Good morning, and welcome to the Ionis conference call to discuss phase III BALANCE study results. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Wade Walke, the Senior Vice President of Investor Relations. To lead off the call, please begin.
Thank you, Dave. Hello, and thanks everyone for joining us today to discuss the results from our phase III BALANCE study of olezarsen in patients with familial chylomicronemia syndrome, or FCS. These were presented yesterday at the American College of Cardiology annual meeting and were published simultaneously in the New England Journal of Medicine. Before we begin, I encourage everyone to go to the investor section of the Ionis website to view yesterday's ACC presentation, as well as the press release we issued yesterday and the slides accompanying today's webcast. I would first like to draw your attention to slide two, which contains our forward-looking statement. Our discussion today will contain forward-looking statements based on our current expectations and beliefs. Such statements are subject to certain risks and uncertainties, and our actual results may differ materially.
I encourage you to consult the risk factors contained in our SEC filings for additional detail. On today's webcast, our CEO, Brett Monia, will start us off by opening with some opening remarks. Dr. Sam Tsimikas, Senior Vice President, Global Cardiovascular Development, will discuss our olezarsen development program and the severe manifestations of FCS, and will cover some of the results from the BRIDGE study that were also presented yesterday at ACC. Jonathan Birchall, Chief Commercial Officer, will provide an update on our preparations to deliver olezarsen to patients with FCS. And Kyle Jenne, our Chief Global Product Strategy Officer, will join us for the Q&A portion of the call. We're very pleased today to be joined by Dr. Erik Stroes, Professor in the Department of Vascular Medicine at Amsterdam University Medical Centers. Dr. Stroes is a preeminent leader in the field of lipidology.
He presented the BALANCE data yesterday at ACC and is the lead author of the New England Journal of Medicine publication. So we're extremely pleased to have him present the BALANCE data for you today on our call. With that, I'll turn the call over to Brett.
Thanks, Wade, and thanks, everybody, for joining us this morning to discuss the exciting data from the BALANCE study, evaluating olezarsen for the treatment of familial chylomicronemia syndrome or FCS. We are very pleased to have Dr. Erik Stroes with us today to present the BALANCE data and provide his key insights into their significance for patients with this devastating disease. So to get started, I'd like to begin by discussing the key role olezarsen plays in our business strategy, a strategy that's now focused on creating next-level value by delivering our medicines directly to patients. Ionis was founded on the principle of turning groundbreaking science and technology into new transformational medicines, and olezarsen represents this founding principle in action. Today, we're on the cusp of independently delivering a steady stream of new transformational medicines to patients, beginning with olezarsen.
Establishing our co-commercialization partnership with AstraZeneca for WAINUA, our novel treatment for hATTR-PN, was an important step to efficiently prepare Ionis for our first and subsequent independent commercial launches. WAINUA is the first Ionis-branded marketed medicine. The U.S. launch is off to an excellent start, and our global strategy to bring WAINUA to patients around the globe is progressing on track. Following WAINUA, we expect the launch of olezarsen around the end of this year, making olezarsen our first medicine we independently deliver to patients. After olezarsen and FCS, we expect donidalorsen for the prophylactic treatment of hereditary angioedema, or HAE, to be our next independent commercial launch. With positive data from the phase III OASIS HAE study in hand, we're preparing our regulatory submission to the FDA, while our European partner, Otsuka, is preparing to file in Europe.
We have an efficient and scalable commercial organization in place for these and future commercial launches, and we're also establishing global access to our medicines for patients around the world. Beyond our near-term commercial opportunities, we have a rich and advancing mid and late-stage pipeline, with multiple value-driving data readouts expected through next year and beyond. We're also continuing to expand our wholly owned pipeline, with several new medicines advancing into the clinic this year. This includes six new medicines from our industry-leading neurological disease pipeline. And in parallel, we're continuing to advance and expand our technology with an aim to address more diseases with significant unmet need. So now, let's return to olezarsen and the exciting opportunity olezarsen offers for FCS. FCS is a severe, rare, and under-recognized disease characterized by very high levels of triglycerides, leading to an extreme risk for acute, potentially fatal, pancreatitis.
Many patients suffer repeated attacks throughout their lives, often beginning in childhood or even infancy. Given its rarity, and with no approved treatments in the U.S., FCS is often misdiagnosed or missed entirely. FCS represents a disease of severe unmet need, which makes us even more pleased with olezarsen's clinical performance and BALANCE. The results overall from this study support the potential for olezarsen to make a profound difference in the lives of people with this devastating disease. In BALANCE, olezarsen worked as designed, substantially reducing triglycerides by potently and selectively targeting APOC3. Olezarsen demonstrated a favorable safety and tolerability profile consistent with the profile seen with our other LICA medicines. And most importantly, olezarsen demonstrated a substantial and clinically meaningful reduction in attacks of acute pancreatitis. Validating for the first time that reducing triglyceride levels can provide a meaningful reduction in the risk of acute pancreatitis.
These results increase our confidence that, if approved, olezarsen will be well positioned to be the standard of care for FCS. They also further reinforce our confidence in olezarsen's potential for success in the much larger sHTG indication. Looking ahead, our regulatory submissions are right on track, positioning olezarsen for its first potential approval in the U.S. by the end of this year. And our sHTG development program is also progressing well, with data from all three of our phase III studies expected next year. Before I turn the call over to Sam, I'd like to thank the patients, the families, and clinicians who have participated in the BALANCE study and contributed to the positive results we're reporting today. And with that, I'll pass the call over to Sam to provide an overview of our olezarsen development program, followed by a look at the clinical manifestations of FCS. Sam?
Thank you, Brett. We are developing olezarsen for two indications resulting from severe elevations of plasma triglycerides: familial chylomicronemia syndrome, or FCS, and severe hypertriglyceridemia, or sHTG . FCS is a rare disorder affecting up to 13 people per million in the U.S. sHTG is a significantly larger population than FCS. We estimate that there are greater than three million patients in the U.S. alone. FCS and sHTG are associated with acute and chronic symptoms, including pancreatitis, and current treatments are not effective in lowering triglycerides to an optimal level to prevent complications associated with severely elevated triglycerides.
This slide displays an overview of the FCS portion of our olezarsen development program. On the left is our BALANCE study. This is the pivotal study of olezarsen in FCS patients. In a moment, Dr. Stroes will walk you through the data from the study, which were presented yesterday at the ACC meeting.
The results demonstrated robust reductions in ApoC-III and triglycerides, favorable safety and tolerability, and importantly, marked reduction in acute pancreatitis with olezarsen treatment. Additionally, our expanded access program for olezarsen is now up and running in the U.S. as a pathway for patients with FCS to receive olezarsen ahead of a potential approval. Olezarsen was recently granted breakthrough therapy and orphan drug designations in the U.S. for this disease, and we are preparing to submit an NDA in the U.S., putting us on track for a potential approval by the end of this year, assuming priority review. We are also preparing it to submit applications for regulatory approval in the EU and Canada this year. On the left side of this slide is our BRIDGE study.
This is our supportive exposure study for our FCS regulatory filings, which evaluated olezarsen in patients with high cardiovascular risk and moderately elevated triglycerides, defined as triglyceride levels greater than 200 mg/dL . This study also had a small number of sHTG patients who had triglycerides over 500 mg/dL . The results of this study were also presented at the ACC yesterday in a late-breaker session. In this study, olezarsen demonstrated significant reductions in ApoC-III and triglyceride levels, showed meaningful reductions in ApoB, non-HDL cholesterol, and markers of CV risk, and a favorable safety and tolerability profile. Importantly, we believe these data support the overall positive olezarsen profile for the treatment of people with severely elevated triglycerides.
We are pleased to have the results from both BALANCE and BRIDGE studies published in the New England Journal of Medicine yesterday, simultaneously with the presentations at ACC. Our olezarsen development program for sHTG is shown here. Our sHTG pivotal studies, CORE and CORE2, in people with triglyceride levels greater than 500 mg/dL , are progressing well. CORE and CORE2 are expected to be fully enrolled soon, position us for data from these in our supportive ESSENCE study next year. ESSENCE is our supportive exposure study for our sHTG regulatory filings, which evaluated olezarsen in patients with HTG and triglycerides between 200 mg/dL and 500 mg/dL. I am pleased to report that enrollment in ESSENCE is now complete, with over 1,400 patients in the study.
