AGM 2021

Jun 2, 2021

Slides

Please provide an update on Ionis for you today. 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 sorry. Starting with Stan Crook. Stan Crook, 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 thirty years at Ionis. And more than that, over he provided thirty years of outstanding leadership to the company. We will 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, Bro Casselman, after eight 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 Liscalzo has now been appointed chairman of the board for Ionis Pharmaceuticals. Joe has served on the board for seven years now, and I've very much enjoyed working with him 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, Eleni Diaz. Eleni 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 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 three individuals round out a truly outstanding group of 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 will 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, that and and and a future that we will continue to deliver transformational medicines to patients on and bring new marketed products to the to to patients for for a very long time. However, before I focus on where Ionis is today and where we're headed, did want to spend just a moment on, the past, and in fact, the recent past and the and more specifically, the recent announcement in March when Roche informed us that they were terminating the phase three 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 tominiracin to change their their lives and 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 the learnings from this phase three 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 will continue to do so for many, many years to come. Ionis was built today on a commitment to innovation, thirty years of innovation at our core, innovation in science, in research, in drug development and in innovation conducting our business activities over that period of time. And innovation will always be at the core of Ionis Pharmaceuticals. And we're gonna use this thirty years of what we built with a focus on innovation to bring Ionis to even greater successes. And we're gonna focus on going forward on three key objectives. The first objective is launching of a new business model for for Ionis to bring even greater value to the company. This business model will 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 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 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 in 2026. So how are we doing against these three 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'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 partnered 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 much well on our way in achieving this goal. Today, we have six ongoing Phase III studies at Ionis. And by the end of this year, we expect to have seven, possibly eight phase three studies in progress. Tofersen, our phase three program in ALS is due to readout in the fall of this year. And we have additional phase three 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 these 12 plus medicines that'll be that we're projecting to be on the market in 02/1926 will primarily come from two leading franchises, from the Ionis drug discovery and development pipeline, Neurological diseases as well as cardiometabolic drug discovery activities. In our neurological franchise, today, have three ongoing phase three studies, 11 medicines in clinical development, three of which are wholly owned Ionis drugs today. Our cardiometabolic franchise is equal as equally productive with three ongoing phase three studies, 14 medicines in clinical development, six of which are wholly owned medicines by Disease indication for neurological disease, of course, is or disease indications for neurological diseases, of course, are led by SPINRAZA, our transformational medicine for all forms of spinal muscular atrophy. Spinraza continues to perform very well on the marketplace today as blockbuster. In the first quarter of this year, we achieved greater than $500,000,000 in revenue, which exceeded the fourth quarter of twenty twenty, and we expect continued growth for SPINRAZA well into the future. Today, there are more than eleven thousand 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 it an even greater 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 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 they're not doing as well as as had hoped who 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 from our neurology franchise. Today we have four 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 dementia, 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, are addressing all major cardiovascular disease risk factors that are essentially known today for the that cause cardiovascular and cardiometabolic diseases, including drugs that manage lipids that cause atherosclerosis or other cardiovascular types of diseases. PCSK9 program is moving very nicely to manage LDL cholesterol. Our APOC3 franchise for the management of triglycerides and buprenorphine for the treatment of mixed dyslipidemias, as for an example. Our antithrombotic drug, factor eleven LICA or factor eleven LRX, is in a phase two b study for the prevention of thrombosis in patients at risk for thrombosis. In addition, we are targeting other risk factors such as transthyretin the treatment of heart failure or or or cardiomyopathy, and pelicarcin, which targets another risk factor, lipoprotein little a, which causes atherosclerosis, stroke, and heart attacks. And then