So welcome everybody, to the 44th annual TD Cowen Healthcare 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. The TTR cardiomyopathy panel here was action-packed, so I definitely wanna start with that. There's a lot to talk about pipeline-wise, geographic atrophy, we're gonna talk about tomorrow at the eye and the ophthalmology panel. And a lot of your pipeline's gonna 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 , Q3 months, you know, subQ in the physician's office. Where do you see your, your niche, or where do you see the initial usage, I would say?
Yeah, 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. You know, we're only six 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, you know, 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, 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 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, you know... 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, is in newly diagnosed patients, not switches. So, we're learning that. We're learning that, that the market is still wide open for WAINUA, and, and we, 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, and the incidence, there was a discussion on the panel, whether it still is an orphan. Unquestionably, it's still an orphan, but I think what the point they were 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, you know, 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's office if there's heavy renal involvement. And a nephrologist is probably very unfamiliar with TTR disease. It can present in a gastroenterologist's office. It could present in a neurologist's office. Of course, it could present in a cardiologist's office. All of this 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 gonna be the strategy to deliver, you know, to those 80%+ 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, diagnosis is much better. And that's largely because cardiologists are used to diagnosing a heart failure indication, right?
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, you know, pretty quickly look to TTR cardiomyopathy as a potential cause of the heart failure that they can diagnose fairly rapidly. So, you know, so we, we, you know, so cardiomyopathy is indicated or is, is diagnosed a little bit quicker in polyneuropathy, but we're very committed to fixing that with polyneuropathy.
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.
Yeah. 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... You know, we're working very closely together on the back room services for the launches, such as market access, medical, and all that. They're distinguished where we are distinguished is that they are responsible for the field force, whereas we are responsible for the patient-facing, you know, 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, or they're actually doing on-site training with the patients?
Both. Both. Virtual training is definitely a very important part of this process because, you know, 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 just to get out there. So it's a lot of virtual, but it's also, you know, seminars. You know, in-person meetings, gatherings, and those sorts of things.
Yeah. And, do you have any sense, and 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 geographic territories around the globe, such as Portugal, Brazil, Sweden, and maybe in Japan as well. So those are certainly hotspots 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, the prevalence. And, you know, this is a global disease, and that's what we're going after.
Yep. Question from the audience. Yeah.
[audio distortion]
You want to repeat the question maybe?
So the question basically is whether or not, genetically diagnosed presymptomatic patients are being... You know, 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-TTRansform and, you know, your latest announcement. At 1,400 patients, you have sufficient power to look at subgroups, you know, based on combination usage, mono, based on severity. You have a subgroup MRI study, imaging study as well. You know, obviously, some of the competition's been talking about with the smaller study, that they are not as convinced that the combo use will be reimbursed. And they're sort of... The way I think they presented it, they're almost feeling a little bit more have a higher conviction that mono is going to work, and if they have an activity sort of in the ITT population, that's, you know, that's almost great. You have not made the same comments about combo, either 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 a stabilizer 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 have 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 two years ago when we upsized our study to become, by far, the largest study ever conducted in TTR cardiomyopathy. By far. That it helps ensure for a successful outcome and the richest data set possible in this 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, will go right onto 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 a 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, you know... An analogous situation is in oncology, when several different chemotherapy or other targeted delivery, targeted strategies will be added onto 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 healthcare 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.
When you're talking about in CARDIO-TTRansform, because we've been getting these questions, a mono patient, to your point, is going to be a newly diagnosed or 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-TTRansform.
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, you know, indicates that it's going to provide greater benefit for patients, over a stabilizer, that'll 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 going to, you know, 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, that will be a switch to a silencer. So it... 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, you know, That's, it's a little premature.
Yeah. But in CARDIO-TTRansform, to be on a combo arm, how did that work? Would 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 had 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? In, as they came into our study. We allow drop-ins during the course of the study, but the percentage or the number of patients is very, very tiny, that actually came into the study as monotherapy and then were dropped in onto 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 it started separating from placebo, maybe even 18 months or so. So it's not going to really have much impact on the outcome, the, these drop-ins.
Yeah. 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 on because of the enrollment and how you shifted away from areas that had tafamidis?
Yeah. Our objective, our goal was to have a good balance, a relatively even balance between tafamidis usage in naive 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, where tafamidis is not available. The first sites, not surprisingly, in our CARDIO-TTRansform study, you know, really a landmark study in this patient population, were in the U.S., 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. It 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?
