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

David Lebowitz. I am one of the biotech analysts here at Citi. And thank you for attending the Citi 18th Annual Biopharma Conference. Happy to have on stage with me from Ionis from warm San Diego. Oh, it's pretty warm here today as well, actually. I guess if you could start by introducing yourselves and then maybe walk through the top-level mission of Ionis and the technology behind that mission.

Sure. Happy to. Thank you for having us, David. I'm Beth Hougen, Ionis' Chief Financial Officer, and I've been with the company now for over 23 years. So I'm looking forward to talking a bit more about Ionis today because we really are in the midst of an important transformation for the company.

And I'm Wade Walke, I'm the Head of Investor Relations.

So let me take a couple of minutes and answer your question about Ionis and what our mission is today and what we're focused on. It's -- as I said, it's a really exciting time to be at the company. We spent the first 30 years or so of our history, really developing RNA-based therapeutics, the technology, building a deep rich pipeline, a deep culture embedded across the company and a dedicated employee base and a healthy financial position as well. Today, However, we're now going to -- instead of partnering all of our drugs, we're going to hold on to our drugs and bring them to the market ourselves as our primary business model. And that's a huge change for the company. We've really spent the last 2, 2.5 years or so, 3 years, building the commercial capabilities necessary to do that. And imagine taking a 30-year-old company and completely changing the business model and building commercial capabilities, medical affairs capabilities, capabilities to prioritize the pipeline in therapeutic area franchises and all of the enabling functions that, that requires as well. It's been a tremendous effort, but one that we have all embraced with tremendous enthusiasm because we know the value that we're bringing through our technology and through the pipeline, and we're looking forward to seeing that translate into value to patients and shareholders. So it's been a really good year so far today. So far, we've seen very positive eplontersen Phase III data. That's our nearest to market Phase III drug, and maybe we'll talk a little bit more about that in detail. We've also -- are moving olezarsen in donidalorsen forward in Phase III development towards the market. All the commercial capabilities I just talked about are being bought to -- being brought to bear on preparing to launch those 3 drugs, eplontersen with AstraZeneca and olezarsen and donidalorsen ourselves. Additionally, our Phase III pipeline has expanded. We now have 8 drugs in Phase III development for 10 different indications. So that's been an exciting advancement this year. SPINRAZA continues to be a market leader, and we hope, along with Biogen that Biogen brings it back to growth. We think it's eminently suited for that. And then QALSODY was recently approved for SOD1 ALS. So it's the first disease monitoring therapy for ALS. And while it's a small patient population, it's a really important advancement for these patients in this community. And it's really important for Ionis as well as is our second neurodegenerative disease drug behind SPINRAZA. So it's a really important validation of the technology and how it can bring medicines to bear on these intractable diseases. I mean, of course, it's Ionis, so we wouldn't -- it wouldn't be Ionis if we weren't doing technology advancement and that's something that's really important to who we are and will continue to be an important part of what we do.

You spoke about the transition and business strategy from partnering to pushing forward. How -- I mean it was -- it's a long time and there were a lot of partnerships over many, many years, a lot of inertia behind it. What type of endeavor was that to actually shift that strategy?

It is a big -- it's a big endeavor. Really Brett Monia when he came in as CEO in January of 2020, for some of you who may not know, Brett was a founding scientist at Ionis. So he's been with the company through the entire 30-some-odd years of our history. And frankly, he built this most of our existing pipeline as a scientist and the Head of Drug Discovery and development. But what Brett recognized is that partners have a very important place to play, particularly as you're developing technology and you're advancing a relatively young company and financing the company. But you lose certain aspects of value, you lose control, and we wanted to have that control. We wanted to have that value for ourselves. And frankly, we wanted it for the patients. That was really important. So we were surprised as we thought through this at the leadership level and went to the Board with this proposition to change the business strategy, how much tremendous enthusiasm there was through the entire Board and all the way down into the leadership of the organization and, frankly, down all the way through the entire company. So the excitement about doing this. Frankly, what we heard was what took you so long? So people are really excited about it. As I said, we're looking forward to seeing our name on the first package of eplontersen when it goes out with AZ. That's our fingers crossed.

