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

All right. Good afternoon, and thank you for joining Guggenheim's Genomic Medicines and Rare Disease Conference day 2's last half of our session here. I am Debjit. I'm one of the analysts representing the Guggenheim Therapeutics team. It's my privilege to host Ionis Pharmaceuticals' Executive Vice President of Research, Dr. Eric Swayze. Eric, thank you for your time today.

Well, thank you very much for having us on. Appreciate the opportunity.

Awesome. So let's just dial straight into it. Ionis' platform obviously has come a long way since mipomersen. You've been here for, you just said like, what, 24 years. You've experienced the whole highs and lows here.

So can you walk us through the key changes designed to sort of address the initial concerns that everybody had about injection site reactions: thrombocytopenia, renal signals across the board?

Yes, sure. 28 years, actually. Just had my 28th anniversary, so never did I dream that I would be working for the same biotech company for 28 years when I came out of grad school. So it's been a great ride, and I've really enjoyed it. And part of the thing that I really enjoyed was our continual relentless focus on improving our platform and improving our technology. When we started, there was no RNA therapeutics. There was no antisense technology and we really had to dig down and find ways to make it work. And not everything we tried worked, and some of the things we tried that worked turned out to meet some pretty big improvements to work well and become successful commercial products. And I think we're well on our way to doing that. If you look and contrast, some of the first drugs that we had that were FDA approved, I think mipomersen was the first systemically approved antisense medicine. It was really pioneering and trailblazing at the time, but it wasn't a successful commercial product. And we continued to improve the platform. And I can just highlight that class of chemical and compare it to where we are now with the advent of the LICA platform, which increases delivery to the desired target cell type and target tissue, which increases potency by about 30 fold. This means the difference between a 300- or a 200-milligram a week subcutaneous injection. And we're now doing 45 milligrams a month, is the clinical dose for eplontersen and olezarsen, 2 of our lead Phase III programs. And so it's really been transformational for the pipeline in terms of the profile of the drugs. And when we get the dose down and get the drug targeted to where we want to go, we saw all of the side effects basically banished and it was very much a dose phenomenon. And we have drugs that aren't showing that and have very clean safety profiles in large Phase III studies, and we're excited about that platform. And we could talk later about other improvements we're making with new chemistries and other LICA technologies. But really, our continual focus on innovation and improving the platform has dramatically changed the profile of our drugs. And I think we're poised to make them successful commercial products.

So it's just basically the dose and the LICA contribution, improving potency, which has led to this current [ groups of ] Phase III programs with a relatively clean safety profile. That's the ...

I mean we've also tweaked the design of some of the molecules suddenly. So for example, eplontersen has a little bit reduced phosphorothioate content in certain key regions of the backbone, which would reduce things like pro-inflammatory effects that are due to some of the phosphorothioate. But I think the real key is the targeted delivery and the increase in potency we see with the GalNAc LICA platform for liver delivery, and it's really been transformational. So pretty much across the board, it's been a 20- to 30-fold increase in potency, which allows us to both dose less and dose far less frequently because the half-life of the drug supports a monthly or a bimonthly dosing profile very nicely.

Great. Then you just alluded to investments -- ongoing investments to further improve on the backbone technology. So maybe we can talk a little bit about your partnership with Bicycle or Aro or other -- initiatives that you're bringing forward right now?