finally, we have two drugs in development today that are being developed for for the treatment of refractory hypertension. So now what I'd like to do is take you through our phase three programs, provide you an update on these programs, what their status is, and and where we see them headed. Today we have five drugs in phase three development being tested and evaluated in six phase three 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 three studies severe rare diseases such as ALS, but also very highly prevalent diseases such as Lp, little 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 three studies. As I said earlier, we're expecting phase three 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 three readout in the fall. So now what I'd like to do is focus first on our neurological disease franchise, phase three programs, tofersen and ion three sixty three. Tofersen is being developed for the treatment of a form of ALS called through the mutations in a gene called SOD one, SOD one ALS. I think everybody recognizes the fact that amyotrophic lateral sclerosis or Lou Gehrig's disease is a is a fatal disease with a with a very large unmet medical need. It's a severe disease that that that is that is occurs due to decline in function 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. Filfersen is targeting a genetic form of ALS due to mutations in the gene SOD1 or superoxide dismutase type one. This is a toxic gain of function disease, which means that the overproduction or the production of the of the protein is what's causing this form of ALS. This is the second most common genetic form of ALS. A l we know that ALS has over a hundred mutations that have been identified today in 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. One point four thousand patients estimated in G7 countries. Again, this is a severe, severe form of ALS. It's an 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. So tofersen targets the root cause of SOD1 ALS. SOD1, we've demonstrated in phase onetwo studies in patients with SOD one ALS robust reductions in SOD one with strong trends in improving outcomes, slowing down progression of this disease. This led to the initiation of the phase three study called VALOR, which is now fully enrolled and due to readout in the fall of this year. In addition, our partner Biogen and Ionis have also initiated this year a second phase three study called ATLAS. ATLAS is is is a study 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 one of two drugs in development today for ALS that is in phase three development. Our second phase three drug for ALS is ION three sixty three, 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 SOD one, phos mutations cause motor neuron degeneration through a toxic gain of function mechanism, as I mentioned, causing destruction of neuronal cells, inguinal cells, and rapid deterioration of the of the motor function of the central nervous system. So ION three sixty three is a wholly owned phase three program targeting FUS ALS. We're targeting the root cause of 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 fuss ALS drug, ION three sixty three, in patients with fuss ALS. And and based on encouraging results from that study, it supported our decision to move into phase three 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 INT-three sixty three are two drugs in our ALS pipeline today. We also have IONIS C9Rx, which is in a phase one two 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 next year for this program. And then fourthly, we also have a we have ION five forty one, which is in phase one two development for broad ALS. This drug targets ataxin two for the broad ALS population, and this study, this phase onetwo study, is well along the way. And we're looking forward to additional programs for the treatment of ALS coming to the to the clinic in the future. So now I'd like to focus on three phase three drugs that are that are that were developed from our cardiometabolic franchise, eplontiracin, inosapac APOC3 LRX, and pelicarcine. These three drugs utilize our most advanced targeted most advanced targeted delivery chemistry called LICA chemistry, and which gives the which confers to these drugs excellent potency, excellent tolerability with the convenience of once a month administration or or even less frequent. Now let me take you through these three drugs, starting with efontersen, which was previously referred to as Ionis TTR LRx. In fatal disease characterized by the formation of TTR amyloid deposits in various organ systems that 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 can be very short, or it could be 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 two hundred and fifty thousand around the globe. It is often fatal, as I mentioned. And certainly, our LICA medicine, eplomteracin, 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 and truly changing in a beneficial manner the standard of care for patients suffering from TTR amyloidosis. So as I mentioned, efalanteracin utilizes our most advanced chemistry, our targeted delivery chemistry called LICA chemistry, with high potency, excellent tolerability, targets the root cause of TTR amyloidosis. And in phase one development in normal volunteers, we demonstrated greater than ninety percent reductions in transthyretin, the TTR protein, the cause of this disease, in these normal volunteers with excellent safety and tolerability. So epilomteracin today is in phase three development. And in fact, it is in two phase three 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, It uses utilizes