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

Good morning, everyone. My name is Jess Fye. I'm one of the biotech analysts at JPMorgan. And we're continuing the 2020 Healthcare Conference this morning with Ionis. We're going to host a Q&A session with the management team right after this. It's just down the hall in the Olympic room. You can follow me down there if you're interested. But for the presentation, I'm going to turn it over to the company's CEO, Brett Monia.

Good morning, everybody, and thank you for coming so early to this presentation. And thanks, Jess, for the introduction. These are my forward-looking statements. I recommend them to you to review at your convenience. These are indeed new days at Ionis Pharmaceuticals as I, Brett Monia, take on a new role at Ionis as the Chief Executive Officer, as Jess mentioned. It's a role that I'm incredibly excited about and very much looking forward to. And I'm confident that under my leadership, I'll be able to bring Ionis even greater successes and achievements and to new highs in the future. As a founding scientist at Ionis some 30 years ago and reflecting back on my experiences as both a science leader and as a business leader at Ionis, I couldn't be more proud of what we've accomplished at Ionis over the years that we've been at this. I mean, after all, when you really break it all down, when you really look at it, we essentially created a new sector in the biotech industry called RNA therapeutics, a new sector that is delivering new medicines, transformational medicines year over year over year. We're very proud of that. And of course, that's a history to be very proud of. But it is history. And as the Chief Executive Officer of Ionis, I am, of course -- we'll use history as experiences to make an even brighter future for our patients that we serve. But I'm focused, totally focused, laser focused on the future. And on -- and focused on the future and as a new leader of this fantastic, wonderful company, I, of course, start with a vision. My vision for Ionis for the future is bold, it's simple and may be a little ambitious, but it's one that I really do believe we can achieve at Ionis. It's a vision in which I believe this can be the best, most productive biotech company ever in the history in the health care industry and in the history of biotech, that will serve patients, putting patients at the center for the treatment of severe diseases worldwide. And I believe we can do that because of the technology that we invented, a technology that is growing and expanding and delivering transformational medicines year-over-year over year and a pipeline that is delivering medicines. That our pipeline is very large, diverse, delivering medicines and will continue to deliver medicines as well. In addition, I believe that we have the people to deliver this company into even new highs in the future, a group of individuals, a workforce that is incredibly dedicated to making this vision a reality. So how will we accomplish this vision? Well, we will continue to focus on innovation and scientific excellence, like we always have at Ionis Pharmaceuticals. And we will leverage our financial strength, financial strength that we created and financial strength that we will utilize to expand the scope of antisense to deliver even more medicines in the future to patients in great need. We will expand the scope by substantially increasing the delivery of transformational medicines year-over-year over year to patients, once in a lifetime breakthroughs year-over-year over year. We will also increase and diversify our investments in technology to make antisense -- the antisense platform even better to deliver even more medicines to patients and to increase the scope. And we will invest in new technologies that complement what antisense does today and adds to our reach in human therapeutics. And in addition, we will prioritize the growth of the Ionis-owned pipeline and build our commercialization strategy to maximize commercial value for the Ionis-owned products that reach commercialization. It's very ambitious, very exciting. Of course, every vision starts with the beginning, and the beginning is where we are today. Where are we today at Ionis? Well, we are the leaders of the technology we created, a technology called RNA therapeutics, that we've led the creation of. We envisioned it, we validated it, and we delivered on the antisense dream. And our leadership gap is widening. We have a very large pipeline, an expanding pipeline and a pipeline that's delivering medicines to patients. The Ionis-owned pipeline is now a top priority for us, and we will and are increasing our investments for our commercialization capabilities, and that will be a top priority going forward. And as I mentioned earlier, we have the financial strength to do all of this. We are in the strongest financial position ever in the history of this company. And 2019 was our best year ever for Ionis Pharmaceuticals. Last year, we achieved approximately $1 billion in total revenue to Ionis Pharmaceuticals and hundreds of millions of dollars in net profitability. In addition, we have an outstanding, very attractive cash position, more than $2 billion in our cash position. That enables us, again, to do the things we want to do to accomplish that vision that I just outlined for you. So what are the near term -- what are the value drivers from our pipeline today and in the near term? Well, there's a lot. We have 3 commercial medicines now on the market that were approved over the last few years. SPINRAZA is the standard of care for all forms of spinal muscular atrophy. It's a miracle drug, changing the lives of patients with SMA of all forms. This drug, SPINRAZA will continue to perform well in the future, and we're very excited about the work that our partner -- our commercial partner, Biogen, is