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

Hello. I'd like to welcome everyone to Ionis' Investor Day. Hopefully, everyone is able to see the presentation slides. However, if you'd like to download a copy of today's presentation, you can get a copy of the Events resource tab that's located on the left-hand side of the screen, or you can go to our website where we have a copy that you can download from the Investors section of ionisph.com website. [Operator Instructions] Following today's event, we will provide a replay of this webcast, which will be available on Ionis' website for a limited time. 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. Our presenters for today's event are Brett Monia, Chief Executive Officer; Sam Tsimikas, Senior Vice President of Global Cardiovascular Development; Frank Bennett, Chief Scientific Officer; Onaiza Cadoret, Chief Corporate Development and Commercial Officer; Beth Hougen, Chief Financial Officer; and Eric Swayze, Executive Vice President of Research. And now I'll turn the call over to Brett.

Thanks, Wade. And let me add to Wade's introductory comments, let me also welcome all of you, our listeners and participants for today's Ionis 2020 Investor Day presentation. We're very pleased to have you attend and participate in today's presentation. And we're very excited and thrilled to present on the tremendous progress and advancements we're making at Ionis, all of which we believe will provide great benefits to patients, caregivers and our shareholders. Unfortunately, we are forced to adapt rapidly once again because of the ever-changing COVID pandemic. We were planning a remote but live video presentation from the stage of our new conference center in Carlsbad, California today. However, the state issued a new stay-at-home order or a lockdown yesterday due to a spike in COVID, and we had a change of plans to a slide audio presentation instead. That's a bit unfortunate, but we think today's format will work out just fine and capture all the key elements we want to convey. We're very pleased to have all of you, our listeners attend and participate so let's go forward. These are, in many ways, new times at Ionis, and in some ways, we're evolving to becoming a new company. For years, we've been recognized for excellence in research, early drug development with some late-stage success recently and for excellence in scientific innovation, deservingly so. And we'll never stray from this. In fact, we will strengthen our abilities in these areas going forward. However, this year, we set out to build on all of this to become an even stronger company that will provide even greater value well into the future. We have created a premier late-stage development pipeline position to deliver a vast number of new products to the market, a late-stage pipeline that we believe is second to none. We're moving rapidly to build and expand the Ionis non-partnered pipeline and building our commercial organization to support this pipeline to maximize its value. We're making new investments in technology. It is expanding the breadth of our reach to provide new medicines to tackle new disease areas, ensuring for a rich future of commercial products. This is what we'll discuss today. Here's our agenda for today. As a reminder, we did several deep dives this year into our 2 key franchises and 1 emerging franchise. We did a deep dive into our neurology franchise in early summer, reviewing the great progress we're making in our premier neurology pipeline. And we did the same for our cardiovascular franchise in late summer, another industry-leading franchise. And we delved deeper into our rapidly emerging pulmonary disease program this past fall. So in the interest of the time we have today, we'll focus primarily on new areas. We'll cover the rapidly growing Ionis-owned pipeline, highlighting our Ionis owned neuro and cardiovascular franchises, along with several key assets in those franchises that we're particularly excited about. And these presentations, features will be led by Sam and Frank. We'll also focus on our plans and progress towards building out our commercial strategy, capabilities and where we are in implementing these plans. And Onaiza will lead this discussion. Beth will then lead a presentation intended to provide a view towards the tremendous financial value of our pipeline today and how we see it going in the future. Eric will then highlight the progress we're making in advancing our technology for drug discovery, highlighting several key areas of priorities. And then I'll wrap up with an early look at our 2021 priorities and a vision towards future goals and expectations for the company. But before we do this, I want to start by reminding you what we set out to accomplish at the beginning of this year. Indeed, this year, we established and pursued a very aggressive agenda to advance Ionis in many new and important ways. We set out to prioritize and grow the Ionis own pipeline while moving towards and building our commercial plans to maximize the value of that pipeline. We also set out to aggressively advance our entire pipeline to ensure for a future rich and new and important commercial products. And we work to advance our technology in many important ways, with all of this contributing strategically for our leadership position in RNA therapeutics. And I'm very proud to say that we accomplished all of this and much more. And here are some of our key achievements for the year. We invested in building our commercial plans and capabilities, and we implemented them. We expanded substantially the Ionis-owned pipeline, and we accelerated all of this through the acquisition of our commercial affiliate, Akcea, giving us access not only to commercial capabilities while improving efficiencies, but also to a pipeline of products that we believe in and want full access to and ownership of. We initiated more Phase III studies, now 6. And we advanced new delivery platforms, oral and pulmonary. All this is making us a stronger, more focused and even more competitive organization, positioning us nicely for a strong and sustained future growth. 2020 was certainly a year of substantial pipeline growth and success. We grew our Phase III pipeline from 4 to 6 clinical studies with the start of our TTR LICA cardiomyopathy study and our APOCIII LICA FCS Phase III study. We reported positive proof-of-concept data for 5 mid-stage programs. And the sixth, today, will be highlighted by Sam, our angiotensinogen LICA program for hypertension. We exceeded our goal of initiating 10 new mid-stage clinical studies, and we made solid progress in aerosol and oral delivery. Assets in our late-stage Phase III pipeline are all progressing on track for their scheduled readouts. This includes the 2 Ionis-owned LICA programs. One for treatment of TTR amyloidosis, TTR-LRx and the second APOCIII-LRx for the treatment of triglyceride disorders. Also, our Phase III programs in neurology targeting SOD1-ALS and Huntington's disease are moving forward nicely, the Phase III data expected next year in SOD1-ALS. Pelacarsen, our LICA medicine targeting the cardiovascular risk factor, Lp(a) is enrolling rapidly in the 8,000 patient cardiovascular outcome trial. All of these programs, along with the progress we're making in our mid stage pipeline, are setting us up very well for a potentially vast increase in the number of new products reaching market applications and commercialization through 2025. And this covers severe rare diseases like ALS, Prion and Huntington's disease, along with several drugs, tackling broad cardiovascular indications. The number of opportunities shown here is obviously very impressive, and opportunities continue to grow because our pipeline continues to advance successfully. In January, when I first showed this slide, there were 13 product opportunities, potential filings. Today, there are 20. And moreover, more than half of these potential new approvals are within the Ionis-owned pipeline, giving us control of these programs and options that allow us to focus and prioritize those programs that bring the greatest commercial value to Ionis. And as we manage our development and commercial strategy for the Ionis-owned pipeline in parallel, of course, our partners we work closely with and who understand our technology are progressing many of our key programs towards approval and commercialization, providing even more value to Ionis, substantial value. And finally, the technology advantages we made in 2020 were many and strategically important for our continued growth. In medicinal chemistry, we are markedly extending the duration of action of our drugs in the CNS, potentially setting us up for biannual or annual dosing. And we're identifying new targeted delivery strategies opening up new organ systems for drug development in the near term. We made great progress this year validating new delivery strategies for lung applications and have made great progress towards achieving commercially viable oral delivery. And we made several key investments in Genomics this year, ensuring for a rich pipeline of genetically validated drug targets for years to come. All this is setting us up for an exciting future success with substantial growth. Moving forward to today's agenda. As I said earlier, we'll focus today's presentation on some key areas that we didn't have the opportunity to delve deeply into during the year. We'll focus on the Ionis-owned pipeline; our commercial strategy; a view towards the valuation of the Ionis pipeline; and key technology priorities and advancements. And with that, I want to turn the podium over to Sam Tsimikas, Senior Vice President of Cardiovascular Development at Ionis. Sam?

Thank you, Brett. I would like to review the cardiovascular disease franchise ongoing at Ionis, and then particularly focus on the Ionis-owned assets. Cardiovascular disease is well-known to be the leading cause of death in the U.S. and worldwide in developing countries. And of course, this has been and will continue to be a key area of focus for Ionis Pharmaceuticals. In this slide, the next slide, as you can see the number of -- you can see that we have 7 major programs ongoing in almost all areas of cardiovascular disease. And let me just take a minute to go through each one of the programs in a bit of detail. You start on the bottom left with transthyretin amyloidosis or ATTR. We already have an approved drug called TEGSEDI for polyneuropathy. And we are now developing AKCEA-TTR-LRx for both polyneuropathy that's hereditary as well as wild-type and hereditary cardiomyopathy. And going around the wheel, we have Factor XI LRx with our partner Bayer. That's an advanced Phase IIb studies for thrombotic disorders and in particular in patients that have very high-risk of bleeding that would otherwise benefit from this particular type of approach. We have the first-in-class, best-in-class drug in Pelacarsen for treating lipoprotein little a that is elevated and causes cardiovascular disease and aortic stenosis. And this is already underway in a large Phase III outcomes trial. We have Ionis AGT-LRx, which you'll hear about in more detail in a little bit. This is for treating resistant hypertension as well as heart failure. At the AHA, we presented data on ION449 with our partner, AstraZeneca, and this is targeting PCSK9, and I will review for you in a bit some of the details from that study. Continuing around the wheel. We have Vupanorsen with our partner, Pfizer. Vupanorsen treats mixed dyslipidemia, so elevated triglycerides, elevated LDL-cholesterol that's manifested as elevated non HDL cholesterol. And this is in late-stage Phase IIb. And hopefully, a Phase III study will start 2021 with our partner, Pfizer. And finally, we are the company of FCS. We have developed the rationale and the therapy for Familial Chylomicronemia Syndrome, where WAYLIVRA is approved in the EU. But we have Akcea APOCIII-LRx that will be -- continue to -- an advance in FCS as well as more broader indications that I will review for you in a little bit. Next slide. So let me just take a couple of slides to review ION449. We believe ION449 targeted PCSK9 has the potential to be best-in-class for reducing PCSK9 and LDL-cholesterol level. As a summary of the AHA, we showed substantial and durable reductions in LDL-cholesterol in a Phase I study with a very favorable safety and tolerability profile. On the next slide, you can see some of the results from that Phase I study. Note here, there's a placebo group and multiple doses, single doses of ION449. And if you look on the left slide, you see very potent reductions in PCSK9 plasma levels with a single dose that stayed down up to 16 weeks after that injection. Notice on the right, in the LDL-cholesterol that we were achieving over 70% reduction in LDL-cholesterol with a single dose. To put this in context, PCSK9 inhibitor antibodies lower LDL-cholesterol approximately 60%, and inclisiran lowers LDL-cholesterol approximately 50%. And so you can see here that as we move forward into the development of this program with multiple doses, this does have the potential to be the most efficacious PCSK9 inhibitor on the market. On the next slide, just to summarize then, we do believe this has potential for best-in-class. The update from the AHA is that the multiple ascending dose cohort has completed its Phase I study. We will report this data with AZ in the future, but we can tell you that the safety and efficacy data continues to be favorable in the multiple dose population. And finally, we disclosed last week that an ongoing -- that a Phase IIb study has just been initiated with a very rapid accelerated path to get to Phase III and get this drug on the market for patients with continued elevations of LDL cholesterol. Now for the rest of the presentation, I would like to focus on Ionis-owned assets. And the 3 that you see here are AKCEA-TTR-LRx, AGT-LRx and APOCIII-LRx. Now before I go into the details, I want to show you a video that describes the unmet need and how we're addressing that unmet need in patients with Familial Chylomicronemia Syndrome. So please play the video, and then I will continue on the presentation when that is completed. [Presentation]