our lipochemistry, which is brings you tremendous advantages to to the profile of the drugs. We've shown very nice reductions in TTR protein in phase one, and the two ongoing phase three studies are well underway in enrolling with the polyneuropathy phase three study due to readout next year. Our second drug in phase three development for from our cardiometabolic franchise is Ionis APOC3 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. APOC3 is the master regulator of triglyceride levels in the body and 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, that are that that patient populations that suffer from high triglycerides. This includes the familial chylomicronemia syndrome patient population or FCS, which is a rare population. And and these patients suffer from metabolic diseases due to very high triglycerides well above a thousand 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 three mount three million people in The US. And then patients with triglyceride elevations on the order of one hundred fifty to five hundred milligrams per deciliter or so suffer from or are high risk for cardiovascular disease. This is a very large population of patients that suffer from or are at risk for cardiovascular disease due to high triglycerides estimated in the tens of millions. We are focusing APOC3 LICA on two 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, APOC three LICA, based on its mechanism of action and based on its chemistry or 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 APOC3 LRx, a wholly owned product, a 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 more than ninety percent 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, SHDG, in the second half of this year. And then our third drug from our cardiometabolic franchise that's in phase three development today is pelicarcen. Ionis apo, formerly known as Ionis apo little a l r x. Pelicarcen targets a risk factor called lipoprotein little a. This is a risk factor that's highly prevalent. LP levels, are genetically determined at birth. And if you have abnormally high LP levels, you are at risk for cardiovascular disease such as stroke, and heart attack, and and atherosclerosis. And in fact, the higher the level of LP, greater the risk of cardiovascular disease that you have. Not surprisingly, LP is recognized as a major independent risk factor for cardiovascular disease, and there are no ways to manage Lp levels. There are no approved pharmacological therapies that can control Lp levels in the body. The prevalence of this disease is very large. As I mentioned earlier, greater than eight million people around the globe are estimated to have Lp driven cardiovascular disease. And as I mentioned earlier, there are no treatments to manage this disease. It is 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 driven cardiovascular disease. So pelicarcen targets, like the other drugs were that were developing, the root cause of disease, Lp driven cardiovascular disease. In a phase two study, I'll remind you that in which we tested pelicarcen in patients with cardiovascular disease and high Lp levels, we were able to normalize Lp levels in those patients. Approximately ninety eight percent of the patients in that study, were able to normalize their Lp levels in the phase two study, giving us great confidence that we're certainly hitting the target that we want to hit and giving us confidence in our phase three study. The phase three study is referred to as Horizon, which is now well underway and enrolling rapidly with phase three data expected in 02/2024. So those are our five Phase III drugs in development today, being tested in six Phase III studies. Now I'd like just like to give you a glimpse into what we believe will be our next phase three 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 c one inhibitor. This insufficiency in c one inhibitor cause hyperactivation of a pathway called the precalcryne bradykinin pathway. The symptoms of this disease, as I said, are very severe, resulting in excess swelling of various organs and and systems in the body, including the arms, legs, 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 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 with PKK LRx that is responsible for HAE, the kallikrein bradykinin pathway. PKK LRx is designed to to block the production of pre kallikrein, lowering the levels of kallikrein and bradykinin, bringing them to normal levels, and resulting in prevention of of HAE. And like our other phase three drugs from our cardio cardiometabolic pipeline, PKK LRx is another LICA medicine with that that that benefits from all the all the benefits of of the LICA platform. It 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 in the 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, placebo controlled study, in patients with HAE, in which patients were treated with either placebo or PKK LRx over a seventeen week period of time. What we showed in this study was that we demonstrated a ninety percent 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 five and seventeen in this study, and that's relevant because it takes a few weeks for the drug to get on board and get to steady state concentrations. If we look at when the drug is fully on board between weeks five and seventeen, we were able to actually achieve 97% mean reduction in monthly HAE attacks versus placebo. And moreover, during this time period, ninety two percent of the patients in this phase two study had no attacks had zero attacks compared to zero percent of patients in placebo having zero 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 sub q self administered injectable. It utilizes our highly advanced LICA chemistry with the potencies and the tolerability advantages that that it offers. And and certainly, the phase two 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 three. 