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

Good afternoon. Welcome to the Ionis Pharmaceuticals 2020 Annual Meeting of Stockholders. My name is Brett Monia, I'm the Chief Executive Officer of Ionis Pharmaceuticals. And I'm really pleased to have all of you participating in today's meeting. I also want to reach out and express my gratitude and thanks to all of our long-standing shareholders of Ionis and our supporters and friends of Ionis Pharmaceuticals over the years. We really appreciate your dedication and especially, your commitment to our company and our cause. Today's meeting is a little unusual for our stockholder meeting in that is being conducted virtually. Normally, our meetings are held in person at our headquarters in Carlsbad, California, and it's -- and the in person meeting is something we really enjoy. We really enjoy meeting our shareholders and our friends. But nevertheless, this is where we are today due to the current situation that we're in. And I believe that you'll still find this meeting very, very informative, hopefully enjoyable as well. And I also believe that you'll find the progress we're making at Ionis this year and how we're set up to make great, great progress for many years to come, also quite impressive. So at this point, I'm now going to shift over to the slides of the slide presentation. And while we're doing that, we did it already, I want to remind you that we will be taking questions. And you can submit your questions through your question portal on your computer, and we will be doing those at the end of the presentation. And in addition, Beth Hougen, the Ionis Chief Financial Officer, will be joining me during the Q&A session in case there are some questions that are better suited for her to answer. These are my forward-looking statements, I recommend them to you to review at your convenience. Ionis Pharmaceuticals has always been, is today and will always be committed to the science -- and to science and to medicine all through -- in the purpose of serving the patients that are at the center of everything we do. Ionis was founded by Stan Crooke. Stan had a vision to create a new platform for drug discovery called antisense and establish where in a world in that vision he had, we couldn't -- we wouldn't have been able to -- we could create a new platform for drug discovery that can provide medicines, provide drugs to patients where other drug modalities failed or were unable to achieve success in various ways. That vision today is a reality. Today, antisense is proven. It's a validated technology that's providing medicines, very important medicines, transformative medicines to patients in great need around the world. In addition, through the leadership of Stan and Ionis in creating the antisense platform, we also created a new sector in the biotech industry called RNA-targeted therapeutics. And through our leadership came many followers who joined in into this sector and with related technologies, they too, are bringing medicines forward, and we applaud that because the patients are the ones ultimately that benefit from this. So now the starting point, of course, for me as the CEO is where Stan left off. And I start with my view and as the new CEO of Ionis and this is where I begin, with Ionis, with identifying a vision for Ionis that will bring Ionis to even greater successes in the future, greater heights, if you will. And that vision is -- involves the delivery of a vast increase, a vast number of new medicines for patients that are desperate for hope, desperate for new treatments for untreatable diseases today -- in short to be the leader of innovation in biotech by providing hope and transformational benefit now for millions of people, millions of people around the world suffering with severe diseases. And I believe we can do that. I'm confident we will do that. And we'll do that by focusing on innovation, in scientific excellence as we have in the past. We will expand and invest in our technology and by -- to expand scope of our technology, identify drugs, bring drugs forward that we can't even deliver today. But in the future, I see us delivering medicines to patients that are in great need for additional disease indications. And we'll also do that by increasing and diversifying investments in new technologies, technologies that complement our antisense platform and brand-new platform technologies that do things that maybe antisense cannot deliver today. We will continue to support our partner programs, who are bringing our medicine, our precious medicines through late-stage development and to commercialization. But in addition now, in parallel now, we will prioritize the growth of the Ionis-owned pipeline and optimize our commercialization strategies in order to maximize the value to Ionis, to its shareholders and of course, to patients of each one of our precious medicines to the maximum extent possible. And we can do all this. We have a very strong financial position that allows us to do that. And we will use that leverage, our financial real strength to be able to accomplish all of these goals for the future. And as I mentioned earlier, our key goal in this vision is to substantially and consistently, vastly increase the delivery of our transformational medicines to patients in great need in the short-term and for many years to come. This is what a snapshot of the next projected set of potential commercial opportunities looks like from the Ionis pipeline. We're anticipating 10 or more new drug applications for both broad and rare diseases through 2025, starting as early as next year with our first of several drugs for ALS, amyotrophic lateral sclerosis, our SOD1 drug, where we're looking to potentially file next year. And then what you can see is a gradual steady increase in the number of medicines we project to potentially reach the market for severe diseases -- for all of them are severe diseases -- for rare diseases, such as Huntington's disease and ALS and prion, and also for your broad disease indication, such as cardiovascular disease, metabolic diseases and maybe infectious diseases like HPV. Ionis is stronger than ever, and we're off to a great start in 2020. We're executing on all of our strategic goals. Our commercial products are performing well. Our Phase III pipeline is impressive. It's large and it's on track to achieve many potential approvals in the near future, both in the short and in the long term. Our mid-stage pipeline is setting us up for additional Phase III studies next year -- this year, next year and for years to come. And our technology and our pipeline is advancing at record pace. I'm very proud of the team we have at Ionis. It's a dedicated and resilient workforce. And it's this resilience and dedication to the Ionis mission and dedication to the patients we serve that has allowed us to effectively manage through the challenges of COVID-19. And in fact, despite the challenges imposed on us and everyone, we are well positioned despite that to achieve our goals in 2020 and our future goals beyond 2020, despite this pandemic. And one of those goals, of course, is that we -- is the filings for new drug applications, 10 or more through 2025, which we are on track for. One of our objectives this year was to have 6 or more clinical proof-of-concept readouts from our mid stage pipeline. We're right on track. We already have 2. We reported earlier this year positive Phase II data for APOCIII LICA, our APOCIII LICA medicine for hypertriglyceridemia and vupanorsen, our previously referred to as angiopoietin-like 3 LRx or LICA medicine for cardiometabolic diseases. And we're planning additional clinical readouts, proof-of-concept readouts later this year for both rare diseases as well as for large disease indications, such as hypertension. Furthermore, we're planning to readout clinical data for novel routes of delivery for [ lung disease ]. One is for the delivery of our ENaC drug in patients with cystic fibrosis, delivered by a pulmonary route, by aerosolization directly to the lung. And with our partner, AstraZeneca, in a cardiovascular disease space, we're planning to readout data from our clinical study to evaluate oral delivery for one of our antisense medicines in the area of cardiovascular diseases. We are in a very strong financial