doing with this medicine. TEGSEDI, the first ever RNA-targeted therapeutic for the treatment of TTR amyloidosis. This drug is now available for patients with the indication of polyneuropathy, TTR amyloidosis, and is doing well. WAYLIVRA, the first and only medicine for the treatment of a rare disease called familial chylomicronemia syndrome or FCS, is now being launched by our commercial affiliate, Akcea, and is off and running and doing well. Right behind these commercial medicines is a number of Phase III programs that are performing well, doing well and are reaching the finish line to become available for patients in great need. These are transformational medicines potentially that are moving forward, 2 drugs for neurodegenerative diseases, terrible neurodegenerative diseases: our Huntington's drug, that is now in Phase III development; our first of many drugs coming forward for Lou Gehrig's disease, amyotrophic lateral sclerosis is advancing forward, targeting a form of ALS called SOD1-ALS. And then 2 other drugs that are being developed for broad indications: APO(a)-LRx, which was discovered at Ionis and co-developed with -- between Ionis and our affiliate, Akcea, is now in Phase III development for a very large population; and the follow-on to TEGSEDI, our newest chemistry called LICA, which I'll talk about more later on in my presentation, is now a follow-on to TEGSEDI, which will be -- is being developed for all forms of TTR amyloidosis. Right behind these 4 Phase III programs are more than 10 Phase II starts that are expected in our pipeline this year. More than 5 Phase III starts are expected between this year and next year following the 4 Phase III programs that are already in progress. And when we look ahead at what are the potential NDA submissions, new drug applications for the future, we're looking at more than 10 potential applications based on the productivity of our pipeline, the Phase III pipeline, between -- over the next 3 to 5 years or so. Very exciting performance from our pipeline. This is what our clinical pipeline looks like today. It is broad, it is large, and it is diverse, with more than 40 medicines in development, in clinical trials today, ranging from Phase III, as I mentioned, with a very robust Phase II pipeline that will continue to feed our Phase III pipeline for years to come; and of course, many drugs in Phase I. It is adverse, as I mentioned. The 2 largest franchises in our pipeline are in the cardiometabolic disease space and in the neurology drug discovery disease space. In addition, we have other rare disease drugs that we're developing that are performing well. And we're in infectious diseases, oncology, ophthalmology and in other areas. Our preclinical pipeline is also large, diverse and is very exciting. Last year alone, and this reflects the efficiency that our technology provides, more than 10 medicines reached development last year. Across many therapeutic areas, half of those were in the neurology disease space with many Phase I starts. And we're going to do the same thing this year with many new drugs entering development from our -- from utilizing our technology, on the delivery of new drugs into development, and we'll have many Phase I starts as well from our preclinical pipeline. I did want to draw your attention to the neurology preclinical pipeline. It is large, and it will get larger, and it's growing. I already showed you 6 medicines in our clinical pipeline for neurology. There's a lot more coming. And I want to spend a few minutes on our neurology platform. I believe that we have the premier #1 program for neurology drug discovery development in the industry, and it's coming, and it's growing. As we all know, neurological disease is a huge enormous unmet medical need. Yet, despite the fact that this unmet medical need exists, most pharma companies have exited neurology space or have slowed down their programs or have looked to other companies to access assets because their technologies, their small molecules, their antibodies are not delivering. They're failing because they don't -- they cannot target the root cause of these neurological diseases with the platforms that they have available to them. It's the exact opposite at Ionis. Ionis is delivering medicines for all kinds of neurological diseases. Today, we have a validated platform. We have proofed mechanism of action across all -- many different drug programs, many different diseases in neurology. We have proof of efficacy, proof of safety and commercial success, and we're not sitting still. Our drug discovery platform, our technology is improving even further in the neurology space, providing greater efficacy, less frequent dosing for patients. And we're even moving into new areas like neuromuscular diseases, where we're applying our drug systemically for neuromuscular diseases like Duchenne and myotonic dystrophy and so forth and so on. So we're not sitting still. These are the areas we're working in, in neurology today. It's very broad. If you can think of a severe unmet medical need in the neurology space, we're in it. This isn't just aspirational. These are drugs that are on the market, in clinical trials or will soon be in clinical trials in the future, broad diseases like Alzheimer's disease and Parkinson's disease, severe rare diseases like prion disease, Lou Gehrig's disease, Huntington's disease, Angelman disease. And the list goes on and on, and it will grow. This, of course, is the product of the Ionis pipeline and also the many partnerships we have in the neurology space. But I also want to emphasize the fact that the Ionis neurology drug pipeline is rich and growing and will continue to expand. The Ionis-owned pipeline is already in your severe epilepsies, for example, in your leukodystrophies, in your severe ataxia, there's prion disease, Lafora's