Good morning, and welcome to Ionis's conference call to discuss the mechanism and biology behind olezarsen and the top-line results from the phase III BALANCE study. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Wade Walke, Senior Vice President of Investor Relations, to lead off the call. Wade, you may begin.
Thank you, MJ. Thanks, everyone, for joining us today. During our call today, we'll discuss the biology of FCS and review the positive top-line results from the phase II BALANCE study of olezarsen, and provide an overview of our plans to deliver olezarsen directly to FCS patients, assuming approval. Before we begin, I encourage everyone to go to the investor section of the Ionis website to view the press release we issued this morning, as well as the slides we will be using on today's webcast. I'd 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.
Our agenda for the call today will be as follows: Brett Monia, Chief Executive Officer, will provide an introduction. Sam Tsimikas, Senior Vice President, Global Cardiovascular Development, and the leader for the olezarsen development program, will review FCS biology and the significant needs these patients have for a safe and effective treatment. He'll also review our olezarsen clinical program and then discuss the positive top-line results from the phase III BALANCE study. Next, Onaiza Cadoret-Manier, Chief Global Product Strategy and Operations Officer, will discuss our commercial plans and preparations to provide olezarsen to FCS patients, assuming approval. And now I'd like to turn the call over to Ionis CEO, Dr. Brett Monia.
Thanks, Wade, and thanks, everyone, for joining us this morning as we discuss the positive data from our FCS BALANCE study and our plans to provide this important new investigational medicine to FCS patients. We believe olezarsen represents one of the most meaningful opportunities in our pipeline today. As our most advanced wholly owned medicine, the positive top-line results from the phase III BALANCE study represent a significant milestone on Ionis's path to commercializing our own medicines. Our preparations to launch olezarsen and our other near-term commercial opportunities, eplontersen and donidalorsen, are nearly complete. As a result, we're ready to take the next important step in the evolution of our business, delivering a steady cadence of new medicines to patients in need.
We also continue to make excellent progress across our other two key strategic priorities, and I look forward to talking to you more about our progress in these two areas, in addition to our pipeline and our commercial plans at next week's Innovation Day event. Now turning attention to FCS. FCS is a severe, genetically driven disease in which patients lack the ability to metabolize triglycerides, which results in a significant risk of acute, potentially fatal pancreatitis. In the U.S., there are no effective treatment options approved for patients with FCS. It is because of this clear unmet need that we have worked so hard to make the promise of olezarsen a reality for FCS patients.
Today, we're pleased to report the positive results of the phase III BALANCE study of olezarsen, our medicine designed to target apoC-III and reduce the serious complications associated with extremely high triglycerides in FCS patients. As Sam will review shortly, olezarsen at the 80 milligram dose demonstrated statistically significant reductions in triglycerides, robust target engagement, and a highly favorable safety and tolerability profile, consistent with the profile seen with our other LICA medicines. In addition, olezarsen demonstrated substantial and clinically meaningful reductions in acute pancreatitis attacks. This is remarkable because it is the first time a lipid-lowering therapy has ever achieved a result like this in a clinical trial setting. Based on these results, together with our potential first-mover advantage, we believe that olezarsen, if approved, could be an important new treatment for patients with FCS.
Looking ahead, our next step will be to file for marketing approval in the U.S. and E.U. in the first half of next year, positioning olezarsen for its first potential approval as early as year-end 2024, assuming priority review in the U.S., with a launch to follow shortly thereafter. In addition to our clinical development program for FCS, we also have an ongoing program for patients with severe hypertriglyceridemia, or sHTG. phase III studies in sHTG patients are ongoing, and we expect those studies to read out in late 2024 or early 2025, depending on how enrollment goes. 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 highly positive results we reported today.
With that, I'll pass the call over to Sam to discuss the urgent need associated with FCS, after which he'll review the positive BALANCE study top-line results. Onaiza will then review our commercial strategy and launch preparations. I'll then provide some concluding comments, and we'll open the call up for questions. And with that, I'll turn it over to Sam.
Thank you, Brett. Before I begin, I'd like to thank the patients, families, and clinicians who participated in the BALANCE FCS study and made today's important announcement possible. We understand how difficult it can be for patients with familial chylomicronemia syndrome, or FCS, to live with a disease that negatively affects their quality of life. They need to think ahead about what they can and cannot eat and constantly worry about the food they eat could give them severe abdominal pain or sent into the emergency room with acute pancreatitis. These patients lack the ability to metabolize triglycerides from their diet, and as a result, develop chylomicronemia, a form of milky plasma that contains excessive amounts of triglycerides. This leads to several complications, including acute pancreatitis. It was for these patients that we set out several years ago to develop a new medicine to address this serious problem.
