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

So welcome, everybody, to the 44th Annual TD Cowen Health Care Conference. I'm Yaron Werber from the biotech team. And it's a great pleasure to moderate the next session with Ionis with Brett Monia, who really needs no introduction, the CEO. Brett, good to see you, as always.

Good to see you, Yaron.

Thanks for joining us.

Great to be here.

So lots to talk about. There's been -- the TTR cardiomyopathy panel here was action-packed. So I definitely want to start with that. There's a lot to talk about pipeline-wise. Geographic atrophy, we're going to talk about tomorrow at the ophthalmology panel, and a lot of your pipeline is going to get covered here at this conference.

So let's maybe just start with WAINUA. Just whatever you can share so far in the launch in TTR-PN. How is that going? The auto-injector is getting great marks versus Amvuttra, q 3 months, subcu in the physician's office. Where do you see your niche or do you see the initial usage, I would say?

Yes. Sure. Happy to start with WAINUA. We couldn't be more proud of the approval of WAINUA that we achieved late December last year for ATTR polyneuropathy, another treatment option for patients for this disease. It's a disease that many of you may be surprised to know that less than 20% of patients today with TTR polyneuropathy, a fatal progressive disease, are on any treatment today for the disease. So this is a really important -- this is a market that needs to be developed. WAINUA is really set up to really reach a lot of patients for TTR polyneuropathy. We think that the launch is going really well. We're only 6 weeks into it, folks, with the approval in December. But right now, everything is tracking as planned. We're pleased with the enthusiasm by HCPs for WAINUA. We're pleased with what we're hearing from our nurse case managers, which are the face with patients that are -- disease education, teaching the patients how to administer WAINUA, everything. Patients are enthusiastic, and we're not having any challenges on reimbursement as well. So we're very pleased with the initial launch of WAINUA.

When you're looking at -- Amvuttra had a little bit of a lead. What has that launch taught you so far?

Well, the Amvuttra launch is still really relatively early on in which the majority of patients, based on what we're hearing, are switches from existing treatment like ONPATTRO, which is -- makes complete sense. What that's teaching us is exactly what I touched on already in that this is a market that's largely untapped. So it's -- although we welcome switches. And we're seeing some of them in our initial launch, switching from existing treatments to WAINUA. Where the real unmet need is, where the real market opportunity is in newly diagnosed patients, not switches. So we're learning that. We're learning that the market is still wide open for WAINUA, and we are planning to tackle it.

What's the major issue with diagnosis in PN? Because in cardiomyopathy, we're hearing the opposite, right? The incidence and diagnosis of TTR is actually increasing. In the incidence, there was a discussion in the panel whether it still is an orphan -- unquestionably, it's still an orphan. I think what -- the point we're trying to make is there's hundreds of centers now for TTR. Is PN just overlooked because of the symptomatology, lack of testing?

It's the symptomatology. It's the diagnosis. For polyneuropathy -- there are many causes of polyneuropathy, diabetic polyneuropathy -- CMT often gets confused with TTR polyneuropathy. It gets misdiagnosed. It also appears in different physicians' offices, physician areas of specialty. So it can present in a nephrologist office, if there's heavy renal involvement. It can -- and a nephrologist is probably very unfamiliar with TTR disease. It can present in a gastroenterologist office. It can present in a neurologist office. Of course, it could present in a cardiologist office. All of this is -- makes it difficult to diagnose the disease because of that. So what we and our co-commercialization, co-development partner, AstraZeneca, are doing is to really educate, educate, educate all of these specialties to ensure that patients are being diagnosed rapidly and they're being made aware of WAINUA. And we think that this is going to be the strategy to deliver to those 80%-plus patients that currently have TTR polyneuropathy that are not on treatment today. You're absolutely right. The diagnosis in cardiomyopathies, particularly the wild-type cardiomyopathy patient population, which is the vast majority of TTR cardiomyopathy, more than 500,000 patients today are estimated, diagnoses much better. And that's largely because cardiologists are used to diagnosing a heart failure indication, right? And then based on the success that tafamidis has had in the U.S. market particularly, there's better disease awareness, so that physicians, cardiologists are actually able to pretty quickly look to TTR cardiomyopathy as a potential cause of the heart failure that they can diagnose fairly rapidly. So cardiomyopathy is indicated or is diagnosed a little bit quicker in polyneuropathy, but we're very committed to fixing that with polyneuropathy.