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 the ATLAS tofersen presymptomatic study in SOD1 ALS, and there's more coming. Our phase three study for APOC3 LRX and SHTG, severe hypertriglyceridemia, our Angelman syndrome Phase III 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 thousand and twenty six. And again, as a reminder, most of these medicines will come from two 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 two franchises such as PKK, LRX, or 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 pelicarcen for Lp 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 PKKLRx for HAE and eplentirsen 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, our building on 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 Haugen, our Chief Financial Officer, to join me as well as Oneza Katteray, Chief of Corporate Development and Commercialization, to join me as well. So stay tuned, and we'll be back in a moment. Welcome back to the question and answer session of today's Ionis shareholder meeting. Feeling or filtering the questions and taking the questions will be Wade Walker, Vice President of Investor Relations, and Wade will be feeding us the questions here to Beth, Oneza and myself, Brett Monia. And so Wade, do we have some questions? We do. And for those of you that are on the platform and you want to ask a question, please click on the Q and A button down at the bottom of the screen and type in a question. Our first question involves the PKK LICA program. And the question is, you released or only reported data from patients with type one or type two 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 one and type two data, and will it be released? And do your plans for phase three include patients with normal c one inhibitor? So we that's absolutely correct that our Phase II study included Type I, II and III. But there were really one or two Type III 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 dataset 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 present the full dataset. And I'd also remind, investors who are interested that a paper was published, with investigator initiated study of two patients. One of them had normal c one inhibitor, and the patient showed significant reduction in in attack rates. That's right. That was a type three 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? Yeah. It's a great question. You know, we're still working through a massive data set from the phase three 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 a allele selective inhibitor potentially. We certainly have a lot of experience in developing allele selective inhibitors for HD 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 APOC3 LICA programs. Question is, will you consider outlicensing ex U. S. Rights in order to shift risk and fund commercial rollout in The United States? So TTR LICA and APOC3 LICA are two 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 two assets ourselves today. And whatever we choose to do for these two drugs with respect to partnerships in the future, whether it be commercialization or what what have you to bring the maximum value to the company that we could possibly can 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 This is from a shareholder who also has shareholder clients. It says 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 financial? Question. We know we are we are disappointed, frustrated by the performance of the stock price. And and trust me when I say that the senior team at Ionis pays 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 tilmenosyn phase three outcome. That's a big setback in the eyes of many. What we're pleased about is we see no read through to the neurological platform. As I took you through, we think that it's one of the richest for most robust platforms, and we're very much looking forward to the toposyn phase three data later this year to really to really demonstrate that again from from our platform. I think that, you know, that is was a there 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 year and a half 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 and our phase three 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. The 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 two or Gen 2.5 alone. Do you have a strategy to upgrade the pipeline drugs with LICA plus 2.5 chemistry so they could be more competitive in the marketplace? Indeed. Our PCSK9 Gen two point five 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, based on real clinical data, some of which was presented at the last year. And we have more data. Phase 2b study is ongoing. It's a select dose, potentially move that drug into phase three development later this year. And it was really the gen 2.5 component to that LICA medicine that allowed it to really put put out that 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 two LICAs are outstanding drugs in their own 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 three, soon to be four drugs with with gen two LICAs are in phase three development, soon to read out in in the first, if not first, best in class potentially best in class medicines. If we were to convert those drugs over to gen two point five down the road, we would have to factor in lots of lots lots of different things. What will the ten two point five give us over over gen two? Is it worth it? Because the gen twos are performing very well. Do we need it? Like, we probably needed it for PCSK9. This was a highly competitive field to further advance, you know, our competitive edge. And and and should we do it for life cycle management to continue the franchise for for much longer periods of time? So as 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 two Gen two LICAs are performing exceptionally well. The next question is regarding potential share buyback. The question is how you considered a share buyback with cash on hand. Well, we did a share buyback, what was it, one point years ago, Beth? And we've talked about it, but why don't you take that? Sure. Happy to. 