Yeah, 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 mid-year 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 for to, you know, to, to approach or hit our original target for blinded events in this 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, you know, it 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, 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.
Uh, or, the following year. Yeah, yeah. As early as next year, if it read out, if we ran it out to full, it would be around mid-year 2026.
2026. Okay. Got it. Okay, any more questions on CARDIO-TTRansform or TTR? Okay, then let's talk about donidalorsen. The HAE, the OASIS study, has read out positively. I'm assuming the data is gonna be probably late May at the EAACI in Valencia, Spain, which I believe is in May. It's kind of what I'm thinking you might have it. I know you can't say a lot, you know, pre-data. You said you worked on the Q4 weeks and the Q8 weeks. Looking at the historical data, one would imagine a Q4-week dosing scheme is gonna be slightly better than Q8 week in terms of maximizing the effect size. Obviously, Q8 can still be competitive, just given that what the bar is currently with TAKHZYRO.
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, mid-year 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. We have highly 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 subsets of patients that are just perfectly fine on every eight 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 four-week dosing, with a simple self-administered, you know, auto-injector. And then, if you're feeling good and you're feeling comfortable with the treatment, you can go to every eight weeks. And you know what? If you get an attack, you can come back to every four weeks and be well protected, or you can be perfectly fine on every eight weeks. This is dosing flexibility that is not offered by any other prophylactic treatment today. So we believe that donidalorsen offers checks basically the three boxes that patients and treaters have been looking for in a single treatment: efficacy, convenience, and really good tolerability.
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, we'll present later this year, we're also gonna be presenting two 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, they're willing to switch. Second, we're gonna have the data to 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 this switch study. In fact, we've expanded it because there was interest in more patients wanting to come in. So we're gonna present that. We're also gonna 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 gonna be a fulsome data readout that includes the phase III data, but more as well.
In the phase III, patients can also switch from Q4 to Q8, or they have to stay on whatever they were on?
In the open- label?
In the open-label.
They can switch to every eight-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 eight-week dosing.
And at what point do you think 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, like, the efficacy will unlikely be part of the label because this is not a controlled study. We don't have a placebo group.
But we're going to publish this data and publish it extensively. And that'll be good enough for us to be able to make claims with... Not claims, but, you know, 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 overall safety database for the filing, as will our open label extension data and our phase II data, which, you know, we published now in the New England Journal, which will be elevated to a pivotal study. So we'll actually have two pivotal studies to be able to speak to in the label.
Okay. I was gonna move to 582 , the Angelman program from the phase I/II HALO 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 a 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 the 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 gonna see?
Is it gonna be mostly data from the first three or also the OLE?
So just to remind the audience, make sure, you know, 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 QALSODY, as our tau program, which has shown proof of concept in the clinic, excellent safety and tolerability. That's what we're seeing in the 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 lasts about 3 months and about 4 doses. Then patients roll over into a long-term extension, which has now been extended to last for up to 3 years after, after they roll over into the study.
We have a good number of patients that have now surpassed the one-year mark in the long-term extension. The study's fully enrolled, obviously, and we're looking forward to sharing data midyear this year. We're collecting all the data we possibly can collect to this study to give us confidence that we can design a proper phase III study and with a high 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 gonna be talking about that. We're gonna be looking at efficacy endpoints such as Bayley-4, SAS, CGI, but also all the subdomains within these groups, right?
We're gonna wanna look at, and we will look at, cognition improvements, motor function improvements, sleep patterns, communication improvements, and, 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 gonna be looking at patient populations, right? In our study, we have newborns, we have adolescents, 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 gonna inform on our ability to be able to make, you know, to have confidence in the proper design of a phase III study with, you know, 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 is it maybe more next year?
I think end of this year could be a bit of a stretch. I wouldn't rule it out. You know, 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. We like our pace.
Yeah. 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. There's a... You know, this is an open-label study, a very, very good point to highlight. But there is really good natural history data, both published, as well as we have internal natural history data, that we think is gonna be very valuable when we look at our, you know, our results from the study to be able to compare it to natural history. What we reported preliminarily last year at FAST was that a majority of patients seem to be doing better, and we weren't... And that was in part one of the study. That wasn't even the long-term extension, that was in part one of the study patients appeared to be doing better. And that the natural history data that exists today, it looked like what we were seeing was 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.