Ionis Pharmaceuticals, Inc. (IONS) Earnings Call Transcript & Summary

Great. Good morning, everyone. Welcome. My name is Jess Fye, large-cap biotech analyst at JPMorgan, and we're continuing the 44th Annual Healthcare Conference this morning with Ionis. You're going to hear a presentation from the management team, and then we're going to go into some Q&A. So if you have any questions in the room, just raise your hands, and someone will bring you a microphone or you can submit them online, and I can read them off the iPad up here. So with that out of the way, let me pass it over to Ionis' CEO, Brett Monia.

Thank you, Jess. Good morning, everybody. Thanks for joining me today for today's presentation. As Jess said, I'm Brett Monia, CEO of Ionis, now entering my seventh year as CEO of the company, and I couldn't be more thrilled to present to you the remarkable progress that we've made over the last couple of, 3 years at Ionis, but more importantly, how the momentum we've built over the last couple of years has set us up for far great success this year and for many years to come to drive substantial accelerating growth, the accelerating value for all Ionis stakeholders. These are my forward-looking statements. So six years ago, Ionis, when I moved into the CEO role, set out on a new course and the evolution of the company to evolve the company from an R&D organization to a fully integrated commercial stage leading biotechnology company with one objective in doing so in mind, to drive accelerating value for all Ionis stakeholders to drive accelerating growth for all Ionis stakeholders. And I'm proud to say -- very pleased to say that in 2025, we arrived. In 2025, for the first time in our remarkable history, we launched independently, our first two independent commercial launches, TRYNGOLZA and DAWNZERA, and I'm also pleased to say that those launches are off to excellent, excellent starts, and I'll touch on that. Those launches as well as our other launches with our partner pipeline are based on groundbreaking science that has driven and created an amazing innovative, deep, broad pipeline of medicines that have supported successful launches because of the fact that they've continuously delivered breakthrough clinical trial results. And based on all the success we've had over the last 2 to 3 years and what we're set up to achieve this year and for years to come, we are on a clear path to accelerating revenue growth, sustained positive cash flow and substantial value creation for all Ionis stakeholders. Here are some of our recent achievements over the last 2, 2.5 years or so by the numbers, if you will. Over the last couple of years, we've achieved six positive Phase III data readouts, resulting in 4 approved medicines, TRYNGOLZA, DAWNZERA, WAINUA and QALSODY that have now been successfully launched and they continue to be launched successfully on the market today. Of those launches, two, as I mentioned, are independent launches by Ionis, our first 2, TRYNGOLZA, for familial chylomicronemia syndrome, and DAWNZERA as a prophylactic treatment for hereditary angioedema. And we're set up to continue to deliver groundbreaking medicines to patients to the market for years to come, as we have created one of the most exciting deepest late-stage pipelines in the industry with 11 medicines in Phase III development today set up for a continuous supply of Phase III readouts and product approvals. We could not have been more pleased and proud of the on-time approval of DAWNZERA as a novel therapeutic for HAE prophylaxis. DAWNZERA works through a very novel mechanism of action. It is the only -- first and only RNA-targeted medicine for HAE prophylaxis. The opportunity is clear. There's more than 7,000-or-so patients in the United States that suffer from this genetic debilitating disease. We recognize the fact that there are prophylactic treatments on the market today to treat and prevent HAE attacks from occurring. It's also very clear that current treatments are inadequate. Patients are not satisfied with the availability of prophylactic treatments today, they're not satisfied with the efficacy that they provide, the tolerability they provide and the lack of convenience for patients. DAWNZERA has a compelling product profile that is set up to achieve all of the unmet needs that patients are looking for in HAE prophylaxis, better efficacy, better tolerability and much better convenience. DAWNZERA was approved on time on August 21 of last year by the FDA in the U.S. and the launch started in September and it's off to a very, very good start. We're seeing prescriptions being written by highly motivated HCPs across all segments of the community, including patients switching from prior prophylactic treatment to patients that are on prophylactic treatment switching to DAWNZERA. Even patients that were never on prophylactic treatment before they manage their disease with on-demand treatments are trying prophylactic treatment for the first time, and they're choosing DAWNZERA and newly diagnosed patients. So the FDA approval and the launch is off to a very good start, and we're looking forward to the European approval this quarter and launch in Europe as well. Today, our largest therapeutic franchises, the areas