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

So I'm happy to be monitoring the discussion with the Ionis team. We'll do mostly Q&A. And if anyone in the audience has questions, please raise your hands. And hopefully, more folks will filter in throughout. But maybe we can start, Eric or Onaiza, do you want to give just kind of an overview, high level of the R&D pipeline, some of the key later-stage assets and the cadence of readouts over the next year or so?

Yes. I'll start. We've got a pretty full pipeline, as I think most people know. And we had a pretty eventful year so far to date with lots of news and lots of advancement of the pipeline. So I'm going to start with eplontersen. We had a positive interim Phase III readout for eplontersen in the polyneuropathy space, partnered with AstraZeneca, and we plan to file to the FDA for approval later this year based on that data. That drug is also in a Phase III for cardiomyopathy, TTR amyloidosis. And we have announced a couple of changes to that trial, including the latest one up in the patients to 1,400, and I'm sure we'll have some questions about that, but now we have the largest cardiomyopathy trial, which we think is the most -- give us the most robust package to compete in what we expect to be a very competitive marketplace for TTR cardiomyopathy, great clinical opportunity. We also just this weekend, released open-label extension data on our HAE program, where we have donidalorsen, which is a PKK inhibitor. And we saw a very nice maintenance of what we hope is best-in-class profile in a Phase III trial that's being tested now with a monthly therapy for HAE. We also have been progressing our olezarsen program, which is another Ionis wholly-owned asset in addition to donidalorsen that we intend to commercialize ourselves, as we become a commercial stage company. And that program has a readout in a rare disease, FCS, a Phase III study that was fully enrolled this year, slated for next year. And then we've got 3 additional Phase III studies that got started for a much broader indication, severe hypertriglycerides, which is patients who have triglycerides greater than 500 and those trials are underway, and we'll read out '24. Beyond that, we have the tofersen program partnered with Biogen, where we had positive data presented by Biogen on early start versus late start tofersen, that NDA has been accepted, and we have a PDUFA date in April for that drug, very optimistic about the tofersen works. It lowers neurofilament. So we're excited about that program. We also have another late-stage asset that I'm particularly -- I think it's particularly cool as pelacarsen. This lowers LPA. It's testing a novel hypothesis in cardiovascular risk reduction that's independent of LDL partnered with Novartis. It's in an 8,000-patient cardiovascular outcome study, which has reached full enrollment this year. I guess quick there on the pipeline beyond that, in the technology space, we continue to progress our technology. Monday, we announced a partnership with Metagenomi, which expands Ionis into the gene editing space, and help solidify what I believe is we're trying to build an all modality genetics medicines company where we can use the best modality to make the best drugs for patients and we can talk about that. And we continue to progress other areas of our technology. One is a new backbone chemistry that I think gives us a lot of versatility. We have 2 drugs that have just transitioned to development, which used backbone chemistry both neurology drugs. One partnered, one Ionis wholly owned and both in patient populations that are pretty big and we think will really benefit from what I hope will be extended duration using that backbone chemistry. And the last is our Bicycle collaboration, which is LICA strategy, which is designed to target our drugs to muscle, cardiac and skeletal muscle. And we'll probably have a drug that uses that technology sometime next year that will transition to development. And given the way it's going to probably be an siRNA, which might, which I think will be our first siRNA into development. I quit there. You can talk about any and all of those things.

All right. Excellent. Thank you, Eric. So let's talk about TTR just start. So you showed some interim data from the eplontersen polyneuropathy study this past summer, which certainly look favorable on safety, but we have yet to get details on efficacy. Maybe just kind of walk us through where that study is? When we should see the 18-month data and your comfort based on everything you've seen that this drug has a competitive profile with the other subcu silencer are out there.