So with that in mind, let's go to eplontersen. PDUFA date coming up for polyneuropathy in December. If you could run us through the data presented thus far, and try to, I guess, juxtapose it into what the need is at present in that space.

So let me start with the mean, because I think it puts the drug in context. It's interesting in polyneuropathy, there's about 40,000 patients globally, with pure polyneuropathy as well as with mixed phenotypes. So patients who have polyneuropathy but maybe also have symptoms of the cardiomyopathy indication. Of that 40,000 patients less than 20% of those patients are currently treated with an approved therapy today. So that's tremendous headroom for us to be able to take a drug like eplontersen into this market and really create a meaningful presence for eplontersen. And our focus is going to be not on switching patients. That's not really the best use of our resources and AstraZeneca's resources, but rather on the new to silencer patients, the patients who haven't had a treatment to date. And that's where we're going to focus our efforts. And we think eplontersen's profile is eminently suited for that. It's the Phase III data we reported about a year or so ago and the 35-week interim data was very positive, and that profile continued through 66 weeks and we reported those data in April of this year at AAN. And what I'll tell you is the 3 co-primary endpoints were all statistically significant. Starting first with the reductions in TTR at 82%, 83% or so. And that translated, as you would expect, into very meaningful statistically significant reductions, improvements in mNIS+7, a measure of neuropathy progression and then really importantly, into quality of life. And that's really what physicians and patients are focused on for these very sick patients as their quality of life. So at 35 weeks, 66 weeks, we saw continued improvement in both of those measures. And then we continued the study past the 66-week readout for 80 to 85 weeks and we reported those data that showed continued improvement in mNIS+7 consistent with the -- consistent reductions in TTR. We also saw the consistent stabilization of quality of life. So all of that, I think, sets us up very nicely for the drug in the market. Additionally, we saw statistical significance across all 4 secondary endpoints and a very favorable safety and tolerability profile, very much like what we've seen across our entire LICA platform to date. So that, combined with the ability to self-administer with an auto injector by the patient, wherever that patient happens to be, we think is going to make this a very competitive drug in the marketplace.

You spoke about how you've given how underpenetrated the market is, it's not necessarily that we shouldn't think of in terms of a switch. But on some level, you must be heartened by it since Amvuttra's launch, it actually that thesis in the way it's validated because their overall TTR polyneuropathy franchise has accelerated, suggesting that the shift in the delivery has changed the growth of the overall -- of their product, which yours is more similarly profiled to the more recent product, Amvuttra.

Yes. Exactly having subQ injectables in the market, I think, is certainly preferred and particularly with a very favorable safety profile. Our first gen product was a subQ, but it was administered once a week at a high dose. And so this shift to once monthly subQ auto-injector. So really, you don't even see the needle. It's painless. It's going to make, I think, a really big difference for these patients. So absolutely.

Now outside of the comparison of the monthly dosing versus 3 monthly dosing. And of course, there's the -- you can auto inject versus having to go into a physician to inject. How the mNIS scales used between these 2 drugs are different, which makes it difficult to make a true comparison. How does the case get made one versus the other when in a new patient, not new to therapy, they're getting probably going to get from two different ends of the spectrum, showing the profile?

Yes. No, it's a great question. Do you want to hit that one?

