All right. Good morning, everyone. I'm Ellie Merle, one of the biotech analysts here at UBS. Very happy to have Ionis Pharma here with us for a fireside chat this morning. Joining us from Ionis is Beth Hougen, Chief Financial Officer. Beth, thank you so much for joining us.
Oh, thanks for having us.
Maybe before we jump into the specific programs, you guys have probably one of the largest pipelines of any of the companies I cover. Can you give us kind of a high-level overview of maybe what you view as the most important milestones for the company in the next 12 months?
Sure, absolutely. This is, as you know, a really exciting time to be at the company. We have a very rich late-stage pipeline. And we've been embarking over the last, oh, nearly five years on shifting our business model so that we're not only discovering and developing our medicines, but we're going to be delivering them to patients ourselves. So our focus in the next, say, 12-18 months is going to be very heavily on regulatory actions and new product launches, much as it's been this year as well.
So we've got coming up here very shortly, in a few weeks, we hope, approval for olezarsen, one of our most meaningful opportunities in our late-stage pipeline. So we anticipate approval for that drug here on December 19. And we're ready to launch it. We're excited about those opportunities. And we can talk a little bit about that.
Following behind that, we hope to have European approval for Wainua, our drug for ATTR polyneuropathy that's approved in the U.S. and other countries around the world. But we're looking forward to the European approval here shortly for that drug. And then as we get into next year, we have the approval, we hope, for donidalorsen for HAE in the U.S., possibly in Europe as well, and the launch of that drug. And then we have multiple phase three readouts, two in particular from our wholly owned pipeline.
That would be severe high triglycerides with olezarsen. And that's in the second half of the year. And then pelacarsen, which is not wholly owned, that's with Novartis. That's a drug in phase three development for Lp(a) driven cardiovascular disease. And then we have our late-stage neurology asset that's wholly owned, zilganersen for Alexander disease.
We expect phase 3 data for that, and then a host of mid-stage pipeline readouts, so the next 12 to 18 months, and then well beyond that even. It's a really rich catalyst-driven event period for us.
Absolutely. Well, maybe starting with FCS, your first independent commercial launch. Maybe sort of what's the latest that you're hearing in terms of the physician feedback and how we should be thinking about the demand here?
So olezarsen is, as I said, it's one of our most meaningful opportunities in our wholly owned pipeline. And we're looking forward to bringing it to patients for two different indications. But both of them are related to severe high triglycerides. The first one, as I mentioned, we're looking for approval here very shortly for FCS, which is a rare disease. And it really is. Think of it this way.
Your triglycerides are in the thousands, potentially tens of thousands. So extremely high triglycerides. And what that means is these patients suffer from a host of various different symptoms: brain fog, severe abdominal pain constantly. And really, the most severe symptom for these patients is acute pancreatitis. And that could be fatal. And at a minimum, it lands them in the hospital fairly frequently. Once you get one attack of acute pancreatitis, you often will get more.
They will happen more frequently. So you want to make sure you get these patients down below that risk. That takes a very powerful drug. olezarsen has demonstrated in phase 3 the ability to do that. We've seen very, very significant reductions in triglycerides. As a result, we also saw a significant improvement, I would say a substantial improvement, very clinically meaningful in acute pancreatitis. For example, we had 11 cases of pancreatitis in the placebo arm. We only had one in our 80-mg treatment arm. So we're looking forward to bringing this drug to the market. We're ready to go. There's about, oh, call it maybe 1,000 patients or so in the US. Our medical affairs team has been in the field. They've been talking with physicians, identifying treating physicians, looking for patients, identifying patients, educating on the disease.
And so we've got our team built out today. We've got a full commercial organization now. We've got sales, marketing, medical affairs, as I said, market access. In addition to having all of that ready to go, everyone's on board, trained. We've finished our mock launches. We're just waiting for the approval at this point. We also are executing on a very novel omni-channel strategy in marketing to be able to reach the physicians and reach these patients. And we're also putting in place a top-tier patient engagement model that will provide these patients with the support that they need from when they receive their prescription all the way through to treatment and being able to stay on drug.
And so we think that will also be very important for these patients. And I think very helpful for the physicians as well.
So right now, there's a lot of excitement at the company, a lot of excitement in the physicians and with the patients. And we're looking forward to getting the drug into the hands of the patients.
