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

Good afternoon. Welcome to Ionis Pharmaceuticals Annual Meeting of Stockholders for 2022. My name is Brett Monia. I'm the Chief Executive Officer of Ionis and I'm really thrilled to provide you with you an update on the great progress we're making at Ionis today. These are my forward-looking statements that I recommend to you to review at your convenience. Today, Ionis is a leading fully integrated biotechnology company, well positioned for substantial growth in the near-term and in the long-term. And the evidence for this is compelling and clear. Today, we have a commercial portfolio of 3 medicines in our commercial, helping our commercial portfolio, led, of course, by our blockbuster medicine SPINRAZA for spinal muscular atrophy. And that portfolio is expected to grow and grow fast and substantially based on our leading -- industry-leading rich, mid- and late-stage pipeline, a pipeline chock-full of many potential transformational medicines that are rapidly advancing the market. In addition, our technology is advancing at a rapid pace based on the investments we have made over the last several years, that is allowing us to tackle diseases tomorrow that we cannot tackle today, and extending our leadership position in RNA-targeted therapeutics. And we have a compelling financial profile. The financial strength to invest in all of our priorities here at Ionis to ensure we maximize substantial growth for our shareholders, for Ionis, for our patients and to achieve our vision of becoming one of the best, greatest, most productive biotechnology companies of all time. Today, we have 2 leading therapeutic franchises and 1 rapidly emerging therapeutic franchise. Our leading therapeutic franchises are in cardiovascular diseases and in neurological diseases. In cardiovascular diseases, we are addressing many of the major cardiovascular disease. Risk factors today, we have 4 ongoing Phase III trials and 9 medicines in clinical development in our cardiovascular pipeline today. Our neurological disease franchise is addressing many major severe neurological diseases, 3 ongoing Phase III trials in progress and 11 medicines in clinical development in tackling neurological diseases. And we have a specialty rare pipeline that's emerging led by our Phase III drug, donidalorsen, for the treatment of hereditary angioedema. We have a very rich Phase III pipeline today, 6 medicines in Phase III development across 8 different indications. These medicines are being developed for severe rare diseases as well as severe broad indications with prevalence estimated in the millions for some of these indications. These drugs are expected to readout from the Phase III pivotal studies and a steady cadence of readouts starting this year, next year. And as far as we could see from this Phase III pipeline through 2025. We also have a rich mid-stage pipeline that will be supplementing many of these Phase II drugs that will be moving into Phase III development to continue Phase III readouts for many years to come. This is what our Phase III neurology pipeline looks like today. There are 3 medicines in development for neurological diseases. They're all targeting severe, rare neurological diseases, tofersen. Our lead drug for amyotrophic lateral sclerosis, ALS, targeting a genetic form of ALS due to mutations in the SOD1 gene. Our ION363, targeting another genetic form of ALS, in which patients develop ALS due to mutations in the FUS gene. And then eplontersen for hereditary TTR amyloidosis with polyneuropathy. Before I do a deeper dive into several of our Phase III programs, I want to provide a brief update on our SOD1-ALS drug, tofersen. Last year, as many of you I'm sure know, we're disappointed that the Phase III VALOR study in SOD1-ALS did not hit its primary endpoint. However, there was from that VALOR Phase III study as well as from limited open-label extension data, encouraging signs that patients were doing better clinical signs, several clinical endpoints appear to be trending in the right direction that was suggesting that tofersen was truly benefiting patients with SOD1-ALS. In addition, there were substantial decreases in a biomarker called neurofilament light chain or NFL in patients treated with tofersen. NFL is a key well-recognized biomarker of axonal injury and neurodegeneration, giving us further encouragement that tofersen was truly benefiting patients with SOD1-ALS. Based on these results, our partner, Biogen, opened up an expanded access program, which has gone very well. Today, there's 133 patients in the EAP across 31 countries in their indications are receiving tofersen. And very importantly, tomorrow, new data from longer treatment open-label extension from the Phase III VALOR study, which patients have been treated for a minimum of 12 months will be presented at the European ALS meeting called ENCALS and I point you to do that for an update on tofersen. Based on all of this, this progress Biogen remains actively engaged with regulators on potential next steps for tofersen. We, at Ionis, remain committed to treating all forms of ALS, genetic causes such as tofersen for SOD1-ALS, our ION363 for ALS due to mutations on the FUS gene, as well as for broad ALS, nongenetic ALS, if you will, or sometimes referred to a sporadic ALS. Our drug, ION541, targeting ATXN2 is in a Phase I/II study in nongenetic ALS and is enrolling very well. And we're expecting additional programs targeting ALS for sporadic ALS to reach development in the near-term. Our cardiovascular Phase III pipeline is equally exciting. Today, we have 3 medicines in development in Phase III studies, olezarsen, eplontersen and pelacarsen. All 3 of these medicines benefit from our transformationally advanced LICA chemical platform that provides high potency, great efficacy and with very attractive safety and tolerability. These drugs are targeting rare indications as well as very broad indications with prevalences and upwards in a millions. Olezarsen is in Phase III development for 2 indications, a rare genetic form of high triglycerides, severe triglyceridemia due to genetic causes called familial chylomicronemia syndrome or FCS, and then a very large triglyceride patient population, severe hypertriglyceridemia, SHTG, as estimated with the prevalence in the millions in the United States. Eplontersen, as I said earlier, is in Phase III development for hereditary TTR polyneuropathy. That same drug is in Phase III development for a much broader indication, much broader prevalence in cardiomyopathy, patients suffering from amyloid -- TTR amyloid buildup in cardiac tissue. And pelacarsen, our drug that's partnered with Novartis, targeting a cardiovascular disease risk factor called lipoprotein a is in Phase III development and going very well. This is a prevalence of more than 8 million patients suffering from cardiovascular disease due to high levels of Lp(a). We're expecting Novartis to complete enrollment in this cardiovascular outcome trial involving upwards of 8,000 patients in this Phase III study to complete enrollment this year. And then from our emerging specialty rare pipeline, donidalorsen