And just remind us commercially in PN, what is AstraZeneca's role in the U.S. versus yours? They're obviously going to be the lead ex U.S.

Yes. So we're working jointly at the table on broad commercial strategy. Our participation in co-commercialization is in the U.S. market. They have responsibility for commercialization fully outside the U.S. Their primary role -- we're working very closely together on the backroom services for the launches such as market access, medical and all that. They're -- where we are distinguished is that they have -- are responsible for the field force, whereas we are responsible for the patient-facing responsibilities, such as nurse case managers. So we're working directly with patients on disease awareness, how to do self-administration, self-injections, help them through a reimbursement process, for example, and so on.

Got it. And so the nurse case managers, are they doing mostly virtual training? They're actually doing on-site training with the patients.

Both. Virtual training is definitely a very important part of this process because these patients are spread out. A lot of these patients are in rural communities, not just in centers of excellence. In fact, probably the majority of patients are outside centers of excellence today. And that's really a big opportunity for these undiagnosed patients to get out there. And so it's a lot of virtual, but it's also seminars, it's in-person meetings, gatherings and those sorts of things.

Yes. And do you have any sense on for PN now, what percentage of sales, at least for -- have been U.S. versus ex U.S. for the class?

Oh, for the class. Overall, it's pretty well balanced. TTR polyneuropathy is endemic to certain territories around the globe such as Portugal, Brazil, Sweden and maybe in Japan as well. So those are certainly hot spots for diagnosis and for treatment. But other than that, it's pretty well balanced between U.S. and outside the U.S. for TTR polyneuropathy prevalence. And this is a global disease, and that's what we're going after.

Yes. A question from the audience, yes?

The use of prophylactic treatment in [indiscernible]?

[ Did you ] get the question maybe?

Yes. So the question basically is whether or not genetically diagnosed presymptomatic patients are being -- we're seeing treatment there. No silencer today has been approved for presymptomatic disease. With that said, because of the awareness of treatments like WAINUA, diagnosis is happening earlier and earlier in disease, and symptoms are being searched for such that we're able to treat patients at the earliest stages of disease. Certainly, patients with a family history are being -- is a key focus, right, to search for -- once we have one patient that is diagnosed, we can look at the rest of the family and determine whether or not they are eligible for treatment, but they do have to have symptoms. These drugs are not approved for presymptomatic conditions right now.

So let's switch to CARDIO-TTRansforms and your latest announcement, at 1,400 patients, you have sufficient power to look at subgroups based on combination usage, mono based on severity. You have a subgroup MRI study, imaging study as well. Obviously, some of the competition has been talking about with the smaller study that they are not as convinced that the combo use would be reimbursed. They're sort of -- the way I think they presented it, they're almost feeling a little bit more -- having a higher conviction that mono is going to work. And if they have activity sort of in the ITT population, that's almost great. You have not made the same comments about combo, the reimbursement side or your conviction in your data. Can you talk a little bit about what makes you so confident about the case for combo?

Sure, Yaron. So let me start with this. This is an enormously untapped market, right? The unmet need in TTR cardiomyopathy is vast. There's room for several players, right? Treatments today, such as stabilizers like tafamidis, are benefiting many patients, not all, but patients are continuing to progress. So there's a big, big opportunity here for better treatments for this disease. We believe that we have the optimal trial design, all right? All contemporary studies to date were originally powered based on the ATTR-ACT tafamidis study, which was done, what, 10 years ago or so, based on the placebo progression rate in that study. The demographics has shifted based on disease awareness primarily but also better methodologies to diagnose disease. Based on that, patients are being diagnosed earlier in their disease. You have to do longer trials or you have to do bigger trials. We recognized that 2 years ago when we upsized our study to become, by far, the largest study ever conducted in TTR cardiomyopathy, by far. That helps ensure for a successful outcome and the richest data set possible in this big, big opportunity. We're not there that this is only a monotherapy market. Based on extensive market research we have done and our partner, AstraZeneca, has done independently, we agree that monotherapy is a big opportunity. Newly diagnosed patients with TTR cardiomyopathy, if the data supports, we'll go right on to a silencer. Patients that are progressing on tafamidis rapidly could be switched over to a silencer, right? However, patients that are receiving some benefit from a stabilizer, if you have the data that shows that patients are actually going to do even better with the silencer on top of that, the case will be made, right? HCPs are going to want to prescribe. Payers will reimburse for that because this is a fatal disease, not -- an analogous situation is in oncology when several different chemotherapy or other targeted delivery -- targeted strategies will be added on to enhance survival rates. So it's a dynamic market. Monotherapy is going to be very important. We think we're well positioned, especially with the efficacy we're seeing with WAINUA, the ability for patients to self-administer and not have to be administered by a health care provider, the convenience of self-administration once per month and also the global presence of AstraZeneca as a leader in heart failure around the globe. We think we're well positioned to do that. But this is a dynamic market, and we think we're going to have the data to actually be able to point to, look at our data with monotherapy, and it's going to be very well powered. Look at our data in combination. And if there's a benefit in combination, we think we're going to be really well positioned to be able to reach those patients.