FCS is a rare disease characterized by inability to clear plasma triglycerides due to loss-of-function variance in the gene lipoprotein lipase, or LPL, or in related genes required for optimal LPL activity. This loss of LPL activity results in triglyceride levels greater than 880 mg/dL , but levels in patients with FCS often reach 10- 100 times above normal levels of 150 mg/dL . The effect of extremely elevated triglycerides on the circulation can be seen in this image on the bottom, right of the slide. When initially drawn, the blood from an FCS patient can appear straw-colored or milky due to very high levels of triglycerides. After sitting for a few minutes, the triglycerides separate and float to the top of the vial, as shown here. The most severe complication associated with FCS is recurrent episodes of acute pancreatitis.
FCS also leads to a number of debilitating chronic symptoms that can impede activities of daily living and quality of life, including nausea and abdominal pain after eating, severe fatigue, and impaired memory and comprehension, among others. Conventional triglyceride and lipid-lowering therapies, such as fibrates, omega-3 fatty acids, or statins, have minimal to no effect in people with FCS, and there are no treatments approved for FCS in the U.S. A severely restrictive diet that limits dietary fat to less than 20 grams per day and eliminates alcohol can help patients manage their symptoms, but compliance is often a challenge in the long term. Acute and recurrent episodes of pancreatitis are the major complication of FCS.
While the median age of diagnosis with FCS is around 24 years of age, with patients generally diagnosed after one or sometimes multiple episodes of pancreatitis, attacks have been documented to occur as early as 30 days after birth. In these patients, triglycerides accumulate to a, such a degree that they ultimately obstruct pancreatic ducts. This pushes digestive enzymes into the pancreas, which leads to severe pancreatic inflammation, characteristic of acute pancreatitis. Compared to people with normal triglycerides, hypertriglyceridemia-induced acute pancreatitis is associated with substantially worse outcomes, including higher rates of multi-organ failure, ICU admission, and prolonged hospitalization. It's also associated with higher mortality and higher in-hospital mortality compared to other causes of pancreatitis. Furthermore, with each event, the risk of acute pancreatitis events increases, and the prognosis worsens with each event.
This is why the goal of treating FCS is to reduce the incidence of these events and their related complications. A diagnosis of FCS can be made by identification of genetic variants that result in loss of LPL activity, or in the case of an indeterminate genetic test or when genetic testing is unavailable, FCS can be diagnosed using established clinical criteria published in 2018, known as the Milan criteria for FCS diagnosis. These clinical criteria, alone or together with identification of causal variants, are necessary to distinguish FCS from conditions with overlapping phenotypes, such as sHTG. FCS, sHTG, and HTG all have unique genetic and clinical profiles. These differences are important in understanding the significance of the BALANCE data in FCS and how we would expect it to compare with results from studies in sHTG patients.
FCS, which is typically characterized by triglycerides greater than 880 mg/dL , is associated with a complete or near complete loss of LPL activity, resulting from homozygous or compound heterozygous variants in the LPL gene or in related genes required for LPL activity. These variants result in markedly reduced triglyceride clearance and a significant resistance to triglyceride-lowering therapies in people with FCS. Conversely, people with HTG and sHTG, characterized by triglycerides of greater than 150 mg/dL or greater than 500 mg/dL , respectively, have normal or near normal levels of LPL activity. Secondary factors like diabetes, obesity, or metabolic syndrome often compound the risks associated with high triglycerides in these patients. Importantly, because of the normal or near normal LPL activity, HTG and sHTG patients are generally less resistant to triglyceride-lowering therapies compared to those with FCS.
This is a high-level summary of the two pathways by which triglycerides are broken down or cleared, and how ApoC-III regulates these processes. In this first and most efficient pathway, LPL breaks down triglycerides present in triglyceride-rich lipoproteins, or TRLs, such as chylomicrons and VLDL into free fatty acids. These TRLs are the yellow spheres shown in the graphic on the right side of the slide. The chylomicrons are these large particles shown at the lower left corner of the graphic, and VLDL is represented by the smaller particles seen at the top right of the graphic. In this second less efficient pathway, TRLs are cleared by the liver. In this figure, you see that the elevated levels of ApoC-III in plasma inhibit LPL activity and slow clearance of triglyceride-rich lipoproteins, which results in elevations of serum triglycerides.
In FCS patients, the loss of LPL activity results in very high plasma triglyceride levels because they are entirely dependent on the second, less efficient liver-mediated triglyceride-rich lipoprotein clearance pathway. This is also the reason for their resistance to triglyceride-lowering therapies. On the other hand, HTG and sHTG patients who have LPL activity are generally less resistant to triglyceride-lowering therapies than FCS patients and than sHTG patients. We would expect to see a greater magnitude of triglyceride reductions with similar reductions in ApoC-III. This is what we observed to date in our studies of olezarsen in people with FCS, sHTG, and HTG. This slide shows a summary of the positive data from the phase II-B BRIDGE study of olezarsen. BRIDGE evaluated olezarsen in patients with HTG, defining the studies having triglycerides greater than 200 mg/dL , plus cardiovascular risk.
This study also looked at a small number of patients with sHTG, defined as having fasting triglycerides over 500 mg/dL . Similar to patients we are evaluating in our pivotal CORE and CORE2 studies. With olezarsen 80 mg, 93% of patients with moderately elevated triglycerides at baseline achieved normal triglyceride levels, which is less than 150 mg/dL within six months of olezarsen treatment. Olezarsen also demonstrated statistically significant placebo-adjusted reductions in ApoC-III of 73% and 71% at six and 12 months, respectively, and statistically significant placebo-adjusted reductions in triglycerides of 53% and 55% at six and 12 months, respectively.
In patients with sHTG, olezarsen treatment resulted in robust ApoC-III reductions of 86% and 91% at six and 12 months, and triglyceride reductions of 83% and 86% at six and 12 months, respectively. Based on similar patient profiles among sHTG patients in BRIDGE and the CORE studies, and consistent with the mechanisms for triglyceride clearance, we expect to see a similar level of triglyceride reduction in the CORE and CORE2 studies as we saw in the sHTG cohort in BRIDGE. This is supported by preliminary unblinded data we are seeing from the CORE and CORE2 open label extension study, where all patients receive 80 mg of olezarsen monthly. So to recap, patients with FCS, sHTG, and HTG have distinct clinical profiles.
FCS is the only one of these indications characterized by a loss of LPL activity, which results in resistance to triglyceride lowering treatments. Olezarsen demonstrated robust ApoC-III and triglyceride reductions in patients with sHTG and HTG in the BRIDGE study, where 93% of patients treated with 80 mg of olezarsen achieved normal triglyceride levels with six months of treatment. Furthermore, HTG , sHTG data from the BRIDGE study showed robust triglyceride reductions consistent with our expectations for patients with LPL activity that is consistent with preliminary data we're seeing from the phase III open label study of olezarsen in patients with sHTG. These data increase our confidence that we will see substantial triglyceride reductions in the CORE and CORE2 studies. Importantly, olezarsen demonstrated favorable safety and tolerability across all study populations.
In total, the data we have seen from studies to date increase our confidence in olezarsen's potential to make a profound difference in the lives of people with FCS and sHTG. Here now to present the BALANCE study results is one of the academic leaders in the field of lipidology, who also cares for patients with FCS on a daily basis, Dr. Erik Stroes. Dr. Stroes.
Thank you very much, Sam. It's a privilege for me to share with you the data from the BALANCE study, which we presented yesterday, and these are my disclosures. Next. So Sam told you very elegantly about pancreatitis. Let me briefly share with you my clinical perspective. I've been treating FCS patients for more than 25 years now, and I've seen more than 20 patients pass and stay with FCS. I've lost two patients with pancreatitis, one at the age of 21, another one at the age of 29. So pancreatitis is not something we just mention, it's something which really for us, a clinical problem. And you heard Sam telling there is no current therapy there to significantly reduce triglycerides. So these patients are walking around with, from my perspective, going to be a time bomb, and we don't have anything to actually change this.