we invest in most in discovery, development and commercialization are in cardiometabolic diseases and in neurological diseases. Two areas with immense unmet medical need and 2 areas where Ionis has consistently delivered groundbreaking medicines across Phase III outcomes and to the market, for both rare, severe disease indications as well as highly prevalent disease indications. What I'm going to do now in the next few moments is to touch on some of the achievements we made from our cardiometabolic franchise and then to move over to our neurological disease franchise before talking a little bit about what this means with respect to the financials for the company. Olezarsen is a wholly owned medicine that is positioned to be the new standard of care for diseases associated with severely elevated triglycerides, a transformational medicine for patients living with these -- with debilitating symptoms resulting from high triglycerides. We're targeting two patient populations for olezarsen. The first is a rare, severe disease indication called familial chylomicronemia syndrome. There's about 3,000 people in the United States today for this rare genetic disorder. We have demonstrated -- I'm sorry, these patients suffer from a whole risk -- a whole list of debilitating symptoms, but the biggest risk that they suffer from is a risk of a potentially fatal acute pancreatitis attack. In parallel, we're pursuing a much larger disease indication called severe hypertriglyceridemia, SHTG. This is not rare. More than 3 million people in the United States today suffer from severe hypertriglyceridemia, SHTG, with over 1 million people considered to be high-risk SHTG patients, high risk for a severe potentially fatal acute pancreatitis attack. So these patients suffer from many of the debilitating symptoms that FCS patients suffer from, but they also, most importantly, suffer from the risk of potentially fatal acute pancreatitis attack, and current treatments for SHTG are grossly, grossly inadequate. TRYNGOLZA, the brand name for olezarsen was approved by the FDA in late 2024 and launched in January of last year for familial chylomicronemia syndrome, based on a compelling product profile regarding efficacy, tolerability and an attractive safety profile. TRYNGOLZA is the first FDA-approved medicine for FCS. It offers not only great efficacy and tolerability profile, but also the convenience of once per month self-administration using a low-volume simple auto injector. We're thrilled with the success of the launch to date. We launched in January, as I said last year, we've seen quarter-over-quarter meaningful revenue growth for the launch of TRYNGOLZA in the United States. And for the full year, our growth -- our net revenue for the U.S. launch is -- exceeds $100 million in estimate, over about -- more particularly $105 million in 2025 is our net product U.S. product sales for TRYNGOLZA in 2025. In parallel with the development and launch of TRYNGOLZA for FCS, we were pursuing the much larger indication that I referred to severe hypertriglyceridemia, SHTG. We conducted the largest pivotal program ever conducted in SHTG over 1,000 patients treated with SHTG with olezarsen. The two pivotal studies are referred to as CORE and CORE 2. The primary endpoint in these studies was fasting triglycerides at 6 months, but we also had very important key secondary endpoints and exploratory endpoints, including the adjudicated event rate of acute pancreatitis at 12 months in this study and other key endpoints such as reducing triglycerides below key risk levels, 500 milligrams per deciliter, which is the risk level of triglycerides associated with acute pancreatitis and even patients driving down the triglycerides into the normal range below 150 milligrams per deciliter. Last year, in -- at the American Heart Association, we presented groundbreaking results for olezarsen in severe hypertriglyceridemia, where we demonstrated on top of standard of care remarkable reductions in the primary endpoint, triglyceride -- fasting triglyceride levels at 6 months, 72% reduction on top of standard of care of triglycerides at 6 months in our core study. And not only did we see a -- this level of triglyceride reduction in the study, we were also demonstrated that 86% of patients were able -- we were able to drive their triglyceride levels below the risk threshold for acute pancreatitis below 500 milligrams per deciliter. And more than half of patients were able -- we were able to drive their triglyceride levels down into the normal range. These results were remarkable, but what was even more remarkable were the results that we reported on acute pancreatitis event rate. What we showed is that we were able to reduce the event rate, acute pancreatitis event rate by 85% at 12 months in this study, groundbreaking results that had never been shown before in this patient population. In addition, based on the potency, based on the efficacy we demonstrated reducing acute pancreatitis attacks, we were able to also show that the number of patients needed to treat to prevent a potentially fatal acute pancreatitis attack in the overall population was 20 patients. And in the high-risk patient population, that is patients that are above 880 milligrams per