Ionis Pharmaceuticals Inc (IONS) September 2026 Conference Transcript

Okay. Thanks everyone for being here. My name is Yanan Zhu. I'm one of the biotech analysts here at Wells Fargo. It is my great pleasure to be joined by Brett Monia, CEO of Ionis Pharmaceuticals. Thank you, Brett, for being here. Thank you, Yanan. Good morning, everybody. It's great to be here. I was wondering if you can start us off with the overview of the company and then we can jump into questions.

Sure. Happy to. I'll be brief, though, because I know you have a lot of questions, Jan, and we want to get to those. But as expected, this has been a highly eventful year for IONIS. We've had several really important positive strategic outcomes this year, and we've also had some disappointments. Not surprising. When you're consistently seeking to deliver breakthrough treatments in therapeutic areas, new therapeutic areas, sometimes you have disappointments. But I really do want to emphasize the incredible success we've had this year already. We've had two FDA approvals, both in areas where there is high unmet need and were first. Tringolza for severe hypertriglyceridemia, Zambastro for Alexander disease, both wholly owned products. And we're anticipating a third FDA approval by our partner, GSK, later this year in chronic HBV, again, another breakthrough producing unprecedented clinical functional cure rates in patients with chronic HBV. We've had three phase three readouts this year, and we are on track for two more. And the pipeline, in addition, continues to deliver and go very well. We initiated a phase 2 study for ion 775 and severe hypertriglyceridemia that supports twice or once a year dosing. As a follow-on to Tringolza, we started a phase 2 study in Dravet syndrome using a very important new chemistry that we've created that supports potentially once per year dosing, twice a year or once a year dosing. And I can go on, but maybe we should just open it up for questions. But it truly has been a strategically successful year so far.

Right, right. It's been a very eventful year for sure. I actually wanted to start with Andrewman syndrome, one that you didn't have any update. But I think a lateral update from ultragenic programs has caused some investors to react. I don't know if you can touch on when you saw that result, were you surprised and anything that you think investors should or should not read through to your program?

Yeah, so sad for the Angel Wins community. We really feel for them. This is a community that has been in desperate need for a treatment. They've been disappointed many times with unsuccessful clinical readouts. With that said, we see zero read-through to our program. You know, prior to the readout from the program that you just referred to, we've been signaling to the investor community and to anybody that will listen to us for well over a year that although we were hopeful that the study would show signs of success, we were not very optimistic that it would be successful for several reasons, but most notably, Yanin, is the fact that despite the fact that their molecule and our molecule are using similar mechanisms of action, a mechanism of action that we actually pioneered and published on for the first time, and they have similar potencies based on a whole host of data that we've generated, they were dosing substantially lower than us. And that's because that they ran into toxicity issues in the clinic and pre-clinically that forced them to be capped their dose to be capped substantially lower dose and we were concerned that they were under dosing we do believe that that was the culprit in their study at the end of the day our program of course rides the heels of a proven platform in CNS diseases let's not lose let's not forget that Ionis is the only company that has delivered organ nucleotide successes that have been FDA approvals in the clinic to date, proven platform that has delivered Spinraza, Zanvastro now, CalSati, and proof of concept even in Alzheimer's disease with our tau program. So we're dosing at the maximum dose that we think at the maximum dose we set out to dose at and we think that we've max out, we will max out on efficacy when our study reads out next year. We fully enrolled this year, this study, and we're looking forward to data in the second half of next year.

Got it, got it. Thank you, that's very, very helpful. Let's touch on LPA. So this is a very surprising result. It's a very, it's a good target with a lot of backing from human genetics. When this data read out from Novartis, your partner, can you share your thoughts on what might be the cause for the study to not turn up a positive result and what does this mean for the program and perhaps also for the LPA field?

Yeah, so this is another first for Ionis Discovered Medicine to test the LP little a hypothesis, if you will. That is to address an independent risk factor that's been strongly associated with cardiovascular disease. High levels of LP little a are strongly associated with cardiovascular disease. So we set out to determine whether or not it could be modifiable with a pharmacological intervention, in pellicarsin, by lowering pellicarsin to normal levels. And that's what we did in this study. We got substantial lowering of LP little a that were similar to what we reported in our phase two study on the order of 75% to 80% reductions in LP little a. We saw good safety in the study, and those reductions in LP little a really normalized a lot of patients. unfortunately it didn't result in a successful outcome on mace a four-point mace endpoint and the study was what did not achieve statistical significance in the primary endpoint it also didn't see achieve benefit demonstrate benefit in this subgroup of patients that were at higher risk in the study so it's unfortunate the drug did what it was supposed to do with respect to lowering LP little a with good safety but it may implicate LP little a as an independent risk factor but one that may be unmodifiable at least in this patient population that all other risk factors are well controlled LDL hypertension are very well controlled and and as a secondary prevention maybe it's just not modifiable we'll see we don't see a path forward for Pella Carson Novartis is going to be presenting the full phase 3 data at a Medical Congress as soon as they can so maybe later this year so stay tuned for that but unfortunately we

