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

[Audio Gap] My name is Brett Monia. I'm the CEO of Ionis. I'm very pleased to provide an update on Ionis for you today, and I'm very pleased that all of you are joining us for today's presentation. Before I get started, I would like to first announce for our shareholders some changes to the Ionis Board of Directors, starting with -- I'm sorry, starting with Stan Crooke. Stan Crooke, after today, will be stepping down from the Ionis Board of Directors. Stan, of course, is the founder of Ionis Pharmaceuticals and has served as the CEO and Executive Chairman for over 30 years at Ionis. And more than that, he provided 30 years of outstanding leadership to the company. We'll very much miss Stan going forward, but we're very pleased by the fact that Stan will be continuing to serve on Ionis as a scientific adviser going forward. In addition, Breaux Castleman, after 8 years of outstanding contributions to Ionis as a Board director and as a member of the Audit Committee, will also be stepping down off the Board after today, and we'll very much miss him as well. Other changes to the Board include the following. Joe Loscalzo has now been appointed Chairman of the Board for Ionis Pharmaceuticals. Joe has served on the Board for 7 years now, and I very much enjoyed working with him over those -- over that time, and I'm very much looking forward to continuing to work with Joe going forward. In addition, we're adding a new board member, Allene Diaz. Allene is coming to Ionis Pharmaceuticals Board of Directors with extensive experience in the building of commercial organizations in the pharmaceutical industry and in the marketing of such products, capabilities that we're very much looking forward to, to complement the rest of our talents on the Board. And Joe Wender, recently appointed as Lead Independent Director of the Board, will continue in this role. And these 3 individuals round out a truly outstanding group of directors on our Board, a group that I very much enjoy working with but more than that, look forward to working with to bring Ionis to even greater success well into the future. So these are my forward-looking statements, which I recommend to -- you review at your convenience. So my presentation today is we'll focus on Ionis Pharmaceuticals today, where we are today as well as the future of the company, a future that we believe is incredibly bright in the future that we will continue to deliver transformational medicines to patients and bring new marketed products to the -- to patients for a very long time. However, before I focus on where Ionis is today and where we're headed, I did want to spend just a moment on the past, and in fact the recent past, and more specifically the recent announcement in March when Roche informed us that they were terminating the Phase III study for the Huntington's disease trial involving our drug, tominersen due to the conclusion that they came to that the drug was not providing benefit to patients and would not provide benefit to patients if the study continued to its natural completion. Obviously, we were disappointed by this setback, but it's a setback that Ionis can certainly absorb considering our rich mid-stage and late-stage pipeline that I'm going to take you through in a few moments. In addition, it was, of course, a very, very big disappointment for the patients who were depending on tominersen to change their lives and treat -- provide a treatment for this devastating disease going forward. Nevertheless, we continue to work with Roche to work through the data, and we believe that the learnings from the Phase III study will teach us a great deal about the disease and also increase our probability for success in developing new drugs for Huntington's disease going forward, including potentially drugs from our own pipeline. So now for the future and the present for Ionis Pharmaceuticals. Ionis today is a leading biotech company delivering transformational medicines to patients in great need, and we'll continue to do so for many, many years to come. Ionis was built today on a commitment to innovation, 30 years of innovation at our core, innovation in science, in research, in drug development and innovation in conducting our business activities over that period of time. And innovation will always be at the core of Ionis Pharmaceuticals. And we're going to use these 30 years of what we built with a focus on innovation to bring Ionis to even greater successes. And we're going to focus on -- going forward on 3 key objectives. The first objective is launching of a new business model for Ionis to bring even greater value to the company. This business model will allow us to now commercialize drugs from our own pipeline, our wholly owned pipeline, and deliver these drugs to the market, drugs that we choose to commercialize ourselves, bringing even greater value to the company. And by doing this, we will also be expanding our commercial capabilities, which we're well along the way in doing and prioritizing the Ionis wholly owned pipeline. The second key objective for the company will be to expand and enhance the scope of our drug discovery capabilities. That is to be able to build out our technologies and our platforms so that we can tackle diseases that are very difficult to tackle or even impossible to tackle with our current platform today. And then thirdly, we're going to deliver a large number of new transformational medicines to the market for many years to come. Our goal and our -- and what we're projecting are 12-plus marketed medicines on the market by -- in 2026. So how are we