So if we could proceed to the BALANCE study. This is a phase III study, placebo controlled, with olezarsen 80 mg or 50 mg, as compared to placebo, and the primary outcome was at six months of triglyceride lowering. You see the patient disposition. Overall, 66 patients were included, 23 in placebo, 21 in the 50 mg, and 22 in the 80 mg dose. And we'll come back to that later. But there was an open label extension study, and as you may appreciate, the 60 patients who completed the entire study all chose to continue with the open label extension study, which makes sense because of the good tolerability and the good results we're presenting here. In the next slide, you see the baseline characteristics. Note that these patients were not that old, approximately around 40.
There was no obesity because they were born with a disorder, so they were kind of brainwashed to use a low-fat diet, and their BMI was normal. And look at the triglyceride numbers. We are not talking about the 150, which we have ordinarily. This is more than 20-fold increase. So this is really the extreme of the extreme, which also underlines the genetic diagnosis of these patients. In the next slide, you can actually see the efficacy on the underlying mechanism, the ApoC-III reduction. The olezarsen 80 mg provided a 73.7% reduction at six months and an 81% reduction of ApoC-III production with reduced plasma concentrations. The 50 mg showed a 65% and a 77% at 12 months.
For us, clinically, it's very comforting to actually see, if you look on the right, on the waterfall plots. You can see that virtually all patients responded throughout the 12-month periods with a significant reduction in ApoC-III. Mind you, the two patients in both group who don't have a lowering of ApoC-III were all patients who failed to complete the entire 12-month period. In the next slide, you see what it's all about, reduction in triglycerides. In the 80 mg, after six months, we saw a 43.5 placebo-corrected triglyceride reduction, and at 12 months, a 59.4% reduction in overall triglyceride count. The 50 mg provided a 22.4 at six months and a 43.8 at 12 months. And also here, waterfall plots show a very favorable reduction in triglyceride numbers. Now, here is something that's really interesting.
Usually, when I take two or you actually take a big fat load, your triglycerides increase from, let's say, 150 mg/dL to 210 mg/dL, and it's cleared very rapidly. Within hours, you actually don't see anything. Now, in FCS patients, we know that the lipolytic pathway is completely down. So the biggest problem here is the huge variability. Look at the placebo group. You can see that the triglycerides are all over the place. And actually, this variability is indeed the risk because if they use fats, you get a lot of chylomicrons, as Sam already told you, and these chylomicronemia actually are thought to be the cause of pancreatitis. Now, look what happens in the 50 mg, the 80 mg group.
You not only see the triglyceride reduction at the pre-specified endpoints at six and 12 months, but if we actually look at the comprehensive integrated response throughout the entire year, you can see an area of the curve reduction of approximately 40%, for the 50 mg, and up to 56% for the 80 mg group. And it's exactly this reduced fluctuation in the lipid levels established by the olezarsen ApoC-III reduction, which is considered to translate into a reduced pancreatitis events. And now the most important slide for me and the most important finding, and note, this is the unique finding. I've never seen this before. Now we actually seem to have something which reduces pancreatitis, the major threat for these patients. On, on the left, you see that the olezarsen groups have fewer and delayed events in pancreatitis.
On the right, you can see that if we translate it into the hard numbers, in the placebo group, there were 11 pancreatitis events, and the first event was already nine days after randomization. In the 50 mg groups, there was only one event after 102 days, and in the 80 mg, there was one event after 357 days. That's approximately an entire year. And if you look at the totality of these data and you integrate the olezarsen groups, you can see that the overall event rate was reduced by 86%-90%, comparing olezarsen to placebo groups.
More importantly, if we then also look at the clinically relevant reduction in all-cause hospitalizations and inpatient days, it was very good to actually see that the all-cause hospitalization with olezarsen treatment was reduced from annualized 0.76 to 0.1. And if they were admitted to the hospital, look at the duration. It was reduced from a mean annualized days of 6.56 to 0.5. So actually, this also illustrates that triglyceride reduction reduces not only pancreatitis event rate, but it also reduces the severity of the pancreatitis if it occurs. Most importantly, favorable in safety. If we're going to treat patients prolonged, what about favorable safety? Well, if you look at these data, what stands out in our safety data is a severe adverse events, was much more common in the placebo group as compared to the intervention groups.
That actually makes sense because if we look at the severe adverse events, it was predominantly the abdominal pain events which occurred in the placebo group, which makes sense because it's a hallmark of FCS patient with persistent hypertriglyceridemia. There was no imbalance in liver, renal, or clinically relevant thrombocyte numbers, and there were no bleedings observed in these patients. So in conclusion, we see that olezarsen 80 mg resulted in a clinically meaningful benefit in FCS patients with a substantial and sustained ApoC-III reduction throughout the entire 53-week follow-up period, a statistically significant reduction in triglycerides in the 80 mg at six months. And for the first time ever, as I've seen, a significantly lower number of pancreatitis events, both fewer and later.
This combined with a favorable safety and tolerability of this compound, actually, we can say that it's these data support the potential of olezarsen as a novel therapy, not only to reduce triglycerides, but also to reduce acute pancreatitis in these patients with familial chylomicronemia. With this data, I would like to hand over to Jonathan. Jonathan?
Thank you, Dr. Stroes. Based on these excellent results we've seen in the BALANCE study, we're extremely pleased about what olezarsen could mean for people with FCS, their caregivers, and the physicians who treat them. FCS is a severe, rare, and potentially deadly disease characterized by extremely high triglycerides and an extreme risk of acute, potentially fatal pancreatitis. FCS has a median age of diagnosis of just 24 years. This means that oftentimes this devastating diagnosis is confirmed when people are young, in the prime of their life, perhaps starting a new career or building a family. However, due to the lack of awareness among physicians, FCS is often misdiagnosed. This means that patients can go for years or even decades and see many, many physicians before finally receiving their diagnosis of FCS, only to find that there are no treatments available for their disease.
These patients endure severe and potentially deadly consequences of their disease. In addition to acute pancreatitis, which is twice as deadly in patients with FCS compared to those with normal triglycerides, these patients are burdened by a host of debilitating chronic symptoms, including severe abdominal pain, crushing fatigue, intense cognitive symptoms, such as impaired memory or comprehension, which patients often refer to as kind of an FCS brain fog. The heavy burden of FCS on patients and caregivers also includes a high economic burden. Patients with FCS report difficulty in finding and maintaining full-time employment due to frequent hospitalizations and days spent at home managing their debilitating chronic symptoms. The costs for these hospitalizations and healthcare services can be extensive for patients, for caregivers, and for the healthcare system. Here are some of the same hospitalization data from the BALANCE study that Dr. Stroes showed you a moment ago.
From these data, we can see a dramatic difference in hospitalizations and time spent in hospital resulting from olezarsen treatment. We believe the potential to reduce hospitalizations and the time spent in hospital will be extremely meaningful to patients and payers alike. From a payer perspective, these hospitalization data further strengthens olezarsen's profile. In fact, in our work to fully characterize the economic burden of FCS, we gained insights from over 15 U.S. payers, representing roughly 150 million lives, telling us that payers are aware of the need to prevent the severe complications associated with FCS. One payer told us that they're very focused on reducing hospitalizations and other costly services.
While another said, "Reducing pancreatitis and persistent organ damage is key." And a third told us, "In response to a drug profile like olezarsen's, a trend in improving acute pancreatitis would be great. Outcomes data would be a home run." This commentary is representative of what we've heard from payers across the board, consistently showing a willingness to cover a medication like olezarsen. The feedback from the marketplace as a whole has been similarly positive. And based on the data from the BALANCE study, including acute pancreatitis outcomes, reductions in hospitalization, favorable safety, and tolerability, and the simplicity of a monthly self-administration with an auto-injector, we believe olezarsen is positioned to address the needs of physicians, payers, and patients with FCS.
