All right. Good morning, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz, one of the Biotech Analysts, and it's my pleasure to introduce Brett Monia, CEO of Ionis Pharmaceuticals. Just a reminder, the format for today is a fireside chat. But before we start, I just need to read a quick disclosure. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, I'll hand it over to Brett. Thanks for joining us. Maybe you can start with a couple introductory comments before-
Yeah.
-hopping to Q&A.
Thanks, Mike. Good morning, everybody. It's great to be here, Mike. Thanks for the invite. As expected, and not surprising with a pipeline as deep and rich as ours, we were expecting a highly eventful year for Ionis, and that's exactly where we are, with a lot more to come in the remaining months of the year. We're on track this year to push three breakthrough medicines across the finish line through the FDA. Three drug approvals, we already have two. Severe hypertriglyceridemia breakthrough medicine, TRYNGOLZA, was approved a few days early in June, and just last week, we had the approval of our first wholly owned neurology medicine, ZANVASTRO, for Alexander disease, the first disease-modifying treatment ever approved by the FDA.
We're expecting a third FDA approval in October with our partner, GSK, for chronic HBV, a real breakthrough that's actually producing unprecedented functional cures in this patient population. We've also had expanding our phase III pipeline. We completed enrollment in our phase III Angelman trial, which is on track for data in the second half of this year. We're pleased to see new phase III starts from our partners, salanersen. The first follow-on to SPINRAZA for SMA that is on track to produce a medicine with even deeper efficacy than SPINRAZA based on biomarker data with once-per-year administration, and then s apablursen started phase III development with our partner Ono this year with a profile that has the potential to be best in class for polycythemia vera. Mid-stage pipeline continues to produce as well.
We are thrilled with the first-ever proof of concept for our tau program with Biogen, diranersen, which showed unprecedented improvements in cognition and other functional benefits as well. Our follow-on to TRYNGOLZA, proof of concept as a once-a-year or twice-a-year administration as a follow-on to TRYNGOLZA, ION775 in severe hypertriglyceridemia, which is in phase II development. With a pipeline as deep and with so many events happening, there's always disappointments. We were disappointed with the negative outcome of the CARDIO-TTRansform study for eplontersen and TTR cardiomyopathy. Despite the fact that we had remarkable reductions in TTR that were as good as anything that's out there today, approximately 80% reduction with good safety and tolerability, didn't hit the composite primary endpoint.
That was a key focus at ESC a couple of weeks ago, where the conclusions were clear that the reason why we didn't hit the primary endpoint was because there was no added benefit on top of a stabilizer. However, the monotherapy group, that is patients that weren't on stabilizer at baseline, has a ratio that's as good as anything that's out there in TTR cardiomyopathy. It has a ratio of approximately 30% reduction. We're working on potential next steps there. Last week, we were also disappointed with the outcome of the pelacarsen phase III trial in Lp(a) cardiomyopathy. We're looking forward to our partner, Novartis, presenting the full data set there.
But on top of those disappointments, we have a really, really strong pipeline, and we're really proud of all the successes we've had and the launches that are in progress, which are going quite well.
Great. Thanks for that introduction. A lot going on and a lot to cover here. Maybe we'll start just with the sHTG launch. You're, I think, two months in now. Still very early here, but maybe just talk about what you're seeing there in terms of trends and how that's all progressing.
We're pleased to have delivered the first real breakthrough for severe hypertriglyceridemia with an incredibly strong, positive, clean label. Unprecedented reductions in acute pancreatitis. This is the outcome that patients are most fearful of, that physicians are most fearful of, a potentially fatal acute pancreatitis attack. There has been no meaningful treatments for severe hypertriglyceridemia before TRYNGOLZA emerged and was approved by the FDA. As a reminder to everybody, this is a label expansion.
Our first indication was familial chylomicronemia syndrome, FCS, a rare population of about 3,000 people in the United States. That launch was going exceptionally well right up to the label expansion, right up to the approval for severe hypertriglyceridemia. Then we expanded the label, adjusted the price from a rare disease price to a price that's more suitable for a highly prevalent disease. Prevalence of more than 3 million people in the United States.
