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

Good morning, and welcome to the 2020 Ionis Cardiovascular Franchise Webcast. As a reminder, this webcast is being recorded. At this time, I would like to turn the call over to Wade Walke, Vice President, Investor Relations. Wade, please begin.

Thank you, Sarah. Before we begin, I encourage everyone who has not launched the webcast, to proceed to the Investors section of the analyst website to find a link to this webcast and the related slides. I would like to draw your attention to Slide 2, which contains our forward-looking language statement. We will be making forward-looking statements which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail. With me on today's webcast are Dr. Brett Monia, our Chief Executive Officer, who will open the webcast; Dr. Sam Tsimikas, Senior Vice President, Global Cardiovascular Development and the Director of the Vascular Medicines and Professor of Medicines at the University of California at San Diego, who will provide an overview of our LICA medicines targeting APOCIII and angiopoietin-like 3, for which Phase II results were just presented at the ESC meeting. He will also discuss our medicine targeting Lp(a), which is currently in Phase III. Dr. Sanjay Bhanot, Senior Vice President, Chief Medical Officer and Franchise Head for our metabolic and liver disease franchise will provide an update on Ionis Factor XI LRx targeting coagulation Factor XI for the treatment of thrombosis. Dr. Richard Geary, Executive Vice President of Development, will discuss AKCEA-TTR LICA, targeting TTR cardiomyopathy and IONIS-AGT- LICA, targeting the treatment-resistant hypertension. And then Brett will wrap up the call and open it up for questions. And with that, I'll turn the call over to Brett.

Thanks, Wade. Good morning, and thank you for joining us on today's webcast to review our cardiovascular franchise. As the global leader in RNA-targeted drug discovery and development, we continue to focus on innovation to expand the scope of our success and impact in delivering more medicines and even greater value to patients in need. This year has certainly been an unusual and quite extraordinary year for many reasons, including, of course, the challenges imposed by the COVID-19 pandemic. Yet through Ionis' innovation and the resiliency and commitment demonstrated by the Ionis team, we're emerging stronger than ever, positioning ourselves for even greater achievements. We have the right people, the right technology and the innovative spirit necessary to elevate Ionis to even greater levels of success. We will achieve even greater success by focusing on our foundation of innovation and scientific excellence, like we've done since the beginning. And we'll do this by broadening the reach of our antisense platform technology, which is clinically and commercially validated, enabling us to target an even broader spectrum of therapeutic areas by prioritizing and expanding our Ionis-owned pipeline while optimizing our commercial capabilities. And we'll strengthen our focus on developing first-in-class and best-in-class medicines to transform the lives of patients and deliver our innovative medicines to the market. Today, we have a pipeline of over 40 medicines targeting virtually all major therapeutic areas where new treatment options are desperately needed. We're investing deeply in our pipeline and in particular, the Ionis-owned pipeline. And the performance of our pipeline is setting us up well to achieve our goal of filing for market approval of 10 or more new medicines, each with a transformational profile through 2025. This pipeline includes rare diseases like ALS and Huntington's disease, but also many common diseases, such as Lp(a) -driven cardiovascular disease, which impacts millions of people worldwide. Last month, we did a deep dive into our neurology franchise, a franchise that we believe is the premier drug development franchise for neurological diseases in the industry. We feel the same about our cardiovascular disease franchise. We believe our cardiovascular franchise is also a leading franchise in the industry, and this is our focus today. Before we dive into our cardiovascular disease program, we should touch on our LICA platform. For those of you new to Ionis, LICA stands for Ligand-Conjugated Antisense, and all of our cardiovascular disease medicines in the clinic today are based on this technology. A few years ago, we set out to more effectively manage oligonucleotide protein binding, particularly focused on ligand receptor-mediated drug delivery in order to further improve the performance of our antisense medicines. This endeavor has been extraordinarily successful with the first success of this approach being our liver LICA a strategy which utilizes the GalNAc ligand to target our drug specifically and selectively to the hepatocyte in the liver, truly a breakthrough advancement for liver targets. Our livery technology precisely delivers our medicines to the intended target organs and cell types, thereby vastly reducing the dose and exposure of the drug to other organs and cell types. As of today, we have 15 liver LICA medicines in clinical testing, reproducibly demonstrating high potency with excellent safety and tolerability. The impact of this technological advancement is profound and has transformed our pipeline. Our LICA pipeline of potentially transformative medicines is growing at a rapid pace. And as shown here, 9 of our 15 LICA medicines in the clinic today are cardiovascular medicines, many of which could enter the market over the next several years. What does all this mean? Well, we have taken a comprehensive approach towards the treatment of cardiovascular disorders that has resulted in one of the largest cardiovascular drug discovery pipelines in the industry. We believe we have created a leading pipeline to treat many different diseases in great need for better treatment options, especially for cardiovascular diseases. And we're targeting the key drivers of cardiovascular disease with our technology, which provides confidence we will deliver best-in-class medicines time and time again. And with that, I'll turn the call over to Sam to start us off with a review of the positive Phase II APOCIII-LRx and vupanorsen data presented at the European Society of Cardiology Meeting earlier this week. Sam?

