Conference Transcript - IONS 2026-05-12

Jason Gerberi, Analyst — BofA Securities

All right, everybody, we're going to get going with our next company presenter at the B of A Annual Healthcare Conference. My name is Jason Gerber. I cover biotech and pharma, and pleased to be introducing Ionis Pharmaceuticals and Brent Monia, CEO. So, Brent, thanks so much for joining us. Thanks, Jason. It's great to be here. So the conversation, I think, is not surprisingly going to start with just the commercial opportunity for Olazarsin in SHTG. and you've got an important FDA action date coming up here, June 30th. So maybe just talk about how you're positioning for your first major launch. As a company, commercially you've launched this drug, Tringolza, for an ultra-orphan indication, but now you're migrating to the big leagues with a very big market, a more complicated, probably end market, I would imagine. And so maybe just level set in terms of how Ionis is getting ready for kind of a transformational event for you as a company.

Brett Monia, CEO

Yeah, sure. Let me begin with FCS, though, because that's the current indication for tringolza, patients with a genetic cause of severely elevated triglycerides. The commercial launch for tringolza has been very, very strong, very positive. And, you know, the HCP demand or patient demand for patients that have FCS has been very, very strong and continues to get stronger and stronger week by week. That's been driven by the overall therapeutic profile of the medicine as well as the sentiment from both patients as well as HCPs who are managing these patients. These patients are feeling really good. They're seeing their triglycerides plummet, many of them well into the normal range, and they're seeing a prevention of acute pancreatitis, which, of course, they live in fear of all the time. That launch will continue through the expected SHTG launch that you referred to in June 30th, a PDUFA day June 30th, with priority review and breakthrough therapy designation. You know, we reported phase three data for SHTG last year that was just groundbreaking, with an 85% reduction in acute pancreatitis and triglyceride reductions on top of standard of care that exceeded 70%, really, really groundbreaking results. And we're leveraging that data. We've leveraged that data to get priority review. This is a multibillion-dollar product opportunity for Iona. It's a wholly-owned program, and it puts us into prevalent diseases for wholly-owned programs and launches, as you referred to. We are well-prepared to launch into this multibillion-dollar product opportunity. We have hired and trained our field team. They've been out in the field educating on severe hypertraglyceridemia for cardiologists and the chronologists, lipid specialists, but they've also been identifying accounts, physicians who are managing these patients with high numbers, high volumes of patients that are being handled by these physicians. So we're targeting these patients. We're identifying the high prescribers, and we're going to be ready to launch in June, assuming an on-time approval on June 30th.

Jason Gerberi, Analyst — BofA Securities

So when we think about the key learnings from the FCS launch and how they're applicable to SHTG, I recall when you were initially launching FCS, there was a lot of discussion we had about patient finding, right, genetic component to the disease. Here, when we think about something much more broad, right, Those early adopters of Tringolza for FCS, how important are they to SHTG early adoption? And maybe just talking about how much broader you need to reach now with the SHTG indication once that's received.

Brett Monia, CEO

Well, it's very important because the physicians who manage FCS patients are also managing SHTG patients, and we build tremendously positive sentiment in that community because they see the efficacy and the excellent safety, the tolerability that Tringolza is offering. And what we're hearing from those physicians is, this is great for my FCS patient. I've identified more FCS patients. I want to put them on Tringolza. When can I get access to Tringolza for my severe hypertriglyceridemia patients, which, of course, on a volume basis, they're seeing many more of there. So launching from FCS to SHCG has provided a big advantage for us. And, of course, you know, we were first to market in FCS. We're going to be well ahead of any competition first to market in SHCG, which is going to be really important.

Jason Gerberi, Analyst — BofA Securities

Okay. You know, in third quarter, there will be some competitor data for another APOC3 modulating agent. You know, and you'll have about a one-year head start to the competition. and I'm just kind of curious how you view the competitive dynamic, right? Like, is one-year first-mover advantage material or ultimately, hey, this is a big market, two players, more than enough to support two players, and it may actually be advantageous to have two companies out there investing in and building out this market opportunity?