doing against these 3 key objectives? Well, first, in the evolution of our business model, we are -- we will strive to create an excellent commercial organization that matches the excellence we've created over the years in research, drug development and in our business. And we're making -- we've made many key steps along the way already to achieve this goal. First, we reacquired our commercial affiliate, Akcea Therapeutics. This was important for several reasons, most notably because it allowed us to bring in excellent, highly talented individuals to commercialize and build out our wholly owned pipeline and get us ready for commercialization of drugs that we choose to bring to the market ourselves. In addition, the acquisition of Akcea allows us to bring in full value for the pipeline of drugs that we're very excited about, drugs that we discovered and put into Akcea years ago. This includes partner drugs as well as drugs that are now Ionis wholly owned. We're also well on our way in building out our commercial capabilities and building out and prioritizing our wholly owned pipeline and expanding our infrastructure to set us up for a successful commercialization activities in the future. How are we doing in expanding and enhancing the scope of our drug discovery capabilities? Well, we're doing very well, actually. We have made a priority of strengthening our internal efforts on human genomics, and we've also established partnerships in human genomics. And this is important because our focus here is to continue to identify drug targets that have a human genetic linkage to them to enhance our probability for success and to continue to replenish our pipeline of genetically validated targets well into the future. In addition, we have strengthened our targeted delivery capabilities internal by significant investments internally as well as through external partnerships and collaborations, and we expect possibly to even do more collaborations in the future. And thirdly, we've launched additional initiatives in medicinal chemistry and new routes of delivery that will continue to allow us to tackle new diseases going forward, and we're prioritizing these activities today. And we've begun now to explore potential new platforms to diversify our platform capabilities for drug discovery in the future and to complement what we're doing in the antisense platform. Our third objective is to deliver 12-plus new marketed medicines in 2026, and we're very, very much well on our way in achieving this goal. Today, we have 6 ongoing Phase III studies at Ionis. And by the end of this year, we expect to have 7, possibly 8 Phase III studies in progress. Tofersen, our Phase III program in ALS, is due to read out in the fall of this year. And we have additional Phase III starts that are planned for the second half of this year, as I mentioned. And also well into 2022, additional Phase III starts are expected. And all of this sets us up for a steady cadence of Phase III readouts every year, with some years having more than one readout, including this year with our tofersen SOD1 ALS drug. These 12-plus medicines that will be -- that we're projecting to be on the market in 2026, will primarily come from 2 leading franchises from the Ionis drug discovery and development pipeline, neurological diseases as well as cardiometabolic drug discovery activities. In our neurological franchise, today, we have 3 ongoing Phase III studies, 11 medicines in clinical development, 3 of which are wholly owned Ionis drugs today. Our cardiometabolic franchise is as equally productive with 3 ongoing Phase III studies, 14 medicines in clinical development, 6 of which are wholly owned medicines by [Audio Gap] disease indication for neurological disease, of course -- or disease indications for neurological diseases, of course, led by SPINRAZA, our transformational medicine for all forms of spinal muscular atrophy. SPINRAZA continues to perform very well on the marketplace today as a blockbuster. In the first quarter of this year, we achieved greater than $500 million in revenue, which exceeded the fourth quarter of 2020, and we expect continued growth for SPINRAZA well into the future. Today -- there are more than 11,000 patients on SPINRAZA today. There's a lot -- the prevalence is higher than we originally thought it was when we first started our SMA program. And because of that, there's a lot of room for growth. In addition, we continue to enhance with our partner, Biogen, the profile of SPINRAZA by conducting post-marketing studies that will further enhance the profile of this drug, giving an even great competitive edge against the competition. For example, the DEVOTE study, in which we're examining higher doses of SPINRAZA in patients with SMA is well underway. And the objective there is to demonstrate even greater efficacy by examining these higher doses. In addition, the post-marketing response study is in progress. This is a study in which we're evaluating SPINRAZA in patients that are doing suboptimally. They're not doing as well as had hoped, went on gene therapy, then they're being converted over to SPINRAZA. The objective there is to demonstrate that these patients will benefit from SPINRAZA after suboptimal treatment with gene therapy. SMA is our leading indication in neurological diseases, but it's only one of many in the clinical pipeline today in our neurology -- from our neurology franchise. Today, we have 4 drugs in amyotrophic lateral sclerosis in development, and I'll be taking you through these drugs in a little bit. We also have drugs in development for dementias, such as Alzheimer's disease and