And when you're talking about in CARDIO-TTRansforms -- because we've been getting these questions, a mono patient, to your point, is going to be a newly diagnosed or a progressive patient, right? The combo can either be right away on top of tafamidis or mono and then a tafamidis drop-in? Maybe talk about just how that works in CARDIO-TTRansforms.

It's all to be determined, Yaron. It's going to really be data driven. I mean if the monotherapy data for the silencers, which we expect, based on its mechanism, is really -- indicates that it's going to be -- provide a greater benefit for patients over a stabilizer, that will be what's going to be prescribed right off the bat for newly diagnosed patients, and that's going to be a lot of patients. For patients that are receiving some benefit on tafamidis, which is a very well-tolerated drug, so there's not a side effect profile that's kind of -- that docs are going to want to get their patients off of tafamidis, and you have data that your combination is actually going to add additional benefit, the combination is what's going to happen. If the patients are progressing rapidly and they're really getting very little benefit from tafamidis, that's going to be a switch. That will be a switch to a silencer. So -- and again, to make projections on what HCPs are going to prescribe and what payers are going to pay before there's any data is...

It's too early.

It's a little premature.

Yes. But in CARDIO-TTRansforms, to be on a combo arm, how did that work? The patient had to be on tafamidis and then they got eplontersen on top of it? Or they could have started with eplontersen, they could be newly diagnosed, and if they're progressing, they could have added on tafamidis?

The vast majority of patients in our tafamidis subgroup have been on stable tafamidis coming into this study. Let me add that our study, which is now, as I said, is more than 1,400 patients is well balanced between monotherapy and tafamidis. But the vast, vast majority of patients in the combo arm have been on tafamidis, stable, and they're progressing, right, as they came into our study. We allow drop-ins during the course of the study, but the percentage to the number of patients is very, very tiny, that they actually came into the study as monotherapy and then were dropped in on to tafamidis. And even for those patients, even though it's small numbers that dropped in, remember that the tafamidis -- the efficacy that was seen in the ATTR-ACT study really didn't first kick in, wasn't observed for like over a year after being on tafamidis [ where they start ] separating from placebo, maybe even 18 months or so. So it's not going to really have much impact on the outcome, these drop-ins.

Yes. Okay. So that's why the drop-ins are going to be pretty low. But the usage of tafamidis in that study wasn't capped, but I imagine it's going to be less than 30%, maybe 40% or depending because of the enrollment and how you shifted away from areas that had tafamidis?

Yes. Our objective, our goal was to have a good balance, a relatively even balance between tafamidis [indiscernible] patients in our study. It wasn't a hard cap, but it was a cap we were able to manage. And we managed that by being able to prioritize sites where tafamidis is available or tafamidis is not available. The first sites not surprisingly in our CARDIO-TTRansform study, really a landmark study in this patient population. We're in the U.S. U.S. is where tafamidis is readily available. So you could imagine that we saw a spike initially in tafamidis usage in our study. Well, during the course of the study, as we were monitoring usage, we were able to shut down enrollment in those sites and really prioritize sites where tafamidis, outside the U.S., is not available. And it worked perfectly. They worked perfectly. We were able to get a big uptick in monotherapy, and we landed right about with the demographics, which is exactly what we were targeting.

Okay. Got it. And I think the data could be as early as 2025.

