I can introduce our next company presenter at the BofA Annual Healthcare Conference. Pleased to be introducing Ionis and CEO Brett Monia. Jason Gerbery, I cover Smith Camp Biotech at BofA. And Ionis has been at the forefront of developing therapies, RNA-targeted therapies with this ASO platform and expanding into other modalities, earlier stage, which we might get into as well. Brett, I do not know, coming out of the quarter in the year, maybe, you know, we did a dinner last night and a lot of focus is on your APOCIII targeted program, which is more near-term, but you have a lot going on both this year and next year. I do not know, one of the challenges with Ionis is you have a lot of programs and you gotta hone people in and focus them in.
Where would you focus us in as we start our conversation? I imagine I know where it's gonna go, but I figured it's good for the group to hear it.
Yeah, sure. First of all, thank you for the invitation, Jason. It's a pleasure to be here. Let me start here. We're really proud and excited about all of the recent success that we've had over the recent past. We've had a lot of positive pipeline news and now a successful independent launch. You know, TRYNGOLZA is a very important success for Ionis. It represents our commitment and now achievement to evolve Ionis into a commercial stage, fully integrated biotech company. We're really encouraged by the Q1 launch data so far for TRYNGOLZA and familial chylomicronemia syndrome, FCS, the first and only treatment that's now available for this devastating, severe, rare disease indication. Things are going very well there. We're looking forward to the rest of the year for TRYNGOLZA and FCS.
Right behind TRYNGOLZA is our second independent anticipated launch, donidalorsen for hereditary angioedema. We're looking forward to an expected approval in August of this year, the due for date of August 21, and we're ready to go. We also are looking forward to independent pipeline additional phase three data this year. The second indication for TRYNGOLZA, olezarsen, the generic name, for severe hypertriglyceridemia, a very large, highly prevalent population of patients with high unmet need, again, due to severely elevated triglycerides. We're expecting data this quarter for the safety Essence study and next quarter for the pivotal study, CORE and CORE 2 We're also expecting phase three data for our wholly owned-Alexandra disease program towards the end of this year, a severe, rare leukodystrophy that there are no treatment options available. Of course, we have a rich pipeline of partner programs.
We're expecting four phase three readouts and launches over the next three years from our wholly owned pipeline with substantial economics towards coming to Ionis if they're successful. All of this is setting us up for substantial and sustained revenue growth, and for positive cash flow, becoming positive cash flow in the relatively near term. Things are really looking really positive at Ionis. We're really looking forward to the future.
Got it. Okay. I probably won't spend a ton of time on FCS just because ultimately it's going to be usurped by sHTG, but nonetheless, I think it's important over the next two years before sHTG comes online that investors see, you know, Ionis can go out and commercialize a drug, can build a market and execute. As we think about what the launch looks like, this is a market where there's a bit of a wide range maybe in epidemiology out there. There's questions about how many patients are in the treatment pool versus sort of the heavy lifting to kind of build and pull more patients into the treatment pool.
Mm-hmm.
How much of it is the doctor's got these patients, they're in their office, maybe doesn't recognize or diagnose versus patients needing to be more aware of symptoms and coming in and now realizing they have a treatment option available to them?
Yeah. Severe hypertriglyceridemia is defined as triglycerides 500 milligrams per deciliter and above. Normal triglycerides are 150 and below. The greatest risk for having elevated trig, severely elevated triglycerides is the risk of a potentially fatal acute pancreatitis event. What we're seeing, what we know, based on all the work we've done with HCPs, all the recent market research we've done and engagements with the HCP community and the patient community is that patients, particularly patients that are above 880 milligrams per deciliter, which puts them at even higher risk for acute pancreatitis, or patients that are above 500 that have had a history of acute pancreatitis, are already being aggressively treated by cardiologists, endocrinologists, lipidologists, and even some primary care docs.
I guess, sorry, I guess I was more meaning the FCS opportunity, and are those patients in the pool, treatment pool, or are they needing to be made more aware of treatment options to come into the treatment for those with either genetically or clinically defined FCS?
Yeah. FCS, so FCS patients is really a severe form of severe hypertriglyceridemia. It's all in the same pool.
Yep.
FCS patients are being managed by the same HCPs that will ultimately manage sHTG. It really is, the success we're having in the FCS launch really does provide a real, you know, takeoff point for sHTG. It really builds on the sHTG momentum. Of course, there's a lot more HCPs that are managing sHTG that don't see FCS patients, but all of the FCS HCPs are managing patients with sHTG.