in Phase III development, as a prophylactic treatment for hereditary angioedema, enrolling well, the prevalence estimated to be more than 20,000 patients with this rare genetic disease in the U.S. and EU with data expected from this Phase III study in 2024. So Ionis' business model has evolved. Today, we are building and working and preparing for the first commercial launches from Ionis ever from drugs that we deem appropriate to bring forward to the market ourselves to maximize value to our shareholders, to our patients, to Ionis, to all stakeholders. Last year, about 6 months ago, we presented at our Investor Day our strategy for moving and advancing to the market here at Ionis. That strategy will focus on 2 core franchises, our cardiovascular franchise and our neurology franchise. In addition, we will use -- we will also take advantage of other opportunities if it makes sense to do so outside of our core assets, assets that they have high probability success or in attractive markets and within our capabilities. We will focus our commercialization efforts in the United States for both rare and broad indications, and we will build commercial excellence globally to ensure that our drugs through distributorships or other types of partnerships are reaching our patients on a global scale. We will expand in a disciplined manner. Over time, our pipeline -- our wholly owned pipeline will expand beyond our near-term commercial assets, and we will expand our infrastructure at the right time outside of the United States. And we will continue to partner strategically. We will co-commercialize when appropriate to enable greater patient access and availability and out-license assets outright at times if it makes sense to do so if those assets are outside of our core areas or strip our capabilities. Today, we have 3 near-term commercial opportunities eplontersen, olezarsen and donidalorsen. All 3 of these medicines benefit from our highly advanced and attracted LICA chemical platform. Eplontersen is being developed for TTR amyloidosis, all forms of TTR amyloidosis is in Phase III, as I already said, with a high prevalence for this disease in the hundreds of thousands of patients, especially suffering from cardiomyopathy. Based on the data that's been generated to date with eplontersen, this drug really has the possibility, has the potential to change the standard of care in a very meaningful way for patients suffering from TTR amyloidosis with a very attracted market opportunity. Eplontersen has blockbuster multibillion-dollar market potential. Our second near-term commercial opportunity is olezarsen. Olezarsen being developed for patients suffering from severe -- severely elevated triglycerides for 2 indications, the first Phase III data readout is expected next year, and we're ahead in this market. It's a very attractive market in patients suffering from very high triglycerides, potential first-in-class treatment and best-in-class treatment for patients suffering from different types of diseases with severely elevated triglycerides. This drug also has blockbuster market potential. And then there's our third near-term commercial opportunity, donidalorsen. Donidalorsen is being developed in Phase III as a potential best-in-class prophylactic treatment for patients suffering with a rare genetic disease, called a hereditary angioedema. Prevalence is shown here on this slide, Phase III data expected in 2024. And the market opportunity for donidalorsen is very attractive for Ionis. Now I'd like to do a deeper dive into our 3 near-term commercial opportunities, starting with eplontersen, our lead medicine for treatment of TTR amyloidosis. TTR amyloidosis remains a very high range that having a very high unmet medical need. It's a progressive disease due to the production of misfolded TTR protein from the liver, which deposits and forms amyloid in various organ systems, causing organ system destruction and rapid decline in quality of life. And eventually, it is a fatal disease. There are 2 indications, we're pursuing a rare genetic form of the disease called hereditary TTR polyneuropathy with the prevalence of approximately 40,000 patients globally, and then a much larger indication that involves both hereditary causes of the disease as well as nonhereditary forms of the disease that produce cardiomyopathy in a much larger patient population, as I said. We have a comprehensive Phase III program in process that to maximize the value of eplontersen on the market today. Our NEURO-TTRansform study is a multicenter open-label study, Phase III study with 168 patients enrolled with the primary endpoint be an mNIS+7, which is a -- is an instrument to measure neurological disease -- peripheral neurological disease progression. In addition, we have a co-primary endpoint of TTR as the target, TTR lowering at week 35. And we're expecting data from this Phase III study midyear this year. And then our CARDIO-TTRansform study focused on patients suffering from TTR cardiomyopathy both hereditary patients as well as wild-type patients. This is a global randomized, double-blind, placebo-controlled cardiovascular outcome trial, involving 140 weeks of treatment in up to 1,000 patients to be enrolled, with data expected in the first half of 2025. We also have several other studies in process as well as being planned that we collectively refer to as TTRansform Beyond. These are studies to further enhance the profile of eplontersen to generate data, to show that this drug truly is a leading class molecule for the treatment of amyloidosis and to win on a very competitive, very attractive market. Last year, we announced a strategic partnership for eplontersen with our partner, AstraZeneca, our long-standing partner, AstraZeneca. It's a very important partnership for eplontersen to set it up to win in a very competitive, but yet very large market opportunity. And it's a partnership that is very complementary. Both sides are bringing complementary skills to the table to maximize the successor for eplontersen. And Ionis, we're bringing our industry-leading experience and development of efficient drugs as well as our vast experience in TTR amyloidosis. We also have a very important and substantial seat at the table for commercialization of eplontersen in the United States. AstraZeneca, of course, brings with it its global capabilities, its global leadership in the commercialization of cardiovascular diseases. Together, we believe that this partnership will maximize success for eplontersen in a very compelling market. And as I said before, a market that's compelling, but it was also competitive. So where are we with eplontersen, current status and next steps. Well, the NEURO-TTRansform study had completed enrollment last year. We actually exceeded enrollment in the Phase III study with data expected midyear this year. And if the data supports, we will file for marketing authorization this year as well and launch the drug next year. Our CARDIO-TTRansform study is the largest TTR cardiomyopathy study ever conducted, and it's largely because it's designed to benefit in a very broad patient population that suffers from TTR