disease, and a lot more is coming into the Ionis-owned -- Ionis-owned neurology pipeline is a top priority. And the Ionis-owned pipeline is not just limited to neurology. It goes well beyond neurology as well. We have a rich pipeline of medicines at mid-stage development for rare, non-neurological diseases, such as hereditary angioedema, acromegaly, beta-thalassemia as well as in the cardiometabolic space and renal space as well and in oncology. And again, this will grow as we go into the future. Okay. So what are some of the mid- and near-term commercial opportunities for Ionis from our pipeline these days and how are they performing? Well, there are many opportunities, and they're performing on track. We have 4 -- as I mentioned earlier, we have 4 Phase III programs in process right now that will potentially deliver transformational first-in-class medicines to patients in desperate need. Two of them are in the neurological disease space. Both are very severe diseases that I mentioned, the first being our Huntington's disease program. As a reminder, in our Phase I/II study, we demonstrated potent and substantial reductions in mutant Huntington, in patients with Huntington's disease with very attractive safety and tolerability. Based on these data, Roche licensed this program from us and is now in the middle of a pivotal Phase III study that's due to read out soon. In addition, we are well -- we are in the Lou Gehrig's disease space, ALS space, substantially. We are projecting multiple medicines for different forms of ALS, different causes of ALS. As a reminder, ALS has multiple causes, genetic causes as well as nongenetic causes that sometimes cause sporadic ALS. We are working in all these areas. And our most advanced drug targets a genetic form of ALS called SOD1-ALS, and this drug is in Phase III development. In our Phase I/II study with Biogen, we demonstrated not only potent and substantial reductions in mutant SOD1 protein in patients with ALS, symptomatic ALS, but we also provided strong evidence that these patients were doing better, looking at multiple clinical endpoints in our Phase II study. Based on these results, Biogen quickly licensed the program early and advanced this drug into Phase III development. This, of course, is great for SOD1-ALS patients if this drug performs well in Phase III. But it also bodes extremely well for all patients with ALS because it has the potential to be the first-ever disease-modifying drug for ALS in history. Two other drugs in Phase III target broad indications, and they utilize our most advanced chemistry called LICA chemistry, which I'll touch on a little bit more in a few minutes. One of these is our drug that targets a cardiovascular risk factor called APO(a). Think of APO(a) as cholesterol. When you have high levels of APO(a), you're at high risk for cardiovascular disease like stroke and heart attack and so forth. Unfortunately, there are no ways to manage high levels of APO(a) despite the fact that this disease afflicts approximately 8 million to 10 million people worldwide. In our Phase II study with our affiliate Akcea, we demonstrated that we can normalize essentially in all patients with high Lp(a) levels and cardiovascular disease in a Phase II study with excellent safety and tolerability with this medicine. Based on these results, Novartis licensed the program and advanced this drug into Phase III testing, which is underway now in a broad cardiovascular outcome trial that's due to readout in the near future. Our other drug, our fourth drug that's in Phase III development today is also for a broad indication. As I mentioned, it's the follow-on to TEGSEDI, our LICA medicine, that is indicated -- we believe, it will be indicated for all forms of TTR amyloidosis. And we believe it will be the best product for all forms of amyloidosis in the future. Our Phase I data with this medicine showed substantial and potent reductions of TTR levels in our normal volunteers, greater than 90% and with also with excellent safety and tolerability. What does the future look like for new medicines that will potentially reach commercialization? It's pretty bright. Shown on this slide, you can see the -- really a tidal wave, if you will, of potential new drug applications over the next few years. And you can see it building. Next year, we're projecting data readout and a potential filing for SOD1-ALS with our partner Biogen. And then you could see year-over-year, more and more medicines potentially reaching filing for potential drug approvals for diseases as broad as the ones I described, Lp(a) and other cardiovascular broad indications, just like our angiopoietin-like 3 program and HBV and in the severe indications like beta-thalassemia and Huntington's and, as I mentioned, SOD1-ALS and our TTR LICA program. Really, really a bright future for commercial products for Ionis Pharmaceuticals. So what about technology. We're a science-driven organization, now with innovation at our core and that will continue to be the case years to come. And we continue to advance the technology to expand the scope at Ionis. We're making substantial investments to do this, including improving and optimizing and further optimizing the screening process by which we identify the drugs that we move into the clinic. The goals here and what we're achieving are more drugs, better drugs, and we're moving into the clinic faster. We're making substantial investments in human genomics to identify novel targets, to continue to feed into our pipeline for years to come, genetically validated targets. I believe we have the most robust, the largest pipeline of genetically linked targets, genetically linked to human disease targets in the industry, and we're going to continue that. Genetic investments, of course -- genomic investments, of course, also increase the probability of success in your