don't see a path forward for Pella Carson got it yeah thanks for those thoughts let's touch on another recent development cardio transform so I know you and I'm sure everyone in the field has hoped for the combination to produce even a greater efficacy than silencer or stabilizer alone however the result did not point that way so could you you know help us understand the result in a combo part of the study and also help us understand what you know the the past or

the next steps for the program yeah so I really want to highlight that we had three presentations related to Eplon-Tursin and ATTR cardiomyopathy at ESC last week, all high-quality presentations in large forms at the meeting. The overall study outcome and then the focus on the subgroup in combination with tefamidus, if you will, or stabilizers. The study did not hit its primary endpoint in the composite of cardiovascular mortality and events serious CV events in the overall population however in patients that were not on stabilizer at baseline we call this the monotherapy group we saw remarkable efficacy we saw efficacy that's similar to the only other silencer that's on the market today with respect to a risk reduction of nearly 30 percent risk reduction we saw TTR reductions that were as good as anything that's been out there today around 80% TTR reductions all good safety in the phase three study so the monotherapy worked very well but unfortunately there was no added benefit in combination with stabilizers we had more than 50% of patients down on stabilizer at baseline and then that that the involvement of Tefaminis, or stabilizer in the study, grew as the study continued with lots of drop-ins as tefaminis became the standard of care, not only in the United States, but in Europe and elsewhere. That would have been fine had there been added benefit on top of the stabilizer, but unfortunately there was none. That was not only the conclusion of IONIS at AstraZeneca, that was the conclusion of an independent academic group that presented a meta-analysis at ESC last week when they said there's no added benefit in any studies conducted to date in combination of a silencer with a stabilizer, including this one and other ones that have come out. Recently, that is one reason that the study didn't hit its primary endpoint. the second reason is that tefaminis actually performed pretty well in this study remember patients are being diagnosed much earlier in disease today unlike the phase 3 study for tefaminis in a tract 10 years ago where patients were being diagnosed with late-stage disease and we're assuming it was difficult to impact their disease course patients are being diagnosed much earlier today the stabilizers actually performed very well as monotherapy and And we just couldn't add to the benefit that The Feminist was achieving in our study. But the study was executed very well. The monotherapy group performed exceptionally well. And AstraZeneca is weighing their options. They haven't made any definitive decisions. We're helping them, of course, in any preparations and discussions with Path Forward. but I would hold off and wait to hear from AstraZeneca later this year on whether there is a path forward as a monotherapy for Eplon-Turcin in ATTR cardiomyopathy. I do want to say that in polyneuropathy the launch continues and the drug is very effective and patient uptake continues to be relatively be strong and it's a good drug unfortunately the study design caused it not to be successful in the overall population great great so I was wondering of course it's all pending the decision-making by your partner and you on the path forward I was wondering you know in that process could you walk us

through the justifications, perhaps, arguing for next steps for the monotherapy, and also perhaps if that path worked, what is the use setting, use case for monotherapy?

Great question. My personal opinion, I think there's significant justification to bring eplontersin to ATTR cardiomyopathy patients because patients deserve options. Today, there's two stabilizers and there's one silencer. patients deserve other options and eplontersin offers differentiates from the other silencer that's on the market in several ways most notably it can be administered by the patient themselves doesn't have to but you know self administration using a simple auto injector doesn't rely on being administration by a healthcare provider we think that that's important for patients as a choice but the bar is high I mean let's not fool ourselves here FDA generally does not accept submissions with with failed primary endpoints and studies but you're asking in my opinion I think patients deserve choices I see no reason why silencer cannot be used as first-line treatment it's it's it's it's the combination that we and experts that were it was highlighted at ESC last week there's probably no path forward for combination usage of a stabilizer and a silencer let's not lose sight of the fact that we're targeting the same pathway with a silencer and a stabilizer right we're targeting ttr whether we stabilize it or we knock it down we silence it uh we maxed out um but i see silencers they can be used as frontline therapy absolutely the risk reductions was as good as stabilizer just there was no added benefit on top or you can use a stabilizer as frontline and some physicians you it's gonna be on patient preference or do they want an injection once every month or a few months so or do they want to take a pill a couple times a day it's really gonna come down to preference I think but there's no reason why it can't be used as frontline or or or second line treatment I also want to add Yanin that this is a big market and there is room for multiple players first line second line you know in and we don't really know what the ceiling is for ATT or cardiomyopathy it's a big big market opportunity great great let's talk about tringosa in severe hypertrachrystidemia you have a launch

