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

Great. Hello, everyone. Thanks for joining us at the Needham & Company Virtual Healthcare Conference. My name is Chad Messer. I'm one of the senior biotech analysts here at Needham, and it is my pleasure today to be joined by Patrick Swayze, Head of research at Ionis Pharmaceuticals, to discuss -- I don't think we'll hit them all, but many of the exciting programs that are going on at Ionis. So if Patrick, if I could just -- Eric, excuse me, if I could just jump in...

I'm very excited to be messed up -- mixed up with the guy who did Dirty Dancing. So...

I am of that generation where the mental crossover is almost inevitable.

All right. With that, ALS, obviously a really big area for Ionis right now. You've got multiple programs, both wholly owned and partnered, and a really exciting readout that's coming up later this year. Maybe just set the stage broadly on that disease. And then from there, we can get into some of these programs and some of the data we should be expecting.

Yes. Sure, I'd love to. So I mean, ALS is -- really was our first foray into neurological diseases many, many years ago when you're asking basic questions about can we deliver antisense medicines to the central nervous system? And will they modulate their targets there and can they make a difference? And so we've been interested in ALS and committed to trying to do something for ALS patients for many years. There's obviously no good therapies for ALS. And the nice things that appeal to us is there are several genetic forms of ALS where the underlying genetics and pathology that's driving the disease is very well known and very well understood. And the first one we tackled was SOD1-driven ALS, which is well known to be caused by a toxic gain-of-function mutation in a gene called SOD1, which drives aberrant pathology in motor neurons and causes degeneration and loss of function and ultimately death for the patients. And since it was known to be -- the gene was known and the mutations were known and the pathology was known, it was a nice first proof of principle to think about lowering SOD1 in the CNS and lowering it in the motor neurons to see if that made a difference. And preclinically, it did make a difference in the mouse. Mouse models of ALS for SOD1 are pretty good and do a reasonable job at [ recapitulating disease ]. So that ultimately led to our tofersen program, which is partnered with Biogen, is -- I can't remember the exact number of patients, about 100 patients, I think, in the Phase III VALOR study, which is scheduled to read out later this year. And this is taken directly to Phase III by Biogen after looking at our Phase I/II data where we did an experiment where we had some faster progressing mutations in the patient population and saw what we consider to be remarkable efficacy effects where the drug caused soft progression of these fast-moving ALS patients that have the most severe mutations. And so certainly, we're enthused about that program. And to us, it really speaks to whether or not we can make a difference in ALS with the genetic medicine that really addresses the root cause of the disease. And this will be one of the first readouts for that type of therapy.

So maybe we can spend a little bit more time on VALOR, sort of remind us of what the primary endpoint is and kind of what -- I mean, you said you saw some fantastic efficacy data in Phase I/II. What's -- what would be -- what's sort of the bar for good data in Phase III? I know obviously, there's very little to treat this disease. So having an impact is the sort of 1 bar. But...

Yes. So it's right around 100 patients on 100 milligrams monthly of tofersen. And there's a range of patients with different mutations, and so the intention is to get a label for treatment of all patients with SOD1 ALS. So a 24-week study, I believe, and that's based on the fairly early readout we got in the Phase I/II study. The endpoints are common ALS functional measures. ALSFRS is a functional rating scale a variety of clinical signs for people who have ALS and also look at other things such as force vital capacity and other functional measures. You mentioned the bar. I think the bar is really seeing any benefit either in slowing the rates of progression or in some of the fast-progressing mutations. We really saw a stopping of progression in the Phase I/II trial. So obviously, we hope to see the biggest effect we can. But in ALS, as you said, there's nothing for this patient population, so any benefit would certainly be a boon to patients.

Okay. And so that's a Biogen study and the guidance is just later this year or is that -- is there anything more granular?

I don't have anything more granular. It's a readout sometime this -- later this year.

All right. Well, certainly one of the exciting things we're looking for from you guys this year. So SOD1 isn't the only set of mutations that you guys are going after. You also have program for [ 9 ] mutations, a little time there. And then you've got some broader -- some treatments to treat broader populations as well we could talk about after.