deciliter or who had a history of acute pancreatitis. The number needed to treat was only 4 patients to prevent a potentially fatal acute pancreatitis attack. And again, I want to emphasize, this was after only 12 months of treatment, groundbreaking, groundbreaking results. So olezarsen is positioned to be the first -- or the new standard of care treatment for severe hypertriglyceridemia and become Ionis' first wholly owned blockbuster medicine. In addition to the remarkable efficacy that we reported that I just took you through and that we reported last year, olezarsen also demonstrated a highly favorable safety and tolerability profile in the study. It offers the simplicity of once per month self-administration using a simple auto injector. And Ionis has a substantial first-mover advantage to bring this novel mechanism of action to treat SHTG patients to the market. Our supplemental NDA to follow the FCS indication was filed late last year, and we're expecting to launch in 2026, and we've been granted breakthrough therapy designation. Prior to us unveiling the Phase III data for olezarsen in SHTG, we had guided toward a peak product revenue opportunity of -- to exceed $1 billion. Based on these remarkable results, our Phase III results, we have recently upgraded our guidance to greater than $2 billion in net product revenue for Ionis for olezarsen in SHTG. Behind olezarsen is a growing wholly owned pipeline for Ionis in cardiometabolic diseases. We actually have a follow-on molecule now that's going to reach Phase II development this year, ION775, that is -- that will move into SHTG patients this year that offers the potential for once per year or twice per year, self-administration using an auto-injector. We're also moving forward with new approaches to target cardiometabolic diseases, including targeting cardiac myocytes directly, through targeted delivery strategies using a novel approach to TfR1 targeting on cardiac myocytes. In parallel, our partnered pipeline in cardiometabolic disease continues to progress exceptionally well. Examples of this are eplontersen for ATTR cardiomyopathy, a co-development, co-commercialization partnership Ionis -- between Ionis and AstraZeneca with Phase III data in the second half of this year and pelacarsen for Lp(a)-driven cardiovascular disease with Phase III data expected in the first half of this year with our partner Novartis. We also have a targeted delivery strategy in process in Phase I development, targeting cardiac myocytes using our novel approach to TfR1 targeting with our partner, AstraZeneca, that's in, as I said, in Phase I development. Switching gears to neurology, neurological diseases, an area -- therapeutic area where Ionis leads in RNA-targeted medicines. We have a proven platform and proven capabilities for delivering groundbreaking medicines for neurological diseases. We've done it time and time again. Examples of this are SPINRAZA conceived, discovered, developed by Ionis as the first-ever FDA-approved medicine for spinal muscular atrophy. QALSODY, the first-ever FDA-approved medicine for a genetic form of ALS, and WAINUA for peripheral polyneuropathy due to mutations in the TTR gene. Right behind these approved medicines is a rich pipeline, one of the richest in the industry in neurological diseases. Today, we have six wholly owned medicines in clinical development for neurological diseases, devastating neurological diseases, including Zilganersen for Alexander disease, ION582 for Angelman syndrome, and we're about to start a Phase I study in Dravet syndrome. And our partnered neurological disease pipeline continues to advance very, very well. Examples of this are salanersen, a new follow-on molecule for SPINRAZA for spinal muscular atrophy using Ionis-discovered medicines that supports once per year dosing for SMA patients, and our tau program with Biogen for Alzheimer's disease, and our Huntington's program with Roche for Huntington's disease. We are incredibly proud and pleased with the Phase III results that we reported in September of last year for Zilganersen for Alexander disease. Alexander disease is a severe, typically commonly fatal leukodystrophy, in which there are no effective treatment options available today, no disease-modifying treatments available today. We reported unprecedented clinical results for Zilganersen in patients with Alexander disease, the first and only investigational medicine to show a disease-modifying impact, clinically meaningful disease-modifying impact in patients with Alexander disease. We are granted breakthrough therapy designation. This medicine is positioned as, of course, as a first-mover to transform the treatment landscape for families, physicians, patients living with this devastating neurodegenerative disease. We've recently opened up an expanded access program. The enthusiasm for this program has been very brisk, very strong, and we're looking forward to submitting our NDA this quarter and getting to launch this medicine in the second half of this year. Right behind Zilganersen is another promising wholly owned medicine for a neurological devastating rare genetic neurological disease, ION582 for Angelman syndrome. Angelman syndrome is a severe neurodevelopmental disease affecting