Today, I'm pleased to say that we are right where we should be in preparing to launch olezarsen for the treatment of FCS, our first independent launch as a fully integrated commercial organization. We are executing on our patient, physician, and payer-focused launch strategy. Importantly, with first mover advantage and an efficient patient and physician-focused commercial organization, we are confident that, if approved, olezarsen is positioned to become the standard of care for the treatment of FCS. Here's what we're doing today ahead of this exciting launch. Our field medical team has been out contacting physicians for nearly three years, building disease awareness and urgency to treat through education on identifying and ultimately diagnosing FCS. We've conducted extensive market research to identify the physicians most likely to diagnose FCS and treat patients with olezarsen, assuming approval. These are the physicians we will focus on most after launch.
Using omni-channel capabilities, we will extend our reach efficiently to reach a broader pool of potential treating physicians. Leveraging the capabilities we have developed for the launch of WAINUA, we are also building a world-class patient and caregiver support team to help patients through every step of their treatment journey. This includes helping patients to obtain access and copay support, training patients on olezarsen's self-administered auto-injector, among many other services. The goal of this team is to provide a seamless customer experience that helps patients get on treatment and stay on treatment. Coming up this summer, we plan to hire our customer-facing sales team. This team will be sized appropriately for this rare disease population, and again, we will leverage omni-channel capabilities to efficiently extend this team's reach as is required.
We've definitely got a very exciting year ahead of us as we advance olezarsen towards the market for people with FCS. Directly ahead, we look forward to filing for regulatory review in the U.S, E.U, and Canada, positioning us for our first potential approval of olezarsen in the U.S. before the end of the year. Our development program for olezarsen in the larger sHTG indication is also progressing well. We look forward to data from our CORE, CORE2, and ESSENCE studies next year, while we continue to advance our sHTG launch preparations, which are also well in hand. And with that, I'll turn it back to Brett.
Thanks, Jonathan. Olezarsen represents one of the most meaningful opportunities in our pipeline today, and we expect olezarsen to be our first independent commercial launch. And with the positive results from the BALANCE study we've now reported, we're confident that olezarsen is positioned to be the standard of care for patients with FCS. The positive results from the BALANCE study also increase our confidence in olezarsen's potential for success in the broader sHTG indication. But olezarsen is far from the only program driving momentum for Ionis this year. Looking ahead, we expect additional approvals of WAINUA outside the U.S. and the potential approval of QALSODY in Europe. We also look forward to reporting full data from our phase III study of donidalorsen in patients with hereditary angioedema around the middle of this year.
From our rich mid-stage pipeline, we look forward to reporting data for IONIS-FB-L Rx in both IgA nephropathy and geographic atrophy, ION582 in Angelman's disease, and ION541, our ALS medicine targeting ataxin-2. 2024 is certainly shaping up to be an eventful and exciting year for Ionis. We've arrived where we are today by being focused on a clear vision and a clear set of strategic objectives to achieve our vision. Building and advancing our pipeline and delivering medicines that we conceive, we discover and develop directly to patients is a top priority for Ionis. We've established Ionis as a leader in cardiovascular and neurology, drug discovery and development with one of the richest mid and late-stage pipelines. Our pipeline is delivering. We reported multiple positive key readouts over the past year and are positioned to deliver additional important results in the near term.
We also expect to add more whole new medicines to our pipeline this year and for many years to come. In parallel, our partnered programs are progressing on track with key phase II data readouts planned this year and important phase III readouts next year and beyond. We're extending our leadership position in oligonucleotide therapeutics by expanding and diversifying our technology, further optimizing our capabilities for existing therapeutic areas and opening up new areas for drug discovery. All of this sets us up to continue bringing a steady cadence of new and potentially transformational medicines to the market for many years to come. With that, I'll now open the call up for questions. Dave?
We will now begin the question-and-answer session. To ask a question, you may press star, then one on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing the key. If at any time your question has been addressed and you would like to withdraw your question, please press star then two. Our first question comes from Allison Bratzel with Piper Sandler. Please go ahead.
Hey, good morning, and, thank you for taking the questions. So I'm, you know, just looking at some of the subgroup analyses you referenced from the BRIDGE trial. It looks like olezarsen conferred really high triglyceride lowering in the sHTG patient subset, something like 80%. I mean, could you talk more about the read-through to CORE and CORE2, and also just expand on the unblinded open label extension data you referenced, and just what gives you confidence in success in those trials? And just secondarily, you know, looking at the sHTG BRIDGE subgroup, there looked to be a really high placebo response. So I know this is small N, but do you believe that would be representative of a placebo response in a larger study? Thank you.
Thank you, Ally, for the question. This is Brett. So, before flipping it over to Sam to expand on this, I'll just make a couple of quick comments. Yeah, the small number of patients that we had that qualified for the BRIDGE study, that were true sHTG patients, that is above 500 mg/dL , without necessarily having cardiovascular involvement, was really impressive, greater than 80% reductions at our 80 mg dose. And, we think it does speak directly to the mechanisms that are different between sHTG, underlying triglyceride management versus FCS, which Sam talked about earlier.
We want to be guarded on expanding anything more about what we've said about the early observations we've made in the open label extension in the core studies, beyond just saying what we said, which is it's encouraging because we don't want to get ahead of the readout of that study and, you know, and we just want to manage that until the study reads out fully. But now let me send it over to Sam. Sam, what do you think about the patient cohort and the placebo effect that we saw with those patients above 500 mg/dL?
Yeah, thanks, Brett, and good morning, everybody. So, you know, we tried to allude to the reason for our expectation that patients with sHTG should have a more favorable response to ApoC-III inhibition, and that has to do with the fact that they do have fairly normal or slightly reduced LPL activity. They also have very high ApoC-III levels, so the target is high, and they can bring both mechanisms into the effect. I think you're seeing some of that in the BRIDGE study. You are right that the placebo group had a reduction also, so we have to be careful how we interpret that.
But if you look at the kind of the totality of data that we published so far, from phase I, the prior phase II, BRIDGE, FCS, et cetera, what we are seeing a trend there that the sHTG patients are likely to be the best responders for this particular indication. And so we'll have to wait and see. In the CORE study, we're going to have very large numbers, but we're cautiously optimistic that we're going to have a very good response, relative to what we're seeing now in BRIDGE.
The next question comes from Gary Nachman with Raymond James. Please go ahead.
Hey, guys. Good morning. This is Denis on for Gary. Thanks for taking our question. Congrats on the strong data. Just given how rare the FCS indication is, and this would be the first drug approved for this indication in the U.S., can you talk about your expectations regarding diagnosis? How easy will it be to identify those early patients, and what do you think payers will require for coverage? And then can you just give a quick update on the enrollment status for the sHTG, sHTG trials? Are you enrolling at the rate you'd like to be enrolling at now? And are you comfortable with how the sites have been screening those patients? Thanks so much.
Thanks, Denis. Before I turn it over to Jonathan, to address the diagnosis, how we're going to go find these patients, and the payer question you had, let me just start with saying that the enrollment for the studies for sHTG are going extremely well. The ESSENCE study, as Sam mentioned, in his presentation, is completely enrolled with more than 1,000 patients with mildly elevated triglycerides to round out our safety database. And CORE, and CORE2, with nearly 1,000 patients in total, will complete enrollment very soon, with data expected in the second half of next year.
So we're pleased with the enrollment, and we're pleased with the quality of the patients we're seeing, and we're pleased with the performance in a blinded manner that olezarsen is offering in that study. Jonathan, would you like to talk a little bit about how we're going to find these FCS patients and the payer question?
Yeah, absolutely. I think Sam gave you a good overview on how FCS patients are diagnosed, and we're confidently behind the epidemiology and incidence rates that we've referenced, one to 13 per million. And the fortunate advantage we're in, is we've been in this therapy area for a number of years, and we've got a long history here, and we're certainly known to the physicians who treat these patients. So we're fairly confident that we've got a good understanding of where these potential patients are, and that'll give us focus at launch. Obviously, we don't expect this to be a huge patient population. It's rare disease, but that kind of transitions to your questions on the payer.