This is positioned to be a blockbuster, and we're on track to achieve our goal of $3+ billion peak product sales in the United States. The launch is going well. We're liking what we're seeing on all aspects of the launch to date, the metrics that we're assessing. First of all, we're thrilled with the excitement by the HCP community. I'm sure you've done your research, you've talked to your docs. They're all saying how excited they are about TRYNGOLZA and their enthusiasm to want to treat and write scripts and get their patients on this drug, particularly those patients that are at high risk for acute pancreatitis. The launch is going well. We're excited about the enthusiasm. We're excited about the scripts that are coming in. July and August were very good months.
We're excited about what we're seeing from the payer community, the coverage that we're getting for TRYNGOLZA. Although, of course, at this stage of the launch, most coverage is going through a medical exception process with prior authorizations. But we are getting policies in place, and based on those policies, as well as all the other conversations we're having with payers, we're getting coverage to label, right? Not just the high-risk patient population, but the label. That is anyone that has triglycerides above 500.
We expected the patients that were going to be prioritized in this study would be those high-risk patients by physicians, endocrinologists, cardiologists, lipid specialists, and that's what we're seeing. These are the patients that have triglycerides through the roof, above 880 mg per deciliter, are at high risk for acute pancreatitis attack, with debilitating effects on the pancreas, of course, long-term.
Those that have had a history of acute pancreatitis. Around 700,000, 800,000, 900,000 patients that are at high risk. Those are the ones that we're seeing the scripts written for first, not surprisingly. I could also tell you, though, we are seeing some scripts coming in that are in the non-high-risk category. Patients that are in the 500-800 range without a history of acute pancreatitis. So, that's getting out there too, but the priority for us and the priority with HCPs is the high-risk patient population. I could also say that we're excited or we're really pleased how well the dosing is resonating with the HCP community. We are the only medicine that offers dosing flexibility of 50 mg or 80 mg per month. So if administered using a simple auto-injector.
That dosing flexibility, as I said, has resonated really well. We're seeing scripts come in with the 50 mg dose, and physicians are looking at the response to 50 mg and seeing if their patients are at goal, that is below 500 mg per deciliter, they're fine. We're also seeing scripts coming at 80 mg right out of the gate.
Remember, the 80 mg dose is what's approved in FCS. We have a lot of docs that are managing FCS patients and are really pleased with the performance of TRYNGOLZA in FCS, and they're saying, "Why start at 50 in my sHTG patients? Just roll it right through, and get those patients to the max dose." We're also pleased how the response by the community, the physicians, and the patients because we require no monitoring in this study. It's a simple administration. Really no significant step edits.
Your patients will need to be on a triglyceride drug, like a Fibrate or a fish oil or something like that, before going on to TRYNGOLZA. All these high-risk patients are already on these drugs, right? They're still not at goal. It's not really a step edit, it's just getting those patients identified and bringing them onto TRYNGOLZA. This is a new category. We're developing a new category. We're going to build this market. It's going to take a little bit of time, but we're pleased with the way the enthusiasm for the drug, and we're pleased with everything we're seeing with the launch today. We're looking forward to providing a more detailed update at our Q3 earnings in a few weeks.
Yep. Great. Sounds like things are on track there, but maybe you could talk about keys to driving the continued success of the launch, kind of near term and then longer term.
The keys are disease awareness and drug awareness. Making the physicians aware of the remarkable profile that TRYNGOLZA offers. Efficacy, convenience, tolerability, and the dosing flexibility that I highlighted with no monitoring in the study or for the drug. That has resonated really well. Launching off of FCS. All the docs that manage FCS patients also manage sHTG patients, and that experience has been so positive that we've really been able to build off of that leverage. Focusing in addition to physician HCP awareness and education is patient awareness. Know your triglycerides. Get them measured. Omnichannel. Direct to consumer dissemination of information. The risks of high triglycerides. We're going from the top, pushing down. We're going from the bottom, pushing up the patients. As I mentioned already, focusing on payer coverage. Ensuring that we have a strong HCP and Patient Support Program.