Yes. So there's multiple ones. The ones -- some of the ones we've talked about are the collaborations with companies like Bicycle and Aro. Those are new LICA technology platforms. So LICA is an acronym for Ligand Conjugated Antisense, and it really means targeted tissue delivery. And the idea here is to take some sort of ligand that binds selectively to the surface of a cell or a tissue of interest and increase the fraction of the administered dose of the drug that's delivered to the intended target or cell type. That's what GalNAc LICA platform did for the hepatocyte in the liver, and we're looking to do that broadly for multiple tissues. The collaborations you mentioned with Aro and Bicycle are -- and the Bicycle one, in particular, is meant to take advantage of transferrin receptor 1 targeting, which has been shown to deliver drugs to the muscle tissues, both skeletal and cardiac. And so our Bicycle relationship is an exclusive relationship with them for bicycles, which are small peptide -- bicyclic peptide molecules, and they have devised a family of these that binds transferrin receptor 1, and we have an exclusive license to use those for all RNA therapeutics, including both ASOs and siRNAs. And we've shown in some data that I was able to present at the Investor Day last year, and Bicycle's presented in a couple of meetings, very nice targeting of both ASOs and siRNAs to both skeletal and cardiac muscle tissue, resulting in 10- to 20-fold improvements in potency in preclinical species. And we're very enthusiastic about that and are moving that platform forward aggressively to try and get it into drugs to open up new tissues for us, targeting the muscle effectively. And as you know, we have a cardiovascular franchise that we're very keen on and are looking to open up the cardiomyocyte as another cell that we can practice antisense in.

So if I understand this correctly, then given the focus on transferrin receptors and muscle indications where you can simultaneously targets striated muscles across the board, Duchenne muscular dystrophy, does that something sort of ring a bell to you guys down the road?

We're well aware of that target and the opportunity in those spaces. We haven't disclosed our timing or our initial spate of targets for these indications. But there's many. You're well aware of competition in the space. So we're being a little bit circumspect about exactly what -- disclosing our plans in the space, but there's a whole host of neuromuscular targets. There's a whole host of cardiovascular targets that we're interested in. And we think the technology is going to work. So we're broadly pushing it forward.

So with this transferrin targeting approach, you're not necessarily over-reliant on x amount of arginine residues in the peptide just to avoid that renal signal that you normally would see for targeted peptides?

Yes, I think these aren't -- so I'm trying to remember our structure. I don't think there's any arginines in there. This is -- they're actually reasonably hydrophobic, the bicycles that we're working with as well as the lead ligands that we have from our collaborators at Aro. They're not polycationic by any stretch of the imagination. We've looked at those -- I mean the polycations have had a fairly sordid history, and we've looked at these mechanisms of uptake and have generally discarded them as not being useful due to toxicities. But the bicycles are very different. They're reasonably hydrophobic molecules, not abnormally so. So we don't have any solubility or synthesis problems when we conjugate these to oligos. They go on very easily, and they bind in this nifty little cleft between -- right the corner of the apical domain of the transferrin receptor. The Bicycle team has gotten crystal structures. It's a very nice small molecule ligand event. And the real benefit of this type of technology, especially Bicycle but also Aro is the size of the ligand. And so the bicycle technology, those compounds are 1,500 to 1,800 in molecular weight and ASO is 6,500 to 7,000. So they add a reasonably small fraction to the total weight of the drug. Whereas if you look at some of our competition in the space, they're using monoclonal antibodies or Fab fragments. Those are 150,000 molecular weight or 50,000 molecular weight, respectively. So the ASO or siRNA, for that matter, turns out to be a very small fraction of the administered drug. And so we're looking at the overall product presentation thinking if we have to deliver 3 mg per kg of an ASO to a person to get effect in the muscle, that might be 3.5 to 4 mg per kg of a bicycle ASO conjugate, which is very doable, small increase in the drug fraction. If you're going to convert that to a monoclonal antibody ASO conjugate to do the same thing, it would be grams of total drug product. And so we think that's one key advantage of the small ligand technology such as that with the Bicycle platform.

That's interesting. And then just to stay on this topic because you just opened up so many options here, endosomal escape and nuclear localization for things like dystrophy -- muscular dystrophy. Doesn't that become significantly more feasible with your approach with Bicycle as opposed to a mAb-based approach?

