Hello everyone. My name is Mitchell Kapoor. I'm a Senior Biotech Analyst at HC Wainwright. I'm joined today by Brett Monia, the CEO of Ionis Pharmaceuticals. Brett, thank you so much for joining us today.
Thank you, Mitch. It's great to be here.
Maybe to set the stage for our discussion, you could just give an overview of where the company is at today. You've had a lot of recent updates, big pipeline, but what's the focus, you know, of Ionis Pharmaceuticals today? What are the key initiatives? We can go from there.
Yeah. Wow, we've enjoyed some extraordinary success, progress over the last couple of years, really highlighted by this year where, you know, we've had some recent big, big, successful outcomes. Just three weeks ago, we had Donidalorsen, the first ever RNA-targeted medicine for prophylactic treatment of hereditary angioedema, approved by the U.S. Food and Drug Administration. We could talk about that. We're well into the launch now, executing operationally. Although it's early days, it's going well. Of course, just last week, right after Labor Day weekend, we shared top-line data from our Olazarcin Phase III study in severe hypertriglyceridemia. Remarkable, remarkable outcome for this prevalent disease that really is in desperate need for more effective treatments to manage triglycerides and acute pancreatitis. Truly remarkable outcome in that study.
We're preparing for a supplemental NDA to get that drug approved on the heels of the first indication for that medicine, Tringolza, which is now launched for familial chylomicronemia syndrome, or FCS. That's just the tip of the iceberg. There's been a lot of success, and the pipeline continues to deliver over and over again.
Great. With the limited time that we have today, a lot of it will focus on Olazarcin and Donidalorsen just because it's the most recent updates for the company, a lot of focus on that. One of the most interesting things that came out of the CORE and CORE 2 studies recently was the 90% rollover into the open-label extension, which kind of highlights the patient appetite for Olazarcin in the SHTG population. Is there anything you could say about, now that these patients are in the open-label extension, what are you seeing in terms of persistence, adherence, and tolerability in these patients? How do you think it will predict real-world use of Olazarcin?
Yeah, it's really remarkable. A study that enrolled more than 1,000 patients has such a high enrollment rate into the open-label extension. A 12-month study, more than 90%, as you said, have elected to roll into the open-label extension. I think it really reflects, first of all, the excellent tolerability and the safety profile that Olazarcin has demonstrated. It is also recognition by these patients that they want, they need more effective treatments to manage severely elevated triglycerides. Remember, most of these, all of these patients are on treatment, right, to manage their SHTG, and they're inadequate. They're already sold that they need better treatments. They're on fibrates, omega-3 fatty acids, statins, and so on, yet they still elected to enroll into this study. They get it.
They get the need to reduce the risk of acute pancreatitis that can be fatal, to reduce the risk of diabetes, organ failure, and so on. I think it reflects the tolerability profile and the serious unmet need for more effective treatments to manage severely elevated triglycerides.
Great. The acute pancreatitis reduction is a huge potential impact on commercialization. You showed 85% acute pancreatitis reduction. The next question we have is how do you translate that into the payer models? Will you publish formal health economic data to accelerate broad access? How do you see that playing out with payers?
Yeah, so I mean, the results were, like I said, were incredibly positive. We achieved 72% mean reductions of triglycerides on top of standard of care in these patients with triglycerides in the order of 800, 900 or so in our studies, and with an 85% reduction in acute pancreatitis versus placebo. Highly statistically significant and the first time ever demonstrated. Now in the HCP community, the physicians that treat patients with severe hypertriglyceridemia, acute pancreatitis was a remarkable achievement. It proved the hypothesis that's been out there for decades that if you can lower triglycerides in this patient population, you'll get them out of harm's way for acute pancreatitis. They are already convinced that you need to lower triglycerides in this patient population to do so substantially.
On the payer side of things, and on the pricing side of things, having that acute pancreatitis data is incredibly important to really demonstrate not just the reduction in a biomarker triglycerides, which have been linked to AP, but actually to show to payers that you're going to keep patients out of the hospital, prevent mortality potentially, prevent recurrent acute pancreatitis, which is common in this patient population for years and years to come if you can just manage their triglycerides. From a payer standpoint, it's going to be incredibly important to get coverage quickly for patients. It also allows us to, it gives us leverage for optimizing pricing once we get to that highly prevalent disease or condition, severe hypertriglyceridemia.