frontotemporal dementia. We also have drugs for Parkinson's disease and synucleinopathies in clinical development and leukodystrophies. And I can tell you that even by the end of this year, there'll be more neurological disease drugs in the clinic for other indications as well and more to come in the years to come. Our cardiometabolic franchise is equally impressive. Today, we're addressing all major cardiovascular disease risk factors that are essentially known today for, of course, cardiovascular and cardiometabolic diseases, including drugs that manage lipids that cause atherosclerosis or other cardiovascular types of diseases. Our PCSK9 program is moving very nicely to manage LDL cholesterol, our APOCIII franchise for the management of triglycerides and vupanorsen for the treatment of mixed dyslipidemia for an example. Our antithrombotic drug, Factor XI LICA -- or Factor XI-LRx, is in a Phase IIb study for the prevention of thrombosis in patients at risk for thrombosis. In addition, we're targeting other risk factors, such as transthyretin for the treatment of heart failure or cardiomyopathy, and pelacarsen, which targets another risk factor, lipoprotein(a), which causes atherosclerosis, stroke and heart attacks. And then finally, we have 2 drugs in development today that are being developed for the treatment of refractory hypertension. So now what I'd like to do is take you through our Phase III programs, provide you an update on these programs, what their status is and where we see them headed. Today, we have 5 drugs in Phase III development, being tested and evaluated in 6 Phase III studies. The drugs are listed here on this slide. And what you can see also on this slide are the disease indications and the prevalence. The prevalence is worth noting because it demonstrates that not only are we targeting in these Phase III studies severe rare diseases such as ALS but also very highly prevalent diseases, such as Lp(a) cardiovascular disease, which is afflicting millions of people around the globe. And what you can also see on the right is when the data readouts are expected for these Phase III studies. As I said earlier, we're expecting Phase III data readouts every year for as far as the eye can see from our late-stage and mid-stage pipeline, including this year with our tofersen Phase III readout in the fall. So now what I'd like to do is focus first on our neurological disease franchise, Phase III programs, tofersen and ION363. Tofersen is being developed for the treatment of a form of ALS called -- due to mutations in a gene called SOD1, SOD1-ALS. I think everybody recognizes the fact that amyotrophic lateral sclerosis or Lou Gehrig's disease is a fatal disease with a very large unmet medical need. It's a severe disease that occurs due to a decline in -- a functional decline in motor function, paralysis, respiratory function due to degeneration of neuronal cells and glial cells in the central nervous system. It's a rapidly progressing form of neurodegenerative diseases with survival lasting only a few years after symptom onset typically. In addition, there are many -- several different causes of ALS that have been identified today, several different genetic causes due to mutations in genes that cause ALS. And then there's also the broad ALS, which is -- in which no known genetic linkage to this form of ALS has been identified to date. Tofersen is targeting a genetic form of ALS due to mutations in the gene, SOD1 or superoxide dismutase type 1. This is a toxic gain-of-function disease, which means that the overproduction or the production of the protein is what's causing this form of ALS. This is the second most common genetic form of ALS. We know that ALS has over 100 mutations that have been identified today in the SOD1 gene, many of which have been linked to ALS, SOD1-ALS. And some of these mutations are very -- cause a very rapidly progressing form of ALS. Tofersen targets the root cause of SOD1-ALS. It blocks the production of SOD1 in the CNS. The prevalence of this rare disease is shown here, 1,400 patients estimated in G7 countries. Again, this is a severe, severe form of ALS. It's invariably fatal with no treatment options available for really any form of ALS today. So this has the potential to be the first-in-class product and certainly transformational for families and patients suffering from this genetic form of ALS. Tofersen targets the root cause of SOD1-ALS. SOD1, we've demonstrated in Phase I/II studies, in patients with SOD1-ALS, robust reductions in SOD1 with strong trends in improving outcomes, slowing down progression of this disease. This led to the initiation of the Phase III study called VALOR, which is now fully enrolled and due to read out in the fall of this year. In addition, our partner, Biogen and Ionis, have also initiated this year a second Phase III study called ATLAS. ATLAS is a study in which tofersen is being tested in patients with SOD1 mutations who have yet to develop symptoms of ALS. So they're presymptomatic. And of course, the goal here for this study is to prevent the disease onset from ever occurring. Tofersen is 1 of 2 drugs in development today for ALS that are -- that is in Phase III development. Our second Phase III drug for ALS is ION363, which targets FUS-ALS and is a wholly owned product of Ionis Pharmaceuticals. So FUS-ALS, like SOD1, is due to a mutation in a gene called FUS, which is a toxic gain-of-function disease. It is the third most common genetic form of ALS and is a very fast-progressing form of ALS. Like SOD1, FUS mutations cause motor neuron degeneration through a toxic gain-of-function mechanism, as I