Clearly, from a payer perspective, we know, given certainly some of the clinical outcomes you've heard today in BALANCE, along with some of the economic impact that acute pancreatitis has on the hospitalization data, that this is meaningful for payers. Our market research has been overwhelming, that they're supportive of providing coverage for olezarsen and for FCS as a rare disease.
Great. Thanks so much.
Thank you, Dennis.
The next question comes from Jason Gerberry with Bank of America. Please go ahead.
Hey, good morning, guys. Thanks for taking my questions. Curious, you know, do you foresee LDL impact in the sHTG trials being more similar to BRIDGE or to BALANCE? Any mitigation strategies you have in place, in these phase III sHTG trials? And then if you can just, speak to your assumptions regarding how the AP data, the acute pancreatitis data in FCS might be reflected in your product labeling, and just any, any confidence that you'll be able to kind of, communicate that, that aspect of the value proposition to prescribing, physicians. Thanks.
Thanks, Jason. So, before I turn it to Sam, to address the, you know, what we expect on LDL, responses to olezarsen in sHTG and how that compares to BRIDGE and BALANCE, let me just address the label. So of course, the label is ultimately decided by the FDA, and we do not want to get ahead of ourselves there. However, we are preparing to submit to the FDA imminently. And, we're feeling pretty confident that we will be able to have a good amount of positive data on acute pancreatitis reduction in the label, in addition to the positive results that we got on FCS, potentially even the reduction in hospitalizations as well. So we're feeling good about the label.
We expect, you know, we're hopeful that olezarsen will be indicated for FCS patients in conjunction with proper diet. Sam, would you like to talk a little bit about the lipoprotein biology and impact in these different patient populations on LDL? And I would also love to hear Dr. Stroes follow you with his perspective as well.
Sure, yeah. Well, the bottom line is, that we're not worried about the LDL changes because they're all expected, and let me explain why. And these patients have high triglycerides, they have a lot of VLDL, and the cholesterol is stuck there, and so it doesn't convert normally to LDL. So what you see is in FCS, the average LDL is about 15, and in sHTG, about 60. And so what we're doing here is we're correcting that defect on the triglyceride part, and then it normalizes what happens to the LDL. So the LDL is not necessarily increasing, in an abnormal way, it's going back to its normal baseline. Some of these patients are going to have high LDL if they didn't have this triglyceride disorder.
So you would just treat it in a normal way you would treat with anybody that has an elevated LDL. You can put them on a statin, you can do whatever you need to do for their LDL, but now you've corrected the LDL, and you've also corrected the triglyceride disorder. So we're not worried about it. It's part of the pathophysiology, and I would say just expected part of the, part of the whole process of correcting the triglyceride part. Dr. Stroes?
Yeah, let me be clear. This is a complicated area. There's a lot of debate about triglycerides. Now, in FCS, as Sam alluded, LDL is completely irrelevant. In familial chylomicronemia, we're talking about lethal pancreatitis, so here, triglyceride reduction is key. And this is completely different from the trials like the BRIDGE trial. So in BRIDGE, you're actually talking not about the triglyceride content, about the cholesterol content, as Sam alluded, which is hidden within these triglyceride particles. So for BRIDGE, okay, what happens to ApoB? And it was very good to see in BRIDGE, that ApoB, the atherogenic particle for cardiovascular disease, reduced by -18%, which is a very good result. So when we talk about LDL, there's no relevance for the FCS, but there's a high relevance for what actually happens in the BRIDGE, and there it was positive.
Thank you, Dr. Stroes. Thank you, Jason.
The next question comes from David Lebowitz with Citi. Please go ahead.
Thank you very much for taking my question. Could you run us through the differences that would be in genetically defined FCS versus those who would be both genetically and phenotypically defined as FCS, and what impacts that could have on treatment efficacy?
Thank you, David. Dr. Stroes, it would be very insightful if you could provide your perspective on the definition and the diagnosis of FCS patients, genetic versus non-genetic, and then I'll follow up with a comment.
Thank you for this outstanding question because this is key. This is the most relevant question that you actually could ask. Because in FCS, we have five known genes, which, if homozygous, cause FCS because LPL is deficient. Now, as Sam showed, if you have the clinical diagnosis, so then actually we don't truly understand the pathophysiology, we know that there's an overlap in the phenotype. So they can have severe hypertriglyceridemia, and they can have pancreatitis risk. So if there is a true clinical diagnosis, then you still have some LPL activity residual, so you would expect a somewhat higher response, which resembles what we see in severe hypertriglyceridemia.
Now, what we show in the BALANCE study, that even in the worst of the worst population, so where LPL is completely absent, there we actually see a more than 50% reduction in triglycerides and a reduction in acute pancreatitis. Now, in the clinically diagnosed, the data would only be expected to be better because you have this dual mechanism of action, that you have two pathways whereby you reduce the triglyceride-rich lipoproteins. So I think the BALANCE sets the bar high because even in the worst population, we see this result. It can only become better in there where there's the clinical diagnosis. Sam?
Thanks, Eric. Yeah, I would agree with that, and don't have much more to add. We have a little bit of a hint of that in the APPROACH trial. You can read through the in some of the results. But we are the first to kind of get insights into these processes, so sometimes it's not always clear. But I think the bottom line is that the more lipoprotein lipase activity you have, the better response you will have in the system.
Jonathan, I would, I want to get your input on what payers you think payers will prioritize to reimburse FCS patients for FC that have FCS with, you know, for treatment of olezarsen before. So I just want to mention again, David, that we are pursuing an indication statement of FCS as an adjunct to diet, not necessarily genetic testing. That doesn't mean that, you know, the FDA obviously has final word on that, but that is what we will be pursuing. However, the payer story is maybe a little different. Jonathan?
Thanks, Brett. Yeah, I think you're absolutely correct. We would expect FDA to remain consistent with indication statements, where they try and provide consistency across products, particularly when they're in similar therapeutic areas. Obviously, from our point of view, the FDA approval is really the starting point, but critically after that come the payers. The payers, I think, when you're talking about rare disease and potential rare disease pricing, are very careful about making sure that the use of the product is controlled to the most appropriate patients. I think you've just had both the clinical opinions on who an appropriate FCS patient is. I think the payers will definitely want to ensure that these patients are appropriately diagnosed before they provide access, and that's clearly critical.
Jonathan, just to add on this, it's interesting. The other rare disease, which we see a lot, is homozygous familial hypercholesterolemia. There, the identical discussion has been had with the FDA. Do we only allow genetically confirmed homozygous familial hypercholesterolemia, or do we also allow the clinical diagnosis? I'm happy to see that slowly the FDA is allowing the clinical diagnosis of homozygous FH, although obviously that's a different disease, but it gives hope.
Thanks for taking the question.
Thank you, David. Next question, please.
The next question comes from Jay Olson with Oppenheimer. Please go ahead.
Oh, hey, congrats on these impressive results, and thank you for providing this update. In BALANCE, can you talk about what happened to the two patients on olezarsen who had acute pancreatitis events? Were those events caused by eating a fatty meal? And recognizing the massive lifestyle restrictions associated with following a super low-fat diet, could you expect FCS patients on olezarsen to be able to eventually return to a relatively more normal diet in terms of fat content and still avoid acute pancreatitis episodes? Thank you.
Thank you, Jay. I'll ask Sam to address the two pancreatitis events, the one in the 50 mg dose and the one in the 80 mg dose that we did see. I don't think we know too much about it, but maybe Sam, Sam could expand on that. And I'd also like to have Dr. Stroes talk a little bit about whether he thinks that patients will be able to have a slightly more normal diet once on a treatment like olezarsen. Sam?
Yeah. Thank you. That's a good question. We've actually looked at our data very carefully in that regard to find predictors of pancreatitis. And surprisingly, or maybe not surprisingly, it's very hard to identify a specific cause in these patients. And part of the reason that you can't link what they ate the day before to the next day, because when they eat triglycerides, the chylomicrons in their circulation could be from, like, the week before. There's also a lot of differences in terms of what they eat, when they eat alcohol, et cetera. So we did not identify any specific dietary issue in these two patients, like the day before, that we could relate to it. The only thing that we could say is that on average, the placebo patients have a lot of excursions.