We are emphasizing and prioritizing making the scripts that docs want to write. Bringing that all the way through the process in the most seamless, easiest way possible. It's really important to us, and our Patient Support Program is a top priority, and it served us very well in FCS and off to a good start in sHTG, and we think it will serve us very well in the sHTG launch. I want to emphasize we remain very confident in our peak product sales of $3+ billion in the U.S. It's going to take a little time to get there, but we're confident we're going to get there, and we're really looking forward to a big big 2027.
Great. I also wanted to just ask your view on these third-party scripts. A lot of people are taking a look at them. What's your sense there?
Yeah. We don't believe that the Symphony scripts and IQVIA are a good measuring stick for what's happening in the launch. Like most companies do, we block our data. We have several specialty pharmacies now that we're utilizing, not just one that we use for FCS. So you really can't compare the FCS data with the sHTG data and extrapolate. It's dangerous. It's unreliable. We really caution against that. Instead, I'd point you to the color we're looking forward to providing at our end of Q3 earnings, and then next year at our full-year earnings in, I think, February of next year. So we're very cautious of that. We don't believe the data's reliable.
Yep. Understood. Can you maybe talk about the reaction to the safety profile of TRYNGOLZA that you're seeing? I guess, liver fat has been one area. Is that an issue, not an issue? What are you hearing?
We're hearing everything is positive about the safety profile for TRYNGOLZA. Again, I said it twice now, I'll say it again. There's no monitoring for anything, LFTs. We have a very clean profile. Liver enzymes are clean. Everything is clean. We're really pleased with the adherence. Patients are getting onto drug. They're seeing their triglycerides plummet, get to normal, and in most cases, in many cases, the adherence is excellent. The HCPs are enthused about it. Liver fat is small. It's on target. It wanes with continued treatment while triglycerides are being maintained, and highly controlled, AP is being continued to be controlled. It's an on-target effect. We know how APOC3 works. By inhibiting APOC3, we're substantially and very rapidly lowering triglycerides in these patients, and one of the pathways that we're lowering triglycerides is through the liver and the clearance.
We see a small increase in liver fat. It's not even statistically significant at 50. In many patients, most patients get to meet your goal at 50 mg. At 80, we saw a slight increase that was statistically significant at the end of the phase III study. With continued dosing, it wanes and comes back to baseline. The liver is adapting to this. We have a competitor program. There's a competitor that is following us. They're behind us by about a year or so. We're expected to come in on sHTG and get approval. Although they didn't evaluate nearly the number of patients that we did, we evaluated because we really wanted to flesh out the full profile, like what do we need to know for TRYNGOLZA? We evaluated 250 patients by MRI. They evaluated a few dozen.
Even with that few dozen at ESC, it was clear that you saw a numerical increase in fat. So it's an on-target effect that's completely manageable, most importantly, by the HCP community, it's a non-issue. It really never was an issue.
Right.
Now the fact that they see it come back down to baseline with continued treatment, it's even less of an issue.
Yep. Makes sense. You mentioned the competitor. I do not know if you can maybe talk a little bit more about key points of differentiation. Since they might get to the market next year, what impact could that have on your launch?
Yeah. We are first to market by about a year, like I said. We actually believe that having two players, like a duopoly, is very few in this massive market opportunity. More than 3 million people that are inadequately or not adequately being addressed with current treatments. We actually think that that is going to provide an opportunity to grow the market, share a voice, better disease awareness by having two players actually expand the market with all of that. But we are going to take advantage of our first-to-market strategy.
Our strategy is to build those contracts with payers, build first-mover advantage to get to those high-risk patients first, bring them onto TRYNGOLZA. We are confident once they come onto TRYNGOLZA, they are going to be really pleased with the experience that they have, the HCPs, as well as the patients. As far as differentiation, the two drugs look very similar.