Yes. I'll take that one. So eplontersen is a pretty large space for us, both for polyneuropathy and cardiomyopathy indications. Paul, you're right, we released the 36-week data, which is an interim set of data. We can file on that data in the U.S., but we have to wait actually for the full set of data, the 66-week data to file in the EU. So we've been actually like really measured about what we're releasing? At what time, one, we don't want to compromise the EU filing in any way. And we're also in a very competitive area. So we're actually making sure that we're releasing that as in a measured way as well. But it looks really good. We had just over 80% serum TTR reduction, which is one of our core end points. We saw that pretty rapidly and nice sustainability at 36 weeks. We still have to see the 66-week data we had a nadir there. We -- so we released statistical significance in our co-primary endpoints. The other one was mNIS+7. So data is looking really good there. And we can say both in mNIS+7 and Norfolk Quality of Life, which is actually a really meaningful endpoint for clinicians as well. We're seeing some clinically meaningful improvement in patients as well. So we're excited. This is a really great start for us in terms of getting into amyloidosis. And just as a reminder, I think we forget this is that the polyneuropathy indication is for both PN and mixed phenotype. So we really do have 40,000 patients that are available to us. Less than 20% of these patients are diagnosed and treated currently. So there is a lot of room for improvement. And these patients present not just in neurologist office, but also in cardiology. So going at this in a [ coco ] perspective with AstraZeneca really gives us a really strong advantage because they're already in there with their heart failure drug. And have those relationships. So it's going to be a really nice launch. We're looking forward to it. We're expecting filing by the end of this year. So a few more weeks left to get that in, and it's a 10-month review process, so we should here next year.

Okay. Great. Maybe more specifically on efficacy. Your confidence level that the effect size for this drug is going to match what we saw with vutrisiran clinically? Can you speak to that because...

Well, probably not more than we've spoken to. I can talk to you -- so the scientist in me will say that when -- if you believe the TTR reduction is consistent with the benefit that you're going to see, which is the scientific hypothesis, the TTR reduction is very comparable. It's superior to drugs in the marketplace, and it's very comparable to what else is out there. So I would point to the TTR reduction that we have and we did report as being supportive of the beneficial profile of eplontersen in general, and it being competitive in the market.

Okay. When might we see that full data?

We'll probably present the full data set when we have the full data set from the trial, which is the week 66 data some time and probably at a medical meeting somewhere.

Okay, okay. On the cardiomyopathy Phase III, I know it's been talked about -- you talked about on the call. But -- is there anything else you can sort of say about what you're observing with respect to the event rate relative to your original expectations in that trial?

I can start and then kick it over to Onaiza. It's probably not more than we've said on the call, but just to reiterate, the landscape, we think, is clearly changing from the tafamidis trial when they ran the ATTR-ACT study. Patients are being diagnosed earlier. They're healthier and which is great for the patients, and it should actually be good for therapies because if you intervene earlier in most of these diseases, it's more beneficial, but you have to study them longer. And so we just think that the landscape of TTR cardiomyopathy is different. And we've been paying attention to the landscape, looking at the totality of data, both the demographics of patients, how many are on tafemidis, how are not, what's their stage of disease and also event rates. And that's caused us to both extend the trial and increase the number of patients. And so we now have 140-week trial with 1,400 patients. As I said in the intro, it's by far the largest study and we think it's a really good experiment. And maybe Onaiza can comment on how she thinks that will translate to the commercial marketplace with AZ, where we think we have a really good situation with a great partner and a good drug.

Yes. No. Well said. I think strategically, we've always wanted a data set that's going to be really rich in this population. We have very different geographical markets here. We have tafamidis as good first-line use already in cardiomyopathy in the U.S., less so outside of the U.S. So we think to really kind of have play the long game here and have the best set of clinical evidence. When we're going into the marketplace, it's important to have both sets of data. And both sets of data are on tafamidis and naive to tafamidis as well, and we're looking to get these studies powered so we can a cardiovascular risk reduction to have the best data set in both subpopulations as well. So that's going to be really important. And as Eric said, these patients are [indiscernible] Class I, II, III. So we'll able to also do some really good subsegmentation of population data for physicians, as they're making the choices for the types of patients that they have sitting in their office as well. Yes, it's exciting data set that's coming up. It will be the most robust of any other cardiomyopathy trial going on.