mentioned, causing destruction of neuronal cells and glial cells and rapid deterioration of the motor function of the central nervous system. So ION363 is a wholly owned Phase III program, targeting FUS-ALS. We're targeting the root cause of ALS mutations in FUS. We're targeting the FUS gene and blocking the production of this toxic gain-of-function protein. We've shown in animal models that we can halt the progression of the disease and prevent motor neuron loss in models of FUS-ALS. We also have supported a compassionate use study with an investigator at Columbia University with our FUS-ALS drug, ION363, in patients with FUS-ALS. And based on encouraging results from that study, it supported our decision to move into Phase III development. We have a very innovative pivotal study design, designed to achieve potentially rapid acceleration to the market. And as I mentioned, the Phase III study is now enrolling. We are committed to treating all forms of ALS. Tofersen and ION363 are 2 drugs in our ALS pipeline today. We also have IONIS-C9Rx, which is in a Phase I/II study in patients with a genetic -- another genetic form of ALS due to mutations in the gene called C9ORF. This is the most common form of the genetic form of ALS, and data is expected to read out in the first half of next year for this program. And then fourthly, we also have -- we have ION541, which is in Phase I/II development for broad ALS. This drug targets ataxin 2 for the broad ALS population. And this study, this Phase I/II study, is well along the way. And we're looking forward to additional programs for the treatment of ALS coming to the clinic in the future. So now I'd like to focus on 3 Phase III drugs that are -- that were developed from our cardiometabolic franchise planters, eplontersen, IONIS-APOCIII-LRx and pelacarsen. These 3 drugs utilize our most advanced targeted delivery chemistry called LICA chemistry and -- which gives the -- which converts to these drugs' excellent potency, excellent tolerability with the convenience of once-a-month administration or even less frequent. Now let me take you through these 3 drugs, starting with eplontersen, which was previously referred to as IONIS-TTR-LRx. [Audio Gap] and fatal disease characterized by the formation of TTR amyloid deposits in various organ systems, which causes multi-organ failure, typically dominated by the failure of the heart system, causing cardiomyopathy, or the peripheral nervous system or both. This is a progressive disease that results in a rapid decline in quality of life and often, quite often, death. And depending on the individual and other circumstances, life expectancy could be very short or it could be longer. This is a relative -- this is a highly prevalent disease when you look at the entire population of TTR -- patients suffering from TTR amyloidosis, estimated with a prevalence of greater than 250,000 around the globe. It is often fatal, as I mentioned. And certainly, our LICA medicine, eplontersen, has the potential to be the best-in-class medicine for the treatment of all forms of TTR amyloidosis, thereby being transformational for patients and truly changing in a beneficial manner the standard of care for patients suffering from TTR amyloidosis. So as I mentioned, eplontersen utilizes our most advantaged chemistry, our targeted delivery chemistry called LICA chemistry, with high potency, excellent tolerability, targets the root cause of TTR amyloidosis. And in Phase I development in normal volunteers, we demonstrated greater than 90% reductions in transthyretin, the TTR protein, the cause of this disease in these normal volunteers, with excellent safety and tolerability. So eplontersen today is in Phase III development. And in fact, it is in 2 Phase III studies today, one for the hereditary polyneuropathy indication, the same indication as TEGSEDI; as well as the broader indication, the cardiomyopathy indication due to TTR amyloidosis. Like our other drugs, we're targeting the root cause of this disease, TTR, utilizes our LICA chemistry, which is -- brings you tremendous advantages to the profile of the drugs. We've shown very nice reductions in TTR protein in Phase I, and the 2 ongoing Phase III studies are well underway in enrolling with the polyneuropathy Phase III study due to read out next year. Our second drug in Phase III development for -- from our cardiometabolic franchise is IONIS-APOCIII-LRx. APOCIII-LRx is being developed for the management of diseases related to high triglycerides. We all know that elevated triglyceride levels are associated with many major medical issues, including an increased risk for cardiovascular disease as well as metabolic disorders such as diabetes and acute pancreatitis, which often can be fatal. APOCIII is the master regulator of triglyceride levels in the body and is -- also not surprisingly, has been identified as an independent cardiovascular risk factor. There are several different populations that have been bucketed, if you will, the patient populations that suffer from high triglycerides. This includes the familial chylomicronemia syndrome patient population or FCS, which is a rare population. And these patients suffer from metabolic diseases due to very high triglycerides, well above 1,000 milligrams per deciliter. A second bucket involves patients suffering from triglycerides above 500 milligrams per deciliter. This is referred to as severe hypertriglyceridemia, or sHTG. And this is not a rare disease. In fact, in the United States alone, this disease is estimated to have a prevalence of more than 3 million people in the U.S. And then patients with triglyceride elevations