Thanks everyone for being here. My name is Yanan Zhu. I am 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 is 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 will be brief, though, because I know you have a lot of questions, Yanan, and we want to get to those. But as expected, this has been a highly eventful year for Ionis. We have had several really important positive strategic outcomes this year, and we have also had some disappointments. Not surprising when you are consistently seeking to deliver breakthrough treatments in new therapeutic areas, sometimes you have disappointments. But I really do want to emphasize the incredible success we have had this year already. We have had two FDA approvals, both in areas where there is high unmet need and we are first. TRYNGOLZA for severe hypertriglyceridemia, ZANVASTRO for Alexander disease, both wholly owned products.
And we are 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 III readouts this year, and we are on track for two more. The pipeline, in addition, continues to deliver and go very well. We initiated a phase II study for ION775 in severe hypertriglyceridemia that supports twice or once a year dosing. As a follow-on to TRYNGOLZA, we started a phase II study in Dravet syndrome using a very important new chemistry that we've created that supports potentially twice a year or once a year dosing. I can go on, but maybe we should just open it up for questions. It truly has been a strategically successful year so far.
Right. It's been a very eventful year for sure. I actually wanted to start with Angelman syndrome, one that you didn't have any update. I think a latter update from Ultragenyx programs has caused some investors to react. I don't know if you can touch on when you saw that result, were you surprised? Anything that you think investors should or should not read through to your program?
Yeah. So sad for the Angelman's 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. Prior to the readout from the program that you just referred to, we've been signaling to the investor community and to anybody that'll listen to us for well over a year that although we are hopeful that the study would show signs of success, we were not very optimistic that it would be successful for several reasons.
Most notably, Yanan, 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. That's because they ran into toxicity issues in the clinic and pre-clinically that forced their dose to be capped, substantially lower dose, and we were concerned that they were underdosing. 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 forget that Ionis is the only company that has delivered oligonucleotide successes that have been FDA approvals in the clinic to date, proven platform that has delivered SPINRAZA, ZANVASTRO now, QALSODY, and proof of concept even in Alzheimer's disease with our tau program. We're dosing at the maximum dose we set out to dose at, and we think that we will max out on efficacy when our study reads out next year. We fully enrolled this year, the study, and we're looking forward to data in the second half of next year.
Got it. Thank you. That's very helpful. Let's touch on Lp(a). This is a very surprising result. It's a good target with a lot of backing from human genetics. When this data readout 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 Lp(a) field?
Yeah. This is another first for an Ionis discovered medicine to test the Lp(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(a) are strongly associated with cardiovascular disease. We set out to determine whether or not it could be modifiable with a pharmacological intervention, pelacarsen, by lowering pelacarsen to normal levels. That's what we did in this study. We got substantial lowering of Lp(a) that were similar to what we purported in our phase II study on the order of 75%-80% reductions in Lp(a). We saw good safety in the study. Those reductions in Lp(a) really normalize a lot of patients. Unfortunately, it didn't result in a successful outcome on MACE, a four-point MACE endpoint.
The study did not achieve statistical significance in the primary endpoint. It also didn't demonstrate benefit in the subgroup of patients that were at higher risk in the study. It's unfortunate the drug did what it was supposed to do with respect to lowering Lp(a) with good safety, but it may implicate Lp(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. As a secondary prevention, maybe it's just not modifiable. We'll see. We don't see a path forward for pelacarsen. Novartis is going to be presenting the full phase III data at a medical congress as soon as they can, maybe later this year. Stay tuned for that. Unfortunately, we don't see a path forward for pelacarsen.
Got it. Thanks for those thoughts. Let's touch on another recent development, CARDIO-TTRansform. I know you, and I am 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. Could you help us understand the result in the combo part of the study and also help us understand what the path or the next steps for the program?
Yeah. I really want to highlight that we had three presentations related to eplontersen in ATTR cardiomyopathy at ESC last week, all high-quality presentations in large forums at the meeting. The overall study outcome, and then the focus on the subgroup in combination with tafamidis, if you will, or stabilizers. The study did not hit its primary endpoint in the composite of cardiovascular mortality and 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 a remarkable efficacy. We saw efficacy that is similar to the only other silencer that is on the market today with respect to a risk reduction of nearly 30% risk reduction. We saw TTR reductions that were as good as anything that has been out there today, around 80% TTR reductions, all with good safety in the phase III study.