Yes. I mean, I guess the first one I'll talk about is Ionis-owned program in contrast to the other programs, which is a program targeting a mutation called FUS. Also given -- also causes a familial ALS. This is a little bit more rare than the SOD1 patient population. But we think it's a good commercial opportunity and this is Ionis-owned program. And this is a bit of a unique program in that it was originally developed by some academic physicians who were interested in treating patients in kind of an n-of-1 type format and they worked with us to use a FUS algo called Jacifusen after the first patient that took the drug. That program is going to start a Phase III, an Ionis-owned program very shortly for the treatment of FUS-driven ALS. This is similar to SOD1 in that it's again a pathogenic gain-of-function mutation, causes aggregates of -- admiral aggregates of FUS protein in the cytoplasm and disrupts its normal function and causes toxic gain of function. So we're -- and good preclinical data also in models of FUS-driven ALS, we're hopeful that can make a difference for the FUS ALS patients much like we believe that the SOD1 drug, tofersen, will make a difference for the SOD1 ALS patients. The next one we tackled was, as you mentioned, the C9ORF72. This is a gene that is linked to the most common cause of familial ALS mutations in the C9ORF72 gene. These are caused by pathogenic repeat expansions in the C9ORF72 gene. Again, causing ALS FUS was pretty well believed to be a toxic gain-of-function mutation in the C9ORF72 gene. Here because of the nuances in the way the RNA is processed, we have made a drug that only lowers the allele of this gene that has the pathogenic repeat expansion. And so we're lowering just the pathogenic form of C9ORF72 with our antisense drug. This program published a lot of research on C9ORF72. A lot of excitement around targeting that gene since it was discovered not too long ago and have a drug in Phase I/II clinical trials with Biogen, looking for early signs of benefit or maybe of safety, of course, is Phase I/II but looking for benefit in the C9ORF72 ALS population and hopefully set us up for later-stage trials. That trial is to read out sometime later this year, perhaps early next year, depending on how the timing goes. Then the next one we have is also part with Biogen is ION541 is what we call it. It's a drug targeting ataxin 2. Unlike the other programs we talked about, this is a drug which we believe will be amenable to treatment of all forms of ALS. And it does this by lowering a protein called ataxin 2, which has a genetic association where certain mutations in ataxin 2 predispose people to have ALS. So it's not a genetic cause of ALS really but it's an association with ALS and an association with sporadic ALS. And the way we believe this drug works is by lowering ataxin 2, this modulates the pathology that's very common ALS with a protein called TDP43, which has been associated with a toxic gain of function of mislocalized TDP43. And we've shown preclinically that by lowering ataxin 2, we can reduce this pathology in models of ALS and primary motor neurons. So we're optimistic and hopeful that this drug can make a difference in all patients who have ALS as opposed to just genetic forms. So we're very committed to ALS, broadly interested in ALS with Biogen and also on our own, Ionis, and trying to tackle this terrible disease.

I think just before we leave ALS, you guys have spent so much time studying these different genetic forms and just the underlying biology of disease generally. Any difference in, say, severity of disease across these different -- I know even for tofersen and SOD1, there are -- inside the SOD1 gene, there are faster and slower progressing, but across these different genetic mutations, any difference? Anything that would be important to consider for study design? And then for the for the ataxin 1 -- 2 program, is that something that could be combined with the more targeted genetic mutations in ALS? Is that something you've even looked at preclinically?