on the order 150 to 500 milligrams per deciliter or so suffer from -- or at high risk for cardiovascular disease, this is a very large population of patients that suffer from -- or at risk for cardiovascular disease due to high triglycerides estimated in the tens of millions. We are focusing APOCIII LICA on 3 -- on 2 patient populations today in development, the rare patient population, the FCS patient population; as well as now the severe hypertriglyceridemia patient population, sHTG. This drug, APOCIII LICA, based on its mechanism of action and based on its chemistry, our LICA chemistry, has the potential to be the very best in the class for the management of triglyceride disorders of all forms, including FCS and sHTG, and certainly has the potential to be transformational for patients suffering from these diseases. So APOCIII-LRx, a wholly owned product -- pipeline product for Ionis Pharmaceuticals, has shown very potent reductions in triglyceride levels, including in a Phase II study that we conducted. This was in patients with cardiovascular disease and that had very high triglycerides. In fact, in this study, we were able to achieve potent reductions in triglycerides in these patients. And in fact, we were able to get, in more than 90% of these patients, triglyceride levels below the threshold associated with metabolic diseases and cardiovascular diseases. The Phase III study in FCS called BALANCE is now actively enrolling patients and is underway. And we're planning to initiate the Phase III study in severe hypertriglyceridemia patients, sHTG in the second half of this year. And then our third drug from our cardiometabolic franchise that's in Phase III development today is pelacarsen. IONIS-APO, formerly known as IONIS-APO(a)-LRx. Pelacarsen targets a risk factor called lipoprotein(a). This is a risk factor. It's highly prevalent. Lp(a) levels are genetically determined at birth. And if you have abnormally high Lp(a) levels, you are at risk for cardiovascular disease such as stroke and heart attack and atherosclerosis. And in fact, the higher the level of Lp(a), the greater the risk of cardiovascular disease that you have. Not surprisingly, Lp(a) is recognized as a major independent risk factor for cardiovascular disease, and there are no ways to manage Lp(a) levels. There are no approved pharmacological therapies that can control Lp(a) levels in the body. The prevalence of this disease is very large, as I mentioned earlier. Greater than 8 million people around the globe are estimated to have Lp(a)-driven cardiovascular disease. And as I mentioned earlier, there are no treatments to manage this disease. It's commonly fatal due to heart attacks and strokes. And certainly, this drug has the potential to be another first-in-class product to reach the market and certainly transformational for patients suffering from Lp(a)-driven cardiovascular disease. So pelacarsen targets, like the other drugs we're -- that we're developing, the root cause of disease, Lp(a)-driven cardiovascular disease. In a Phase II study, I'll remind you that -- in which we tested pelacarsen in patients with cardiovascular disease and high Lp(a) levels, we were able to normalize Lp(a) levels in those patients. Approximately 98% of the patients in that study, we were able to normalize their Lp(a) levels at Phase II study, giving us great confidence that we're certainly hitting the target that we want to hit and giving us confidence in our Phase III study. The Phase III study is referred to as HORIZON, which is now well underway and enrolling rapidly with Phase III data expected in 2024. So those are our 5 Phase III drugs in development today being tested in 6 Phase III studies. Now I'd like -- just like to give you a glimpse into what we believe will be our next Phase III drug, and that drug is IONIS-PKK-LRx. PKK-LRx is being developed to treat a rare genetic disease referred to as hereditary angioedema. This is a severe genetic disease. It's due to -- it's caused by insufficiency of a protein called C1-inhibitor. This insufficiency in C1-inhibitor causes hyperactivation of a pathway called the prekallikrein-bradykinin pathway. The symptoms of this disease, as I said, are very severe, resulting in excess swelling of various organs and systems in the body, including the arms, leg, face, intestinal tract and throat. And if you get excess swelling in the throat, it can be fatal due to suffocation. Furthermore, this disease -- the onset of these HAE attacks are unpredictable. So there are no known causes of these attacks. And therefore, patients live their life with the uncertainty of having an attack at any moment in their life. There are approved prophylactic treatments for HAE. However, there still remains a very large unmet medical need, an unmet medical need for better efficacy. Many of these patients on these drugs continue to experience breakthroughs and certainly a strong desire for more convenient drugs, easier to tolerate drugs. We believe IONIS-PKK-LRx fits that bill to be a potential best-in-class medicine for HAE. We're targeting the pathway with PKK-LRx that is responsible for HAE, the prekallikrein-bradykinin pathway. PKK-LRx is designed to block the production of prekallikrein, lowering the levels of prekallikrein and bradykinin, bringing them to normal levels and resulting in prevention of HAE. And like our other Phase III drugs from our cardiometabolic pipeline, PKK-LRx is another LICA medicine with -- that benefits from all the benefits of the LICA platform. [Audio Gap] is estimated to be more than 20,000 in the United States and in Europe. It's certainly a potentially fatal