Efficacy, very, very highly efficacious. AP reductions, we like our data a lot. We are looking forward to more details of our competitor's data. We saw what was presented at ESC, but we really do want to see the publication. It is really important to really get into the details and that kind of thing. So it is hard to say, but overall, there are no surprises. The two drugs should work similarly. We are getting identical reductions of target APOC3. They should translate to similar efficacy, and we welcome two players in this really large market opportunity.
Yep. Makes sense. Also, in your prepared remarks, you mentioned ION775, your next-gen program. Maybe talk a little bit more about that in terms of the data you have seen and timelines and path forward, if you can.
Yeah. When I became the CEO, I guess this is my seventh year now, not only did I commit to fully integrating the company and building our wholly-owned pipeline, delivering our medicines, I also committed to expanding and diversifying our technology. ASO, the newest chemistries, like I mentioned, salanersen, that is an Ionis chemistry that is supporting once per year dosing for SMA. We have more coming. Our Dravet syndrome program is using that same chemistry. We have expanded into siRNA. siRNA is more durable in the liver, we know that. But we have been able to take it to the next level with Ionis' experience, the capabilities, chemistries, and so on. We have applied that to a follow-on to TRYNGOLZA.
Recognizing that a once per year dosing or maybe twice a year dosing at a minimum, we can easily achieve that, but maybe push it to once per year dosing could really matter from a convenience standpoint for HCPs and patients, and we think our phase I data supports that. We tested ION775, an Ionis-discovered, we are using our chemistry, SI, that showed incredibly durable reductions of target, APOC3 triglycerides, all good safety and tolerability, dose-dependent. That was a normal volunteer study in patients with mildly elevated triglycerides. That was presented at ESC, published now as well. Kind of old news, though. We have already launched into phase II development in sHTG, and we are enrolling quickly. Our goal is to protect TRYNGOLZA. It is a blockbuster. We are the ones that innovated. We are the ones that came up with this program.
We are the ones that came up with this target for this disease. We want to make sure that we have next waves of approaches for this market opportunity. It is an open label study purposely so that we can look at the data daily and look at target reduction, safety, and triglyceride reduction, and so that we can select the dose and dose interval and get into phase III development as rapidly as possible, potentially next year.
Great. What is your thought on the strategy there? Is it a replacement for TRYNGOLZA? Is it for a different patient population? What is the early thinking?
To be determined.
Okay.
We'll see what the profile looks like. Our team is going to be doing the market research. Could it be complementary to TRYNGOLZA, or would it be the next best-in-class molecule for sHTG overall and it could take everything over? We'll see about that. I suspect it'll be complementary-
Yep.
-to TRYNGOLZA, and we may be able to position it in different ways so that it offers something that TRYNGOLZA doesn't offer, and TRYNGOLZA could offer something that ION775 doesn't offer. To be determined. We need to get into phase III and move it quickly. We're working on the phase III design now. I expect it won't look that different than our phase III program for TRYNGOLZA, just FDA has requirements. But we think we'll be able to trim those timelines down and move even faster than what we did for the phase III program for TRYNGOLZA.
Yep. Understood. You mentioned in your starting comments here about CARDIO-TTRansform and the data was a little bit disappointing. Maybe you can expand on that and what you think happened there, and then also what's the latest thinking on next steps. Is that evolving at all or where is that currently?
Yeah. As I mentioned in my opening comments, we were disappointed that we didn't have a positive outcome against the primary endpoint in the CARDIO-TTRansform study, eplontersen for TTR cardiomyopathy. We had 80% reductions in TTR, which was pretty much the best you can do in this population, at least for current drugs that are out there that are addressing this disease. Good safety, good tolerability, but we didn't hit the primary endpoint. We all expected that the stabilizer that was primarily used in this study, and we had 56% of patients on tafamidis at baseline.