I'm not sure that's really true. We have fairly equivalent performance on a molecule per molecule or a molar basis, for the chemists in the audience, I don't show my roots, of delivery of the drug. So if you deliver one molecule of ASO conjugated to a monoclonal antibody or one molecule of ASO conjugated to a bicycle, the potency based on the ASO delivered, not the total drug, is about the same. And so I think that what's happening is the ligand, be it mAb or a bicycle or a Centyrin via the Aro collaboration, binds to the surface of the cell, if internalized. And what we think is happening is the oligo has been cleaved, and we actually design our linkers such that they're cleaved inside the cell, and we'd like them to be cleaved fairly quickly. Our GalNAc LICA technology that's in eplontersen, for example, we know is cleaved within minutes to hours inside the cell and is completely removed in 24 hours. And so it's almost a prodrome-like strategy. And then the ASO is delivered to the endosomal-lysosomal system. And we know that as the endosomes are processed and mature, a fraction of the ASO is able to escape. And I think that it continuously escapes over time and delivers drug into the active compartment. We also know that ASOs, once they are outside of the endosome, i.e. in the cytoplasm, they're rapidly taken up into the nucleus and they like to stay there. So they can go to where the target sites are really quite well. And we've seen that they distribute very well to the nucleus, for example, if you wanted to target a nuclear-retained RNA. So I'm not really worried about our distribution changing with the LICA strategy, and we're not actually trying to change our intracellular distribution so much as to change the macro cellular distribution, i.e. shift distribution from the kidney to the liver or the liver and the kidney to the muscle.

Appreciate that. Now the topic of stereoselectivity with antisense oligos comes up off and on. I know you guys have tried it. You probably gave up on it. I believe 2013 was the first time I saw an article from you guys on stereoselectivity.

[ You ] read our paper.

Any thoughts on that? I mean that's my job.

Actually, it's fascinating science. And we read with great interest the work from the [ Water ] group on the newer methods of making stereoselective oligonucleotides. We tried this -- when I first joined then Isis Pharmaceuticals in the '90s, we were working on this because we thought it should make a difference. And the synthetic methods were really hard. And so the [ Water ] synthetic method is very nice, and it allows you to make stereoselective. They're not completely stereo [ pure ]. That's very difficult to do that, but they're stereoselective. And we thought it should make a difference. And that's why we work -- did that work that's in the paper you cite. And we -- to much surprise to those of us who were doing this work, we didn't see huge differences. We could make active compounds inactive by converting them to a diastereomeric form that didn't support the enzymatic mechanisms, for example, but we couldn't ever see big shifts in potency to the positive side or distribution for that matter. And it was a little bit of a puzzle, and we made lots and lots of compounds, published the paper that you cite and didn't find a lot of value. And I know that there's -- we have competitors in the space who believe otherwise, and we follow their work carefully and are always trying to look for opportunities for the chiral control to make a difference. We just haven't found huge differences. And I would also say that many of the more subtle differences, for example, you can stabilize certain unstable sequences, we think there's other ways to do that with different types of modifications that we can talk about that they have -- where it's easier to add stability, easier to control, easy to synthesize and actually give bigger effects.

Appreciate that. So as you think about this technology evolving, 28 years, as you mentioned before, RNA editing is now coming into vogue, again. It's not something which is new. But given the scaffold advantages, companies like Ionis have, is that an avenue that you guys are likely to pursue?

So certainly RNA editing is an interesting technology as is DNA editing for that matter. Great interest to us. We're following it closely. We have stated publicly that we're looking to diversify our technology platform. So it's what all I can say on that one, so stay tuned. And we're definitely looking in the space to try and add complementary technologies to our arsenal of tools that we have to go make drugs with. I would love to have a really robust, great platform to be able to RNA edit that was simple and as easy to deliver as antisense oligo. I think it's fairly complicated and has a ways to go, but it certainly is something of interest to us that we've been fooling around with in our core research teams.

Got it. Then let's talk about your -- the SPINRAZA program with Biogen. Recently, extended dosing has become an option. What's facilitating that both from the changes to the structure? And what kind of durability does that imply for the next-gen Euro programs?