The monotherapy worked very well. But unfortunately, there was no added benefit in combination with stabilizers. We had more than 50% of patients on stabilizer at baseline. The involvement of tafamidis or stabilizer in the study grew as the study continued with lots of drop-ins as tafamidis became the standard of care, not only in the U.S., 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 is 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 did not hit its primary endpoint. The second reason is that tafamidis actually performed pretty well in this study. Remember, patients are being diagnosed much earlier in disease today, unlike the phase III study for tafamidis in ATTR-ACT 10 years ago, where patients were being diagnosed with late-stage disease, and it was difficult to impact their disease course. Patients are being diagnosed much earlier today. The stabilizers actually performed very well as monotherapy, and we just could not add to the benefit that tafamidis was achieving in our study. But the study was executed very well. The monotherapy group performed exceptionally well. AstraZeneca is weighing their options. They have not made any definitive decisions. We are 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 eplontersen in ATTR cardiomyopathy. I do want to say that in polyneuropathy, the launch continues, and the drug is very effective. Patient uptake continues to be relatively strong. It is a good drug. Unfortunately, the study design caused it not to be successful in the overall population.
Great. I was wondering, of course, it is all pending the decision-making by your partner and you on the path forward. I was wondering 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 is significant justification to bring eplontersen to ATTR cardiomyopathy patients because patients deserve options. Today, there are two stabilizers and there is one silencer. Patients deserve other options, and eplontersen differentiates from the other silencer that is on the market in several ways. Most notably, it can be administered by the patient themselves. Self-administration using a simple auto-injector. It does not rely on being administration by a healthcare provider. We think that that is important for patients as a choice. But the bar is high. Let us not fool ourselves here.
FDA generally does not accept submissions with failed primary endpoints in studies. But you are asking me my opinion, I think patients deserve choices. I see no reason why a silencer cannot be used as first-line treatment. It is the combination that we and experts that were, it was highlighted at ESC last week. There is probably no path forward for combination usage of a stabilizer and a silencer. Let us not lose sight of the fact that we are targeting the same pathway with a silencer and a stabilizer, right? We are targeting TTR, whether we stabilize it or we knock it down, and we silence it. We are maxed out. But I see silencers as 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 for some physicians, it is going to be on patient preference. Do they want an injection once every month or a few months? Or do they want to take a pill a couple of times a day? It is really going to come down to preference, I think. But there's no reason why it can't be used as frontline or second-line treatment. I also want to add, Yanan, that this is a big market and there is room for multiple players. First line, second line, and we don't really know what the ceiling is for ATTR cardiomyopathy. It's a big market opportunity.
Great. Let's talk about TRYNGOLZA in severe hypertriglyceridemia. You have a launch going on. This is the first quarter for this indication. It only started a couple of months ago. But 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 from the study.
Yeah, sure. As I mentioned in my opening comments, we've had several very important strategic successes at Ionis this year. The FDA approval of TRYNGOLZA for severe hypertriglyceridemia was an enormous breakthrough in this massive patient population. In the U.S., 3 million people plus have sHTG, many of whom are being treated, but the treatments are inadequate. They're fibrates or fish oils or statins, which barely lower triglycerides at all. Unlike TRYNGOLZA, which shows 70%, 80% reductions in triglycerides on top of those medicines. And the FDA approval included 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.
We were very pleased with this breakthrough treatment, wholly owned medicine that we launched within a few days after the approval. We're pleased with the momentum of the launch to date in the U.S. We had drug in channel within a day. We had scripts received the day of approval. And the momentum is good. 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 the definition of sHTG. It's for people with severe hypertriglyceridemia, as an adjunct to diet and exercise, which is defined as triglycerides 500 mg per deciliter and above, as a treatment to reduce risk of acute pancreatitis. That's the label. But, as we expected, physicians are prioritizing those patients that are at the highest risk to come into TRYNGOLZA.