clinical trials because you have more confidence that the drugs are going to be successful in those studies based on the target that you select. We continue to pioneer new routes of delivery, expanding the scope of antisense, as we did in the central nervous system for our neurology drug discovery program, we continue this. We have an oral program that's now in clinical trials. That will read out later this year. A once-a-day tablet for a cardiovascular indication that we think we have -- based on technology that we developed, that we think we've achieved commercially viable oral delivery. Very exciting. And as is our pulmonary program, where we've optimized delivery to the lung. And we're expecting data, potential validation of that approach later this year, which could open up many new opportunities for Ionis in -- for pulmonary diseases, such as IPF and COPD and severe asthma and so on. And of course, we are the leaders in medicinal chemistry of oligonucleotides, and we continue to grow our leadership margin compared to everyone else in the field, and we continue to invest in medicinal chemistry. We're developing new chemistries that will expand the reach of our drugs to even more organs, more cell types, provide more convenience to patients with very infrequent dosing as well as oral delivery and overall enhance the performance of our drugs from a safety and tolerability profile as well. One of the biggest breakthroughs in antisense medicinal chemistry at Ionis over the last couple of years, over the last few years, has been our LICA platform. As a reminder, LICA chemistry is a chemistry that delivers the medicine directly to the cell type of interest while minimizing exposure to other organs and cell types in the body. This strategy greatly enhances drug performance by improving potency substantially, improving patient convenience substantially by requiring less frequent dosing, as I mentioned, opening up new organ systems and cell types as well. We have validated our LICA platform in 2 organ systems today. One of those is in the pancreatic beta cell, which is really an amazing accomplishment considering the fact that antisense drugs without a LICA chemistry do not get into pancreatic beta cells at all, completely refractory to antisense drugs. However, with our LICA chemistry, we have proven that we can get these drugs into the beta cells with exquisite potency and with excellent safety and tolerability so far in preclinical models. And our late-stage drug discovery program is now capitalizing on this. And we expect new drugs for diabetes, for example, to reach clinical testing and development in the near future. The other organ system, of course, is our liver-LICA platform, which is, of course, where we have our greatest experience. We have demonstrated across essentially all of our medicines, our LICA medicines, for liver targeting in the clinic, substantial improvements in potency on the order of 20 to 30 fold or greater compared to our non-LICA counterparts, with enhanced dosing flexibility as once-a-month or once-a-quarter subcutaneous dosing for these medicines. This is what is enabling oral delivery, as I mentioned earlier. So we believe that the Gen 2.5 chemistry with LICA will make commercially viable oral delivery feasible and with excellent safety and tolerability. And I say that based on a wealth of data from our database in which we have tested more -- 16 LICA medicines in the clinic, more than 1,000 patients treated to date and hundreds of patients treated for up to a year with excellent safety and tolerability. So stay tuned for this. This is what our liver-LICA platform looks like. It's broad. It's diverse, and it will continue to grow. As not a surprise, with the pipeline is productive as ours and a technology that's advancing as much as ours, there will be numerous catalysts, potential catalysts, a lot of news coming out of the Ionis pipeline and with our technology this year, as it has been in the past; with new clinical trial starts; multiple new Phase III studies that will begin this year in addition to the 4 that are already in progress, we already announced 1 last week, our TTR LICA for cardiomyopathy is now in Phase III development for that as well as in polyneuropathy; many new Phase II initiations as well and clinical readouts; clinical readouts such as our APOCIII LICA drug for cardiovascular disease and angiopoietin-like 3 LICA drug for cardiovascular disease and other areas as well; as well as technology improvements such as our oral data that we're expecting to read out this year; and as I mentioned before, our pulmonary program is expected to read out this year, which is very exciting. So to wrap up and provide a few take-home messages for you. As a reminder, again, this is a technology, RNA therapeutics that we pioneered, validated and have now delivered to the biotech sector, to patients in great need. And we believe that our leadership will grow in the future based on the advancements we're making. We have a very strong financial position that's allowing us to do all the things we want to do to make Ionis the very best in the industry. We're advancing the pipeline. We're also advancing the technology. And the Ionis-owned pipeline is a top priority. And it will continue to grow as we build commercial capabilities to maximize commercial value for the Ionis-owned pipeline for years and years to come. Obviously, this builds tremendous momentum for Ionis today. We have tremendous momentum today, and we're going to build off that momentum today and in the future to raise Ionis to even greater achievements, greater highs and greater successes well into the future. Thank you. Good morning, everybody. Hi. Welcome, and thanks for coming. My name is Brett Monia. I am with Ionis Pharmaceuticals, and I am the Chief Executive Officer, and joining me is Beth Hougen.