Outside the U.S., of course, outcome data is often even more important to drive payer and pricing because the desire to have outcome data much more in Europe and elsewhere compared to the U.S. Very important for payer, very important for pricing, and a truly remarkable demonstration that's never been shown before.
Absolutely. We think that's amazing data. Assuming it receives approval in the SHTG population, we're seeing three entry points. I think maybe that's been corroborated by some of your statements, but would be curious to hear your thoughts on the patients who are above 500 mg per deciliter without prior acute pancreatitis, those who are between 880 and 1,000 at very high risk, even without a history of acute pancreatitis, and then the patients who are above 1,000. Where do you see Olazarcin making inroads first in SHTG populations before broadening into the broader 500 to 880 segment without acute pancreatitis?
There are more than 3 million people in the U.S. who are classified as having severe hypertriglyceridemia. That is, triglycerides above 500. Normal triglycerides are 150 and below. They are at risk for the problems that I already highlighted, most importantly, risk of acute pancreatitis, which can be fatal. We are going to focus first our market strategy on the high-risk patient population, like you say. That's really the patients that have had a history of acute pancreatitis, right? Because once you've had one event, the chances of having another event go up exponentially. It continues after that until you can have complete pancreatic failure and multi-organ failure. The second segment, and it's about 50,000 people in the U.S., is much larger. It's patients that are above 880 milligrams per deciliter, which is about 600,000 people in the United States. What's so special about 880?
880 is when your triglycerides are packaged almost entirely as chylomicrons, not in lipid particles like VLDL, but they're now in chylomicrons, which cause occlusion of the pancreatic capillaries and cause pancreatic failure. These patients are at the highest risk for acute pancreatitis. That's the second segment that we're going to focus on, those two segments. Eventually, we will evolve or we will emerge and expand into patients that have high triglycerides and have other comorbidities like diabetes, heart disease, or hypertension. Coupled with their high triglycerides, it puts them at high risk for all kinds of problems. That'll be sort of where we evolve into, and that gets us into the million patient plus segment in the U.S. We can expand from there. That's certainly a lot to bite off right out of the gate, and it's a really, really high unmet need.
We're really excited about being first to market with this new class of RNA-targeted medicines that are really going to have a substantial benefit to patients with SHTG.
Yeah, and GLP-1s are used in some of these populations that may overlap with diabetes, obesity, metabolic syndrome. These overlap with SHTG, but GLP-1s have a modest effect on lowering TGs with the risk of pancreatitis. It makes it a controversial choice in this setting. Wondering how you see, you know, Olazarcin, is it going to be positioned complementary in diabetics to GLP-1 or maybe as a safer alternative?
The GLPs are, of course, being approved for diabetes and for obesity. Our drug is for severe hypertriglyceridemia. I think your point is that there's a lot of overlap, right? A lot of times for SHTG, patients have severely elevated triglycerides and can be obese or diabetic. They will be used complementary, but they won't be used in place of each other. Like you said, GLP-1s have a modest reduction in triglycerides, nothing like the 72% or so mean reductions that we're seeing for Olazarcin in our study. They come with an added risk of pancreatitis. It's the exact, you know, it's kind of contraindicated in that sense to be used in patients that are at high risk for acute pancreatitis.
I could tell you that although it wasn't the most common con-med in our study, everybody in our study were on standard of care, fibrates, fish oils, and statins were the most common. We had patients that are on GLP-1s in our study, and they benefited from Olazarcin. Absolutely complementary.
Gotcha. Very helpful. OK, RNA medicines are new to the cardiometabolic community. What do you see as the biggest barriers to physician adoption, and how are you addressing those ahead of the launch?
Yeah, we actually have seen a lot of enthusiasm for RNA-targeted medicines. Of course, we're not a vaccine. We're targeting RNA. We're either modifying the function of the RNA, or in the case of Olazarcin, we are promoting the degradation of the RNA, thereby for APOC3, thereby blocking the production of the protein APOC3 from the liver. The enthusiasm by the medical community has been overwhelmingly positive. They love the fact that we're doing cutting-edge science. They love to be working with cutting-edge medicines like this. You know, today we have seven FDA-approved medicines from Ionis Pharmaceuticals. There are other companies working on RNA-targeted medicines too, of course, with success. We're expecting several additional, many additional medicines that will be approved, not just for severe rare indications, but for broad indications that are coming, like Olazarcin for severe hypertriglyceridemia, cardiovascular disease, and so on.