Yes, it certainly could. It's a little bit difficult to look at preclinically, given the models tend to be more specific for the specific genetic forms. I think that if we show a benefit of the ataxin 2-lowering drug in patients who have TDP43 pathology, any patient with that type of pathology should benefit from that therapy. So -- and for example, C9ORF72 ALS has TDP43 pathology in most cases so it definitely is a thought and could make sense to do so. I think it's probably best asked in the clinic after we establish efficacy with a single agent. And then you asked about rates of progression of various mutations. That's certainly true. Now C9ORF72 is -- there's different numbers of repeats which can affect the severity of the disease. It's the same type of mutation. For SOD1, there's -- as you mentioned, there's a variety of different mutations, which can have fairly dramatic differences in rates of progression. But we put a lot of thought into the VALOR study and powered that study and the endpoints carefully to try and demonstrate that we can show a benefit in a variety of different mutations that have different rates of progression. FUS also has the same thing. There's more severe mutations and less severe mutations.

All right. So I think maybe we can move on to some other programs. But before we do, I just want to remind anyone listening in the audience that at any time, you can type questions into the question box and if we have time, we'll get to those at the end. You don't have to wait. In fact, I've been encouraged to have people do them as early as possible since they can take a minute or 2 to appear. But maybe we can move on and spend a couple of minutes on tomersen -- I'm sorry, tominersen for Huntington's disease. Not everything works out in drug development with as many programs as you guys have. We're bound to get some non perfect news. Maybe just like to hear your comments on what we heard about -- there's no new safety signals but sort of a risk-reward stopping enrollment in the study. And any -- what that tells you about that program or any other programs or read-throughs?

Yes. Well, it's a tough month for Huntington's patients. So there's some bad news from us and also some bad news from our competitor, Wave, who is also trying to make a difference in Huntington's disease. And it's really unfortunate for the patients in the community. They put a lot of hope and thought in these programs. Been great to work with the Huntington patient community, and it's really sad to see that those drugs weren't working as well as we hoped. I do think -- I can't say much more about the data than what we've talked about publicly and Roche has talked about publicly. As you mentioned, there was a safety monitoring board that reviewed the data and stopped dosing. They have then stopped the trial but they're continuing to follow up patients, stop dosing for lack of a risk benefit and then highlighted there was no new safety issues. So I think it's fairly straightforward to interpret what the issue was. And I do think it's specific to this particular program. We certainly feel like we're engaging the target. We show very clearly with the tominersen program that we were lowering in Huntington and the CSF. All our preclinical data suggest that we were broadly lowering mutant Huntington throughout the CNS in humans as well as preclinical species. I think we have lots of supporting data showing that our drugs broadly work. And for whatever reason, the Huntington drug wasn't giving the benefits we'd hoped in this trial.

Okay. So I mean, possibly just the science and the target and the impact of the target not being what we had hoped it to be. Is that a reasonable...

Yes, we really have to unpack -- with Roche, we have to unpack all this data. So I mean, it's the largest experiment ever done in Huntington's disease. There was nearly 800 patients on trial. A couple of different doses of the drug. Obviously, the genetic cause of Huntington's disease is well known, and we were lowering the genetic cause of the disease, which is known to be a gain-of-function target. That being said, Huntington's disease is a little bit more complex. It's slower progressing than ALS. It's a whole brain disease instead of contrasted to ALS and SMA is a motor neuron type disease. Whether or not it's easier to reverse or improve the function of motor neuron relative to the types of neurodegeneration that goes on Huntington is unknown, and whether or not we have time to make a difference in the disease by lower mutant Huntington is unknown and whether or not we treat it early enough is unknown. So I think there's a lot to learn in the Huntington's disease space from this trial. And as Roche gets to analyze the data and deconstruct it and look at all the features of the data set, and they will report them, too, by the way. Roche is very engaged in Huntington's disease. And I think that they feel the responsibility of the community to make this data known and the investigators on the trial will demand it. So I think we'll learn a lot from this, and hopefully, pave a way for better Huntington's therapies to come and their experience that will make a difference.

Yes. So as you mentioned, they are continuing to follow the patients and there's an open-label extension associated with that. So hopefully, we'll get some of those questions that you elucidated answered and be able to use that for future drug development. Maybe moving on and sort of keeping with some of the later-stage programs that you guys are involved with. APO(a) has always been a fascinating target to me, is sort of an independent cardiovascular risk. It's one that's been around a long time. It's been known about. No one's ever really been able to drug it. So talk about experiments that can only be run with antisense, at least human experiments. I kind of view this as one of those as well. Maybe just talk a little bit about the HORIZON study with Novartis and what you think this drug could mean for patients.