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 in the what value there is in the late stage pipeline as well as in the mid stage 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. Yeah. This was a, a real flyer, an investigator study that, was conducted, in Brazil. We were contacted by an investigator in Brazil who was, you know, experiencing the pandemic in, in very bad ways. And, the bradykinin pathway has been linked to poor outcomes in patients with COVID infections. So he asked if he can do a single site investigator study. We provided the drug to him. The data is still under is being analyzed. So we should have a data by the second half of the year. The next question is two 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 will will allow us to achieve commercially viable oral delivery for 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 we're at the bioavailability that we wanna achieve that we think is necessary to be commercially viable. And and we're also working with our partner AstraZeneca to help develop this platform going forward. 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 one 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 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. You know, 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 while we better understood the the 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 was just an effect in the in the lung in in in 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 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. We've had a couple of questions asking about how our eplontirsen differs from Alnylam's patisiran. Very different. Patisiran is a is a is an unmodified double stranded RNA molecule that is delivered intravenously every three weeks and requires premedication with steroids to to to dampen pro inflammatory effects, infusion reactions in patients that get this nanoparticle formulated siRNA. Very different. It's a subcutaneously administered LICA medicine. It's a single stranded molecule, an antisense molecule. Single stranded. It's administered very low volume, subcutaneously, auto injector. Patients self administer at home once per month. So you can see how ONPATTRO and eflandersen differ. They differ quite a bit with respect to the profile for the patient and the route of administration, the convenience, and so on. Next question is, what can you do to move even more quickly to advance the pipeline? Well, we have that conversation pretty much every day at Ionis. What can we do to get drugs into phase three? How can we speed up enrollment? How do we get phase two drugs, you know, moving faster and so forth and so on? You know, I think we're doing everything we can today to advance the pipeline to the late stage development and to the market as quickly as we can. As I mentioned, we have the financial wherewithal, the strength to be able to invest in all aspects of the business, including the pipeline. And I can tell you, I can assure you that we are investing significantly in the development organization, to expand the development organization, to expand the wholly owned pipeline, to move these drugs forward as rapidly as possible. And and and and also, would say that being a very nimble, relatively small organization like Ionis gives us the ability to move drugs faster into through development and onto the market. It's just the nature of a small company like Ionis. And and that is another aspect of hanging on to some of the drugs, many of the drugs from our wholly owned pipeline ourselves and bringing them through phase three that represents significant advantages, efficiency and speed. And and that's another factor. We'll certainly never let a drug sit because we don't have the resources for a drug. Every drug should move. And that's why we partner. We partner when we if we decide that we don't want to necessarily prioritize a drug for our own pipeline to bring it to the market. Next question is regarding muscle targeting LICAs. Where do things stand with respect to such technology, and how far is muscle targeting LICA drug from the clinic? And will your first muscle targeting like a drug treat myotonic dystrophy? This is a highly competitive space, as I'm sure the person that asked the question knows for it's a very good question. There are various approaches to develop RNAi molecules, antisense molecules for muscle delivery. We're in there too. We're working hard in various work streams, research work streams. And I believe that we're getting close to identify a lead molecule, a lead ligand for targeted delivery to muscle, which will enter we're hoping will enter development by the end of this year. And when I say this, I was referring to just now includes both work that we're doing ourselves for the wholly owned Ionis pipeline with targeted delivery to muscle as well as with our