Ionis Pharmaceuticals, Inc. (IONS) Earnings Call Transcript & Summary

Good morning, and welcome to Ionis' 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 III 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 Investors 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 2, 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 will also review our olezarsen clinical program and then discuss the positive top line results from the Phase III Balance study. Next, Onaiza Cadoret, 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. And 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. 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 2 key strategic priorities, and I look forward to talking to you more about our progress in these 2 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 result -- or risk of acute potentially fatal pancreatitis. And 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. And today, we're pleased to report the positive results of the Phase III Balance study of olezarsen, our medicine designed to target APOCIII 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 EU 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 will 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 who made today's important announcement possible. We understand how difficult it can be for patients with familial chylomicronemia syndrome, or FCS, to live with 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, who would give them severe abdominal pain or send them to 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 have set out several years ago to develop a new medicine to address the 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 is 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, having too much of it in the blood stream leads to severe complications. Triglycerides 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 also highly enriched with multiple copies of APOCIII 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 or 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 to 100x 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 floats 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 to 12 hours after a meal. But in patients with FCS, it accumulates, they 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 diets 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 the loss of LDL activity, which resulted 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 2 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 fatty meal, the body needs to remove them from the circulation as soon as possible. This occurs via 2 mechanisms, both of which are regulated by APOCIII. The first involves LPL, which metabolizes triglyceride and makes the particle smaller. You can visualize this as an ice cube melting. The second mechanism uses 3 liver receptors shown here in the middle of the slide to remove TRL from the circulation. Since FCS patients lack LDL activity, they're entirely dependent on the second less-efficient clearance mechanism as the only way to clear chylomicrons. Patients with FCS have 5 to 10x higher levels of APOCIII 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 result in severe inflammation associated with acute pancreatitis. In view of the critical role in affecting TRL metabolism in patients with FCS, we created olezarsen and designed it to decrease the production of APOCIII. We believe that by preventing APOCIII 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 APOCIII is associated with a positive effect, which we aim to replicate with olezarsen. People who carry a novel mutation in the APOCIII gene have no circulating APOCIII 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 the high-fat meal, the increase in plasma triglycerides is significantly blunted. This is the same biological effect we were hoping to replicate with olezarsen inhibition of APOCIII 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. The left is an overview of our program supporting our FCS indication. This program consists of a Phase III 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. The positive Balance study results in hand our Phase IIb supportive study on track to complete later this year, we plan to file for marketing approval in the U.S. and EU 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 3 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 filings 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 subcu injection for 12 months. Patients in the study were expected to be on background lipid-lowering therapy. Primary efficacy endpoint in Balance is percent change in fasting triglycerides from baseline to 6 months of treatment compared to placebo. Key secondary end points, including reduction in triglyceride at 12 months, reduction in the target APOCIII 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 would generally balance across key parameters. Most patients were in their mid-40s, and most patients had average weight and BMI typical for FCS patients who were 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 percent change from baseline for APOCIII levels over the 1-year treatment time line. The gray line represents the placebo group, which shows an increase in APOCIII levels over the course of the study. The orange and magenta line represent a 50-milligram and 80-milligram dose groups. Dose-dependent effect was noted in the reduction of plasma APOCIII and placebo-adjusted reductions continued to improve through 12 months. At 6 months, a 74% reduction in APOCIII was present in the 80-milligram 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-milligram dose, but the dose-dependent reductions increased at month 12. But what was unprecedented and most clinically meaningful was a substantial reduction in acute pancreatitis achieved in both dose 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-milligram dose group and 0 events occurred in the 80-milligram dose group. In the placebo group, 7 out of 23 patients or 30.4% had at least 1 pancreatitis event, 1 out of 21 patients or 4.5% had a single event in olezarsen 50-milligram group and 0 out of 22 patients or 0% in the olezarsen 80-milligram 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 APOCIII and particularly chylomicrons maybe 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 for 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 Oniaza.

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 to 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. Health care 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, and when I'm 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 due to patients' abnormal 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 health care system. Turning to our research on how payers may interpret olezarsen 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 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 2 years now, our field medical team has been actively engaging with health care providers, learning about what they want in the new treatment while also raising awareness about the signs and symptoms of FCS. They -- 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. And 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 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 omnichannel to extend the reach and effectiveness of our field 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 APOCIII reduction and significant reductions in triglycerides, importantly, 100% reduction in acute pancreatitis at the 80-milligram 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 need. 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. And 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. And with that, we'll now open the call up for questions. MJ?