position at Ionis. We're very proud of that. It allows us to accomplish all of our strategic goals, and we're already off to a great to start in 2020. In the first quarter, we reported revenue of $133 million, with more than half of that coming from our commercial products, and we are within having a -- we also have a very strong cash position. Despite the COVID-19 pandemic, we reaffirmed our 2020 financial guidance on revenue, operating expenses and on profitability. So now let's turn our attention to our commercial products, starting with SPINRAZA. SPINRAZA is a foundational medicine for all forms of spinal muscular atrophy. It's a blockbuster medicine, and it deserves to be a blockbuster medicine, considering how much benefit it provides patients for all forms of SMA. Our first quarter results were very strong up for this year for sales. SPINRAZA demonstrating continued growth, and we expect continued growth for SPINRAZA this year and for years to come. More than almost 11,000 patients are now on SPINRAZA therapy around the world and that's going to grow. Furthermore, our partner Biogen had recently, this year, reported the start of a new Phase II/III study referred to as DEVOTE in all forms -- in patients with all forms of SMA. The objective of this study is to demonstrate even greater efficacy for SPINRAZA by increase in adults, by testing higher doses of SPINRAZA over the current commercially used dose of SPINRAZA. And of course, we can do that because of the exquisite pristine safety profile that SPINRAZA has demonstrated in real-world studies. TEGSEDI, our medicine, a transformative medicine for the treatment of patients with hereditary TTR amyloidosis and polyneuropathy. With our partner, Akcea, we demonstrated consistent quarter-over-quarter growth, with strong growth in the United States. Furthermore, we are launching more new countries in Europe all the time. Currently, we have commercially available TEGSEDI in 13 countries and had recently announced or recently have achieved reimbursement approval for additional countries, just as recently as Portugal. And that's very important because Portugal is an endemic population for TTR amyloidosis. Furthermore, our partners at PTC are continuing the launch of TEGSEDI in Brazil, another endemic population for TTR amyloidosis and expanding on their reach in Latin America. WAYLIVRA, the only medicine approved as a treatment for familial chylomicronemia syndrome, or FCS, is launching through our partner Akcea in Europe. And our partner PKC is planning to file for potential approval in Latin America in the second half of this year. Very important, based on very productive and encouraging meetings we've had with the FDA already this year, we're on track to refile WAYLIVRA for FCS in the United States this year. And our confidence is building that this drug will be approved and made available for FCS patients in the U.S. in the future. So now let's turn our attention to the pipeline. And this is where I'll spend most of my presentation this afternoon. We have a very large clinical pipeline. This is what it looks like. It's very large. As I said, it's broad across many disease indications, and it's very mature, multiple programs in Phase III development and a real rich pipeline of Phase II programs that set us up for many new pivotal studies in the near future. Of course, we have early development in Phase I, and we're expecting and projecting to add many new medicines to the pipeline this year, as we've done in the past and we'll do in the future. It's a tough pipeline to digest. It's large. But this is what I think I am personally most proud of, and I know people at Ionis are proud too, when thinking about our pipeline. Today, we are delivering medicines and are poised to deliver medicines for essentially all major severe diseases today that afflict humans. This includes diseases for neurological diseases, neuromuscular, cardiovascular, metabolic diseases, lung diseases, cancer, genetic causes of blindness, nongenetic causes of blindness through disease and even infectious diseases. Furthermore, we're delivering medicines and our employees to deliver medicines for ultra-rare diseases that affect hundreds of patients around the world, rare diseases that affect thousands of patients around the world. And your very large indications, your very -- your common diseases that affecting -- that are affecting millions and millions of patients around the world. We're very proud of the scope of our drug pipeline. Our 2 most advanced franchises, our neurological-disease franchise and our cardiometabolic disease franchise, in each of these franchises today, we have 10 or more potential breakthrough medicines in the pipeline or on the market. I'm going to focus on these 2 franchises during the course of my presentation to really drift -- dig down in some of the programs in these franchises as we go forward. In addition, I'll focus on a third aspect of our pipeline, the Ionis-owned pipeline, the pipeline of medicines that we are prioritizing, bringing forward into -- further into development and many of these we will bring to the finish line, as well through the finish line. Here, we have 10 medicines currently in clinical development, and this will grow. And I will focus also part of the presentation on the Ionis-owned pipeline as well. So let's start with neurological. Our neurological disease pipeline. Let's look at some of the progress we've made already this year. Big breakthrough. We've completed with our partner Roche, enrollment in the Phase III generation HD-1 for Huntington's disease, with data expected in 2022. This pivotal study is so meaningful to Huntington's patients. And of course, to Ionis and everybody that supports Ionis, and it's now in progress, ready to readout. As I mentioned, Biogen initiated a new study Phase II/III study to evaluate higher doses of SPINRAZA to make -- to achieve even greater efficacy for SPINRAZA to examine higher doses in SMA. Our Phase III study, VALOR, examined tofersen in patients with a genetic form of ALS, SOD1-ALS, is on track with data expected in 2021, and this year was granted orphan drug designation by FDA. Another medicine for ALS, another form of -- a genetic form of ALS, previously known mutations with a gene called C9, is on track. We received fast track designation in the United States, is in Phase II and is on track for readout next year. So next year will be a big year for ALS for patients and, of course, for Ionis with 2 readouts in ALS. In addition, ION541, our first of several medicines we expect to bring to the clinic for the larger ALS population, the sporadic population is expected to start clinical testing very soon. Our medicine that targets tau, MAPTRx, is progressing on track in patients with Alzheimer's disease and with our partner in Dynacure, we advanced a new medicine into clinical testing for centronuclear myopathies. So now when we dig down a little bit deeper into 2 of these programs, our Huntington's disease program and our SOD1-ALS program. Starting with tominersen, our medicine for Huntington's disease. I think most people are aware what a terrible disease Huntington's disease is. It's a devastating and fatal genetic neurological disease. It's characterized by progressive physical cognitive degeneration. It's been described as having all the worst aspect, symptoms of some of the worst neurodegenerative diseases including ALS, Parkinson's, Alzheimer's, simultaneous, all combined. And worst of all, it's a genetic disease. So it's handed down from parents to children. And oftentimes, children see their parents or siblings or family member or other family numbers succumb to this disease in a devastating way. And they live in fear that they, too, may have the Huntington gene and have a similar fate. This disease typically still begins with symptoms in the third decade of life and then disease progresses from there, resulting in -- eventually in death. And of course, there are no treatments or cures for this disease. So that's a description of how devastating Huntington's disease is for patients and families. However, I thought it would be insightful to hear directly from a patient who is in fear of Huntington's disease. He lives it every day. His name is Charles Sabine, and I hope you enjoy this video. [Presentation]