Thank you, Brett. We believe our cardiovascular franchise will deliver first-in-class or best-in-class medicine to patients by targeting broad areas of cardiovascular disease, including lipid disorders, hypertension, heart failure, cardiomyopathies and thrombotic disorders. For today's discussion, we will focus on 6 the following medicines: APOCIII-LRx for elevated chylomicrons and triglycerides; vupanorsen, formerly known as AKCEA-angiopoietin-like 3-LRx for treating disorders of LDL cholesterol and triglycerides; pelacarsen, formerly known as AKCEA-APO(a)-LRx, for elevated lipoprotein(a); Factor XI-LRx for thrombosis; TTR-LRx for hereditary and wild-type cardiac amyloidosis; and AGT-LRx for treatment-resistant hypertension. Earlier this week, we had the privilege to present in late-breaking clinical trials at the Euro Society of Cardiology meeting, 2 medicines targeting triglyceride-driven diseases. We presented positive Phase II data results from AKCEA-APOCIII-LRx and vupanorsen. We will begin the discussion by covering a APOCIII. APOCIII is a protein that is produced in the liver and is a key regulator of triglyceride-rich lipoproteins, or so-called TRLs, and plays an integral role in triglyceride metabolism by 2 mechanisms: one, it increases triglyceride levels by inhibiting lipoprotein lipase, which breaks down triglycerides to free fatty acids for energy metabolism; and two, by slowing clearance of TRLs, which allows their accumulation in blood as elevated triglycerides. So if lipoprotein lipase or related enzymes do not function properly, dietary-derived chylomicrons and liver-derived triglycerides build up, leading to familial chylomicronemia syndrome, or FCS, and multifactorial chylomicronemia syndrome, or MCS. Elevated triglycerides are associated with 2 major medical issues. First one, if they are highly elevated, at levels greater than 500 to 880 milligrams per deciliter, they can cause acute episodes of pancreatitis, which is associated with significant morbidity and mortality. If modestly elevated in the range of 150 to 500 milligrams per deciliter, they are associated with high risk of cardiovascular events. APOCIII is highly linked to plasma triglycerides and genetic studies have shown that subjects with lifelong, very low levels of APOCIII have significantly lower levels of triglycerides and a corresponding lower risk of cardiovascular disease. This provides the rationale for targeting APOCIII to reduce the risk of cardiovascular disease in broader populations. We designed APOCIII-LRx to reduce the production of APOCIII. In a previously published Phase I/II study in healthy volunteers with elevated triglycerides, APOCIII-LRx demonstrated potent and dose-dependent reductions in APOCIII protein and triglycerides. This slide shows the current Phase II study design, which was presented at ESC. The objective of the study was to evaluate the safety and efficacy of different doses and dosing frequencies of APOCIII-LRx. This is a multicenter, randomized, double-blind, placebo-controlled study of 114 patients, with either a clinical diagnosis of cardiovascular disease or patients who were at high risk for cardiovascular disease due to multiple risk factors. Patients were treated with APOCIII-LRx or placebo via subcutaneous injection for at least 6 months with some patients being treated for up to 1 year. APOCIII-LRx achieved statistically significant dose-dependent reductions in fasting triglycerides compared to placebo, reaching a mean 60% reduction at the 50-milligram monthly dose versus a 6% increase in placebo, leading to a net 66% placebo-corrected reduction. Importantly, at this dose, as seen on the bottom panel on the right, more than 90% of participants achieved serum triglycerides of less than 150 milligrams per deciliter compared to only less than 5% in the placebo group. At these levels of serum triglycerides, the risk of cardiovascular disease is significantly reduced and suggest this drug must -- would allow most patients to reach appropriate triglyceride goals. This robust level of potency in reduction is not feasible with currently approved standard of care therapies. APOCIII-LRx also met multiple secondary endpoints. As you can see from this slide, as you read from left to right, significant reductions were present in APOCIII, VLDL cholesterol, non-HDL cholesterol and ApoB. Additionally, statistically significant increases were present in HDL cholesterol. In the Phase II study of APOCIII-LRx, positive efficacy results were accompanied by a favorable safety and tolerability profile, as you can see on this slide. In summary, in this Phase II trial with 6 and 12-month exposure, patients achieved robust reductions in APOCIII and triglyceride levels with the majority achieving triglyceride levels below 150 milligrams per deciliter, a recognized threshold for cardiovascular risk. Based on these positive results, we are rapidly initiating a broad Phase III clinical development program, starting with a registrational study in patients with FCS, later this year. We are planning to develop APOCIII-LRx for the rare but more common condition, MCS, or multifactorial chylomicronemia syndrome, estimated to be 25,000 to 30,000 patients in the U.S. In addition, we are evaluating APOCIII-LRx for broader indications, including patients with triglycerides greater than 500 and for the reduction of cardiovascular disease events in patients with triglycerides between 150 to 500 in the cardiovascular outcomes trial. I will now discuss vupanorsen, our second medicine with data presented at the ESC. Angiopoietin-like 3 is a key regulator of triglyceride and LDL cholesterol, is a liver-derived protein that inhibits lipoprotein lipase, leading to elevation in triglycerides. It also enhances liver output of lipids, resulting in elevated LDL cholesterol. Conversely, natural history studies show that patients with complete loss of function of angiopoietin-like 3 have reduced triglycerides and LDL cholesterol. Genome-wide association studies show the patients with partial loss of function of angiopoietin-like 3 have a reduced risk of cardiovascular disease. An association of angiopoietin-like 3 and disorders of insulin sensitivity and hepatic steatosis have been described, which was the reason these aspects were tested in the current Phase II trial I will describe. Vupanorsen is our LICA medicine specifically designed to reduce the production of angiopoietin-like 3. In a prior Phase I/II study, dose-dependent reductions in angiopoietin-like 3 of up to 85% after 6 weeks of treatment were associated with reductions in all atherogenic lipoproteins, except Lp(a), which is not associated with the angiopoietin-like 3 pathophysiology. In this Phase I/II study, substantial reductions were noted in triglycerides, LDL cholesterol, VLDL cholesterol, with a favorable safety and tolerability profile. I will now discuss our Phase II results of vupanorsen. This study was designed to evaluate the profile of the drug in patients with 3 distinct abnormalities to guide future development. Patients were required to have all 3 of the following parameters: hypertriglyceridemia with triglycerides grade at 150 milligrams per deciliter, hepatic steatosis with hepatic fat fraction greater than 80% and type 2 diabetes. This likely represents the hardest to treat lipid phenotype and the results should be interpreted in this context. Patients were randomized to vupanorsen, 20 milligrams weekly, 40 milligrams every 4 weeks, 80 milligrams every 4 weeks or placebo via subcutaneous injection for 6 months. The primary efficacy endpoint was a change in triglycerides from baseline at 6 months. Vupanorsen demonstrated statistically significant dose-dependent reduction in fasting triglycerides compared to placebo at all dose levels. At the 80-milligram monthly dose shown in red in this slide, a 53% reduction in plasma triglycerides was observed. In addition to meeting the primary endpoint, dose-dependent reductions were also present and secondary endpoints, including angiopoietin-like 3 VLDL cholesterol, non-HDL cholesterol and total cholesterol compared to placebo. Importantly, significant and robust reductions, mean 60%, were also noted in plasma APOCIII levels. There were no significant changes in hemoglobin A1c or hepatic fat fraction. Shown on this table, in this slide, vupanorsen was generally well tolerated and demonstrated a favorable safety and tolerability profile. Based on this profile of vupanorsen, which is primarily manifested by changes in triglyceride metabolism with reductions in angiopoietin-like 3 as well as APOCIII, our partner, Pfizer, is planning to initiate a Phase IIb study before year-end, focused specifically in patients with cardiovascular disease and elevated triglycerides. This will determine the optimal dose for a planned Phase III cardiovascular outcomes study in a similar population targeting angiopoietin-like 3. As you can see, we are clearly excited about these programs that have the potential to be transformative disease-modifying therapies, targeting triglyceride-mediated diseases. Both programs are rapidly advancing to the next stage of clinical development and have the potential to help many patients suffering from cardiovascular disease. APOCIII-LRx has the potential to treat FCS and MCS and patients with triglycerides greater than 500, all of which are geared to reduce pancreatitis. It also has the potential to treat a broader population and reducing cardiovascular disease risk. Angiopoietin-like 3-LRx can be used to treat patients with mixed dyslipidemia with elevations of triglycerides, non-HDL cholesterol and LDL cholesterol. Now I'd like to discuss a different cardiovascular disease risk factor, Lipoprotein(a) , or Lp(a), which has a different pathophysiology and is an independent risk factor from triglycerides and LDL cholesterol. Lp(a) particles are composed of apolipoprotein A and apoB-100. Lp(a) is a circulating lipoprotein and elevated levels are well recognized cardiovascular risk factor. Lp(a) is genetically determined and those with elevated levels of Lp(a) are at increased risk for cardiovascular disease and aortic stenosis. Lp(a) is highly prevalent with approximately 20% of the general population having elevated levels. In addition, it is estimated that at least 8 million people worldwide have had a prior cardiovascular event and also have elevated levels of Lp(a). There are no approved pharmacological therapies to lower Lp(a). Statins tend to raise Lp(a) and niacin and PCSK9 inhibitors have modest but clinically inadequate Lp(a) lowering effects. Elevated levels of Lp(a) cause cardiovascular disease and aortic stenosis through multiple mechanisms, including direct atherogenicity due to the LDL moiety that is part of the Lp(a) molecule, anti-fibrinolytic activity associated with the apolipoprotein A component and the high content of pro-inflammatory oxidized phospholipids. Shown here is the relationship between elevated levels of Lp(a) and cardiovascular risk in patients from the general community, i.e., those without prior cardiovascular disease. Lp(a)'s atherogenic [indiscernible] significant risk at level of greater than 50 milligrams per deciliter. AKCEA-APO(a)-LRx, now termed by the generic name pelacarsen, is designed to reduce apolipoprotein A in the liver, a key component in the assembly of Lp(a) particles. The Phase III Lp(a) HORIZON study is currently enrolling patients and pelacarsen was [indiscernible] granted Fast Track Designation by the FDA. We recently published the results of the Phase II study of 286 patients who had elevated Lp(a) levels greater than 60 milligrams per deciliter or approximately 150 nanomoles per liter as well as established cardiovascular disease in the New England Journal of Medicine. Shown here is the Phase II study design, testing various doses and dose regimens as well as safety and tolerability parameters. A dose-dependent reduction in Lp(a) levels is noted, reaching a mean of 80% reduction with 20-milligram weekly dose equivalent to 80 milligrams monthly. Drawing your attention to the yellow bar on the far right-hand of the chart, shows 98% of patients in this group achieved Lp(a) levels less than or equal to 50 milligrams per deciliter or approximately 125 nanomoles per liter at the highest dose, considered thresholding guidelines as optimal levels to minimize risk of cardiovascular events. In addition to these potent effects on Lp(a), there were significant reductions noted in LDL cholesterol, ApoB and oxidized phospholipids. This was the largest and longest study conducted in patients with elevated Lp(a). We demonstrated robust dose-dependent and sustained reductions in Lp(a) levels in patients treated for at least 6 months, with some patients being treated up to 1 year. In addition to the very potent Lp(a) reductions, pelacarsen demonstrated favorable safety and tolerability profile. Based on these exciting data, our partner Novartis, has launched a Phase III Lp(a) HORIZON study, and patients are currently being enrolled. This is a cardiovascular outcomes trial involving 7,680 patients with cardiovascular disease and Lp(a) greater than 70 milligrams per deciliter, which is approximately 175 nanomoles per liter. Patients are being randomized to pelacarsen 80 milligrams subcutaneous monthly or placebo, and the primary endpoint is a reduction in major cardiovascular events, including cardiovascular mortality, nonfatal myocardial infarction, stroke and urgent coronary revascularization. The treatment period is expected to last approximately 4 years with 993 primary MACE events occur. The trial will be considered positive if a significant reduction in MACE occurs in the overall group with Lp(a) greater than 70 milligrams per deciliter or in the subgroup of Lp(a) greater than 90 milligrams per deciliter. We expect data from this study in the 2024 time frame. As you can clearly see, we are optimistic about all these programs. Each program has the potential to address an unmet medical needs in the liver abnormalities in millions of patients with or at risk for cardiovascular disease. And with that, I will now turn the call over to Sanjay to discuss our Factor XI program for thrombosis.