Okay. Let's continue with the presentation. I think what you saw in the video is a very poignant example of the severity of disease that can occur when somebody has very high triglyceride levels, the fact that these patients are often misdiagnosed and that now we have hope for these patients. We've spent approximately 10 years working on this program. And I think with APOCIII-LRx, we can finally expand on WAYLIVRA and continue this hope for these patients that have currently no other options for therapy. So let me now review for you APOCIII-LRx. This targets APOCIII, which is very involved in all triglyceride disorders. And in terms of a brief summary, from our development plan, we just reported Phase II data. And an important aspect of that was that 91% of our patients, in that particular study, were able to achieve normal triglyceride levels. The drug has favorable safety and tolerability profile. And just last week, we started our Phase III program in FCS with this drug. And that study should recruit very fast and is ongoing at the moment. Now we're going to provide more details later, but we plan on additional Phase III study in the first half of next year that we will describe the details for you in due course. As a brief background, I'd like to just review APOCIII and why this is such an important target for lowering triglyceride levels. APOCIII is a small protein. It's made in the liver and very strongly regulates all aspects of triglyceride metabolism. It is known that if you have elevated levels of APOCIII that it's an independent cardiovascular risk factor for not just pancreatitis but cardiovascular disease. So depending on your level of triglycerides, there are 2 main phenotypes that are seen with elevated triglycerides. One is acute pancreatitis, when the triglycerides are highly elevated, over 500 milligrams per deciliter. And these patients can have significant complications, including up to a 6% in hospital mortality. The patient who have more modest elevations of triglycerides develop cardiovascular disease. Now if we focus on the cartoon on the right, I will just briefly show you why APOCIII is such an important regulator and why inhibiting it can lead to substantial benefits. If you look at all those yellow particles, these are all lipoproteins with different sizes. Chylomicrons and Chylomicron remnants on the bottom left are derived from the diet and particularly -- and specifically fat in the diet. And so these can cause pancreatitis. On the top right, you see VLDL and IDL, these are particles that are made in the liver and can cause cardiovascular disease. APOCIII, when it latches on to these lipoproteins, inhibit their recognition by the receptors that you see in the liver and slower their clearance. And therefore, these particles accumulate in the plasma, can cause cardiovascular disease and pancreatitis. The second thing that APOCIII does is it inhibits an enzyme called lipoprotein lipase, which remodels these particles into smaller particles that allow you to then break down the triglyceride into fatty acids for energy or storage into adipocytes. So you see here, there are 2 mechanisms that APOCIII affects all lipoprotein -- or all triglyceride-driven diseases. And that by inhibiting that production of that protein, you can theoretically treat every one of these complications. Next slide. Now where is the market for this drug? First of all, Familial Chylomicronemia is very rare. It's a genetic disorder. There are about 3,000 to 5,000 patients globally. This can be addressed from the rare disease perspective. But the more common indications are severely high triglycerides, greater than 500 and is estimated there are 10 million patients globally. And these are patients that, as I mentioned earlier, develop pancreatitis as their primary manifestation of this disorder. And even more common is modestly elevated triglycerides 150 to 500. There's an estimated 50 million patients globally, and these patients develop cardiovascular disease. So we have the opportunity with APOCIII-LRx to address each one of these patient subsets as we go forward in our development program. A little bit of summary of recently presented data from the European Society of Cardiology. This was a Phase II study. This was designed more to look at the cardiovascular disease indication. It recruited patients that had cardiovascular disease and triglyceride levels 200 to 500. The primary endpoint was a change -- percentage change in fasting triglycerides at 6 months. It met its primary endpoint of triglycerides lowering with a very favorable safety and tolerability profile. Now importantly, as you know from the statin world, the question always comes up, well, what percent of patients get to go? And how do you have an effective therapy as a monotherapy? So if you look at the graph here, what it shows you on the Y axis is the number of patients that get to triglycerides under 150, which is considered to be normal level. And then on the bars, you see the different doses and dose regimens. So with a low dose of 50 milligrams every 4 weeks, note that 91% of our patients achieved normal triglyceride levels. And so what this basically tells you is, if you were to do a trial with this drug, you can be pretty much assured that everybody, almost everybody would get to a level that is no longer a risk factor. So we feel great about this result, and we're looking forward to the development of this drug in additional indications. So on the next slide, you can see our development strategy. As I mentioned, we've already initiated the Phase III FCS study. We know the investigators, we know the sites, we have great relationships in this area, and we feel like this is going to be a study that's going to be recruited fast and give us the results we anticipate. The next phase of this, which we will describe in early 2021 is that we plan a Phase III broader indication. And ultimately, we like to look at additional indications that are even larger in the longer term as we go forward. So with that, let me now switch over to AKCEA-TTR-LRx. This targets transthyretin amyloidosis for both polyneuropathy and cardiomyopathy. And this really expands our exciting franchise into broader areas, particularly in the cardiovascular arena. As a summary of where we are to date in our Phase I trial, we demonstrated robust target reductions of greater than 90%. We had a favorable safety and tolerability profile. And a subcutaneous injection such as this will allow flexibility at-home monthly self administration, which is a big bonus for a lot of these patients that are elderly and have difficulty traveling, particularly in the COVID era. And of course, we now have our Phase III CARDIO-TTRansform study underway, which is actively recruiting patients. On the next slide, I like to just review the disease for you. First of all, this is a fatal disease, and it affects approximately 250,000 patients worldwide. Amyloid deposits, due to TTR, accumulate in all the major organs in the body. And you can see on the right here, it is associated with multiple phenotypes, including ocular, cardiovascular, renal, orthopedic, GI and neuropathy. But the key aspect that seems to get patients into trouble or cardiovascular complications, particularly heart failure and sudden cardiac death. And one of our trials, as I will mention -- describe, specifically what addresses that need. Additionally, nephropathy -- I'm sorry, neuropathy is a major complication, particularly symptomatically for a lot of these patients. So we can address, theoretically, all of these manifestations with a focus on the 2 that I mentioned. Now if you look at the natural history of these patients, they tend to have a rapid decline, particularly in the quality of life and the life expectancy is 3 to 15 years on average. But in patients with cardiac involvement, it's only 2 to 5 years, which is probably worse than most cancers that now occur. So on the next slide, I'd like to show you our Phase I data. This is in volunteers. It was a Phase I dose escalation, placebo-controlled study. And if you review the graph on the right, 3 doses that were given 45, 60, 90 milligrams, had very robust reductions in TTR, up to 94%. And the shaded area represents the treatment duration. Note the small red arrowheads on the bottom show monthly injections. So these patients receive 4 injections in 3 months. And note the potency and efficacy of this drug in that even 3 months after the last dose, we still have substantial reductions in TTR in the plasma. So in the next slide, I'd like to show you the 2 trials that we currently have ongoing and are actively recruiting. The first trial is NEURO-TTRansform. These are patients with hereditary ATTR polyneuropathy. And the trial is going to have 140 patients, randomized 6 to 1, AKCEA-TTR-LRx will be 1 arm and then an Inotersen arm will be in 20 patients. At week 35, they will have an interim analysis of mNIS+7, which is an accepted endpoint. And then a top point, the Inotersen patients will convert over to AKCEA-TTR-LRx. That study would then go to week 65, which will have the co-primary endpoints of mNIS+7, a Norfolk Quality of Life questionnaire, and these are accepted endpoints for this particular disease. So that trial is ongoing and actively recruiting. The second trial that we have is CARDIO-TTRansform. This is in both hereditary and wild-type transthyretin cardiomyopathy. This is the largest study ongoing for this disorder. It's going to recruit 750 patients, 1:1, and it's going to go for approximately 30 months. And then the endpoints at that point will be adjudicated. So these 2 trials will provide -- if positive, will provide a novel approach for treating both polyneuropathy and cardiomyopathy and to amyloid TTR deposits. Next slide. Okay. With that summary, let me now switch over to Ionis AGT-LRx. Targeting AGT for treatment-resistant hypertension is a novel approach. And as is well known, hypertension is one of the most important disorders in cardiovascular disease and one of the leading causes of mortality. And blood pressure lowering is accepted by regulators as an endpoint. And to get a blood pressure drug approved, you don't necessarily need to have a cardiovascular outcomes trial because of that. So on the next slide, you can see the prevalence of hypertension. It's arguably one of the most prevalent disorders in cardiovascular disease. On the left side shows the worldwide prevalence. And it's estimated that there's 140 million patients with treatment-resistant hypertension and about 1.1 billion people with hypertension. In the U.S., the number of patients with treatment-resistant hypertension that we are targeting is approximately 10 million. And these patients have much higher risk for cardiovascular events than garden-variety hypertension. Let me take you through on the next slide, a brief, very brief review of why we think targeting angiotensinogen clearly represents an elegant and perhaps better approach than using the current therapies, which are ACE inhibitors and angiotensin-receptor blockers. If you look on the right cartoon, ANG I, ANG II, particularly ANG II promote vasoconstriction and heart failure. And the way we address that is we give ACE inhibitors or angiotensin receptor blockers or even renin inhibitors which aren't used much due to side effects. These drugs all work in the kidney. And one of the problems patients have is they get hyperkalemia and they get renal failure when you inhibit these pathways in the kidney. However, the majority of angiotensinogen is made in the liver. And so if you inhibit angiotensinogen in the liver all these downstream products now get addressed and perhaps get addressed more completely. And therefore, the hypothesis for this particular approach is that we will have a same or better efficacy for blood pressure and heart failure, but we will then allow the kidney to have its normal homeostasis and hopefully will prevent some of the side effects that you see from the current therapies. So with this in mind, this program is fairly advanced, but perhaps not as well-known publicly. We've already actually performed 3 trials. One in normal volunteers. And then we have 2 Phase II trials that we just completed. And then one of them is a patient that had mild hypertension that was controlled, were weaned off their ACE/ARB and then use the AGT-LRx as monotherapy. And the second study, which I'll show you a slide on on the next slide is patients with uncontrolled hypertension who are already on 2 to 3 anti-hypertensive medications, one of which had to be an ACE or an angiotensin receptor blocker. So on the next slide, let me show you the design of this study. This is a pilot study. And note here that the patients are randomized 1:1 -- sorry, 2:1 to one and then they're dosed weekly. Now for high blood pressure treatment, the blood pressure changes minute to minute. It's debatable whether you want to use a very long-acting course of therapy in case patients have complications. So in this study, we're using a weekly dose, and the patients are treated for 8 weeks, and then there's a follow-up period. And on the next slide, I will show you the high level findings. So just to remind you, these are patients who are already on uncontrolled hypertension. This is an add on-therapy. This is what a doctor would do in the clinic. Because these patients are already on their therapies, and we don't necessarily want to take them off, they're uncontrolled, we need to now add drugs to their regimen to get them controlled. And the main findings are seen here in the middle of the slide. The mean change in the systolic blood pressure was 12 millimeters of mercury. And to remind the audience, anything over 5 is a drug. So the diastolic blood pressure reduction was 6 millimeters of mercury and the percent reduction in patients reaching goal, in this case, less than 140 milligrams per deciliter, was 50%. these patients were fairly advanced in their hypertension, 2/3 were on 2 drugs and 35% were on 3 drugs. So we are showing efficacy on top of standard of care. Now importantly, as part of the hypothesis that I mentioned, we had a very favorable safety and tolerability profile. No patients developed hyperkalemia or renal failure and, therefore, we feel very confident that we will continue to see such results going forward. Now we're going to show you the detailed data for this in an upcoming conference very soon. And so we're not going to give you any more details at this point outside what you see here. Now on the next slide, I'm going to show you our market opportunity and also our current development plan. Based on the favorable Phase II data, we're now initiating a Phase IIb study in patients with uncontrolled hypertension, all of which need to be on 3 or more medications. This will start very soon. We have a second study in patients with heart failure with reduced ejection fraction that will also start next year. We believe this drug itself, will be able to address both uncontrolled hypertension and heart failure, and we're looking forward to advancing this forward to regulatory and pivotal type trials for approval. However, because of our technology, that you'll hear more from Eric later, is advancing quickly, we also will perform a third study in this area, a Phase I study with ION904. This is AGT-2.5-LRx. This is with our new cET chemistry that perhaps is not so new anymore, but it is with that chemistry. And this drug will then be evaluated for both less frequent subcutaneous administration, if the disease process allows that, or perhaps even oral administration. As you will see, it's a very, very potent compound. So we have a very robust program in hypertension and heart failure, and we look forward to providing you more results for those as these programs go forward. So to finish then, what I hope I was able to present to you is that we have multiple medicines targeting the major cardiovascular risk factors. This spans from very rare populations to -- from 3,000 to 5,000, 2 populations that are in the hundreds of millions. And we believe that our -- at least 3 of these Ionis-owned drugs and the rest of our pipelines that are partnered represents substantial commercial opportunities for Ionis that will ultimately help our patients have less cardiovascular complications. So with that, I'd like to end here and then present this now to Frank Bennett, our Chief Scientific Officer, who will review our neurological pipeline.

Thank you, Sam. Over the next few minutes, I'll summarize our neurology program. There is a tremendous unmet medical need for new therapies to treat neurological diseases. We have known for years the molecular cost for most major neurological diseases, yet we do not have effective disease-modifying therapies with the exception of spinal muscular atrophy and TTR polyneuropathy. In both these examples, it was Antisense Technology developed by Ionis that was the basis for the first disease-modifying therapies for these neurodegenerative diseases. So building off the success of SPINRAZA and TEGSEDI, we'll continue to deliver transformational medicines because we have a well-validated platform. This includes proof of mechanism ranging from cells in culture to human subjects, proof of the efficacy, proof of safety and commercial success. Our drugs target all the major brain regions and cell types in the CNS. Ionis scientists created a broad scientific foundation for our neurology program, which we are now broadly building on to create our exciting pipeline in neural drugs, one of the largest in the industry. And finally, we're not resting on our laurels. We continue to improve Antisense Technology by increasing the potency of our drugs, decreasing dosing intervals, broadening the cell types and tissues we can practice, all of which further increase our leadership advantage. Next slide. Ionis is leading the way in treating the root cause of a large number of neurological diseases. This slide shows 14 antisense drugs discovered by Ionis scientists that are either on the market or currently in development to treat a broad range of neurological diseases. These diseases exhibit pathology in a variety of regions in the CNS including the spinal cord, cortex, cerebellum hippocampus and deeper brain structures. We are developing antisense drugs for a broad spectrum of diseases, which include neurodegenerative diseases like ALS and Huntington's, and neurodevelopmental disorders like Angelman syndrome. We are developing antisense drugs for common diseases like Alzheimer's and Parkinson's as well as rare diseases like Prion and Alexander's diseases. This we're tackling within our drug discovery group. There are a number of Ionis wholly owned medicines in our neuro pipeline, which include our TTR amyloidosis drug, that Sam just spoke about. A drug for treatment of Prion disease, Alexander's disease, Lafora and ALS. Onaiza will describe our commercial strategy for these drugs shortly. Today, I'm going to focus on Prion disease and our ALS drug because they are examples of our neurology assets we plan to commercialize. ALS is a fatal neurodegenerative disease with no effective therapies. The disease is characterized by loss of motor neurons, resulting in paralysis, respiratory failure and ultimately, death. It is a rapidly progressive disease with an average survival of 3 to 5 years from symptom onset. There are approximately 55,000 patients who have ALS in the G7 countries. Patients who have no known genetic cause for their disease account for approximately 85% of ALS cases. While patients who have a known genetic cause are about 15% of cases. For some cases of genetic ALS, the patient may not have had a family history of ALS as the mutation may occur for the first time in the affected individual. This is especially true in ALS patients with fast mutations. Ionis and our partner, Biogen, have 4 drugs currently in development for both genetic forms of ALS and all forms of ALS. The most advanced program is tofersen, which is in a Phase III study in ALS patients with SOD1 mutations. We expect that study to read out next year. Our ALS drug targeting patients with a mutation in the C9orf72 gene is currently in a Phase I/II study. C9orf72 is the most common form of genetic ALS. Data from the Phase I/II study should be available next year as well. Ionis is developing an antisense drug for the treatment of ALS patients with FUS mutations, and we expect to start a pivotal study for that program early next year. And finally, ION541 is an antisense drug currently in a Phase I/II study targeting ATXN2, which is being developed broadly for all forms of ALS. In addition to the drugs highlighted on this slide, we continue to discover new drugs for all forms of ALS. ION363 is a wholly owned antisense drug for the treatment of ALS patients with FUS mutations. It is the first drug in development that specifically target FUS-ALS, which is the third most common genetic cause of ALS. We plan to start the pivotal study early next year. Sadly, patients with FUS mutations tend to have a particularly fast progressing form of ALS, with some mutations resulting in death within 6 to 9 months from symptom onset. There is a good genotype to phenotype correlation in patients with FUS ALS mutations. FUS is an RNA binding protein normally localized in the nucleus. The mutations in the FUS protein cause the protein to aggregate in the cytoplasm, which results in self stress and death. Motor neurons are particularly sensitive to this stress. ION363 is designed to selectively reduce the expression of a FUS protein. The FUS antisense drug prevents motor neuron loss in preclinical FUS-ALS mouse models. This program is unique in that we have already had clinical experience for the drug. Our collaborator, Dr. Neil Schneider at Columbia Medical School, has already treated several ALS patients with FUS mutations with ION363 through a compassionate use IND. We plan to leverage this data and initiate a pivotal study that should provide a very rapid path to the market. Next, I'll describe our Prion drug, ION716, which is being developed for both genetic and sporadic forms of the Prion disease. ION716 targets the RNA that codes for Prion protein which is the root cause of the disease. We are pursuing 2 different indications: one is presymptomatic patients who have a genetic risk for developing Prion disease; and the second are patients who have developed symptoms, which include both genetic patients who have become symptomatic as well as sporadic patients with no known genetic cause, with the latter being the larger population. There are approximately 2,000 patients in the U.S. for both these populations, and we plan to start a study next year. Prion disease is a severe neurodegenerative disease caused by misfolding of the prion protein into a toxic form called proteinaceous scrapie protein. It is a rare, rapidly progressing and uniformly fatal neurodegenerative disease. Symptoms include difficulty walking, speaking and rapidly developing dementia. There is no cure or effective treatment to-date. ION716 targets the RNA that codes for the prion protein, which is the root cause of the disease for both the genetic forms as well as patients who have the sporadic form of the disease. In preclinical mouse models of prion disease which mice are inoculated with a toxic form of the prion protein, the animal start dying around day 100. If we treat with an antisense drug before the animals develop symptoms, the antisense drug significantly delays disease onset shown in the blue lines and increase the survival comparable to the genetic knockout, which is the orange dash line. A single dose of ASO is given at the time animals started exhibiting symptoms. We still have an extension of survival, although less than the [indiscernible] prior to symptom onset. Based on these and numerous other studies, we believe that ION716 will provide benefit to patients who have both the genetic risk of developing Prion disease and those patients who already have disease symptoms. So in summary, Ionis has pioneered the application of Antisense Technology for neurological diseases. Antisense is a well-validated technology that can be used to target disease-causing RNAs broadly throughout the CNS. It has been validated both clinically and commercially. Ionis scientists and clinicians have created a broad neurological disease pipeline that spans from rare diseases to common diseases. And by targeting RNA, we're directly able to translate modern genomics discoveries to therapies. In the case of SMA, treatment before symptom onset either prevents the disease or results in a much less severe form of the disease. This sets the stage for a variety of inherited neurological diseases, including Prion disease. Next, I'd like to end my talk by sharing a short video of a family who had to deal with Prion disease. This video shows a well-known endocrinologist and friend of the company, Dr. Bob Henry, and his family who at the time of the video were dealing with this disease. Danny, could you please start the video? [Presentation]

Hopefully, you can appreciate why we're so passionate to find a therapy for Prion disease and other diseases we work on. And with that, I'll now turn the stage over to Onaiza, our Chief Commercial Officer.