amyloidosis, diverse patient population that's really going to position this drug as a best-in-class molecule for TTR cardiomyopathy. It's on track to complete enrollment in 2022 and this year, and for data readout in the first half of 2025. Our second near-term commercial opportunity that we're preparing to launch here at Ionis is olezarsen for the management and treatment of outpatients suffering from severely elevated triglycerides. Olezarsen really has the potential to be a transformational new approach for the treatment of patients suffering from severely elevated triglycerides. We know the elevated triglyceride are associated with many major medical issues, including acute pancreatitis that can be fatal, high risk of cardiovascular disease, and there are no good treatment options available to manage severe hypertriglyceridemia today. The target for olezarsen is APOCIII. It is a liver-derived protein that is the master regulator of triglyceride metabolism in body. And we have shown in Phase II with olezarsen, now olezarsen is highly effective in reducing triglyceride levels in patients with very elevated -- highly elevated triglycerides with excellent safety and tolerability. APOCIII it is also a validated cardiovascular disease risk factor. And as I mentioned before, we are targeting 2 patient populations: FCS, and stent the broader indication of severe hypertriglyceridemia. Like eplontersen, we have a very broad comprehensive Phase III program for olezarsen to maximize its success on the market. We have the BALANCE study, targeting the rare genetic cause of severely elevated triglycerides called familial chylomicronemia syndrome, FCS. This is a global, randomized, double-blind, placebo-controlled study involving about 60 patients with FCS, primary endpoint is triglyceride reduction compared to baseline at 6 months, and we expect data, as I said earlier next year. And then for the broad population. The population that it affects millions of people severely elevated triglycerides. We have 2 studies that are planned or in progress. The CORE study is in progress. This is a global pivotal study in up to 540 patients with severely elevated triglycerides with 500 milligrams per deciliter primary endpoint and the same is BALANCE, triglyceride lowering at 6 months with data expected in 2024. And then we're about to initiate a second supportive confirmatory pivotal study called CORE-2, involving somewhat smaller sample size 390 patients, same primary endpoint, same time frame for the primary endpoint to readout and for its data to readout from the CORE-2 to coincide with the readout of CORE. Our go-to-market strategy and our plans for commercializing olezarsen in the market is a plan that will evolve with time. We will start and focus on the first readout from our FCS Phase III study, focusing on FCS patients, trying to serve these patients again, triglycerides above 1,500 milligrams per deciliter and a genetic cause of the disease. And that has a prevalence estimate about 3,000 to 5,000 patients or so. As the CORE study reads out, we will then move to a patient population that we refer to as the early adopter population. These are patients who triglyceride above 1,000 milligrams per deciliter at high risk for pancreatitis potentially fatal pancreatitis, a prevalence that's estimated to be about 1 million people in the United States. And then with time, we will move forward to the broad -- even broader population, the SHTG population with triglycerides about 500 milligrams per deciliter associated with cardiovascular disease with the prevalence estimated above 2 million patients in the United States. So current status of olezarsen and next steps. First, I want to point out that we published our really attractive or impressive Phase II data in the European Heart Journal earlier this year. The BALANCE study in FCS. We're expecting full enrollment soon with data expected next year. And then the CORE studies are progressing very nicely. CORE is rapidly actively enrolling, with data expected in 2024. And then the confirmatory supportive of the study CORE-2 is expected -- to start soon with data readout again in 2024. Our next near-term commercial opportunity that we're preparing to launch here at Ionis is donidalorsen. Donidalorsen is a prophylactic treatment for hereditary angioedema with a profile that has the potential to be a best-in-class prophetic treatment for this disease. Hereditary angioedema or HAE is characterized by unpredictable painful and potentially fatal attacks. It's a severe rare genetic disease that's caused by a dysfunctional gene called C1 inhibitor. The lack of C1 inhibitor causes hyper activation or over activation, if you will, of a pathway called kallikrein with the prekallikrein path which leads to excessive production of a chemokine called bradykinin, which leads to angioedema massive swelling of various tissue veins, including the arms, legs, face and throat and this can be a fatal event. This is also an unpredictable event for patients. So these patients live their lives in constant anxiety and fear that attack can happen any time. The donidalorsen, the root cause of hereditary angioedema upgraded timing of the production by targeting prekallikrein. We reported last year some very exciting, very compelling Phase II data in patients with HAE with donidalorsen. We demonstrated substantial reductions in HAE attacks that were rapid and sustained reductions over the 17-week treatment period that were 90% lower versus placebo in that full 17-week treatment period. And if you look at weeks 5 to 17 after the first dose or the second dose when the drug gets fully onboard, we actually upped that to 97% reduction in monthly HAE attack versus placebo and what was really remarkable an unprecedented for a prophylactic treatment was that more than 90% of patients during this treatment period were completely attack-free compared to 0 patients on placebo that were attack-free. Truly, a potential best-in-class HAE profile. Based on this data, we rapidly moved donidalorsen to Phase III development, the Phase III study that's underway, the pivotal study, the registration supporting study is OASIS. It's a global pivotal study, in which we're targeting approximately 84 HAE patients in which we're dosing monthly with donidalorsen as well as every 2 months over a 24-week period. The primary endpoint in this Phase III study is the same as the Phase II study, time normalized HAE attacks with data expected in 2024. And then we also have a collection of studies that are in progress and planned to further enhance, further promote the profile for donidalorsen in the HAE community, in the HAE market to win and to maximize success on the market. We call these collection of studies called OASIS plus. This includes the global open-label extension study, in which patients from OASIS will rollover into to demonstrate and to establish durable protection over long periods of time against HAE attacks. In addition, we're about to begin a new study, we sometimes refer to as the SWITCH study. That is open to HAE patients that were previously treated with other prophylactic therapies and then are moving over to