Yep. Are you surprised at all? I don't know if there's any, any anecdotes you can share in terms of, like, since you've got in the market, how many patients did these HCPs tend to see with FCS? You know, I'm just wondering how that process is going. You put up a maybe a better than expected one Q, and so I guess I'm wondering how to think through kind of what the next few quarters or two years look like.
Yeah. We are, like, as I mentioned in my opening, very pleased and encouraged with the launch of TRYNGOLZA in FCS to date. We're pleased with the dynamics across the board. We have patients that are a good segment of patients that are genetically confirmed as well as patients that are clinically diagnosed, a really nice mix of cardiologists and endocrinologists prescribing TRYNGOLZA to patients with FCS. We're seeing really great coverage and, through the medical exception process, fast, very efficient coverage. The payers are recognizing the unmet need here is severe disease. We're also starting to put policies in place that are also covering patients that are genetically diagnosed or clinically diagnosed. We're seeing reauthorizations. We're seeing patients get reauthorization even through the medical exception process. We couldn't be more pleased.
This is a rare disease. HCPs that manage FCS patients, they're managing just a handful. As I mentioned before, these same HCPs are managing, you know, dozens and maybe even, you know, far more than that just with sHTG.
Mm-hmm.
One of the things that, I don't know if it was a surprise, but it's certainly been very encouraging is that as we approach HCPs and make them aware of TRYNGOLZA for FCS, they're coming back to us, and asking, when can they, when will they be able to use this drug for their sHTG patients because they're managing FCS and sHTG patients. They're very, very much looking forward to prescribing for sHTG. You know, our launch was based initially on getting essentially all of our U.S. patients converted, clinical trial patients in the U.S. converted to commercial. We've accomplished that. There's also a lot of patients that have been previously diagnosed with FCS and we're really doing well in that pool.
All the work we did prior to launch, in identifying all our medical team and identifying potential patients is also paying off. That is really where we have to focus for the next subsequent quarters, is patient identification because the vast majority of the up to 3,000 people with FCS in the U.S. are not diagnosed today. We are working through that, both genetic as well as clinical diagnosis of more FCS patients.
Do you see a meaningful difference? I know you're in the process of getting a European approval, of the markets in terms of how the products are going to be viewed by the ultimate paying authorities, in terms of how policies will be set around utilization. You've got the ultra rare pricing point in the U.S. I imagine that it wouldn't be magnitudes of order different in the U.S. setting, but I don't know how you'd sort of maybe frame the two different market opportunities.
Yeah. The prevalence of FCS in Europe is about the same as the U.S. based on our estimations. We're under review now. We expect approval in FCS this year. We have secured our commercial partner for OUS commercialization, Sobi, and we have a lot of history here. We have a lot of experience in FCS in Europe with the drug that we brought forward, Volanesorsen, which is an early generation antisense inhibitor against APOCIII for FCS. And Sobi is commercializing that drug, so they have a lot of experience there. The definitions of FCS in Europe may be a little bit more strict, may require more genetic confirmation.
Mm-hmm.
We don't rule out the possibility of clinical diagnosis. There are methods that are established in Europe for clinical diagnosis of FCS. It's called the Milan criteria. In North America, it's the North American FCS criteria. So we think it'll be very similar to the U.S., but the prevalence and the, you know, and the expectations and certainly the uptake of TRYNGOLZA, we think is gonna be very, very successful in Europe as it is so far in the U.S.
Okay. Let's pivot to sHTG. It's an important readout. I believe it's third quarter, where you have your phase three data readouts for this program. I'm curious how you'd frame clinically meaningful benefit in this setting, be it either triglyceride lowering or proportion of study subjects getting to, you know, a more normal threshold, which is something that we often hear from physician KOLs, that the ability to get patients out of the danger zone is really important to them. Maybe, ahead of the data, I'm kinda curious how you'd frame clinically meaningful signal here.
Yeah. As mentioned earlier, high unmet medical need, highly prevalent disease patient population, cardiologists, endocrinologists, lipidologists that treat these patients basically throw everything at them that they can to get their triglycerides down. Patients with that are above 500 or even higher, fibroids, fistulas, all patients are essentially on this and they can't really budge their triglycerides. That's why they're looking so, so much to a drug like TRYNGOLZA to really substantially reduce their triglycerides. We have the Essence study, a safety study with more than 1,400 patients with mildly elevated triglycerides. It's a safety study to support the highly prevalent disease opportunity from a safety exposure database standpoint in the eyes of the FDA . That study is gonna read out in this quarter, the primary endpoint being triglycerides, but of course, what's most important is safety in that study.