That hope, of course, that Charles refers to is tominersen, a potential breakthrough medicine for Huntington's disease, potentially the first and only disease-modifying medicine that targets the cause of Huntington's disease. We have demonstrated robust sustained reductions in mutant Huntington protein in patients with a favorable safety and tolerability profile vulnerability, and not surprisingly, regulators have prioritized this program for review. As mentioned, the study, tominersen, is now in Phase III development. This program is now phased development in a randomized, controlled study, placebo-controlled study. And as I also mentioned earlier, this study is now fully enrolled with approximately 800 patients with Huntington's disease. In addition to the placebo-controlled group, there are 2 other treatment arms, tominersen being administered every 8 weeks and tominersen being single-served every 16 weeks. And after 25 months of dosing, all patients will get access to tominersen in an open-label extension study. The results of this study are expected in 2022. Now I'd like to move on to amyotrophic lateral sclerosis, or Lou Gehrig's disease, another rapidly progressing fatal neurodegenerative disease. ALS in its core has met -- multiple causes. Genetic forms, genetic causes of ALS are called familial, and non-genetic causes of ALS, called sporadic. And regardless of the cause of ALS, the result was the same. It's a devastating and rapidly progressing disease that eventually results in paralysis and death within a few years despite having normal cognitive capabilities. The 2 primary genetic causes of ALS are due to mutations in SOD1 and another gene called C9ORF. Death typically happens within 3 to 5 years from symptom onset. So very fast. However, there are other patients, due to the nature of their mutation or other factors, even in sporadic ALS that are referred to as rapid progressors. These patients often resolve after symptom onset, and death within 9 to 12 months after symptom onset. It's very important. Remember that, for the rest of my presentation, it will come up again. These rapid progressors. We are committed to treating all forms of ALS. The Phase III study for SOD1 is on track and with data expected in 2021, and as I mentioned, our Phase II program, C9ORF-ALS, also is expected to readout next year, so it's a big year again for ALS next year. And our next -- our first medicine, several that are coming in ALS, starting with ATXN2 is going to start clinical testing very soon. So now let's look at tofersen, our Phase III program, our first program and our most advanced program for ALS to this day. We have shown that treatment with tofersen in a Phase I/II study demonstrated reductions in SOD1 protein, the cause of this disease in the central -- in the CSF. Moreover, we demonstrated in this Phase II study benefit to patients after only 3 months of treatment, benefits on various forms of function and including lung function, respiratory. It was well tolerated. And based on these results, our partners have advanced this medicine into the VALOR Phase III pivotal study very quickly. This slide shows the results, the efficacy results from that Phase I/II study, which we evaluated tofersen in patients with SOD1-ALS. And remember, this treatment period was only 3 months. So it's a very relatively short period of time of treatment. I want to draw your attention to the color key. Shown in blue are patients treated with placebo during this period. And shown in orange are patients treated with tofersen. And what you can see, a downward trajectory means that disease is progressing and getting worse and worse and worse. Here, you can see is that patients on placebo during -- over 3 months, continued to progress, the disease got worse on the functional rating scale as well as on lung function. However, patients treated with tofersen had disease stabilization. Their disease got no worse compared to when they started the trial. So when we look at it, the evidence was very strong that we stabilized the disease. I also want to draw your attention to the dotted lines. The dotted lines represent a subgroup of patients that I referred to earlier as fast disease progressors. These are patients, again, that due to the nature of their SOD1 mutation or for other reasons, their disease progresses extremely rapidly. And you can see that in the placebo group -- patients that received placebo. However, the rapid progressors treated with tofersen had the disease stabilization that was the same as the patients that were not fast progressing. It's very exciting results and very encouraging for our Phase III VALOR study. This is the design of the VALOR Phase III study. It will enroll 99 patients with SOD1-ALS and with the primary endpoint efficacy and white being ALS functional rating scale that I just showed you that we used in the Phase I/II study. The treatment period is for about 6 months or so, after which all patients will move into an open-label extension, [ this drug or placebo ], orphan drug designation. Enrollment is due to complete soon. And again, data readout next year. I'd like to introduce you now to someone named Chris Snow. Chris Snow is -- has SOD1-ALS. But despite having SOD1-ALS, he is thriving 1 year after being on tofersen. Chris, when he was diagnosed and he was diagnosed 1 year ago, in June of 2019, he was diagnosed as a fast progressor, with SOD1 ALS. And he knew what this meant, he knew the fate. Because before his diagnosis, he witnessed the devastation of this disease on his father, his uncles, his cousin. Within 1 year of diagnosis, they succumbed to their disease. Luckily, shortly after diagnosis, Chris entered the Phase III VALOR study. He completed the study in January and now continues the open label extension taking tofersen, and very importantly, he's doing well. He is feeling stronger, he is performing physical activities, playing with his children, making sure he's winning the fight on ALS. And now I'd like to provide some compelling evidence that Chris is indeed winning his fight against ALS with tofersen: A video that his wife, Kelsey, provided a few months after Chris completed the VALOR Phase III study, 9 months after symptom onset and diagnosis, about the same time his family members succumbed to this disease. [Presentation]