Yes. So well, first off, I mean SPINRAZA is obviously a transformational medicine that has changed the care of SMA. We're proud of that, and I think it's a great drug. We're excited that Biogen is continuing to invest in SPINRAZA itself with the studies like the DEVOTE study to look at higher dose of SPINRAZA to actually try and increase the efficacy of SPINRAZA, which is already, we think the most efficacious SMA drug out there and has been shown to give effects in a broad age range of patients. They're also doing things like adding it on to gene therapy and looked -- and also adding it on to the small molecule competitor to try and show that SPINRAZA can enhance the overall profile when used in combination. And you were referring to recently, we announced with Biogen, a licensing of a follow-on for SPINRAZA. And the objective here was to extend the dosing interval beyond 3x a year to hopefully yearly, 9 months a year, yearly type dosing -- and we did that by doing a couple of things. One, we modified the backbone, and this is a new backbone chemistry that I, unfortunately, can't disclose exactly what it is. We're being a little coy about at the moment. But what that does is it increases potency about threefold for splicing type indications. And then we've also shown that this backbone and this chemistry is exceptionally durable. And so if we have preclinical data that supports continued maintenance of the splicing effect of the follow-on molecule for a year in preclinical species. So we think that we'll be able to if -- if the clinical data pans out, hopefully extend the dosing interval and make a much -- a very attractive follow-on type product. And yes, it's also amenable to other splicing indications. And so we look forward to bringing that forward in other disease areas.

Got it. The termination of the C9 program, again, Biogen. You guys convinced it is sort of the hypothesis of target engagement or some of your competitors sort of with different modalities came and suggested this could be PK and not so much target engagement?

Yes, I can't speak to what our competitors said, and I'm a little confused as to what they could say based on the data. I'm confident I've seen more data than they have. We're confident and Biogen is confident that we tested the toxic gain of function hypothesis. I can't go into much more details than was in our communications with Biogen but as you know, C9 biology is a little bit complex. The -- there's multiple initial hypotheses that came out of the initial genomic work. They very clearly identified the expanded repeat in C9ORF72 as being causal for C9-ALS and C9-FTD. And one of them was actually a loss of function hypothesis. And by -- because the expanded repeat decreases translation of the C9ORF protein, the other was toxic gain of function with the RNA and especially these dipeptide repeats. To add more complexity to that, there was an antisense transcript that goes the other way that also contains an expanded repeat that makes a different set of dipeptides and could have different properties. We, along with Biogen, thought the predominant hypothesis to test was the C9ORF72 transcript toxic RNA hypothesis. There's a reasonable amount of preclinical data to support that, make good sense to test that in patients. We made what we thought is a great drug, and I think that it's consistent with all of our other antisense drugs. We have measures to measure target engagement. We're comfortable with our dosing. So what I can say is that we're very comfortable that we tested the toxic function hypothesis and the data didn't support it, and that's why we jointly made the decision to discontinue the program.

Got it. And this obviously then has no implications for what's happening with SOD1, where you saw a pretty interesting target engagement but probably got blindsided by the short duration of the study.

Yes, I think it's a very -- they're actually very different outcomes and very different causes of the events that unfolded. I mean the VALOR study was a Phase III trial where truthfully, the decline in the placebo patients that we saw in the Phase I/II wasn't repeated in the time frame that we employed in the study. And there with -- in the VALOR study, I actually think we saw good target engagement that was reported. And to me, really create reduction of neurofilament light chain, which is getting to be a reasonably accepted biomarker of neuromuscular decline in neuromuscular disease. And so those reductions in neurofilament light chain thought a really impressive proof of biology, so to speak, that the drug is doing what we wanted it to do. And what we just didn't see was a change in a -- steps in change in the clinical outcome measure that was used in the ALSFRS scale in the time frame we looked at the study. Again, we're -- Biogen has publicly communicated that they're continuing to look at open-label data and think about their strategy going forward. That program is certainly alive and not terminated. And we're hopeful that over time, the benefits that we saw in our filament light chain reduction will translate into a clinical benefit. And I would also point out that in that study, essentially all of the clinical endpoints we looked at, we're trending in the right direction. Basically, we just missed the primary. And this is very different than the C9 study, where new time Biogen will present the data, we just didn't have evidence for support of hypothesis, where I think with the tofersen program in the VALOR study, there's a lot of evidence for supporting the hypothesis that lowering mutant SOD1 protein, which has been really well linked to the pathogenicity of SOD1 driven ALS, is a good strategy and will work eventually.