disease resulting from, as an example, suffocation due to edema in the throat. And certainly, PKK-LRx has the potential to be the best-in-class product for the treatment and management, prophylactic management of HAE. Today, we believe it does. And certainly, if so, it has the potential to be transformational. And we say that -- and we draw this conclusion not just because of the wealth of preclinical data that we have and the Phase I data that we have but also the Phase II data that we reported, top line data for earlier this year. This was a Phase II study, a placebo-controlled study in patients with HAE in which patients were treated with either placebo or PKK-LRx over a 17-week period of time. What we showed in this study was that we demonstrated a 90% mean reduction in monthly HAE attacks compared to placebo, which was highly, highly statistically significant. In addition, if we look at the time period between weeks 5 and 17 in this study -- and that's relevant because it takes a few weeks for the drug to get on board and get the steady-state concentrations. If we look at when the drug is fully onboard between weeks 5 and 17, we were able to actually achieve 97% mean reduction in monthly HAE attacks versus placebo. And moreover, during this time period, 92% of the patients in this Phase III study had no attacks, had 0 attacks compared to 0% of patients in placebo having 0 attacks during this time period, very, very exciting and impressive Phase II data that sets us up very nicely to move into Phase III development. So PKK-LRx targets the pathway that's at the root cause of HAE. It's a very conveniently used drug as a once-a-month, low-volume subcu, self-administered injectable. It utilizes our highly advanced LICA chemistry with the potencies and the tolerability advantages that it offers. And certainly, the Phase II data, we believe, supports the potential for a best-in-class product for the management of HAE. And as I said, the Phase III study is in planning, and we're hoping to get that study underway soon potentially by the end of the year, if not in the early part of next year. So we have a very, very exciting, rich late-stage pipeline of Phase III drugs that I just took you through. And that's a rich agenda for Ionis and our partners who are developing these drugs alongside the drugs that we're developing in Phase III. And this year, in 2021, we also set out with a very aggressive agenda on pipeline readouts that we said we were going to have throughout the course of this year. And now I'd just like to take you through, if you will, a report card -- scorecard on how we're doing against those planned pipeline events. These events include data readouts as well as key study initiations from the pipeline. We've already had several Phase II readouts or several pipeline readouts from various studies in the first half of this year. And the second half of the year is looking to be a very rich part of the year for additional pipeline readouts, including the full data set for PKK-LRx in HAE, the MAPT data in patients with Alzheimer's disease and, of course, the tofersen Phase III data in patients with SOD1-ALS in the fall of this year. We're also well on our way to achieving our goals for study initiations. Many study initiations have already occurred this year, as you can see on this slide, including the post-marketing studies for SPINRAZA, the ATLAS tofersen presymptomatic study in SOD1-ALS. And there's more coming, our Phase III study for APOCIII-LRx in sHTG, severe hypertriglyceridemia; our Angelman syndrome Phase I/II study to start in the second half of this year; and as I mentioned earlier, potentially IONIS-PKK-LRx Phase III in HAE. The performance of this pipeline this year as well as the Phase III pipeline that I just took you through over the last little bit sets us up very nicely to achieve our objective of 12 or more marketed medicines in 2026. And again, as a reminder, most of these medicines will come from 2 leading franchises in the industry, our neurological disease franchise, both wholly owned and partnered; our cardiometabolic franchise, wholly owned and partnered; as well as drugs -- some drugs outside of these 2 franchises such as PKK-LRx for HAE. So today, at Ionis, the pipeline is advancing and advancing at an accelerated pace. In addition, our technology is advancing and expanding to tackle diseases today that were unapproachable in the past. We are certainly pioneering new markets with drugs like tofersen for SOD1-ALS and pelacarsen for Lp(a)-driven cardiovascular disease. And we're making -- we're changing the standards of care for patients in a beneficial manner with new drugs to reach the market, like PKK-LRx for HAE and eplontersen for TTR amyloidosis. We're investing in all aspects of the business to ensure that Ionis is as successful and grows at a pace that -- with an accelerated pace of growth in the future, including investments in our research organization, our wholly owned pipeline, building out our commercial capabilities and more. All of this are being allowed because of -- permitted because of the strong financial position that we are in at Ionis today. And all of this sets us up very nicely, perfectly for accelerated growth for the company well into the future. And with that, I think I'll stop there. I'll just -- we'll just take a couple of minutes to set up for the question session of the presentation. I'm going to ask Beth Hougen, our Chief Financial Officer, to join me; as well as Onaiza Cadoret, Chief of Corporate Development and Commercialization, to join me as well. So stay tuned, and we'll be back in a moment. [Break]