Thank you, Frank. As Frank just passionately conveyed, patients such as Dr. Bob Henry motivate us to do what we do, work to deliver life-changing medicines for underserved patients and provide hope to lead longer and better lives. This purpose carries a tremendous responsibility for our team, from research to development and now to commercial use. We are committed to bringing these medicines to the thousands of patients out there who are waiting, like Justin and Dr. Henry. As you've heard from both Sam and Frank, we have an incredibly deep portfolio of life-changing medicines which, in the commercialization of these medicines, enable us to meet significant unmet need, pioneer new markets and change standards of care to help hundreds and thousands of patients, not just Justin and Bob. Our commercial priorities are threefold, with the objective to drive value for patients, providers and shareholders. Our focus initially will be on rare diseases, and these range from ultra-orphan indications to high rates of prevalence in diseases such as acromegaly, hereditary angioedema and certainly TTR cardiomyopathy with an estimated prevalence of 200,000 patients. Second is to pioneer new markets where our products can slow down or reverse the course of the disease and have the potential to save lives. We also aspire to create new standards of care, where in many markets, there have been a dearth of new products and patients have suboptimal care. And third, we take the pace at which we work to bring these medicines to patients seriously, as we know many are counting on us, giving us the privilege of launching multiple products over the next 5 years. The Ionis commercial strategy at high level is large, diversified, late-stage and addresses significant unmet needs. As Brett said, we have about a dozen Ionis-owned medicines, and this portfolio has depth in neurology, cardiology and breadth in hematology, endocrinology and pulmonology. This diversification across a breadth of rare disease assets, coupled with the higher probability of success we get from a well-curated platform technology through the drug development cycle provides us the potential to launch 6+ products in the next 5 years. With a dozen late-stage assets, we have the optionality and the choice to make decisions on clinical data readouts and commercial decision-making. This is a great position to be in as we join the ranks of other successful rare disease companies who have started off with fewer shots on goal and a less diversified portfolio to begin their entrée into commercialization. We expect to establish 2 core franchises in cardiology and neurology and potentially launch products in hematology, endocrinology and pulmonary. Today, we are already a commercial presence in neurology and cardiology with TEGSEDI and WAYLIVRA in Europe. As we look outwards in the near future, we have the ability to significantly grow these franchises with the depth of the portfolio that is emerging, for example, with prion in neurology and our expansion in ATTR cardiomyopathy in cardiology. We also have new product opportunities that can emerge into new therapeutic areas, such as theme, endocrinology and pulmonary. And lastly, as you can see, we have new products, such as Sam discussed earlier, in resistant hypertension and new indications associated with high triglycerides and pancreatitis. You will also hear from Eric about our advancements in aerosol delivery that give us reason to believe that ASOs can reach new genetically validated targets with product opportunities emerging in cystic fibrosis and broader conditions such as COPD. This diversified portfolio gives us significant optionality to be opportunistic and make choices to expand from rare to broad rare and in the future to common diseases. Now we look at our diversified portfolio in 2 ways: one, where we are pioneering new markets and one where we are changing standards of care. Let's first take a look at the several products that are pioneering new markets, where there are no approved treatment options. Just as we did with WAYLIVRA in Europe, we are looking at rare diseases in Alexander's, FUS-ALS, Prion and SCA diseases to bring new treatment options, where we will meaningfully impact patients, their families and health care providers while reducing burden on the health care system. As Frank shared with you, we have a rich, deep and diversified portfolio in neurology. We will be investing in this as one of our core commercial franchises, where we believe we will have multiple launches through 2026. These launches range from TTR in polyneuropathy, GFAP for Alexander's disease, FUS for ALS; and prion, a potential of 4 in the next 5 years, followed by several new disease areas of high unmet needs such as the SCA diseases. Beginning with prion, we have the opportunity for 2 indications in presymptomatic and symptomatic patients and a potential accelerated path based on the high unmet need. As the franchise adds the other products, we benefit from customer-facing synergies with an overlap of call points on neurologists and pediatric neurologists and other synergies in our hub and patient support services. And these launches are in a closed window of time ranging from between 18 to 24 months. I will highlight one of the important medicines that you can relate to, especially after seeing the video depicting the urgency of the need from the family members of Dr. Bob Henry. ION716 targets all forms of prion disease with first and best-in-class potential. We target the root cause of the disease and inhibit the production and accumulation of prion protein. This can help the patients who are already symptomatic by reversing the disease or delaying disease progression and improving survival. In presymptomatic patients, we look to prevent for delay in onset in genetic carriers. Developing this market prior to product launch will be important as timely diagnosis is a key driver for treatment impact. The awareness that a new treatment option is being developed will help the advocacy organizations in their outreach efforts to patients and treating physicians. And educating on the need to get genetic testing done in carrier families will be important. Prevention, as we know, before onset of symptoms is a critical intervention leading to improvements in disease progression and survival. Initiatives with our medical affairs group on scientific exchanges, deepening our advocacy efforts even further and proactively dialoguing with payers on the value proposition for this drug are all market development initiatives we will be furthering in 2021. ION716 has the potential to be the first approved treatment in prion, with over 2,000 patients in symptomatic and 1,000 in presymptomatic, many of which are already identified through registries. As in all rare diseases, we expect this prevalence to grow as it often happens when a treatment option arrives in the market and the investment made on education, improved diagnosis and patient identification. This first-to-market product has the potential of greater than $500 million globally. Our next segment of products transforms standard of care and drives market growth, as such, they also bring meaningful impact to patients and providers. And they are ranging from acromegaly, hereditary angioedema to elevated triglyceride diseases. As Sam reviewed with you earlier, our cardiovascular franchise is more robust than any other in the RNA therapy space, targeting a full spectrum of CV diseases. I am just focused on our TTR-LRx targeting disease caused by misfolded transthyretin program. We will be expanding our amyloidosis franchise with TTR-LICA in 2 indications. With our Phase I study showing greater than 90% target reductions, we have confidence in yielding positive Phase III results. Our Phase III studies are designed to demonstrate efficacy in polyneuropathy. And in cardiomyopathy, we have a cardiovascular outcomes trial with a composite endpoint targeted to yield data in subgroup populations with or without standard of care. This, combined with the flexibility of monthly at-home subcu auto-injector administration is a strong profile to enter this large [ market ]. How large is the ATTR market? Well, we have about 250,000 patients worldwide for both polyneuropathy and cardiomyopathy. And as Sam reviewed with you, the fatality associated with this disease, this presents a multibillion-dollar on product opportunity for the combined franchise. As the TTR market expands and the treatment paradigm evolves, we are in a strong position to become foundational therapy. We're seeking to gain approval from both PN and CM in the U.S. and EU. Our CARDIO-TTRansform trial is the largest cardiomyopathy outcomes trial in ATTR patients. And this gives us the opportunity to gather data in subgroups of patients treated with and without standard of care. This is important to position us well in this dynamic and evolving treatment paradigm. We expect to get data in both CV outcomes and also meaningful morbidity measures, such as hospitalizations and functional measures important for patients, providers and payers. TTR is well positioned for sustainable competitive advantage. Executional excellence, enabled by the in-market experience with TEGSEDI also sets us up for great success. We have experienced medical affairs team to continue deepening our KOL relationships and further generating real-world evidence. We have a very strong patient support system, one, with the COMPASS genetic testing program to identify ATTR patients and to support patients throughout their journey with Akcea Connect. And we demonstrated the ability to gain strong formulary positioning and reimbursement in both the U.S. and the EU. This well positions us for a strong commercial launch. So a key step in advancing our commercial strategy was the acquisition of Akcea, which we finalized in early October. I am pleased to report that the integration is going smoothly and is well ahead of schedule, with all functional groups advancing their full integration efforts. In commercial, the core capabilities in payer access and reimbursement, health economics, outcome research and new product strategy, among others, have been instrumental in advancing our new products commercial strategy. Upon evaluating Akcea's business operations, we have made the decision to enter into a distribution arrangement with Sobi for TEGSEDI and WAYLIVRA in Europe. We will continue to hold the global license and the marketing authorization for TEGSEDI and WAYLIVRA. And as such, we'll maintain presence in Europe. This will enable us to build on the core KOL relationships we have established for our future products. Regulatory and supply chain responsibilities will also remain with Akcea to ensure we deliver these important medicines to the region. And importantly, this transaction allows us flexibility to reinvest resources to support our commercial plans for the future. We will continue to leverage and adapt Akcea's strong capabilities that have been built to serve rare disease patients and key stakeholders in the health care ecosystem as we advance the commercial plans for the large and deep portfolio we have. Our commercial model is based on continuous innovation to adopt new technology and tools to serve our patients along their journey of diagnosis, treatment and living a close to normal life on therapy as possible. Utilizing big data, building predictive analytical tools and adopting more virtual tools as we all have needed in this COVID period will be important advances, and to ensure we stay deeply committed to advocacy and thought leadership. The tools in genetic testing and patient support services that Akcea has built continue to be foundational for our go-to-market platform. So as I've reviewed already with you, our neurology and cardiology are core franchises that we plan on investing in. It is also important to note that the breadth of our portfolio also presents product opportunities in other disease areas. First, in acromegaly, with GHR, we have the potential for better control and alleviate the breakthrough symptoms with monthly at-home self-administration. In hereditary angioedema, a competitive market, we have shown that we have greater than 98% of proenzyme activation as reported in the New England Journal of Medicine in the fall. This has the potential for excellent efficacy and delivering a profile that's highly effective at preventing attacks with high durability of response. And excellent tolerability and at-home administration. TMPRSS6 for beta-thal is also uniquely positioned provide the dual benefit of managing anemia and iron overload in a single treatment. As you will hear from Eric later, we are making advancements in aerosol delivery of antisense, and there are many genetically validated targets uniquely addressed by antisense. ENAC-2.5Rx demonstrates strong potential as a novel treatment for cystic fibrosis and COPD. In CF, we have a Phase I/II study that has commenced and this rare disease has a prevalence of 30,000 patients in the U.S. We also have another discovery target for the treatment of idiopathic pulmonary fibrosis, with well over 100,000 possibly even 200,000 patients in the U.S. And with ENAC in Phase II for COPD, this is another area where we could potentially expand into a common disease in the future. So in summary, we are privileged to have the opportunity to commercialize Ionis-owned medicines and deliver transformational medicines to patients who are counting on us, building upon TEGSEDI and WAYLIVRA today with up to 6 plus launches in the next 5 years. We aspire to create durable franchises in our core areas of neurology and cardiovascular and opportunistically launch products in hematology, endocrinology and pulmonology. I'll now turn the call over to Beth.