Appreciate that. Before we talk about the programs in Phase III currently, I just wanted to sort of bring up something that somebody has asked me via e-mail. Typically, from a Phase I/II setting to a Phase III, you normally see a pretty significant [ haircut ] in response rates, right? Now with traditional, let's say, monoclonal antibodies or small molecules, is that a generalizable team with antisense as well. I haven't seen that big haircut in response from Phase I/II to Phase III. But do you think that's ... Go ahead.

Well, I was going to ask if you're speaking of response rates in terms of the target engagement or pharmacodynamic response or a clinical response?

Clinical response.

Yes. I mean, I think -- so I guess I'll speak to the first one, which you didn't ask. But I think our target engagement has been quite consistent. And that's one thing I focus on as a research nerd is, are the drugs working to do what we intended them to do in multiple patient populations. And there, for the most part, we've had pretty good success in the translatability of antisense drugs to engage their target consistently across patient populations, which I think obviously helps for the platform. And then in terms of clinical response, I think that then becomes less a function of the drug platform and more function of the patient population and the disease and the clinical trial design. And there, I suppose that we then end up with the same issues and problems that drug developers have dealt with for years in getting good trials designed with the right patient populations, which can always be tricky.

Got it. And olezarsen then, you're going after 2 different size markets. The strategy and the pricing consideration that we should start thinking about right now?

Yes. So again, I'm not a commercial person. We're following the science here. So you did say 2 very different markets. The first one of these is our balance study for FCS where we have up to 60 patients who have exceptionally high triglycerides. And here, of course, the objective is to lower their triglycerides to an acceptable level and decrease the frequency of adverse events that these patients experience among many like pancreatitis. There that, as you highlight, is a fairly rare disease population. We felt it's very important to treat these patients that they're in severe medical need. There is nothing for these patients in the U.S. WAYLIVRA, a precursor drug is approved in the EU for these patients. But it is a rare disease. And obviously, if it was only that disease, you would expect concomitant pricing for that. The next indication, which we're actually very excited about it and I think it's a great opportunity for the olezarsen drug is this severe high triglyceride market, where in contrast to the FCF patient population market, there's millions of patients that suffer from triglycerides that don't give them FCS but are in this greater than 500 bucket, which the FDA recognizes as a patient population in need of treatment. And there we have this ongoing core study, which is up to about 450 patients, where the primary endpoint is just change in fasting triglycerides from baseline at 6 months. There, we should have data in 2024. Again, this drug is given once a month subcu. And we think it's a great looking market. And obviously, the pricing for that market would be different than an FCS market alone. And we feel very good about our commercial case for this drug. It's a wholly owned Ionis drug, and we're looking to take it forward as an Ionis drug in our new commercial exercise. So we think it's a great program and are really enthused that olezarsen is looking like -- has the profile that it does and looks terrific and moving forward to [indiscernible] program.

Got it. So in line with the prior question on the clinical effect from Phase II to Phase III. The HAE study, enrolling about 3x as many patients in the Phase III study. Just a question from the audience, [indiscernible]. How confident are you the response rates or keeping 90-plus percent patients attack-free can be reproduced?

I mean that's the objective. We certainly hope so. The -- my view of our Phase III program is the objective is to extend the Phase II program and just replicate it in a larger patients sample. That Phase II data was terrific. We thought the attack rate reduction was really impressive, and we were really happy with the rate of that the attacks went down too because that obviously matters to patients is how fast their attacks get controlled in addition to getting near complete control of attacks. So that's the objective there. We understand that this is a competitive marketplace. And our -- we view our drug as potentially best-in-class, and that's what we want to show in our clinical program so that we can compete in this competitive marketplace. And so -- that's why we're looking at -- also looking at Q4-week and Q8-week dosing. The Phase I data on this drug shows pretty durable suppression. And if you look at the target reduction at the end of our Phase I period and then look at the follow-up, which was, I believe, more than 2 months on the follow-up time, the target expression was about the same. So we think there's good support for that extended dosing interval. And think that having 2 options for patients, either a Q4-week or a Q8-week will be good and will give us extra leverage -- extra advantage in this market.