Yes. So I'm tickled you brought it up. Sometimes, that one gets overlooked. So this is a Phase III program, as you mentioned, partnered with Novartis. The drug is called pelacarsen. And as you alluded to, it targets this mRNA that codes for a protein Lp(a), which is an independent risk factor from LDL cholesterol for cardiovascular disease. And I think it's estimated at 15% to 20%, maybe 17% of the people in the world have elevated Lp(a). And elevated Lp(a), much like elevated LDL, has been correlated with increased incidence of cardiovascular disease. And so what I think this means is if you have high LP(a) and normal LDL, you have a cardiovascular risk. And what we're doing with Novartis is testing the hypothesis that lowering Lp(a) in people with established cardiovascular disease will make a difference in the outcome of their disease. And so that's what the HORIZON study is. They've got nearly 8,000 patients enrolled in this study, plan to enroll, with Lp(a), greater than 70 milligrams per deciliter and a history of cardiovascular disease. This is a drug that's given monthly via subcutaneous injection. It's 80 milligrams a month in this trial, and it makes use of our LICA technology, which directly targets the drug to the hepatocytes in the liver. The hepatocytes are what makes Lp(a) and assembles it on to the particles in the bloodstream, which then contribute to cardiovascular disease via increased atherogenicity, increased anti-fibrinolytic activity and also pro-inflammatory effects. So it's a nice target, as you mentioned. It's -- I don't know any other good way to drug it than with antisense-type patients that will lower expression of the protein-inhibiting synthesis. And it's a very common risk factor for cardiovascular disease. So there's about 8 million people, I think, worldwide with Lp(a)-driven cardiovascular disease. So I think it's a very exciting program. And Novartis has been fantastic in getting this program up and running. And we're tickled to have one of our drugs in such a broad patient population. And so just beyond how neat the program is for people with cardiovascular disease in this particular genetic form, it speaks to the safety of the LICA platform that we can do large patient outcomes trials and the efficacy of the drugs and hopefully will make a great product with an 80-milligram subcu monthly injectable.

Yes. No, really exciting. 8,000 patients receiving this LICA drug in and of itself, massive undertaking. Has there been any guidance for Novartis on what to expect on either enrollment or data? Or are there any interims or anything that they've shared?

Let me try and remember that. I mean it's a big study. I think we'll have data sometime in the 2024, 2025 time frame, if I got that right. It's -- so they've been going very quickly and very fast with this program. Novartis is doing a great job.

Yes. Well, that sounds about right for a large cardiovascular study. So maybe just sort of pressing my advantage as the moderator on topics of interest. Another LICA program you have that treats an interesting cardiovascular target is vupanorsen, ANGPTL3. So this one sort of regulates have been much more complicated, in my mind, anyway, sort of placed in the sort of lipid pathways with effects on triglycerides and cholesterol. Can you just talk about that science a little bit? What patient populations you think might benefit for this? And maybe what we should look for from the TRANSLATE study from Pfizer?

Yes. So vupanorsen is a drug. So vupanorsen, we have a family of these LICA drugs. So much like pelacarsen, it's a drug that uses our LICA technology. It targets a different protein. This is angiopoietin-like 3, which has a very strong genetic association to cardiovascular risk if it's mutated. And loss-of-function mutations in that protein have shown very nice profiles and reduce cardiovascular risk. It lowers all atherogenic lipids, not Lp(a). So it lowers triglycerides and it lowers LDL, most pronounced, and then all forms of -- various other forms of atherogenic LDL-like particles by lowering angiopoietin-like 3. So the patient population that benefits, I would think the most from this, are really mixed dyslipidemia-type patients that have higher LDL and some level of high triglycerides. And I put that in contrast a bit to another drug we haven't talked about yet, Ionis-APOCIII-LRx, which is a drug that targets APOCIII, which lowering that protein lowers triglycerides pretty much exclusively. And so there, you'd have a patient population with just high triglycerides that would benefit from the APOCIII drug, whereas vupanorsen will be more beneficial in a mixed with lipidemic patient population. Pfizer has licensed this program from us and is now running a Phase II trial, TRANSLATE trial. Trying to get the dose and get the dose dialed in for ultimately what would be a Phase III outcome-type trial in patients with cardiovascular disease and trying to make the benefit in that disease.