Brett Monia, CEO

In the United States alone, there's more than 3 million people with severe hypertriglyceridemia. about 400,000 of those patients today are being treated ineffectively, really, with generic vibrates and fish oils. So this is a growth market. This is an untapped market, a market with high medical need, and there's room for multiple players, and more players in this space that deliver effective medicines will only grow that market out even further. With that said, we're really thrilled, and we believe it's a big advantage to be first to market, because it allows us to identify those high-volume treaters and get to those high-volume treaters, those treaters who are treating the patients that are at the highest risk for acute pancreatitis or cardiovascular disease, which will be the priority to get those patients in as quickly as possible. So we're going to access to those patients more rapidly and secure those patients. As I said, the experience which involves an FCS has been wildly positive, so we're expecting that sentiment to translate to SHTG. Patients will stay on drug and will continue to accelerate that by really over a year advantage to market. In addition, it allows us to set up accounts with payers and build the relationship with payers, set price, which we did, our WAC price for SHTG. So, you know, there are lots of different advantages that we're taking full advantage of as a first to market for SHTG.

Jason Gerberi, Analyst — BofA Securities

So these drugs are effectively being positioned as pancreatitis sparing drugs, right, ultimately from the core study results. And so as you think about these individuals who've had past events, right, I would imagine they are that initial first adopter, right, of the therapy, most highly motivated. Is that your sense? Are these the patients, is your feedback from physicians, KOLs, that these are the types of patients who might be more asking about when a therapy like this can become available? Are they because of these past events perhaps under the care of a specialist who might be aware of clinical stage data as opposed to maybe more of a community-based doctor?

Brett Monia, CEO

Our out-of-the-gate focus will be on the high-risk patient population. One segment of that high-risk patient population are patients that have a history of acute pancreatitis. The other segment of that population is patients that have triglycerides, 880 milligrams per deciliter and above. They're at high risk for their first-time AP event if they haven't had one yet. The motivation by patients that have had an AP event in their past is extremely, extremely high, as it is HCPs, of course, because there's nothing they can do for patients that come to an ICU with an AP event. It's incredibly painful. Patients don't want a second event. So they are highly motivated. However, HCPs that are managing patients with triglycerides 880 and above, whether they've had an AP event in the past or not, are also highly motivated because they want to prevent that first AP attack from happening. Once you've had one AP attack, the chances of having additional attacks goes up exponentially, leading to organ dysfunction and destruction. So HCPs are highly motivated whether or not they have had a history of AP or not, but certainly patients that have had AP, they don't want another one. All right, great.

Jason Gerberi, Analyst — BofA Securities

Maybe just help reconcile. You revised the pricing in advance of the SHTG launch for pricing to be more in line with a broader market opportunity that is SHTG. you know i guess just trying to understand that versus some comments recently about you know wanting to wait payers wanting to wait until they see a final label to have more meaningful discussions is that just mechanical right like payers just need to fundamentally have a label or are there specific label outcomes yeah that that you feel like are going to drive you know access relatively a pa to label uh like a pa that matches study entry criteria Because if that were the case, that would suggest broad access, I would argue.

Brett Monia, CEO

So let me start with the $40,000 WAC price that we announced for SHTG that went into effect on April 1st, how we got there. That price was the product of a year and a half, maybe even two years of research with payers and HCPs. We first had to, once we had the phase three data, to understand which HCPs are going to prescribe tringolza to which SHTG with what priority, based on the phase three results. As I mentioned, the phase three results were groundbreaking. We then took that HCP demand research to payers to understand where their limits would be with respect to putting in place blocks, NDC blocks or other blocks that would delay access for patients due to price being too high. We believe that we've threaded the needle perfectly to maximize access and to maximize value with a $40,000 WAC price. The conversations, the discussions we've had with payers has been deep, intense, very positive, very productive. We are aligned on the $40,000 WAC price. We do not believe the label is going to impact access in any way. We kind of know what the label is, and that's what we presented to payers. We received breakthrough therapy designation, which basically gets translated to the ultimate indication statement, which is patients with SHTG as defined by triglycerides 500 and above as an adjunct to diet, and that's the label we expect. We do expect acute pancreatitis to be in the label, probably in the clinical trial section, because the results were so statistically significant and was a pre-specified secondary endpoint, and it's important to have it in there. With that said, we don't think that that's going to drive adoption because everyone's aware of the AP data already through publications and presentations, and certainly the payers are aware of it, and that has resonated extremely well with them to prevent ICU hospitalizations, prevent potential fatal outcomes, and so on, so. Paired discussions are going really well.

Jason Gerberi, Analyst — BofA Securities

Is there not a point to be made, you know, the omission of the language that is in some triglyceride lowering therapies, you know, front page that say this drug has not been studied for pancreatitis reduction, whereas you've now studied it, I imagine that label language will be deleted from a Tringles label per SHCG, is that right? And can sales reps not sort of allude to the fact that that label language is now omitted?