[Operator Instructions] Today's first question comes from Yanan Zhu with Wells Fargo.

And congrats on the data. I was wondering about the AP reduction that you've achieved, 100% reduction in 80-milligram arm. I was wondering, is it possible that this could get into the label. Is this analysis prespecified 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?

Onaiza, would you like to talk about our expectations for the AP in the label?

Yes. Thanks for the question, Yanan. As you know, I mean, we can't really project what the FDA will do, but we do believe that 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, Yana, we couldn't be more pleased with the safety profile and tolerability profile that we saw in the Balance study, but maybe Sam, the lead clinician on the program, could talk a little bit more about his perspective on label.

I think overall, the drug was extremely well tolerated. As I mentioned, 90% of the patients completed the study. There's no rhyme or reason to the discontinuation. We did mention the one patient that had an unrelated death that was occurred. Otherwise, there was nothing -- no signal in any major system organ that you would predict would be related to the drug or any issue with that.

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 -- liver abnormalities relative to the placebo. There was no renal issues. Platelet issue is an interesting one because we know for many years that 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 to [ go ] throughout the study.

The next question comes from Luca Issi with RBC Capital.

Great. 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 no clinically meaningful thrombocytopenia. I wonder if you can expand a little bit more on it. I believe in the Phase II, you had 10%, 15% 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 to may explain that? And then maybe, Brett, bigger picture, wondering if you can comment on what's the BD strategy for the asset at this point.

I can address it lately. I think I addressed it already. There was no concerning signal in the platelet, kind of abnormality is outside of the fact that the patients often will come in with low platelet counts. Our entry criteria is 100,000, so just keep that in mind. The issue with the 50-milligram 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 [indiscernible] over the last week, not just the last meal. So there's a lot of variability that occurs in these patients and as part of the challenge of doing these trials. So as you can go back and look at our volanesorsen data, there's a lot of bouncing around of the triglycerides. So that could 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 of 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 of the 50-milligram dose tell 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.

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.

The next question comes from Debjit Chattopadhyay with Guggenheim.

Congrats on the data. This is Robert on for Debjit. Two 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. Where these within the 12-month period? And how does the dropouts play into this data calculation?

There was no specific pattern that we saw in dropouts. It's just kind of a random throughout the course of the study. So I can't say that we identify any specific cause for those. There are only fixed, only 10% which is actually lower than a lot of the trials, 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 basically tells us that this is a drug that these patients have been waiting for, and that this tolerated very well. I'm sorry, repeat the second part, I kind of missed your point about what were you asking about the 50-milligram dose?

Yes, of course. So did the dropouts occurred 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 12-month data, Robert. They dropped out.

Got it. And how was the pancreatitis accounted for if the patient drops out? That was the second part of the second question.

Well, if a patient had a pancreatitis event, it was obviously [indiscernible] they dropped off for unrelated reason, then it just becomes part of the denominator.

The next question comes from Gena Wang with Barclays.

Maybe just follow the previous question. So if they drop out, is there any agreed methodology with FDA regarding like how to [ imputate ] the data like MMRM, any methodology you have agreed on?

Our -- Gena, our process for adjudicating drop outs and pancreatitis events has been completely negotiated with the FDA as a starting point in the trial. So yes, it's been all discussed and agreed to with FDA.

Okay. And then 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 tested up to 50 milligram. And the related question is for the CORE and CORE2, Phase III registration study for broader indication, what is the dose you're using for that? Or you were testing for these 2 studies?

Sorry, there must be some confusion, Gena. 80 milligrams and 50 milligrams were the doses in the Balance study from the start. In fact, we 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 has been and we expected it to be the most efficacious. So right from the get-go, we planned 50 and 80 and it was -- that was -- those were 2 of the 3 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 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 a positive acute pancreatitis outcome in the SHTG studies.

The next question comes from Joseph Stringer with Needham & Company.

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?

Sam, maybe you can talk a little bit about what we know about background therapy, Onaiza, follow with this.

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 with the randomized trial, we anticipate that each of the groups, the 3 groups will be balanced in background therapy. So 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 [indiscernible] because we have top line data, we haven't looked at our own data to get that granularity. We'll be able to get 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.