Our goal was to improve their chances for a life without the constant threat of acute pancreatitis and to improve their quality of life. It's because I've seen firsthand the heavy burden FCS places on these patients that I'm pleased to talk to you today about a potential new medicine that could effectively treat this disease and its complications. But before I review the olezarsen Phase III BALANCE study top-line results, I want to provide an overview of what causes FCS and how we designed olezarsen to help these patients. Triglycerides are a type of lipid that is essential for multiple biological functions, and having too much of it in the bloodstream leads to severe complications.
Triglycerides are either derived from the diet or made by the liver and are transported in the blood to various tissues, like muscle adipose tissue, in particles called triglyceride-rich lipoproteins, or TRLs. TRLs are highly enriched with multiple copies of apoC-III on their surface, which impedes clearance of these particles, resulting in their accumulation in plasma. The TRLs most commonly associated with FCS and acute pancreatitis are the chylomicrons and chylomicron remnants, shown here on the top right in black. These are dietary-derived and directly reflect the fat intake during meals. The other TRLs, shown in blue, are IDL, VLDL, and VLDL remnants. These are made by the liver and exported to the circulation as a method to export excess energy to muscle and fat cells. These particles are more closely associated with cardiovascular disease.
FCS is a rare disease in which the majority of patients develop acute pancreatitis. These patients have genetic mutations that result in deficient activity of the enzyme lipoprotein lipase, or LPL, or proteins that facilitate LPL activity. LPL is responsible for breaking down the triglycerides found in VLDL and chylomicrons. Lack of LPL activity results in fasting triglyceride levels that can range from 10-100 times higher than normal levels. The vial of blood on this slide is from an FCS patient. Typically, the layer above the red cells is a light yellow color. In this patient with FCS, dietary-derived chylomicrons in the blood float to the top and are seen as a layer of fat above the red cells. In people without FCS, dietary fat clears from the blood in 4 hours-12 hours after a meal.
But in patients with FCS, it accumulates and may not clear for days, weeks. In addition to pancreatitis, FCS patients also suffer from a number of chronic conditions such as nausea, diarrhea, and severe abdominal pain, particularly after eating. Patients also experience debilitating fatigue and cognitive impairment, including difficulties with memory and comprehension in what patients call brain fog. These and other symptoms make it difficult for patients to work and to carry out activities of daily living. For these patients, current triglyceride-lowering therapies are not effective at lowering their triglyceride levels. Their only option to reduce the risk of pancreatitis is an extremely difficult-to-maintain diet that limits fat intake to less than 20 grams per day or the equivalent of less than 2 tablespoons of olive oil. An important distinction between FCS patients and other patients with elevated triglycerides is the genetic component that underlies each group's elevated triglycerides.
FCS patients can be diagnosed through both clinical criteria and genetic confirmation. Genetic variants are associated with a loss of LPL activity, which results in an inability to break down the triglycerides carried in TRLs, such as chylomicrons and VLDL. On the other hand, many non-FCS patients with high triglycerides have more than one genetic variant in genes that are associated with triglyceride metabolism and/or clearance. Patients with severe hypertriglyceridemia, or sHTG, can often have two or more of these genetic variants, often together with a second contributor, such as diabetes, metabolic syndrome, or obesity. To prevent complications from the accumulation of chylomicrons after a fatty meal, the body needs to remove them from the circulation as soon as possible. This occurs via two mechanisms, both of which are regulated by apoC-III. The first involves LPL, which metabolizes triglycerides and makes the particles smaller.
You can visualize this as an ice cube melting. The second mechanism uses three liver receptors, shown here in the middle of the slide, to remove TRLs from the circulation. Since FCS patients lack LPL activity, they are entirely dependent on the second, less efficient clearance mechanism as the only way to clear chylomicrons. Patients with FCS have 5-10 times higher levels of apoC-III, which delays clearance of these chylomicrons. This in turn, in a complex series of events, ultimately obstructs pancreatic ducts, causing digestive enzymes to leak into the pancreatic tissue instead of the intestines, which results in severe inflammation associated with acute pancreatitis. In view of the critical role in affecting chylomicron metabolism in patients with FCS, we created olezarsen and designed it to decrease the production of apoC-III.
We believe that by preventing apoC-III accumulation on chylomicrons and chylomicron remnants, that these particles will clear faster and thereby prevent the most serious complication of FCS, acute pancreatitis. Natural history studies provide evidence that inhibiting apoC-III is associated with a positive effect, which we aim to replicate with olezarsen. People who carry a null mutation in the ApoC-III gene have no circulating apoC-III levels. The result of this mutation is a dramatic reduction in plasma triglycerides in the range of 30 milligrams per deciliter, compared to normal levels of less than 150 milligrams per deciliter. Furthermore, on challenging these people with a high-fat meal, the increase in plasma triglycerides is significantly blunted. This is the same biological effect we were hoping to replicate with olezarsen's inhibition of ApoC-III production.