Thank you, Sam. Thrombosis is the formation of blood clots, which is an underlying cause of heart attacks, strokes and pulmonary embolism, and it continues to be a leading cause of morbidity and mortality. Although anticoagulant therapies are useful for many patients, not all patients benefit from currently available drugs. The main issue with anticoagulation is that we're always walking a very fine line between preventing blood clots and causing bleeding. On the one hand, we want to give enough drug to reduce the risk of thrombosis. But as we increase the dose, we also increase the risk of bleeding. In fact, the risk of bleeding restricts our ability to give effective antithrombotic treatment, especially for high-risk patients. And it becomes very difficult to maintain patients within a defined anticoagulation range without routine monitoring. Additionally, antithrombotic therapy must be discontinued prior to surgical procedures, putting patients at risk for thrombotic episodes. Patients are also at risk of bleeding episodes when anticoagulants are then switched around at the time of the procedure. These significant challenges limit the use of anticoagulants in a variety of therapeutic settings, including patients with atrial fibrillation who have a high risk of bleeding as well as those who have cardiac diseases. Therefore, there is a significant need for a therapy that can produce an antithrombotic effect with minimal bleeding risk. In contrast to existing anticoagulants, IONIS-FXI-LRx has a unique mechanism that could enable a superior benefit risk profile with the potential to be used in a broad array of indications. We know that people with high Factor XI levels are at higher risk of venous and arterial thrombosis than those with low levels, who, in turn, are at a reduced risk of venous thrombosis. Additionally, patients with congenital deficiency of Factor XI don't typically exhibit spontaneous bleeding. Furthermore, we know in preclinical models that if you inhibit Factor XI, you can reduce thrombosis without increased bleeding. So let's take a minute to understand the role of Factor XI in the clotting process. Clotting is initiated by tissue factor exposed at the sites of injury, which initiates clotting through the extrinsic pathway. There is an amplification loop that involves Factor IX and Factor VIII, both of which are hemophilia factors, and we know clinically that deficiencies of these factors are associated with bleeding. Now if you look at the left-hand side of the slide, you will see that Factor XI is positioned above Factor IX. And Factor XI is a second amplification loop, which can be activated by Factor XII from above or by thrombin from below, and it serves to further propagate and stabilize the clot through Factors IX and Factor VIII. Factor XI, therefore is positioned to propagate clotting, but it is not essential for hemostasis. And this is the main reason why we can dissociate the antithrombotic effect from the bleeding effect by targeting Factor XI with IONIS-FXI-LRx. As shown on this slide, the top panel illustrates that our antisense compounds can very selectively inhibit Factor XI without affecting other coagulation factors, which enables us to evaluate their effects on thrombosis and bleeding in animal models. The bottom 2 left panels show representative data comparing the effects of Factor XI antisense drugs with warfarin, an older anticoagulant; and apixaban, one of the new Factor Xa inhibitors. Taking a closer look at the blue lines with squares, what you see is that as you increase the dose of warfarin or apixaban, you reduce thrombosis, as you would expect. But if you look at the black lines with diamonds, the lines moving up and to the right, you see that as you increase the dose and reduce thrombosis, you pay a price with increased bleeding. Now if you look at the panel in the bottom right with Factor XI antisense, you see that as you increase the dose of the antisense drug targeting Factor XI, thrombosis is attenuated. But there is no increase in bleeding. So in animal models, we were able to dissociate the antithrombotic effect from an increased bleeding risk by inhibiting Factor XI with an antisense drug. After completing a Phase I study in healthy volunteers with IONIS-FXIRx, we then moved into a Phase II study in patients undergoing total knee replacement. The objective of this Phase II study was to compare several doses of IONIS-FXIRx with the standard of care, enoxaparin, which is a low-molecular-weight heparin. It's important to understand that there are 2 key aspects in patients undergoing knee surgery. First, these patients have a risk of developing venous thrombosis or VTE. And second, this procedure is associated with bleeding. Results from our study demonstrated that patients treated with IONIS-FXIRx experienced a robust and sustained decrease in Factor XI levels and substantially reduced incidents of VTE with fewer bleeding events compared to enoxaparin. More specifically, we observed a sevenfold lower incidents of VTE in patients treated with 300-milligram of the antisense drug with numerically fewer bleeding events as compared with enoxaparin-treated patients. We subsequently evaluated the effects of IONIS-FXIRx in patients with end-stage renal disease, or ESRD, on hemodialysis, which is a large population of approximately 2 million people globally who are prone to access thrombotic events, including myocardial infarction and ischemic stroke. These patients also have a marked increase in bleeding risk due to which antithrombotic therapies are often avoided in these patients. In our study, we saw dose-dependent reductions in Factor XI, as shown on the slide, which were consistent with results from the Phase II study in patients undergoing total knee replacement. Importantly, major bleeding was not observed in patients treated with IONIS-FXIRx despite administering it in addition to heparin, which is routinely used to prevent coagulation in the dialysis circuit. Additionally, initial analysis suggested that IONIS-FXIRx reduced severe clotting events in the dialysis circuit beyond the standard use of heparin, which were very exciting initial data. So in summary to this point, we have validated our Factor XI program as a promising new therapeutic approach for thrombosis, by which the antithrombotic effect can be dissociated from bleeding risk. Our clinical data complements earlier data in preclinical models as well as data from patients with congenital Factor XI deficiency. Looking at our Factor XI program, it really has the potential to be best-in-class. We can use our drug for both arterial or venous thrombosis, and we have already demonstrated a low bleeding risk in several target populations. As Brett discussed earlier today, our LICA technology has had profound effects throughout the portfolio and, in particular, for a cardiovascular franchise. Another example can be seen here with IONIS-FXI-LRx. The LICA version shares many similarities to the parent molecule. It has the same sequence as IONIS-FXIRx and therefore, selectively reduces plasma Factor XI activity without affecting other coagulation factors. What separates the LICA version from the parent drug is our ability to deliver a significantly more potent drug targeting Factor XI and with a monthly dosing regimen. We have now completed a Phase I study in healthy volunteers in which Ionis Factor XI LICA demonstrated robust and sustained Factor XI reductions, greater than 80% at the 80-milligram monthly dose. Ionis Factor XI LICA was well tolerated, supporting monthly dosing for future Phase II/III studies. What's next for Ionis Factor XI LICA? Bayer plans to initiate a Phase IIb study later this year in patients with end-stage renal disease, a patient population in which we previously demonstrated statistically significant dose-dependent reductions in Factor XI levels with the unconjugated parent Factor XI antisense compound, without any increase in major bleeding. While the initial focus will be in end-stage renal disease patients, there is potential for multiple additional indications for Ionis Factor XI LICA. We see it having a place where you want to get a better balance between the antithrombotic effect and safety. And IONIS-FXIRx could provide a much safer option anticoagulant therapy. And with that, I'd like to hand the call over to Richard, who will provide an update on our programs targeting TTR cardiomyopathy and treatment-resistant hypertension. Richard?

