyopathy study. Why didn't you wait until the PN data before making the decision since that data are coming soon? 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. That's one. Then also for Beth, the $20 million that you got from AZ for Eplontersen development costs, is that the kind of number we should expect on a quarterly basis, or is there some upfront loading in there? 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 IIb data that read out? Thank you.
Can I take the Eplontersen question?
Sure. I'll take the first question. Related to timing of this amendment, as Brett said, again, we've been mulling this over for quite some time, and the timing of it was one of the key considerations. We felt that the timing now was really kind of ideal for implementing the change such as this one. Why not wait until NEURO-TTRansform? Well, firstly, it's just a very different patient population that we enrolled in NEURO-TTRansform, so we just don't see how this would inform us whatsoever with regard to CARDIO-TTRansform. Secondly, the CARDIO-TTRansform changes are really driven by their intentional desires for a particular sort of balance in the population characteristics that Brett had outlined. Beth.
Sure. On the $20 million, the way to think about that is it's the 55% of our fully loaded Eplontersen broad phase III development expenses in the first quarter. When I say fully loaded, that means external expenses, internal FTE expenses, and CMC expenses. That $20 million is essentially 55% of what we incurred in that phase III program in the first quarter. 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 III program are gonna continue to grow.
The 55% that AstraZeneca is responsible for will also grow, and you'll see that each quarter. It's the same amount. Let me say this just differently. The development expenses and the 55% of revenue are for the same quarter. There's no offset, there's no loading, there's no lag in that. They're aligned. As expenses grow each quarter, so will the 55% of revenue under the Eplontersen joint collaboration revenue line.
Gary, regarding PCSK9, you think about it like this. It's the same patient population that was treated in ETESIAN. That's why that study is so important. It's actually the same 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. That would be the phase III patient population.
Okay, great. When is that study gonna start? I may have missed it. I jumped on late.
No problem. Actual study start hasn't been disclosed, but what has been is that AstraZeneca will make a decision on phase III development in the second half of the year. Remember, there's a study ongoing to confirm the phase III dose. So that not necessarily the same dose that was in ETESIAN, right? They're looking to really solidify the phase III dose in SOLANO. That study is wrapping up. It's really coming to a completion. That's the basis of the delay in making a decision.
Okay, great. Thank you.
Yeah.
The next question will come from Mani Foroohar with SVB Securities. Please go ahead.
Yes, thanks for taking my question. Not to beat an entirely dead horse, but I wanna talk a little about the commercial opportunity and strategy around your approach to TTR 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? How do we think about the pricing opportunity prior to and then after tafamidis genericization in the U.S. versus EU markets?
Onaiza, would you like to take that?
Sure. Hi, Manny. How are you? Great thinking over here in terms of the Eplontersen strategy. I'll kind of start off with, I think, you know, 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 dataset that we're gonna get, as Eugene said, is really important for all players, including payers as well as clinicians.
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 tafamidis as well as naive, because we're gonna have you know in this very dynamic market a set of patients that are gonna be either naive to therapy or you know a lot, particularly in the U.S., treated on tafamidis. They're gonna look for what is your clinical evidence you know for these patients, and how do I actually treat them if they're already on tafamidis, and how do I treat them if they're naive. We will have both datasets 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 as a very sick patient population, you know, and in terminal disease. They are not gonna 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 stepped through in this situation, which is one of the questions obviously we had. We're expecting actually a relatively open environment from a payer perspective. Obviously, they all go through prior auths, but nothing onerous in terms of, you know, huge requirements and/or step through therapies as well.
We'll price accordingly to where the clinical value proposition is coming out, which is gonna be a very robust set of clinical evidence.
Great. That's really helpful. Thank you.
Thanks, Mani.
The next question will come from Joseph Stringer with Needham & Company. Please go ahead.
Hi. Thanks for taking our question. A quick one from us on cimdelirsen and acromegaly, the phase II readout, excuse me, second half of this year, monotherapy. What reduction in IGF-I or perhaps a % of patients that have normalized IGF-I would you be looking for or that would give you confidence in this program going forward? Thank you.
Eugene, you wanna take that?
Sure. Really the remaining need here is being able to achieve normalization of IGF-I, and that's really the bar that we set for this drug both in a monotherapy setting as well as in the add-on setting. Outside of that, I can't really speculate what the threshold in terms of responder rate that would get us really excited. We're obviously planning for very positive readouts in terms of IGF-I normalization.