Very encouraging of course, for the SOD1 program, but it's also very encouraging for our ALS franchise. For the first time, we believe we are modifying the course of ALS in the way that nobody has ever been able to do in the past. The tofersen SOD1 underway, C9 Phase II for C9-ALS underway, both with data expected next year. And then as I mentioned, we're moving now into sporadic ALS, with ION541, targeting ATXN2. So now I'd like to take a short detour and remind you about our LICA chemical platform, our LICA medicines. LICA stand for Ligand-Conjugated Antisense and it's a technology we developed here at Ionis and have now validated with [indiscernible] molecules. As a reminder, LICA technology precisely delivers our medicines to the intended target organs and cell types thereby, vastly reducing exposure of drug to other organs and cell types that we don't want the drug -- where we don't want the drug to go. Our liver LICA platform is the most advanced and it is enabling tremendous benefit to patients and providing great value to those patients as well, by precisely delivering this medicine to the hepatocyte in liver. We are increasing reproducibly, with potency of our molecules 20 to 30-fold. Also providing great convenience for patients as at-home subcu administered dose, low dose, 1x a month or less frequent, all with excellent safety and tolerability across 16 liver LICA medicines in development today. And based on the learnings we've made from liver LICA, we have established and have expanded our investment in LICA medicines to develop new LICA medicines to tackle other organs and other cell types in the same way -- cell types like [indiscernible] skeletal muscle and immune cells and others, and we're making tremendous progress and we're looking forward to sharing the results of that progress later this year and next year and for years to come. This is what our liver LICA pipeline looks like, 16 medicines in clinical testing, a very robust and mature pipeline with multiple assets in Phase III development, mid-stage pipeline as well. And so far, across many therapeutic carriers, including broad diseases and rare diseases. So now I want to shift over to our cardiometabolic pipeline, and the reason why I did that detour for LICA is because almost all of our cardiometabolic programs and many other programs as well, are utilizing our LICA medicines today to drive even greater value for patients and to take advantage of the profile that LICA medicines offer. Progress this year in 2020 are currently in our cardiometabolic pipeline [indiscernible] AKCEA-APO(a)-LRx granted fast track designation and the Phase III study is progressing on track. We reported positive top line Phase II results for vupanorsen, our LICA medicine who targets angiopoietin-like 3. In addition, we initiated a Phase I study of ION532 for a genetic form of kidney disease, targeting APOL1. And in addition, using a LICA medicine in our cardiometabolic program, we're on track to potentially validate commercially viable oral delivery and talk about that later this year. So now let me dig down a little deeper into 2 of these programs, the APO(a)-LRx program for cardiovascular disease and also vupanorsen, our angiopoietin-like 3 LICA medicine for metabolic diseases. Starting with our APO(a)-LRx. Lipoprotein(a) is a major risk factor for cardiovascular disease. If you have elevated levels of Lp(a), you're at high risk for cardiovascular diseases. Very importantly, there are no approved, no effective pharmacological therapies to lower Lp(a) levels of cardiovascular disease due to high Lp(a) levels. And that include statins, that includes diet and exercise and so forth. Very importantly, also, this is not a rare disease -- 8 million or more patients who are believed to have Lp(a)-driven cardiovascular disease and again with no treatment options available. What we've shown with our LICA medicine is selective and robust reductions of Lp(a) in patients with cardiovascular disease. And we did that in a Phase II study, which was the largest and longest study conducted in this disease-patient population. What we showed was robust durable dose-dependent reductions in this risk factor of Lp(a) in patients treated for extensive periods of time, between 6 to 12 months of treatment. Moreover, 98% of the patients, these are patients with cardiovascular disease. So they've had a heart attack, a stroke, due to high Lp(a) levels. 98% of these patients, while we were able to drive their Lp(a) levels down below the threshold as recognized to be associated with cardiovascular diseases, along with favorable safety, tolerability, excellent [indiscernible] and excellent patient convenience. Based on this exciting data, our partners at Novartis launched into the Phase III HORIZON study. This is a cardiovascular outcome trial involving approximately 7,500 patients with Lp(a)-driven cardiovascular diseases or with disease and the endpoints are cardiovascular events, including mortality, hospitalization and events in that study. The treatment period is expected to be about 4 years, collecting these types of events. Enrollment is underway. Program fast track -- that received fast track designation with data expected in the 2024 timeframe. So now flip over -- let's shift over to another LICA medicine, vupanorsen, that targets angiopoietin-like 3 LICA. So targets angiopoietin-like 3. Angiopoietin-like 3 is another genetically linked target for cardiovascular and metabolic diseases. It's a regulator of various forms of lipids, triglycerides, cholesterol and also controls metabolism in various ways. Elevated levels of angiopoietin-like 3 are associated with risk of cardiometabolic diseases, including heart attacks, cardio -- and other forms of -- aspects of cardiovascular disease and also metabolic disease such as insulin resistance. Angiopoietin-like 3, of course, is designed to knock down, drive down the levels of angiopoietin-like 3 and it does so. And we've shown that in a positive top line Phase II data that we reported earlier this year. This is the design of that Phase II study in patients with metabolic diseases treated with vupanorsen. This study enrolled 105 patients. We examined various dosing regimens in this study. And the primary objective was a reduction in fasting triglycerides. In the study patients were treated for approximate level or for about approximately 6 months or so and then patients were allowed to move into a follow-up period, with -- and receive continued treatment. And as I mentioned, we reported positive top line data earlier this year, and this is what the positive [ blind ] data looks like. We showed statistically significant reductions in fasting triglycerides, dose-dependent reductions and other factors that are important, angiopoietin-like 3, APOCIII, LDL-cholesterol and other forms of cholesterol, all compared to placebo with a favorable safety, tolerability profile, and we plan to report the full data set at a medical meeting later this year. Our partner on this program, Pfizer, is preparing to launch this program into Phase III development for cardiovascular diseases. But first, they will optimize the dose for that Phase III study by conducting and initiating the Phase IIb study, a dose-ranging study in patients with cardiovascular disease later this year. So now I'd like to move into the Ionis-owned pipeline. You can see how it has performed in 2020 already. Two Phase III studies are now underway, examining the benefit of TTR, of our follow-on to AKCEA-TTR -- our TTR LICA medicine, the CARDIO-TTRansform Phase III study, now was initiated this year and our NEURO-TTRansform study, which was initiated last year, are both progressing nicely. In addition, we reported positive top line Phase II results for our APOCIII LICA medicine. We initiated 2 Phase II studies with our -- with additional LICA medicines already this year under hereditary angioedema, our PKK LICA medicine and one for beta-thalassemia, our TMPRRS6 medicine. In addition, we initiated a Phase II study for [ ENaC ] molecule in patients with cystic fibrosis, and we initiated an additional [ MASH ] program as well. Further, we've advanced our medicines from the Ionis-owned pipeline for the treatment of neurological diseases, which will be reaching the clinic soon, diseases such as Alexander's disease, prion and [indiscernible] diseases. So now let's get into 2 of these programs: The TTR LICA program, the Phase III programs for TTR amyloidosis, and our APOCIII LICA medicine in patients with established cardiovascular diseases, starting with TTR LICA for TTR amyloidosis. Another devastating disease and fatal disease, TTR amyloidosis. This is a disease that's projected to affect hundreds of thousands of people around the world. It's characterized by deposits of the protein TTR, transthyretin, extracellularly in a range of organ systems resulting in multi-organ failure. Patients commonly with this disease suffer from, and succumb to, neuropathy, peripheral neuropathy, cardiac disease, cardiomyopathy, kidney disease and so on. This disease can be caused by the transthyretin protein, whether it's mutated, a genetic form of disease