going on this is the first quarter for this indication only started a couple of months ago but I hope you could you I'm wondering if you could share with us what have you been seeing regarding the launch momentum I guess some focus could be patient demand which patient population are being prescribed the drug currently any insurance hurdles and any pushback on the liver fat finding yeah sure so as I mentioned in my opening comments we've had several very important strategic successes at Ionis this year and the FDA approval of

Tringolza for severe hypertriglyceridemia was an enormous breakthrough in this massive patient population in the US three million people plus are being treated with SHTG or have SHTG many of whom are being treated but the treatments are inadequate their fibrates or fish oils or statins which barely lower triglycerides at all, unlike tringolza, which shows 70, 80 percent reductions in triglycerides on top of those medicines. And the FDA approval included a reduction, a highly statistically significant and really powerful reduction in acute pancreatitis events, the outcome that is most significant for people with severe hypertriglyceridemia in the indication statement, even though AP, acute pancreatitis was a secondary endpoint and the approval was six days early so we're very pleased with with this is breakthrough treatment wholly owned medicine that we launched within a few days after after the approval we're pleased with the momentum of the launch to date in the US we were we received we put we had drug channel within a day we had scripts received a day of approval and and the momentum is is good we're seeing lots of cardio we're seeing prescriptions coming from cardiologists endocrinologists lipid specialists and not surprisingly as we expected they are prioritizing those patients with the highest risk let me remind everybody that the label is for is the definition of SHCG it's for for people with severe hyper triglyceridemia as an adjunct of diet and exercise which is defined as triglycerides 500 milligrams per deciliter and above with with as a treatment to reduce risk of acute pancreatitis that's the label but But as we expected, physicians are prioritizing those patients that are at the highest risk to come into gergulza. Those are patients with a history of acute pancreatitis. Those are patients with triglycerides that are so high, 880 or above, that they're at a very high risk of acute pancreatitis, whether or not they've had an event or not in the And that's what we're seeing come in primarily from the physicians. Payer discussions are going quite well. We're very pleased. You know, we did a lot of payer research prior to setting price, as we went from a rare indication, FCS, to a prevalent indication, SHTG. And we've had many productive discussions with payers since then as well. And we're pleased that payers are not pushing back on covering to label, Not just the high-risk patients or anything like that. It's paid to the label, 500 milligrams per deciliter and above. But with that said, physicians, rightfully so, are prioritizing those high-risk patients. And, you know, we're expecting a steady launch. Physicians, you know, need to be educated on the label. They need to be educated on the dose options that we have approved. Some of them might like to bring their patient in to do a triglyceride measurement prior to prescribing or getting their patient on drug, and then just the normal operations that are happening in a launch in a highly prevalent disease with very busy doctors. But we're pleased with the enthusiasm, the sentiment, the need that we're hearing for for Tringolza, for SHTG, and we're pleased with the momentum that we've built so far.

Great. You know, definitely looking forward to quarterly updates for continued momentum on that launch. I was wondering, you know, how reliable are the third-party vendors that capture prescriptions this is the specialty pharmacy situation so it's not always reliable but you know we see some increases in scripts in through those third-party channels can we use that kind of to triangulate and trying to predict sales no I we advise against that we've been advising against it because we believe that the symphony IQ via data is is inaccurate and we would recommend against that we block our data we have several different specialty farm pharmacies you

know not just one so several and the data is unreliable so we've been advising against using that data but I want to emphasize that we're pleased with the momentum that that we've created for the launch to date. I see.

You do have a four-year guidance for the Tringolza sales for the four-year. Are you comfortable with the guidance?