Absolutely. And I know you mentioned there's an internal countdown clock to the PDUFA. So after approval, how should we think about sort of how quickly you can distribute the drug? And more specifically, I know we've talked about how this is an ultra, ultra rare condition. In terms of those patients, sort of where are you and the prescribers as well? Where are you in identifying who the patients are and what proportion maybe you've identified and figured out where they are? So my question is basically, how quickly can this launch?
We're ready to go, as I said. We hope to get drug in channel very quickly after approval. Our approval PDUFA date is December 19. We're right up against the holidays. We're prepared for that eventuality. We expect to get drug in channel very quickly and in the hands of patients very shortly after that. We've got our open label extension patients in the US who we'd like to convert over to commercial drug as quickly as possible. We've got patients on our EAP that we want to be able to move over to drug as quickly as possible. I think it's important to remember, though, when you have a rare disease that hasn't had a treatment in the past, like FCS, your focus is on educating around the disease. You've got to find the physicians who can treat these patients.
You need to educate about the disease. And then you need to help those physicians bring those patients into the office and get them identified, diagnosed, and then on treatment. So all of that is work that we've been doing with our medical affairs team for the last couple of years or so. And it will continue as we launch this drug. That'll be a key focus. And that will continue as our launch momentum picks up. And I think you should expect it to go, the launch to go like it would with any rare disease where you haven't had a treatment before.
This is a market development opportunity. And we know these patients. We know many of these KOLs because it's a space that we've been in for a while, as you may know. And so I think we're looking forward to that.
The prevalence for this disease is really like many rare diseases, not well defined. It's about one to 13 per million in the U.S. Kind of hard to know exactly until you start, until you have a treatment, frankly. Once you have a treatment, then I think it will become much easier for folks to really understand this is the patient and this is the disease, and now we have a treatment and we'll be able to get those patients on drug.
Absolutely. And you also have a competitor on your heels, FCS, although you certainly have a lead from a timing perspective. Maybe how do you see olezarsen differentiated and how you see the competitive landscape playing out?
We have first mover advantage, as you said, probably about nine months or so, maybe a little bit longer. And we are moving with a great sense of urgency as a result. Taking full advantage of that first mover advantage is critically important for us, to your point. And so we want to make sure that we're capitalizing on that advantage. olezarsen has demonstrated in phase three very significant reductions in triglycerides, which was critically important. And as I mentioned earlier, the ability to impact acute pancreatitis is so important for these patients.
Physicians know that you need to get these patients into a range of triglycerides that gets them out of danger of acute pancreatitis. The fact that we had such a significant. I shouldn't use the word significant because it wasn't statistically significant. But what I will say is it was clinically meaningful.
As I said, I think there was about a 90% reduction in acute pancreatitis attacks in the phase 3 study. That's a very important differentiator. And so we are very focused on ensuring our phase 3 data is known. It was published in the New England Journal of Medicine earlier this year when we presented at the ACC. And we'll also be focusing on really building on the KOL relationships we have. As I said, we have an omni-channel strategy in our marketing efforts that will reach these physicians and these patients. And we'll be building on all of that to capitalize on our first mover advantage.
Feel free to just skip this question. I'm sorry to ask. In terms of the label, do you expect to potentially have the non-genetically confirmed FCS patients in there or even just commercial usage there?
Yeah. So what I can tell you, we're in the late stages of our regulatory review with the FDA. So what I can say is we anticipate the label to be something like for FCS, for patients with FCS as an adjunct to diet to reduce triglycerides. I think that's the key here. We expect a very broad label. That's what I can say.
Interesting. I mean, that certainly would widen the potential population, but I'll leave it there.
Yeah.
Turning to FCS and the phase three reading out in the second half of next year, that's certainly an important catalyst for you guys. What should we be looking to see? I mean, we know there's potent lowering of triglycerides. But I guess what should we be looking to see in terms of maybe other endpoints?
Severe high triglycerides is the broader patient population, as you know, potentially hundreds of thousands, possibly millions of patients with triglycerides above 500 mg/dL or 880 mg/dL, which are really the thresholds for the acute pancreatitis, which is, as I said, the most severe symptom that these patients really struggle with. What we're hoping to see in our phase 3 study, we have a very broad phase 3 study, two pivotal studies, CORE and CORE2, and then a safety enhancing study called ESSENCE. Very large phase 3 program, fully enrolled. We anticipate data in the second half of next year. We expect to see, based on the FCS phase 3 study, a significant lowering of triglycerides. We anticipate that that will translate to improvement in acute pancreatitis. That's what we would hope to see for these patients.