We have safely treated many tens of thousands of patients chronically on the market today as well. You could double that for clinical trials very safely with our medicines. We're actually very pleased with the positive receptivity of the HCP community for this new class of medicines.
Great. The price of Olazarcin at $10,000 to $20,000 looks quite modest on a per-patient basis. Once the volume scales, the budget impact could be huge for payers. How do you avoid payer pushback on pricing and preserve net price durability as the market broadens?
Yeah, just to level set for everybody. Today, Olazarcin, brand name Tringolza, is approved and is launched for the rare disease, familial chylomicronemia syndrome, which is severely elevated triglycerides due to a genetic cause. SHTG has no known genetic cause of the disease. It's a common disease. Today, Tringolza is launched with a rare disease price, not surprising. When we get into SHTG and we launch in SHTG, we will bring that price down to match a highly prevalent disease like SHTG. We have to, and we will, thread the needle such that we ensure patient access, that patients who need this drug can get this drug, both from a cost standpoint, from a payer standpoint, coverage, and so on, but also to make sure that we bring the value to our shareholders, the value to Ionis that is appropriate and we should receive.
The $10,000 to $20,000 range that you highlight was preliminary when we first began to think about what the pricing step down would be from a rare disease to a common disease. We still have a lot of work to do. That was prior to having data. Certainly, the acute pancreatitis data and the magnitude of triglyceride lowering that were achieved in our Phase III study will provide more leverage for pricing. We have a lot of work to do between now and the early fourth quarter of next year when we launch this drug on making sure we get the right price to ensure patient access and to drive value for our shareholders.
Great. When would you expect ex-U.S. momentum for Olazarcin and SHTG? Is that something that could be a reality in 2027, or is it something that is a little bit further out?
The first step is to get Olazarcin launched in Europe for FCS. We're expecting the approval in Europe very soon in the second half of this year. We have a partner, a commercial partner in Sobi to launch this drug. They're excited about the opportunity for FCS. They're really excited about the data we shared last week in SHTG. We expect to start seeing revenue for FCS next year. It'll take some time to get onto the market for SHTG. It'll probably be sometime after that.
OK, great. Core and core two data will be presented later this year. We're targeting a medical meeting. What analyses should we expect to see? Would it be responder breakouts, absolute AP event counts, subgroup safety? Could we assume AHA might be a viable venue?
AHA, we'd be thrilled to be able to present the full data set at AHA with simultaneous publication. You know, we don't know that yet. We're still working through the submission and the acceptance for a late breaker. That's certainly our goal. The data, we're going to present as much data as we can. Do realize that we still are going through the data. It's a lot of data. What we reported last week was top-line data. We will report on the details of the acute pancreatitis. For example, how does the 50 milligram dose compare to the 80 milligram dose? How did the first pivotal study core compare to core two? Recurrent versus first-time AP events in this study. We're going to try to go through all of that. In addition to that, AP was a key secondary outcome.
We'll look through all the other secondary outcomes, like effects on VLDL cholesterol, remnant cholesterol, ApoB 100. How many patients were we able to drive below 500? Get them out of the definition of SHTG. What % of patients were we able to drive below 150? Normal triglyceride levels is really exciting. I could tell you that we achieved both of those, you know, and you'll see the numbers on % when we share the data. Of course, more details on safety and tolerability, which was very favorable. We'll do everything we can to get all that data out there in a medical presentation. It'll certainly be contained in a publication simultaneously.
Very exciting. We're looking forward to that. Switching to Donidalorsen for a bit, we're a couple of weeks into the launch now. Could you just talk about what you're seeing in terms of early signals? Would you expect this to be a switch market, naive market, and are you seeing any indication that that's tracking as such?