We're very pleased. Like I said, we're very pleased with the launch. I could just only reiterate what I just said, is that the launch has gone according to plan. We're on track. We're seeing tremendous enthusiasm for tringolza. We do have a quick start program. I want to emphasize that we are getting patients on drug quickly. We also have patient support programs for tringolza to make sure patients understand how to administer tringolza and they understand the disease and what to expect and we're also emphasizing the need for physicians to get those triglycerides measured fairly quickly after they go on to patients go on to tringosa because they're what they're going to see and what they are seeing is substantial reductions in triglycerides on the order of even better in many cases than what we saw in our phase three study with no no AP events so we're pleased about that and we're also confident in our peak product sales in the US of three billion dollar plus based on everything we're seeing in the launch and the label to date. So we're feeling very good about the launch.

Great, great. On the competitive front, Arrowhead reported their Shasta 3.4 pivotal data at ESC.

I was wondering how do you view that product's profile and how do you think uh this uh you know that pending launch uh could uh uh impact your outlook for tringolza um there the phase three data that was presented at esc was um there were no surprises at ionis it was as expected we see a profile that's that's very similar to tringolza the um you know i do want to caution folks that to compare apples to apples their primary endpoint was triglycerides at 12 reductions at 12 months compared to baseline hours was triglyceride reductions at six months placebo adjusted if you look at media if you look at our median data at 12 months it's basically the same as theirs if you looked at our their triglycerides placebo adjusted ours actually looks because they had a significant very significant placebo effect in their study you know our acute pancreatitis data is highly competitive a little bit better but it's simply the profiles look very similar our safety is clean we have no monitoring in our study although there's been some confusion about that we have a very clean label you asked about hepatic fat before yeah and I didn't answer that last part of the question. You know, we are 100% convinced that this is a non-target effect where we see a small increase in hepatic fat by lowering the target, APOC3, in this study. We evaluated 250 patients or so by MRI looking at changes in hepatic fat. We saw a small increase, particularly at the high dose, not statistically significant at the 50 milligram lower dose and with continued dosing as we presented several times now continued dosing we see a return to baseline of hepatic fat with no clinical sequelae no issues no concerns by the HCP community they saw in their study too now they only evaluated 30 years a few dozen patients so it's obviously not statistically significant wasn't powered but you can see the you numerically an increase in in in hepatic fat it's a non-target effect and but it but most importantly it's of no consequence in the eyes of HCPs never was your goals as a very clean profile we're first to market and we're taking advantage of that and and as I said the launch is going well we're first market by a year or so and we also have the advantage of offering two dose levels 50 milligrams which was at which was highly competitive and then the 80 milligram dose which is even more competitive and and we're seeing prescriptions coming in at 80 we're seeing prescriptions coming at 50 you know and and we can that's that's definitely resonating very well with the cardiology communities to be able to be able to look at two different dose levels and see how patients do it 50 and then before bumping it up to 80 milligrams or they just start at 80

milligrams and patients are doing very well great thanks but for those those color I was also wondering about your at your eyesight sRNA program for SHTG you presented data at ESV and you also had publication so wondering you know help us review that data how does that data compare with tringosa with Redemplo for example and how did that come into your you know overall SHD strategy yeah so we're now you know after investing in expanding our technological

base the chemistries and other know-how delivery methods new methods for delivering ASOs, siRNAs to target organs, we invested in five, six years ago, are now starting to reach the clinic. Our first SI, IONUS discovered SIs using IONUS know-how and chemistries are now reaching the clinic. In the liver, SIs are more durable than standard ASOs or IONUS ASOs by a few months and we've been able to use our know-how and chemistry to further increase that to six nine nine twelve months once dosing in the clinic we know there's how to do this we have selected ion 775 as a follow-on to tringolza it's tough to beat the efficacy of tringolza I mean that bar is very high but maybe we can do it really it's focused on convenience as a once or twice per year self administered treatment for shtg to you know just just to protect the franchise that we created the the first we were first market and we want to protect that with by offering it convenience advantages for patients if they if they want that our phase one data that we presented at ESC completely supports twice or once per year dosing with excellent safety and remarkable April C3 reductions on the order of 90-plus percent. It was dose-ranging. And triglyceride reductions that were, you know, just were truly remarkable. Remember, I shouldn't say remember, in our phase one study, we evaluated patients with mildly elevated triglycerides. You can only lower the triglyceride so much when you're mildly elevated. We were basically normalizing all the patients. We expect even greater reductions in SHCG, where the triglycerides start at very high baseline values. And in fact, we started our phase 2 study in SHTG as an open label study, so we're continuing to monitor triglycerides and APOC3 reductions in safety because we want to select dose and dose regimen frequency as quickly as possible to get phase 3 started as quickly as possible as a follow-on to Tringol.