Let's review the overall development plan for olezarsen and show you how the top line results from the BALANCE study fit into the larger program. On the left is an overview of our program supporting our FCS indication. This program consists of a phase II study, an open label extension study, and a phase IIb study that we designed to provide the patient exposure needed to support the NDA filing. With positive BALANCE study results in hand and our phase IIb supportive study on track to complete later this year, we plan to file for marketing approval in the U.S. and E.U. in the first half of next year. Assuming priority review by the FDA, olezarsen could be approved as early as year-end 2024 in the U.S. We are also conducting three phase III studies in support of our sHTG indication, much larger patient population.
Our pivotal studies for this program are called CORE and CORE2, both evaluating olezarsen in patients with sHTG who have triglycerides over 500 milligrams per deciliter. In our third study, ESSENCE, we are evaluating olezarsen in patients with triglycerides above 200 milligrams per deciliter. The purpose of ESSENCE is to satisfy our patient exposure requirement to support marketing approval for the sHTG indication. We estimate data readout for CORE, CORE2, and ESSENCE in late 2024 or early 2025, depending on enrollment, putting us on track for potential regulatory filing in 2025. And now let's review the positive top-line results from the BALANCE study. BALANCE is a global randomized, placebo-controlled study that enrolled 66 adult patients with FCS and fasting triglycerides greater than 880 milligrams per deciliter during screening, with the majority of patients having a history of pancreatitis. All patients were genetically confirmed.
Patients were randomized in a 2:1 ratio to either 50 or 80 milligrams of olezarsen or placebo, administered monthly by Sub-Q injection for 12 months. Patients in the study were expected to be on background lipid-lowering therapy. The primary efficacy endpoint in BALANCE is percent change in fasting triglycerides from baseline to 6 months of treatment compared to placebo. Key secondary endpoints, including reduction in triglycerides at 12 months, reduction in the target ApoC-III, and reduction in acute pancreatitis attacks. Following completion of the phase III study, patients could enter into an open label extension. This slide shows the patient disposition from the study. Over 90% of patients finished the study. I'm pleased to tell you that 100% of the patients who completed treatment chose to enroll in the open label extension.
From this slide, you can see that baseline characteristics in the study were generally balanced across key parameters. Most patients were in their mid-forties, and most patients had average weight and BMI, typical for FCS patients who are compliant with the recommended restricted fat diet. The majority of patients had experienced at least one pancreatitis attack in the last 10 years, and a significant number of patients have experienced at least one attack in the last 5 years. This graph shows the mean % change from baseline for apoC-III levels over the 1-year treatment timeline. The gray line represents the placebo group, which shows an increase in apoC-III levels over the course of the study. The orange and magenta lines represent the 50-milligram and 80-milligram dose groups. Dose-dependent effect was noted in the reduction of plasma apoC-III, and the placebo-adjusted reductions continued to improve through 12 months.
At 6 months, a 74% reduction in ApoC-III was present in the 80-mg dose, which increased to 81% at 12 months. Now to the primary and key secondary results of the study. The results I'm showing you here today are unprecedented. Not only did olezarsen demonstrate a significant dose-dependent effect on the primary endpoint of triglyceride reduction at 6 months with the 80-mg dose. But the dose-dependent reduction increased at month 12. But what was unprecedented and most clinically meaningful was the substantial reduction in acute pancreatitis achieved in both those groups compared to placebo. A total of 12 acute pancreatitis events occurred in the study in a total of 8 patients. 11 of those events occurred in the placebo group. 1 event occurred in the 50-mg dose group, and 0 events occurred in the 80-mg dose group.
In the placebo group, 7 out of 23 patients, or 30.4%, had at least one pancreatitis event. One out of 21 patients, or 4.5%, had a single event in the olezarsen 50-mg group, and zero out of 22 patients, or 0%, in the olezarsen 80-mg group had an event. These results of olezarsen represent the first time any lipid-lowering therapy has demonstrated a reduction in acute pancreatitis events. It also suggests that targeting apoC-III, and particularly chylomicrons, may be the key difference between olezarsen and other therapies targeting triglycerides. We also observed a favorable safety and tolerability profile for olezarsen in both those groups. Overall, treatment-emergent adverse events or TEAEs were higher in the placebo group compared to the olezarsen groups, primarily due to pancreatitis events. There were no serious TEAEs related to study drug.
There were no clinically meaningful cases of thrombocytopenia, renal, or hepatic safety signals, and a low incidence of mild injection site reactions. There was one death reported in the study, which was deemed not related to study drug. We are planning to present more detailed results from this study at a future medical conference, and we are also planning to publish these results. So to summarize, we are extremely pleased with the top-line results from the BALANCE study. We believe that the efficacy and safety profile demonstrated by olezarsen in the BALANCE study positions it to be the standard of care for FCS patients. If approved, olezarsen could be the first approved medicine for FCS patients in the U.S. and the first medicine that we will deliver directly to patients. With that, I'll turn it over to Onaiza.