And outside of what's available in the current competitive landscape, the CSL Behring mAb and then there is a long-acting mAb, which is still not the clinic. How do you see these as these playing out? Clearly, there are 3 -- not CSL, but the long-acting mAb is probably good 3, 4 years behind you guys at this point?

Yes. I mean we've been looking at the CSL's drug because that's much closer to market as well as lanadelumab, which is obviously the -- on the market and the standard of care really. We think we have a very competitive drug. And -- we like PKK a lot. It's a target. It's pretty much directly on mechanism as opposed to Factor XII, which is a little bit removed. So we're focused on our drug and moving our drug forward and getting our drug to market. And getting the commercial work done to do a good job introducing it to the marketplace. Again, another wholly owned Ionis drug that we're excited about having in our portfolio and commercializing ourselves.

There's been a lot of interest on the cardio TTR program. The way the primary end point was struck [indiscernible]. So just the thought process behind how you guys decided to go with this study versus what some of your competitors have done with 6-minute walk test, which is probably noisy. And then the concurrent tafamidis use, which sort of reflects our real-world setting. Thoughts on that?

Yes. So we like -- you won't be surprised that we like our Phase III program. We're tickled at AZ liked our Phase III program in the recently concluded license agreement, a co-commercialization agreement with AZ. It's the largest Phase III program. We have 750 patients in the cardiomyopathy program, again, monthly dosing of 45 milligrams. And here, the primary endpoint, unlike the BridgeBio program is cardiovascular outcomes and death. That's -- we think that's the key endpoint to study in this patient population and that you need to generate this outcome data for having a good commercial product in what is really enticing and we think it's a great market and a growing market. And again, tafamidis is on the market, right? So the standard of care is tafamidis. And so we designed our program to try and reflect real-world usage. How we think the drug would be used in many real-world situations, which is applied on top of the standard of care and ask the very sensible science question, if you add our drug, which reduces TTR on top of a drug which stabilizes the TTR, that's still there. Do you get a better effect than the stabilizer alone. And how does that compare to the effect of our drug alone? Is the effect of our drug alone going to be good enough? Or do you get even better effect with a stabilizer? So I think it's a real nice science experiment. And -- like the trial design, we expect about 50% of the enrolled patients will be on tafamidis and 50% naive. So we feel like we have the power and the patients in the study to ask that question. And look forward to the data coming up in a couple of years from now.

So the patients who are tafamidis naive, could they then -- if they have disease progression, do they go on to tafamidis or how should we understand that dynamic?

So I'm not intimately familiar with that. I believe it's physician choice. And I don't know if they're locked down once they start. Sorry, we'll have to follow up with you on that.

Got it. I appreciate it. Then LP(a), I mean, this is -- you guys have already started the Phase III more than a year ago, but there is competition here. Maybe just sort of help us understand the differentiation of Pelacarsen?

Yes. I mean there's another really neat program that I think is cool. It's a testament to -- we talked -- we began this by talking about the platform and it's a testament to how the platform has evolved over time. There's a drug that we had a parent molecule in Phase II studies. We knew that LPA was a neat emerging target. We're excited to have a drug there and the profile was good enough. And we retooled the compound a bit. We changed some PS content in the -- in between the low residues and added the GalNAc and improved potency 30-fold result is Pelacarsen. And the -- we're thrilled that Novartis licensed it and thrilled that they moved it into this nearly 8,000 patient outcome study very rapidly actually. And we have a drug that is 80 milligrams a month. in an outcome study where it's now 50% enrolled. So there's roughly 4,000 patients to date on this drug. Nice-looking tolerability profile. We're very pleased with the program. And I think it highlights the generality of our platform technology now and how we can really translate these into drugs that are amenable for broad patient populations. And for Pelacarsen, we have competition. We're in the lead though, by quite a lot because of our experience in the area and our early start and our partner being nicely aggressive and moving forward quickly. So we're really focused on our drug and our program. And as is Novartis and getting that clinical trial done, I think they're -- at a 2025 readout and potential filing, everything works well. Signed program and the competition is behind us.

Fesomersen should read out with Bayer shortly, I guess, first half '22. What's the go/no-go trigger decision there?