Those are patients with a history of acute pancreatitis. Those are patients with triglycerides that are so high, 880 mg or above, that they're at very high risk of acute pancreatitis, whether or not they've had an event in the past. Payer discussions are going quite well. We're very pleased. We did a lot of payer research prior to setting price, as we went from a rare indication FCS to a prevalent indication sHTG. 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 pay to label 500 mg per deciliter and above. With that said, physicians, rightfully so, are prioritizing those high-risk patients. We're expecting a steady launch.
Physicians 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. We're pleased with the enthusiasm, the sentiment, the need that we're hearing for TRYNGOLZA for sHTG, and we're pleased with the momentum that we've built so far.
Great. Definitely looking forward to quarterly updates for continued momentum on that launch. I was wondering, how reliable are the third-party vendors that capture prescriptions? This is the specialty pharmacy situation, so it's not always reliable, but we see some increases in scripts through those third-party channels. Can we use that to triangulate trying to predict sales?
No. We advise against it. We've been advising against it because we believe that the Symphony IQVIA data is inaccurate, and we would recommend against that. We block our data. We have several different specialty pharmacies, not just one, so several. The data is unreliable. So we've been advising against using that data. I want to emphasize that we're pleased with the momentum that we've created for the launch to date.
I see. You do have a full year guidance for the TRYNGOLZA sales for the full year. Are you comfortable with the guidance?
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 TRYNGOLZA. 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 TRYNGOLZA to make sure patients understand how to administer TRYNGOLZA, and they understand the disease and what to expect.
We're also emphasizing the need for physicians to get those triglycerides measured fairly quickly after patients go onto TRYNGOLZA because 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 III study, with no AP events. We're pleased about that, and we're also confident in our peak product sales in the U.S. of $3+ billion based on everything we're seeing in the launch and the label to date. We're feeling very good about the launch.
Great. On the competitive front, Arrowhead had reported their SHASTA-3 and SHASTA-4 pivotal data at ESC. I was wondering: How do you view that product's profile, and how do you think that pending launch could impact your outlook for TRYNGOLZA?
The phase III data that was presented at ESC was, there were no surprises at Ionis. It was as expected. We see a profile that's very similar to TRYNGOLZA. I do want to caution folks that to compare apples to apples their primary endpoint was triglyceride reductions at 12 months compared to baseline. Ours was triglyceride reductions at six months, placebo-adjusted. If you look at our median data at 12 months, it's basically the same as theirs. If you looked at their triglycerides, placebo-adjusted, ours actually looks better because they had a very significant placebo effect in their study. Our acute pancreatitis data is highly competitive, a little bit better, but certainly 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, Yanan, and I didn't answer that last part of the question. 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 the 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 mg lower dose. With continued dosing, as we've 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 it in their study too. They only evaluated 30 or a few dozen patients, so it's obviously not statistically significant. It wasn't powered. But you can see numerically an increase in hepatic fat. It's a non-target effect.
Most importantly, it's of no consequence in the eyes of HCPs, never was. TRYNGOLZA has a very clean profile. We're first to market, and we're taking advantage of that. As I said, the launch is going well. We're first to market by a year or so. We also have the advantage of offering two dose levels, 50 mg, which was highly competitive, and then the 80 mg dose, which is even more competitive. We're seeing prescriptions coming in at 80 mg. We're seeing prescriptions coming in at 50 mg. That's definitely resonating very well with the cardiology community, to be able to look at two different dose levels and see how patients do at 50 mg, and then before bumping it up to 80 mg, or they just start at 80 mg, and patients are doing very well.
Great. Thanks for those color. I was also wondering about your siRNA program for sHTG. You presented data at ESC, and you also had publication. Wondering, help us review that data. How does that data compare with TRYNGOLZA, with Redemplo, for example, and how did that come into your overall sHTG strategy?
Yeah. We're now, 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 Ionis-discovered siRNAs using Ionis know-how and chemistries are now reaching the clinic. In the liver, siRNAs are more durable than standard ASOs or Ionis ASOs by a few months. We've been able to use our know-how and chemistry to further increase that to six, nine, 12 months once dosing in the clinic. We know how to do this. We have selected ION775 as a follow-on to TRYNGOLZA. It's tough to beat the efficacy of TRYNGOLZA. 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.