Maybe moving on to a wholly owned program. We recently got some positive data from PKK-LRx, another LICA program in hereditary angioedema. Can you maybe just talk us through that data and tell us what you think next for this program?

Yes. So pretty exciting data. And I think that we just released top line so far. We'll have a presentation some time to really work through the data. So this is, again, a LICA drug, which lowers -- targets a gene called prekallikrein, which is the precursor to kallikrein and then activates the bradykinin pathway. This is well known to be heavily implicated in a disease called hereditary angioedema, where patients have debilitating attacks that are caused by an imbalance in the kallikrein bradykinin pathway that can be life-threatening. And there's several medications out in this space so it's actually a competitive marketplace. So kind of the standard of care, there would be lanadelumab, which is an antibody that targets kallikrein. So we're on the same pathway as that. But we think we have a terrific drug and could potentially be best-in-class therapy in this pathway as a prophylactic for hereditary angioedema. So the name of the game here is reducing the level of attacks in patients. And we had -- we were encouraged, first, by the characteristics of this drug at 80 milligrams a month in the Phase I/II study that was -- we recently published the New England Journal Medicine, we were getting greater than 90% suppression of the pathway. Very clean molecule, nice safety profile. It's a once-a-month subcu injectable, maybe once every 2 months if we tweak the dosing right. Nice durability and a very clean profile. And so we think that it would be a very attractive drug for this patient population. In a couple of compassionate use cases, also published in the New England Journal, we showed reduction in attack rates in this paper, which finally were translated to the Phase II that we released top line on where we treated HAE types 1 and 2 patients with 80 milligrams of drug once a month for 17 weeks, I think, and saw a pretty dramatic reduction in attack rates. So greater than 90% reduction in weeks 1 to 17, a 97% reduction in weeks 5 to 17, which is really when the drug would be expected to be working with 1 dose. It takes a couple of doses to get to steady state and get maximum target suppression. And then I think in the week 5 to 17 window, we had greater than 90% of the patients completely attack-free compared to non-placebo patients. So we think the drug clearly is working. As I mentioned, it's very tough, very well tolerated and convenient once-a-month flow volumes subcu injectable that we think nicely competitive in this marketplace. And so we're thinking through our plans for moving it aggressively forward into Phase III development.

Okay. Well, yes, certainly excited to look for the detailed presentation of that. As you mentioned, competitive marketplace so the details are, as always, important, perhaps more so. So one of the next readouts that we'll be getting is for your ENaC program, and this is in cystic fibrosis. Can you, a, talk about the unmet need there and maybe set the stage for the data? But this is also your first pulmonary delivery drug, so that's kind of important. We're branching out here with delivery methods. Are there other opportunities to exploit that technology that we should be looking forward to?