Thank you, Sam. Based on the robust BALANCE data, we are extremely pleased about what olezarsen could mean for the FCS community, which includes caregivers, physicians, dietitians, and importantly, the patients who live with this debilitating disease. Based on genetics, the estimated prevalence of FCS is 1-2 per million patients worldwide, with more patients clinically suspected. These patients are at extreme risk for acute, potentially fatal pancreatitis and suffer from severe daily symptoms that impact their quality of life. Healthcare professionals currently do not have much choice in their armamentarium to treat FCS. Current treatment options are simply not effective. In our market research, aimed at fully characterizing the needs of patients, we invariably heard that FCS impacts every aspect of these patients' lives. Acute pancreatitis is the most severe manifestation of FCS.
Patients report feeling depressed and powerless to control this risk and often live in constant fear of their next attack. FCS patients report that they often know when an acute pancreatitis attack is coming on, based on the severity of their daily chronic symptoms like fatigue, nausea, and vomiting. With one patient telling us, "I don't even have to have my TG levels checked. When I am in danger, my body tells me, and there's very little I can do about it." Another hallmark of FCS is the cognitive symptoms such as forgetfulness, poor concentration, and brain fog, which often lead to difficulty holding down a job and difficulty maintaining relationships. As Sam discussed, FCS patients have a substantially higher risk of acute pancreatitis than to patients with normal triglyceride levels. In fact, 67% of FCS patients have been hospitalized as a result of an acute pancreatitis event.
FCS patients also have up to a tenfold increased risk of a repeat attack. They suffer significantly worse outcomes, with FCS patients twice as likely to suffer persistent organ failure or to die as a result of an acute pancreatitis attack, compared to patients with normal triglycerides. When they have an attack, patients with FCS are also admitted and readmitted to the hospital more frequently and are admitted for longer stays and more often go into the ICU compared to patients with normal triglycerides. The need for hospitalization is a substantial burden on patients and their families, and it represents a significant cost to the healthcare system. Turning to our research on how payers may interpret olezarsen's value to patients with FCS, our market research included 15 U.S. payers representing 150 million lives. Payers understand this disease and the lack of treatment options for these patients.
In terms of insurance access and availability, our research tells us that payers understand that FCS is rare, severe, and potentially fatal. As such, we believe the positive BALANCE data will support broad patient access in FCS... One PBM leader said there is no treatment for these individuals other than dietary restrictions, which, from a quality of life perspective, must be terrible. The drugs available don't lower triglycerides enough to reduce organ damage or pancreatitis. Another said, "The clinical benefit of current treatment options is pretty minimal. Medications have little effect, and it is hard to follow those diets." Payers appreciated our product profile in blinded testing before the results from our phase III BALANCE study, where the base case showed a strong trend in reduction in AP events. During testing, one payer said, "A trend in improving AP events would be great.
Outcomes data would be a home run." Today, we are finalizing preparations for each of our near-term commercial launches, and 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. Our priorities as we approach the market with olezarsen are focused on ensuring patients get the treatment they need. For two years now, our field medical team has been actively engaging with healthcare providers, learning about what they want in a new treatment, while also raising awareness about the signs and symptoms of FCS. Today, our work is multifactorial as we prepare for launch. We are developing an algorithmic method to identify potential FCS patients, utilizing and integrating various lab, EHR, and claims data.
We are working with physicians to develop criteria for identifying which patients should get genetic testing. Additionally, we are building the infrastructure needed to ensure olezarsen's supply is in the channel upon launch and are close to finalizing our specialty pharmacy provider. As our launch window approaches, we plan to add our customer-facing team. We intend to build a sales account management team to support this launch, augmented by omni-channel, to extend the reach and effectiveness of our sales force. Olezarsen not only represents a potentially important new medicine for FCS patients in need, but it is also our first opportunity to establish Ionis' commercial presence. So when we launch olezarsen, assuming approval, we intend to do so in a way that represents the excellence that Ionis is known for. A key element of this goal is our Olezarsen One customer approach.
Olezarsen One is our sales and customer-facing model that we are designing to ensure patients have a seamless experience with olezarsen. Today, we are building a team that will support patients and physicians at every step of the olezarsen journey. Summing it up, we are extremely pleased with this opportunity we have with olezarsen. We know that physicians understand the risks and the need for effective medicines for patients with FCS and currently have no effective treatments. These positive results from the BALANCE study demonstrated very robust apoC-III reductions and significant reductions in triglycerides. Importantly, 100% reduction in acute pancreatitis at the 80-mg dose. With these data, we believe that olezarsen has a highly attractive profile for adoption by clinicians and patients. With the potential FCS approval, Ionis is poised to launch our first medicine in a potential steady stream of new medicines for patients with unmet needs.
With that, I'll turn the call back over to Brett.