Thanks, Sanjay, and good morning to everyone on the call. TTR cardiomyopathy is a fatal disease that impacts more than 240,000 people worldwide. It is characterized by the accumulation of TTR protein in the walls of the heart, in particularly, the left ventricle, the main chamber responsible for pumping blood. These deposits cause the walls of the heart to thicken and become stiff, resulting in an inability of the heart to pump blood out efficiently, leading to congestive heart failure and ultimately, death. So clearly, there is a tremendous need to develop a therapy for those impacted by this devastating disease. Knowing this, knowing the TTR cardiomyopathy biology as well as we do and based on the clinical experience with inotersen for TTR polyneuropathy, we, along with TTR investigators, began to look at inotersen as a possible treatment option for cardiomyopathy patients. Today, there are 2 ongoing investigator-initiated studies, evaluating the safety and efficacy of inotersen in both wild-type and hereditary TTR cardiomyopathy patients. The most recent study to initiate is being conducted by Dr. Rodney Falk at Brigham and Womens Hospital. This study was started about a year ago and has enrolled well. There isn't much to report on for this study today, but stay tuned for updates in the future. The more mature study, initiated more than 5 years ago, is being conducted by Dr. Merrill Benson at Indiana University Medical Center and continues to provide encouraging results. As of February 2020, there were 27 actively enrolled patients with 5 patients on treatment for more than 5 years. Results from this ongoing study were recently published in Amyloid: the Journal of Protein Folding Disorders. These results continue to support the conclusion that cardiomyopathy patients are doing better than their untreated counterparts based on improvements seen in the 6-minute walk tests and reductions in left ventricular mass. Furthermore, the safety and tolerability profile over multiple years of treatment remains strong, and the drug-related adverse events have been mild. And it's this inotersen data that demonstrated long-term benefit and a favorable safety and tolerability profile that gives us confidence that our follow-on, AKCEA-TTR-LRx, will provide benefit to these patients with TTR cardiomyopathy. So TTR-LRx is in the Phase III CARDIO-TTRansform study in patients with TTR cardiomyopathy. We are actively enrolling patients and expect to complete enrollment next year and have data from this study in 2023. TTR-LRx demonstrates all the benefits of our LICA medicines: more potency, improved convenience and better tolerability. The rationale of this study is based on the preclinical work we performed investigator studies, which we just touched on and most importantly, the robust target reductions TTR-LRx demonstrated in the Phase I study of healthy volunteers. Shown here is a dose-response comparison from 2 independent Phase I studies. The curve on the right is from TEGSEDI, and our follow-on TTR-LRx is on the left. Looking at both curves together, you can see that both medicines produce robust TTR reductions. What this graph illustrates is just how potent the TTR-LRx version is with an improved potency of at least 30-fold compared to the parent unconjugated TEGSEDI. This gain in potency enables patients to go from a weekly subcu to a monthly subcu, reducing the number of treatments by 75%, while maintaining TTR reductions in excess of 90% and an excellent safety profile. Shown here are the reductions we demonstrated in a Phase I study in healthy volunteers. As you can see from the graph on the right, we are able to show dose-dependent reductions. And at the highest dose, we achieved a mean reduction in TTR levels of 94%. TTR-LRx was generally well tolerated and demonstrated a favorable safety and tolerability profile. So based on these data, we move directly into the Phase III study. We expect to enroll up to 750 patients with wild-type and hereditary forms of TTR cardiomyopathy, each receiving once-monthly doses of TTR-LRx. This is a global cardiovascular outcome study, so we will be evaluating cardiovascular deaths and related cardiovascular events, including hospitalizations. As I mentioned earlier, enrollment is progressing well, and we're planning to have data in 2023. Finally, I'd like to turn your attention to an exciting ongoing program, our IONIS-AGT-LRx program for the treatment of resistant hypertension or TRH for short. Like many of the diseases we've discussed today, TRH puts patients at extreme risk for cardiovascular events in the need of a disease-modifying therapy. TRH is a form of hypertension that is uncontrolled despite being treated with at least 3 blood pressure medications, and if left untreated, increases the risk of stroke and also fatal and nonfatal cardiovascular events. In the U.S., there are approximately 75 million adults with hypertension. And of this, there are approximately 5 million with treatment-resistant hypertension. IONIS-AGT-LRx is a generation 2 LICA medicine we designed to inhibit the production of angiotensinogen, or AGT, in the liver in order to decrease blood pressure. A mainstay of hypertension treatment today, renin-angiotensin inhibitors work primarily in the kidney and by interfering with kidney homeostasis can be associated with elevated potassium levels and can lead to arrhythmias, renal failure and death. By inhibiting the most proximal pathway of the renin-angiotensin system and mostly avoiding the kidney, it is anticipated that our approach may be safer and more effective. We have demonstrated in preclinical models of hypertension that angiotensinogen reductions in excess of 90% can be achieved, resulting in significant lowering of blood pressure. We have since completed a Phase I and 2 Phase II studies evaluating AGT-LRx in hypertensive patients of RAAS inhibitors as well as patients with uncontrolled hypertension, including all patients on ACE inhibitors, or angiotensin receptor blockers. Here, you see the study designs for the 2 Phase II studies we expect to report later this year. On the top of the slide, you can see the study in patients whose blood pressure was controlled on either an ACE or an ARB medication. For obtaining proof of concept, these patients had their medications washed out before initiation of treatment with AGT-LRx. The second study enrolled patients with uncontrolled hypertension despite being on 2 to 3 anti-hypertensive medications, one of which was an ACE inhibitor or an ARB. This study will potentially demonstrate whether additional blood pressure reduction can be achieved in patients already treated with standard of care, ACE and ARBs. Combined, the 2 studies will provide proof-of-concept data for late-stage development of AGT-LRx. In summary, we've demonstrated in preclinical models of hypertension that angiotensinogen reductions results in significant lowering of blood pressure. There's a lot of excitement surrounding this program and data from both Phase II studies is expected this year. We look forward to providing these results. So stay tuned for details. With that, I'd like to return the call back to Brett.