Brett Monia, CEO

Yeah, absolutely. We do not expect, obviously, it was studied for AP outcome, and it was highly successful. So it will, that statement will not exist in the label. In fact, we'll have AP data we expect to have in the clinical trial section of the study. The other point I think might be worth mentioning is guidance of clinical trial or clinical treatment for FCS and SHTG. the guidelines. Tringolza is indicated in the guidelines for FCS, and we expect that tringolza will be in the guidelines for SHTG pretty quickly after approval as well. These guidelines were adjusted very quickly, and tringolza was singled out as a treatment for FCS, and we think the same thing will happen for SHTG.

Jason Gerberi, Analyst — BofA Securities

That recommendation presumably will be tied to the pancreatitis outcome benefit. I know there's some theoretical possibility, right, that in, like, a comorbid diabetic patient, lowering trigs might actually have cardiovascular benefit, but that hasn't been studied. I doubt it will ever be studied. But if you can speak to how you'd envision guidelines and recommendations evolving within the launch of the product.

Brett Monia, CEO

I think the guidelines will be focused on the triglycerides. If patients are above 500, They need an APOC3 inhibitor, and tringolza will be the first one out there by a long shot to be the treatment to manage SHTG. It will not be in the guidelines for managing cardiovascular outcome because we didn't study that outcome, as you pointed out. With that said, although the high-risk patient population that we're focused on is primarily patients that are above A80 and or have a history of acute pancreatitis, There are a lot of patients that have triglycerides well above 500 that have cardiovascular disease. And those are the other comorbidities that round out the million-plus high-risk patient population. Cardiologists recognize that having triglycerides that high disposes them to cardiovascular risk, and they're going to want to get those triglycerides down to the normal range, which we achieved more than 80% of the time in our SHTG phase 3 trial. So we do believe that that's going to be an added benefit for the sentiment towards prescribing tringolza is also those patients that have a history of cardiovascular disease because it's recognized that this is a contributor to cardiovascular disease.

Jason Gerberi, Analyst — BofA Securities

Okay. And then just circling back to price, I believe both you and your competitor have declined to speak specifically about kind of what gross to nets would look like over time. But can you just maybe remind us about payer mix? Because I imagine with the government plan patient, there will be some mandatory, you know, rebating that needs to be offered. And I would imagine, like, rare orphan comps and maybe even oncology drugs might be a good proxy for maybe the spread between gross and net. So any high-level commentary that you can offer?

Brett Monia, CEO

I mean, what we can say is that, you know, when we first discussed the market opportunity in the U.S. for Tringolz and SHTG in January of this year, we assumed the net price that we announced of $10,000 to $20,000. We were still doing our market research, so we had a lot more work to do, a lot more payer research to do. That was the net price that was in the U.S. As we developed our HCP demand research and then had our payer engagement research completed, we settled on the $40,000 WAC price. That's going to bring us in meaningfully higher than our original net price, which is the main driver behind our upgrading our peak product sales in the United States to be beyond $3 billion. We upgraded it from $2 billion to above $3 billion, and that's because our net price will be higher. in that 10 to 20K range. Other than that, we're really not going into more detail about net pricing and rebating at this time.

Jason Gerberi, Analyst — BofA Securities

And maybe a few questions just on safety. Olizarsin safety looks pretty pristine. Do you think this is going to be an easy drug to administer? You know, monitoring requirements can sometimes be at a layer of complexity for drugs. Do you think this will be a drug that has many safety monitoring requirements tied to it in the SHTG setting?

Brett Monia, CEO

Yeah, no. I mean, first of all, FCS has no monitoring. It's a clean drug, and no monitoring was required. That's one of the reasons why the launch has gone so well in FCS. And we don't expect monitoring in SHCG. Why would we? It's a very clean profile, extremely clean profile, and we don't see the need for monitoring at all. And right now, all of our discussions with the FDA have been going very smoothly, and that supports that conclusion.

Jason Gerberi, Analyst — BofA Securities

Yeah, because what I wondered is there's obviously going to be blood work done to determine patients' triglyceride level at baseline. I imagine they may look at something like liver fat at baseline and whether or not there might be any sort of requirement to follow and look at how both of those clinical measures are over time. It could presumably be done in the same measurement.