Thank you, Onaiza. With today's positive phase III readout for olezarsen, we are one step closer to delivering our first wholly owned drug to patients. As our most advanced wholly owned medicine, the positive top-line results from the phase III BALANCE study represent a significant milestone on Ionis' path to commercializing our own medicines. We look forward to presenting more detailed data from BALANCE at a future medical conference. Our progress with olezarsen, together with the progress we're making with our other near-term commercial opportunities, eplontersen and donidalorsen, supports our goal to deliver a steady cadence of new medicines to patients in need and to drive value for all Ionis stakeholders. With that, we'll now open the call up for questions. MJ?
Of course. Thank you. We will now begin the question-and-answer session. To ask a question, you may press star, then one on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star, then two. At this time, we will pause momentarily to assemble our roster. Today's first question comes from Yanan Zhu with Wells Fargo. Please go ahead.
Hi, thanks for taking my questions, and congrats on the data. I was wondering about the AP reduction that you've achieved, 100% reduction in the 80 milligram arm. I was wondering, is it possible that this could get into the label? Is this analysis, you know, pre-specified in a way that's consistent with being added to the label? That is the question. And also, could you talk about the discontinuation and also the AE rates? Is there any particular AE that led to discontinuation, and is that of any concern? Thank you.
Would you like to talk about our expectations for the AP and the label?
Yeah. Thanks for the question, Yanan. You know, as, as you know, I mean, we can't really project what the FDA will do, but we do believe that the, the rare disease nature, the lack of treatment options, and the fact that we have a robust data set, will allow for some really great discussions on what we want in the label. We are really believing that the 80 milligram dose, the triglyceride reduction, and the acute pancreatitis event, data, should be part and parcel, of the label.
And, as Sam summarized, Yanan, we couldn't be more pleased with the safety profile and tolerability profile that we saw in the BALANCE study. But maybe Sam, as our lead clinician on the program, could talk a little bit more about his perspective on that.
Yeah. I think overall, the drug was extremely well tolerated. As I mentioned, 90% of the patients completed the study. There was no rhyme or reason to the discontinuation. We did mention the one patient that had an unrelated death that was, that occurred. Otherwise, there was nothing, nothing, no signal in any, any, any major, you know, system or organ that you would predict would, would be related to the drug or any issue like that.
Oh, great. I just want to confirm, there's no liver signal or platelet signal in the study, correct?
That's correct. There were no liver increases in liver test abnormalities relative to the placebo. There was no renal issues. The platelet issue is an interesting one because we know for many years that these, some of these patients have low platelet counts. In fact, about 25% of the patients in FCS have platelet counts that are abnormal. So a lot of the patients in our study had low platelet counts, but we did not see any signal related to the drug that concerned us at all, and everybody continued the dose for our study.
Got it. Thank you very much for taking the question. Congrats again.
Thanks, Yanan.
The next question comes from Luca Issi with RBC Capital. Please go ahead.
Mm-hmm. Well, great. Thanks so much for taking my question, and congrats on the data. Maybe a quick one, Sam. I want to just follow up on the prior conversations on platelet. I know you mentioned you know clinically meaningful thrombocytopenia, but wondering if you can expand a little bit more on it. I believe in the phase II, you had, you know, 10%-16% of patients with platelet drops below 140,000 per microliter. So wondering if the data today is generally consistent with the phase II. And then maybe also for the 50 milligrams, just wondering if you can comment on why that dose didn't hit the stats on triglycerides. Wondering if there's anything in the baseline characteristics or any other reasons that may explain that.
Then maybe, Brett, bigger picture, wondering if you can comment on what's the BD strategy for the asset at this point? Thanks so much.
I can address the platelet. I think, you know, I think I've addressed it already. There was no concerning signal in the platelet kind of abnormalities outside of the fact that the patients often will come in with a low platelet count. Our entry criteria was 100,000, so just keep that in mind. The issue with the 50 mg dose, one of the things that's interesting about FCS, unlike other lipid disorders, is that because these patients lack lipoprotein lipase activity, they're extremely sensitive to dietary fat intake. And that could be sensitive over the last week, not just the last meal. So there's a lot of variability that occurs in these patients. And that's part of the challenge of doing these trials.
So as you can go back and look at our sourcing data, there's a lot of bouncing around of the triglycerides, so that can be taken into account. But what matters is the area under the curve. So sometimes you get unlucky where you measure the triglyceride level, and we just barely missed it. It was 0.07, the P value, so it wasn't far off. And at the end of the trial, it was very different and continued to decline. So I think we'll be able to provide more granularity on this down the road, so you can see that, but we're not concerned at all about that 50 milligram dose. I think the platelet—I'm sorry, the pancreatitis data tells you the real effect on these patients.
Patients care about whether they have abdominal pain and whether they have pancreatitis, and only having one case in the 50 milligram dose tells you it was highly effective.
Right. And, Luca, regarding your third question, we are preparing to bring olezarsen to the market ourselves, and as Onaiza covered in depth a few minutes ago. So we're not seeking a partner, and we're prepared to launch.
Not even ex-U.S.?