Great. Okay. One question that I don't think was asked in your earnings call and that is with your study now being twice as big as it was originally only planned, could this allow you to potentially take an interim analysis?

So I mean we have the potential for an interim built in. The trial is both event-driven and time-driven. So it could stop earlier, if we have a certain number of events, and we could choose to take an interim. Again...

It's so big, maybe you could even take a small powering hit to take that risk.

If possible. And so we can make that decision by looking at the totality of the data as the trial unfolds.

Okay. Okay. All right. Well, we'll stay on our toes for that then.

I would just say that we feel that we added the patients, and we don't think we took much of a time hit because enrollment is going really well. And so we're looking for data in 2025 and really want to have a nice full package. So as Onaiza said, we're playing a long game.

All right. Great.

There's no -- if we overpowered, then we'll read out earlier. It's no downside.

Yes. Now on the population that gets eplontersen and tafamidis, when you were discussing and designing this trial, how did you come about a hypothesis for the actual risk reduction you add on top of the standard of care?

When we first designed the trial, we were looking at how dynamic this market is and where it's shifting to. So in anticipation of kind of where the puck is going, we said, strategically, we wanted a data set that was on tafamidis as well. And we designed it with the ATTR-ACT study in mind, original design as well, right, with the taking a look in that trial and assumed all of our patients in the trial would be on tafamidis, so it was powered with that.

So I guess more specifically, if you're sitting around the table and you're saying, okay, tafamidis, the risk reduction is 30%. How would you kind of come about a hypothesis for the actual risk reduction you would add on that?

I don't think we've disclosed the exact numbers on this, but we did go out and talk to clinicians is on top of tafamidis, what would you find clinically meaningful, and we set the bar right there.

Okay. Okay. Okay. Makes sense. Anything else to add on TTR? Okay. Do you want to review the recent data you just presented for donidalorsen? Specifically, as you kind of now approached the pivotal study, how are you thinking about the efficacy and kind of commercial relevance of the once monthly and every other month drug regimens for this drug?

So the pivotal study is ongoing. The OASIS Phase III started and headed towards readout and -- this is Ionis owned assets so Onaiza is all over this one, eager to commercialize it for Ionis.

Yes. So I mean, Paul, hypothesis and kind of reason to be for HAE stays the same with the OLE reading out this past weekend. We did a lot of work on this and did some good research with physicians, with patients as well as payers. And like the #1 kind of choice set for physicians right here and for patients right now is attack-free rates. It's got to be the top tier in terms of how they are going to choose the therapy. And as you saw from the data of this past weekend, we were able to see that we have durable kind of zero attack rates at 99.6% over the study period. And the second element of the data set that's really important and also really important commercially is how fast we get there. So just our mean attack reduction rates at like close to 96% after 1 dose. And if you take a look at the market leader, which is Takhzyro at Q2 weeks, they get their out of 26 weeks and at only 75% zero attack rate. So we have a very, very competitive profile from an efficacy perspective. Next, in order of hierarchy for patients as well as for physicians, it's really just good tolerability, safety, seeing all of that. We have pretty easy-to-use auto-injector 80-milligram dose. So all things being said, if the markets at Q2 weeks, our Q4-week profile looks really good. We've seen some data now for the Q8 week. I think that's your question. And we'll make that determination kind of at the end of the Phase III, if we'll have both doses on the market or not, but the Q8-week profile is really good coverage right now. So it's good coverage for patients who want to -- might miss a dose or go a little bit longer, and it's the very young population. So for them, it's meaningful.

How do you think about preparing to launch this drug in a super competitive market that seems to change every year?

It's -- so I think it's really good dynamic market, but we kind of know exactly where it's going. So it's easy to predict, right? I mean, like it's pretty clear criteria in terms of what physicians are looking for. So a couple of things I would say when we designed the Phase IIIs with our development group, we obviously have our Phase III design, but we knew from a market dynamic, which is a switch market. We would need alongside the Phase III another study that will -- we call it our switch study as well, which I think will be really important for physicians because they want to see that they can actually switch from one therapy to another without having breakthrough attacks. And with our fast onset, we're pretty confident we'll be able to deliver on that. The other data point I look at is ORLADEYO as an oral was launched and they got some good switching sentiment there as well, right, off of Takhzyro because they have a very, very painful viscus injection. But we also know that there is a good switching behavior that's already in the marketplace. So with our switch data and our great zero attack rates and easy to use once monthly, we believe we'll be able to get that dynamic in the marketplace.