Yes, that's correct. If the study -- so we have the option to read out the study along the way, including as early as first half of next year, second half of next year or if the study were to read out through its full 140 weeks, it would be around midyear next year. We will make that decision, and we and our partner, AstraZeneca, have been already doing a lot of scenario planning dating back to last year. What would the blinded events need to be to approach or hit our original target for blinded events in the study to basically draw us to conclude that we're there? Or if anything else we see in this space that suggests to us that -- weighs in on our effect size or anything like that, we can read the study out earlier or let it play out to the end. Where our objective is, of course, to get to the market as early as possible, but not at the cost of having the richest, most competitive data set available for this market, which is, as I said earlier, is a vast opportunity with a big unmet need.

Okay. So it could be early next year depending on event rate or by mid-next year based on 140 weeks.

Or the following year, yes. As early as next year, if it read out. If we ran it out to the full, it will be around midyear 2026.

'26. Okay. Got it. Okay. Any more questions on CARDIO-TTRansforms or TTR? Okay. Then let's talk about donidalorsen. The HAE -- the OASIS study has read out positively. I'm assuming the data is going to be probably late May at the ECAII or ECAAI (sic) [ EAACI ] in Valencia, Spain, which I believe is in May. It's kind of when I'm thinking you might have it. I know you can't say a lot, free data. The -- you said you worked on the q 4 weeks and the q 8 weeks. Looking at historical data, one would imagine a q 4 week dosing scheme is going to be slightly better than q 8 week in terms of maximizing the effect size. Obviously, q 8 can still competitive, just given what the bar is currently with TAKHZYRO. But between Phase II and Phase III, normally, there is some decrement in efficacy, right? I would expect some decrement here as well. Is that sort of reasonable to expect? I think we've seen that in all the studies.

So I don't want to comment on the data ahead of our presentation later this year -- midyear this year on what the event or the HAE reduction rates will be. What I would like to say and will say is that we're very pleased with the data with [ high ] statistically significant reductions in HAE attacks at 4 weeks and also at 8 weeks. And it's fair to say that the 8 weeks isn't as strong as 4 weeks. However, it's more about HAE attack rates, right? It's also about what percentage of patients are attack-free, right? If there is a good number of patients in the 8 weeks that are attack-free, well, that's an option for patients. That provides dosing flexibility for patients, right? There could be a subset of patients that are just perfectly fine on every 8 weeks. And it's less about a mean reduction as it is about, well, you can come on to donidalorsen with great protection with every 4 week dosing with a simple self-administered auto-injector. And then if you're feeling good and you're feeling comfortable with the treatment, you can go to every 8 weeks. And you know what, if you get an attack, you can go back to every 4 weeks and be well protected or you can be perfectly fine on every 8 weeks. This is dosing flexibility that is not offered by any other prophylactic treatment today. So we believe that donidalorsen offers -- checks basically the 3 boxes that patients and treaters have been looking for in a single treatment: efficacy, convenience and really good tolerabilities. Simple -- low-volume injection, subcutaneous injection with a simple auto-injector that the patient can self-administer themselves. In addition to the Phase III data we plan to read out -- present later this year, we're also going to be presenting 2 additional studies. We have the only study that's ever been conducted in HAE prophylaxis in which we're actually examining switching from an existing prophylactic treatment to our drug. This is a study with more than 60 patients that enrolled. The fact that more than 60 patients eagerly enrolled into our switch study, first of all, teaches us that patients want other treatment options, are willing to switch. Second, we're going to have the data that speak to HCPs and say, okay, you're convinced that you want to switch to donidalorsen. Here's how you do it so that the patients don't have any gaps in protection and we're not seeing gaps in protection, right? We're actually able to transition them from one treatment to our treatment very effectively. We're very pleased with what we're seeing in the switch study. In fact, we've expanded it because there was interest and more patients want to come in. So we're going to present that. We're also going to present long-term durability of donidalorsen in the Phase III study -- in our Phase III open-label extension study, which is really showing promise. So it's going to be a fulsome data readout that includes the Phase III data, but more as well.

And then the Phase III patients can also switch from q 4 to q 8? Or they have to stay on whatever they were on?

In the open-label?

In the open-label.

They can switch to every 8 week dosing, provided they're attack-free for a period of time with monthly, and then it's up to the HCP's discretion to be able to switch them over to every 8 week dosing.