The sHTG CORE and CORE 2 study is to read out in the third quarter. What we have heard directly from a large number of HCPs that manage these patients is that they're looking for anything that can substantially lower their triglycerides on top of standard of care. Our clinical trials are on top of standard of care. These patients still have sHTG. They're above 500. Nearly 50% of our patients are above 880 in our phase three trial. These patients are at a high risk, almost around 20% or so, in the CORE study. Patients have a history of acute pancreatitis. They just wanna get their triglycerides down.
Our experience in FCS, and in our Bridge study, the safety study for FCS that we presented last year, we're seeing placebo-adjusted reductions of triglycerides in the 50% range, or so. That's a huge win. If we can cut triglyceride levels in these patients in half.
Mm-hmm.
You're gonna get a lot of patients out of a significant risk of acute pancreatitis and other comorbidities. That's really what we're looking to.
You'd have a patient presumably who maybe gets an omega-3 or a fibrate and gets 20%-30% reduction, and then you're getting that patient, you're taking them down another 50%.
That's correct. I mean, that's the range that we were expecting based on our experience in FCS and in mildly elevated triglycerides from the Bridge study. Yeah, about a 50% reduction, give or take, is a big win on top of standard of care.
Yep. When you hosted a KOL webinar recently on sHTG, one of the things that I took away is your market segmentation is that, like, you really see the opportunity here is a patient who's highly afraid of another pancreatitis event, and so likely to adopt therapy as a means to mitigate and prevent that from happening. You're gonna generate data around pancreatitis. We all know that the event rates are a little fuzzy, right, to characterize, but you are seeing event rates on a blinded basis. That's encouraging. I'm just wondering if you can talk about what we'll expect to see at least in 3Q.
I know that you've talked in the past about pooling the two studies so that you can have a more robust data set, AP for acute pancreatitis. I'm wondering if when we get that update, we'll be able to have a sense of, have a support data set around pancreatitis at least on an Eric trend, which is important, I think, to both U.S. and U.S. markets.
Yeah. So we just, touch on, you said about patient segmentation. Clearly, patients that have had a heavy event of triglycerides above 100 are highly, highly motivated to get on a drug like TRYNGOLZA. The acute pancreatitis is incredibly, incredibly, dris and essentially fatal. It can cause pancreatic failure, it's high risk for diabetes and other organ failures, as well. Puts them in the ICU for more than a week time on average. They are highly motivated indeed. And that's a lot of people. HCPs that have patients that have triglycerides of 880 who don't even have a history of acute pancreatitis are already convinced that they need to take care of their patients.
It's analogous to having cholesterol, you know, in the multiple hundreds, LDL cholesterol of hundreds to be put on a treatment by an HCP to manage cholesterol so you don't get that first heart attack. It's the same, in the eyes of HCPs when you have severely elevated triglycerides. That's our target. That's our first tranche of focus for our commercial launch is those patients and those HCPs. The CORE and CORE 2 studies to read out in the third quarter of this year, primary endpoint is triglycerides. Obviously we are gonna present that in our top line data, or announce that in our top line data for safety and tolerability will also be in our top line data for CORE and CORE 2.
If we have the adjudicated AP data, we will certainly share in our top line data, but we have to first make sure we have all of the events properly adjudicated before we speak to them. What we are planning to do for sure is to present both Essence as well as the CORE and CORE 2 studies at medical meetings in detail, following top line data, you know, second half of this year. Yes, we're doing everything we can to power AP. It's not powered for AP.
Mm-hmm.
Of course, these are segmented endpoints. The AP event rate in sHTG is not well understood. It's actually studies like ours that are gonna really help establish AP. As you know, we had a statistically significant reduction in AP in our FCS study, but sHTG is an unknown. We'll see. Yes, indeed, we are seeing blinded AP events in our phase three study. We're doing everything we can to maximize the signal by pooling the CORE study and the CORE 2 study sHTG, which is over 1,000 patients. We're also looking at a 12-month time point in the study for the AP secondary endpoint to maximize the duration of, you know, time exposure to the drug and accumulation of potential events, whereas our primary endpoint on triglycerides is at six months with a six-month follow-up.