And then we would be ready to file for regulatory approval with those phase 3 data and bring that to the market, hopefully in 2026. So that would be one of four launches that we anticipate in the next three years with olezarsen and FCS first, followed by donidalorsen for HAE, olezarsen for severe high triglycerides. And we've also got zilganersen for Alexander disease, amongst other partnered programs that could be coming to market as well.
Yeah, certainly transitioning into a commercial stage company, which is exciting.
It is. It is.
I did want to ask about TTR, but maybe just quickly, I'll ask about expenses. I mean, launching, I mean, HAE is competitive, but also on the smaller side. But FCS, I mean, now we're starting to talk about larger populations. How should we think about the scale of the sales force buildup and some of the sort of costs associated with this?
So our focus is on ensuring that our expenses, our investments are behind these launches. We have, as I said, we've got these four wholly owned assets, drugs that could come to market in the next three years. And so obviously, that is a very significant focus for us from an investment perspective. But interestingly, we've been able to really manage our expenses. R&D expenses are staying relatively stable. And we expect that to continue for the foreseeable future. And where we are building, obviously, is in sales and marketing. So our SG&A expenses are growing. For FCS, for olezarsen, that's a relatively small sales force. Our field force all in is in the 20-30 people range in the U.S. For HAE, it's a bigger opportunity, still a rare disease.
We would expect to be increasing our field teams to be able to cover that, probably more in line with what you would see in other products with other companies that are in that space, probably in the 75-80-ish range of field force all in. And then when we get to severe high triglycerides with olezarsen, it is a much larger patient population, as I said. But we would expect to be able to reach them with a field team about 150-200 or so folks. So we will be growing those field teams, but not to the large cardiovascular field teams as you might see in some of the other bigger companies. What that means is we anticipate our operating expenses to grow in the mid- to single-digit range for the next year or two.
And then as we bring these much larger indications to market, potentially growing a little bit more beyond that. But it's all going to be in line with the revenue opportunity we see ahead of us. And I think that's what's really important here. We're investing behind these launches and in line with the revenue opportunity. So we're very disciplined in how we're investing and how we're building our organization. And we're going to continue that discipline as we bring these drugs to market.
Absolutely. So turning to TTR, can you remind us how the CardioTransform study differs from a design perspective versus HELIOS-B and sort of how you think that could position you longer term in the market?
Sure. We recently saw positive phase 3 data from HELIOS-B, which was very encouraging to us because it demonstrated the real value of the silencer mechanism. That reads through to Wainua and cardiomyopathy in our view. Our CardioTransform study is more than 1,400 patients. It's the largest study in this patient population that's ever been conducted. We think that has significant benefits. One of the things that there were some gaps, frankly, in the data from HELIOS-B. We think having a much larger study, more than double the size of HELIOS-B, is going to give us the opportunity to potentially fill those gaps with data from our study. That data could be very important in the marketplace and could be a very significant differentiator. In addition, we're running a number of imaging studies that are sub-studies using MRI and scintigraphy.
And these sub-studies, I think, will also be very important in bringing forward data on how Wainua is potentially affecting cardiomyopathy in these patients. And so we think that could also be a very key differentiator in the marketplace.
Absolutely. And how should we think about the latest timing for your base case around when we will get the Phase 3 data?
Based on the data that we saw from HELIOS-B, top line data, and then followed by the ESC data, we think it's really important to take CardioTransform out to its conclusion of 140 weeks. That would put us in the second half of 2026 for data. We and AstraZeneca spent a great deal of time with the data that we saw, analyzing those data and thinking about the impact to Wainua and the CardioTransform study. We believe that this gives Wainua the very best opportunity to bring that differentiated data set to the market and to put Wainua in a position to really be the treatment of choice for these patients. This is a huge market opportunity, as you know, and growing.
We want to make sure that we're entering this market with the most robust data set we possibly can to ensure Wainua's success in the marketplace.
Absolutely. And what we saw from Alnylam prior to the readout of HELIOS-B was kind of a tweak to the SAP plan, particularly something that enabled them to look at the open label extension after sort of the primary treatment period. Is this something that you would be considering?
Well, right now, we've got the study is moving forward. And we're pleased with the study design that we have. And we will continue to do what we think is in the best interest of the drug.
Great. And something that's been pretty topical lately is the discussion of Part B versus D and the different reimbursement dynamics. I guess maybe first, just before I ask about some of these different dynamics, how much do you think reimbursement will matter? From a prescribing perspective, are physicians going to prescribe the drug that they think is best? Or are there going to be meaningful differences in how the drugs are covered that could affect prescribing?