more than 100,000 people with no -- with -- in major geographies with no effective treatment options available today. The unmet need is massive. We reported highly encouraging Phase II data from a Phase II study called HALOS, 1.5 years ago, where we demonstrated consistent and meaningful evidence of clinical improvements across all aspects of clinical function, cognition, communication, motor function. And last year, we reported new data from a long-term extension from patients that rolled over from HALOS into the long-term extension, demonstrating continued improved benefit in clinical outcomes in patients with Angelman syndrome. We were granted breakthrough therapy designation for this program as well. We initiated the Phase III REVEAL study last year in 2025, and we're expecting to complete enrollment this year with Phase III data in 2027. So I think it's fair to say that Ionis has been delivering a steady cadence of groundbreaking new medicines to patients to the market over the last 2 to 3 years, and we're anchored by WAINUA, TRYNGOLZA and DAWNZERA, which I've already covered. And we're well positioned, well positioned to continue a steady cadence of new medicines reaching patients in the market for years to come, including this year, where we're expecting FDA approval and launch for olezarsen in SHTG, Zilganersen for Alexander disease. And based on the positive Phase III data that our partner, GSK, reported last week for bepirovirsen in chronic HBV, we expect that medicine to be approved this year and launched as well. And the beat goes on in 2027, assuming positive Phase III data this year that we're expecting for 3 programs from our partnered pipeline, pelacarsen would be launched for LP(a)-driven cardiovascular disease in 2027, eplontersen for ATTR cardiomyopathy and sefaxersen for IgA nephropathy. And then more medicines to follow, including our Angelman syndrome ION582. This -- what this means, the steady cadence of medicine is that by the end of this year, Ionis will have launched as a fully integrated commercial stage biotechnology company for independent launches. And by the end of next year from our partner pipeline, 4 key partner launches. This, of course, is incredibly important for the patient -- for patients, for the medical community. It's also very important for Ionis from a revenue-generating standpoint. This is what the revenue looks like the revenue from our marketed products, planned launches from our near-term product approvals at peak sales. From the Ionis wholly owned pipeline, Ionis-owned medicines, we anticipate from a -- in a probabilized manner. So not everything has to be successful, the Phase III readouts nor the market success, more than $4 billion in potential annual peak product revenue from our wholly owned pipeline from our partner medicines on royalties alone, more than $2 billion in annual peak royalties, and that doesn't even include substantial milestones, development milestones and commercial milestones and some exceeding more than $6 billion in revenue for the company at peak. And this supports our commitment for -- to achieve sustained positive cash flow for the company. We're on a clear path to sustain positive cash flow, and we're on track to achieve cash flow breakeven in 2028 with growing positive cash flow to follow. Key drivers of this, of course, are the new product launches that I just took you through, growing royalty revenue. We have, today, a very strong financial foundation to support all the investments we need to make to ensure success for our products on the market. And, of course, as we've always done, disciplined expense management. So we've made remarkable progress over the last couple of, 3 years. We're poised to remain -- to achieve even greater success, even greater progress this year with a number of key catalysts in 2026. Here are those catalysts by the numbers. We're expecting five Phase III data readouts this year. You can read the medicines there. I've covered -- I've touched on all of them so far. And we have one already accomplished bepirovirsen for chronic HBV; four, NDA submissions; three, commercial launches, including two independent launches, olezarsen for SHTG and Zilganersen for Alexander's disease, and a rich mid-stage pipeline that's going to produce a number of important readouts, any of these Phase II readouts that are positive supports -- will support the program to advance to pivotal Phase III studies. These include our partner program on tau for Alzheimer's disease, our partnered program on Huntington's disease, targeting HTT, and our wholly owned alpha-synuclein program for multiple system atrophy and our Prion disease program. So to conclude, I'll leave you with this. Some of the key take-home messages. Ionis is leading the way and has built a leading cardiometabolic disease portfolio and neurological disease portfolio that has delivered groundbreaking medicines and will continue to deliver groundbreaking medicines well into the future. This is and will continue to drive accelerating revenue growth supporting our objective to achieve positive -- to achieve cash flow breakeven in 2028 and a clear path to sustained positive cash flow. And with that, I'll stop there. Thank you very much for your attention.