It's possible these two patients had excursions also, but on average, they don't in the whole study. We'll have to look into this a little bit more carefully, and maybe we'll find an answer, but chances are we're not. We're going to have to just get larger databases as we go forward and try to identify any factors going forward.
Yes, Sam, I fully agree. It's the one thing which is interesting, the what Sam already explained, it's the postprandial peak, which is also very relevant when we think about pancreatitis. Now, if you lower fasting triglycerides, your postprandial peak or area under the curve will also decrease quite profoundly. So let me very carefully state that we maybe hope to see some slack in this very rigid diet, but at present, I would be very careful. It's not likely that you can completely say in these very rare patients, you can say, "Well, you can skip all your diet restrictions," but there could be some further loosening of the very strict, horrible fat restriction.
Great. Thanks for taking the question.
The next question comes from Yanan Zhu with Wells Fargo Securities. Please go ahead.
Great. Thanks for taking the question. Sorry, I'm sorry for the noise. I'm at an airport. So was wondering, for the acute pancreatitis events, you know, 80 mg group, I think the top line data from last year was that there was no AP event, and with this read out, there was one event. Could you speak to that? And also, in terms of the go-to-market strategy and pricing, I think you alluded to that sHTG probably warrants a very high rare disease drug pricing. But thinking ahead for the sHTG launch in 2025, 2026 timeframe, how do you think the price could change there? Thanks.
Thank you, Yanan. I'll ask, I'll have Jonathan address the pricing for FCS and sHTG. I'll take the first part of the question. When we first re-reported out the top line data, it was top line, we did report zero events, AP events, in the 80 mg dose cohort. Our clinical team then really dug much deeper into the data, and we thought we identified a typographical error on a calendar date, which we thought could have been an event within the treatment period time. We brought that to the adjudication committee, the DSMB adjudication committee, and we asked them to take a closer look at it, and they confirmed that that was one event right at the end of the study. That was that one year, almost one, near one year mark during the treatment, the slide that we showed, which happened. So that's all that was. Jonathan, pricing?
Thanks, Brett. Yeah, great question on pricing. As I alluded to earlier, we're expecting to go with a rare disease pricing strategy for the first FCS indication. Clearly, as we've discussed today, that's a relatively small patient population. However, there's a huge unmet need, as I think you've heard this morning. And importantly, we believe we've had some excellent data in the BALANCE study, whether that's the acute pancreatitis data or the hospitalization data, which coupled with the insights we got from payers, means that we'll be able to achieve reimbursement in that population. Obviously, the second indication that is a couple of years away is a very different patient population. There's potentially one million patients in the U.S. with triglyceride levels over 880 mg/dL, possibly three million over 500 mg/dL. That represents a large patient number.
At that point, we'd expect to transition our pricing strategy to one more accustomed to more routinely used, mainstream cardiovascular medicines. Obviously, at this point, as you've heard from Sam, we don't have data, so we don't have a true understanding of the benefit of the product in that indication. And until we get that, we won't be able to confirm any, specific pricing. But I hope you, I hope that gives you some insight into how we're thinking about it.
Got it. Thank you.
Thank you, Yanan.
Next. The next question comes from Jessica Fye with JP Morgan. Please go ahead.
Hey, guys. Good morning. Thanks for taking my question. Curious about your expectation for the rate of acute pancreatitis in CORE and CORE2. Recognize that that should be a lower rate than in the FCS population, but we've also got larger studies here. So curious how you think about the intriguing possibility or, or likelihood of being able to show a separation on pancreatitis events in that sHTG population.
Thank you, Jess. Great question. Sam, to you to address, you know, what we think we're going to see with respect to incidence of AP, and maybe Dr. Stroes could talk a little bit about what he expects that we're going to read out on AP and sHTG, where we think we'll land.
Yeah. Well, I think there's a couple of themes here. Of course, we can't predict the future, but one of the themes is that if you look at the volanesorsen data and the olezarsen data, we're basically getting single-digit events in the treated arms. So we anticipate most of the pancreatitis events that we're going to see in these CORE studies are going to be in the placebo group. So we're cautiously optimistic, but we have to wait. We're going to use look at pancreatitis as a secondary endpoint, so we're confident from that regard, where we're going to put it. Now, what about the numbers? Well, as you look at these studies, we have 66 patients in BALANCE. In the prior sHTG study, we had 114 in volanesorsen. We had five cases of placebo, zero in volanesorsen.
In these two studies, we're going to have close to 900 patients, and we'll be able to actually analyze the data separately and together. So we're going to be about nine times larger than any study that we've done so far in sHTG. And so we feel good about it, but we have to wait for the data, and you know, we'll see how it goes.
Thanks.
Yeah, it's very complicated. So we know, as I showed you, that the risk increase in FCS is ridiculously high. Now, at SHTG, we know that from the value of 880 mg/dL onwards, there is an increased risk. But I think Ionis made a very wise choice to put a secondary endpoint because, despite the fact that you have a tenfold higher study, you have to weigh this with the lower risk since you don't have the genetically confirmed FCS diagnosis. So I'm looking forward to the integrated overall evaluation, and I think that's what regulators want to see, because we know that there's a continuum of increased triglycerides and increasing the risk. So it's very difficult to predict the true prevalence of new-onset pancreatitis in the CORE studies. And it, we know one thing, it will be lower than in the BALANCE study.
Can I just chime in with a follow-up? Do you guys see, or are you able to track the kind of overall blinded rate of AP events as they accrue in the CORE studies?
Yes, we can, Jess, and I don't wanna go too far on talking about, you know, unblinded data, but I can say that indeed, we are seeing in, you know, it's unadjudicated for the most part today, but we are seeing blinded AP events in the CORE studies.
Thanks.
The next question comes from Paul Matteis with Stifel. Please go ahead.
Hey, this is James on for Paul. Thanks for taking our question, and congrats on the data. I just wanted to follow up on the Bridge sHTG subgroup. And so, you know, you mentioned that you expect to see that, like, a similar rate of trig reduction on drug, but that sounds like maybe you're hoping for, like, a lower placebo response. I guess, one, is that a fair way to describe it, that you're hoping for a lower placebo response? And two, I guess, what is that placebo-adjusted delta you're looking to get and think you need, and, you know, what gives you confidence you can get there? Thanks.
Sam, take that. Just wanna make one quick point. The placebo group in that subgroup of patients above 500 mg/dL in the BRIDGE was four patients, four people. So with more people in a properly sized, you know, placebo group, we would expect that noise. If it is indeed noise, we expect it to be reduced considerably. But Sam, maybe you can talk a little bit about that and the magnitude of TGs that matter most for to show reductions on in the CORE studies, what we're looking for.
Sure, yeah. Well, you know, I think if you look at the placebo changes in our other studies, for example, in BRIDGE and in the prior phase II study, they are less than 10%. So that should be what we're gonna see, somewhere ±10%. In the first phase II study, it was actually an increase of, like, 7%. So the placebo-adjusted reduction with the 50 mg dose was actually 69%, right? So when you kind of look at that number, now the BRIDGE was a little bit less, less of a difference.
So, you know, the 83% that we saw in these four, you know, small number of patients, you have to take that with a bit of grain of salt, but it does tell you the potential for the drug to really have a very potent effect, 89% reduction in ApoC-III. So maybe the truth will be somewhere, you know, around there. We can't say it's gonna be that good, 83%, but, we're feeling confident that, those patients will respond well. They have very high ApoC-III levels. They start high, so they should go very low, and, we just need to get the trial done and, and get you the real data. But, it should, you know, we feel confident that we're gonna have a really good reduction based on what we've done so far.
Makes sense. Thank you.
The next question comes from, Debjit Chattopadhyay, with Guggenheim Partners. Please go ahead.
Hey, good morning. Could you elaborate on the likely comorbidities one is likely to encounter in the CORE 1 and CORE2 studies and how that might impact the overall safety versus what we saw in the BRIDGE study?