Okay. Okay. Great. Can I ask you, Eric, about the AGT program? You didn't mention that in your prepared remarks. Any reason why?

Well, it's not -- it's mid-stage asset, I would characterize it as and...

Because that data is coming really soon, right? We're going to get a combo study in a heart failure study, is that right?

So I think we're looking at the AGT program as a whole. We have, as you know, 2 molecules. We have the first molecule we made, which is first-generation methoxyethyl drug, and then we have a follow-on, which is -- I can't remember the number, which is a gen 25 molecule And we're looking...

They're both LICA?

They're both LICA. We think the second molecule will hopefully support monthly dosing. We're looking at that in a first-in-human study, and we also have a heart failure study ongoing with the first molecule as well as resistant hypertension. And we're going to -- we kind of want to get all of the data assembled together for the AGT program because if we started showing some data, the first question we'd be [indiscernible] what are you going to do with this? And we don't know what we're going to do with the program until we see all the data on both molecules and in both studies. And that's probably going to come sometime next year truthfully.

Okay. Yes. Okay. Makes sense. The reason why -- part of the reason why I asked is just the heart failure study, I feel like it's super under the radar. The treatment-resistant hypertension study, I mean, I think we can agree that probably as a pretty good probability of success and answer some important safety questions. But how the heart failure thesis there, how speculative is that? Like do you look at that as kind of just -- I'm not saying a shot in the dark, but like do you -- or do you think that's...

I look at it as an experiment. And like any experiment, you have a basis for running the experiment and thinking about why it might work.

What's the basis?

Well, so it's -- angiotensinogen inhibits the RAS pathway. And our drugs do this by targeting specifically the liver. And so you're targeting liver-derived angiotensinogen, but sparing lowering angiotensinogen in places like the kidney where you might not want to do it or it might be precluded in a heart failure setting that the patients can't use ACEs or ARBs because of the renal effects. So we're really testing liver-derived angiogenesis whether or not that can provide a benefit in heart failure. I think it's a good experiment, and we'll need to run it to see how it looks.

There are a lot of patients who are not being treated because of the RAS intolerance as well. It's a good dynamic in the market.

And the treatment-resistant hypertension study, is that study going to give us a clear answer on the safety of this mechanism, combined with an ACE and ARB? Can you sort of speak to that?

Well, we're certainly looking for hypertensive effects. We had some data that we've presented post that suggested that we were okay. So I can't tell you what the study is going to say before we tell you what the study is...

No, I don't mean just like -- is that study set to fully answer this question. Really what I mean, Eric, was is this a question that needs to be answered with longer-term data where ACE/ARB combinations and long-term studies don't give you the outcomes benefit you would expect? Or is it going to be answered in the shorter term?

I'm talking about safety of combination. I think the longer the term that you have the better, but I think that the studies to date that we've done and also some other companies that are in the space have done suggest that it's a reasonably viable approach.

Okay. Okay. All right. We can move on because there's so many drugs to cover. It's overwhelming olezarsen. So that's going to have some data next year. And is that going to be your first independent drug launch?

Yes, FCS will be our first independent drug launch right after PNS. So we expect the BALANCE study, as Eric said in his opening remarks to be reading out next year, and then we hope to have it on market the year following.

Severe hypertriglyceridemia is the bigger market.

It is.

A lot bigger. What are you hoping to see in that study in terms of triglyceride lowering. Obviously, you want to see clean safety, to feel comfortable that you can kind of compete in this huge market but one that has many therapeutic options, some of which are very cheap.