Tafamidis is the standard of care. That was the only way to really run the study today. As t afamidis is standard of care in the U.S., and as the markets grew outside the U.S., we saw lots of drop-ins too. The belief was that tafamidis, there was a lot of room for improvement, right?
Based on studies that were done 10 years ago, the ATTR-ACT study. But those patients were very sick, and patients are being diagnosed much earlier in their disease today, and tafamidis did better than what most people had expected because patients were being treated earlier in their disease. That was our control group. That would've been okay had the combination of silencer plus a stabilizer showed added benefit compared to the control, but it didn't.
We didn't see any added benefit of combination. That was the conclusion of an independent academic group's meta-analysis at ESC last year. There's no evidence that the combination from any study shows added benefit. Nothing deleterious, but nothing beneficial. That was the Achilles heel in the study. That's the study that needed to be done. Tafamidis is the standard of care, and we needed to see if we can improve efficacy.
In retrospect, maybe it wasn't surprising. We're targeting the same pathway. A stabilizer is stabilizing TTR, and we're blocking the production of the TTR, so maybe we've maxed out on efficacy. Silencers work great on their own. Stabilizers appear to work very well as well on their own. We think ultimately, it'll come down to patient and physician preference, which ones they choose, but we don't think there's a path forward for combination for silencers and stabilizers. With that said, in the group that wasn't on stabilizers at baseline, the efficacy was remarkable. We saw nearly a 30% relative risk reduction in the patients that we call the monotherapy group that weren't on stabilizers at baseline. There was a lot of drop-ins, but still, they weren't on stabilizers at baseline, and that was comparable to the other silencer that was approved for TTR cardiomyopathy.
The monotherapy data looks great. Our partner and us, AstraZeneca and we, are weighing next steps. You will probably have more clarity of that by the end of this year on whether or not we will pursue the monotherapy indication or not. Just stay tuned for that.
Okay. If we just stick with the pipeline and want to get your thoughts on the Angelman program, maybe just give us a brief background there and-
Yeah.
-obviously, a competitor shared some data and read through.
Yeah. It was very disappointing when we learned about the failed phase III study with the lead program, the program that was in advance, utilizing the same mechanism that we are utilizing. This is a mechanism that we created. We were first to publish on it. We are basically targeting using an antisense strategy to upregulate the paternal UBE3A gene to basically replace a loss-of-function disease with the missing protein, UBE3A protein.
It is a really elegant mechanism. They were using the same mechanism. They saw what we published, and they licensed in a drug. They licensed in a drug from an academic group that did some screening and found a molecule. I am going to really highlight the fact that it is not routine to find an optimal molecule to do these kinds of things. It takes us years to optimize potency, durability, and minimize off-target effects to reduce toxicities.
They licensed the molecule, and unfortunately, it caused issues on the safety side that caused them to be capped. Their dose was capped, so they couldn't go above 14 mg. Our phase II research study program ongoing is 80 mg. The two drugs are equally potent, so the potencies are the same, so you can imagine that maybe they underdosed. That's what we believe. In fact, when we did our phase II study, called HALOS, we evaluated 20 mg quarterly, which is kind of in that range of 14 that they looked at in their phase III program, 40 mg, and 80 mg quarterly. At 20 mg, we kind of saw some hints of activity, but we weren't convinced. When we went to 40 mg quarterly, we were convinced that we were seeing clear evidence of benefit.
When we got to 80 mg, our phase III dose, we got a little bit better, but it looked like we were maxing out on efficacy. Unfortunately, we think that they underdosed in the study. It's devastating for the community. We've been ensuring the community that's in such desperate need for a disease-modifying treatment for this large patient population, the Angelman syndrome population. We will be the first to test the hypothesis because we believe that we're in the therapeutic range, the doses that are needed, and we believe that our phase II data HALOS study strongly supports that. I also mentioned that our long-term extension data, that we're now 18 months, data cuts 18 months and beyond, from the phase II HALOS study, and the efficacy is holding.