donidalorsen to demonstrate, maintained and maybe even improve efficacy with good safety and tolerability. This is a very exciting market, the HAE market. It's an established and growing market, a market that has a potential of more than -- today is more than $1.5 billion and growing, especially prophylactic treatments are growing here. It's a well-defined U.S. patient population and a well-defined prescriber base. There's estimated to be about 6,000 HAE patients in the United States, and there's a large unmet need that remains despite the availability of prophylactic treatments, these patients continue to suffer from breakthrough unpredictable, severe attacks despite being treatment. We think donidalorsen is the answer for those patients. And these -- and of course these patients experience -- continue to experience significant fear and anxiety because these attacks, again, are highly unpredictable. Donidalorsen as a potential to be a best-in-class -- has the best-in-class profile based on our Phase II data, based on efficacy, its onset of action, its safety, tolerability and its convenience as a once per month or less frequent at home self-administered agents. So where are we with donidalorsen. Well, we were very proud to have published our Phase II data in the New England Journal of Medicine earlier this year. The OASIS pivotal Phase III study is actively enrolling and on track for data readout in 2024. And the collection of those studies, the sportive studies, OASIS plus, are also moving forward nicely on track. So now I've taken you through our rich Phase III pipeline. And I've also taken you through 3 Phase III drugs that we're preparing to launch here at Ionis over the next several years. Right behind that Phase III, rich pipeline is a large Phase II pipeline, a pipeline that has many drugs in our cardio -- from our cardiovascular franchise, our neurology franchise and our emerging specialty rare franchise that has the potential to be transformational agents. And if successful in Phase II has this highly likely potential to move into Phase III, further enhancing our Phase III pipeline, providing a continuous supply of Phase III assets in the long-term -- for the long-term. All this sets us up for substantial revenue growth for the near-term, medium-term and well into the future. Our revenue growth, of course, also received contributions from our partnerships. We refer to these -- this revenue is R&D revenue. We will continue to gain revenue from our existing commercial products, of course, and led by SPINRAZA, our blockbuster medicine for SMA. But in the near-term, we're expecting a very large number of molecules, products, assets to reach the market to substantially increase the growth of Ionis, our revenue growth and in the medium to longer term. You can see a tidal wave of new products that we're projecting to potentially reach the market to really maximize our revenue growth, maximize growth of Ionis, maximize success for our shareholders and all stakeholders. We're also continuing to invest in our technology, and it's paying off in many, many important ways. Investments in medicinal chemistry for example, having an impact on extending our dosing intervals, enhancing our therapeutic profile even beyond the attractive profiles that we're generating today. We plan to incorporate these new medicines into new drugs that well into the pipe, but also into existing programs for life cycle management for existing therapeutic areas or drugs that are in the -- on the market today or in development. A great example of this is our follow-on to SPINRAZA, which is expected to reach clinical testing soon for SMA. We're also developing new LICA strategies that go beyond liver LICA, opening up LICA strategies for muscle and pancreas and maybe even lung opening up diseases like neuromuscular disease, heart failure, targeting the heart directly and metabolic diseases. And we'll continue to validate new routes of delivery, just like we validated intrathecal delivery for CNS. We're well on our way to validating additional routes of delivery to open up new disease areas, new organ cell types, further strengthening our leadership position in RNA-targeted therapeutics. This is a really exciting year for Ionis. We have a lot of pipeline -- advance a lot of pipeline readouts. We've already had quite a few in the first half of the year. As you can see on this slide, and tomorrow, we're expecting another pipeline update, tofersen, as I mentioned earlier, in which Biogen will present at ENCALS, an update on the open-label extension for tofersen in SOD1-ALS, and we're very much looking forward to the Phase III interim readout for eplontersen in TTR polyneuropathy midyear this year. And then you can see in the second half of the year, we have a whole host of Phase II readouts and Phase IIb readouts that we're very much looking forward to, as well as key study initiations in technology advancements, advancements that we expect to reach development this year. We are very strong financially, and this is so important. Today, we are well capitalized with multiple sources of revenue that allow us to make all the investments we need to make in the company across our business to maximize success for Ionis, for our shareholders, for all stakeholders, building out the Ionis wholly-owned commercial portfolio, building out our commercial organization, expanding and diversifying our technology and getting our drugs to the market and winning on market. All this is expected to lead to substantial growth for Ionis. And we're doing all of this with corporate responsibility in mind, focused on our employees, our people. A fantastic group of employees that are highly dedicated to developing drugs and helping patients. And of course, they were devoted to our patients and dedicated to our patients, our environment, our communities and continuous innovation here at Ionis. So we're very proud of the fact that we published our corporate responsibility report in December last year, we're looking forward to providing further updates in this report in the future. So to conclude, Ionis is indeed a leading fully integrated biotechnology company today well positioned for accelerated growth, maximizing success for all stakeholders. We have many attractive product opportunities, rapidly approaching market, a growing and advancing Phase III pipeline, and we are now fully integrated. Research, excellence, development excellence and now a commercial organization of excellence, all coinciding together. We're making substantial investments in our technology that's paying off. Advancements are extending our leadership position and expanding our ability to tackle diseases tomorrow that are we can't tackle today, all of this leading to a sustained delivery of transformational medicines in the near-term and in the long-term. Thank you for listening. With that, I would now start -- I will now pause and take a short pause and then open it up for a question-and-answer session, instructions for the question-and-answer session are shown on this slide. And we look forward to seeing you back for the Q&A period in about 5 minutes or so. Thank you. [Break]