We're doing everything we can, and we'll share the data if we have it.
Is the challenge to having all that data adjudicated by 3Q, the longer 12-month follow-up period, and maybe not having all of that data in-house, whereas you'd have the six-month triglyceride lowering data in-house for sure? I'm just trying to maybe follow up on that point around that maybe these.
It's not that because all of the patients on the primary end, all the patients that read out at six months have to be followed up for another six months, so that all patients will have been followed for 12 months. It really comes down to whether our central adjudication committee has all the data properly accounted for, for us to at least share the data when the top line data comes out. I think we'll be able to share the data though.
Okay. So sounds like 50% placebo-adjusted triglyceride lowering, you know, at least a numerical trend on acute pancreatitis and safe. That would be a home run for you. Is that fair?
That would be a grand slam.
Yeah.
Is in this highly prevalent disease or patient population. Again, there's pent-up demand by HCPs to really get a drug like TRYNGOLZA to manage their sHTG patients. They believe in APOCIII as a new paradigm for managing triglycerides, really over triglycerides. We're proud of the fact that Ionis innovation is what led to the discovery of APOCIII as a target. We were the first to validate it and bring forward the first marketed drug to target APOCIII.
I think you've framed maybe a million patients or so that are in that higher risk buckets of either 880 milligrams of triglyceride level or 500 with a prior AP event. That would be maybe the initial low segment after, and then there may be additional broadening of the market opportunity subsequent to that. I know that's gonna be data driven by subsequent kind of before market studies or how would you kind of outline the initial opportunity and then how you may broaden over time?
HCP education. The expansion from that initial tranche of about a million people in the U.S., above 500 with a history of AP and above 880, is the initial focus of that, as I say, as we said, but then it comes down to HCP education that if patients are above 500, you still need to get them within guidelines. There are established guidelines.
Mm-hmm.
In the cardiology community, in the endocrinology community, if your patient is above 500, you need to put them on any and all medications to get their triglycerides down below 500 because they're at risk of acute pancreatitis. That's why so many of these patients are on fibrates and omega-3s now because they're trying to get the guidelines. With the availability of TRYNGOLZA potentially for sHTG, now that'll be another tool in the toolbox to manage sHTG patients 500 above. That comes down to HCP education. Post-marketing studies, we will consider those, but I don't think they're essential. I think it's really about education.
Yep. I think you've mentioned, if you're addressing a market of that size, the ultra-rare pricing kind of paradigm really can't exist anymore. You've talked of thinking the $50,000-$20,000 as sort of a tentative preliminary number. Do I have that right in terms of how, where do you see kind of like the price range ultimately within sHTG, if you had to put brackets around it?
I think you have that right with the caveat that we're still working through it.
Yeah.
It'll also, we need to see the data and what the data will support. I think that's reasonable.
Okay. Any U.S., OUS particulars with this data set that we need to be mindful of in terms of the filings and how, what the regulators care more about? Do the studies broadly support kind of a global filing strategy?
Yeah. The guidelines are, global, to get patients below 500 if they're, if they have sHTG. And the approval will be based on, we expect the approval to be based for sHTG in Europe to be based on triglyceride lowering, as well. Payer requirements are always a little bit more strict outside the U.S. than they are in Europe.
Mm-hmm.
There may be a requirement for some trends in acute pancreatitis outside the U.S. for payers to cover. We expect that not to be needed in the U.S. There might be a little bit more pressure on the need to convince that patients are at or that there's a benefit on AP for sHTG, but that remains to be determined.
Okay. Let's shift to Pelacarsen, the Lp(a) lowering approach as a secondary prevention strategy for cardiovascular disease. You've got a phase three outcome trial through your partner, Novartis, looking at MACE outcomes. I generally believe, like, there's a perception that you, this trial's maybe more enriched than the Amgen Ocean trial in terms of patients and, and some of the events that were explicitly outlined to get into the trial, even though there were some differences, I think, in the Lp(a) levels at baseline. But I, I think you've published some baseline demographic data. You know, how, how do you see, you know, this trial ultimately enriched for success? And you've been through two interims now. You're going to, I guess, a final update next year. You know, how do you think things are tracking, generally, with this trial?