Great. Thank you. And as a reminder, if you have a question, please raise your hand, or you can send them to me up here on the iPad. So I wanted to start with olezarsen or TRYNGOLZA. And I guess, first, with that sNDA filing now in for SHTG, has it been accepted? Can you speak to whether you're going to get priority review?

We submitted the supplemental NDA just before Christmas. So it's a 60-day process before we'll hear about -- or 30-day process before we'll hear about acceptance. And at that -- and we did request priority review, so we'll hear about it at that time.

Okay. And I guess, what can you share about the TRYNGOLZA launch in FCS so far? Like what are you learning about patient adherence, persistence?

It's overwhelmingly positive. We're hearing so many great stories about patients living with this devastating disease. Their ability to live daily lives without body pain, without going to the hospital for recurrent acute pancreatitis events. We're seeing patient stories that are just incredible. And that is emanating to the health care providers, the physicians that treat these patients, leading to reauthorizations. Physicians finding new patients to treat them as well. It's really a breakthrough for this patient population. Everything has been incredibly positive.

How are you preparing for the launch in SHTG? So how do you think about the initial target population? Should we think about a steady ramp or more rapid uptake? Like could there be a bolus of early adopters?

Yes. So the SHTG launch will be our third -- Ionis' third commercial launch with Alexander's to follow. It's funny. Our first three commercial launches have all been -- will be very unique. Each one will be different. We started FCS, where we were first to the market and patient identification was so critical, and that has been such an important factor in the success we've had in the launch in FCS to date. We've done a great job in identifying patients. And of course, the drug has performed. Our second launch in DAWNZERA, we came into a market where there are preexisting treatments and that's a switch market. And there, it's a very different strategy, getting patients understand -- physicians understand the opportunity that DAWNZERA offers. And now our third launch, we're moving into a highly prevalent disease indication, right? High -- incredibly high unmet need, millions of people with SHTG. So a new strategy. We're building off the success of FCS and the sentiment by the endocrinologists, the cardiologists, pancreatologists, that have experienced TRYNGOLZA in FCS is resonating incredibly well for the SHTG opportunity. Physicians are asking when can I put my patient on -- my other patient -- my FCS patient is doing great, and when can I put my other patients on to have SHTG onto olezarsen. They just, of course, have to wait until we get the indication. We're prepared. We'll be prepared for the launch. We'll be prepared for the launch if we achieve priority review, that would be in July. Of course, a standard review will take us to October, November, but where we have built our field team, they're essentially all hired now. They're being trained, ready to go, assuming the prior early approval, and they're being trained on this. And they will be focused on FCS and SHTG education. FCS patients finding SHTG education until we get the label for SHTG. We've hired about 200 individual field force to support the SHTG opportunity, and that's scalable, Jess. If we see that we need to add more or so, we can do so. There's incredible enthusiasm for people wanting to come to Ionis to be part of this story.