Thank you, Onaiza. Good morning, everyone. I hope you are as excited about this next step for the company as we are. It's a privilege for me to spend some time, putting all that you've heard so far from all the others into context from my vantage point. We're in an enviable financial position. We have a strong balance sheet. We have an efficient capital structure and we have multiple sources of revenues that provide us with substantial cash flows on an annual basis. These 3 pillars of our financial strength enable us to execute our capital allocation strategy of advancing our pipeline and technology, building our commercial capabilities and continuing to invest in our strategic priorities. We have the financial resources we need to invest in the commercialization initiatives Onaiza just spoke of, and to continue to invest in our pipeline and technology. In doing so, we expect to build substantial value for the patients who rely on us and for you, our shareholders. Today, we generate revenue from our marketed products and revenue from our partnered programs. But that's only a small piece of our value. We estimate the market opportunity from our rich pipeline is well in excess of $15 billion with a significant portion from our Ionis-owned medicines. You've heard Sam, Frank and Onaiza talk about our cardiovascular and our neurology franchises. We believe the medicines in mid and late-stage development in these franchises represent major drivers of value for Ionis. Importantly, the launch time lines for these medicines mean we can begin generating revenues and cash flows from the first of these medicines in the next 18 months or so. We expect to launch at least 1 new medicine every 12 to 24 months from then on. I think of our rich pipeline as an ocean of drugs coming to market, year after year on a steady, consistent cadence like waves coming to shore. With that vision in mind, let me walk you through why we are so excited about our future and the financial performance we see before us. Our mid- to late-stage medicines are poised to generate a substantial amount of revenue. So you might be wondering how is it that you're going to be able to estimate the potential revenue from all of these medicines. In the interest of time, let me give you a high-level perspective, beginning with our cardiovascular franchise. And as our medicines advance towards the market and our commercial readiness efforts advance, we will provide additional insights and more details on market opportunity. Our cardiovascular franchise includes many first-in-class and/or best-in-class medicines, targeting a full spectrum of cardiovascular disease risk factors, including lipid disorders, hypertension, heart failure and thrombotic disorders. We expect these transformational medicines to begin reaching the market in the next few years. The AHA estimates the cost of cardiovascular disease in the U.S. alone is in excess of $200 billion. And yet cardiovascular disease remains a leading cause of death worldwide, as Sam mentioned. Our sources estimate the market today in excess of $75 million (sic) [ $75 billion ] for the cardiovascular diseases the medicines in our pipeline address. In our mid- and late-stage pipeline, we have medicines to treat all the major cardiovascular risk factors. And each of these medicines has the potential to be a multibillion-dollar drug. It's important to note that several of these medicines have first or best-in-class potential. For example, we are first in developing our APOCIII-LICA medicine. This drug has the potential to be first-to-market and best-in-class with robust triglyceride lowering and a favorable safety profile. The FCS market opportunity is hundreds of million dollars alone. And that market opportunity is even larger if we successfully expand into other broader indications. TTR-LICA also could be a multibillion-dollar drug, and both of these are Ionis-owned medicines. In addition, we have several partner programs that also have multibillion-dollar market opportunity. Vupanorsen and Pelacarsen each could be first and best-in-class, as Sam described. And last week, our PCSK9 medicine advanced into a Phase IIb study and is expected to move quickly to Phase III. The compelling Phase II data we reported means that this medicine could be a best-in-class PCSK9 inhibitor. And behind these 3 programs, we have several more medicines with blockbuster potential. Importantly, our partners incur the hundreds of millions of dollars needed to conduct late-stage development and commercialize these medicines, enabling us to use our financial resources to bring to market our Ionis-owned medicines. For our partnered medicines, we share in the commercial success through royalties, in some cases, up to the low 20% range. Given the multibillion-dollar market potential of these medicines, these royalties can be quite substantial. And remember, they drop straight to the bottom line of the profit. Just as an example, Pfizer has stated that they believe Vupanorsen could be a mega blockbuster drug, with a market size in excess of $3 billion. Many of the medicines on this slide can have similar market sizes. And when you add them all up, our cardiovascular franchise could easily have a market opportunity in excess of $10 million. The neurology disease market is a nascent market poised for substantial growth. Today, the market for the disease is represented on this slide. All that we are working in is estimated at slightly more than $15 billion. Of course, the vast majority of that is from Alzheimer's disease therapies. While significantly smaller than the cardiovascular market, the neurology market represents tremendous growth opportunity as many of the diseases on this slide have no therapy. The socioeconomic burden of neurological diseases is estimated to be 10x greater in cancer, due to the general longevity of patients with neurological diseases even though many of these diseases are ultimately fatal. It's striking that an estimated 45% of the patient population in neurology remains unserved. They either have no access to treatment or have treatments with poor efficacy or side effects. So as we bring new medicines to market, we anticipate the market will grow. We also know that once the disease has an effective and safe treatment, the market grows through disease awareness, improved diagnosis and patient identification efforts. This is particularly true for rare neurological diseases. New disease-modifying treatments also bring the potential for patients to live longer, better lives. We've seen this with SPINRAZA. You'll remember that the initial addressable SMA patient population was estimated at about 25,000 to 30,000. Today, we believe that population is at least 60,000. Neurological diseases are devastating to patients and their families. And sadly, many of these diseases, as I said, are fatal. And unfortunately, many of these diseases have no treatment today. Of those that do, the vast majority only manage patient symptoms. There is tremendous need for disease-modifying therapies to treat people with neurological diseases. This large unmet need also presents an exciting market opportunity, one that our Antisense Technology is uniquely capable of addressing. Because our medicines address the root cause of the disease, they can do much more than just treat disease symptoms. Our medicines may be able to change the course of these diseases by slowing, halting or potentially even reversing the effects of the disease. And by bringing to market first-in-class, truly transformational medicines, we believe we can establish the standard of care for these devastating diseases. As Onaiza discussed, we have a large and growing franchise of Ionis-owned medicines for neurological diseases. We are preparing to bring these to market, with the first medicine potentially launching as early as 2023. And together, these medicines represent a multibillion-dollar market opportunity. TTR-LICA for polyneuropathy and our medicines for Prion disease are the 2 largest opportunities in our Ionis-owned neurology franchise today. Additionally, we have partnered neurology medicines primarily for diseases with large patient populations, such as potentially Huntington, Alzheimer's and Parkinson's disease. Each of these medicines could be a multibillion-dollar drug as well. The first of our partnered neurology medicines could be on the market as soon as 2022. And we share in the substantial market opportunity for these medicines through the royalties we earn. And as I said, the commercial revenue we earn from royalties is 100% profit, helping to drive earnings growth. We are poised to realize substantial value from our neurology franchise as we advance medicines to the market that can potentially establish the standard of care for the millions of patients living with neurological diseases. I hope I've helped you a little bit to see the substantial value that we see in hand today in our leading cardiovascular and neurology franchises. We also have a number of potentially best-in-class Ionis-owned medicines we are advancing to the market and other therapeutic areas, including for pulmonary diseases. Over the next several years, we anticipate bringing many new medicines to the market. Conservatively, we could have 12 or more medicines on the market by 2026, with the first of these coming to market as soon as 2022. And today, we earn a substantial revenue from our marketed products with SPINRAZA as the cornerstone. As we deliver new medicines to the market, we project they will drive double-digit revenue growth and substantial earnings growth. Our prolific research engine and world-class research and development organization ensures we can continue this growth well into the future. And with that, I'll turn the call over to Eric to talk about the exciting advances we are making in our technology.

Thanks, Beth. As you and Onaiza demonstrated, we're on the verge of unlocking a tremendous amount of value for our patients and shareholders. While we take great pride in our accomplishments, we're not sitting still. In research, we are always focused on the future and are continuously working to improve our technology in order to provide the best possible medicines to patients. Today, I'd like to focus on a few key investments that are producing value now who are poised to do so in the very near future. First, we continue to push hard on our chemical technology in order to expand target organs and improve potency and therapeutic index. Next, we continue to optimize designs. This sounds simple, but really isn't, and it is a meaningful advance in performance. Additionally, we are pursuing new LICA approaches to open up new tissues for therapeutic opportunities. And we are advancing new routes of delivery, such as aerosol delivery locally to the lungs and oral delivery with our liver LICA drugs. We also continue to exploit cutting-edge genomic technologies and look at new technologies, but that's a discussion for another time. Our mission is to make the best possible RNA-targeted therapeutics, making good antisense oligonucleotide drugs requires chemical technology. That's because the parent molecules of our drugs, RNA and DNA, have many limitations as drug molecules. First, they have insufficient affinity for their target RNA. This limits potency. Second, they have poor pharmacokinetics, meaning they distribute poorly in animals. This is due to poor bio-stability and rapid excretion into urine, the result is the requirement for frequent high dosing. And these are problems that the pharmaceutical industry has addressed with other natural products for over 100 years using medicinal chemistry. Since we aspire to have the best chemical technology, we've always invested continuously with a broad medicinal chemistry program and we continue to do so today. Doing so, we created a novel set of chemicals by modifying every part of nucleic acid that wasn't involved in target recognition. This produced the key technologies we use today: MOE, cET BNA and LICA. And of course, we haven't stopped our efforts in medicinal chemistry and are continuing to produce new chemical technologies that will further improve performance in the future. A key chemistry we use in our current drugs is MOE. The addition of the MOE side chain greatly improves stability by preventing attack by nucleases. This provides sufficient stability in biological systems, like animals or patients, to use multiple backbone chemistries, including the native phosphodiester backbone. It also increases binding affinity for target RNA. This combines with increased stability to give very large potency improvements. It will also improve the safety profile, which dramatically increases therapeutic index and combine with the potency gains. Furthermore, by optimizing the design of our specific drugs, which really means optimizing the exact structure of our molecules, we've been able to greatly improve both potency and the duration of action of our MOE drugs. An example of this design optimization is shown here for our neurology medicines which are designed to reduce expression of target RNAs. Shown on the left is the potency and duration of action of several neurology drugs labeled by the year they entered development. The left panel shows the potency of the drugs in human transgenic mice. In dose response studies, you can see the curve shift to the left for drugs that entered development starting in 2015. This demonstrated potency improvements of roughly fivefold since a couple of our earliest neurology drugs entered development in the 2013 time frame. To the right of the potency curves are duration of action studies. But we look at a time course of target reduction after a single dose of drug is given. It is evident that the duration is greatly increased for the newer drugs, with this new dose persisting well beyond 3 months after dosing. This target reduction and durability translates to primate, as shown on the right, and we are confident these benefits will translate to humans and become evident as we report data on our newer neurology medicines that are now in early clinical development. We optimize all of our neurology medicines to have the profile like the 2020 drug shown and believe this will support quarterly, biannual and perhaps longer dosing intervals for our newer neurology drugs. Another key chemistry is our cET BNA chemistry, which we have also called Generation 2.5. This further improves binding affinity relative to MOE, providing a further increase in potency and therapeutic index about another fivefold. It does this while maintaining or improving upon the stability of MOE, which maintains the extended dosing interval benefit. Importantly, these benefits facilitate antisense activity in tissues with lower accumulation of drug, like tumors, where our cancer drugs have demonstrated efficacy. Encouraged by the performance and safety record of cET, we are now bringing drugs using this chemistry into development for multiple therapeutic areas in multiple tissues. And we think these early efforts are demonstrating continued improved performance and will continue to do so. One of these areas is aerosol administration of ASOs for pulmonary diseases. We think our cET BNA technology has opened up the treatment of these diseases as we have shown that our drugs both distribute broadly and work effectively throughout the lung with aerosol administration. IONIS-ENAC-2.5Rx is our first pulmonary medicine using this technology and we think is performing well, as I'll describe over the next couple of slides. In exploring the lung as a target organ, the first thing we did was demonstrate that our cET BNA drugs distribute broadly to the lung after aerosol administration. This is shown on the top left panel where the brown stain represents the drug. Note that we see drug deposited deep in the lung, all the way down to the alveoli. Next, we demonstrated target reduction throughout the lung. This is shown in the left bottom panel where the pink stain is the target RNA. It is clearly shown via staining where the pink is reduced upon treatment with an ASO and PCR quantitation that the drug is reducing its target RNA broadly within the lung. We also have activity in all of the major cell types of the lung by fractionation and measuring the target RNA reduction in the individual cell populations. This data is shown on the right, with dose responsive target reductions shown for multiple cell populations. Knowing that we could effectively target the lung with cET BNA chemistry, we began a drug and discovery and development program. Our first target was ENaC, which is a sodium channel involved in maintaining proper hydration of the lung. We have demonstrated the utility of ENaC ASOs in multiple models of cystic fibrosis and mucus related diseases, 2 of which are shown here. Importantly, shown on the left panel, the ENaC ASO worked equally well even in a model with established mucus. This suggests that ASOs can easily penetrate through mucus and will work deeply in the lungs of cystic fibrosis and COPD patients. The benefit of ENaC reduction in a cystic fibrosis lung disease model is shown on the right, where a 40% reduction of ENaC gave benefits such as demonstrating reduction of mucus positive airways and reduced inflammation. Our ENaC program has transitioned to clinical development and has now progressed to Phase II trials in both cystic fibrosis and COPD with chronic bronchitis. Our Phase I study demonstrated a favorable safety profile, which is very important for our first foray into the lung with the cET BNA ASO chemistry class. We also saw nearly a 60% decrease in target ENaC mRNA at the 75-milligram per week dose as measured in bronchial brushings. This is terrific as the level of ENaC reduction is more than we believe is required to demonstrate pharmacology and benefit patients. This is the first time an antisense medicine delivered directly to the lung via aerosol administration has shown a significant reduction in target mRNA levels. Importantly, we also showed a good correlation between exposure and target reduction, as shown in the graph on the right. This gives us good confidence in the ability of weekly aerosol dosing to effectively engage targets in the lung. We believe this success opens up the opportunity to treat many diseases of the lung where there is much unmet medical need. These include cystic fibrosis, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease or COPD and severe asthma. And there are many exciting targets for these diseases, including, well, genetically validated ones. Antisense Technology is ideally suited to tackle many of them, and we believe there's a lot of future in our -- future value in our pulmonary franchise. Another example of the ability of our cET BNA chemistry to expand opportunities for antisense medicines is our ability to effectively target the kidney. Our first clinical program in this space is a precision medicine approach for the treatment of chronic kidney disease by targeting APOL1. This gene is strongly associated with increased risk for renal disease in African-Americans who happen to have a high frequency of the risk alleles. In preclinical work, we've shown that lowering APOL1 provides a benefit in a diseased model expressing the mutant human gene. This is shown in the graph on the far right, where an interferon challenge in the model caused proteinuria which was completely prevented by treatment with ION532. ION532, which is partnered with AstraZeneca, is currently in Phase I clinical trials. Another key technology for Ionis is our Ligand platform. LICA or ligand conjugated antisense uses a ligand which binds to the proteins on the surface of a targeted cell population to directly -- to direct the antisense drug to that specific cell and/or tissue type. We have shown that multiple ligands can be conjugated to antisense molecules. These include carbohydrates, peptides, antibodies and fragments of antibodies as well as small molecules. In turn, these LICA drugs can target multiple different tissues. These include liver, pancreas, muscle and many others, which are at early stages of research. Our liver LICA technology uses a carbohydrate-based ligand to direct antisense drugs to the hepatocytes in the liver by binding to a receptor called ASGR. This results in selective uptake into hepatocytes where the bound drug is taken up by endocytosis and is then released into the cell where it can bind the target RNA. We've shown a version of this slide in the past, demonstrating that liver LICA produces dramatic increases in the performance of our ASOs for hepatic targets. This version is updated with additional compounds such as PKK-LRx and TTR-LRx, both of which show exceptional improvements in potency. Some data on our PKK-LICA drug currently in Phase II trials for hereditary angioedema is shown here. This drug is, in my opinion, a fantastic molecule in asset and is a great example of an optimized MOE design. First, as shown on the right panel, it's very potent with an ED50 at around 20 milligrams per month. This represents a 30x improvement over the non-LICA parent drug. Second, it has a long duration of action, with target reduction shown on the left panel with increasing doses persisting well beyond 3 months after the cessation of dosing. These 2 properties combine to create what we believe will be a best-in-class medicine for hereditary angioedema, with a low volume, monthly, bimonthly or perhaps quarterly injectable, giving maximal suppression of the bradykinin path. We currently have 13 liver LICA medicines in clinical trials, and we think they have demonstrated an outstanding safety and efficacy profile. Over 1,200 subjects have been treated with over 400 on treatment for 6 months or longer. We've seen no safety concerns related to platelet, liver or kidney signals, no flu-like symptoms and a very low incidence of mild injection site reactions. And as Sam has described, these medicines have shown excellent efficacy in multiple diseases with several in large late stage trials. We've extended our liver LICA drugs to also incorporate the cET BNA chemistry. In preclinical studies, we demonstrated that this combination of both chemical technologies results in large potency gains and produces molecules with outstanding profiles. ION449, and which targets PCSK9 and is partnered with AstraZeneca is our first clinical program that uses this approach. As Sam discussed earlier, we think this could be a best-in-class PCSK9 inhibitor. I'd like to highlight the potency and efficacy of reducing PCSK9, where a single 20-milligram dose gave more than a 50% reduction, and greater than 90% reductions were achieved at the highest doses, with significant target suppression persisting from months after dosing. Another cEt BNA LICA drug that will soon enter clinical trial is ION904, targeting angiotensinogen. We view this as a follow-on for AGT-LRx, which Sam discussed earlier today, with the goal to improve potency to support lower doses and potentially even oral administration. In preclinical work, we have shown nearly 15-fold improved potency for ION904 in transgenic mice. And it is slightly better than the PCSK9 ASO ION904, which I just showed human data for. Importantly, we find the potency gains in transgenic mice translate to humans, which suggests that ION904 will get least as well as the PCSK9 drug we have human data for. I'd now like to talk a bit about the oral delivery of antisense medicines. First, we know it's not impossible because we've previously succeeded demonstrating and publishing 5% to 10% oral bioavailability in humans with an early ASO. However, this formulation was not commercially viable due to the low potency of the molecule we were using. The potency of our current liver LICA medicines now makes oral feasible. This is because most liver LICA drugs required less than 100 milligrams total dose per month to achieve the desired efficacy. And since ASOs have long half lives, they will therefore, accumulate in tissues over time, even with the low doses achieved via oral delivery. Some simple math can illustrate how this could work. 40 milligrams per day at 5% oral bioavailability would give 2 milligrams per day, taken over 30 days will equal up 60 milligrams a month. This is well within the range of a typical liver LICA dose, especially a drug like ION449. Shown here is work that supports the potential for oral delivery of ION449, which was presented at the recent AHA meeting by our AstraZeneca colleagues. The left panel shows the efficacy of the surrogate ASO after intrajejunal administration to rats is similar to that achieved with subcu administration at doses consistent with the observed 5% oral bioavailability. The middle panel shows 7% liver bioavailability of ION449 at either 3 or 20 milligrams given daily to dogs for a month via oral tablets. This is very important, as we think dog is the best model of oral administration in humans. The data on the right demonstrates the ability of ION449 to lower LDL-cholesterol in nonhuman primates after 14 days of daily administration. All of this supports the potential for oral delivery of ION449, which is why it was advanced to clinical trials. I'd next like to take a minute and update you on the status of our PCSK9 program. First, Ionis and AstraZeneca are committed to bringing the best possible PCSK9 ASO drugs to patients and have been collaborating on both subcu and oral formulations. As Sam has discussed, ION449 subcu has a potential best-in-class profile and is advancing rapidly towards Phase III development. As I have just shown you, we generated preclinical and early clinical data, giving us confidence, that we can achieve effective oral delivery of ION449 and other ASOs with the current formulation. However, based on ongoing research and our experience to date, we believe we can improve upon the current oral formulation. We've, therefore, decided to stop the ongoing Phase I oral PCSK9 study. We believe in the potential of oral and Ionis and AstraZeneca will continue to broadly work together to further optimize the oral delivery of ASOs, including ION449. As I said a few slides ago, we think we are just at the beginning of oral administration of antisense drugs, and I believe it's an achievable objective to deliver the vision of a commercially viable oral ASO. On the left is a slide that Sam showed earlier, which shows the potency, efficacy and durability of our TTR LICA drug. We think this profile could support oral administration. The simulation on the right demonstrates this. The blue line represents a simulation of the 45 milligram monthly subcu dosing, and the blue dots represent the observed data from the graph on the left. The yellow line is a simulation of the daily oral dose of 32 milligrams of TTR-LRx, assuming 5% oral bioavailability. It's apparent that it gives exactly the same efficacy in the same time frame as the 45 milligram per month subcu dose. As a reminder, we've already achieved 5% to 10% oral bioavailability in humans with the previous drug. Because of our belief that we can achieve commercially viable oral formulations, we are expanding our oral delivery efforts to include Ionis-owned medicines. In addition to working with AstraZeneca on ION449 and potentially other ASOs, we've increased our internal investment in oral research to optimize oral formulations in order to achieve our goal of greater than 5% bioavailability agreements. We plan to initiate candidate development for at least one Ionis-owned program in 2021. Candidates for this include TTR-LRx, PKK-LRx, ION904, targeting angiotensinogen and ION547. Of course, success here will further enhance the commercial value of these Ionis-owned programs. As I referenced earlier, we have LICA programs geared towards expanding the use of LICA in multiple tissues. I'd like to touch on 2 of these programs. The first target is the beta cell of the pancreas, with a GLP-1 peptide ligand conjugated to an ASO that binds to the GLP-1 receptor and facilitates uptake and activity in this previously impossible to target cell type. The second targets multiple muscle tissues by using ligands which target transparent receptor type 1. First, we have used our GLP-1 LICA technology to target the beta cells of the pancreas. This is shown from mouse on the left panel, with the dose response demonstrating a GLP-1 LICA ASO potently reduces the beta cell specific target FOXO1. The middle panel shows a picture of the drug working in action. The image shows a mouse pancreatic islet, which is full of beta cells. The pink is the target RNA. It can clearly be seen that with the GLP-1 LICA ASO treatment, the target RNA is reduced within the islet, which nicely demonstrates the specific targeting of the GLP-1 LICA ASO. On the right, data demonstrating target reduction in isolated beta cells from the pancreas of mini pigs. This is important since pigs have a similar pancreatic architecture as humans, which gives us further confidence that we can translate this approach into humans. We've identified an optimal GLP-1 peptide for our LICA strategy, and the next steps are to couple this with a great beta cell specific target, identify a human candidate for development. We've also demonstrated proof of principal data on the ability to target muscle with ASOs conjugated to transparent receptor 1 or TfR1 -- or TfR1 binding layers. In this case, we use an antigen binding fragment or FAB targeting TfR1 as the ligand of choice. The cartoon on the right illustrates how a ligand conjugated ASO can use TfR1 binding to transit from the blood stream into the muscle tissue. This improved uptake translates into increased potency as demonstrated on the left for 4 different muscles. The blue bars show dose responsive reduction for TfR1 FAB conjugated ASO targeting the muscle specific RNA DMPK with potencies in the range of 1 to 2 mg per kg. In contrast, the parent ASO, which is shown in the gray bars, works effectively, but requires much higher doses. Our muscle LICA programs are aggressively advancing based on this data, and we expect to have the first entry development in 2021. In summary, as our continuous investment in our technology, which allows us to keep our leadership position in RNA-targeted therapeutics. cEt BNA is being deployed broadly in clinical programs, which improves potency in established tissues and opens up new tissues for exciting therapeutic opportunities. Optimized designs using our existing chemistries improved potency and duration of effect. This provides for monthly to quarterly dosing for the liver LICA programs, and we think potentially greater than 6 month dosing intervals for CNS programs. Liver LICA has and will continue to deliver in value within frequent low volume injectables as well as the potential for oral administration, including Ionis-owned programs. And importantly, the LICA program is expanding to more tissues. Pancreas has progressed with the next step to bring a drug forward and proof of principle and muscle has been achieved. We are working hard to get muscle LICA drugs into development. And with that, I'll turn the call back over to Brett, who can close up this portion of the call.