Yes. I guess, I'll talk about that first, which is one of the key things to us is, and a follower of Ionis will note that we like to attack areas where we can target our drugs and get our drugs delivered and have efficacy. And so we've focused heavily on our neurology franchise and our cardiovascular franchise, where we've had good success. And the ENaC data, I think, sets the stage for an emerging franchise in pulmonary disease. There's lots of unmet medical need in pulmonary disease from cystic fibrosis, which is pretty well treated for many patients. However, there is a subset of patients that had mutations that are not amenable to treatment with, for example, Trikafta but then moving on to diseases like COPD and asthma and idiopathic pulmonary fibrosis. There's a whole host of pulmonary diseases that are not well treated these days or that have a lot of unmet medical need. And so the key -- one of the key for us with the ENaC program was the ability, with the Phase I data, to show target engagement in patient in -- this was healthy volunteers with our drug that clearly showed that we were on the dance floor, so to speak, within regard to the ability to modulate targets in the lung with aerosol administration. So we gave -- status have been presented, so we gave weekly doses where 75 milligrams a week of the drug was giving a north of 50% down-regulation of ENaC. Very encouraging data. Sets us up to do further ENaC experiments in multiple diseases. And we have both trials ongoing in cystic fibrosis and also COPD with this molecule. But also broadens the scope because once an antisense drug works against target S, there's a pretty good -- it increases the likelihood that you can make it work against target Y, you kind of know your dose. So we have another drug in Phase I clinical trials for -- it's an undisclosed target but another indication in pulmonary diseases, and we've got more coming. So I think it does set us up for a pulmonary franchise and expanding our space, our scope of activities in that space. As far as the ENaC program and the unmet medical need, I would say, the most obvious one is for the 10% to 20% or so of patients that have cystic fibrosis that have mutations that are not amenable to therapy such as Trikafta, which is directly modulating CFTR function and restoring that loss of function. And ENaC makes sense for doing that because ENaC can be inhibiting the sodium channel. ENaC, it can rehydrate the lung, which is what loss of the chloride channels, the CFTR does, it helps -- it dehydrates the lung. And by inhibiting the sodium channel, you can restore that osmotic balance in the lung, rehydrate the lung, increase mucociliary clearance and hopefully have a benefit in patients. We've shown very clearly in preclinical models that, that works, inhibiting ENaC. It's been a bit of a popular target and some other companies have tried it. But inhibiting ENaC in -- broadly in the periphery causes hyperkalemia and some renal side effects. And by the way, administering the drug specifically to the lung with aerosol administration, we avoid that because we treat the lung but we don't have enough systemic exposure to lower ENaC anywhere else. And so we think that, that has a place in cystic fibrosis therapy, both for the patients that aren't amenable to CFTR modulators and hopefully on top of CFTR therapy, we can provide an active benefit. And the Phase II data that we released top line data for was really a Phase IIa safety study, so the key thing was showing safety in cystic fibrosis patients. But we also released top line data where we had a dose-dependent increase in FEV1 relative to placebo at the end of the study, again, smaller numbers of patients. We don't want to expect to continue with significant significance out of that but we saw the trend moving in the right direction, which sets us up for further Phase II experiments.

Awesome. Very exciting one to be watching both for cystic fibrosis, and as you mentioned, potentially emerging pulmonary franchise out of this technology. And no better person, I'm sure, to be helping guide you guys as you go out on the dance floor with that one. Maybe moving on to another wholly owned program with data coming out soon, GHR LRx for acromegaly, not a disease I know a lot about or a target, I know anything about. Maybe talk a little bit about that and set the stage there.

Yes. So acromegaly is a disease driven by really through growth hormone. And so you have aberrant growth hormone activity, which causes aberrant growth, and patients both suffer aberrant growth features and also they don't feel very good. And so the extra growth hormone has severe quality of life issues. There's -- the standard of care here is somatostatin receptor therapy, which interacts and blocks the effect of growth hormone. By targeting a different site that we are, what we're doing is reducing growth hormone receptor in the liver, which mediates growth hormone signaling from growth hormone, binds to the growth hormone receptor and then triggers the production of IGF-1 by the liver. IGF-1 then drives the aberrant growth effects. And so we think that by reducing IGF-1, by reducing the growth hormone receptor and reducing that signaling, we can really normalize or hopefully normalize and reduce IGF-1 signaling, which will provide a disease benefit. And so normalization of IGF-1 and control of IGF-1 is the name of the game in treating acromegaly. And -- but the active therapies don't actually do that as well as they could, and people have IGF-1 excursions where it will get out of whack. And the patients, they report not being well controlled on their therapies. And so with a Gen 2 LICA drug, what we're trying to do is knock down the receptor, interrupt that signaling cascade, suppress IGF-1 and keep it suppressed over periods of -- over long periods of time. Our drugs work very consistently with monthly subcu administration. And hopefully, that will have a quality of life benefit in addition to lowering IGF-1. So that compounds in a Phase II study in patients on long-acting somatostatin receptor therapy, monthly dosing again, and hopefully, we'll be able to see reductions in IGF-1 and normalization of IGF-1 and coupled with the quality of life improvement in acromegaly patients.