called hereditary TTR amyloidosis or from a nongenetic form called wild-type TTR amyloidosis, the latter which principally affects the heart tissue, cardiomyopathy. Regardless of hereditary or nonhereditary, the result is the same: premature death and a disruption of quality of the life after a few years. And if you happen to have the wild-type form of this disease, following symptom onset, that typically ensues much faster than 2 to 5 years. TTR LICA is our follow-on to TEGSEDI, taking advantage of all the benefits of our LICA medicines today, improving dose convenience for patients as a 1x a month at low dose substrate with administered drugs, excellent tolerability and very high potency as all of our LICAs have demonstrated. We have shown for our TTR LICA medicine, robust reductions in TTR in normal volunteers, reductions that exceeded 90% in these individuals, all with a favorable safety and tolerability profile. And as I mentioned, the Phase III study is enrolling. This slide shows a comparison in 2 independent Phase I studies, the first examining TEGSEDI on the right and the other, our TTR LICA medicine on the left. Looking at the reductions in TTR in these individuals in this Phase I study, what you can see is that both drugs did very well in reducing the cause of this disease, TTR transthyretin. What we can also see is that our LICA medicine is far more potent, demonstrating an improved potency profile of 30-fold, approximately, compared to TEGSEDI, which allows us to [ give ] very low doses and gives us the convenience of monthly administration. What you can also see is that the magnitude of reduction of TTR with our LICA medicine is greater, and we predict that this will result in even greater efficacy compared to TEGSEDI in our Phase III studies. This is what the Phase III study design looks like for our polyneuropathy mutation. The study is called NEURO-TTRansform. This study is in the same patient population that TEGSEDI was tested in Phase III, the hereditary TTR polyneuropathy patient population. It's projected to enroll 140 patients and almost all of the patients will receive TTR LICA -- the TTR LICA medicine. So this is an open-label study. In addition, a very small handful will take TEGSEDI or inotersen, but the vast majority will take TTR LICA. And what's very exciting, what's so very novel about this study design is that it does not have a placebo group. We'll be comparing the efficacy of our TTR LICA medicine to the placebo group from the TEGSEDI -- the Phase III NEURO-TTR study that we did a few years ago. As mentioned, the study is on track, the primary endpoints are the same as in TEGSEDI Phase III study, and it's moving forward nicely. The other Phase III study that has now initiated and is enrolling targets the larger patient population, the cardiomyopathy patient population with our TTR LICA medicine. This is a global study as well, a much larger study, involving 750 patients with wild-type or with hereditary TTR cardiomyopathy, receiving monthly doses of this drug. And it is a cardiovascular outcome trial. So we'll be examining cardiovascular death and related cardiovascular events, including hospitalizations and so forth. This study, as I said, is enrolling, and we'll be prepared for a placebo group and is on track. In fact, both the Phase III studies are now on track, the CARDIO-TTRansform study, and the Phase III NEURO-TTRansform study, with data expected in 2023. And then finally, if I could touch on our APOCIII LICA medicine from our Ionis-owned pipeline. As we mentioned earlier, we reported positive top line Phase II results from this medicine earlier this year. APOCIII is another genetically-linked cardiovascular risk factor, it plays an integral role in triglyceride metabolism. And if you have elevated levels of APOCIII, there's a strong correlation with high triglycerides. Furthermore, we know that severely elevated triglycerides in people such as those with FCS, are at very high-risk of acute pancreatitis, in addition to all the metabolic complications that high triglycerides can produce. APOCIII LICA is the follow-on medicine to WAYLIVRA, just like TTR LICA is the follow-on LICA medicine for TEGSEDI. In the Phase II study that we completed and then presented top line data on earlier this year, we enrolled patients with hypertriglyceridemia, with established cardiovascular disease. 114 patients were enrolled in the study and treatment was for approximately 6 months, with the primary objectives in addition to safety and tolerability, being reductions in serum triglyceride levels. We reported very positive top line data readout this year, statistically significant reductions in fasting triglycerides compared to placebo, with more than 90% achieving triglyceride reductions compared to placebo -- below the threshold that's been linked to, associated with cardiovascular risks, with a monthly injection. We also observed significant reduction in additional risk factor, including APOCIII itself, the LDL cholesterol, remnant cholesterol and others, and an increase in good cholesterol, HDL-C, all in the favorable safety and tolerability profile works. We're planning, just like we are for vupanorsen, to report full data for this program later this year in a medical meeting and to initiate a Phase III study in patients with FCS, with APOC LICA later this year, and we're planning to pursue additional disease indications as well, so stay tuned for that. So now to wrap up, I'd like to just spend a moment or 2 on technology. At Ionis, we continue to invest a great deal in our technology, to further the scope and to expand the reach of our technologies, to open up new opportunities for drug discovery and to bring more new medicines to the patients that we serve. And we will always continue to do that in the future. And this slide shows some of the investments we're making in technology today and what we already see the impact being on these investments. First, improved drug candidate selection processes are well-established now, which are resulting in even greater drug discovery efficiency and improved overall drug profile and performance. We're investing -- we continue to invest, and we have investment. We will continue to invest in the future on genomics, human genomics for a novel target identification to continue to replenish our pipeline of genetically validated or linked novel targets to continue to fill our pipeline for years and years to come. And of course, genetically, when targets bring great value, because they increase the probability of clinical success, because it helps you define your patient population, help validate the target in a real-world setting. We're continuing to advance new routes of delivery as well. Even more patient convenience with oral delivery, which we'll report, try to talk about more later this year, and we're opening up more organ systems and cell types by other routes of local delivery as well, such as pulmonary delivery like for our ENaC program, and intravitreal delivery for eye diseases. Finally, we continue to invest in the medicinal chemistry of our program such as LICA to again, expand scope of our medicines to improve patient convenience, but opening up, really open up new organs, new cell types, such as heart and muscle and immune cells, we further expand the scope of our technology. So we're off to a great start in 2020, and it's just the beginning. Here are some events that will be coming up in the second half of this year that you can look forward to. First, the initiation of the Phase III study for our APOCIII LICA medicine in FCS. In addition, the refiling of WAYLIVRA for potential approval in the United States for FCS. We plan to report the full data sets, our Phase II data sets for vupanorsen and for our APOCIII LICA medicines later this year and to report clinical proof-of-concept results for 4 or more programs from our mid-stage pipeline this year as well. And we continue to populate and put new medicines into the development pipeline. This, of course, sets us up very well, very nicely to achieve our goal to vastly increase the number of medicines reaching the market, reaching patients over the next few years, with a continual increase in potential drug approvals year over year over year starting next year. So Ionis continues to lead the way in RNA-targeted therapeutics. It is a sector, now a validated and very important sector of the pharmaceutical industry that we pioneered, we envisioned, we created and we validated, and our leadership position is growing. We are in a very strong financial position, and we are leveraging that financial position to invest in all aspects of our technology and our pipeline. And that is resulting in the rapid advancement of our pipeline and our technology. And it allows -- that financial strength also allows us to commit to and expand the Ionis-owned pipeline and strengthen and optimize our commercial capabilities. All of this is resulting in a momentum that's accelerating at -- at warp speeds supporting even greater success for Ionis and all the people that support Ionis in -- well into the future. Thank you now, and we'll open it up for questions.