Thanks, Eric. We are very proud of what we've accomplished over the years and as discussed earlier, we're equally proud of the decisions and progress we made this year to set Ionis up for continued and substantial growth well into the future. And now in the remaining few minutes of our presentation, I'd like to provide a brief glimpse into next year. So you can see how excited we are about 2021 and the future beyond that. Indeed, 2021 is shaping up to be a rich year in catalysts and progress across all aspects of our business. We have the tofersen Phase III readout in SOD1-ALS. And as Frank described, 1 of 4 ALS drugs are in development today and serving as a beckoning for the future success of all the drugs in our first-in-class ALS franchise. We also expect to initiate additional Phase III studies, while our ongoing Phase III studies continue to advance forward. Our mid-stage pipeline will readout and advance as well with several 5 or more key pipeline readouts. We'll advance our commercial plans and prepare for our initial launches. And of course, we'll continue to advance the technology with several new programs expected to reach development as products of these advancements, including new pulmonary oral, formulations and a new targeted delivery LICA chemistry. As mentioned, 2021 will be a rich year on pipeline catalysts. And shown here is a deeper dive into what we're expecting from our pipeline in 2021. You can see that we're expecting a rich set of data readouts from our rare disease pipeline, but also in some broad disease indications, including Alzheimer's disease and cardiovascular disease. And we're also expecting several important study initiations, including the Phase III initiations, I referred to earlier. So we believe that Ionis has established itself as a premier biotech, with enormous opportunity for substantial growth for years to come. Today, we have 3 drugs being commercialized. 6 Phase III programs ongoing, mainly across 2 core therapeutic franchises. As we look just several years out, my vision includes 12 or more products on the market, 6 or more Ionis-owned with 12 or more Phase III studies in progress across 3 core franchises that includes new organ systems, validated through new routes of delivery and medicinal chemistry. All of which sets us up to provide great value by delivering transformational medicines to millions of people in need around the world. As we continue to advance our current platform and diversify our drug discovery capabilities through investments in new technologies, all on the backdrop of a strong culture of innovation and dedication to patients. So I'll say it again. With all the progress we've made this year and in years past, Ionis is well positioned to deliver substantial and sustained growth. We'll continue and grow with scientific excellence as our core. We'll now add to this by building a strong and efficient commercial organization of equal excellence, all of which will provide substantial benefit to patients and shareholders for years to come. So that concludes our presentation. Thanks for listening. I'd like to move into our question-and-answer session right now.[Operator Instructions]

Okay. We're back. We've assembled our list of questions, and we'll start with the first one. The first question comes from Paul Matteis at Stifel. Looking forward to the presentation. When you get to it, really helpful, if you understand what baseline blood pressure level was in the AGT hypertension study. And then second part of that question, we'd be super interested to understand the historical tox issues with ACE and ARB combinations and want to look for ahead and outcomes data to be confident that AGT knockdown on top of one of these drugs could remain safe.

Thanks, Paul. Great question. We're really excited about this program, as you can tell. As we mentioned in the presentation, we are planning to present the detailed results from the study at a medical meeting next year. But maybe Sam could provide you some qualitative answers on the types of patients that came into the study and also address your other question about the combinations.

Yes. Okay. This is Sam Tsimikas. So the first question we'll, of course, show this data. But in the second study and the add on therapy. In other words, people who are already on 2 or 3 meds, the blood pressure was -- systolic blood pressure was in the low 150s. So pretty high. In the trial, we allowed patients to get into the trial with a blood pressure upto 170, just to give you a sense of the ranges. Your other question, I think it has 3 layers. Just let me take through each one of them because it is an area that's not intuitive. So whether you use an ACE inhibitor, an angiotensin receptor block or a renin inhibitor in monotherapy, they can all be associated with renal dysfunction because they work in the kidney. And you tend to see that in patients that have heart failure or borderline renal function or reduced renal function. So in other words, in the people that you want to use the highest doses, you're limited because the drugs can have side effects as a monotherapy. The combination of ACE and ARB hasn't really panned out because you're basically targeting the exact same area there. One is the enzyme, the other one is the byproduct of the enzyme. So they're, in a sense, duplicative, and therefore, don't really provide much additional benefit. The data with the renin inhibitors on top of ACE's and ARB's was associated with higher risk of hyperkalemia and renal failure. And so even though renin inhibitors have been approved, they're not used much. And so all 3 of those drugs work in the kidney. And the whole premise here, what we're doing is, we're targeting AGT in the liver. Keep in mind, when you treat hypertension, it's not a renal disease per se, even though some nephrologists like to think of it that way, what it is, is excessive tension in the peripheral arterials throughout the whole body. So when you want to treat hypertension, you don't necessarily want to treat that kidney, you want to treat the peripheral arterial system. I think for heart failure, it's ANG II excessive amounts in the heart. So if you now inhibit AGT in the liver, you should address the issue of the peripheral arterial system and the myocardium sapele, and you allow the kidney to maintain its hemo hemostasis. So the kidney can make its own ANG II in a very small amounts, and that should be enough to maintain normal renal blood flow and not inhibited there and only inhibited in the sites that you're interested in. So the angiotensinogen hypothesis will basically live or die by whether that is true, and our preclinical data suggests that it's true. And our clinical data to date also suggests it's true, and have not seen any renal side effects. So as we go forward, hopefully, we'll be able to have a more efficacious agent or a similarly efficacious agent, but can give it to the patients that really need the drug and the inhibition of the target.

Our next question comes from Josh Schimmer at Evercore. Why should a APOCIII LICA have any greater commercial success in WAYLIVRA. Maybe you can discuss WAYLIVRA's receptivity and territories its approved and its penetration into addressable patients and how APOCIII LICA can improve on that.

Thanks, Josh. So to be fair, WAYLIVRA is just in its launch right now in the early stages of that launch. And in Europe, the launch processes takes time because you go country over country or reimbursement negotiations and then take some time, as I said, to do that. And -- but we think that our LICAs, in general, are going to be -- have the potential to be best-in-class medicines for all of our LICAs, including the follow-on to WAYLIVRA. WAYLIVRA requires monitoring, biweekly monitoring in Europe, which could have some impact on penetrants. Although, like I said, it's early on in the launch, we expect a APOCIII LICA, like all of our LICA medicines, not to have any monitoring requirements and to have the potency, and APOCIII LICA, as Sam showed in his presentation, has a phenomenal potency, very low doses as a once a month, very convenient medicine. So we think that it's pretty straightforward that APOCIII LICA will perform very well in all patient populations with high triglycerides, including FCS. And as for details of patients that are taking -- they are doing well. They're doing very well, and they're very pleased to have an option to treat this disease. Remember, this is the only treatment that's out there today for FCS. And as for the details, other details within the launch, we don't disclose those types of details. We'll hold off on that for now.

Our next question comes from Gil Blum at Needham & Company. APOCIII LICA and CBD patients is likely to be used in combination with other drugs for CBD disease, is there a risk of drug-drug interactions and how will studies assess such risks?

Well, we have a wealth of experience with our platform in antisense drugs in general and LICAs, and that includes LICA medicines in patients on all kinds of standard of care, especially in cardiovascular disease, which is where really we have our greatest experience in the clinic today. Phase II data that Sam took you through for patients who are on standard of care treatments as was vupanorsen in in the angiopoietin-like 3 study. And we didn't -- we don't see any drug-drug interactions in those studies. PCSK9 data that Sam and Eric presented our patients were maximally allowable doses of stand. Who are still on control on their LPO, and we don't see any drug-drug interactions. And it's really not surprising. Our drugs work very differently in small molecules or antibodies. We bind to different repertoire of proteins. We're not metabolized the same way as small molecules drugs nor -- and further, our distribution uptake mechanisms are quite different. So they really are a different class, and we wouldn't expect any interactions with drugs. We haven't seen them. Sam, do you want to add anything to that?

The only thing I would add is we have 12-month data with APOCIII-LRx, and we haven't seen anything. So it really looks very, very clean at this point. I don't anticipate any problems.

I'd also add that we have a very exciting investigator study with Dr. Merrill Benson, Indiana University with TEGSEDI, which he's been treating patients now for 5 years and longer with heart failure. And these patients are doing very well, and they're on your standard heart failure drugs, diuretics and so on. And we don't see any interactions. So we're very confident of our ability to combine them.