partner Biogen, who also obviously has tremendous capabilities protein therapeutics that we can leverage and we are leveraging as well. As far as myotonic dystrophy or Duchenne's muscular dystrophy or other forms of muscle diseases, this is, again, a highly competitive space. We're gonna keep that one ourselves for now. This one relates to the TTR LICA program. How much will it cost to build an organization to sell TTR LICA given that you will be competing with Pfizer, Alnylam and others? And how many sales reps do you anticipate having in the field? That's a good question for you, Anaza. Good. I'll take that one. I ask you that every day. Yeah. So iflantersen for polyneuropathy and for cardiomyopathy will obviously be very different indications, will require different ones. We'll take the larger one, which is cardiomyopathy well over a $10,000,000,000 market. And as you know, you know, you you already have Pfizer on there. So I think your biggest gauge for what's required is just, you know, taking a look at the number of salespeople that they have. And, you know, it's still a rare disease. It's not tremendously that large. This is not going after, you know, the lipid category or anything like that. We're not looking at trying to reach GPs is pretty much still treated by cardiologists. So, you know, you're not talking about, like, a tremendous size of force and and still relatively very targeted as well. I hate to put out numbers on there, so I I think you can kinda guess it's kinda specialty field force type of sizing. That's the way I think about it, if that gives you a gauge. And then but certainly not PCP or GP type type of sizing as well. But exciting indications in both PN and cardiomyopathy, and then, obviously, we also have kind of the mixed disease phenotype in there that allows you to go to both neurologists and and cardiologists over time. So we're looking forward to getting out there and serving patients in a very, very attractive market. Next question is a financial one. At what point would you consider initiating a dividend? I think when you look across the biotech field and you look at even the big biotech companies, they rarely will issue dividends. Again, as we think about capital allocation, thinking about share buybacks, dividends, those types of investment opportunities, if you will, it's just really not where we see the growth for the company. So being able to invest, as I had said earlier, internally in the pipeline, in the technology, in the commercial capabilities that are critical for the success of these drugs, that's where the real growth opportunity is. And so I would say a dividend is not something I see in our near term future and probably not in the longer term future either at this point. Thanks, Beth. Next question is on the GHR LICA program. Can you give more color on your acromegaly asset that we'll read out in the second half of this year? What type of data do you need to see to move this asset to Phase III? So the the data to expect in the second half of this year from our acromegaly pravel let me back up. The the the patients that we're studying in this in this phase two proof of mechanism study, really, is our patients with acromegaly who have uncontrolled disease despite being on somatostatin analogs. And our objective in this study is to control their IGF-one levels, a biomarker, an approvable biomarker for the management of acromegaly. That's what we're focused on, as well as some other measures of quality of life. We're also focused on proof of mechanism, as I mentioned, looking at growth hormone binding protein levels, which demonstrates that we're hitting the target, not very nicely, if if we can demonstrate that. And the data to look look for in the second half of the year is the phase two data along with quite a bit of open label extension data where patients have continued to be treated with our acromegaly drug GHR LRx well after the phase two study completed. So safety, tolerability, proof of mechanism, and and we're also hoping for good indication of effects on the biomarker IGF-one. We're running low on time, so I'm going to ask one more question. Topics. Can you say something about your expectations for the growth of TEGSEDI and WAYLIVRA in the second half of the year? Sure. Beth, would you like to jump on? Sure, absolutely. So I think what's important to remember with TEGSEDI and WAYLIVRA is that we have entered into distribution agreements with Sovi in the Europe for Europe for TEGSEDI and WAYLIVRA and recently with TEGSEDI in North America. So we're looking forward to Sobe really taking over and marketing these drugs, putting forward their field force and their expertise and their reach for both of those drugs. We will from a revenue perspective, we'll be getting a distribution fee rather than product revenues. And so you could expect to see revenues probably decline as a result of that. But that doesn't necessarily mean that product sales are declining. It just means that our portion of those sales is a portion, not 100%. So we still see the TEGSEDI and WAYLIVRA having a future and possibly getting into new markets. But I would say be mindful of the fact that from a revenue perspective, we get distribution fees, not the full product sales. Thanks, Beth. And for those that have questions that we didn't get to or have questions that we've run out of time to answer, please contact the Investor Relations group, and we'd be happy to answer those questions. Thank you, everybody, for all the great questions. Thanks for joining us on today's shareholder meeting, and have a great evening. Thank you.