Good morning. I'm Ionis' Chief Financial Officer. I'm happy to be here.

Happy to take questions. Any questions? Yes.

I have [ a few ] questions. So congratulations. I'm curious, your perspective on how you're going to be as CEO now versus the prior Founder and CEO. In that style, is it the same style? Or you're going to maybe make some changes on anything in terms of facing more the investors?

Good question. Thank you. So the question was how will things be different, will change under my leadership versus our Founder -- Founder's leadership -- our Founding CEO's leadership, Stanley Crooke. Things that worked really well and do -- and we're very good at will continue. We will continue the commitment to science and innovation and in technology and to maximize the reach of antisense by investing in the science. New areas that will be basically a product of the evolution of the company, with the financial strength that we have in the organization, all that gives us the leverage to do a lot more than what we were able to do, and that's what I want to do. In addition to everything that is working very well at Ionis today, we will prioritize the Ionis-owned pipeline and invest in that. We'll invest in new technologies to expand the reach of antisense, and we will develop our commercial capabilities to maximize commercial value of the Ionis-owned pipeline. With respect to visibility, I guess, was the other part of your question, yes, I'll be a lot more outwardly facing. I'll be a lot more available. And one of the aspects that I prioritize, as I get to know more and more individuals in the investor community, is trust. And trust is something that I really want to establish. I want the people to have access to me. I want people to trust me, and I want to -- and I will be transparent with you. And if I ever slip up, let me know.

That sounds good. One of the other debates with the stock, at least the ones my peer says, what will happen when the PTC-Roche drug is approved and how that will impact SPINRAZA. So how would you kind of frame the, I guess, bullish argument for Ionis under that scenario, the approval of that drug.

Sure. And maybe I'll ask Beth to answer that, and I could add to that.

Sure. I'm happy to. So the question is what's the impact, if any, on SPINRAZA and its growth potential when the oral splicing modulators is approved, if approved. So let me start by saying that SPINRAZA delivered another blockbuster year in 2019 with substantial growth quarter-over-quarter and year-over-year. There are now -- they delivered over $2 billion in product sales in 2019 with more than 10,000 patients now on SPINRAZA. So again, a transformational medicine with a substantial -- just a wonderful efficacy and safety profile and a very strong performance in the market. It's approved across 50 different countries. And that is continuing to grow. So from our perspective, while there may be some individuals for whom an oral medication is suitable, we believe that the efficacy and the safety, that's all supported by many, many, many patient years of experience with SPINRAZA, is setting an extremely high bar for the competition. So right now, we're not seeing anything other than continued growth opportunities for that medicine, for SPINRAZA.

And I'll just add to that, and it's very hard to speculate also on the competitive landscape as there's so little data available for the competitors. So it's difficult to speculate. What we know is SPINRAZA. And SPINRAZA, as Beth said, is performing, and we believe and Biogen has said that it will continue to perform and grow in the future.

I have one more. So one of your smaller programs or newer programs, the Angelman syndrome. Could you just compare and contrast that technology or how you're trying to impact that syndrome versus another company, Ultragenyx?