Yes. I don't want to get ahead of our partner there. The program, of course, is Fesomersen targets factor XI. And so this would have an anticoagulant, antithrombotic indications. There, the Phase II is designed to affect safety in the form of major bleeding and clinically relevant nonmajor bleeding events, not so much to affect any thrombotic effects, top line data, as we've mentioned, sometime this year in this end-stage renal disease patient population. We've kind of done this study before with the parent molecule that wasn't a LICA. So Well, hopefully, the LICA molecule will replicate the previous study, which we thought was quite positive and will set us up for a Phase III experiment. I really can't get into the go/no-go criteria that Bayer has that would be getting ahead of our partner and certainly can't get into potential Phase III designs, but there's many of them. And we like Factor XI as a target. I think it's a really good potential antithrombotic and with very minimal leading risk and could be a great drug.

Awesome. That was sort of a great overview of your late-stage programs, some Phase II -- one Phase II and mostly Phase III. So looking forward to a really productive '22 and beyond for you guys. Any closing thoughts you would like the audience to take away?

I'm glad you like our Phase III program. We're pretty happy about it. It took a while to get here. And as you know, we have a very solid pipeline behind it. We have a lot of programs in Phase II. And if you look at our key 2022 pipeline events, there's a lot of things in Phase II that will get revealed and we'll review themselves either as good programs to take forward or ones that we can no longer focus on and focus on, on the winners. And we didn't talk a lot about neurology either, but I'd also like to highlight that we have a lot of neurology programs beyond just the ALS programs we talked about. We have a MAPT program with Biogen, targeting tau, which has been very closely associated with the onset of cognitive symptoms in Alzheimer's disease. They're going to start Phase IIb this year in the MAPT program. We've got earlier-stage programs in PD with Biogen, both alpha-synuclein and MARK2 targeting. And then we have some really exciting programs in earlier stages that are not so much neurodegenerative but in -- I'll call it, more plastic diseases where we might be able to expect some quicker changes than in the neurodegenerative disease where you kind of have to stop the decline. These would include our Angelman program targeting the UBE3A antisense transcript, which has just started clinical trials that's partnered with Biogen and some Ionis wholly owned programs. One is in an Alexander disease, which is a rare leukodystrophy, where we have really spectacular preclinical data, and that's moving forward, and we hope to get a preowned program and preowned [ study ] to start this year. So we have a very active pipeline across multiple areas. And feel great to bring these potential medicines forward for patients.

You mentioned Angelman, maybe just spend a couple of more minutes there. It took a while for you to move that program into the clinic. Any lessons that we should take away from your experience versus what has been seen from the competitor regarding lower-limb paralysis issues as at higher doses?

Yes. I can't speak to exactly what caused their issues. We've been in neurology for a long time and have learned all the things to look for in preclinical evaluations. Hopefully, we learn all of the things. We're learning. We learn more every day, but we've been at it a while and have learned what to look for from both an activity and a safety perspective. And the reason we took a while to get a drug moved forward was primarily an activity issue. So we work hard to build models in animals that have the human gene in them because we feel that's the profile for potency and efficacy of the drug and gives us the ability to predict our human dose and make sure that the molecules are optimally selected to give us what we think is a reasonably predictive dosing regimen. If you look at our doses, they vary a little bit, but they're not off by tenfold. They're within a couple of folds of each other of the clinical doses. And so we do that by optimizing the drug in animals. And the nuances of the Angelman target being a large antisense transcript. It took us a while to build the right mouse. And once we got the right mouse build, then it was business as usual, making the best drug we could make. So I'm very comfortable with the profile of our drug. I think you should look at it kind of like the MAPT ASO in terms of what types of doses we'll be able to use and get to in the clinic. And we think that will certainly give us the ability to test the hypothesis that lowering that antisense transcript can upregulate the suppressed gene, UBE3A and hopefully make a difference to these patients.

Appreciate that. Thank you so much, Eric. Really appreciate your time today, and good luck with all the readouts this year and going forward.

Thank you very much. Appreciate the time talking about Ionis.

Thank you. Thank you.