So we expect in 2027 towards the end of the year that we'll have all the data we need to make a decision on to go to phase three and if and if we really move quickly maybe we'll get it started in 2027 so it's priority got it got it got it so maybe two quick follow-up on that the phase two has studied both moderate and severe HTG maybe that's a standard procedure because you also did that for tringosa but I was wondering is there any inclination to go into moderate HTG? Because that's not an indication for it.

No, there isn't. We designed the phase two study to have enough SHTG patients in this study to answer all the questions we needed answered for our phase three design. But we wanted more patients to ensure that we have all the safety in the study, but it can also contribute to our ultimate phase three safety database to have as many patients in there as possible. It's just to move enrollment quickly. The SHCG patients are harder to find in HTG patients and by combining both we'll get all the information we need in this study to select dose and dose regimen. We don't plan to go after the mildly elevated triglyceride patient population which is particularly at risk for cardiovascular disease at least at least not for ion 775 at this point we don't think the prospects for success in a cardiovascular outcome trial are high enough we're really focused on SHTG this is a multi-billion dollar product opportunity and we're first and we want to we want to continue to hammering away SHT you know to continue to bring medicines forward for SHTG to ensure our continued leadership in this space Got it, got it.

I thought I heard you say the phase three development for ION 775 could be this, hopefully this year, but or next year.

Maybe. Certainly we're going to have all the information we need in 2027 to design our study. Getting a phase three study started is not a trivial task. operationally, it's the blocking and the tackling to do that. But we'll have all the information we need, for sure. That's why we designed it as an open-label study, so we're continuing to evaluate the data as we go forward. The study's enrolling well, and we like what we see so far because it is open-label. The phase three design will probably look like our phase three design for Tringolza in many ways. in most ways. With that said, if there are opportunities to trim timelines based on our experience with trim goals, we will do so. We do believe that even though we have proven that lowering triglycerides through this mechanism will prevent acute pancreatitis largely from happening, we still think it's important to have that data in a label when you launch.

So we're gonna make sure that we also have do everything we can to have a label similar to tringol's just more convenient once or twice a year great yeah yeah we're great to see the the first ionis sRNA program approaching the event in a later stage development perhaps let's also touch on another commercial product down there of HAE this is a very competitive land therapeutic area so based on the launch that you have seen are you incrementally more confident or less confident about

your expectation for this program yeah we're very confident we're confident in our peak product sales in the US 500 million plus we're very based that based on our label based on what we're seeing in the launch, the enthusiasm for Donzera. We're seeing, you know, we're seeing new patients, newly diagnosed patients going on to Donzera. We're seeing patients that were previously on on-demand treatment try their prophylactic for the first time and Donzera being one of them. But most of the patients are coming from switches, primarily Tuxera, which is the market leader in the U.S., but really all profis that are out there we're seeing switches on today. It is a very competitive market and there's a lot of players in this market, but we know Don Zero is doing well, and we think it'll continue to do well. What we're particularly pleased with is not only the switches we're seeing, but patients, once they get an experience with Don Zero, they're staying on treatment. It's very sticky. It's not true for all pro fees we're seeing switches like I said patients often want to switch because the lack of sufficient efficacy or poor tolerability Donzera as a once per month or once every two month treatment is resonated well for convenience simple auto injector and patients are once they get experience with Donzera they're staying on treatment got it got it in the remaining minute minute or two I was wondering could you say a few words about the things that we haven't touched on, like the IGANS program, Any Catalyst, and also the HPV program. Yeah. So, Bepiravirsen is now approved in Japan as a treatment for chronic HPV as Hibsago. And that approval was based not only on the lowering of HPV burden in people with chronic HPV, but the functional cure rate of treatment that is unprecedented, unprecedented cures in these patients. It's going to be launched in Japan next month, and we're expecting approval in the U.S. in October of this year, and that represents the third approval for IONIS this year, FDA approval for IONIS this year. We're also expecting Phase III data for Cifaxosin and IgA nephropathy. That's partnered with Roche this year. That data will be revealed, uncovered, to support an accelerated approval path for Cifaxosin and IgA nephropathy. That will be coming up in the second half of this year, and then Roche will be filing soon thereafter. So, you know, the pipeline is continuing to deliver. I'll also highlight the fact that we initiated a phase two study in Gervais syndrome earlier We're excited about that. And we're excited about the rest of our CNS pipeline, which continues to deliver proof of concept and FDA approvals, so very exciting times.

Thanks. Thanks for all the color and very helpful framing and insights. Thanks, everyone, for being here. Thank you. Thanks, Yan.