Thanks, Richard, and thanks to the rest of the team as well. Today, we provided you with a brief look into our cardiovascular disease franchise, one of the leading franchises in the industry with 9 medicines under clinical evaluation today, addressing virtually all areas of cardiovascular disease. And of course, the great progress we're making to treat cardiovascular diseases is the product of Ionis innovation, and we see even greater success in the future as we continue to invest substantially in innovative ways to advance our technology, expand the scope of diseases we tackle and bring even more benefit and value to the patients we serve. Shown here is just a brief summary of some of the investments we're making and will continue to make to deliver more transformational medicines to the marketplace for many years to come. First, our drug candidate selection process is well established and continues to advance, delivering greater efficiencies and overall improved drug profiles and performance. Second, we're investing in human genomics research to identify even more novel targets to ensure the continuous flow of novel drug targets into our pipeline that tackle the root causes of human diseases. And finally, our focused medicinal chemistry program has greatly improved the performance of our medicines, including novel LICA strategies to open up new organ systems, bringing exponential increases in potency, selectivity and longer durations of effect, all contributing to a reproducible and highly attractive therapeutic profile for our medicines. What does all this mean? We believe we have created the leading RNA targeting drug discovery and development platform that is delivering value today and will deliver even greater value for many years to come. Our pipeline is advancing and expanding keeping us on track to deliver 10 or more marketing applications for a broad range of diseases over the next several years, including medicines for cardiovascular diseases, some of which we highlighted today. Before we open up the call for questions, I would like to take this opportunity to inform you that we plan to host our 2020 Investor Day in early December. So please stay tuned for those details. And with that, Sarah, I'd like to open the webcast up for some questions.