You bet. So there's a couple of things to consider when you're talking about comparisons between trials and especially with the mNIS because there's actually differences between mNIS that's used in our study versus the one used with -- in the Alnylam study. First of all, looking at crosstalk comparisons is always fraught with pitfalls, right? And so you have to like, look at things like are the patient population similar? Are they different? In the case of these 2 studies, they're actually fairly different. It's obviously polyneuropathy patients, but the patients in the Alnylam study were more severe, their placebo arm has progressed much faster than our placebo arm. And to point it out to the placebo arms that were used into the studies are actually historical placebo arms that were used in the first-generation trials, so they're even one step removed. So it's -- so when you have those kind of differences, you can't really use placebo-adjusted numbers because you're just amplifying those differences when you do that. So one of the things to look at and even this still gets tricky is look at what the change from baseline is and like how many patients improved, those sort of things tend to amplify those differences less, but you still have to take those things into account. And then our mNIS scale has a few domains that the Alnylam scale doesn't use. So our range is a little bit wider. And so all in all, you can't really compare absolute to absolute. Now given all of that, the things that we saw in our trial were that the mNIS scores basically, the mean scores reversed from the placebo. The placebo got worse, the mNIS scores on average got better in the treatment group and significantly better, right? And they continue to get better week 35, week 66 all the way out to week 85, the numbers continue to improve when looking at the means. And when looking at improvement of the number of patients who improved for baseline, we saw a majority of patients did improve from baseline, so in line with what we're seeing at the means. But another thing I would point out is that in clinical practice, the clinicians don't use the mNIS+7. That was basically designed specifically for clinical trials in TTR polyneuropathy patients. But what they do look at more closely is like what quality of life kind of measures. And so we also had a Norfolk Quality of Life measure in our study, which also saw improvements throughout the course of the study and saw sustained improvement out to week 85 as opposed to placebo group, which got worse over time. And so when looking at these two parameters, you can see that there's a significant -- basically significant improvements in both quality of life and the measure of neuropathy disease in these patients, which gives it a very attractive profile. Trying to compare the two studies and the two drugs is really hard, I would say, I don't know that you can really draw concrete differences. They both reduce TTR levels, which does -- isn't really impacted by the severity of the disease, about 82%, 83% and when you look at the mean reduction. And so based on that, you would expect the efficacy endpoints to kind of match up. And that's pretty much what we saw. So the drugs look pretty good for TTR patients. We have a very attractive profile. And as Beth mentioned, we're a little bit different because we have the self-administration with auto-injector.

When it comes to the launch in the U.S. and then overseas, to some extent, obviously, Astra being involved, we both play a significant role, certainly, as far as getting into having inroads within like the U.S., where Alnylam might already be competing. But could you talk also about the specific nuances overseas and how the growth dynamic could be different there because a lot of markets are still relatively untapped by TTR.

Yes. It's a great question. And it goes back to that sort of less than 20% of the patients are actually being treated, right? So that goes across the globe. It's not just in the United States. And a large percentage of these patients are outside the United States and in countries in Europe as well as endemic patient populations in Latin America and countries in Latin America. From our perspective, that just continues to give us confidence that there's a real important market opportunity for eplontersen. And with AstraZeneca, our reach is global, right out of the gate, and that's really important. There -- the data, I think, has amplified their excitement about eplontersen for polyneuropathy. They were excited about eplontersen for cardiomyopathy, right out of the gate, it was really what they were focused on when we did our transaction with them a couple of years ago now. But polyneuropathy has become something much more interesting to them as they think about the importance of that for cardiomyopathy, the fact that this really is a systemic disease that it's not two separate indications really, it's one big indication. And the fact that the data are so positive, gives them a lot of excitement about where they can take this drug. So right now, we're planning on filing before the end of the year outside the United States and Europe and possibly in some other countries. And then as we go into next year, expanding out into a whole host of different countries as well. And some of those countries potentially we could be first to market, because there may be markets that aren't currently served by first-generation products. And most recently, AstraZeneca took a license to the Latin America territories. So that further expanded their global reach for eplontersen. And we're excited because, as I said, there's endemic patient's population in some of those Latin America countries, and so we want to make sure that we're getting to those patients.

So you talked about Astra initially, it was the attraction was cardio -- cardiomyopathy. Now the cardiomyopathy space is starting to heat up. Obviously, tafamidis has been there a while. Another stabilizer has presented data. Alnylam is going to be presenting their pivotal data next year and your trial is underway in with data, I believe, 2025. How is this market going to shape up? How do these different types of modalities ultimately fit in one place?