Welcome back. Again, my name is Brett Monia, CEO of Ionis. And we are now in the question-and-answer session for the 2022 Ionis stockholder meeting. Joining me to my left is Beth Hougen; and to my right, Onaiza Cadoret. Beth, do you want to briefly introduce yourself?

Sure, sure. Thank you for having us. My name is Beth Hougen, and I'm Ionis' Chief Financial Officer. I've been with the company for over 20 years now.

And Onaiza?

Sure. Good afternoon, everyone. I'm Onaiza Cadoret, I'm the Chief Product Strategy and Operations Officer for Ionis.

Great. Well, let's start with some questions. Do we have any?

Yes, sure. First question is, as you highlighted today, you clearly have a rich Phase III pipeline. And we hear a lot about eplontersen for TTR amyloidosis and donidalorsen for HAE, but much less about olezarsen. Can you only referenced it today, can you expand a little bit on the commercial case, the unmet medical need for triglycerides, olezarsen program and the general commercial opportunity for the program?

Yes, it's a great question. Thank you for that. Indeed, olezarsen, despite our great efforts, it seems to continue to fly under the radar. We do think it's a great driver as I tried to highlight in my presentation and has a potential for a blockbuster. I'd really like for Onaiza to speak to the potential for olezarsen to really have a big impact on the market.

Yes, I'd be happy to. I think this is -- I think whoever asked the question, it's a great one because we do actually see it's somewhat under the radar. It has blockbuster potential as Brett said. But importantly, actually, we always start as we do in all of our commercialization processes to understand what the unmet need is out there. And this is actually significant, and it's multifactorial. There are multiple sets of population that I'll talk about in a minute. But important to know in an unmet need marketplace, it's really critical to see what is already in place. And the standard of care is actually suboptimal in these patients, right? They have severe elevated triglycerides, which give them several different types of conditions. And what is available to physicians right now and there are in interim and their toolbox for them is really nice and vibrate, very old agents. And even the newer agents, which is [indiscernible] we have very suboptimal efficacy. So with our target of APOCIII and what we've seen in our Phase II data, we are providing about 3x the triglyceride reduction, the magnitude of order which the current standard of care products do. So I think where we have a good product and a tool for unmet need, that's kind of where I say the chemistry in the marketplace actually, we have that. We are very excited about, looking at this patient population in 3 segments, greater than 500 to about 1,000 are at risk for cardiovascular disease. So we expect that, that will have a pretty high treatment rates. Then if you get into the higher level of 1,000 to 1,500 pancreatitis and that's a great interest also from a high-risk perspective for endocrinologists as well cardiologists, and then our genetic marker of the disease, which is familial chylomicronemia syndrome. So a very large opportunity of 3 million patients, great unmet need, first mover advantage, which is pretty significant here in the class, a potential to be first by a significant margin, allows us to do a lot of different things. Shape the market, price the market and then we think about how we're going to bring kind of the unmet need to the physicians together as well. And then lastly, I'd say in addition, we've had a really great conversation with regulatory agents as well. So a nice clear path and for the studies that are designed to meet the regulatory thresholds.

