Good morning, everyone, and thanks for joining us for day three of Oppenheimer's Annual Healthcare Conference. I'm Justin Kim, one of the research analysts at OpCo, and it's my pleasure to host this fireside chat session with Ionis Pharmaceuticals and CEO, Dr. Brett Monia. Thanks for joining us, Brett. It's great to have you here.
Thank you, Justin. Good morning. Good morning, everybody. Thanks for joining.
Maybe just to start off, could you just give us an update on where the company stands today and sort of what lays ahead in 2023 and 2024?
Yeah, sure. Happy to, Justin. We, you know, at Ionis, I am very pleased with the progress we're making across all aspects of the business. We're making great advances in technology. The pipeline is delivering. The late-stage pipeline is growing, and we're looking forward to a lot of updates on the pipeline this year and for coming years. I'm very excited about our upcoming new commercial launches. 2022, we made great progress, and we're building on that momentum in 2023. Some of the events I would highlight to your question, we are definitely looking forward to the tofersen advisory committee meeting, which is next week on for SOD1-ALS, with a PDUFA date of April 25th.
You know, tofersen has the potential to be the first disease-modifying agent for any cause of ALS. That's a really big deal for that field. We're looking forward to the phase III data for eplontersen, the full dataset which is coming up in the first half of this year. We're looking forward to presenting that data based on the week 35 data that we presented at ISA last year. We have high confidence in eplontersen, very high confidence that it will compete in a very attractive market for Ionis. We're looking forward to additional phase III data in the second half of this year. Olezarsen, which is being developed for a rare indication and a broad indication by Ionis, wholly owned.
The FCS rare indication is the data is expected in the second half of this year. We're doing really well in enrolling the sHTG broad indication as well, and that's on track. We're looking forward to completing enrollment in some of our phase III studies this year on time. Our eplontersen for ATTR cardiomyopathy is expected to complete enrollment in the largest study ever done in ATTR cardiomyopathy by mid-year this year. Our HAE prophylactic drug, donidalorsen, is actually a little ahead in enrollment. We're looking forward to completing enrollment in the first half of this year as well. The pipeline is expanding. The phase III pipeline continues to expand, which is our other notable events.
We've already Our partner, GSK, has already initiated a phase III study for bepirovirsen, for HBV, and that's off and running. They plan to present an update, a phase II update in patients with HBV in combination with interferons this year. They're very excited about that. Roche is still on track to initiate phase III development for our effective LICA medicine for IgA nephropathy in the first half of this year. If the, you know, that'll expand our phase III pipeline to eight medicines to, of course, 10 indications, which I think is, I don't know many companies that have a rich late-stage pipeline of that magnitude. Of course, we'll have several mid-stage pipeline readouts throughout the year as well as we always do.
This is 2023 is shaping up to be a highly eventful year, and we're very confident it's gonna be a very, really good year for Ionis.
Great. Great. No, that's really exciting times for the company. Maybe just to start with, you know, what you had mentioned in the beginning around eplontersen. You know, with the recent acceptance of the NDA for ATTR polyneuropathy, you know, can you just talk to us a little bit more about, you know, potential launch there, how you see the current sort of landscape and, what features eplontersen sort of make it exciting to, for the team to be launching into?
Yeah, you know, we're very proud of the progress we're making with AstraZeneca in our first co-commercialization, co-development partnership. We're very much prepared, well prepared for the initial launch in polyneuropathy and of course, for cardiomyopathy is underway as well. We believe, you know, we know that a very small percentage of patients with TTR polyneuropathy are actually diagnosed and treated today. This is not a switch market. It's really a market that's focused on patient identification to get a new medicine to patients as effectively as possible. We are well positioned to do that, capitalizing on, you know, our experience in TTR amyloidosis, genetic testing and all of that with the strength of AstraZeneca globally.
We have several features that we're really excited about eplontersen, it starts with efficacy, right? We're anxiously and excitedly anticipating the week 66 data in polyneuropathy. Based on the week 35 data that we reviewed last year, we think efficacy is a big win for eplontersen. It always starts there, right? We like the convenience of a at-home monthly self-administered medicine with an autoinjector. Very simple tap on the thigh or on the arm, that based on our market research, the vast majority of patients and caregivers prefer than versus some other setting. We also believe that as I briefly mentioned, AstraZeneca brings with it a significant advantage too. Remember, most of these patients with polyneuropathy are mixed phenotypes.
They have significant cardiomyopathy involvement with their disease, they're seen by all kinds of caregivers. They're seen by neurologists, they're seen by cardiologists, they're seen by GI docs, and they're seen by others. AstraZeneca has a very strong presence in cardiovascular disease, they're already, you know, in the offices seeing doctors and so on. We're working very closely jointly with our medical affairs team to really get the word out that eplontersen is coming, we're excited about it. It's a market that's untapped. It's a significant market, we think we have several important advantages that we think, you know, will reach a lot of patients, will reach a sizable amount of patients for polyneuropathy.