We will lead our global ex U.S. strategy for olezarsen, and we're still pulling our plans together on that. So we'll certainly look into various options to be able to distribute or make sure that olezarsen is readily available globally, and we're still working on that. Right now, we're laser focused on filing in the U.S. and EU and getting the drug across the finish line.
Thanks so much. Super helpful.
Thanks, Luca.
The next question comes from Debjit Chattopadhyay with Guggenheim. Please go ahead.
Hey, team. Congrats on the data. This is Robert on for Debjit, and thanks for taking our question. 2 from us. When did the dropouts happen? And related, the 0 out of 22 and 1 of the 22 pancreatitis events in the 80- and 50-milligram doses. Were these within the 12-month period? And how did the dropouts play into this data calculation? Thank you.
There was no specific pattern that we saw in dropouts. They just kind of were random throughout the course of the study. So I can't say that we identified any specific cause for those. And there were only—there were only six, only, you know, 10%, which is actually lower than a lot of the trials, 15%-20% dropout. So we were very pleased with that. The other part of this, as we mentioned, is that 100% of our patients that completed the trial went into the open label extension. So that, that basically tells us that this is a drug that these patients have been waiting for, and it's tolerated very well. Could you, I'm sorry, repeat the second part? I kind of missed your point. What, what were you asking about the 50 milligram dose?
Yeah, of course. So did the dropouts occur during the randomized period or during the follow-up out to 12 months?
Well, what we're only showing you here is the 12-month randomized period. We're not showing you any data beyond that. So everything that we're explaining here is during the trial. So the trial duration is 12 months, then everybody goes into an open label extension.
So what we're reporting is the full 12-month data, Robert.
They dropped out.
Got it. And how was the pancreatitis accounted for if a patient dropped out? That was the second part of the second question. Thank you.
Well, if, you know, if a patient had pancreatitis, then it was obviously counted. But if they dropped out for an unrelated reason, then, it just becomes part of the denominator.
Awesome. Thanks, Sam, and team. Congrats again. Thank you.
Thank you, Robert.
The next question comes from Gena Wang with Barclays. Please go ahead.
Thank you. Maybe just follow the previous question. So if they drop out, are there any agreed methodology with FDA regarding, like, how to impute the data, like MMRM, any methodology you have agreed on?
Gina, our process for adjudicating dropouts and pancreatitis events has been completely negotiated with the FDA, you know, as a starting point in the trial. So yes, it's all been discussed and agreed to with the FDA.
Okay. Another question. Just wanted to know, the 80 milligram, at what point that 80 milligram was implemented? When I look back, the phase I/II study actually only test up to 50 milligram. And a related question is, for the CORE, CORE2, the phase III registration study for broader indication, what is the dose you are using for that, or you were testing for these two studies?
Sorry, there must be some confusion, Gina. 80 milligrams and 50 milligrams were the doses in the balance study from the start. In fact, we stood strong, always felt that the 80 milligram dose would be the dose to go forward with, would be the dose to go forward with. Based on everything we've seen in phase I, phase II, and our other LICA platforms, we expected it to be very well tolerated and safe, and it, we expected it to be the most efficacious. So right from the get-go, we planned 50 and 80, and it was, you know, it was, that was, those were two of the three cohorts, in addition to placebo, in the study right from the start.
Those are the same doses in CORE and CORE2, 50 and 80 milligrams, which, you know, just gives us even greater confidence for a successful sHTG, phase III outcome. We're using the same doses, the same drug, the same, endpoints, TGs, and we're looking... and this gives us even greater confidence that we, are going to achieve an AP, a positive acute pancreatitis outcome in the, in the, sHTG studies.
Thank you.
The next question comes from Joseph Stringer with Needham and Company. Please go ahead.
Hi, good morning. Thanks for taking our questions. Two quick ones from us. Just curious if you saw any differences in efficacy based on background lipid-lowering meds. And then secondly, maybe curious if you could provide some additional color on, you provided some prevalence numbers for FCS, but what do the diagnosis rates look like in this patient population? And maybe how do you envision the typical FCS patient journey to look like from time to diagnosis to an identification to potentially getting on olezarsen?
Thanks, Joe. Sam, maybe you can talk a little bit about what we know about background therapy-
Sure.
and Onaiza follow with them.
Let me just say that our treatment paradigm here is that these patients get olezarsen on top of standard of care or background lipid-lowering therapy. Because it's a randomized trial, we anticipate that each of the groups, the three groups, will be balanced in background therapy. In the past, you would see about 30, 40, 50% of patients be on fibrates, maybe the same number on omega-3 fatty acids and statins. Because we have top-line data, we haven't looked at our own data yet at that granularity. We'll be able to get that for you down the road. But just keep in mind that the effect that we're seeing here is on top of already what they're taking.