Thanks, Onaiza. We're very, very excited about olezarsen.

Sticking with some of the Phase III drugs. This is a pelacarsen program. So for your Lp(a) program with pelacarsen, how does pelacarsen stack up to some of the competing programs, which we've heard about some news recently?

Yes. Pelacarsen, as I said in my presentation, in Phase III development in the cardiovascular outcome trial. Novartis is conducting that trial. And that trial is going very smoothly. As I said, we're expecting to complete enrollment in 8,000 or so patient CVOT this year, the data on track to readout in 2025. There are a lot of followers. I mean, there are a lot of followers across our pipeline. And the reference that the question was asked about the drug -- question was about was is very well behind, quite a ways behind. And it's very important to remember that unlike safer LDL cholesterol, where lower is better. Lp(a)-driven cardiovascular disease is a disease that is driven by Lp(a) levels being above a specific threshold, a threshold that causes cardiovascular diseases. We all know Lp(a). If you have too much of it, you have cardiovascular disease, typically in the range of 60, 70 milligrams per deciliter. We showed in a Phase II study at pelacarsen got nearly 100%. I think it was 98% of the patients and cardiovascular disease in Lp(a) due to Lp(a), elevated Lp(a) levels. 98% of those patients were out of harm's way. They got their Lp(a) levels into the normal range. There's no need to lower it beyond that. That, coupled with the fact that Novartis is a powerhouse, CBD company and is years ahead of the competition, and we're doing pretty good in pelacarsen. Thanks for the question.

And there's a couple of questions on the thrombosis programs, somewhat related. So Ionis has a Phase I study of Factor XI inhibitor ION547 and also the Phase II program on fesomersen for Factor XI. Question -- both questions are how those programs related? Are they complementary competing drugs, how that you differentiate it?

Yes. Very exciting programs. Thank you for the question. Factor XI is much further along than Factor XII. Both our coagulation factors, of course, produced by the liver. We validated -- we were first to validate Factor XI in humans as a potent anti-thrombotic agent that provides minimal risk of bleeding. We were first to do it in the knee clinic surgery, surgical setting in the clinic. That was our non-LICA drug we can drop for LICA version of that drug called fesomersen and that study is about to readout soon in a Phase IIb study with our partner, Bayer. Based on that data, fesomersen is going to be a Phase III-ready asset. So it's very ready to go. So we validated Factor XI, and it's very far along in development. We're very excited. It really is the future of anti-thrombotic therapy in my view. Factor XII isn't that far along. It's wholly-owned by Ionis, so it's not partnered. And -- but we have some validation to do with Factor XII. We have to prove that Factor XII is a good and safe anti-thrombotic. We're confident that inhibition of Factor XII will not produced bleeding. We have to show that it has a potent anti-thrombotic effect. Once we do that, we'll know whether or not these 2 programs will compete or differentiate or whether Factor XII just is not as good as Factor XI. So where we have some clinical validation to do a Factor XII. We're well on our way. We're about to start Phase II development for Factor XII in antithrombins setting. So stay tuned. Very exciting.

And there's a follow-up question, if you will, on. A, Is there an interim look in the Phase III pelacarsen trial and a possible earlier timeframe to it for [indiscernible]?

Yes, that's really a great question for Novartis. Novartis, there is a -- they have said that there is a potential for an interim analysis in that CVOT study. That's what they've said. So I assume it may consider statistical analysis plan and they can pull that trigger if they choose to based on a collection of data that they'll make that call on. But really beyond that, it's a question for Novartis.

And then there's a couple of follow-ups to the pelacarsen program in discussion. One is what the progress of WAYLIVRA and what's happening with WAYLIVRA and how that fits in, and then also how the commercialization of olezarsen and what's on that with regard to first, a rare indication and expanding a too much broader indication strategy for that?

Thank you for the question. I'll take the first one, maybe Onaiza you could talk about the plan to execute olezarsen through the market. So WAYLIVRA is on the market for FCS in certain countries in Europe and in Latin America. So which is our distribution partner is distributing WAYLIVRA in Europe and our partner PTC in Latin America. We decided a couple of years ago to not advance WAYLIVRA in the United States through the FDA because they know olezarsen is coming in. We had a much better drug, it's a LICA medicine and eventually olezarsen will cannibalize WAYLIVRA in the markets where WAYLIVRA is today. And of course, we expect to be fully improved for rare and broad indications in the U.S.