Okay, great. you know, you did mention how the team is really excited to see and sort of unveil the 66-week data. How important will inclusion of those data be to the commercialization process? You know, is this something that, you know, will sort of naturally lend itself to an sNDA submission? Is it something that, you know, with a publication in a medical journal might be sufficient to sort of aid that effort? How should we think about those data and how it would be leveraged commercially?
We are, as you know, our NDA was accepted by the FDA with a PDUFA date of December 22nd. No AdCom is expected. We're preparing to launch in the U.S. based on the 35-week data. As you know, Justin Kim, many geographies outside the U.S. really want to see the full data set, the week 66 data set. With respect to including additional data beyond week 35 for the U.S. market, that'll be a data-driven decision, but we're confident that we're not going to delay approval and launch by submission of additional data.
What will be data-driven will be whether or not a supplemental NDA will bring significant value to the label, for the U.S. and if so, we can do that after market authorization, if we choose to. We'll certainly publish, in, you know, no matter what. That'll be whether we want a supplemental NDA or not will be really a data-driven decision, but we're confident in the 35 week data, and we're confident that eplontersen will be approved, in the U.S.
Okay, great. You know, the eplontersen's application could also extend into cardiomyopathy as well. You know, can you just sort of update us in terms of, you know, the thinking on the CM plan? You noted that the company is running, the largest study there. You know, how important do you think the breadth and depth of that exploration in that population will be towards launching eplontersen in that indication? In what way, do you see those launches as being sort of linked with polyneuropathy.
Mm-hmm.
Do you think there would be any insights with the potential initial launch in polyneuropathy as it pertains to cardiomyopathy as well?
Yeah, I think they're important. I think they're linked importantly. Let me start there and then talk a little bit about the design of the cardiomyopathy study and why we think that's important. You know, we and AstraZeneca were planning to launch in the U.S. prior to the week 35 data. Maybe one or two other geographies. However, once we actually reviewed the week 35 data, we decided to launch more globally. That's because of the strength of the week 35 data and because we think it's important to get out there as quickly as possible and to tell our story quite simply, and to talk about our drug with neurologists. As I mentioned before, it's a mixed phenotype, so we'll be speaking with cardiologists and so on.
We want to get out there. Therefore it's kind of like step one before a big launch in cardiomyopathy. We think it's important. It really sort of greases the skids and gets us moving into this space. As you said, the cardiomyopathy study that we're conducting is the largest by far, really, ever done in TTR cardiomyopathy. Enrollment is going very well. As I said, we're expecting to complete enrollment in by mid-year this year. You know, this field, this space has changed. The patient demographics have changed in this space since tafamidis' ATTR-ACT study read out. Actually, since it initiated. Patients are being diagnosed with milder disease due to better awareness of the disease. As well as better methodologies to detect TTR cardiomyopathy.
As a consequence, not everybody, but the majority of patients are being diagnosed with earlier on in their disease, therefore they have milder disease. Therefore, the empowering assumptions and all kinds of assumptions that led to clinical trial designs based on the ATTR-ACT study, need to be updated, right? That's a different patient population than ATTR-ACT. Our study, we believe, is the only study that takes into account this milder patient population and therefore increases the highly increases the not only the probability of success, but the robustness of the data. What, the size of.
Not only are we being able to take advantage of the changing patient demographics to ensure success for this study, it also allows us to balance the amount of patients that are naive to tafamidis as well as patients on tafamidis. That's really important to have a robust data set for both of those subpopulations because, you know, in the U.S., the vast majority of patients are on tafamidis, and a lot of patients outside the U.S. are on tafamidis. Physicians and patients are going to want to know, how does your drug do on top of a drug like tafamidis? Why should I prescribe both? Do you have the safety data? Do you have the efficacy data? And of course, there are a lot of markets where tafamidis is not available.
Naive patients, and we'll have that data too. Since we upsized the study, I'm very pleased to report that we are getting a very nice balance between tafamidis use in naive patients in this study. We're focused on areas where tafamidis is less available. We're also focused on areas where diagnosis is happening later. We have patients that are less mild in their disease, and it's also allowing us to increase the percentage of patients that are hereditary TTR cardiomyopathy. You know, all of this, it is going to provide, we believe, the most robust data set in this patient population, which is important for the label. It's not just about a P-value, right?
When you do an outcome trial of, you know, in a population of this size, it's a very large patient population. It's also about the robustness of your data, what goes in the label, and we think we're going to have the richest data set for the label of anyone. The study's going very well, and that's sort of the rationale. Everything we had hoped to achieve, based on the upsizing of the study, seems to be happening.