I think what matters most for physicians and the patients, frankly, is going to be it's really the efficacy. First and foremost, it's the efficacy. Then safety. Then you've got an administration profile that I think is important to consider for these patients. I don't think that Part B versus Part D is going to make as big a difference as a lot of people are thinking it may. Part D is not going away.
And in fact, it's become much more patient-friendly, frankly, with the IRA. Starting in 2025, patients will be capped at their out-of-pocket at $2,000. And they'll have the ability to spread that out over the course of a full year if that works for them. So I think there's, and that $2,000, by the way, is across all of their medications. And so these patients are very sick.
They have a lot of different medications that they're on. So this will be very helpful for them to be able to manage the out-of-pocket costs for their medications, including Wainua, assuming that's to market. So I don't think that Part D versus Part B should be as big a driver as some will think. I think where Wainua actually has a real benefit, particularly as you think about cardiomyopathy, and we've seen it with the polyneuropathy launch, is the ability to self-administer wherever you happen to be.
We find that that is a very important benefit for these, not only for the patients, so that they can control their disease, they can have that sense of control over their life, but also for the physicians. It's a lot to stand up a practice where you're having to inject your patients with a really, it's a simple injection.
To be able to have the infrastructure in your office to administer that, to be able to bill that, to be able to purchase the drug, there's a lot that goes into it. We think that that is really a bigger driver than whether it's Part B or Part D, to be honest.
Yeah. It'll be interesting to see this play out, certainly unprecedented in a lot of ways.
I think, to think about this for cardiomyopathy, there's 300,000-500,000 patients and possibly more, and it's growing. You have to get out into the community physicians. You have to get out to these clinics that are in the community. It's going to be much more difficult for them to manage Part B drugs, frankly, than it is to be able to manage with their practices having to bring patients into the clinic. So I think the cardiomyopathy, the ability to self-inject, is going to be very important in cardiomyopathy.
Maybe we can talk about polyneuropathy and in its early days still, but some of the trends that you're seeing with Wainua.
We have been so pleased with the launch of Wainua in polyneuropathy. We launched in late January in the U.S. and have seen sequential quarterly growth. It's been really, really gratifying to see that. Q3 over Q2 was a 44% growth in product revenues. Patients are getting on drug. I can't give you a lot of data. We're not sharing a lot of data with our partner, AstraZeneca, as well. What we can say is the right physicians are treating. We're seeing a broad scope of physicians. Patients who are new to treatment, patients who are switching treatment, patients who are adding on to existing treatment are all getting on to Wainua. That's actually a really important consideration for us, that the right patients are getting on drug.
And we're seeing it not only in naïve to treatment patients, but also in switches and in add-ons, which is kind of interesting as well. We're seeing reimbursement happen very quickly. And that's gratifying to see. That means the physicians are treating the right patients. They're getting through to the payers. The payers are recognizing the value of Wainua. And all of that is going very, very smoothly. So we're encouraged. And we're looking forward to the EU approval here shortly. And we've been approved in a host of other countries outside the U.S. as well.
Add-ons, that's interesting. Can you tell us a little bit more about that?
What I can tell you is, as you can imagine, with tafamidis being approved for cardiomyopathy, it's really the only cardiomyopathy drug out there right now. These patients could have symptoms of cardiomyopathy and polyneuropathy. The mixed phenotype patient is really the most common patient. We know that to be the case. It's reasonable to expect that a patient could have cardiomyopathy symptoms and be on tafamidis and could be showing symptoms of polyneuropathy for which Wainua would be indicated. You can think about it from that perspective.
Interesting. Are you seeing this in the commercial and Medicare segment? Or is it skewing more towards commercial?
That's a good question. Actually, I don't have those data to be able to share. I'd have to get back to you on that one.
Okay. Sorry. I did put you on the spot on that.
No, that's okay.
Great. Well, turning to HAE, which you are also launching soon. It's a competitive market. Maybe can you walk us through sort of where you see your competitive edge in this space and where you see yourself fitting?
Sure. Yeah. We just got the acceptance letter from the FDA. So we have an August 21st PDUFA date, no ad com. And so we're moving, again, with a sense of urgency for our second launch. This will follow very closely after olezarsen and FCS later this year. And so donidalorsen is one of those drugs at Ionis that just kept raising its hand. It just kept demonstrating really strong data at every stage of development. In the phase 3, we had a very broad phase 3 program, by the way. We had the OASIS-HAE phase 3 study in which we saw very significant reductions in attacks for these patients. And then we also had the OASIS-Plus, which was an open-label extension and a switch cohort. And the switch data has been very, very important.