Yes. On the pricing issue, really, we understand there's a big difference between rare disease pricing and pricing in more prevalent diseases. So we fully expect that as we launch into FCS. We know that it's really important to think about bringing this to patients as quickly as possible. So it is the first indication, but we also expect that we're going to go into pricing from a more prevalent disease perspective, but that you can expect for all of the cardiovascular diseases that have sizes and prevalence in the millions as well. So we would -- the FCS patients will actually get that at that prevalent disease price.

Next question is about FUS. How is enrollment going? And is the study report, we're still on track to readout in 2024?

Yes. The FUS Phase III study is enrolling well. And it's on -- continues to be on track in 2024. We're very pleased with the enrollment that's happening so far at ultra rate form of ALS. I also want to mention it was on my slides that I didn't highlighted, I don't think we started that program with an investigator at Columbia University. And in the compassionate use cases before we took it back and developed a number Phase III. Some of that data was published earlier this year, including autopsy data from a patient that was treated with that drug results. The overall results for the patient, while she was alive as well as the autopsy data was very compelling, really providing a lot of encouragement that we're getting to the target. We're lowering the target and potentially patients will do better. I think it's not a lot of data, but it's very encouraging in the U.S. So if you're interested in the FUS program, take a look at that data, it's very interesting.

Another question about the neurology programs. Any update you could provide regarding the program with Roche, coming to medicine and when can we see some -- expect to see any news on that program?

Yes. We're committed to developing treatments for Huntington’s disease. We're disappointed early last year when the GENERATION HD study was terminated early patients continue to be followed, we stopped dosing based on, let's say, the oversight committee or DSMB or what have you, an oversight committee at Roche concluding that patients weren't going to do better if the study continues through the 25 months. I think it was. Nevertheless, Roche continues to follow those patients and very importantly, they continued to analyze all the data from the Phase III study. And that is the largest study by far of a therapeutic in Huntington's disease. So that it was a wealth of data. Earlier this year, Roche presented at a medical meeting findings that suggested in a post-hoc analysis of that data that patients with less disease burden that were younger with Huntington's disease were potentially doing better with cimdelirsen, it's quite encouraging post-hoc data analysis, take it that way. But all or not all, but I should say, but many most, potentially all of the clinical endpoints that were evaluated in that post-hoc analysis were all trending in the right direction, as was neurofilament light chain, a marker of neurodegeneration. So based on that analysis, Roche is planning to initiate a Phase II study in a similar patient population that could to be getting benefit. So they haven't put specific time lines on when they're going to start that study. But they're great partners. They're very committed as we are to bring medicines to the market to patients with Huntington's disease. So they're moving as urgently as possible. So stay tuned for that. It's quite encouraging.

There's a couple of questions on the MAPT program. What is the status of the bioscience drug for MAPT for Alzheimer's? When will the Phase I/IIa data be released? And then when you get to that, I'll...

So the Phase I/II data that Biogen presented last year at the Alzheimer's meeting last summer was very impressive. We demonstrated in that study -- the study was in mild Alzheimer's patients, so it wasn't designed to show improvements in cognition. What it was designed to do was to select a dose for a follow-up Phase II -- to a much broader follow-up Phase II study based on safety tolerability, but also based on tau reductions. The reductions we saw in tau in the CSF which is, of course, reflective of what's happening in the CNS, where substantial tremendous reductions in tau levels in the CSF, these reductions were durable that lasted many months following cessation of dosing. So that data was presented at the Alzheimer's meeting last summer. I believe our partner, Biogen, is planning to prepare a publication with that data. And then the next step is for them to initiate a much larger Phase III study in patients with Alzheimer's disease. And they haven't put out timing on that yet, but stay tuned, it's moving forward very well.

So the next question was regarding the Phase II. Biogen plans to dose every 3 or 6 months in the Phase II MAPT trial that has less treatment than the Phase I. And can you comment on that?

Love to. Good question. We're learning a lot about how to optimally dose our drugs in -- for CNS applications. Remember, we were the ones that pioneered the administration of anti-thrombotic to the CNS, we had of course, with SPINRAZA and babies and then in SMA adults and then so much more experience now that we've done over time and continue to refine our molecules, our chemistries as well as understanding how best to dose focusing on dosing frequency, if you will. Many -- most of our molecules are moving into development nowadays are showing a similar profile as MAPT that we believe will now allow us to dose biannually with existing chemistries, for example, potentially we're seeing long-lasting effects for several of our drugs in the CNS. So that is -- I believe that that's going to become the norm, not the exception. I also want to remind you that we also have new chemistries coming forward for CNS applications, right? In January this year, Biogen licensed from us and Ionis discovered invented chemistry for a follow-on molecule to SPINRAZA that we are hopeful will get us to every 9-month dosing or every -- or once a year dosing. That study has not started by Biogen in SMA yet, but it will start soon. So I guess the short answer is the technology continues to advance, and we continue to optimize applications for CNS, for systemic applications and more.