Well, Ultragenyx is taking a similar approach to Ionis, but what they're doing is using older chemistries to target the same sort of mechanism that we're doing. We, of course, have the most advanced chemistries. We have the most advanced screening processes to develop drugs for RNA-targeted therapeutics. But the mechanisms are similar, but they don't have the experience that we have, nor the chemistries that we have and the technology we have to offer.

Are you -- when are you going to have data for that?

We're planning to start clinical trials this year, so it will take some time.

Can you maybe just talk a little bit about some of the milestones coming out. But one of the challenges in really understanding the story and its completeness is just understanding what some of the target dates are for the clinical programs and some of the readouts. Any additional transparency you can provide in kind of the near term at least or the next 12 months?

Sure. And so the question is what are some of the near-term readouts from Ionis. I'll take a crack at that. Beth, if I miss anything, please jump in. In the near term, we're expecting Phase II data from the APOCIII LICA program. This is obviously a LICA medicine. That is in patients with high triglycerides and cardiometabolic diseases. This is being developed with our commercial affiliate Akcea, and data is expected to read out soon. In addition, the Phase II program for angiopoietin-like 3 LICA in patients with high triglycerides, fatty liver disease and cardiometabolic disease is coming to a conclusion. And that data -- remember, that program was licensed to Pfizer last year while the Phase II study was in progress, and that data we're expecting to read out in the near term as well. In addition, more towards the second half of the year, we have data coming from our oral program, which is for a cardiovascular indication, our pulmonary disease program and other rare diseases such as our hereditary angioedema program and our acromegaly program. And I think that covers it. Anything I missed?

Beta thalassemia. TMPRSS6.

Yes. So we have an ongoing open-label study, Phase II study, for -- with our TMPRSS6 medicine for beta-thalassemia intermedia. So we will be monitoring that study on an ongoing basis. And it's possible that we'll also be able to provide updates on that program second half of this year. Remember, this is a -- this, I believe, is a very exciting drug. That has the potential not only for beta-thalassemia intermedia but also alpha thalassemia and MDS and potentially other indications that are related to low hepcidin levels. And we showed in a Phase I clinical trial that we were able to achieve very impressive biomarker results, effects on iron, effects on transparent saturation, effects on hepcidin levels and so forth. So it's possible that we'll read that -- we'll have some data to read out on that second half of this year.

Sorry, just, Brett, you mentioned 2 programs to read out in the near term. What does that mean, near term? Is that like this quarter or next quarter?

Let's just say soon.

Any update on the Huntington's program?

Yes, sure. You want to? I can do it, and you can fill in.

Yes.

So updates on the Huntington's disease program. Obviously, we're very excited about that -- this program. Roche is very excited about this program. A lot of attention is being devoted to this program. The Phase III program is on track and is enrolling briskly and is due to -- and Roche said that the Phase III data is due to read out in the 2022 time frame, at the latest. In addition, the open-label extension study and the natural history study that's in progress, that is a mirror image, if you will, of the patient population in the open-label study is moving along. Roche is planning to review that data towards the end of this year. And depending on opportunities to present the data, they will either present it late this year or, more likely, early next year, first half of next year on that program.

Yes. You may see some incremental updates over the course of the year. But I think the clinical data that people are looking for is likely going to be, I would imagine, late this year, early next year, as Brett said.

Yes, congrats, Brett. I was just wondering, as long as they just have that considered for a long time for [indiscernible] R&D programs, so what sort of changed in terms of your thoughts on pulmonary diseases or your CF program? Why do you think this could be more successful?

So what have we done compared to the past to believe and have confidence that our pulmonary programs will be successful is the question. Thanks for that. It's a good question. As I'm sure you know, based on your question, we have tested oligonucleotide therapies in the clinic in the past with earlier generation chemistries, Gen 2.0 chemistry. One program -- the program was targeting IL-4 receptor alpha. And in that program, we did show target engagement in the bronchial brushes as well as good safety and tolerability, but we didn't have the potency that we needed to make it work as a once-a-week inhaled dose. So we -- as we usually do, we went back and improved the technology. We started beginning to look at Gen 2.5 chemistry, which is about 5 to 10-fold more potent than Generation 2.0 chemistry. We did a lot of preclinical work. We did testing in animal models of various forms of fibrosis, including CF, including models that had thick mucus linings. And we were able to show substantial target engagement, efficacy and even reversal in models of CF. So that gives us the confidence. Of course, we have to prove it. And we have this study -- a study in progress and more coming, delivering our drugs by aerosol. The first program targets the sodium channel in the epithelium, the ENaC target. And that's in normal volunteers, wrapping up now. And we will also examine the performance of the drug in some patients with cystic fibrosis as well. This drug has the potential to be an agnostic drug for -- regardless -- agnostic to mutation for cystic fibrosis. So it could be added on to CFTR modulators potentially, if it's successful, but it goes beyond CF. We're also planning to develop this drug for chronic bronchitis and potentially severe asthma and other indications as well. And it's the first of multiple drugs that are in our pipeline that we're bringing to the clinic. Other questions?