Too early to say on what types of patients, switch patients, newly diagnosed patients that are coming out of Donidalorsen. I mean, it's just been three weeks. I can tell you that operationally, our team has done a fantastic job. First of all, we had our first scripts coming into Ionis Pharmaceuticals hours after the announcement of the launch from HCP. That's pretty cool. We then had drug in channel within a week and drug in patients' hands within three weeks. We actually have patients now self-injecting using the autoinjector Donidalorsen as a prophylactic for hereditary angioedema. We think that bodes really well for the success of this launch. This is a switch market. In the U.S., more than 70% of patients with hereditary angioedema are on a prophylactic treatment already. However, patients are not satisfied.
The current treatments either are not providing the efficacy, safety, tolerability, or convenience that they desperately need. We believe Donidalorsen checks all three of those boxes. We have switch data. We have a clinical trial that we conducted, a prospective switch study, which we invited patients that were on standard of care today for prophylactic treatment of hereditary angioedema to come onto Donidalorsen and to show that we can safely switch them with no gaps in protection. We were 100% effective at doing that. There was no breakdown in coverage. We were able to further reduce their attacks. More than 60% further reduction in attacks compared to their baseline values on their previous treatments. In an independent survey on quality of life and how patients were doing, more than 80% of patients said that they prefer Donidalorsen over their previous treatment. It's a switch market.
It'll take some time to get those switches happening, right? It's not unlike Tringolza for familial chylomicronemia syndrome, which is the first ever FDA-approved medicine. Here, it's going to take a little bit of time to launch these or to switch these patients over. We're confident we're going to be successful.
While it's a switch market, obviously the data showing that people prefer Donidalorsen, would you expect to generate real-world data after launch that shows patients prefer this and we should move this into the first line?
Yeah. We believe that Donidalorsen will be used in first-line treatment because of the advantages that I highlighted already on efficacy, convenience, and tolerability. The convenience, Donidalorsen can be administered either every four weeks or every eight weeks using a simple autoinjector, a painless autoinjector that takes 10 to 15 seconds to administer. There's no reason why newly diagnosed patients could not be on Donidalorsen. We expect to have that. As I said before, that's the minority of the patients in the U.S. Most are on a treatment. Newly diagnosed patients, and by the way, diagnosis happens typically within the first 10 years of life. These are young individuals that get diagnosed with this. Our drug is indicated for 12 years and older. Newly diagnosed patients, we don't see any reason why they couldn't go on to Donidalorsen. The majority will be switches.
We think we're going to do really well in switching patients over.
As expected, Donidalorsen could be a $500 million opportunity at peak. Can you kind of give us the sense of what you're thinking about the ramp to peak? Is that a slow, steady cadence, or are there inflection points to get there?
It'll be steady, but it'll be slower than a drug that is first to market, right? Because of the time it's going to take to switch patients, the time it's going to take for patients to set up appointments with their allergist or their immunologist and say, OK, I want to switch, or the HCP says, I want to switch you. OK, this is how you do it. Let's get it going and that kind of thing. It'll just take a little bit longer. $500 million plus is the revenue expectations that we have stated, but that's for the U.S., of course. Outside the U.S., we have a partner, Otsuka, who will also add to that. It'll take a little bit of time to ramp it up, but we're confident we're going to get there.
Great. If you could just, you know, give us the next 12 to 18 months ahead for Ionis Pharmaceuticals and what you think could be some valuable inflection points for the company that investors should watch for.
A lot. There's a lot going on, a lot of exciting upcoming events. Of course, we're looking forward to the full data set for Olazarcin in SHTG. We have six Phase III readouts between the remainder of this year and next year with both wholly owned programs and our partnered program, including our drug for Alexander's disease, severe rare leukodystrophy. That's wholly owned by Ionis the second half of this year. Next year, we have Pelecarcin with our partner Novartis for Lp(a)-driven cardiovascular disease. Another outcome trial, start cardiovascular outcome trial in the second half of next year. Epilanthusin, brand name is Wainua, which is approved for TTR polyneuropathy. We expect Phase III data for TTR cardiomyopathy, another blockbuster opportunity like Olazarcin in the second half of next year. Additional Phase III readouts from our partnered pipeline next year as well.
We're going to share quite a bit of this data in early October at our R&D Day, which we call now Innovation Day, of our pipeline, our commercial strategy, our financial plans, and the technology advancements that we're making. I recommend to everybody to join us for that.
Great. A super exciting year ahead. Really appreciate your time, Brett. Thank you all for joining us today in the room.
Thank you. Thanks, Mitch.
Thanks again for joining us.