Yeah. This is another landmark trial. We seem to, we're proud of the fact that we're at the forefront of so many of them. The, you know, Lp(a) is an independent cardiovascular risk factor, which means that patients are at high risk for heart attack, stroke, potentially death, related to cardiovascular disease, due to high Lp(a), independent of LDL cholesterol, independent of hypertension, independent of anything else, diabetes, and so on. The baseline paper that our partner Novartis shared really shows how, how really well conducted this study is with a, although the inclusion criteria was at 70 milligrams per deciliter, which is well above, in the range of risk for cardiovascular disease. The median number is 108 in that study. The powering looks impressive with a, you know, the overall population, a hazard ratio of 0.8.
In a subpopulation with patients 90 and above in milligrams per deciliter, the hazard ratio is 0.75. Really well conducted study. We expect 80%+ reductions in Lp(a). Yes, we have now cleared two interim analyses that were based on efficacy, futility, or safety. Green light go. We are looking forward to this landmark result from the HORIZON phase three study in the first half of next year. There are no more interims.
Yep.
We're ready to roll. It's a big, really exciting time in the cardiovascular world because of this trial.
It was initially published something like 900- 1,000 events needed to occur. Are you, I imagine, privy to the blinded data that the events are tracking to where they need to be to have it?
Yeah.
You know, deliver data by the time you're hoping?
Novartis is a great partner for this program. We have a very transparent relationship. We work with them. We have Ionis leaders, development from our development team on the steering committee. Yeah, we work close. We see what's happening with Novartis.
Okay. Maybe talk a little bit about what you see as the clinical support versus the genetic data that supports the role of Lp(a). I think primarily, like, what do you ascribe greater weight to here, in terms of confidence that this target? I think we've seen with other genetically defined targets like HDL, the outcome trials did not work. As you say, it's a landmark trial. It's the first trial in the space. I guess that's the main risk that people focus in on.
There are not good pharmacological approaches for lowering Lp(a), because everything that's been out there to date that people have looked towards for some to build some confidence in a successful outcome are based on small reductions in Lp(a), like PCSK9 inhibitors, which have marginal reductions in Lp(a). There's some apheresis data that filter out Lp(a) in Europe that has shown evidence of benefit in these patients long term. That's nice, but it's all about epidemiology. It's all about the epidemiology data that really shows independent of all other risk factors, LDL, hypertension, what have you, that high Lp(a) levels are associated with high risk for cardiovascular disease. The higher the Lp(a) is, the higher the risk.
It's really mostly driven by the epidemiology data, and there's a lot of it. You know, one of the great things about being, you know, having a company as innovative as Ionis is that when you're first, it brings risk, right? You're the first readout for a drug for, you know, targeting a new risk factor, like Lp(a). You also have the benefit of being first to market by years in the study. The study's well executed, well conducted, well designed, and we're looking forward to the data.
Mm-hmm.
In the first half of next year.
Do you mind us how you've kind of defined this addressable market? You know, one thing that we hear from some physicians is a lot of these patients, if they're just treating to prevent an MI event, oftentimes patients just don't treat, right? I don't know, there's, you know, how would you kind of segment and define this market given those dynamics that are out there? We've seen some analogs with other drugs that address risk factors in these different.
Yeah. The way patients that have had a card, they typically will have a cardiovascular event. If it's a really knowledgeable HCP, even before they have an event, a cardiovascular event, they'll measure Lp(a). I mean, if it's super high, in either case, what an HCP does is try to manage all their other risk factors because they can't manage Lp(a). Get their LDL down, get their hypertension controlled, get them on antidiabetic medicines if they have high glucose, all of that. That's because they can't do anything with Lp(a).
Once an inhibitor, once Pelacarsen, for example, is potentially approved and the data supports that, we're putting patients, getting patients out of harm's way that have high Lp(a). It'll be used alongside drugs to manage other risk factors like LDL cholesterol because those other drugs don't manage the Lp(a) level. So it'll be added on top of a statin if patients have multiple risk factors, for example, LDL and Lp(a). If a patient has TTR amyloidosis, it'll be measured on top of a TTR drug alongside a Pelacarsen and those sorts of things. It's independent and has to be directly controlled. We believe that HCPs will understand this. They have a long history of doing this kind of thing.
Today, since there's no treatment, they'll just use whatever they can to get them out of harm's way for other, to control other risk factors.
All right. We're pretty much out of time. Brett, thanks so much for joining us at the conference.
Thanks, Jason. It was a pleasure.