[Operator Instructions] Our first question comes from Yaron Werber with Cowen.

Yes. So a really great presentation. We definitely appreciate it. So I have a couple of questions. Maybe the first one, Brett, a little bit more strategically, I mean, you have obviously now treatment-resistant hypertension potential product, which is cardiovascularly focused, and it's not necessarily primary care, although it might have a more cardiology, I imagine. Then you have your -- your FCS program, the APOCIII, so you can take into orphan but then go broad. And then you have a Pfizer relationship and Novartis relationship. So number one, is there any noncompetes between Pfizer and Novartis in the APOCIII that can lead them? Is there any reason all of you can go into a broad market and sort of compete to a certain degree? And then I have a follow-on question as well.

Sure. Thanks, Yaron. So our cardiovascular franchise, as you recognize, is very big, and the opportunities are enormous for both broad indications and rare indications, and we believe and Pfizer certainly believes and Novartis believes and we believe, that are our partners as well as Ionis that the opportunities -- the drugs that we have in our pipeline that are moving towards commercialization, all have unique profiles that represent disease populations that are distinct with very large unmet medical needs. For example, Lp(a) is a risk factor for cardiovascular disease. It's not being addressed by vupanorsen or by APOCIII LICA. And the rare disease populations are very attractive for Ionis. And in the large populations are -- strategically more -- makes more sense to go with partners like Novartis and Pfizer. Vupanorsen and APOCIII LICA are very interesting and very exciting programs with some overlap in their profile, but they also have very distinct populations that we believe represent big opportunities for patient populations with unmet medical needs. Sam, why don't you take us a little bit through the profiles and the patient populations that we think are uniquely targetable with angiopoietin-like 3 target medicine and an APOCIII LICA target medicine.

Sure. I think there's obviously the overlap in the triglyceride, but there are some differences. So APOCIII is really involved in 2 areas, as I mentioned: one is inhibiting lipoprotein lipase; but the other one is in clearing TRLs, triglyceride-rich lipoprotein. So this is why it works in FCS. If you don't have LPL activity like you do in FCS patients, then you need to have another mechanism through which APOCIII mediates hypertriglyceridemia. So APOCIII is very, very well suited for clearing these triglyceride-rich lipoproteins, whether they're an FCS or multifactorial chylomicronemia, which is a combination of things, maybe 1 gene and obesity and diabetes, et cetera, that are poorly controlled. And of course, it's amenable to these larger indications to lower triglycerides. It does not have an effect, though, on LDL cholesterol. So that's usually neutral at the patients who have lower triglycerides. And in FCS patients, they have very low LDL. So you tend to see a little bit of a rise in the LDL, but it's still below normal. On the other hand, angiopoietin-like 3, it appears to have that overlap with lipoprotein lipase with APOCIII, but also is -- functions in inducing output of VLDL in the liver. And so that eventually gets remodeled to LDL. So if you look at the natural history studies of angiopoietin-like 3, it really is more amenable to treating mixed dyslipidemias. People have a combination of, say, remnant cholesterol, which is kind of the high triglyceride patients, but also high LDL. So you can find clinical scenarios where one might be more suited than the other. So if you have a pure hypertriglyceridemia patient, that could be good for APOCIII. But if you have somebody who also has high LDL, that could be a good patient to have angiopoietin-like 3 inhibition as your primary mechanism.