Brett Monia, CEO

We don't expect hepatic fat fraction to be measured at all in the real-world setting on the market at baseline or any other time. let me level set here a little bit so in our phase 3 study we reported a small increase in liver fat in patients with SHCG that was dose dependent it was small but most importantly there was no clinical sequelae, no clinical outcome, no adverse events, reactions related to that so there's nothing to monitor, there's no correlation with ALTs MRI imaging of a lab observation that has no clinical consequences is just not something that would be required. It's just an observation. It's also an on-target effect, Jason. We know this from a competitor program that has a silencer that reported in phase two, a dose-dependent increase in liver fat, and it makes complete sense. What we're working through using the APOC3 mechanism of action are two pathways that are substantially and rapidly lowering triglycerides out of the circulation. One is to break down the VLDL particle, the triglycerides, into fatty acids. The second is to clear it through the liver very rapidly. And the liver does a very good job of clearing out the fat that's being shunted through. But there was some residual liver fat that we saw at the 12-month time point in the phase 3 study. What I can tell you, though, is that we continue to monitor these patients that are in the open-label extension, And we're seeing, as expected, that the liver continues to compensate and clear out the liver triglycerides. We're seeing a return to baseline at one year, which further continues to get to baseline at two years. And we're going to report that data at a medical congress later this year. So we don't expect any monitoring.

Jason Gerberi, Analyst — BofA Securities

Is it crazy to think, I think, with the way liver fat went down, it was not GAUNAC-mediated ASO, that this is just noise?

Brett Monia, CEO

I don't think it's noise. I think whey-livera is a very different class of molecules. As you mentioned, whey-livera, which was a first-generation non-Galnac molecule, was not directed precisely and exclusively to the liver. It was also used at a very high dose, a dose that's 15-fold higher than what we use for tringols. That's because it's not a Galnac. The way liver is probably affecting APOC3 in other tissue beds, including the GI tract, which if you inhibit APOC3 in the GI tract, you will block chylomicron absorption and other aspects of triglyceride metabolism. So we think that it's a different animal entirely in that it's broadly distributed, whereas tringolz is distributed precisely to the hepatocyte, and that's where we're getting our effect.

Jason Gerberi, Analyst — BofA Securities

Okay, and then lastly, just the status of your semi-annual APOC3 modulating therapy, when could we get an update on next steps, and how quickly could something like that move through development?

Brett Monia, CEO

Quickly. It's a high priority for us, and it's focused entirely on less frequent dosing, semi-annual dosing or once-per-year dosing, And that conclusion is supported by the phase one data that we reported last year in patients with mildly elevated triglycerides, where following cessation of dosing, we're seeing a lasting lowering of triglycerides in APOC3 that's approaching a year in duration with very, very high potency. We're going to start the phase two study in SHTG patients very soon, and we expect to wrap that study up pretty quickly, and we're already discussing next steps to initiate phase redevelopment. So we're moving that forward rapidly. It's an entire, the focus is entirely on less frequent dosing. It's going to be hard to match, you know, to exceed the data that we've already generated in SHTG for Tringolza. So it's really less frequent dosing.

Jason Gerberi, Analyst — BofA Securities

Maybe shifting gears to Don's era in the HAE launch, this one is exceeding our expectations so far in the early goings. I know you guys have been firm that, you know, you think this is an underappreciated therapy and a big value add to the HAE setting. So maybe early observations in the launch, anything exceeding your expectations. I know this is largely a switch market as you frame it, and so I imagine the early adoption is primarily coming from switches. So anything you can say to help us better understand what's going on in the early days there?

Brett Monia, CEO

Yeah, the demand by patients and HCPs has been very high for Donzera as a prophylactic treatment for HAE. As you know, there are several other products already on the market for HAE prophylaxis, so this is a switch market, unlike Tringolza, where we're first to market. And the launch execution has gone exceptionally well. We're very pleased with the demand. We have a free drug program to get patients on top of Donzera as quickly as possible. It's about a month of free drug, and then that allows them to get the experience, and then they're moving over to commercial very rapidly. So we're really, really thrilled with execution on free drug as well as on commercial drug. But we're thrilled about the demand for the drug and the compliance. Patients are staying on drug, reporting very, very positive experiences. What has really been a surprise to us has been how much the mechanism of action has really resonated with HCPs. They're so used to antibodies and small molecules, been treating these patients for their whole careers. Something new. We're targeting RNA for the first time, something different. And, of course, the profile has supported that as well. It's a switch market. We're seeing switches from all other available prophylactic treatments today. The majority, of course, are Takeda, Texero, because that's the majority of patients that are being managed today is on that medicine. But we're seeing switches from all the other prophylactics. We're seeing switches from on-demand treatment. And we're also seeing newly diagnosed patients coming on to Donzera. So we're really pleased with the launch. It's going to be a big year for Donzera.

Jason Gerberi, Analyst — BofA Securities

And you mentioned the free trial program. What does the conversion rate look like once you're in that program? And do you have a line of sight? Is there a big queue of patients that are entering into the free drug program?