So you raised the peak expectation for this product from $1 billion to $2 billion. Curious kind of like what bridges you from 1 to 2? Was that expectations for better volume? Maybe you could commend a higher price, international, U.S., kind of what are the ingredients to double the peak?

Yes. It's based on research we've done with the HCP community, it's volume, it's volume. The enthusiasm for the reduction in acute pancreatitis was so overwhelming that when we did our market research, we did market research before we had the Phase III data. And when we had the Phase III data, then we doubled down on that, of course, to do -- to ask HCPs, physicians, also our payers engagements on what they think about this profile and the enthusiasm just doubled. I mean it was just incredible. So it's a volume thing. We're expecting physicians to be even more motivated to treat patients that are at high risk, but even patients that are -- that maybe don't have a history of acute pancreatitis that are between 500 and 880, we'll maybe even get some of those patients because of the enthusiasm for the data we presented last year.

If there are a couple of moves just to turn it around the other way, if there are a couple of risks to achieving that new kind of 2 billion peak target, what are the risks?

Risk is a new launch. Launch has always come with some uncertainty. But you asked about a bolus. I could tell you that that unlike those other 2 launches, which are very different patient finding and switching for the other -- our first 2 other launches. Here, there are patients waiting. Physicians are -- many physicians are treating thousands of patients with SHTG already with inadequate treatments, fibrates, omega-3 fatty acids, statins. So they're waiting for something better. So although I wouldn't call it a bolus, it's going to be a different type of launch. It's going to be faster than for DAWNZERA or for FCS, just because of that. I really -- I have a hard time finding risk associated with that, except for just what's the uncertainty of a new launch at any time, but right now, physicians are very eager to prescribe olezarsen for SHTG, which is -- which I think is going to bode really well for the launch.

And what's the latest thinking on pricing once you get into SHTG and how are you engaging with payers to ensure broad access?

Prior to the Phase III data, we've done extensive engagement with payers and HCPs to understand the enthusiasm for HCPs to prescribe olezarsen for their patients and payer research to understand what the key inflections would be that would limit access, right, to patients or make it more difficult for physicians to prescribe olezarsen for SHTG. We've done a lot of work. And then, we doubled down on that work after we got the data, right, after we got the data. We're working on it now. Obviously, today, we're -- TRYNGOLZA is being -- is at a rare disease price and that price will come down. We provided guidance last year of a net price of $10,000 to $20,000 in the U.S. or $10,000 to $20,000 for SHTG that's where we are still today, but we have a lot of work to do. We're obviously at the high end of that now of that range based on the remarkable data we reported, but we're still doing our work. So stay tuned. And once we come to our conclusion, maybe at approval, we'll share that.

Okay. Maybe switching to WAINUA, eplontersen, how is the commercial uptake going in polyneuropathy? And what are you seeing just in terms of kind of new patient starts versus switches, prescriber mix, stuff like that?

Yes, very good. The launch of WAINUA continues to go very well in hATTR polyneuropathy. We're seeing strong demand for the drug. We're seeing volume, continuous quarter-over-quarter increased volume in patients. We're seeing a good mix, 60-40-or-so commercial to Medicare. We're seeing some switches, but it's almost mostly driven by newly identified patients. We're co-commercializing in the United States with AstraZeneca, and it's a great team effort in patient identification. And it sets us up really well for the second indication. We're looking forward to the much larger indication cardiomyopathy with Phase III data in the second half of this year. And based on the overall success we're having WAINUA in polyneuropathy, I think it bodes really well for a much larger indication. Patients are really -- it's really resonating well, the ability to self-administer using a simple auto injector, the profile, the efficacy is remarkable. And we think that that's going to translate and exponentially -- at an exponential level in the much larger cardiomyopathy indication.

So when that cardiomyopathy data reads out, what kind of represents a win -- and what would the home run data for cardio transform look like?