What about Akcea? You guys have a substantial investment there. The management has turned over. How can you, I guess, better either monetize or get more value for Ionis from that affiliate?

The question is about Akcea and how to get -- bring more value to Ionis from our commercial affiliate, Akcea. So we're very excited about Akcea's future. We think Akcea is on the right track to deliver a lot of value in the future. Under Damien McDevitt, our interim -- he's the interim CEO at Akcea, I believe that organization is well on track to deliver a lot of value in the future. He's done a fantastic job in organizing and moving the company forward. And the value is going to come from their agenda. They have a really exciting agenda, and it's -- it goes well beyond TEGSEDI and WAYLIVRA. Getting WAYLIVRA approved in the U.S. is the #1 objective, which, of course, there's no competition for...

What's going on with that? Because that's been talked about for...

We're having very productive discussions with regulators on WAYLIVRA to get it across the finish line in the U.S., and we're hoping to advance it forward this year.

But there's no new studies that have been done since the response letter. Is that correct?

There are no new studies for WAYLIVRA that have been done, except for the partial lipodystrophy study, which read out. What there is, is a lot of data. That wasn't available to regulators when we filed originally. There's data from the partial lipodystrophy study, which was very positive, excellent safety with efficacy, reduction in liver fat. We also have a substantial amount of data from ongoing open-label extension studies that we're continuing around the globe as well as the commercial launch. So there's a lot more data. The agenda goal for Akcea goes well and beyond TEGSEDI and WAYLIVRA, though, it also includes TTR LICA, which we believe will be the drug of choice for all forms of TTR amyloidosis in the near future. Akcea has that to commercialize as they do APOCIII LICA, which is really an amazing-looking drug for -- as a follow-on to WAYLIVRA for FCS, potentially partial lipodystrophy as well. And even broader indications like the above 500 triglycerides and maybe even broader indication beyond that, the lower than 500 triglycerides. So Akcea has a lot of opportunity to bring tremendous value to themselves and to Ionis well into the future. And we're excited about them.

I was wondering if you could provide an update to the C9ORF72 program as well as any updated thoughts on approaching sporadic ALS.

Yes. So how are the other drugs in addition to SOD1-ALS performing and what should the expectations be? Yes, we're very excited about ALS. I tried to highlight that in my short presentation that we're going after, with Biogen, to tackle all forms of ALS, sporadic and genetic. SOD1 is the first of many. Our C9ORF, which represents a population at least 5x larger than SOD1-ALS, the genetic form of ALS, is in Phase II development. And it's progressing on track, and it is due to read out from the Phase II study next year. For sporadic ALS, we have active drug discovery programs with Biogen well underway, and we're expecting new drugs to reach development in the near term for sporadic as well. Yes, sir?

Regarding your commercial U.S. products, are you facing any [ competition ] from generic manufacturers at the press conference?

Generic competition? No. We have no generic competition for SPINRAZA, TEGSEDI or WAYLIVRA at this time. Other questions?

Since you mentioned WAYLIVRA, so what is the [ status ] in the U.S. at this time, [indiscernible] probably submitted? What's going on specifically in that?

We have had -- the question is what is the status of discussions with regulators on bringing WAYLIVRA to potential approval in the U.S. All we're saying at this time is that we've had productive discussions with regulators last year, and we're continuing them this year, and we're paving a path forward to a potential filing in the near future. But that's what we're saying about that. We also -- I would also add to that, that there's a lot of interest from the patient advocacy community in the United States that is also expressing a strong desire to get this drug available in the U.S., not just in Europe. Other questions? If not, I guess we'll wrap up. Everybody, thank you for coming. Have a great day, and enjoy the rest of your meeting.