Yeah. I would just add here that both sets of data on monotherapy and in addition to SSAs are gonna be really important here from a market perspective as well. We'll have both sets of data. The people are still seeing good breakthrough attacks over here. 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.
The next question will come from Salveen Richter with Goldman Sachs. Please go ahead.
Hey, thanks. This is Matt on for Salveen. Just going back to 449, could you guys discuss your thoughts on market strategy or pricing? Separately, could you give us an update on your ALS programs? In particular, when should we expect phase I/II data for 541? Thanks a lot.
For 541, that's our ataxin-2 drug, and 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. Of course, you know, we're very much looking forward to that. That could go to phase III based on, you know, if the result is positive. Onaiza, would you like to talk a little bit about, you know, commercial opportunity? I don't know if you can really touch on pricing much, for PCSK9, but why don't you go for it?
Yeah, sure. Really large market, you know, about 11-16 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 prevention. 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, you know, good momentum, I would say, in terms of aggressive guidelines to treat, which I think will help this entire market growth substantially. ION449 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.
Just to put it into context, we're looking at about the 50% range, you know, for Leqvio, about the 60s for the mAbs, and we're looking at in the 70s for For our PCSK9, which is gonna be a really substantial improvement in LDL lowering. 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, you know, area that we actually wanna go into in terms of the reimbursement schemes as well. It's really well-positioned to do well, but you know, the efficacy profile, the best-in-class efficacy is what's gonna kinda drive the go-to-market strategy for this agent.
Next question.
The next question will come from Myles Minter with William Blair. Please go ahead.
Thanks for the questions. Just in your prepared remarks on ION449, you did say AstraZeneca is gonna make a formal decision on the phase III in the second half, but the commentary on the call today seems to be like that's well and truly going ahead. Brett, can you just clarify what prepping for phase III development actually means? Is that just getting these phase II 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 III is started up in the second half? My last one is just on the muscle LICA 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, tox studies? Thanks.
Thanks, Miles. This is, AstraZeneca is not planning to start phase III development from, you know, from a stop position after the ongoing SOLANO data readout. They're very much preparing for phase III now. That includes making the drug, getting the drug ready, and then that's explaining the protocol. Protocol's being developed, and they're preparing for an end-of-phase II meeting. You know, we're working very closely with them on this program. All that is in motion. All that is happening. We're really just waiting on finalizing protocols and getting ready for regulatory interactions. You know, obviously, they've had regulatory interactions previously, but now this is the end of phase II interaction for prep for that and getting the drug ready.
Yeah, all those wheels are in motion. As far as the economics of that, Beth? Sure. We've already earned a substantial amount of revenue from this program. As we look forward to the next steps, there aren't any milestones associated with phase III. 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 teens. Muscle LICA, Eric?
Yeah, sure. What we've stated was we have an objective to advance one muscle LICA 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 pre-clinical 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. Yeah. I mean, we're just to put a fine point on that, Myles, Eric, under pressure to move several muscle LICA into development because the data's really looking great. I also wanna remind you that we have our own muscle LICA programs, Ionis wholly-owned. We also are working on neuromuscular diseases with Biogen, and we also have an excellent partnership with AstraZeneca in cardiovascular disease, aka cardiac.
We have a lot of balls here and things are moving forward both. What will be first is less important than I think the gist of your question, which is we're expecting to have a rich pipeline of muscle LICA drugs in development in the future.
Fair enough. Thanks again to all of us.
You got it.
The next question will come from Yale Jen with Laidlaw & Company. Please go ahead.
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-TTRansform trials, does that include any patient with a mixed phenotype? In other words, with a polyneuropathy patients or simply purely all in cardiomyopathy?
Yeah, no, this 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, but really are manifestations of the same pathology in different organ systems. Yeah, we are looking at neurological endpoints appropriate for the patient population. You know, Yale Jen, that's it's an interesting question. There's more and more attention in this field being paid to the neuropathy symptoms that patients with wild-type cardiomyopathy have. It's a very relevant question. It's something we are paying very close attention to, and it will be something we're assessing in the CARDIO-TTRansform study, like Eugene Schneider said. Thanks for the question, Yale Jen.
We're unfortunately over time, so we're gonna have to close the call. I really do wanna thank everybody for joining today and participating on the call. You know, 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 of the year. Until then, thanks very much, and everybody have a great day.