Sam, comorbidities in CORE studies, any relation, do you think that patient population is gonna have similar comorbidities as we've seen in BRIDGE?
I think they're gonna be actually more severe. And for example, diabetes should be fairly high. It's gonna be over 50% or more. There's gonna be a fair number of pancreatitis cases, which we didn't see in the BRIDGE trial, right? Because those were all lower. There's gonna be cardiovascular disease along with the pancreatitis. And these patients, by the way, are gonna be intensively treated as part of our protocol. We don't want anybody to claim that these were undertreated in terms of looking at the olezarsen response. So most patients are gonna be on two drugs or more. So it's gonna be a well-characterized population. They're gonna have obesity, they're gonna have diabetes, they're gonna have history of pancreatitis, they're gonna have a lot of metabolic disturbances, inflammation, high CRP.
So I think there would be higher risk than from the perspective of metabolic disease than BRIDGE, but they're probably gonna be typical of what's out there, and these patients need to be, you know, comprehensively treated, and this isn't even any one aspect of their treatment.
Got it. And one follow-up: On the commercial side in Europe, how much of the prior infrastructure do you still have available? Or what's the spend gonna look like to launch in Europe?
So, Debjit, just a quick reminder that our earlier generation molecule Waylivra, which is now commercialized for FCS in Europe, is being managed by a distributor, Sobi, in the E.U. market. So, our commercial organization is minimal in Europe today, almost non-existent. However, our commercial strategy is to focus on the U.S. market for our launches. So, that's what we're preparing for now, and as Jonathan laid out earlier, we are prepared, as right where we should be, for the independent launch of olezarsen in the United States, as soon as we get approval.
We will identify and seek and secure ex-U.S. commercial partners to ensure that olezarsen is available globally. We're very pleased with the interest in olezarsen that we've had to date in partnering not only in Europe but around the globe. So stay tuned for that. But we are focused on the U.S. market, and our capabilities will be ready to go as soon as we get approval.
Thank you.
The next question comes from Luca Issi with RBC. Please go ahead.
Oh, great. Thanks so much for taking my question. Congrats on, on the data. Just a quick question for Sam and Dr. Stroes. Maybe following on the prior conversations on the impact on cholesterol, have you done any imaging? Have you performed any coronary CT angiography? Again, given the impact on ApoB and non-HDL, just wondering if this drug can maybe even have an impact on coronary plaques. So again, any call there, much appreciated. And then maybe, Brett, following on the prior questions on CORE and CORE II and the blinded AP event rate. In a scenario where the event rate is lower than your projection, do you have flexibility to make the trial longer and/or larger, similar to what you have done for PPR cardiomyopathy? Thanks so much.
Sam, you want to take the what we're doing on imaging?
Yeah. So first of all, let me just emphasize that our focus here is FCS and sHTG, so we really need to get these patients treated for pancreatitis. However, what your question is alluding to, the cardiologists, you know, they wanna go beyond that. And so right now, even though we're focused on the higher populations, we would like to get some profile-enhancing data to help with some of these discussions later. So you saw the ApoB data, it's fantastic in BRIDGE. But we have built in two kinds of imaging in the CORE studies. One, we're actually doing MRI scans of the liver in both CORE studies. And if you recall, we published a meta-analysis of our three volanesorsen studies, and we've had between a 20% and 50% reduction in hepatic fat fraction in each one of the studies.
So that was the average. Olezarsen is similar to volanesorsen in that regard, in terms of the drug and the mechanism. So we want to see if we can actually reduce liver fat, along with having all these benefits on pancreatitis and the metabolic corrections of triglycerides. On the other side of it, in the ESSENCE study, which is more of a cardiovascular population, we have built in the largest CT angiography study in the lipid space for triglycerides. It's gonna have a very large number of patients, and we are gonna be looking at both plaque volume and plaque characteristics. We also would be able to look at pericoronary fat content, and we're gonna be able to look at liver fat with the CT.
So we're gonna have a wide variety of imaging technologies to put into play for looking at the coronary arteries, the pericoronary fat, and the liver in these patients. So hopefully, that will give us additional insights to go beyond what we're currently focusing on, but that's, that's for later. But we are gonna have that information available at the same time as the other studies read out.
Sam, I agree it's for later, but as you're, you're being a little bit modest, because what we learned over the last 20 years, we have extensive data showing that the cumulative LDL burden is a critical determinant of the total plaque volume at the coronary, coronaries. But now we also know that we have drugs that can lower LDL to enormously low levels. The biggest challenge now is that we're facing all these obesity, diabetes patients, where LDL is not the problem, but the cholesterol in the triglycerides, the moderate triglycerides, is the problem, and we don't have any drug to combat that. Now, there is already data showing that indeed, ApoB and remnant cholesterol also correlate in that patient category with the total plaque volume. So if we extrapolate these data, I think you've been critical in making this such a beautiful, large trial.
Because if we now can extrapolate the lessons from LDL lowering to reducing ApoB remnant cholesterol, also reducing total plaque volume, I think that's going to be a crucial step in transitioning this drug from the solution for FCS to also being a solution for resolving residual remnant cholesterol risk in the cardiovascular arena.
Thank you, Sam. Thank you, Dr. Stroes. Luca, as you know, our primary endpoint, which is what we're laser-focused on in the CORE studies, is triglyceride lowering. And as Sam and Dr. Stroes just took you through, we have a lot of profile-enhancing studies throughout, you know, ESSENCE and the CORE and CORE2 studies to further round out the profile for olezarsen, in addition to, you know, what we hope to see in acute pancreatitis events. As I mentioned earlier, we are seeing events in a blinded manner. They'll still require adjudication, and the study hasn't even completed enrollment yet, so we still have a good year to go to accumulate more and more events.
You know, we don't, I see no such scenario in which we would delay the study in any way and impact our extensive first-mover advantage to get to the sHTG market and patients by making the study bigger or making the timeframe longer. We will complete enrollment in CORE and CORE2 soon, and then read the study out next year. As a reminder, I think Sam mentioned this earlier, we will look at AP events not only in CORE and CORE2, but we can also pool those two studies to have the largest dataset for acute pancreatitis, you know, to potentially be able to measure differences in acute pancreatitis. You know, we saw zero events, almost zero events.
One event in 50 mg group for FCS in the BALANCE study and one event in the 80 mg group. And if that in any way translates to the sHTG population, you would think that the majority of events, if we are indeed accumulating events in the study, are gonna be in the placebo group. We'll have to prove that. But if FCS in any way translates to sHTG, we should be in a pretty good place.
Thanks so much. Appreciate it.
The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.
Thank you for taking our question. This is Tommy on for Salvin. Just to follow up on a previous question about payers, how are you thinking about the receptivity for covering olezarsen in patients before they have events, versus in patients who already have a history of events? Thank you.
That's a great question, Tommy. Jonathan, please, please take that.
Thank you. I think in the FCS patient population, the history of acute pancreatitis is pretty large. It's about 85%, so that's pretty overwhelming that these patients have had an event. And once you've had one event, I think the history would dictate that you're more likely to have a second event. So I think the BALANCE data and the significant difference in the AP events means that from a payer perspective, I don't think there's any sort of further subgroup or cuts to that overall patient population that's fundamentally got a huge unmet need with no current treatments available. This is a condition that you know, physicians have been desperately trying to treat and to help these patients for a long, long time.
I think we've talked at length today about the economic benefits that potentially have also been demonstrated in BALANCE, and therefore, we don't really see a difference in the overall FCS patient population. They need, and they have to benefit from a treatment like olezarsen.
And Jonathan, I would add it. I think from a clinician point of view, it would be ethically unacceptable if we were actually told that these patients with an extremely high lifelong risk on acute pancreatitis, as Jonathan said, to say, "No, we're gonna wait for your first event, and only then can you start this drug." It's a rare disease, and mind you, the first event could be a fatal event. So I don't think that they will actually restrict it to only FCS who have had a pancreatitis event; it would be highly unacceptable from a clinical point of view.