So another question on technology. Ionis have a few job postings related to gene editing. What's the status of Ionis' gene editing programs? And if they exist, what would be unique about them is compared to some competitors' programs?

We have -- thank you for that question. We have industry-leading research organization here at Ionis that is continuously evaluating many different technologies, many different platforms. Our goal is to become the leading genetic medicines company of all time. And that includes antisense. That includes RNAi. That includes other platforms that we -- if we deem are worthy of us conducting drug development in, we will do so. We're working DNA editing, we're working in other areas, too. And this is all consistent with the strategic imperatives that I laid out in 2020. When I said our 3 key objectives are to bring drugs to the market ourselves and to become a fully integrated biotech company, to diversify our technology base, our platform technology base, including DNA editing and to maximize -- bringing in abundance in molecules, medicines to the market in the near-term and in a sustainable manner. I can't hold these researchers back here at Ionis. They'll pursue all kinds of things, and that's just one area that they're pursuing. So we're looking to hire some experts in DNA editing. We'll see where it goes.

Couple questions about LICA. One is relating to some competitors who have LICA targeting CNS and other competitor targeting lung. The question is, does Ionis have any LICA's for these tissue types?

Yes, it's another technology question like you said. Great question. Thank you. We have a broad comprehensive LICA program, as I'm sure you all know, a lot of experience in the liver with LICA more than 5,000 patients now treated a liver LICA, reproduce the excellent safety, potency, tolerability, efficacy. And based on everything we've learned about liver LICA we're expanding that to other tissues such as skeletal muscle, cardiac muscle, lung tissue, pancreas. We've had good success in pancreas and muscle already. We're also looking at LICA strategies for the CNS and in the lung, too. I can't comment on competitors' programs. There actually hasn't been a lot of data. I think there's been things written in some announcements here and there, but there's been anything published in a scientific peer review journal. So it's hard for me to comment on that. But let me assure you that I believe we have the most comprehensive LICA platform for anybody in RNA-targeted therapeutics. And I believe they're advancing new LICA's for new organ systems into development, hopefully, by the end of this year.

Continuing on LICA, can you describe some of the potential benefits of your muscle LICA program, particularly relating to the [ Bicycle ] and potentially Arrow collaboration?

We are very pleased with our Bicycle and Arrow collaborations. These collaborations are focused on developing novel ligands, targeting cell surface receptors using our LICA strategy to enhance drug delivery to specific cell types. Both of these strategies offer the potential to use ligands that is molecules attached to our [indiscernible] to drive them into the cells, we want to drive them to ligands that are very low molecularly compared to, for example, large monoclonal antibodies or other things that are using muscle LICA strategies. We believe that there are lots of advantages to this strategy, including more convenient dosing regimens. We believe -- strongly believe that the subcu route is in our LOE and LICA strategies for muscle are well within reach. So we don't have to go intravenous. Easier to manufacture, simple medicinal chemistries, so we can do chemical modifications and enhance the drug-like properties, reduce cost of goods, easier to manufacturing, so on. So we're really focused on low molecular way ligands that can deliver our drugs to various tissues and cell types, and that's what Arrow and that's what Bicycle brings to the table. The collaborations are going exceptionally well, and we're very pleased with the progress we're making.

And this is the last question. Why are you so confident that you can successfully penetrate the established HAE market that appears to relatively well served by several company marker products?

That's a great question for you, Onaiza.

So I was going to wrap it up. Well, first, I'll say, I don't think it's well served. There is -- we tested our TPP, just when we got our Phase II data. And I have done a lot of these in my lifetime that never seen a set of physicians and patients so excited to have this product. There is an unmet need that is [indiscernible] on 0 attack rates, which is the efficacy marker in the marketplace. There are multiple dimensions of efficacy, but that one seems to be the most important. And if you see our Phase II data, which published in the New England Journal of Medicine and you will see that and we get there with the 97% attack rate in a very fast period of time, which is the other efficacy dimension because you're taking this medication from a prophylactic perspective, you want to get there as fast as possible, and we get there in about 1 dose. So it's very meaningful. It's very meaningful to patients. It's very meaningful to give them the confidence in the freedom to be able to do this prophylactically. And then -- if you take a look at what's in the marketplace right now, you have a lot of agents, which is true in the prophylactic market, as Brett said, it's growing pretty rapidly. But the unmet need is also around the ability to take a low volume, very easy to use injectable and at self-help administration as well, again, to speak to the freedom that it brings. And that actually isn't available to all patients right now. We have the markets more in every week stage versus every month. And it's a very strong profile that we bring together with efficacy, with safety, tolerability as well as the package on the self-administration of the dosing.

Yes. Thank you. And thanks, everybody, for participating. This has been a great set of questions. We're really very thoughtful, and we hope we addressed your question sufficiently. Thanks again for joining us for our stockholder meeting this year, and we look forward to seeing you again down the road. Have a really great day. Take care.