The next question actually is 2 questions here from Yaron Werber at Cowen. Is there an analysis at week 35 of the TTR LICA versus placebo in the neuro TTR transform study? And if so, what is the endpoint?

Yes, there is an analysis at week 35. It's the primary endpoint. It's mNIS+7 and Norfolk Quality of Life and TTR reductions as well, of course. And that is the -- endpoint -- it's the same endpoint as in the Phase III study for TEGSEDI. And when we released the data on -- it's, of course -- yes, next year, we're planning to release that -- or not next year. But when that data comes out in the 2022, 2023 time frame, we expect to potentially file on the data.

And the second question he has, are you planning on releasing the Phase II data for the ATT LICA study from the mild -- in patients with mild treatment-resistant retention? Sam?

Yes. The answer is yes. We're -- we've -- we will be -- we have submitted abstracts for all of the hypertension studies that we've done. So you should be able to see that next year some time.

Great. And Josh Schimmer at Evercore has a related question. Can you explain why a 12-millimeter mercury improvement in blood pressure is clinically meaningful in the ATT LICA Phase II study? And how that compares to other types of antihypertensive meds?

Yes, that's a good question. I think if you look epidemiologically, even 2 to 3 millimeters of blood pressures difference in large groups is associated with lower cardiovascular event rates. So it doesn't take a lot because you have it essentially for a long time for 24 hours a day, right? So in terms of drug approval, if you look at most of the antihypertensive drugs, they get about 5 millimeters of mercury. So if you can get 5 millimeter as a mercury's reduction, placebo-controlled, correct that you have a drug. If you get 10 millimeter, you have a really good drug. And so this compares very, very well to what is typically approved for hypertension. And now this is a small study. So you have to take that with a grain to solve. But nonetheless, as we go into Phase IIb, we'll be able to look at the dose-dependent effect of that and then give you more information on that and choose the dose for the Phase III or doses for the Phase III as we look forward.

Josh had a related question on that study as well. Was the AGT blood pressure reduction placebo controlled? And what would be the expected placebo effect in this kind of a study?

Yes. This blood pressure was pre-imposed AGT. We do have the placebo data that we'll be presenting that. When you do blood pressure trials, there's this natural tendency of patients to take their drugs now regularly and also watch the salt intake. So there always is a small placebo effect. And it depends on where you start. If you start a very high blood pressures, like in renal deneration, you might get 10, 15 millimeters of placebo. If you start with guard variety hypertension, it'll be lower. So there is going to be a small placebo effect. I would suspect it's going to be less than 5 millimeters for the sort of trials we're doing. And that may change, depending on your patient population and the number of patients you have. There is variability. So this is why Phase IIb is really going to be the key for understanding the true phenotype of any hypertensive drug that you study.

We have a couple more questions on the AGT program from Gena Wang at Barclays. How do you see your AGT program differentiated from the Alnylam program?

Now my understanding of the Alnylam program right now is the first study was in patients that have hypertension, but no meds. That's the lowest hanging fruit, so to speak, because if you are no med, it's very easy to show a reduction. What we have done is the latest trial is one that's very close to the target population, which is 2 or 3 meds. And so it's harder, of course, to show a benefit when you have to do it on top of 2 or 3 meds because by definition, those patients are resistant. So I think based on my understanding of the public information, we're actually ahead from the perspective of the types of patients that have been studied. In terms of the drug and the mechanism, they're obviously very similar. And so I don't think there's going to be much differentiation on the target of the drug. And it will really depend on the ultimate target population and where that focus is. We're looking this sound as an add-on therapy because when a physician is on 2 or 3 meds, even though there's a natural tendency, both physicians and patients to want to remove drugs, that's the case where you have to add on drugs. So you really can't say well, I'm going to take away you may see an [indiscernible] and give this drug to you, you have to find a way to get their blood pressure down on top of existing therapy. So we've tried to simulate what a practicing physician would want to do with their patient, which is add-on therapy. And I think this is where the value of this drug will be in people that are truly resistant. And we're not looking to replace generic drugs here. We're looking to treat patients at a very high risk -- cardiovascular risk that we can't control their blood pressures.

Thanks. The next question comes from Luca at RBC. Congrats on the AGT, pretty robust data package with 27 patients and 12 millimeters of mercury average reduction. How should we think about the patient to patient variability, did you see an effect across the board? Or are there any patients more likely to respond? And finally, any thoughts on your program versus Alnylam? So I think you already answered that.

Yes. Well, one thing that people need to realize about this field is that there's very little data on plasma levels of AGT outcomes. And so we're actually generating that through very large epidemiology studies like MACE. But in terms of the variability, there's always going to be variability. And the way you reduce that is you basically do larger studies. And so there are always going to be some nonresponders. In hypertension, you're never going to get 100% of people responding. Remarkably, so far, our data looks quite good. We have a very uniform response. There were 2 or 3 patients that you might consider as nonresponders. We couldn't really find anything obvious to explain that. But keep in mind that the RAS system doesn't control every part, every aspect of hypertension, right? We have a sympathetic nervous system. So if you have kind of a nervous type patient, they may be more driven by epinephrine, norepinephrine, RAS may not be -- those patients may not respond as well to RAS inhibition. So you have to keep in mind that all inputs the blood pressure, we're addressing one of them here. And so there's always going to be people that don't respond as well. The question is, can we identify the ones that will. And I think we can do that by the included criteria of our trials and the trial design in the Phase IIB.

The next question comes from Jessica Fye at JPMorgan. You mentioned that it was debatable whether you want a long-acting therapy for AGT LICA in the event of side effects. Was that comment just with respect to clinical trials development? Or does that apply to bigger picture in the commercial setting as well? Thinking ahead, should we expect you to develop AGT LICA all the way through approval or shift focus to the AGT 2.5 LICA product to commercialize that one? Also, what do you think the appetite is for an injectable therapy in uncontrolled hypertension?

Okay. There are 3 questions. I hope I can remember. So, Wade, remind me if I forget them, but the -- let me just answer the one about what I mentioned is the duration of therapy. So right now, all blood pressure meds are given daily, and their half lives are really 8 to 12 hours. I don't think this field is ready to go to 3 months. And the reason for this is as follows. A lot of our patients that are going to have resistant hypertension are frail, they're not a robust 50-year-old man who can tolerate a low blood pressure. They're going to be in their 70s, multiple core morbidities, multiple meds, they're going to be frail, there'll be at risk of falling and getting subdural hematoma or breaking their hip. So we have to be very careful when we do the development here, not to overshoot. And what I mean by that is, in a typical day, they may just be fine, but if a patient gets flu, or, God forbid, COVID or they get something where they get salt depleted, they're going to be hypotensive for a long time. And so the question is that you really want to market something every 3 months in that scenario before you have really good safety data. And the answer is no, in my opinion, we should take a different approach and not give a drug that then will take a long time to wear off. So that's part of the question is, I think, both for drug development and whether the field is ready for a long acting or longer duration therapy, it's debatable at this point. I think there'll be a lot of nervous physicians when patients got hypotensive, what to do with them. So that's, I think, part of the question in the first one. In terms of commercialization, we think we have a drug. AGT-LRx is a drug we now have 3 studies. 2 of them have proof of concept. It looks safe. We haven't seen any side effects, and we're going to develop this as a stand-alone drug. The advantage of the 2.5 is we will have options, whether we can do subcu once a month. If it turns out to be that safe, we can do oral if we want. There are many patients that don't like injections, even though that's kind of the rage right now. And that's our focus, right, we're injectables, but there are patients that don't like injections. And when you go to 140 million people, oral, having the oral availability is a big plus, I think. And so it will be options -- the new compound will give us the option to do what the field dictate in terms of that aspect of it. And then injectable for hypertension is -- there are some advantages to that. One of the problems with people who have uncontrolled hypertension is besides the fact that they don't truly respond is some of them are noncompliant. And that's a big problem in clinical medicine. And so if you can give an injection and have that covered with less frequent versus daily, for example, that could be an advantage to some patients, not all of them. So the answer is, I don't know if we're ready for everybody to be on injectable, but for some patients, it would be actually beneficial in terms of compliance. So it could be a mixed answer in that regard.

Okay. Jess, also has another question related to the TTR LICA program. For the Phase III trial with TTR LICA or hereditary TTR polyneuropathy, with the interim analysis of week 35 trigger an early stop to the trial. If so, what's the bar for an early stop based on mNIS+7?

Thanks for the question, Jess. The week 35 would trigger potentially a filing for approval. Not a stop. Remember, there's no need to stop the patients on the study because it's an open-label study. All patients are on TTR LICA, and they would continue to receive the drug and receive and get benefit, and we would get more and more experience with the drug. But what that would do is trigger us to prepare for a filing. Remember, TEGSEDI showed highly statistical significant benefit at week 35 on mNIS+7 in our Phase III study. TTR LICA is showing substantially even greater reductions in TTR and TEGSEDI. So we're feeling pretty good about week 35 in early filing. And so no need to stop the study. Endpoint is mNIS+7, and we're feeling pretty confident we'll give a file on that data.

All right. Our next question comes from Yaron at Cowen. Can you discuss your preclinical data on ION363 and whether you have tested the drug in patients yet, what makes you comfortable advancing it to a pivotal study in ALS FUS in early 2021?

Yes. Well, I'd like to toss that over to Frank. Bennett to respond.

Yes. Thank you, Brett. And as I mentioned, this has been a little bit of unusual program for Ionis. We have had an ongoing FUS drug discovery program. When last year, roughly in January 2019, we were contacted by 2 very prominent ALS researchers, Dr. Bob Brown and Dr. Neil Schneider. Who were aware of the work that we're doing and presented to us a patient that they were taking care of who had a FUS mutation, and this patient happened to be a twin where her twin sister died from the disease once she was 18 years of age. So one of the sad things about FUS is it generally occurs in teenagers and is in a very aggressive form of the disease. So we have been working on FUS antisense drug where we had taken it through a number of cell culture and animal studies and had confidence that the drug was well tolerated. And that we were engaging the target, the human FUS gene based on work in transgenic animals. And that furthermore, in the transgenic animals, we demonstrated that we could enhance survival of the animals and preserve motor neuron function. And so when we were contacted by Dr. Brown and Schneider, we started working with them to make the drug available for this particular patient. And that was really a collaboration between Ionis, Dr. Schneider and Brown and the FDA. And we provided the data that we had to enable starting to treat this initial patient. Subsequently, Dr. Schneider has been contacted by a number of additional ALS patients with FUS mutations and has treated, I think, around 10 patients with this ION363. And ultimately, he realized that this is more that he could take on as an investigator, and we agreed, working with the FDA as well as with Dr. Schneider and initiated a pivotal study to make the drug broadly available for all FUS-ALS patients. To date, the drug has been very well tolerated at doses that we predict to have clinical efficacy. It's still early to make any comments on the efficacy of the drug, but the safety profile has been very good, and we've decided to go forward. We're working with the FDA to make it a pivotal study. So that the design of the study would support registration of the drug in no time.

Our next question comes from Josh at Evercore. Were the LICA versions of APOCIII and TTR also being marketed by Sobi in Europe?

Sobi has no rights to the LICAs for APOCIII and TTR. It's a distribution agreement. And again, as a reminder, our subsidiary, Akcea, holds the marketing authorization for those drugs in the EU with the associated functions that are necessary in that capacity. We're preparing to launch those drugs ourselves.

Next question comes from Gil at Needham & Company. Is TMPRSS6 LICA broadly applicable across hemolytic anemia indications?

It is really an exciting drug. It performs so well in Phase I. It hit all the biomarkers, we expect it to hit and the biomarkers are very robust in this pathway. TMPRSS6 is a drug to treat any disorder where hepcidin levels are suppressed, and there are many. Beta Phase II is underway. We're actually expecting to initiate another Phase II study for TMPRSS6 next year and until -- in indications where hepcidin TMPRSS6 releases the break on hepcidin and allows them to be increased, and that normalizes iron metabolism, including red blood cell production. Get to your question? Yes, hemolytic anemia is a disease in which, due to the nature of the disease, hepcidin levels are massively suppressed. So we think TMPRSS6 has a potential in hemolytic anemia as well.

Our next question comes from Tom. It's about the PKK LICA program. As -- if the Phase II study is successful, what will the Phase III look like and will it commence in 2021? Is there an opportunity to move for approval of PKK LICA and type 3 HAE patients based on the Phase II data?

Yes. We're seeing another exciting Phase II program that we'll read out as we're expecting the Phase II randomized study to read out first half of next year. And what we've seen in our Phase I data and elsewhere we're very -- and New England journal case studies that were published this year. We're very encouraged about this drug as a potential best-in-class drug with the convenience advantages to as a once a month low volume injectable. The potential for oral is one of the programs that Eric highlighted in his technology update. We think, and I can tell you, we have experience in type 3. And in peers, small numbers, but the HAE patients with type 3 did well on PKK LICA. We'll look at all the data from Phase II. Phase II data does enroll type 3s as well as type 1s and 2s. We'll look at all the data and decide what the most expedient path forward is to get this drug to market as quickly as possible. As part of the Phase III, could it trigger a Phase III study, absolutely, the Phase II outcome next year, potentially? Well, certainly, if it's positive, we'll start getting ready to launch into Phase III next year. But we actually dose a patient in Phase III now, we'll see how quickly we can move. And as for the study design, we'll see, whether we would want to do some sort of head-to-head or do a -- or controlled or just a randomized controlled study versus placebo or not, to be determined. That's a commercial question as much it is a development question that we're wrestling with right now.

Our next question comes from Luca at RBC Capital. You mentioned both cystic fibrosis and COPD, will you tackle both using the ENaC drug? Or are they separate targets? Thoughts on ENaC differentiation versus Arrowhead?

Well, the answer is yes. It's the same drug, and we're tackling both now. We're now fully enrolled in our cystic fibrosis Phase II study. And with data expected out first half of next year. With our ENaC, we're in the same drug, initiated a chronic bronchitis, which is a form of COPD, Phase II this year. We're underway. So it's the same drug. And we're also considering other indications as well for this drug. As we shared at the CF meeting in October, we showed very nice reductions in ENaC levels in the lungs as a once a week aerosolize drug medicine delivered to normal volunteers. So we know we're engaging the target, and we're looking forward to the Phase II results. As far as differentiation, Eric, do you want to talk about that a little?

Well, yes, sure. We're well ahead. So as Brett mentioned, we're in Phase II in 2 different diseases with the same molecule. We've shown robust target engagement in healings with the drug that is supported by our wealth of preclinical data and Arrowhead doesn't have any data on their molecule in humans. So I think we're well ahead in the indication. And we do know that our drugs are able to get into the lung and work broadly without any type of formulation conjugate or delivery vehicle, whereas siRNAs really don't. So we'll see -- we have to see if the drug performs first before we can really compare to it. We know ours works.