An analogy that I often think about, with to that question is the use of LDL-lowering agents to prevent the first heart attack from happening, right? You do not want to wait for an event to occur before you prescribe a statin, for example. We believe that olezarsen will be positioned similarly to acute and potentially fatal outcome, such as acute pancreatitis. As I mentioned earlier, we're gonna pursue a label; it's the FDA's decision, ultimately, of course, for use of olezarsen in FCS patients as an adjunct to diet, not without genetic testing, without a history of pancreatitis.
The next question comes from Yaron Werber with TD Cowen. Please go ahead.
Hi, this is Brendan on for Yaron. Thanks for taking the questions. Congrats on the data. Just a quick one from us, and apologies if I missed this, but I'm really looking at slides 27 and 28. Just kind of piggybacking on a couple of questions that touched on this. I'm wondering if you can confirm that the couple of FCS patients, it looks like two each in the 50 mg and 80 mg cohorts, who saw the ApoC-III actually increase by 12 months. Those are among the patients who also saw the triglycerides increase, and then if those are also the patients that saw the cases of pancreatitis.
I guess in that same vein, I'm kind of just wondering if you observed anything about those patients that might suggest why they had that response and whether that might potentially be predictive. Thanks very much.
Yeah, the Sam, those, those patients that did not have an ApoC-III reduction dropped out of the study, right?
Yeah. So what ends up happening here is if somebody drops out before the end, we have to impute their values, and we have to impute them according to placebo data. And that's described in the statistical analysis plan in both studies. So what these are are basically imputed values or that somebody dropped out earlier, so we have to assign a value to them. So they look like they're not responding, but it's because they didn't have the final time point. So the explanation is that the other question, I think, was whether. Sorry, was the same patient?
Triglyceride and ApoC-III, no response the same.
Yeah, it's the same thing. They have to impute the values at the end there. So, bottom line is, I don't think we had any true non-responders that stayed on the drug for the duration of the study.
And can I add, having been involved in FCS studies for a lot of years, let's go back to reality. What we actually want to know is the area under the curve for a prolonged time period, because LDL lowering is reproducible and et cetera, and it's stable, and you can measure it on a one-time occasion only. For triglycerides, we know that it's extremely variable, so even if there would be less response on one particular occasion, we still would look at the month period, because diet, we can't put it away, diet always has an impact on triglycerides.
Thank you, Dr. Stroes. Thank you, Brendan. Next question.
The next question comes from Myles Minter with William Blair. Please go ahead.
Hi, Dr. Minter. Miles, thanks for fitting us in, and congrats on the impressive data. So a couple from us. First, can you provide any color or rationale for the spike in triglyceride levels around the six-month time point in BALANCE, in that 50 mg cohort? And does this data confirm then the need for that 80 mg dose, to achieve stable ApoC-III knockdown? And secondly, is 750 mg/dL and below considered a clinically accepted level of triglycerides that's associated with reduced pancreatitis risk, or is there kind of some other clinical benchmark we can look to, and what percent of patients achieve that level in BALANCE? Thanks.
Sam, you want to address that?
Sure. Well, I think Eric alluded to it. When you do these endpoint trials, there are two variables. One is what your drug is doing to your triglycerides. The other thing is, with every single meal these patients eat, if there's a triglyceride in that meal, it's gonna go into your endpoint. And so we believe, it's very hard to prove it, but we believe this likely represents dietary variations right before the endpoint in the 50 mg dose. Because if you look at that curve, you have a nice response at three months, it stays down, and then you have this spike, and then it comes right back down the next month and stays down the rest of the time. So something weird happened there. It's, the most likely explanation is dietary discretion. We're trying to find out more details about that.
If you look at the area under the curve, though, so take away the single time point, you know, 9:00 AM. the day they had their blood test, look at the whole year, the area under the curve is markedly reduced. And I think this is why the pancreatitis is so, so good in a 50 mg dose versus to the one single time point. So I think that's the explanation. It's the variability in triglyceride measurements and small numbers, too. You know, we only had 22 patients in this arm. Remind me, sorry, I blanked on your second part of the question.
What's the relevant cutoff for.
Yeah, the relevant cutoff, yeah. So we know. Yeah, I remember now. Sorry. We know what the cutoffs are for, or the thresholds for getting pancreatitis. Your question, though, is we are the first to try to address that question with this study. This is the first study that's telling us, well if you start high, where can you go get a benefit? And so this is something that the field is gonna have to address. I can't say we know right now, if you get it down to 750 mg/dL or you get it under 1,000 mg/dL or under 1,500 mg/dL, there's some threshold. We need to get more studies in the field and kind of organize them. But what this is telling us is, you know, a 50%-60% reduction of 80 mg dose does the job for the most part. It's not perfect, but it's pretty darn effective.
Sam, let me maybe add a little bit to that. If you look at slide number 29, this is actually the first study where we saw a reduction in acute pancreatitis, which we were thrilled with. But if you look at slide 29, you can see that both 50 mg and 80 mg have a lower frequency of new onset pancreatitis events. So maybe this first trial gives us an insight that saying at which, border pancreatitis will not occur, may be an oversimplification of the true answer to this question. It could actually be, what's the fluctuation in the triglycerides? What's the postprandial increase in triglycerides? We see now that when we come to 1,500 mg/dL , we see a numerical, quite impressive reduction in new pancreatitis events.
So that's not what Joe Brunzell hypothesized more than 30 years ago when he said, "Well, it's all around the 20 mM or..." So this, this is quite new data, and I think if we proceed with all the new studies that come, the CORE and the CORE2 study, hopefully, we will be able to translate that two-dimensional question of what's the border below which you don't have pancreatitis, into what are the totality of factors which reduce the risk of recurrent pancreatitis? And I would predict it's not going to be one single border number of 1,500 mg/dL . It's going to be a little more intelligent and integrated, and, and we really look forward to providing that answer within the next two years or so.
Thank you.
Very helpful. Yep, thank you.
Thank you. Looking at the clock, we have time for one more question.
The next question comes from Kostas Biliouris with BMO Capital Markets. Please go ahead.
Thanks for taking my question, and congrats on the data. Maybe one quick question on the discontinuation rate for the two studies, and what are the major drivers for discontinuations, given that, patients have very limited alternative treatment options, if any? Thank you.
Sam?
I can take that. So for BALANCE, we had six discontinuations. Two patients moved out of the area for where the trial was being done, so they dropped out. One was a voluntary withdrawal, had to do with sort of work-related issues. There was one death that was non-related to the drug, that was number four, and then there were two patients that had a variety of symptoms that were drug-related, so flushing, GI discomfort on the initial dose. So the other 60 patients all went into the open label, which is pretty amazing to think 100% of patients that finish the study go into this. That just tells us for the FCS population, these patients are hurting. You know, they need this drug. They know it, they stay in.
For the sHTG study, these are patients that are completely asymptomatic, and so to them, you're just putting them in a trial and you're treating a biomarker, and they don't really see the benefit of that as much. They're only gonna get treated for a year, and then there's no open label, so they don't have as much motivation. We looked at this, the discontinuation rate in those patients, and there was a hodgepodge of things. There wasn't really anything that we could say that was the reason. So it was a combination of different things. And so I think the FCS tells you, the patients, you know, have had pancreatitis or feel sick from their disease, we're not gonna have that compliance issue. Compliance is a problem, though, if somebody's asymptomatic and sees no benefit to them. So it's a little bit of that.
We'll see what happens in the core studies, where the clinical imperative for these patients is gonna be much higher.
Thank you very much.
Thanks, Kostas. And that brings us to the close of our webcast. So, let me just say in closing, thank you to everyone who participated in our webcast today, and a special thank you for the outstanding input, insights that Dr. Stroes has provided for us today in the webcast, as well as the lead investigator on our BALANCE study. And I want to thank my colleagues at Ionis, Sam, Jonathan, and Kyle for their good work as well. We look forward to providing more updates on the olezarsen program and also all the great progress we're making across the business here at Ionis throughout this year and beyond. So with that, have a good day, everybody. We look forward to talking again soon. Bye now.
The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.