It's interesting Onaiza, who heads up our global product strategy and operations team and really is responsible for so much of the growth in our commercial and medical affairs teams, likes to talk about the fact that the market isn't developing the way that it ideally should have. Ideally, we should have been bringing silencers to the market first and then stabilizers coming behind that. And that's actually not how it's played out really. We've got tafamidis on the market today. And as a result of tafamidis on the market today, new diagnostic approaches for these patients, particularly diagnostic approaches that are far less invasive than in the past. And just the additional disease education and awareness that Pfizer has brought to the space patients are getting diagnosed and identified and diagnosed and frankly, treated much earlier than they used to. That means the patient population is not as sick as they used to be. And most of us designed our Phase III clinical studies in cardiomyopathy based on the ATTRACT study, based on tafamidis' Phase III study. And that was a much different patient population. They were much sicker than the patients are today. And so I think this is a really important shift in the dynamics, something that we really need to be taking very much into consideration. We've seen this in the event rates in our cardiomyopathy study. We've heard it from the KOLs in our study. We've heard it from KOLs outside of our study as well as KOLs, I think of Dr. Fontana in particular, at UCL at the National Amyloidosis Center in London. And her paper where she specifically looks at these patients and how the patient dynamic has changed -- the demographic has changed, excuse me. And her point is you have to take this change very seriously and taken into consideration as you design Phase III studies. And in thinking about all of that, we actually increased our cardiomyopathy Phase III study to 1,400 patients. Last month, no 2 months ago, I guess, now, we fully enrolled that study with more than 1,400 patients, and it is by far the largest Phase III study in this patient population. And we think that's really important to assure that we have powered the study appropriately for success, particularly given the change in the demographics of these patients and the fact that they're less severe. So right now, we think about sort of two classes of drugs. We've got the stabilizers, potentially, there will be two of those. And the silencers and potentially, there will be two of those as well. But it's a $10 million-plus market. And there's lots of reasons to see treatments being combined. I don't think the silencer treatments will be combined but combining silencer with stabilizer makes a lot of sense. And we'll have the data in our Phase III study to demonstrate how that could be valuable to patients and to answer questions that physicians have. We'll have about 50-50 tafamidis treated patients as well as naive to treatment patients on our study, we'll be able to answer questions about hereditary versus wild type. We'll be able to answer, hopefully questions around severity of disease and how does treatment effect. When do you start treating. Is there a point where patients are too far along in their disease to be treated and how they benefit because we'll have knee half Class 1, 2s and 3s in our study and nicely weighted across those. So we think having such a robust data onset coming out of this huge study. It's really been described as a landmark study in a lot of ways. We think that's going to position eplontersen very, very well in this patient population.

When you talk to doctors today in the absence of this data, I don't know a lot of them already believe that the paradigm is headed towards some form of combination. Obviously, costs of the therapies aside, they would like to combine them.

I think there's a lot of truth to that. I think we hear time and again that silencers are the preferred treatment turning off the spigot, if you will, makes a whole lot of sense before the proteins that lay down the plaques lay down on the heart muscle and so forth and damage is starts to accrue to these patients. But it's absolutely the case that you've got tafamidis in the market today and maybe probably all of us have seen Pfizer's direct-to-consumer ads for ATTR cardiomyopathy and the disease education and awareness that they're doing is helping us across the entire market, right? And so the combination therapy, I think, is going to be really important. What we've learned in our payer research is that payers are not going to step edit through tafamidis or through a stabilizer. They recognize the importance to your point exactly, that these are very sick patients and requiring them to work through a therapy like tafamidis first before you get to a silencer doesn't make sense. You want to combine these, you want to turn off the spigot, you want to stabilize the plaques that are already there or that we're not reducing TTR by 100%. So there's still going to be some of that, that creeps in, if you will. So that combination therapy has real value for these patients. So absolutely, we think that's really important. And having data to demonstrate the value is going to be critically important for these physicians and payers.

Is the trial powered enough on both ends of the spectrum as a monotherapy and in combination to demonstrate not only statistical significance overall, but statistical significance in each subgroup.