Our first question is about the LICA drugs. Have you had a LICA drug in preclinical that's failed to advance to Phase I? And correlated to that is have you had a LICA drug in the Phase I that's failed to advance to Phase II?

So the great feature, the great aspect of our LICA platform is how reproducible it has been from a safety, tolerability and efficacy standpoint. And the short answer to that is none of our medicines that, in terms of the toxicology studies, are LICA medicines that fail to go to Phase I, nor have any of our LICA medicines from Phase I failed for Phase II, which we have a 100% track record here.

Okay. The next question is about Moderna and whether or not they may be violating or overlapping with any of our intellectual property, our meds.

So Moderna has a very different approach. They're not targeting our main therapeutics. They're a vaccine company and they're doing other aspects for RNA delivery. Very different technology, nothing I'm aware of that they are infringing any of our patents. But we certainly pay close attention in this field to make sure that anyone that we identify infringing our vast patent estate, that we identify them and do something about it.

Next question is, are there properties of antisense drugs that give them a physical advantage over other platforms for neurodegenerative diseases?

So I'd like to start with that one by reminding people, at least giving my position on neurodegenerative diseases in Ionis. I believe we have the premier neurodegenerative disease pipe -- neurodegenerative-disease pipeline anywhere in the world. We're second to none. And I believe that we're first. We're tackling all forms of neurodegenerative diseases, so any oligonucleotide-based competition, my view is being way, way behind all the achievements we're making and all the advancements we continue to make in the neurological disease space. Single-stranded oligonucleotides have distinct advantages over other types of molecules like double-stranded oligonucleotides when it comes to distribution and natural uptake into cells. So there are advantages when it comes to single -- when it comes to cell uptake for -- in essence based on [ single- versus ] double-stranded molecules in that single-stranded molecules are taken up readily into cells, and we deliver our medicines to the central nervous system with simple saline solution, whereas double-stranded molecules require delivery vehicles. And those need to be sorted out and validated. So I think there are very big differences between the 2 platforms for neuro as well as for non-neuro applications.

Next question is 2 parts. It involves oral delivery of antisense drugs. Will you have any Generation 2+ antisense drugs that you'll be able to deliver orally? And the second part is what's the projected time frame for the first orally delivered antisense drug?

So the key advancement that we've made to potentially deliver on commercially viable oral delivery is potency. Our molecule that's currently being tested in the clinic as an oral once-a-day tablet utilizes our most advanced Generation 2.5 chemistry coupled with LICA. And the potency that these molecules give us go even beyond the potency of generation 2 LICA medicine. It's about another tenfold increase in potency. And it's really that potency increase that we think has a good shot of cracking the -- in cracking commercially viable oral delivery. We have some very potent Gen 2.0 molecules. Not all Gen 2 molecules are created the same. The advantage of Gen 2.5 is the potency. So I wouldn't rule out that we can achieve Generation 2 LICA medicines with commercially viable oral delivery. First, we need to validate this approach. And then certainly we'll be able to understand what the potency is that we need to achieve oral delivery. So I wouldn't rule it out. But right now, we've focused our 2.5 program on oral. And the second part of the question is that we will share data from this oral program later this year, and we're very much looking forward to that. And depending on how successful that study is, that program will continue to advance forward. The other point about oral is that this is a platform. And we're already moving other oral programs forward for chronic diseases, with Gen 2.5 LICA medicines that are coming forward as well. If we're successful in achieving commercially viable oral delivery, of course, this opens up oral delivery for a vast part of our pipeline. And that obviously offers tremendous advantages.

The next question is related to delivery to the lung. Do you have any concerns about delivering antisense drugs to lung through aerosol delivery?

No concerns at this time to speak of. We have a very strong preclinical data package, animal models as well as in our toxicology studies in which we've looked at our ENaC program very carefully from an aerosol delivery to lung in animal models. And we're very [ committed ] by the safety profile we've already experienced in our Phase I normal volunteer study. We'll share some of that data later this year. The other point -- so do I have any concerns about it at this time? We need to flesh that out, of course, and get more data. But right now it seems to be performing quite well. The other point about oral -- I mean about aerosol delivery, is that it isn't the only one. We have 3 drugs now in development for oral delivery, for diseases such as chronic bronchitis and cystic fibrosis and COPD and idiopathic pulmonary fibrosis. So we're excited and we're looking forward to this becoming a new franchise for the Ionis pipeline alongside cardiometabolic and neurological and rare and other indications.