Yes. That's a good question. So one of my [indiscernible] my favorite in the wholly owned pipeline for the severe hypertriglyceridemia. I think there's just -- standard of care has very low triglyceride reduction. So a lot of these patients in the 500 plus, really just don't have a treatment option, fibrates, niacin, Vascepa are all in the 20% to 30% reduction of triglycerides. We do somewhere 2.5 to 3x of that with our Phase II data already, right? So we expect that we'll definitely replicate that in the Phase III, but we might actually even do better. And there are 2 reasons why I believe that. First of all, the Phase II data was done in a less severe population, 200 to 500 trigs. Our Phase III is in the 500 and above. So the higher the trigs, the easier it is to kind of get them down. So we expect the data to be better there. And plus, we only studied 1 dose in the Phase II [ that's 50 mg over setting ] both 50 and 80. So we actually have some really good optionality in the Phase IIIs that are coming out, really large prevalent population like you said, over 3 million patients in the U.S. We have a first-mover advantage and all of our Phase IIIs are ongoing right now, CORE1, CORE2 and the safety study of exon so we need to study about 1,500 patients, right, for approval in the [indiscernible], that's all on track, waiting out on '24.

So I think it's -- I mean I think it's very intuitive why Ionis would see that taking HAE forward independently is a great strategy. For olezarsen, I think it's not a great strategy, but you could -- I mean, theoretically, right, to get the most out of that drug, you could get 400 or 500 sales reps, right? I mean you could have a really big sales force. Does this drug lend itself to a more targeted disciplined rollout that can still maximize value? Like how do you plan for that?

Yes. No, it's a really good question. I've been thinking about it a lot, we have the whole team has been. So 1 of the good things we've done really is just -- I think times are different in terms of commercialization. We have a couple of dynamics. We have a lot more data than we used to have before so we can do a lot of predictive analytics as to where these patients are and where the GPs are referring them to. And we're seeing them showing up in 2 major specialties. So we can have a very specialty kind of focused launch, which coming from specialty businesses, you're looking at sizes of sales teams. We haven't sized it specifically for this market, somewhere between the 150 to 200 range, not 400 to 500. And then with COVID, you've got just a lot of digital use. So we're going to do a very heavy component in digital as well.

Okay. Okay. 150 to 200. Okay. Interesting. So FCS data next year, the other Phase IIIs, readout in 2024. Is that right?

Correct. Yes.

Okay. And for FCS, when you originally launched this, is that going to be 15 sales reps, like small, very targeted?

Yes, it would be very targeted. Very, very targeted, yes. Targeted.

Eric, can you talk to us where you are with Angelman's since that's a very high interest program in the investor community?

Yes, I can. Probably won't be that long a conversation. We're....

I'm going to -- I have about [indiscernible].

I know you will. We're in a first-in-human study. And so...

Is it going to work?

If he designs the sequence.

I certainly hope so. We're in a first in-human study with a molecule that we feel very good about. And I will readily admit that it took us too long to find that molecule. I'm annoyed by that. We worked hard at getting a molecule that we felt would be equivalent profile to something like our MAPT tau, oligo where we have nice clinical data, great dose responsive target reduction and nice durability when we look at patients coming back in the OLE. So that's the type of molecule we wanted. I think it's a great opportunity. And certainly, I love the mechanism where you can inhibit antisense transcript and then upregulate the gene that's deficient in the disease. So again, hopefully, we'll test the hypothesis and it will work.

Yes. No, it's a really cool biology and it's a huge unmet need. What do you think about the data that Ultragenyx has shared? Do you think that there's an efficacy signal in that? And when you look at your Phase I/II study, I know it's first in human, but what is it set up to show. Is it set up to show true proof-of-concept potentially?

Well, it's clinically. I'm going to give you a stale answer and say it's first in-human. So it's set up to show safety. And I think that's what we do. And it's also -- we also are monitoring target engagement. So we're working with Biogen, and they have a great biomarker team. So we want to make sure we're engaging our target. And of course, you always look at clinical endpoints in these types of studies. And if we see something, we'll see something. You asked me about the Ultragenyx data, I would say it's encouraging. From an efficacy standpoint, there's -- it was modestly encouraging. I hope our drug performs the way I want it to.