I don't know if it's powered for statistical significance in each subgroup. Certainly, we believe it's powered for the study at large. We powered the study for 100% tafamidis use and we've -- we're sort of coming out at balanced about 50-50, give or take. So we think the study is appropriately powered, particularly now that it's much, much bigger. What I will say is the tafamidis treatment arm with eplontersen is larger than the other two studies, each individually. So it's a -- even without statistical significance, we're going to have a tremendous amount of data that we'll be able to bring to bear. And that, I think, is going to be really important.

Now with the data sets that came out from competitors, just comparing stabilizers to silencers. Under the more post-tafamidis paradigm, one was able to achieve some level of functional at 12 months, whereas the other was not. But ultimately, that one succeeded in the trial when the more important outcomes data came out. What does it tell you about the silencers versus stabilizers? I mean, obviously, its limited data, we need to know more. But what does that tell you?

Yes. You want to take that?

Sure. I think it's complicated by the fact that this patient demographics have been shifting over time, and so it's hard to make any hard conclusions because of that. But I think with the -- for example, with BridgeBio, when you're looking at that versus tafamidis. When we look at the data we've seen so far, we don't see like a huge difference between those two stabilizers, basically. And for us, it doesn't really make that big of a difference because rest will have -- we'll have data on top of the current stabilizer. And so we'll be able to say if there's benefit on top of it. And I'm not sure it matters which stabilizer you use in that particular case. And so for us, I think what we learned from like the BridgeBio readout recently was that confirm that the patient demographics have shifted basically that their patients were clearly less severe than what you saw in the tafamidis ATTRACT study, right? And all of the current Phase III studies were originally powered based on assumptions from the tafamidis ATTRACT study. And so by adjusting our study based on the more recent demographic shift, we've kind of taken that into account and it confirms our decision to make that change and upsize our study. So I think all of that bodes well for what we've done. I think as far as looking at combination use, I think, Beth is right on is that if you have the data to support different subsets of what you're looking at, then payers and physicians will have the data they need to make whatever decision -- treatment decisions they need to make.

Excellent. I guess the last question, tafamidis is going to go generic at some point. How does that affect your long-term view on the space and how it helps or hurts your growth?

Yes. Again, I don't think it's -- the payer research we've done suggests that it's really not going to have a big impact. We expect that patients are going to -- a great number of patients are going to be on tafamidis or on a stabilizer. So I actually think it's going to have more impact to the other stabilizer, to be honest. Let's so probably to us. Yes.

Excellent. Let's jump over to HAE. We got pivotal data coming up next year, wholly owned. Tell us about that.

So sure. So the donidalorsen Phase III study in HAE patients is -- we're expecting that to read out in the first half of next year. We saw -- as a reminder, we saw some really great data in the Phase II study, where we saw about 97% reduction in attacks in patients in that study. And as we looked at those patients as we followed them for 1 year in open-label extension, we saw that reduction in attack rate continued and it was sustained. And then recently, we reported top line data from the 2-year OLE data where we basically saw sustained out to 2 years, and we'll have more detailed data on that we'll present later this year. But it's been very encouraging to see that the efficacy and the safety profile of that drug in Phase II. The Phase III study is basically wrapping up. We'll have data in the first half of next year. And in that study, we're looking at 6 months. It's basically like the Phase II study, but with more patients, same end points, really similar endpoints, 6 months of dosing, about 90 patients. We're looking at a reduction in attacks in patients over time. So if the Phase III data plays out the same as what we've seen in the Phase II data, then we think we really have a really competitive profile drug for HAE. Now in this particular market, it's very different from, say, eplontersen where less than 20% of patients are on a treatment. In the case of HAE, it's more of a switch market, especially in the U.S. where prophylactic treatment is the preferred use. And so here, we're looking to come into the market with a very attractive drug. The current standard of care is dosed every 2 weeks. It's a large volume injection, the viscus and the efficacy is lower than what we've seen in the Phase II study so far. And so we could have a product that has a very attractive profile that could be dosed once a month instead of every 2 weeks. We are also looking in the Phase III study at every 2-month dosing as well. But our -- we think the primary commercial product will probably be dosed monthly to get the best efficacy, but the 2-month dosing gives us an idea of like what happens if you miss a dose, give people comfort that they can still extend that protection for longer. And so on those results, we're looking forward to seeing those Phase III results soon. And hopefully, fingers crossed, we'll see the same thing we saw in Phase II.