Okay. you know, maybe said another way, is, do you see the sort of trial and the scope as informing how to address the heterogeneity of patients out there when you could be launching that maybe it's not just a naive classical patient, but rather, you know, a variety of mild, severe on or off tafamidis, population that, you know, you physicians have questions that you could then provide answers for? Is that the right way to think about it?
Absolutely. That is, that is the right way to think about it as well. you know, based on the upsizing of the study, we've been able to reach out and emphasize prioritize sites where diagnosis is happening later, right? Think about it this way. Your Class I, Class II, Class III patients, right? We're going to have a rich data set, we believe, of all those classes. We'll be able to actually speak to the potential efficacy of eplontersen in late-stage TTR cardiomyopathy, mid-stage, as well as in early stage. That's a contributor to the robustness of the data set we expect to achieve. Yep.
Okay, great. Maybe talking about other sort of cardiology programs. You did mention a readout expected in the second half of this year with olezarsen. Can you talk a little bit about the, I guess the expectations there and sort of what might the hurdle be for FCS and how that may differ, I guess, from broadly sHTG?
Yeah, sure. The FCS phase III study enrolled fully last year. It's a six-month primary endpoint study with a 12, you know, six additional months follow-up. We're looking forward to that data reading out in the second half of this year, and we're preparing to launch in FCS. You know, these are patients that, although you mentioned cardiovascular, like the broader cardiovascular, these patients definitely suffer, as do the sHTG patients, from atherosclerosis due to severely elevated triglycerides. You know, the main focus is really on the severe acute pancreatitis events that these patients suffer from that can be fatal. A lot of these patients have recurring pancreatitis. Not once they have one, they're going to have another one unless they can get their triglycerides substantially lowered.
That's true for sHTG as well as FCS. FCS will be our first independent commercial launch, so it's very important to us, and we're very much looking forward to that. FCS will get us. You know, we're well known by the patient and disease groups, based on our prior experience with Waylivra, and FCS. We want to reinforce that our position in this patient population with olezarsen. It's very important and that we get out there as quickly as possible with our first independent launch. Similar to what I referred to earlier with polyneuropathy, setting up cardiomyopathy for eplontersen, we believe that FCS sets up sHTG very well for our launch.
sHTG is a large patient population, estimated to be millions of patients in the U.S., with triglycerides above 500. They suffer from pancreatitis events just like FCS patients do, which can be fatal. Getting ourselves in the door with olezarsen and FCS, we believe will set us up very nicely for sHTG a year and a half later or so, for that readout and launch. You know, we think it's very important. It's a nice stepwise transition or advance into this patient population.
In terms of that transition, I mean, for sHTG, do you then see that it's sort of this event-based population that is going to be sort of the initial adopters of potential therapy that, you know, people who have these pancreatitis events are going to be sort of the ones who in the sHTG population are most likely to get onto therapy?
Yeah, absolutely. We've done a lot of market research here in sHTG. We refer to that population, you just sort of described, patients that know they really want a treatment because they have already suffered from pancreatitis events, or they've seen others suffer from them, and they're very scared that they're going to suffer from and be hospitalized due to a pancreatitis event which again, can be fatal. We refer to those patients as sometimes as early adopters. They're the ones waiting for olezarsen to reach the market. That early adopter market itself, we believe is a billion-dollar-plus market opportunity in the United States. That's our target, you know, FCS as well as the early adopters in sHTG.
Of course, we have more work to do to further educate and expand that. The principal prescribers for that early adopter patient population, not only, not exclusively, but primarily are endocrinologists, not cardio-cardiologists, but there's a lot of early adopter cardiologists too for sHTG. That's then our challenge is then to even further expand beyond that billion-dollar U.S. market opportunity to then reach and educate those patients and physicians who are less familiar with the need to lower your triglycerides under about 500. That's a market expansion opportunity for Ionis. That's the strategy and, you know, we're building towards that.
How does that sort of expansion happen between early adopters, and let's say more cardiologists or people who are looking at triglyceride levels, you know, more than sort of events? Is that sort of medically driven? Is it clinically driven? Is it, you know, commercially with payer work? Like, just wondering what are some of the puts and takes around how you get to that expansion and where you see the biggest lift, I guess.
Data and education. We will, you know, we will and are conducting several investigational studies to really drive home the value of olezarsen in cardiovascular disease. Pancreatitis is well accepted. Of course, we'll have data in pancreatitis from our clinical trials as well. But we will conduct and are conducting investigational studies to make the case that, you know, patients will benefit from a cardiovascular perspective with olezarsen as well. And education and drug performance, you know, and get out there once olezarsen launches and is successful to really get out there and educate the cardiovascular community, to, you know, really help manage target levels that are expected by, you know, institutions such as the AHA and so on.