And what we've seen in our switch data is, excuse me, a very significant reduction of continued reduction of attacks. So these patients came into the switch study on a different prophylactic, switched over to donidalorsen, and saw further reductions in their attack rate, which was very encouraging. In addition, we surveyed these patients. And about 84% or so said that they would have preferred donidalorsen. So that was also very encouraging for us. So what we're anticipating with donidalorsen and where we think it fits very nicely into the treatment landscape is it's the only drug that combines very substantial efficacy on a monthly or bi-monthly treatment with really the ability to take a very convenient drug, easy to administer once monthly or once every other month, auto-inject or self-injected, and combining those two aspects.
Right now, you can either have efficacy and a drug that's very hard to take, or you can have a drug that's easier to take, not ideal, but easier, and really suboptimal efficacy. You can't have those two things together. We don't think patients should compromise. The ability to put those two things together, and our data clearly demonstrate that we can do that in donidalorsen, we think is going to shift that treatment paradigm for these patients. That's where our focus is. We think we're going to be able to really help these patients with their attack rates as well as with the convenience. We're going to be able to give them either monthly or every other month dosing, which is quite a shift from where they are today.
Yeah. Absolutely. And maybe just I'll open it up since I know there's a lot of pipeline programs that we could touch on. But maybe what are you most excited about?
That's a great question. I'm excited, and we are excited about our Angelman drug. This is a drug we're moving into phase 3. We should be initiating the phase 3 study in the first half of next year. We have gotten FDA agreement now on the phase 3 design. So we're really excited about that. And we're building off of compelling data that we shared actually at the ASF, the Angelman Syndrome Foundation meeting in July that showed that our drug, it's called ION582 right now, was really having a meaningful impact across a host of various different domains for these patients.
And so we're excited to be moving this into phase 3. Our phase 3 is actually going to be about 200 adult and children Angelman patients. It will include patients with mutations or deletions. So we're going to have a very broad phase 3 program.
We think that's going to be important. It's going to represent the Angelman community in the patient population in our phase 3 study, so that's important. It's also going to be placebo-controlled, and we think that's really important. Placebo-controlled studies are the gold standard for demonstrating efficacy and safety, and the ability to conduct a placebo-controlled study with an intrathecally administered drug, I think, speaks to the safety of our overall neurology platform. We've obviously brought Spinraza to the market. That is a multi-billion dollar drug.
We've brought other drugs forward. We've got a very deep mid and late-stage neurology pipeline, and so we're excited to be bringing this forward. The study will be about 12 months of treatment, and as I said, we're looking forward to getting it underway in the first half of next year and hopefully bringing this drug ourselves to patients.
Yeah. Absolutely. And speaking of the neurology franchise, you have a lot of other interesting programs across tau, Alexander, maybe just with one minute left, a quick overview of those and specifically the timelines there.
Yeah. So our Alexander disease drug is in phase 3 development. And we're expecting data next year from that. So that will be one of those four potential launches in the next three years. It's a small patient population, but one that's in desperate need of a treatment. So we're hopeful for that. Our tau drug is in phase 2 development with Biogen. They recently reduced the size of the phase 2 study because of the data they saw coming out of the phase 1/2 study that showed that they didn't need to power it as large as they had. So that is now fully enrolled. And we're looking forward to data from that here in the not-too-distant future. And then beyond that, we have three new neurology drugs that we have brought into development this year, moving into phase 1 development.
Overall, we have, I think, about 12 drugs in the clinic in neurology. That is a key focus for the company alongside cardiology.
And one last quick one, if I may. How are you thinking about what proportion of these assets going forward you want to keep to yourself versus potential partnerships?
We are focused on our wholly owned pipeline. Absolutely. This is where our focus is. This has been a five-year journey to get us to this point, and we are really excited about the potential value that's in the wholly owned pipeline right now and what's in research coming forward that can continue to fuel that wholly owned pipeline well into the future, so we think with multi-billion-dollar revenue opportunity in our wholly owned pipeline in the late stages now and what could be coming behind that, we're really set up for a very exciting period of growth for the company and value creation, frankly.
Great. Well, exciting times. And thank you so much for joining us.
Thank you for having me. Appreciate it.
Yeah. We appreciate it.