Yes, Yaron, I hope that helps. And then you had a second question, you said?

Yes, yes. Very clear. And then for treatment-resistant hypertension, right, is that something you can keep and just have a cardiovascular-focused salesforce that, in some ways, you already sort of are going to have anyway? Or is that something you'll partner?

For each medicine in our pipeline, we will do what we think will bring the greatest commercial value for our investors, for Ionis and for patients. Our strategy has been and will continue to be to partner for very large indications that require large, very large Phase III studies and global sizable commercialization force. And although we haven't made any specific decisions on it yet, I mean, I think angiotensinogen LICA for hypertension fits that bill. However, we are committed to holding onto medicines even that we will eventually partner much longer through Phase II proof-of-concept studies as we're doing for AGT-LRx to drive to command even greater economic value for Ionis, once we do and if we do eventually partner. But I would say that -- your own, it's that strategy pretty well.

Our next question comes from Tyler Van Buren with Piper Jaffray.

I guess, the first, I have a couple of questions on LICA TTR. On the Benson study that's been ongoing for a while now, you referred to the improved 6-minute walk distance. So could you just remind us what you saw there and how that compares to what we saw with tafamidis? And then also with respect -- secondarily, with respect to the CARDIO-TTRansform trial, the 2020 -- the data in 2023, I guess, I'm assuming that's going to be like an initial 6-minute walk test distance data or an interim readout. We wouldn't expect to get the cardiovascular death or mortality outcomes data by then, right?

Thanks, Tyler. So on the Benson study, we observed, compared to natural history data, improvements in 6-minute walk test over time and improvements that were observed fairly rapidly within 6 months or so in several -- in many patients compared to natural history. And we saw these improvements, and we are continuing to see these improvements in patients, improving with continued treatment with inotersen in that study. In addition, we see improvements in both the hereditary as well as in patients with wild-type cardiomyopathy in the Benson study. And again, that's compared to natural history data where patients are going downhill. Tafamidis also showed some improvements in 6-minute walk test, but it took a lot longer to see those effects. But the effects of tafamidis were positive. And we believe, as is the design of our Phase III study, we were allowing patients to come into the trial on standard of care, which, of course, includes tafamidis, we expect benefit to be additive or potentially synergistic between TTR LICA on top of tafamidis on 6-minute walk test but moreover on cardiovascular outcome. As far as the 2023 data that we referred to, we're -- the 2023 data refers to outcome data. So we're looking at outcome data in 2023. Of course, 6-minute walk test and other secondary and tertiary endpoints will be down too, but 2023 outcome is what we're looking at for that.

Okay. That's helpful. Maybe just a quick follow-up. How much tafamidis usage do you expect in the Phase III? And are you confident that you could get a monotherapy label if the majority of patients are on tafamidis the whole time?

Yes. We haven't gone into the details, Tyler, on sharing what our projections are. We've obviously done a great deal of homework on what we expect to see. We have not placed a cap in this study on allowing tafamidis into the trial. However, we are expecting a substantial population of patients on tafamidis in the Phase III trial in both placebo and in TTR-LRx. And obviously, until tafamidis is approved in certain geographies, those patients wouldn't be on tafamidis, if it's not available to them. In the U.S., it's readily available. And my understanding, everything we've seen is many patients with wild-type cardiomyopathy as well as hereditary cardiomyopathy are on tafamidis. So we would expect the U.S. to contribute substantially to patients on both drugs. We're stratifying for patients. So we believe -- and we believe, nevertheless, based on availability of tafamidis and other things that we will have a substantial number of patients also on monotherapy. And we believe that we'll be able to make comparisons of TTR-LRx alone versus tafamidis alone as well as make comparisons of TTR-LRx plus tafamidis versus tafamidis in the study. So we think we're going to have a wealth of data that will command a very powerful label, including monotherapies.

Our next question comes from Jim Birchenough with Wells Fargo.

It's Nick on for Jim this morning. Just going to the angiotensinogen program. One thing I noticed is that you're dosing at 80 milligrams weekly here versus a monthly dose for the other LICA programs you discussed this morning. So first, why do you need such a high dose? And is there a plan to look at monthly dosing?

Yes. Sam, do you want to take that?

Sure. Well, I think in terms of blood pressure, there's a couple of issues here. The safety-related facts, you don't want to have excessive blood pressure lowering in these patients. So as -- we're using blood pressure medicines on a daily basis, sometimes twice a day and change the paradigm to very, very long-acting drugs in terms of, say, once a month, you have to worry about as a clinician is whether somebody may bottom out their blood pressure and be symptomatic for a long time. So in terms of drug development for a complete new paradigm, you really have to be careful not to overshoot how much blood pressure you get. So that's one reason. We don't want to necessarily dose these patients too infrequently and have an issue. So the 80-milligram dose, we're going through the Phase II studies. We're trying to do dose-ranging. We're trying to figure out what is the optimal dose for x amount of blood pressure. So we'll be able to report a lot of that information going forward later this year when we have actual -- the data to show you. The program is quite advanced, as you've seen. We've already done 3 trials but haven't reported on the data yet. So -- the other part of this is you have to figure out whether the medicine works on top of standard of care, which is very important. And so we're trying to assess its profile in patients that are already on ACE and ARBs. So there's a lot of complexities here in trying to develop an injectable that's potentially long-acting on top of standard of care. So because of this, we're sort of just be very careful in how we develop the drug to make sure that we understand it very well before we go to proof-of-concept in Phase IIb.

Right. And I would just add to that, Nick, that once we get that profile, once we really understand the performance of the drug, the behavior of the drug in these patients and beyond target safety a little bit better, we will consider going to monthly. But right now, this is the strategy we want to get -- which we want to drive the most amount of information from and to ensure safety for patients.

And then for the Phase II, do any of those patients have sort of abnormal renal function on marked hyperkalemia at baseline? And would you be expecting correction or improvement of 6 to 8 weeks of dosing?

