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

Good afternoon, and welcome to Ionis' 2023 Annual Meeting Corporate Update Call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Wade Walke, Senior Vice President of Investor Relations, to lead off the call. Please begin.

Thank you. Hello, and thank you for joining us today on our annual meeting and corporate update. Before we begin, I encourage you to go to the Investors section of the Ionis website where we have posted our slides accompanying today's call. We will be hosting a live question-and-answer session at the end of our prepared remarks today.[Operator Instructions] I would first like to draw your attention to Slide 3, which contains our forward-looking statement. Our discussions today will contain forward-looking statements based on our current expectations and beliefs. Such statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail. I would also like to remind you that eplontersen is an investigational medicine that is currently under regulatory review in the U.S. On today's call, we have Brett Monia, our Chief Executive Officer, who will provide a company overview; and Beth Hougen, Chief Financial Officer; and Onaiza Cadoret, Chief Global Product Strategy and Operations Officer, will join us for the Q&A portions of the call. And with that, I'll turn the call over to Brett.

Thanks, Wade. Hello, and thank you to everyone for joining us. Today marks the midpoint of the year, making this a great opportunity to recap our key strategic priorities, our year-to-date achievements and preview key events coming up in the second half of this year. Before looking at our achievements, let's briefly review our 4 key strategic priorities: First is to deliver an abundance of genetic medicines to the market. Second is to establish an outstanding commercial organization as we prepare for our first independent product launches. Third is to extend our leadership position in oligonucleotide therapeutics by expanding the reach of our technology. And fourth is to ensure we have the financial strength to invest in all key areas that represent the greatest opportunities to drive growth in the near and in the long term. We believe the achievements we're making to advance these key priorities put Ionis in a strong position to reach our goal of driving substantial and sustained growth. And today, our pipeline and technology are delivering and moving us closer to achieving this goal. Our near-term commercial opportunities are performing well and nearing the market. Following eplontersen's positive Phase II results in ATTR polyneuropathy, we look forward to approval in the U.S. in December. We're also preparing to submit additional filings outside the U.S. this year. And we expect to complete enrollment in the eplontersen Phase III CARDIO-TTRansform study in patients with ATTR cardiomyopathy soon. For olezarsen, we expect results from the FCS BALANCE study in the second half of the year, while enrollment in our registrational studies for the larger sHTG indication continued to progress. For donidalorsen, we just completed enrollment in our OASIS-HAE Phase III study, keeping us on track for data in the first half of next year. And we're well on our way with our preparations to launch all 3 of these drugs. And the rest of our late-stage Phase III pipeline is also performing well and has recently expanded to 8 drugs advancing to treat 10 separate indications. Further, our neuro franchise continues to lead in our industry. SPINRAZA remains the global market leader in SMA, demonstrating sustained resilience in the face of competition with the potential to return to growth in the future. And tofersen, now referred to as QALSODY was recently approved in the U.S. for the treatment of SOD1-ALS, joining SPINRAZA as our second approved medicine to treat a devastating neurodegenerative disease and making it first treatment ever approved for a genetic form of ALS. Following SPINRAZA and QALSODY, we have 12 neurological disease drugs advancing in the clinic today, with more drugs expected to enter the clinic soon. We're also making great progress in expanding and optimizing our drug discovery capabilities through advancements in our technology which I'll discuss further in a few moments. Now let's dive a little deeper into each of our near-term commercial opportunities, eplontersen, olezarsen and donidalorsen, which collectively represent a potential multibillion-dollar product opportunity. Our first commercial launch anticipated for early 2024 for eplontersen in ATTR polyneuropathy involves a co-commercialization arrangement with AstraZeneca in the U.S., with AZ responsible for ex U.S. commercialization. The same arrangement is in place for eplontersen for the much larger ATTR cardiomyopathy indication, assuming approval, of course. We and AstraZeneca are working hand in hand with a shared global strategy to address this dynamic market and to bring eplontersen to patients with ATTR polyneuropathy. We're finalizing our preparations to launch eplontersen following a potential U.S. approval in December. We're developing eplontersen to treat the 2 primary forms of ATTR amyloidosis: ATTR polyneuropathy and ATTR cardiomyopathy. Caused by a mutation in the TTR gene, ATTR polyneuropathy has an addressable population of approximately 40,000 patients worldwide. However, fewer than 20% of these patients are receiving approved treatments today. Based on eplontersen's strong overall product profile, we believe, if approved, eplontersen will be an important treatment for this largely untapped patient population. ATTR cardiomyopathy is a substantially larger patient population