The next question asks whether or not the deal that Biogen did with Sangamo will have any tie-in with Ionis.

Yes. I prefer -- I'm really not the right person to comment on the deal that Biogen did with Sangamo. What I can say is that the Biogen-Ionis collaboration is fully embraced as a very important strategic partnership by Biogen and by Ionis. And the collaboration is very healthy, advancing forward. Many new medicines are going to be reached in clinical development with Biogen this year and for years to come, and the clinical pipeline is performing exceptionally well. So the Ionis-Biogen relationship has never been stronger.

The next question asks, concerning the COVID-19 situation, how many or what percentage of Ionis employees work virtually from home?

Yes. That's an unusual question. So, no, it's a good question, it's a questions that actually I have heard from many people recently. The people that are coming to Ionis every day, and we're very appreciative of those people, are the people that have to come to Ionis to do their jobs. This is the research organization, this is the CFC dev chem organization, manufacturing, some folks from our health and safety facilities to keep the place running and myself. I come every day, make sure things are staying on track. It's about -- I estimate about 70% of the Ionis workforce is working from home remotely, and it's going extremely well. Everything that's happening and needs to get done is getting done. We're very -- as I said earlier, I'm very proud of our workforce for their nimbleness and their dedication to be able to work through this COVID-19 pandemic and get everything done that we need to get done. We're looking forward to having some of our workforce to be back over the next few months.

The next question is about the Phase II study with GHR LICA. And the question is, if you combine the Phase II study with extension study that's planned, would that be sufficient for registration? And if not, and assuming that the Phase II study is positive, do you anticipate commencing a Phase III study in 2021?

We're excited about our rare disease programs overall. Acromegaly, our growth hormone receptor, LICA, another LICA medicine, is on track in Phase II and it's going to read out later this year. That's a question that's data-driven, right? If the data supports advancing this medicine rapidly to patients in some setting or another, we'll certainly do it, or at least try to. If the data deserves advancing this program to a pivotal Phase III study, we'll certainly do it. If this data warrants us to go for -- as a monotherapy in addition to the combination work that we're doing right now in acromegaly, we'll do it. But it's really a data-driven decision there, and we're looking forward to the data readouts.

[ Ms. Wang ] asks, a corporation has many stakeholders, and there have been some concern in the past about where the shareholders stand and this person wants to know where do the shareholders stand.

So good question, if unusual question. We believe -- and we're very reliant to our shareholders. We think very highly of our shareholders. We support our shareholders. We want our shareholders, especially our long-term shareholders, to be wildly successful. We believe that focusing on patients and bringing our medicines to those patients and achieving the objective that I outlined before, my vision to bring 10 or more new drugs to the market to now treat millions and millions of people with our drugs around the globe, is the best way for [ pet ] shareholders to benefit, and we want them to benefit. So as shareholders are very important to us and we think that the best way to deliver value to shareholders is to focus on the pipeline and to bring this vast increase in new medicines to the market as fast as possible.

We had some questions today on the Factor XI program. This question asks, is there a chance that this could be an oral drug?

So our Factor XI program is very exciting. And we were first to validate Factor XI as an intrinsic coagulation pathway as a validated pathway to prevent thrombosis, but more importantly, to de-link, to separate bleeding risk from most -- thrombosis prevention. We're currently back there. Our partner is currently preparing to launch into a Phase IIb study with a LICA version of Factor XI. Some people may be wondering why in the Phase II -- well, Factor XI has been in the Phase II pipeline for quite a long time. And the reason is quite simple. We validated the target in end stage renal disease, the non-LICA medicine. And based on the tremendous profile of our LICA medicines, we all agreed there at Ionis, that the best treatment, the best profile for this drug, is in a LICA drug. End-to-end, it'd be the best profile for patients as a once-a-month sub-low dose injectable with great tolerability and so on and so on. So that's what caused the delay. We're about to start the end-stage renal disease study, a Phase IIb study and then we plan to move into Phase III right after that. Yes, it has the potential to be oral. Depending on the potency, it is a Gen 2 LICA. And if it's very potent, and it looks like it's very potent, it has potential to be oral, then we can always identify a Gen 2.5 version, the LICA version for Factor XI, and bring that forward as an oral drug if we -- once we validate commercially viable oral delivery. So -- and that, of course, the oral for Factor XI, the work we did on Factor XI and the validation we work in this pathway, of course, created a lot of followers. There are now antibodies that are going forward, and some people are turning to small molecules, et cetera. And then we paid attention to [ fast delivery ] before we did. Oral separates us from the pack because certainly for antibodies, where the [indiscernible] oral delivery. So it's a good question, and it is potentially in the future. But right now, we're focused on a once-a-month subcu, Gen 2, LICA medicine in ESRD.

A related question is, this person was wondering why the Factor XI drug wasn't on our 2025 list, the 10 or more drugs for NDA filings expected through 2025.

Yes. I have to go back and look at the time lines for that. I suspect it's because the Phase IIb study will take a little longer. And well, [ Phase I ] is complete and then whether or not the Phase III study, which will probably be in end-stage renal disease patients, who had [ put finish up ] in 2025. I wouldn't rule it out. We are -- we did try to be somewhat conservative in the medicines we put on the -- on that slide. That shows potential new drug applications over the next few years. We'd rather overdeliver and underpromise. I wouldn't rule it out. But that's basically after examination of the time line, which I'm more comfortable in pushing it out.

This is a relatively simple one, I think. How many employees does Ionis have now?

How many?

550.

Well 550. That's very good. Thank you.

You're good. Since we're on the topic of Beth, there are a couple of financial questions. This question asked, given your strong cash position and robust pipeline, is there any consideration of initiating a dividend either quarterly, semiannually or annually?

Great question. Our capital allocation strategy, I think, Brett has done a really nice job of outlining. It starts first and foremost with our pipeline and builds from there to our technology. And we want to be able to continue to advance the pipeline, to invest in our commercial medicines, to build our commercial strategy and our commercial capabilities and advance the reach and the breadth of the technology. So first and foremost, that's where we expect to be able to put our money. As far as the dividend, I think we're still too -- it's just too early in the company's history to be able to do something like that, and we have lots of opportunities for creating value through our pipeline and our technology.