And at what point do you think you can -- you will file this year?

We're projecting to file probably soon after midyear in the U.S. Our partner for European commercialization of donidalorsen, Otsuka, is also preparing their MAA for European filing soon.

And at that point, you'll want to have your switch study read out, so you can add that to the label?

We believe that the switch data will -- the efficacy will unlikely be part of the label because this is not a controlled study. This is a placebo group. But we've got -- but we're going to publish this data and publish it extensively. And that will be good enough for us to be able to make claims with -- not claims, but be able to educate physicians and treaters that this is the value of switching your patient and here's the data that supports that. The safety data from the switch study will certainly be part of the safety overall database for the filing as well our open-label extension data. And our Phase II data, which we published in now in the New England Journal, which will be elevated to a pivotal study. So we'll actually have 2 pivotal studies to be able to speak to in the label.

Okay. I was going to move to 582, the Angelman program from the Phase I/II HALOS study. And so I think, along with Biogen, you're now talking about having initial data in midyear. I believe that Phase I included 51 patients, roughly, right, is what you said at the FAST meeting. At the time, you said that there was -- you saw some functional improvement in the CGI Angelman score. You also looked at the Bayley-4, and you saw a normalization and some improvement in EEG delta waves. And if I recall correctly, it was 3 doses monthly and then you go into an open-label extension that has different dosing schemes. In midyear, what do you think we're going to see? Is it going to be mostly data from the first 3 or also the OLE?

So just to remind the audience, to make sure we're level set here, our Angelman's treatment that's in development now in our Phase I/II study is the same chemical platform as SPINRAZA, as [indiscernible], as our tau program, which has shown proof of concept in the -- excellent safety and tolerability. And that's what we're seeing in Angelman's program with 51 patients, as you mentioned, well tolerated, and patients are staying on study. It's a 2-part study. The first part is a dose escalation, MAD portion of the study in which -- which lasts about 3 months and about 4 doses. And then patients roll over into a long-term extension, which has now been extended to last for up to 3 years after they roll over into the study. We have a good number of patients that have now surpassed the 1-year [indiscernible] in the long-term extension. The study is fully enrolled, obviously, and we're looking forward to sharing data midyear this year. We're collecting all the data we possibly can collect in this study to give us confidence that we can design a proper Phase III study and with the highest success -- high probability for success. We're looking at biomarkers. We reported encouraging data on the biomarker EEG delta wave normalization at FAST last year. We're going to be talking about that. We're going to be looking at efficacy endpoints such as Bayley-4, SAS-CGI, but also all the subdomains within these groups, right? We're going to want to look at and we will look at cognition improvements, motor function improvements, sleep patterns, communication improvements and other things to really help us decide on what is the proper design for a Phase III study going forward. What should we focus on? What should we go to the FDA with as a proposal for a Phase III outcome design? We're also going to be looking at patient populations, right? In our study, we have newborns, we have adolescents and we also have adults, right? Should we include all these patients in our Phase III design? Should we focus on the neonates? Should we do a separate study for adults? All of this is going to inform on our ability to be able to have confidence in the proper design of a Phase III study with confidence that we'll be successful.

When do you think you might start Phase III? Is it possible by the end of this year or it's maybe more next year?

I think end of this year could be a bit of a stretch. I wouldn't rule it out. If -- this is a program that we're operationalizing, we're running. Biogen, our partner, has an option to take the program. So then it would go into their Phase III program and then they would do that. If this was a program that we kept and developed in Phase III, we would move at our pace, and we like our pace.

Yes. And there was obviously a big natural history that you have done with Biogen for years and years and years that you can draw on.

Yes. This is an open-label study, a very good point to highlight, but there is a really good natural history data both published as well as we have internal natural history data that we think is going to be very valuable when we look at our results from the study to be able to compare to the natural history. So what we reported preliminarily last year at FAST was that majority of patients seem to be doing better, and we -- and that was in the part 1 of the study. That wasn't even the long-term extension. That was in part 1 of the study where patients appeared to be doing better. And the natural history data that exists today, it looks like what we're seeing is going beyond that, was going beyond the natural history.

Well, terrific. I think we're out of time. Brett, thank you so much for joining us. We appreciate it.

Thank you.

Good to see you.

Good to be here.