Yet another thing to look forward to in the near future. I just wanted to remind anyone in the audience that might have questions. We're down to our last few minutes. If you'd like to ask something, now is your chance. Otherwise, you're going to be subjected to my questions. I'm not going to run out of them, I promise. So another wholly owned program where we got some Phase II data, AGT for hypertension, treatment-resistant hypertension. Can you talk about the target in this disease, the biology there a little bit?

Yes. So the target is angiotensinogen and -- or AGT. And here, the therapeutic goal is to inhibit angiotensin produced from the liver for maximum effects on the RAS pathway, which is also a target of ACE inhibitors and ARBs for -- that are controlling hypertension. But we spare the kidney effects of these drugs by just inhibiting liver AGT. And this allows the kidney to continue to maintain blood volume in electrolyte homeostasis. And the end results should be an effect on blood pressure while not causing hypotension or hyperkalemia. So we think this is a great way to reduce blood pressure about the standard of care. And that was the focus of our Phase II study that we have, again, top line data on where we treated our -- and we added our angiotensin inhibitor on top of the standard of care in uncontrolled hypertension, people who were on maximal hypertensives and were not controlled. And we're able to show a benefit in controlling blood pressure in those patients. So I think it's a very exciting approach for especially treatment of refractive hypertension. Obviously, hypertension has lots of options. And so we really think that uncontrolled hypertension, adding on to standard of care is the right use for this type of therapy in this space. We're also interested in heart failure and in here, we're interested in, again, lowering AGT to try and have a benefit in heart failure by improving the direct effects of angiotensinogen on the heart in exacerbating heart failure. So that's another trial that's starting up.

And maybe just in our last minute, a little bit broader and off of just the specific sort of R&D programs. This is wholly owned, hypertension, heart failure. These are big indications. We've talked through a whole bunch of your different programs. A lot of the ones with big indications like APO(a), for example, whether these large studies are -- they're partnered, right? That's something you've done in the past. Do you think you need a partner for this drug? And what -- when might be a time to look for one?

Yes. So I mean, I guess I'll speak a little bit more broadly for each medicine worth, we think through what's best for that medicine and what's best for patients to get access and maximal access of the medicine to patients and what's best for Ionis' shareholders in trying to retain maximal value for those programs. Pelacarsen is a great example. Vupanorsen is a good example. Those need large outcome studies, large marketing and sales forces. It makes good sense to partner those with people who know the space. Our PCSK9 drug, which had great Phase I data, looks like it could be a best-in-class PCSK9 inhibitor. There's a competitive marketplace that's partnered with AstraZeneca. They know how to compete in the cardiovascular space. For other programs, we're -- we have a new commercial strategy we've discussed to announce where we're intending to commercialize our own drugs. There, we're looking at mostly our neurology and cardiovascular pipeline and try to figure out which medicines are right for us to commercialize. It makes sense for a company like Ionis to commercialize ourselves. So we make a choice for each drug. Some of them like PKK is a good one. That's kind of outside of our core space but the data was great. And so we'll make a decision on that drug and whether or not that fits within our commercial strategy once we start to see data. And for angiotensinogen, that's not exactly the same space as the Lp(a) market, certainly isn't a rare neurology drug either. So I think that one merits a lot of thought, and we're working through our options with that program like we do for a whole.

All right. Well, we're out of time so I think we're going to have to stop there. But Eric, thank you so much for taking us through at least a nice part of the programs going on at Ionis today. Appreciate your time.

Thanks for having me on. Appreciate it.