To just drive home the message that olezarsen is a safe and highly effective drug and patients need it to avoid not only pancreatitis, but also to reduce their risk for cardiovascular disease. It's data-driven, it's drug performance-driven, and it's education.
Okay, great. You know, I just wanted to touch on also your comments on donidalorsen and the maybe better than expected enrollment for the phase III study. You know, this program strikes us as one that could provide the most meaningful revenue for the company, you know, being launched on its own in the near term. I was sort of curious, how do you see the market in prophylactic HAE amongst prophylactic HAE therapies today and where donidalorsen offers, you know, something unique, and is that do you think that's sort of somewhat reflected by the enrollment patterns that you've been observing?
Yeah. A different strategy than what I just described for eplontersen, where very few patients with polyneuropathy are actually been diagnosed or on treatment. For olezarsen in FCS and sHTG, where, you know, there really are no treatments available today. donidalorsen for prophylactic HAE is a switch market, right? Especially in the United States. Outside the United States, prophylactic treatments are just beginning to take hold. That's an open market opportunity that we'll capitalize on. In the U.S. it's really essentially a switch market. Most patients are on Takhzyro. Patients and physicians want better treatment options, and they really want better treatment options based on the gamut, the full gamut. They want better efficacy, they want better convenience, and they want better tolerability.
We believe based on very strong phase II data, as well as now, very long, very impressive, I think, open label extension data in which patients have been treated for a year or longer, that donidalorsen offers to tackle all three of those aspects. We have efficacy in reducing HAE attacks that appears to be superior than anything on the market today or emerging into the market. We check that box. The convenience of a self-administered, at-home, low volume administration once per month with an autoinjector is very attractive based on all the market research we've done to patients. It's painless injection, so the tolerability and as I mentioned, very low volume is also very attractive.
We do believe that our enrollment is going well because patients are very much looking for new treatment options and they're willing to try and switch even in a placebo-controlled trial because they know that they'll have the opportunity to move on to donidalorsen in an open label extension study. Yeah, we think it bodes well and supports our conclusion that patients are ready to switch for a drug like donidalorsen once it's available.
You know, I think one thing that sort of caught our attention has been the monthly administration that has flexibility to be extended further. Where if I recall, Takhzyro only has maybe 20% achieving or less the sort of monthly frequency. I'm curious in terms of the ability to maybe even extend that further. Is that data something that you see maturing from the open label extension? And how long do you think after a sort of a primary readout might those data be available? As you know, commercially that could be a really compelling-
Yeah.
sort of, data point, let's say.
We think the dosing flexibility that donidalorsen will offer as a monthly or potentially as a every two-month dose, self-administered dose is another significant advantage. As you say, Takhzyro is. The vast majority of patients on Takhzyro are being dosed every two weeks. Smaller percentage every month, but if they go to every month, their protection goes down substantially from HAE attacks. Our monthly is stacking up to, you know, to be highly comparable, maybe even a little bit better than their every two-week dosing. Our every two-month data, based on a small sample, but a small sample from our open label extension study looks comparable to their every month dosing. We do have that potential convenience.
We won't need necessarily open label extension data to make a case for every two-month dosing as well as every month dosing, based on open label data. We actually have an arm in our phase three trial that has every two month and it's powered.
Okay.
For significance for every two-month dosing as well as monthly dosing versus placebo. We should have real, you know, real clinically controlled data for bi-monthly dosing when the data reads out next year.
Have you done any sort of physician market research in terms of what that trade-off looks like in the patient or clinician community of, you know, what level of protection a patient or a physician might be comfortable trading off?
What we know is we know that. Yes, we've done a lot of market research and monthly dosing is highly attractive to patients, you know, especially in an autoinjector, self-administered low volume. What we do know, and you referred to it earlier, is that patients are willing to try monthly dosing with Takhzyro, even though their protection could go down, you know, substantially to, you know, in the 60%-70% reduction in attack range for monthly versus more in the 80% range for every two-week dosing. That kind of gives you a threshold for what patients will try.
On the other hand, once they start getting attacks, if they're not fully protected, they go back to the more frequent dosing, at least based on the experience that we've seen with Takhzyro. That kind of gives you a flavor a little bit. You know, we'll see what the data is, but you know, mid-90% reduction in attacks with monthly dosing, we think will drive patients towards donidalorsen.
Okay, great. Well, it seems like we've already run out of time. We couldn't get to all of the really interesting things the company is working on. you know, it's a pleasure to have you, Brett, and looking forward to all the progress.
Thanks, Justin.
Yeah.
It was a pleasure, participating. Take care. Have a great day.
Thanks, everyone.