As you know, this is the largest study by far, never conducted an ATTR cardiomyopathy more than 1,400 patients with data in the second half of this year. It sets us up to have the richest data set across all endpoints that we're looking at in this study. A win is to hit the primary endpoint composite of cardiovascular mortality and cardiovascular hospitalizations, high statistical significance, of course, is a big win. This is a growing market. We can't wait to get to the market. AstraZeneca has estimated this product to be a $5 billion-plus peak market opportunity for this medicine alone, but on the trial design, that's a win, strong, strong positive primary endpoint data. However, because of the size of the study and the demographics of our study, where we have a good portion of patients on stabilizers, we're going to have the richest data set in combination between a silencer and a stabilizer that's ever been generated to date. And that's really important because despite the success silencers are having initially in the cardiomyopathy market, and we'll have even greater success, we firmly believe that in the market, we believed in silencer class over to stabilizer class, stabilizer is still the standard of care. So being able to explain to payers and physicians that you're going to get an added benefit on top of a stable or is incredibly important. We're in position to have the richest data set there. Last year, and because we have so many patients in combination usage, last year, we elevated combination -- the combination subgroup to a key secondary endpoint in our statistical hierarchical plan. So we just -- we want to make sure we get the benefit of that if we do hit stat sig, although really a win is just strong favorable trends showing combination usage would benefit, and that would be for the first time anyone ever showed that.

If you do hit statistical significance in the combo subgroup? Do you think eplontersen gets unique credit for that and the physicians or the market doesn't just read that across to your competition anyway?

What it will mean is absolute upside to WAINUA for eplontersen for cardiomyopathy, we believe. Whether that floats all boats or not, it's perfectly fine with us. This is a growing market, estimated by some to exceed $20 billion. We believe in the silencer class. There's room for multiple. There's really two and that are coming, so that would be fine if that was tailwinds to our competitor program. It's we're going to do extremely well, and we'll be the ones with the data in the pocket.

Okay. And just when you say rich data set, does that mean that you kind of anticipate statistical significance in this subgroup? What is -- like what does richest data set mean?

The richest data set means that based on the size of the study and the percentage, the number of patients in combo use, the number of patients in monotherapy offers the opportunity to have the most meaningful, whether it's stat sig or not, the most meaningful data to convince people that combination usage adds benefit and just look at what our monotherapy does and potentially even look at -- be able to compare, not stat sig, but be able to look at monotherapy versus combination in a single study, because we are going to have more patients in our monotherapy group, in our combination group than any Phase III study in its entirety that's ever been done before. In addition, we are doing -- and we're -- this is unique to our cardio transform study, 2 very, very sizable imaging studies, MRI and scintigraphy, looking at heart's function, heart performance, heart structure, amyloid burden in the heart and that too will be analyzed by subgroups, right? So when I say rich, I mean biomarkers, I mean, heart function structure and, of course, the harder endpoints on mortality and hospitalizations.

Okay. Maybe a similar question, but for pelacarsen, which also has Phase III data reading out. What's kind of a win for that data set versus kind of the home run scenario?

Stat sig on the primary endpoint of cardiovascular mortality and hospitalizations. Lp(a) represents an opportunity in cardiovascular disease that affects 8 million to 10 million people globally with no effective treatment options available for this independent risk factor. Pelacarsen is positioned to get the vast majority of patients below the threshold associated with Lp(a) cardiovascular disease, first to market by 1.5 years, 2 years if this Phase III study is successful. Cardiovascular outcome trials are typically granted, considered to be highly successful if they achieve 10%, 15% positive cardiovascular outcomes. The study is powered for a 20% relative risk reduction in the overall population and 25% overall risk reduction in a subgroup of patients that have super high levels of Lp(a) above 90 milligrams per deciliter. But because there's such a high unmet medical need, in this population with no effective treatment options. I would say that even 10%, 15% would be considered a big win. I'm sure that Novartis would go to the market, it will be their decision, but they would go for approval based on even that outcome.

Okay. Great. We're perfectly out of time, so we'll stop there. Thank you.

Thank you, Jess.