I think just to maybe add to what you were just saying, Wade. One of the things that we're doing because we recognize that this is primarily a switch market is we're running a switch study, and we'll be the only company who's actually done that to be able to demonstrate with data, with strong data, we hope, how confident patients can be and physicians can be in moving from their current therapy to donidalorsen. And we have a rapid onset of action. And that's going to be very important for patients. They'll be able to continue on and move over to the new therapy with confidence that they will not see a breakthrough attacks, the anxiety that these patients experience about the potential for attacks is just debilitating. We want to give them the data and give their physicians the data so that they can be confident in making that change. And so that's going to be a really important part of our commercial package and then we'll be ready when we're ready to launch.

Toward that end, supposing you achieve the continued success on overall attack rate reduction. But in the switch study, how much wiggle room there is there on the breakthrough that interim period at the beginning of -- when you're transitioning from one to the other per attacks that could dissuade a patient from saying, I don't want to take chances.

We want to make sure we show that you can do this and not have breakthrough attacks. I think that's going to be really important for patients. And because we have a rapid onset of action, we believe that that's going to be possible. But that's what the study will show.

Is there any -- going to be any overlap of the therapies in the study? Or are they -- is it one ends, one begins.

It's one end, one begins. I'm pretty sure I'm remembering that correctly. Yes.

Yes. But again, like Beth said, we get maximum reduction within between 1 to 2 doses, and so it's a fairly -- it's a faster onset of action than the current standard of care.

Got it. Got it.

And there's no washout period. So that also helps as well.

Olezarsen, tell us about what's going on there.

Yes. That's our next Phase III readout, olezarsen in FCS patients is due to readout in their Phase III study before the end of the year. And it's a wholly owned asset that we're going to bring to the market ourselves for this ultra-rare indication in FCS. And then later on, we can talk a little bit about that the severe high triglyceride patient population, which is a much bigger patient population. So we're really excited about bringing olezarsen forward. We're looking forward to the Phase III data. We have -- we know that we can reduce triglycerides substantially in this patient population because we've run a Phase III study in a first-generation product and brought that to market outside the United States and in Latin America. So we believe that olezarsen, a once-monthly subQ auto-injector our LICA medicine will be able to demonstrate at least similar efficacy, improved safety and tolerability consistent with the rest of our LICA platform. And we're getting ready to -- we're gearing up to bring that to market today. We would expect to potentially have an approval late next year, assuming priority review and launch shortly thereafter. So everything we're doing right now is to ensure that we have all of the internal capabilities we need and we're bringing on patient education managers for eplontersen, leveraging that for olezarsen, and then we'll start to build our sales force as we get a little bit further along next year, assuming positive Phase III data and the NDA is accepted. So it's exciting.

There's FCS and there, of course, there's the severe triglycerides which is a larger population. How would you compare the challenge of pursuing both opportunities as far as the FDA is concerned, and frankly, competitively, there are other players around as well?

Yes. It's a great point. From a regulatory perspective and from a payer and physician perspective, what we need to demonstrate in FCS as well as in severe high triglycerides is robust triglyceride lowering. We don't have to show cardiovascular outcomes. We don't need to show outcomes in pancreatitis, reduced attack rates in pancreatitis from an outcomes-type trial. And we simply need to show reduced triglycerides. It's very well accepted that, in fact, there are guidelines, well-established guidelines that getting patients below the threshold of acute pancreatitis, which is about 880 mgs per deciliter in triglycerides, gets them out of that risk, and that's critically important. And so our view is with FCS, these patients have a very, very difficult life. It's not just the risk of pancreatitis, but it's the brain fog. It's the severe abdominal pain that they live with every day. It's a very restrictive diet. These patients effectively live with a no fat diet. And when I say no fat, I mean literally two spoonfuls of olive oil at most a day. You guys blew through that in your coffee this morning. I mean, really most of us. I can't. I've tried to do their diet. I can't. I'll ask...