Welcome back to the question-and-answer session of today's Ionis shareholder meeting. Filling -- or filtering the questions and taking the questions will be Wade Walke, our Vice President of Investor Relations, and Wade will be feeding us the questions here, to Beth, Onaiza and myself, Brett Monia. And so Wade, do we have some questions?

We do. [Operator Instructions] Our first question involves the PKK LICA program. And the question is, you released or only reported data from patients with type 1 or type 2 HAE, but the study also enrolled patients with HAE with normal C1-inhibitor. Why wasn't this data released when you talked about the type 1 and type 2 data? And will it be released? And do your plans for Phase III include HAE patients with normal C1-inhibitor?

So we -- that's absolutely correct that our Phase II study included type 1, 2 and 3, but there are really 1 or 2 type 3 patients in that study. So it really just wasn't much to be able to draw a definitive conclusion on. We will share the full data set in the second half of this year. We're targeting a publication and potentially also a presentation in the second half of the year, and we'll certainly share all that data when we presented the full data set.

And I'd also remind investors who are interested, that paper was published with investigator-initiated study of 2 patients. One of them had normal C1-inhibitor.

That's right.

And the patient showed significant reduction in attack rates.

That's right. That was a type 3 patient in that New England Journal paper.

Next question is about the Huntington program. Does Ionis and Roche have any plans to move the allele -- an allele-specific ASO to the clinic to treat Huntington's patients?

Yes. It's a great question. We're still working through a massive data set from the Phase III study with Roche. Roche is taking the lead on that work. And we have a lot to learn before we start deciding on what will be the next step with respect to drug development. Certainly, one potential path forward for the Huntington program once we get through all the data will be to develop an allele-selective inhibitor potentially. We certainly have a lot of experience in developing allele-selective inhibitors for HT -- or HD. We published on this, and we certainly have a drug pretty much ready to go if we choose to go that path. So stay tuned. I suspect by the end of the year, we will know the next steps for the Huntington program.

Next question is about our TTR LICA and APOCIII LICA programs. The question is, will you consider out-licensing ex U.S. rights in order to shift risk and fund commercial rollout in the United States?

So TTR LICA and APOCIII LICA are 2 drugs in our wholly owned pipeline that we're building out our commercial plans for today. What we do, how we manage partnerships for that -- those programs is to be determined still. This is a work in process, but what I can assure you is that we're working hard to develop the markets for these 2 assets ourselves today. And whatever we choose to do for these 2 drugs with respect to partnerships in the future, whether it be commercialization or what have you [Audio Gap] to bring the maximum value to the company that we could possibly bring. So it's a work in process.

Next question is about business development. Are there merger, new partnerships or acquisitions possible in the future?

We don't comment on mergers or acquisitions. That would be inappropriate. Sorry.

There's a couple of questions on this particular topic. So we'll just ask this one question, and I think it will cover the others. This is from a shareholder who also has shareholder clients. So as you have a robust pipeline of drug development in various stages of process, given the stock price has dropped recently in the past few months, what are -- what is the market missing? And outside of potential positive clinical trials, how do you think you can change Wall Street's outlook to have a more positive outlook on the company's future, financially?

Yes. Thank you for that question. We know we are disappointed, frustrated by the performance of the stock price, and trust me when I say that the senior team at Ionis pays us a great deal of attention to how to turn this around all the time, every day. I think we've suffered a little bit from the tominersen Phase III outcome. That was a big setback in the eyes of many. What we're pleased about is we see no readthrough to the neurological platform. As I took you through, we think that's one of the richest or most robust platforms, and we're very much looking forward to the tofersen Phase III data later this year to really demonstrate that again from our platform. I think that, that is -- that was a key setback in the stock price. Other than that, I wish I knew, other than the fact that we did have a bit of a quiet period with key clinical readouts over the last 1.5 years or so. That's all changing now. Our clinical pipeline, as I took you through, is going to have clinical readouts from our mid-stage pipeline in our Phase III pipeline this year -- more this year, next year and for many years to come. And I really do think that, that is what's going to get people's attention and turn things around.

Next question is about the PCSK9 program. The question is I noticed that the PCSK9 drug partnered with AZ could be best-in-class profile drug based on the Phase II data. This drug uses the LICA delivery and Gen 2.5 chemistry. The rest of the pipeline uses LICA plus Gen 2 or Gen 2.5 alone. Do you have a strategy to upgrade the pipeline drugs with LICA to plus 2.5 chemistry, so they could be more competitive in the marketplace?