Another, I think, potentially financial-related question for you is, do you ever expect to spin off, like, some shares to Ionis shareholders?

That's something that we'll have to take that with them under advisement. There's lots of different options. But right now, we're focused on advancing TEGSEDI and WAYLIVRA as we expand into new markets. And advance the medicines in Akcea's pipeline, the ones that Brett very nicely described in his presentation, as we move APOCIII LICA into FCS for Phase III, angiopoietin-like 3 into a Phase IIb and then, of course, APO(a) in its Phase III study in TTR LICA in its Phase III study. So that's our focus right now, and we will consider other options over time.

The next question is -- that goes to Brett. Brett, which drug program is closest to the finish line in terms of being marketable? And this is a 2-part question. What are the top programs that you're excited about?

So our next commercial opportunity is SOD1-ALS. The Phase III data is on track to be out next year. And potentially, Biogen will be filing for approval next year. So that's our next commercial opportunity. And that's really important. Again, I can't emphasize enough how important SOD1-ALS is, not just for the SOD1 patients, but also for the first time, we believe we've demonstrated the ability to correct the course of ALS in a patient population. And we think that opens up our ability to do for other genetic forms and [ broaden ] indications. And I have to say, in Ionis, we have a rich pipeline and there are programs in our cardiovascular disease program [ which are a little amateur ]. It's so exciting because they're affecting many, many millions of patients around the globe, an untreatable risk factor. Also, our rare disease programs. Many of those as well are very exciting, but I have to come back -- I have to come back to ALS because it is a treatment -- it is a disease where there are multiple causes of it. There's never been a treatment for it. And I believe that we -- we're on a precipice of main multiple medicines for all forms of the [ disease state ] in neurological disease. And of course, our contingency program is in -- is right there with ALS as well.

So I think that ALS is one of your later programs then?

Yes. The last and favorite. It's hard to pick the -- amongst your children.

This is a technology question. Your isomer antisense drugs offer an advantage over regular antisense drugs.

We have the premier medicinal chemistry program for all oligonucleotide-based drugs. We established that in 1989, at the end of [ December ] 1989, and we are leaders in -- we evaluated and studied how pure molecules way back and we continue to look at them and revisit them. So we've done thorough examination of the advantages and disadvantages, to which come out on the side of there are new advantages not only disadvantages for these types of -- for this type of chemistry. And we'll continue to look at it, but we're not very optimistic any that there's any significant advantage.

This next program is related to the Huntington program and she asks how long you have the OLE patients and on drug since starting the Phase I study? And have any dropped out during the OLE?

I don't have the answer to -- I think the question was which was the longest a patient has been in the open-label extension so far. And it's been long because they obviously -- this Phase III study started a couple of years ago, and there was a 25-month period. So I can't give you the amount of time. It's quite long. But one of the things regarding drop ins that allowed our partner, Roche, to complete enrollment ahead of scheduling with a slightly smaller sample size is the fact that the compliance, the drop ins were very low, but the clients was very high. The dropout rate in the Huntington program was very low, and that bodes great for the tolerability of the drug and who knows what else. But the dropouts, the compliance has been very favorable for that program, both in the Phase III study as well as in the open-label extension study.

The next question asks about RNAi. Has RNAi new data breakthroughs still allow them to get inside a cell nucleus, where so many of the neuro diseases find their cause? And do you see any technological events allowing them to get inside the cell nucleus?

Yes. I do not. And I said some oligonucleotides work principally in the nucleus, but also in the cytoplasm. We've demonstrated that and published on it. RNAi molecules are -- the risk mechanism works exclusively in cytoplasm. I have not seen any advancements or reasons to believe that there will be advancements, that they'll be able to soon penetrate the nucleus through that mechanism. It's just inherent to the RNAi mechanism.

Another technology-related question is, when do you anticipate a muscle targeting [ AS soluble ] utilizing LICA technology will enter the clinic?

As I mentioned earlier, we're making tremendous advancements in our LICA platform in muscle, is one of the key cellular muscles, one of the key areas of focus. As you may recall, whoever asked the question, we had a program in myotonic dystrophy that we brought into the clinic a few years ago, targeting the mpk, the cause of myotonic dystrophy or the validated target of myotonic dystrophy. And although we show a target engagement in that study, we needed greater potency, which is why we went back to the lab, and [ went back ] to LICA for that indication as well as other indications, like the chains and so forth. We're making great progress on all of our LICAs for skeletal muscle, the cardiac muscle as well. And I'm very excited about what we're seeing. And I think we're ready to talk about some of these programs soon down the road. Why don't we reach the clinic? I don't want to project the date, but I expect to see candidates reaching into the first phase of development very soon, maybe as early as first half of next year, we'll see.

Next we have a couple of pipeline-related questions. When can we expect top line data from the PKK LICA program?

This year. It's one of the programs that we're planning to share data from our mid-stage pipeline clinical proof-of-concept results in 2020. So we expect that our PKK LICA drug will perform well, and we'll have proof-of-concept data to share second half of the year.

Next question is what's the status of your Factor B drug for AMD?

Factor B, a very exciting program. It's a systemic for those that are not tuned into this so closely. It is a LICA medicine, targets the alternative complement pathway, a genetically validated pathway for age-related macular degeneration in geographic atrophy. This program is in Phase II development. It's enrolling with our partner, Roche. And of course, Roche has great experience in ophthalmology, they recognize the value here in this program and this pathway, and it's very -- has many advantages over other programs for eye diseases because it is a once-a-month subcu-administered drug instead of intravitreal-administered drug. But I'm sure it's enrolling, the Phase II study is progressing nicely, and we're on track.

It looks like the last question that we have here asks, can you provide an update on the hepatitis C program time line?

Sure. What I can say is that our partner, GSK, is planning to initiate a Phase IIb study with our HPV medicine later this year. And we're very excited about the program based on the impressive efficacy in patients with HPV that we reported top line data for earlier. So stay tuned on that.

Okay. That's it.

Okay. Well, that's the end of our presentation and Q&A session. I want to thank everybody again for your participation, support for Ionis. And stay tuned, there's a lot more coming in the second half of this year and throughout next year and beyond. Take care. Stay safe. Have a great evening. Bye.