We can't go keto.

Yes. So it's really helping these patients live a more normal life and really affecting their symptoms positively as much as we possibly can as well as getting them obviously out of reduce their risk of pancreatitis. For severe high triglyceride patients, though the patients who are 500 mgs per deciliter to 1000s of mgs per deciliter, their risk is primarily acute pancreatitis. And you need to get them down below that 880 to be able to really get them out of harm's way. And so that's -- we've got a broad Phase III program underway right now for those patients called CORE is the pivotal. CORE2 is the confirmatory pivotal. And then we have a study called ESSENCE that fills out the overall safety database for this indication. That -- those studies should be reading out at the end of next year and possibly into a couple of those studies into early 2025. And what really I think is important with severe high triglyceride patients is that we are able to demonstrate a significant reduction in triglycerides and then hopefully, trends in improved acute pancreatitis, and that will get us to a place where we can start to launch in severe high triglycerides, and there's about 3.5 million patients or so with triglycerides above 500 mgs per deciliter. We obviously don't need to address all 3.5 million of those patients. We actually only need a small fraction of them to really have a blockbuster medication. And what we'll do is we're going to target the aggressive treaters. And there's a group of physicians who believe deeply in reducing triglycerides to reduce risk. And that is -- those are a group of treating physicians we call our sort of aggressive treaters. And we know that if we can bring this drug to them with the data package that shows a reduction in triglycerides similar to what we saw in the Phase II program of greater than 60% or so. That will give us the opportunity for a very important medicine blockbuster potential.

We only have like 1.5 minutes left. So I guess Lp(a) a lot to go on. I have one question. We did have a cardiologist earlier today on the panel. And what I was talking about is, certainly, there's a lot of talk about lowering Lp(a) and the correlation between cardiac benefit. And he being coming from a genetics background was curious about the heterogeneity of the nature of the population. And what type of -- no one really knows because it's never been tested before. When you look forward at that trial, what types of challenges do you see? Obviously, the target is intriguing. But given what we don't know, what type of challenges do you see.

I think because it's the first time that we would potentially demonstrate a cardiovascular benefit in a drug that substantially lowered Lp(a), there's all sorts of potential unknowns. But the thing is that we've known a lot about Lp(a) and there's been a lot of studies over the years. It was actually one of the first genetically determined cardiovascular risk factors identified but it kind of fell out of favor for a while because nobody can do anything about it. You can't change it through diet or lifestyle changes. It's basically genetically set at birth, right? And so you have a lifetime exposure of high Lp(a) if you have the right genetic makeup basically. And about 20% of the population has high Lp(a), greater than 50 milligrams per deciliter is defined as high Lp(a). And that's quite a bit. I mean we're starting with -- in our study with patients who have high Lp(a) and have cardiovascular disease. So it's not -- you're looking at it as a treatment, not as a preventative right now. And so by looking at the more severe patients, and our cutoff is above 50. It's like 70 or above, and we're also looking at subset 90 and above as well who've already had a cardiovascular event, you're enriching for your probability of seeing an effect in this patient population. We know that Lp(a) is a carrier of oxidize phospholipids, which are oxidized phospholipids, which are nasty things for cardiovascular disease. And so there's lots of biology that we know about it. I guess what we don't know is like how much reduction leads to cardiovascular benefit. What's the what's the outcome benefit. I mean most people look at a cardiovascular outcome study to see a minimum like 20% benefit in cardiovascular benefit. We would, of course, look to -- hope to see that or better, hopefully much better. And then how much -- what the magnitude of LPA reduction correlates to cardiovascular benefit is going to be something that we'll have to determine from this study. But based on -- like I said, based on what we know, we think we have a pretty good chance of seeing something pretty substantial. And just to point out in our Phase II study, we saw patients who had high Lp(a), we saw 98% of them get below 50 milligrams per deciliter. So basically, 98% got to target. So I mean I think we have a pretty potent drug, and we've designed the study to give us the answers that we need.

Thank you very much.

Thank you.