Yeah, on the diagnosed incidence rate, we have some data, Joey. And, in lieu of actually sharing like data analogs here, I think maybe we should just start with, like, the reminder that once you have a rare disease and there's an effective treatment option, we actually can get and do a lot more work about getting these patients treated. There hasn't been an approved therapy for FCS to date, right, in the United States, for FCS. So everything that's been used is really just, you know, lack of anything good for these patients at this point in time.
So we expect that with the really robust data that we saw for FCS, particularly not just on a biomarker, but per the disease itself and the acute pancreatitis events, we do expect that having a treatment option then actually increases, goes backwards, to identifying and diagnosing patients. We expect that rate to increase. It is actually pretty low right now, but as I said in our commercial preparation, one of the things we're really focused on is patient identification and utilizing not just kind of, you know, our field medical team in the field, but mostly data sources that we believe have really increased in their ability to identify patients. We triangulate this through claims data, EHR data, lab data, and we're pulling that all together to have more predictive algorithms as to where these patients may be.
We've done a lot of work on patient journey too, right?
Yes, that's part and parcel of the patient identification work as well. We've done a lot in understanding the patient's voice, the HCP's voice, the dietician, where these patients might be, which offices they might be going to. Are they going to the community centers of excellence? What are they being misdiagnosed with as well? So our whole job is to shorten the misdiagnosis cycle and identify these patients. We do believe having such a great drug as olezarsen will really help that process.
We think we'll be able to streamline, streamline that journey to find these patients much faster than what they've had in the past. As Onaiza said, having a treatment and a highly effective treatment will help with that.
Great. Thank you so much for taking our questions.
Thanks, Joey.
The next question comes from Paul Matteis with Stifel. Please go ahead.
Hi, this is James on for Paul. Thanks for taking our question, and congrats on the data. Maybe going off that in terms of this commercial work, how many FCS patients have you guys specifically identified? And then just kind of second, you know, how are you thinking about pricing the FCS indication, you know, 'cause presumably there would be different price points and access points there. So just wondering how you're thinking about that strategy and timing as you guys move forward. Thanks.
Yeah. Thanks, James. So I think, you know, again, I think that the FCS diagnosis is based on... It's a twofold effect, actually. There are genetic tests that are available, and as Sam described, you know, that is how we've used it, very much so in our clinical trials. And there are also clinical symptoms that some physicians also use in the diagnosis of FCS. And both of those combined together can get patients who are clinically suspected into the process of confirming their diagnosis through a genetic test. So we believe using kind of both tools that are available in the real world at this point in time and augmenting that, we do believe we will identify more patients that are currently diagnosed in the system.
As to pricing, you know, as you said, we do have a broader indication coming in sHTG down the pipe. But right now, we're really focused on the FCS indication. We've had plenty of conversations in our research with payers. The fact that this is a rare disease, it's severe, has potentially to be fatal for FCS, and our great data in really you know showing the substantial reductions in acute pancreatitis, we do believe points us in the direction of rare disease pricing, and that will, you know, be in the range of what you see in analogs of other rare disease-priced drugs.
Makes sense. Thank you.
Thank you, James.
The next question comes from David Lebowitz with Citi. Please go ahead.
Thank you very much for taking my question. There were a handful of patients across the study that were previously on volanesorsen, and I was wondering if for those particular patients, you could compare the results of, just in terms of ApoC-III knockdown, and then, I mean, obviously qualitatively, and triglyceride lowering that was seen with the prior therapy.
Interesting question. Yes, Sam, we want to?
Sure. First of all, I think, you know, the issue of volanesorsen treatment is a good one. We are looking into this in a lot more detail. At first look, we're not seeing any major differences. The only thing I can tell you is from the safety side, some of those patients had low platelet counts on volanesorsen, and we did not see that with olezarsen, which is really fantastic. So, so that was a very great thing to actually put those patients in and document that. So we'll be able to give you more information on this when we do our more detailed analysis in the future, in a future presentation.
So far, we didn't see any differences in knockdown of ApoC-III either, so.
. Would the triglyceride lowering to this point have appeared similar?
Yeah. So for the triglycerides, we're not, we're not gonna disclose that today. We're gonna, we're gonna present that in more details at an upcoming meeting. And so we'll be able to give you more information down the road.
I think the question was for the volanesorsen-treated patients. We're not, we're not seeing much difference in TG reduction-
For the volanesorsen group.
in patients that were previously on volanesorsen.
It looks like, you know, for those patients, a lot of those patients had a very similar genetics as we're seeing in this study compared to the rest of the group. So, yeah, no, it looks, it looks about the same. Yeah.
Got it. Thank you for taking my questions.
Yep. Thanks, David.
The next question comes from Miles Minter with William Blair. Please go ahead.
Hi, you've got Sarah on for Miles. Congrats on the data, and thanks for taking our questions. It looks like there might have been less ApoC-III knockdown in the 50-milligram cohort in BALANCE compared to what you guys showed in the phase II population. Did you expect a 1-to-1 translation of this mechanism between the sHTG and FCS patients? And then kind of based on this in the phase II results, do you think that around 75% is the maximum ApoC-III reduction you could achieve with olezarsen?