Next question comes from Michail. For delivery to muscle antisense study using the palmitate ligand to facilitate transcytosis through what doses of endothelium? For oral delivery, is there any analogous ligand conjugation approach that could facilitate transcytosis across the intestinal epithelium, this seems safer compared to enhancing permeability?

Eric Swayze, why don't you take that one as well.

Yes, sure. Michail, we actually tried that with some of the palmitate and other compounds to get across the gut, and that didn't work. And there's good reasons for that. So unfortunately, I don't know of a system that will do that. And so the C10 that we're using orally is a transcytosis mechanism. I would also comment on palmitate and muscle, why it does work, the transferrin receptor targeting approach that I discussed at the end of my bit earlier is far superior, and we think that's a better way to go for targeting muscle.

Next question comes from Jason Gerberry at Bank of America. Can you talk about the unmet need you saw with your PCSK9 program? Is it your view that having greater LDL reduction will translate to better CV outcomes or is rollout of oral therapy the key to the value proposition?

I'll ask Sam. He is the obvious one to answer that question. Also actually to maybe expand on that, if you can also, why we think this drug has a potential to outperform existing therapies on the market today that have struggled a little bit from a market standpoint?

Sure. Well, I think if you look at where the field is going with LDL, there was a concern in the past that we don't want to get it too low, right? So that is gone. We know that the lower the LDL, the better. And so if you have the most potent agent available, you're going to be able to achieve that goal to get patients as low risk as possible. So if you look at the guidelines, they're slowly evolved to go from LDLs of 70 and now the European guidelines have an LDL of 45 for very high-risk patients. And so this drug -- if the data continues to look as it does, we'll be able to differentiate itself from the perspective of having a very potent effect, 10% to 20% more than current existing therapies. So that's going to be very attractive, I think, to physicians, because if you have a patient that has say an LDL 130, you're probably going to choose this drug to get it downer, and there's still very, very inhibitions like that. So the answer is the subcu version is basically a very potent drug, probably the most potent PCSK9 inhibitor as best as we can tell right now with the data we have. And I think that's going to play very well among physicians who now understand lower is better. One of the issues that has come into the field with PCSK9 inhibition is that in terms of the market part that Brett brought up is they were priced very high, initially, for not having -- initially, very strong cardiovascular outcomes. The trial is we're a little bit too short, and then they show cardiovascular mortality, and that have compounded the ability to, I think, get reimbursed. So that's been a historical issue. We have a single strand, the cost of goods is extremely low. Antibodies, as you know, very expensive to make. siRNA has 2 strengths. So it's essentially double expensive. So I think if it's priced responsibly, and it has the best LDL lowering, it really has potential to supplant the current PCSK9 inhibition that's currently being proposed for the patients.

Also from Jason, we have a question on the neuro transform study. When do we expect to have interim data? And do you believe the interim offers read across to the cardio indication beyond safety?

Well, enrollment in the neuro transform study is ongoing, and it's going well. And we expect the interim data, depends on the enrollment, how quickly we get things are enrolled, but we're expecting data in the '22, '23 time frame for that early readout. And is there -- aside from safety, which is pristine for all of our LICAs and so far with this one as well, is there a read-through well? I think -- I believe so. I mean, what we've proven is the hypothesis that for disease manifestations of TTR amyloidosis that are caused by the the formation of TTR amyloid in organ tissue such as heart, neurons, et cetera, GI and kidney that by silencing production through antisense mechanism, we can provide great benefit and we've also had encouraging results in the Phase III study on cardiac endpoints in our Phase III study. And again, I want to bring up an ongoing investigator study in which patients are doing very well in both wild-type and hereditary TTR amyloidosis with cardiomyopathy with Dr. Merrill Benson, Indiana, in which we're really just giving us more and more confidence that by lowering the production of TTR, we're going to benefit patients with cardiomyopathy as well as polyneuropathy.

Our next question comes from James, who asks on the ENaC 2.5 program. Does ENaC 2.5 cause toxicity in the kidneys or any other programs or any other organs? There were talks on social media about the potential safety concerns of this drug. Please confirm.

So that's a great question because we know there are published reports in which small molecule inhibitors of ENaC sodium channel were halted because of on target side effects resulting in kidney toxicity and hyperkalemia because of inhibition of ENaC in the kidney. We're well aware of that before we even started our ENaC program, and it was the first thing we addressed. Is whether or not a locally delivered antisense to the lung once a week will be safe from an on targeted standpoint and, of course, be efficacious, and we prove both of that. And we've actually published preclinical data on this. We not only -- we don't see any reductions in ENaC in the kidney. In our preclinical work, we've done extensive work. We administered this drug systemically, and it doesn't hit the cell types in the kidney that express ENaC, but what's more important is when we deliver it locally to the lung, we don't give systemic -- significant systemic distribution. So it's all in one. That's the way to think about it. And the other thing is the Phase I data that we presented this year showed no changes in biomarkers, potassium levels, et cetera, in patients treated with our ENaC inhibitors. So we're very confident about on target safety.

Our next question comes from Jim Birchenough at Wells Fargo. How do you manage penetration of the thick mucus layer in cystic fibrosis? And do you expect variability and absorption based on the level of patients accretion?

Following -- that was the first question we addressed when we reentered the pulmonary area, preclinically, ENaC was specific for the on-target effects. But one of the first questions we wanted to ask is whether or not our drugs can penetrate a thick CF like mucus lining. And there too, we did extensive work, preclinically in animal models of cystic fibrosis, in which there's a very thick lining in the lungs. And we also did in vitro work from patient samples. We also did nonhuman primate work, and we also did a lot of investigations with experts who know this field very well. And when we look at the potency curves head to head in models with cystic fibrosis mucus -- thick mucus lining versus normal animals, we see no shift. We're actually seeing very similar potencies in this. And with similar distribution in those lungs. So we have to prove it now in humans, and that's what we're planning to do next year. But right now, all the data points to us are being able to get through these linings very effectively.

Jim also has another question on our subcu and oral program. Is there a potential treatment paradigm, where you might use subcu delivery to generate rapid tissue concentration and then use oral as maintenance dosing?

Yes. I suppose we can think of a scenario in which that could make sense. I do believe, and maybe, Eric, you can correct me if I'm wrong. A subcu will get us onboard and active -- faster than an oral administration. And if you need to do that, I suppose we can do that and then have a maintenance therapy with oral. What do you think?

It could, but it would have to be a condition where you needed that rapid onset in a chronic condition where you don't need the rapid onset, the daily oral will get you there anyway. And I was trying to show in one of the simulations that we presented. So we would have that option available to us, obviously, if that was an advantage. All right. Both Josh Schimmer at Evercore and Chad Messer at Needham have a similar question about the PCSK9 program. Josh asked, if you think the ASO platform is ready for oral delivery already or it requires additional formulation work to be ready for oral delivery, can you please clarify? And Chad's question is somewhat similar. Trying to understand what the current status of the PCSK9 oral program is, are you halting it? Or is it continuing? And what's the status of the subcu formulation?

So we stopped, as Eric said in his presentation, we stopped the oral PCSK9 Phase I program with AstraZeneca. In short, because we think that we can identify a better oral formulation based on a wealth of experience we've had, preclinically and also some clinical data that we've generated. We and AstraZeneca have been working to advance the oral platform for particularly for our cardiovascular drugs, but other programs as well for several years now. We're making great progress. That coupled with -- and this answers the other part of the question, with the -- how far ahead the phase -- the subcu drug is for PCSK9, moving rapidly now to Phase IIb and eventually quickly to Phase III, that's where the focus is right now with AstraZeneca, and we support that. We're -- and Eric went into this, we are developing additional formulations now that we think are going to provide even greater bioavailability in the future. And in no way have we given up on oral. We're -- in fact, and we're encouraged more than ever based on everything we're seeing, we just think we can make a better formulation. Eric highlighted a few of the programs we're considering to develop as a oral formulation ourselves from the Ionis owned pipeline. And in addition, we're expanding our research collaboration with AstraZeneca to further investigate oral delivery, not just for PCSK9, but also for the 3 other LICA drugs in the cardiovascular pipeline with AstraZeneca. So stay tuned. We're still -- we remain very enthusiastic about oral delivery.

Is a related question from Dallas [indiscernible] biotech. Can you explain why the bioavailability failed and why you're hopeful across other Ionis programs, again, related to oral?

Yes. I kind of just address that a little bit. It didn't fail because of by availability. We looked at the totality of all the data we've been generating in parallel on the research side as well as what we've been generating in the clinic. And we felt that we can make a better formulation. I mean this is a generation of oral formulations that we think we can improve upon with the next generation. And like I said, we at Ionis, and we with AstraZeneca, are continuing to invest heavily in this area, and we remain confident we can deliver an oral medicine that is commercially viable in the near future, and we're continuing to work on that. That, coupled with the fact that AstraZeneca is so enthused about the subcu program because for all the reasons Sam highlighted, how exciting the profile is for this drug and they want to get it to Phase III as rapidly as possible.

And I think we have 1 last question on oral bioavailability for antisense drugs from Vincent Chen at Bernstein. He's got a multipart question here. What is your sense for the oral availability achieved to date in humans? How far are you from the 5% goal? And what drives the difference in bioavailability seen in humans versus animal models? And then the second part to that question, what are the formulation or chemistry levers you can employ to boost bioavailability? And if boosting bioavailability proves difficult, is there reasonable room to go up meaningfully on dosing instead?

Yes. The -- so I'll ask Eric Swayze to drop in on -- to address the second part of that question. The first part, we're not providing the details of the data we've generated in the clinic to date. As I said, it's based -- our decision with AZ was based on the totality of the data and the great progress we're making on the research side. And as -- I think the other part of that question was preclinical versus clinical mechanisms, was it Wade?

Yes, the difference between bioavailability seen in humans versus...

Yes. We haven't shared that data. We're encouraged by what we actually saw in the clinic so far in our Phase I study, which gives us confidence. I mean, if we weren't encouraged by that data, we wouldn't be investing in oral delivery with AstraZeneca to make a better formulation for the future. Eric, do you want to address some of the levers and knobs we can deal. We can...

Yes. First, I just want to go back and address the oral failed comment, and we actually have succeeded in oral delivery with a previous oligo many years ago, I think was published in 2008 in humans with a drug that's much like the ones we currently have. And the difference is that drug just wasn't very potent. And so you couldn't really expect it to work with a convenient once daily oral. And so when we start to look at our new drugs, even with that bioavailability, which in the paper was, I'll say, in the 5% to 10% range. If we get that, we're fine. And then the second part of the question is, could we tolerate a slightly lower bioavailability and increase the oral dose? And the answer to that is, yes. But you just have to get -- so make sure it's in the range that it's a pill that you want to take once a day, not a handful of 20 of them or something, right. I think there were some other questions on the formulation knobs. The formulation we've been using in the current formulation is C10, which was what was used in our previous paper formulation. We have preclinical data, demonstrated that the way the C10 is used and adding some additional components, which we're not going to talk about right now, can matter a bit. And the totality of the data just convinced us that if we optimize the formulation a little bit, we could do better, and we want to take the time and get it right because it's an investment to move forward, and we think it has great potential. And we want to make sure we have the best possible products.

Next question comes from Salveen Richter at Goldman Sachs. She's asking about the muscle LICA program. Given the proof-of-concept in muscle, do you plan to move rapidly to address the program into the clinic? And when would we expect trial initiation and what indications do you plan to go into initially?

So we are very excited about the progress we're making in muscle delivery with our new LICA strategies. And Eric summarized or shared some of our experience to date. We're getting very close. It's possible we'll move a drug into development next year. We'll bring some final touches on design. And we'll see. As for indications, it is a highly competitive area. And we're going to have to keep that to our vest. Obviously, we have a lot of -- we have experience previously in this area, our DMPK program, myotonic dystrophy showed very encouraging results in patients and what we needed to do was solve the potency problem. And we're well along on our way to solve the potency problem.

Next question comes from Kevin DeGeeter at Oppenheimer. Can you comment on the systemic exposure of the pulmonary delivery for ENaC, how we should think about off target effects?

Yes. I kind of addressed that question earlier. We don't see any significant commercial systemic distribution of our oligonucleotide drugs when we distribute -- when we apply them by aerosol to the lung. We have been investigating this extensively over the years. It's just not significant. So we have not seen nor do we expect to see any on target effects of systemic exposure from our ENaC drug.

Our next question comes from Tara Bancroft at Piper. For the TTR LICA program in cardiomyopathy, you mentioned the 30-month hospitalization mortality readout for filing, but will you be providing 12-month data including 6-minute walk? And could that potentially be used for filing?

I'll take a stab at that. And then, Sam, maybe you could jump in and get into more of the details. But we believe that outcome is, by far, the most important endpoint in a cardiomyopathy study like these where patients are dying of cardiovascular disease to the cardiomyopathy. We'll certainly be looking at functional endpoints, but we think the focus -- but the focus should be on cardiac -- cardiovascular hard endpoints. What do you think, Sam?

Yes. Of course, we're going to be doing serial 6-minute walk tests on these patients, so we'll have that data. But to convince cardiologists to use this drug, you really need to have the hard outcomes, right? So obviously, we'd like to see that part of the trial read out positively. And so we're anticipating having that information is the best from multiple perspectives, clinical, commercial, et cetera. Of course, the 6-minute walk is very important functionally. And so that will be gathered into the whole phenotype of sort of speed of the drug and allow that to be part of the story.

Our next question comes from Mani at Leerink. It looks like by the content of the questions related to the oral PCSK9 program. And he's asking if there were any safety signals that emerged or was a decision to stop the study and move on to a different formulation based on serum concentrations achieved? Or is there some other metric?

As I mentioned earlier, really it's the same answer, Mani. We really examined the totality of all the data we have, preclinical and clinical, and we strongly believe that we can make a better oral formulation in the future and not too far into the future, and we're hopeful to bring a new oral formulation in the development schedule.

Next question comes from Yale Jen at Laidlaw. Congrats, he says. First part of this question is on APOCIII. Of the APOCIII LICA program, of the next larger patient size, broader CV indication, should Ionis support the full study or potentially seek a partner for development and commercialization? I'll stop there, and I have to get a couple of other parts, but I'll do those next.

So the question is for the next large -- for the next study for APOCIII like the next Phase III study, a larger indication, will we pursue that Phase III study ourselves. That's the plan. Yes. We're very close to making some decisions on the next Phase III study for that program, and it will be a larger indication. And we're planning to conduct that Phase III ourselves.

I think the second question we've already answered. So I'm going go to its third question. Sobi partnership in Europe is only for the current generation drug? Or will that last into next-generation drugs? And also more detailed work breakdown between Sobi and Ionis.