Just to protect the franchise that we created. We were first to market, and we want to protect that by offering it convenience advantages for patients if they want that. Our phase II data that we presented at ESC completely supports twice or once per year dosing with excellent safety and remarkable ApoC3 reductions on the order of 90%+ percent with dose ranging and triglyceride reductions that were truly remarkable. Remember, I shouldn't say remember. In our phase I study, we evaluated patients with mildly elevated triglycerides. You can only lower the triglycerides so much when you're mildly elevated. We were basically normalizing all the patients. We expect even greater reductions in sHTG, where the triglycerides start at very high baseline values.
In fact, we started our phase II study in sHTG as an open label study, so we're continuing to monitor triglycerides and ApoC3 reductions and safety because we want to select dose and dose regimen frequency as quickly as possible to get phase III started as quickly as possible as a follow-on to TRYNGOLZA. 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 III, and if we really move quickly, maybe we'll get it started in 2027. So it's a priority.
Got it. So maybe two quick follow-up on that. The phase II study, both moderate and severe HTG. Maybe that's a standard procedure because you also did that for TRYNGOLZA, 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 II study to have enough sHTG patients in the study to answer all the questions we needed answered for our phase III 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 III safety database to have as many patients in there as possible. It's just to move enrollment quickly.
Okay.
The sHTG patients are harder to find than HTG patients. By combining both, we'll get all the information we need in the 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 not for ION775 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 continue to bring medicines forward for sHTG to ensure our continued leadership in this space.
Got it. I thought I heard you say the phase III development for ION775 could be hopefully this year, or next year.
2027.
Or, yeah, 2027.
Maybe. Certainly, we're going to have all the information we need in 2027 to design our study. Getting a phase III 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 III design will probably look like our phase III design for TRYNGOLZA in many ways, in most ways. With that said, if there are opportunities to trim timelines based on our experience with TRYNGOLZA, 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 going to make sure that we also do everything we can to have a label similar to TRYNGOLZA, just more convenient, once or twice a year.
Great. Yeah. Great to see the first Ionis siRNA program approaching the later stage of development. Perhaps let's also touch on another commercial product, DAWNZERA for HAE. This is a very competitive therapeutic area. 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 U.S., $500+ million . We base that based on our label, based on what we're seeing in the launch, the enthusiasm for DAWNZERA. We're seeing newly diagnosed patients going onto DAWNZERA. We're seeing patients that were previously on on-demand treatment try their prophylactic for the first time, and DAWNZERA being one of them. But most of the patients are coming from switches, primarily TAKHZYRO, which is the market leader in the U.S. But really all prophys 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 DAWNZERA 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 DAWNZERA, they're staying on treatment. It's very sticky. It's not true for all prophys. We're seeing switches, like I said. Patients often want to switch because of lack of sufficient efficacy or poor tolerability. DAWNZERA, as a once per month or once every two month treatment, has resonated well for convenience, simple auto-injector. And patients, once they get experience with DAWNZERA, they're staying on treatment.
Got it. In the remaining minute or two, I was wondering, could you say a few words about the things that we haven't touched on, like the IgAN program, any catalysts, and also the HBV program?
Yeah. So bepirovirsen is now approved in Japan as a treatment for chronic HBV as Hibsago. That approval was based not only on the lowering of HBV burden in people with chronic HBV, 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 sefaxersen in IgA nephropathy. That's partnered with Roche this year. That data will be revealed, uncovered to support an accelerated approval path for sefaxersen in IgA nephropathy.
That'll be coming up in the second half of this year, and then Roche will be filing soon thereafter. So, the pipeline's continuing to deliver. I will also highlight the fact that we initiated a phase II study in Dravet syndrome earlier this year. We are excited about that, and we are excited about the rest of our CNS pipeline, which continues to deliver proof of concept and FDA approvals.
Great.
Very exciting times.
Thanks for all the color and very helpful framing and insights. Thanks everyone for being here.
Thank you. Thanks, Yanan.