Right. So the beauty of this target is that it theoretically avoids inhibiting the RAAS pathway in the kidney, which is what triggers a lot of the hyperkalemia and renal dysfunction. So in our current studies, we've gone as low as the GFR of 60. So the answer is yes, some of them do have mild, relatively mild renal abnormalities. But this is where the profile of the drug will really be very important to assess because what we want to do is avoid what happens with ACE and ARBs and other RAAS inhibitors, which is hyperkalemia and renal failure. And so by inhibiting the target in the liver, hopefully, that hypothesis will pan out clinically. And as we move ahead with the development plan, we're going to be studying patients with very low GFRs down to 30 and test that even more intensively.

And we're very excited about this program there.

Our next question comes from Joel Beatty with Citi.

My question is on Lp(a) outcomes trial that's underway with data expected in 2024. With a minimum follow-up time of 2.5 years and 993 events, is there a potential for efficacy to read out earlier than that such as with interim analysis that would be looking at efficacy?

Yes. Of course, the trials are powered based on best evidence, which is a combination of what the event rates are and people with high Lp(a). We know that from FOURIER. We know that from ODYSSEY OUTCOMES. There's always a possibility that it could be early. But right now, it's powered very robustly. And one mistake, I think, that was made in the PCSK9 inhibitor trials is they made them too short and didn't get cardiovascular mortality. So this is powered to get cardiovascular mortality as part of that MACE endpoint. And so the bottom line is we're expecting to go to full time. And of course, if something shows up that is the drug is a lot more effective than is predicted, there could be a possibility that, that could come into play at some point.

Yes. And remember, Joel, there's always a Data Safety Monitoring Board that watches these studies very carefully. And obviously, if there is ever an imbalance, favorable imbalance in mortality, ethically, they would need to bring to the attention of the sponsor, Novartis and recommend doing something about it. So it's monitored along the way, but we are expecting the study to go to this full outcome at this point.

Great. Yes, that makes sense. And then maybe one other question on the TTR amyloidosis program. Could you discuss any differences between TTR reduction and TTR stabilization? And how that might be beneficial for TTR amyloidosis patients?

We think there's a place for both mechanisms for patients with TTR for all forms of TTR amyloidosis. We like our mechanism a lot. We believe it is a more effective mechanism. I mean, it's -- I think it's pretty straightforward to conclude that blocking the production of a disease-causing protein will be more effective than stabilizing disease-causing protein after it has been produced and has done damage. We also believe our data supports that. Our polyneuropathy data was very substantially, significantly positive in patients with hereditary polyneuropathy in tafamidis. Although there were some caveats to the study that was out of their control, like dropouts and so on, still, the efficacy was far more impressive, I believe, for inotersen versus tafamidis in that patient population, we expect it will be more effective in the cardiomyopathy patients, too. And I think the Benson investigator data is strongly supporting that conclusion already as well as in our Phase III study in which we saw substantial reductions in cardiovascular mass and left ventricular mass in our inotersen Phase III study. So we think that there's a place for both mechanisms. We think there's potential for added benefit when combining them. But we prefer our mechanism. We think it will be more effective.

Our next question comes from Chad Messer with Needham & Company.

My congratulations on a very informative presentation. For the angiotensin program, the focus seems to be on uncontrolled hypertension, but for the Phase II, you included a switching study of controlled patients. Just wondering if you could talk about the rationale there? Is that more for scientific purposes of benchmarking safety and efficacy against standard of care drugs? Or is there also potentially some sort of commercial interest or a factor for running that study?

Yes. I can answer that. This is Sam. I think as you think about the world of hypertension, the FDA does not give you a label for resistant hypertension. But the clinical world, that's where we need -- the need is, right? So that's part of the issue there. But more importantly, I don't think people are going to stop a very inexpensive ACE and ARB to show -- to replace with this drug, unless there's some great efficacy or it's additive. So the bottom line is in our design. The first thing we want to do is get proof-of-concept and patients that were responsive to ACEs and ARBs in the first study, we took them off their medication, their blood pressure went up, and then we gave the drug basically as the monotherapy to demonstrate whether or not it works without an ACE and ARB on top. And the second study was to really simulate more standard of care. Patients are going to be on ACE and ARBs and you get additional benefit if you now add ADT inhibition on top. So they have very distinctive scientific purposes in terms of getting proof-of-concept for then using them more in a situation where the clinician would be likely to use them. So I would say most of this is really kind of seeing the profile of the drug with and without ACE inhibitors on board. And the second side is going to be very instructive because one of the issues with ACEs and ARBs is you can't really use optimal doses because of side effects. So a lot of the dosing that you get is really suboptimal. And so by now targeting the RAAS pathway in the liver, you basically have double focus antisense. And so it'll be very interesting how this program goes forward in people that are already on ACE and ARB and whether you get this additional benefit without the added risk. And that's where the critical part of this whole pathway where it's going to reside. And of course, the people that need the most blood pressure lowering is the ones that are already on 3 drugs. So ultimately, you have to get to the point where you're going to be able to use it in people that really need additional blood pressure lowering. And so this is kind of slowly where the program is going to.

Okay. Yes, that makes a lot of sense. Just wondering if you move forward, you go into IIb and then a pivotal study, do you believe that you're going to be able to just focus on the uncontrolled hypertension? Or are you going to have to include other patients in future studies as well?

Well, as I said, the FDA doesn't right now distinguish resistant hypertension versus hypertension, the label will be for hypertension. But the clinical need is in people that are resistant. So this is where we're going to go first. But ultimately, you can envision this being used more broadly, if at that point in time, it makes sense. So the answer is, our focus is going to be on people that need the drug, and there's a lot of them out there. But ultimately, it could be used more broadly in other patients that could benefit, particularly with renal disease that don't seem to benefit as much from current therapies.

Our next question comes from [ Neal Jen ] with [ Blade Law & Company ]