So again, the Sobi partnership is simply a distribution agreement in the EU, does not affect North America commercialization. And our subsidiary, Akcea, holds the marketing authorization agreement with the necessary functions that they are still responsible for. Sobi has no rights to the LICA formulations, the follow ons to take TEGSEDI and WAYLIVRA. And we're running those Phase III studies now, and we're planning and we're preparing to launch those programs. As far as the detailed -- the details on the agreement with Sobi. Beth, did you want to comment on that? I know you can't say much.

Yes. I don't think there's a whole lot we can say right now because we're just waiting for antitrust clearance. But what I can say at a very high level is that the economics are quite favorable. We are retaining a significant portion of the revenues from the products in Europe.

And I think the last part of Yale's question is with the integration of Akcea, are there any other commercial activities or functions needed for the future?

That's a great question for our Head of Corporate Development and Commercialization, Onaiza Cadoret.

Thanks, Brett. Yes, I think there are very many critical capabilities that we look that are important for our rare disease products for the future. I highlighted some of them as we went through the presentation. So particularly in terms of kind of setting up the market in our knowledge and insights on their the analytics capabilities, but also preparing on kind of understanding what the payer access would look like, health economics and outcomes research. Those things are pretty much important in clinical success. And then I also highlighted some of the patient support services and tools that we have in just identifying patients from a genetic testing perspective then kind of caring for those patients from a case management perspective, moving on with our Akcea Connect services. So all of those are -- continue to be important areas that we're working together with and integrating as we plan our commercial organization for future product launches.

Our next question comes from Jim Birchenough with Wells Fargo. Can you discuss efforts to build on leadership and ASO therapeutics with potential complementary technologies and how you think about allocation of capital towards business development?

Well, I'll start that, and I'll ask Frank Bennett to maybe talk a little bit about what we're doing, looking at complementary technologies. We're laser-focused on, as we highlighted in today's presentation on delivering a vast increase in the number of medicines to market to patients, millions of patients worldwide over the next several years. And that coupled with the investments we're making and the tremendous progress we're making in expanding our technology to increase the scope of what we can do with this existing platform that we have today is just moving forward rapidly. And we think all that. That this builds down to leadership position in this field. And we believe that all that will result in strengthening our leadership position in this field. I mean, we -- our eye is focused on expanding the technology and delivering medicines to the market. And the other stuff takes care of itself. We are looking at complementary technologies, and we have been for -- especially this year, but for some time now. And maybe I'll ask Frank to just talk a little bit about what we can share on what we're doing.

Yes. So we are really pinning things into 3 different buckets, where we're looking at technologies that really add on to antisense technology. But I think the nature of your question is what are we doing beyond antisense. And we are looking -- we have a team of people looking at different investment opportunities for us to make in technologies that are different than antisense, but would fit well with the culture of the company. And I think it's really too early to give much more detail than that. But it is an active area of work for the group. And it's a large part of what my job is now going forward.

And as far as the capital, I mean, we're not really putting capital so much in business development, but we do have the luxury of a very strong financial -- having a very strong financial position and allowing us to invest that capital in the technology that Frank referred to earlier and the work that Eric highlighted today that we're prioritizing for the antisense platform as well as building our late-stage Ionis owned pipeline and our commercial capabilities. So that's where the capital is going. That's much from business development.

Our next question comes from Myles Minter at William Blair. Actually, just a couple of questions. Are you defining potential best-in-class PCSK9 ambition with our ION449 drug? And is this on magnitude of knockdown alone? Or is it also due to the dosing frequency or safety tolerability? Very curious as to how you -- how this compares to inclisiran and do patients, clinicians favor knockdown magnitude over the frequency of dosing?

Sam?

Okay. Well, I think very simply best-in-class means what is the most potent drug in terms of LDL reduction? And based on the current data with ION449, even with a single dose, you're getting a 70% reduction in LDL. The antibodies give you about a 60% reduction in LDL and inclisiran about 50%. So if you look at it purely from the LDL perspective, what a clinician wants is to get most of the patients to the goal that they're aiming for. And the best way you're going to be able to do that is to use ION449. You can think of, I think, ION449. And I think it's apropos because it's AstraZeneca, as Crestor, you can think of the antibodies as Lipitor, and you can think of inclisiran and Zocor in terms of potencies. And so the question is, how is that going to pan out in the marketplace? Are there going to be some other differentiators besides LDL that are going to be secondary? Convenience may be one. But does it only matter if it's monthly or every 6 months, if you're not as efficacious. And this is where the rubber is going to hit the road because we want to lower the ELD as much as possible because I know that's what's good for our patients. And so if you have a drug that works lower than 70%, I think we have a winner, and that's what I anticipate, will eventually when it gets to the marketplace.

And I don't think in a winter such as that, physicians are going to be really concerned about dosing frequency. Once-monthly is actually a really compelling dosing frequency in this market.

The next question is about the ataxin 2 program. Can you explain more about the rationale for the knockdown in ALS? Is the preclinical data supporting ION541 from over-expression models alone? And if so, can you comment on the ataxin 2 expression heterogeneity and in the sporadic ALS population and why it would be positioned for all patients?

Yes. Great. Frank, would you mind taking that one?

Sure. This may be -- apologize in advance, a little bit of a complex long answer, but it's important to kind of understand the context. So ALS has a sort of half of an histological change that occurs. And that is that in most ALS cases, you see a translocation of a protein called TDP43 from the nucleus to the cytoplasm where it forms these protein aggregates. And that's observed in most TDP43 cases. There's been a lot of work to document that this translocation that TDP43 causes enhanced pathology. That particular motor neurons are quite susceptible to. So to help address what could fix that TDP43 pathology, a scientist at Stanford, Dr. Aaron Gitler, did a yeast study where he complemented in yeast, trying to identify TDP43 modifiers. And the top hit that came out of that modifier screen was ataxin 2. And that was interesting because then he went back and looked in ALS patients. And there's a population of ALS patients that have an intermediate CAG expansion. So ataxin 2 is a well-known protein -- sorry, well-known gene that causes a disease called spinal cerebellar ataxias. And it's very much like Huntington's disease, where there's the CAG expansion that grows in patients with SCA2. And what he noticed is that in patients with ALS, there's this intermediate expansion. So it's not large enough to cause SCA2. But it was this -- abnormal compared to the unaffected patient population. Subsequently, we've been working with Aaron and have been able to demonstrate in mouse models that if you over express this toxic form of TDP43, that by lowering ataxin 2, we got very similar effects that you saw in the yeast model system that you prolong survival and preserve motor neuron function. So it's sort of a combination of those 3 facts that give us a lot of confidence that this is a drug that would be useful for all ALS patient populations. Not just those patients that have the CAG expansion in the ataxin 2, but broadly, all patients that have a TDP43 pathology. Sorry. That may not have been clear. I apologize.

It's a very exciting program for broad ALS, and we think it has tremendous potential for this patient population. Thanks, Frank.

Our next question comes from Dan. He wants to know, under what scenario would you expand into more common indications, will you pick programs now, or will you wait to see certain data? And if you wait, what data would you need to see to make a decision?

Since we are in broad indications in the clinic already ourselves and plan to do more of this in the future, I'm assuming the question pertains to commercialization. So maybe I'll toss that over to Onaiza to take the lead.

Sounds good. Great. So as I went through the commercial strategy, we're starting off and principally focused on rare diseases, rare to broad rare. But as Brett just said, we have common disease as part of our pipeline, and we will certainly evaluate those for commercialization as those choices emerge in the future. I look at it in a couple of ways. We have -- we're putting a stake in the ground on neurology and cardiology. So let's say, we've established a successful presence in cardiology. It's one of our core franchises, we could certainly see ourselves leveraging that expertise and the opportunity to expand into a common indication there would make a lot of sense for us to pursue. And of course, we're going to look at compelling clinical data and the data readouts as they come along and the commercial attractiveness of the market and how we will differentiate and find a sustainable competitive advantage. So all those criteria will also come into play. But I think that we will look at it opportunistically and have really, again, this wonderful breadth of a portfolio to make those choices along the way.

Our next question comes from Jim Birchenough at Wells Fargo. Could you discuss efforts to build on leadership in ASO therapeutics with potential complementary technologies, and how you think about allocation of capital towards business development?

I mean we discussed that with you already. Yes, we did.

Don't like being answered again. I mean I get it the same way. The next one comes from Do Kim at BMO. For ION716 in prion disease, what would a pivotal program look like? Could you run single-arm studies and use natural history for comparator?

Great question for Frank.

Yes. So as I mentioned, we are actually doing 2 pivotal studies for prion disease. One is in presymptomatic patients. So these are patients who have a genetic risk for developing prion disease but currently do not have symptoms. And that study is predominantly a biomarker readout, where we're looking for reductions of prion protein in CSF of the patients. We've had a number of discussions with the regulatory agencies. They've signaled that they would approve based on that readout. And so we're very confident that, that could be a very quick path to the market is through the pre symptomatic patient population. In addition, we're doing a study with patients who have symptoms. So these are unfortunately, patients that have a very aggressive form of the disease once they're symptomatic. And we'll do a -- likely a controlled study in that patient population where we'll compare the activity of the drug to a controlled preparator group. We're trying to build everything we can into that study to get patients on active therapy as quickly as possible. So there's the number of nuances in the trial design that we have released, but we're very cognizant of the high unmet medical need and a devastating situation those patients in. And so we want to try to make the drug available if it's safe to -- quickly to the patients in the trial.

Next question comes from Vincent Chen at Bernstein. How much experience to date is there with dosing the cfDNA chemistry in patients? Are dose levels expected to be in commercially relevant doses? I realize it may still be early days, but I'm trying to get a sense for how much confidence we can get that the cfDNA chemistry will be well tolerated and its side effects, such as those seen in prior chemistries likely won't occur?

Yes. So I'll take a stab at the clinical experience and then ask Eric to elaborate on why we chose CF chemistry over other DNAs and how we go about doing what we do and build confidence that this is a very safe platform. I'll start with this, Vince. I think many of us sometimes forget the extensive experience we have with CF in cancer. This is our own cancer programs as well as several with AstraZeneca. In cancer trials, you dose to an MTD, typically in your first-in-man studies in patients with cancer. And we go to doses because the safety profile was very attractive for several drugs with CF. It's very high doses. So sometimes we don't even hit an MTD in one -- at least one of those programs. We just stopped dosing as we were at very high levels. And these are doses that are 50x higher than anything we're expecting with a Gen 2.5 LICA. The safety profiles have been good. They've been attractive. We haven't seen anything as a platform or anything else, and these are very sick patients in cancer. In addition, the PCSK9, Gen 2.5 LICA has shown excellent safety and tolerability. And the PNPLA3 program is progressing nicely as well with AZ, and there's others coming along in the pipeline. So you're right, we don't have as much experience with Gen 2.5 or Gen 2.5 LICA as we do with Gen 2 or Gen 2 LICA, but we have quite a bit of experience already in the clinic. And then, of course, a lot went into the selection of this chemistry and how we go about identifying safe molecules before we put them in the clinic. And Eric, maybe you could touch on that?

Yes, sure. When we started looking at this class of chemical, we worked really hard to try and optimize the structure and fine-tune it from the previously known needs to make the safest possible chemistry that we could advance. And then as Brett mentioned, we had a very deliberate approach to take that technology, that molecule into development in cancer patients to demonstrate the safety and the ability to get to doses that mattered in patients. And one of those programs, I think we got over 1,000 milligrams a week in the cancer patients. And as Brett said, we're very happy with the safety profile. And it was only then that we started to move those into other indications. And for the LICA CF, there the doses are very low and would actually be below the doses and we don't think there's any issue. For things like ENaC, again, the doses are pretty low and constrained to local with 75 milligrams per week. And so I -- it might be early for some other tissues, but I don't think it's really early for the chemical and that we've done a pretty good job of derisking it with some of our other clinical programs, and we're excited to move it forward and help it and have it help us open up new tissues.

Thanks, Eric. And Wade, maybe we'll take a couple of more questions around the 3 hour mark now. And I love the enthusiasm, but we're probably going to have to stop at some point.

All right. A couple more questions then. This one comes from James. He's asking about the [indiscernible] collaboration that we have. And asking how close they are to delivering things we need to help with our drugs, our pipeline drugs?

Yes. Frank, would you mind?

Sure. So [indiscernible] is a new startup company that's developing non antibody protein ligands that we initiated a deal with last year. We're about a year into our partnership with [indiscernible] and making very good progress identifying ligands for several key tissues of interest. And it is progressing quite nicely. And our hope is that we can move something into clinic over the next year or so.

Thanks, Frank.

Next question is from James who's asking, can you elaborate a bit more on the LICA strategy for penetrating the blood-brain barrier?

Eric. That's a great question. Can you want to run with that?

So LICA strategies for crossing the blood-brain barrier are very early. We have announced when we first did the Roche Huntington relationship that we were working with them to work on their Brain Shuttle technology. And we continue to be interested in crossing the blood-brain barrier. It's not an easy task and so to get an oligo across the blood-brain barrier with enough drug transited to give good pharmacology. It's theoretically achievable, and we've had some ins of data in that approach, positive data. So we continue to pursue it. But I do think that blood-brain barrier crossing is -- remains a research exercise that would be a future benefit.

Thanks, Eric. Maybe 1 more, and then we're going to have to shut it down.

Last question is from Jason Gerberry at Bank of America. Any reason why we didn't talk much about our Huntington's disease program today?

Oh, we could talk about our Huntington's program all day long. We're so excited about it. I mean we focused today on principally on the Ionis owned programs, our commercialization strategy and the investments and progress we're making in technology. We did a deep dive in neuro and very deep in Huntington early this past summer. So in the interest of time, we just didn't -- we talked -- we showed a few slides and it's progressing very nicely in Phase III. But that's the only reason why we would love to talk all day about Huntington. The study is fully enrolled. I think it's 799 patients enrolled in that study, Frank, and it's due to read out on schedule in 2022, with a potential filing in 2022 as well. And there'll be open-label extension, natural history data that Roche will present next year at some point during the course of the year in some venue to be determined. But don't take away anything about any of the programs that we didn't -- we didn't talk about Lp(a) today either in the interest of time or [indiscernible] or the Huntington program or some of our other ALS drugs. So it's just in the interest of time. We're very excited about Huntington disease. So no -- please don't read into that at all. Okay. Well, so this wraps up the question-and-answer section and the Ionis Investor Day meeting for this year. At the end of this webcast, a short survey will pop up. Please take a few minutes to provide us with your feedback so we can improve our future events, hopefully, which will be in person. Again, thank you for your participation, and we really look forward to providing more updates on the great progress we're making at Ionis throughout next year and for years to come. Best wishes for the holidays, everybody, take care of yourself, stay safe. So we can all get back together again sometime soon, hopefully, in the new year. Bye for now.