Indeed, our PCSK9 Gen 2.5 LICA medicine with AZ does have the potential to be the best PCSK9 inhibitor that's out there today. And we say that not only based on our preclinical data but more importantly on -- based on real clinical data, some of which was presented at the AHA last year. And we have more data. Phase IIb study is ongoing to select dose, potentially to move that drug into Phase III development later this year. And it was really the Gen 2.5 component to that LICA medicine that allowed it to really put out that profile of a potential best-in-class in a very crowded area of PCSK9 with PCSK9 inhibitors based on its added potency. Our Gen 2 LICAs are outstanding drugs in their own right, and they're performing exceptionally well in the clinic. And they're far along -- I mean as I took you through, 3, soon to be 4, drugs with Gen 2 LICAs are in Phase III development, soon to read out and be first, if not first best-in-class, potentially best-in-class medicines. If we were to convert those drugs over to Gen 2.5 down the road, we would have to factor in lots of different things. What will the 2.5 give us over Gen 2? Is it worth it? Because the Gen 2s are performing very well, do we need it? Like we probably needed it for PCSK9 because it was a highly competitive field to further advance our competitive edge. And should we do it for life cycle management to continue to franchise for much longer periods of time? So a long, convoluted answer to a very good question that we'll have to see what we need and what 2.5 would bring to these other drugs. But these 2 Gen 2 LICAs are performing exceptionally well.

The next question is regarding potential share buyback. The question is, have you considered a share buyback with cash on hand?

Well, we did a share buyback. When was it, 1.5 years ago, Beth? And we've talked about it, but why don't you take that?

Yes. Sure. Happy to. We -- as Brett said, we had done one in the past. We've looked at that, obviously, with where our share price is today and believe really firmly that the best allocation of our cash right now is internally in our pipeline. I think Brett took you through a really nice overview of what is in the -- what value there is in the late-stage pipeline as well as in the mid-stage pipeline, investing as deeply as necessary to bring those medicines forward to the market to ensure that they're commercially successful, building out our commercial capabilities and expanding the reach of the technology so that we can continue to retain our leading position as a -- in this field. I think those are the places where ultimately, we're going to see the greatest value for the company. And particularly, as we start to see those Phase III readouts year after year after year, beginning, we hope, with tofersen later this year, reaching our goal of 12 or more marketed medicines in 2026, that's really where I think there's true value for the company.

Next question is again about the PKK program but is asking if there's an update about the drug helping COVID patients, specifically the trial in Brazil.

Yes. This was a real flyer, an investigator study that was conducted in Brazil. We were contacted by an investigator in Brazil who was experiencing the pandemic in very bad ways. And the bradykinin pathway has been linked to poor outcomes, patients with COVID infections. So he asked if he can do a single-site investigator study. We provided the drug to whom the data is still under -- is being analyzed. So we should have data by the second half of the year.

The next question is 2 parts, related to delivery of antisense drugs. One is, is there an update on oral delivery of ASOs and specifically PCSK9 but also in general? And also, what's the status of lung delivery for ASOs?

So we continue to develop a platform that potentially will allow us to achieve commercially viable oral delivery for antisense drugs. We're working -- we're putting quite a bit of resources internally on this to increase the bioavailability and improve bioavailability so that we're at the bioavailability that we want to achieve that we think is necessary to be commercially viable. And we're also working with our partner, AstraZeneca, to help develop this platform going forward. I can't say right now whether we will be, for sure, successful in achieving this. But we're certainly encouraged by the learnings we made from the Phase I study that AstraZeneca did with the PCSK9 inhibitor using the oral route of delivery. And we learned a lot from it, like I said, and we're building on that. So we're encouraged and we're continuing to work on that. So stay tuned. Maybe in 2022, we'll have an update on the oral platform. With respect to lung delivery, this is a very exciting area for the company that we're continuing to pioneer, advance our technology, another example of that. We had a setback in -- earlier last month in our ENaC program in which based on a finding in a chronic monkey toxicology study, we thought it was prudent to stop clinical development of that drug for the safety of the patients in the clinical trial or we better understood the finding, a local effect in the lung, nothing systemic, no read-through to the Gen 2.5 class, nothing like that at all. It's just an effect in the lung in monkeys. We think we'll be able to work through that. We're working hard on that now to come up with different chemical designs, molecules that we think can avoid the observations we've made. And so stay tuned. But we're feeling good that pulmonary certainly -- the pulmonary franchise is certainly in our future. We just have to sort out what's the best design for a pulmonary-delivered antisense drug.