Yeah, that's very insightful questions. A couple of things to start with. volanesorsen was not a GalNAc molecule. This one is, so there's slightly differences in the drugs. ApoC-III is actually made by the intestine and also by the liver. So, when you have liver-directed drugs, you know, there may be a limitation of what the maximum amount you can knock down. We had very robust data. The issue, of course, is that from the clinical perspective, there's a difference between FCS and sHTG, even though they have a lot of commonalities in genetics. The major difference is that FCS patients don't have lipoprotein lipase activity, so the only way they can reduce their chylomicrons and triglycerides is through the clearance pathway.
The sHTG patients have lipoprotein lipase, so one would predict that the FCS patients would be a lot more resistant to getting their chylomicrons down and their triglycerides versus sHTG. And, we'll, we'll be able to, to give you information on that when we, when we provide our CS8 data, which is a lower triglyceride population that's not FCS. So it wouldn't, it wouldn't be unexpected, I thought, you'd have the exact same data over the FCS and sHTG. I think what we'll see in the field is there will be some differences, and the FCS populations will be more recalcitrant.
Right. And just to add to that, Sarah, as we showed today, with continued treatment through 12 months, we actually went beyond 75%. We actually exceeded 80% in ApoC-III, so we don't think we've maxed out there. Where, of course, we have maxed out is protection against pancreatitis events, where we were 100% effective in preventing AP attacks, and you can't do much better than that, of course.
Yep, definitely impressive results. Congrats again.
Thanks, Sarah.
The next question comes from Yaron Werber with TD Cowen. Please go ahead.
Hi, guys. This is Brendan on for Yaron. Congrats again on the data. Thanks for the questions. I just wanted to double-check and make sure I'm kind of understanding the cadence for sHTG correctly. As you're looking at those three studies, CORE, CORE2, and ESSENCE, are you thinking to wait for data between all three to kind of read out and then file with one big package? Or would you maybe file after CORE and CORE2? I guess, I guess assuming they, they read out first, and then potentially apply for, like, a label expansion after ESSENCE reads out. What's kind of like your, your thinking for the cadence of events there?
We will file with the results from all three studies. CORE is the primary pivotal registration study. CORE2 is a supporting study, which is basically a replication of CORE. It's just a confirmatory study, is what I meant to say. And ESSENCE will satisfy the patient exposure database that we need to have for a broad indication, like sHTG. So they'll all go in together, and we expect them all to read out around the same time.
All right, great. Thanks very much.
The last question today comes from-
We have a question?
Yes, the question today comes from Yale Jen with Laidlaw and Company. Please go ahead.
Good morning, and thanks for taking the questions, as well as congrats on the outstanding data. Just want to confirm a few things. First, first of all, are you guys going to only file for the 80 milligram, or also you will consider 50 milligram as part of the filing package? And then I have a follow-up.
Yeah, we're still working out our registration strategy with respect to one dose or two, Yale. Obviously, this is data hot off the press, and we'll work through that, and we will have a pre-NDA meeting with the FDA to discuss that. So we don't know yet. Obviously, it is the 80-milligram dose that'll be our top priority, but whether or not we think there's value in a second dose or not, or whether the FDA would like to have a second dose, the lower dose or not, but we'll see. What we do know is that there's no tolerability or safety reasons why the 80-milligram dose should not be very successful from a regulatory standpoint or commercially.
Okay, great. That's very helpful. And one more question here is that in terms of the commercial, commercial team size for the olezarsen in FCS, what should we anticipate that current, you know, current thought is about that? And if potentially for the sHTG, what the size expansion might be, at this moment?
Yeah. Yale, we're working on what the customer-facing design is and finalizing kind of the sizing of that. We've actually done a lot of work on identifying the right roles for the FCS launch. So, you know, we've really emphasized that this is going to be kind of a holistic customer-facing team, including patient education managers, the sales team, you know, some reimbursement support as well. So the combination of that will be kind of the full size. We haven't finalized kind of the territory design and the targeting at this point in time, so I really am not at the... I actually don't have the data, but I'm also not at liberty to say.
We expect that team to be sizably larger, obviously, as we get into the sHTG expansion, and that indication, we'll do that at a later time as well. There, we have a larger population. Just as a reminder for everybody, we believe that the core specialties for that will be endocrinologists as well as cardiologists.
Thanks, Onaiza. Thanks, Yale, and thanks, everybody, for joining us today to discuss today's really exciting results for olezarsen. Next week, at our Ionis Innovation Day, which we'll host live in New York, we'll discuss olezarsen further, including FCS and sHTG strategy. We'll also provide an update on our preparations to launch our other near-term commercial opportunities, eplontersen and donidalorsen, as well as pre-previewing our next wave of wholly owned programs we plan to deliver directly to patients, and even, and much, much more. Until then, thank you, everybody. Have a great day.