Yes. 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 a reminder that. Once you have a rare disease and there is 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 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 hunt the disease itself and the acute pancreatitis events. We do expect that having a treatment option then actually increases goes backwards to identify 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 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, HR data, lab data, and we're pulling that all together to have more predictive algorithms as to where these patients may be.

And then 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 dietitian, 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 that journey to find these patients much faster than what they've had in the past. And as Onaiza said, having a treatment and a highly effective treatment will help with that.

The next question comes from Paul Matteis with Stifel.

This is James on for Paul. 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, how are you thinking about pricing the FCS indication ahead of the SHTG data because 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.

Yes. Thanks, James. So I think, 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, 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 in augmenting that. We do believe we will identify more patients that are currently diagnosed in the system. As to pricing, 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 showing the substantial reductions in acute pancreatitis. We do believe points us in the direction of rare disease pricing and that will be in the range of what you see in analogs of other rare disease price drugs.

The next question comes from David Lebowitz with Citi.

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 in terms of APOCIII knockdown, and I mean, obviously, qualitatively, and triglyceride lowering that was seen with the prior therapy.

Interesting question. Yes, Sam.

Sure. First of all, I think the issue with the 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 that was a very great thing to actually put those patients 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...

And we didn't -- and so far, we didn't see any differences in knockdown of APOCIII either, yes.

Would the triglyceride lowering to this point have appeared similar?

Yes. So the triglyceride, we're not going to disclose that today. We're going to present that in more details at an upcoming meeting. And so we'll be able to give you more information down the road.

But I think the question was for volanesorsen-treated patients. We're not seeing much difference in TG reduction in patients that were previously on the volanesorsen.

So it's looks like everything -- those patients -- all of those patients had a very similar genetics as we're seeing in this study compared to the rest of the group. So yes, no, it looks about the same. Yes.

The next question comes from Myles Minter with William Blair.

You've got Sarah on for Myles. Congrats on the data. So it looks like there might have been less APOCIII knockdown in the 50-milligram cohort in Balance compared to what you guys showed in the Phase II population. Do you expect a one-to-one 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 APOCIII reduction you could achieve with olezarsen?

That's very insightful questions. A couple of things to start with. Well, volanesorsen was not a GalNAc molecule, this one is. So there's slightly different systems in the drugs. APOCIII is actually made by the intestine and also by the liver. So when you have liver-directed drugs, 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 be able to give you information on that when we provide our [ CsA ] data, which is a lower triglyceride population, that's not FCS. So it wouldn't be unexpected I tell you to have the [indiscernible] over FCS and SHTG. I think what we'll see in the field that there will be some differences in the FCS populations will be more recalcitrant.

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 APOCIII. So we don't think we've maxed out there. Where, of course, we have maxed how is protection against pancreatitis events where we were 100% effective in preventing AP attacks, and we can't do much better than that, of course.

Definitely impressive results. Congrats again.

The next question comes from Yaron Werber with TD Cowen.

This is Brendan on for Yaron. Congrats again on the data. 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 3 studies is CORE, CORE2 and ESSENCE, are you thinking to wait for data between all 3 to kind of read out and then file with one big package? Or would you maybe file after CORE and CORE2, I guess assuming they read out first and then potentially apply for like a label expansion after ESSENCE reads out. What's kind of like your thinking for the cadence of events there?

We will file with the results from all 3 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're all going together, and we expect them all to read out around the same time.

The question today comes from Yale Jen with Laidlaw & Company.

Congrats on the outstanding data. I just want to confirm a few things. 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.

Yes. We're still going to work out. We're still working out our registration strategy with respect to 1 dose or 2, 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 will 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 to lower dose or not, 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 team size for the olezarsen in FCS. What should we anticipate that current thought is about that? And if potentially for the SHTG, what size expansion might be at this moment?

Yes. Yale, we're working on what the customer-facing designed is in finalizing kind of the sizing of that. We've actually done a lot of work on identifying the right roles for the FCS on. So we've really emphasized that this is going to be kind of a holistic customer-facing team, including patient education managers, the sales team, 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 -- 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, 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 will 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 previewing our next wave of wholly owned programs we plan to deliver directly to patients and much more. Until then, thank you, everybody. Have a great day.

Goodbye.