Yes. Okay. Okay. Any questions from the audience?

Are you trying to get someone else to ask your question?

No. I'm just going to repeat this for the webcast. So the question was on the regulatory path for Angelman's and how flexible do we think the FDA is on endpoints?

I'm probably not going to answer that one to your satisfaction either. I think that it's premature to be having discussions. We haven't yet had discussions with regulators on what the pivotal program would look like, but we will be -- if we have data that supports going there, we certainly will do that. I think it's probably premature.

Is that readout coming next year, the first in-human readout?

We haven't given timing on when we'll disclose it.

I think it's on clinicaltrials.gov for like next summer.

We haven't given timing on when we're disclosing data. It's an ongoing trial and what we won't do is discuss data from an ongoing trial, even though it's open labeled. We're not going to do that.

That seems reasonable. Okay. Okay. Fair enough. What do you think is the most under the radar Ionis program that could surprise to the upside in the next year or 2?

Under the radar surprise...

No, you take one. You can't just say, how you know every drug.

Well, I can't say Angelman either since you just asked me about it.

It's not under the radar. We even had an audience question, the first one of the day on Angelman, so it's not under the radar.

That's olezarsen actually, but you already asked that question, Paul, so that's great.

Yes. We continually feel like olezarsen's overlooked. And we think it's a great commercial opportunity. If you ask me about programs, I really like. I'll start to talk about some of our rare neural ones that nearly as attractive commercially as the olezarsen opportunity, but I love our Alexander disease program. I think it's much like some of the other disease spaces we're in, it's not neurodegenerative. It's a glio target trying to modulate GFAP and it's a disease that's driven by overactive GFAP.

[indiscernible] neurodegenerative. So there's more of a window for intervention, is that what you're getting at?

Yes, perhaps.

Okay. When we might get data from that?

We haven't given timing on that one either.

Where is it?

It's again first -- it's a first-in-human study, but it's a very rare disease. So that's one of these that's kind of trying to stretch...

Yes. Potential to be a pivotal -- so it's just a really strong commercial one for us, too. We're looking at it pretty actively and getting ready.

Are you looking into any next-generation strategies for brain delivery?

Absolutely, we're looking at next-generation strategies for delivery to every tissue and every organ. I mean, our drugs administered to the CSF do quite well. They distribute broadly. We're very comfortable with the profile we have. We know we can target all the major cell population. We've been working hard with some of our improved backbone chemistries to improve the duration. So we dose as infrequently as possible in the CNS, and I think we're making good progress. I'll say, we were looking at trough in the blood-brain barrier, but that's an early-stage research project, and it would be amazing for our neurology programs, but it's a ways off. It's a research project.

You're looking at transparent.

We're looking at everything.

Okay. Okay. All right. Okay, great. We're almost out of time, so you don't have to deal with me anymore. But I guess this BD deal, which I thought was really cool.

We should probably talk about that.

Yes. No, I thought that was super interesting. I guess there's a lot of different flavors of editing. Why did you choose what you did? And could we see you build out a whole editing suite over the next couple of years?

So the answer to the second one is yes. We view editing as an additional platform for Ionis, and we aspire and want very much to be a company of multiple modalities, a precision genetic medicines company where we're agnostic to the mode of action. So we will practice ASOs. We will practice siRNAs if they are the right mode of modality, and now we add gene editing to that mix. We thought gene editing was a great place to be because it overlaps with our expertise in oligo medchem and overlap some of our expertise in delivery. There's obviously delivery challenges in editing. And we chose Metagenomi as a partner because we love their suite of tools. I think their scientists really neat how they find their cast proteins by mining the metagenome. And we wanted to have an established player in the space that got us started quickly. So we could get some drugs into development rapidly and learn as we get drugs in development. That's how you learn how to do drug development to develop drugs. So that's the space. And we're in it to try and make it work. And we plan to look at, as you said, different flavors of editing both within the collaboration.

Okay, okay. Great. Thank you both very much. Appreciate it.

Thanks, Paul.

Thanks, Paul.