Brett Monia, CEO

It's very high, the conversion. We haven't reported the specific numbers. We're not going to do that right now. It's competitive, but it's very, very high. And that's because the patients are getting great experiences with Donzera on treatment.

Jason Gerberi, Analyst — BofA Securities

Maybe we've got five minutes, so we'll do some quick hitters here. But we know it makes timely, given you published baseline demographics, I think, over the weekend. How would you kind of level set investors now that we have that data out there, key differences, your trial versus Helios B, and what that either portends in terms of added risk or opportunity, a lot of focus on the TAF combination data sets, right, to sort of be incremental for the silencer class.

Brett Monia, CEO

Well, first of all, as by far the largest study ever conducted in ATTR cardiomyopathy, we're very well powered for a positive outcome. The first silencer that was approved for ATTR cardiomyopathy just greatly supports the likelihood for a highly positive outcome because we're getting TTR lowering as good, if not better, excellent drug profile, and our study is more than double the size of any study that's ever been conducted in this patient population to date. So we're very well powered for the primary endpoint. The baseline demographics that we reported this weekend, really not a whole lot of surprises. is there are more similarities between our program and the Helios B study than there are differences. As we've signaled to well in advance, the demographics continues to shift in ATTR cardiomyopathy. We've been saying that we're going to have more patients on baseline tefamitis that we're going to be adding on to in our study, and that's what we reported, about a 56% at baseline patients on tefamitis, not that much more than Helios B, but more. We also have a higher percentage of patients with New York Health Class III, a higher percentage of patients that are hereditary, which are more rapidly progressors. None of that puts the primary outcome at any risk because our study is so large. It's so well-powered. We actually think it's a real-world setting that's going to generate data that is going to resonate really well with cardiologists who manage these patients because those are the demographics that these physicians are managing today. Patients are on tefamidase. They want to know they're not doing well. They're progressing. What evidence do you have that combination is going to actually provide further benefit? And, you know, our secondary endpoints were laid out, and we're going to have a very sizable subgroup in combination usage that we're going to be able to report on. So if there is a complementary mechanism between a silencer or a stabilizer that stabilizes 50% to 70% and then knocking down the rest with a silencer, we're going to have the data that convince HCPs that combination usage is the way to go.

Jason Gerberi, Analyst — BofA Securities

And if you generate that data, can you talk about that as like a Ionis Astra company-specific benefit that could allow you to swing the competitive pendulum and potentially fulfill the bull case on? I think Eplon-Tursin, and you'd be the only company I think that could promote this data and presumably gets at least into clinical section 14 of the label.

Brett Monia, CEO

That's correct because it is a pre-specified secondary endpoint. We elevated it to that. It's upside. It's significant upside. Our base case, AstraZeneca has reported this as well, is $5 billion product opportunity for WANUA, assuming we replicate the other silencer that has come out, that data. We're well positioned to do that. Additional data that is favorable, including combination usage, is a key differentiator and is key revenue upside for the program. So that'll be a very significant upside.

Jason Gerberi, Analyst — BofA Securities

And where do you expect, you know, given some of the recent announcement on the pre-filled syringe for Part B, where this market's going to go, right, for you? Do you think it's going to be more of a Part D drug, more of a Part B, as in boy drug?

Brett Monia, CEO

So let me first start by saying that the ability to self-administer WENUA by patients themselves once per month has resonated incredibly well in the polyneuropathy launch and will be magnified many, many-fold exponentially in the much larger cardiomyopathy indication. The ability to self-administer is a big, big differentiator. With that said, AstraZeneca felt that flexibility, optionality would be very nice to have. for those centers of excellence that do buy and bill. So they pushed forward a pre-filled syringe that would be administered by a physician as a Part B approach for using a buy and bill strategy. It's really just optionality that they can have. The primary driver for WENUA going forward will be the advantage we have with self-administration using a simple once-per-month injection that's room temperature stable, can be carried around, taken on vacation, and so on. That'll still be the main driver.

Jason Gerberi, Analyst — BofA Securities

Maybe a two-word answer. What are you most excited about between Tau, LP, little a, and Angelman's?

Brett Monia, CEO

All of them. Pella Carson is a big deal. We're looking forward to the data the second half of this year. We're looking forward to the Tau data mid-year this year. What we're hoping to see is data that supports moving to Phase III development as the first tau-lowering drug ever in history, another first potentially for Ionis. And we love the AngelLens program, but it's a little bit further out. We're expecting a complete enrollment second half of this year and then to get the phase three data next year for that program. So I'll leave it there. We're excited about all three of them. Well, thank you. With that, we're out of time. Thanks, Jason. It was a pleasure.