We continue to be convinced that we're seeing strong evidence of benefit, and it continues to support phase III development. We're going to publish that data soon, the long-term extension data for Angelman syndrome. We think we got the right drug, and this is the right mechanism, and this will be the first test of this mechanism to address Angelman syndrome.
Yeah. Great, and if we stick with the wholly owned pipeline and Alexander disease, you mentioned that earlier, recently approved ahead of schedule. Maybe talk a little bit about that program and sort of what it means more broadly for your CNS pipeline.
Yeah. We believe that, I think the evidence is clear, that we have led the way, and we continue to lead the way in developing oligonucleotide therapeutics, ASO, and now siRNA. We're doing a lot of work there, too, for CNS diseases. I mean, it's proven. We have three approved medicines now. You mentioned ZANVASTRO for Alexander disease. Preceding those were, of course, SPINRAZA, the first-ever treatment for SMA, and then QALSODY, the first disease-modifying treatment for cause of ALS, and now ZANVASTRO. We have a rich, wholly-owned, and partnered pipeline of CNS drugs following this, and we're expecting quite a number of readouts next year in addition to the Angelman syndrome phase III program, our mid-stage neuro program will have several readouts next year, too. We're very proud of having delivered the first-ever disease-modifying treatment for this devastating neurodegenerative disease, Alexander disease.
It's caused by the overproduction of a protein called GFAP. We're normalizing GFAP. We're lowering GFAP. We've shown that, and we're having a disease-modifying impact on clinical outcomes in this study. This is an ultra-rare indication. It's estimated to be 300, 400 patients in the United States with Alexander disease. The prevalence is really not well understood. When we unblinded our phase III study, we saw the efficacy, and we opened up an expanded access program immediately, and that expanded access program has actually enrolled pretty much. We were surprised how many patients actually enrolled in that expanded access program. Our focus is to convert our clinical trial patients and our expanded access patients over to commercial as quickly as possible. We're in the process of doing that. We're launched. Of course, patient identification. It's a difficult disease to identify. It's a long patient journey.
Every day these patients aren't on a treatment like ZANVASTRO, they're one day closer usually to death. So patient identification, disease awareness is a big focus for us, and it's going well. Strategically, this is very important for Ionis because we're leaders in CNS diseases. We have a rich wholly-owned pipeline that's growing in addition to our partner pipeline. This is strategic because it's our first wholly-owned launch in neurology. We have so many more neurology drugs. Angelman syndrome we talked about, and then many other programs that are reading out next year that can go to phase III if they're successful. So strategically important for the company, and we're very proud of the fact that once again, we are first in delivering a breakthrough treatment for a patient population that is in desperate need.
Great. Maybe last few minutes here, I want to focus back on your commercial assets and DAWNZERA and HAE. You launched it last year, I think, and maybe just talk about how that launch is going. Seems like you're getting more traction more recently and things are accelerating there.
DAWNZERA is going well. This is very different than any of the medicines I just talked about. This is a highly competitive market in the sense of there are existing prophylactic treatments for HAE that were already on the market when we arrived, when we were approved last August. We are one year into the launch, and more have been coming after that. This is our first test in commercializing our own medicines, not just being first to market, which we usually are, have been, but in a competitive space. I am proud of the team. I really am. I am also proud of the drug. It has a real differentiating profile compared to other treatments that are out there with respect to not only efficacy, which is as good as anything that is out there today. We have achieved that.
The tolerability and the convenience of being able to self-administer once a month or every two months using a simple auto-injector in which the drug is stable for six weeks at a time, longer than that, but the label says six weeks. You could take it with you on vacation and not be worried about having to refrigerate or reconstitute. It is a real easy drug to work with, and that profile, along with the outstanding effort that our team has done to educate HCPs and patients on the opportunity that DAWNZERA offers. Launch is going well. It is a steady growth. We are having a good year for DAWNZERA, and we expect next year for it to continue to grow.
All right. Great. Looks like we are out of time here, so why don't we wrap it up? Brett, thanks so much for your time. We really appreciate it.
Thank you, Mike. It was a pleasure.