with an estimated 300,000 to 500,000 patients worldwide. So ATTR amyloidosis represents a broad global commercial opportunity for eplontersen with a significant unmet medical need. We believe that eplontersen has the profile to meet the needs of these patients. And with our deep expertise in ATTR amyloidosis, together with AstraZeneca's global scale, we're confident in our ability to capture a significant portion of these patients around the world. As we reported at the AAN meeting in April, eplontersen met all primary and all secondary efficacy endpoints in the Phase III NEURO-TTRansform study. In this study, we demonstrated robust and sustained reductions in serum TTR, a halting of neuropathy disease progression with approximately half of patients treated with eplontersen experiencing improvements in neuropathy as measured by mNIS+7 as compared to their baseline study entry values. And approximately 2/3 of these patients experienced improvements in quality of life as measured by the Norfolk Quality of Life questionnaire. And eplontersen also demonstrated a favorable safety and tolerability profile throughout the study. Physicians in our advisory boards have also told us that they believe eplontersen's self-administration profile using a simple auto-injector will be particularly attractive for patients they treat in their practices. Based on these data and its strong overall profile, we're confident in eplontersen's potential to be an important new treatment for patients with ATTR polyneuropathy. The positive efficacy and safety results from the NEURO-TTRansform study also increases our confidence in our ongoing CARDIO-TTRansform study in patients with ATTR cardiomyopathy. CARDIO-TTRansform is the most comprehensive study in this patient population tested to date. We designed and have amended this study to reflect today's ATTR cardiomyopathy treatment landscape, which we believe positions us well to demonstrate benefit with eplontersen in a broad set of ATTR cardiomyopathy patients. We remain on track to complete enrollment in CARDIO-TTRansform midyear with data anticipated in 2025. Shifting gears to our next near-term Ionis commercial opportunity, olezarsen. Olezarsen is potentially our first-in-class treatment for 2 diseases driven by severely elevated triglycerides: FCS, which is a rare and genetically driven disease; and SHTG, which represents a broad patient population. Acute pancreatitis is a well-recognized risk associated with severely elevated triglycerides. It can be fatal and often leads to degeneration of the pancreas. Further, a patient's risk increases exponentially with each acute pancreatitis attack. The first of our 2 indications for olezarsen is familial chylomicronemia syndrome or FCS. FCS is a rare genetic disease characterized by serum triglyceride levels at the top of the range among patients with severely elevated triglycerides. In fact, FCS patients' triglycerides are often so high, their blood appears milky white. These patients are at extraordinarily high risk for acute pancreatitis and experience several other serious clinical symptoms and have very limited treatment options. The second indication, severe hypertriglyceridemia, or sHTG, is a much larger global opportunity impacting millions of patients in the United States alone. These patients are also at substantially increased risk for acute pancreatitis. And similar to FCS, there are very few treatment options to effectively manage their severely elevated triglyceride levels. Olezarsen targets APOCIII, a new approach for reducing triglycerides. And based on the significant triglyceride reduction seen with olezarsen in our Phase II studies, we believe that olezarsen has the potential to provide significantly greater benefit for patients underserved by the current standard of care. Our olezarsen development program for these 2 indications is progressing well. For FCS, the Phase III BALANCE study is fully enrolled, and we remain on track for data in the second half of this year. Assuming positive data, we plan to file for regulatory approval for olezarsen in FCS in the U.S. early next year, and we remain right on track to launch in this indication, assuming approval. And for sHTG, we continue to be pleased with the progress we're making in our comprehensive Phase III program for this broad indication. Our third near-term Ionis commercial opportunity is donidalorsen, which we're developing as a prophylactic treatment for hereditary angioedema or HAE. HAE is a severe and rare genetic disease caused by disregulation of the prekallikrein pathway. This disregulation is unpredictable, is often severe and can be fatal. The overall donidalorsen efficacy, safety and administration profile emerging from our Phase II in ongoing open-label extension study suggests that donidalorsen could really be an attractive and differentiated prophylactic treatment option for patients with HAE. We presented robust efficacy and safety results from our Phase II study last year. And more recently, we reported data from the Phase II open-label extension study in patients treated for 1 year, which showed sustained long-term efficacy with a reduction in HAE attack rates consistent with the results from the Phase II study, demonstrating greater than 95% reduction in HAE attacks. In addition, more than 85% of patients in the open-label extension reported a clinically meaningful improvement in their angioedema quality of life scores with improvements observed in all domains. We also examined the potential for dosing every 2 months in this OLE and reported that 75% of patients who transitioned to bimonthly dosing remained attack-free, demonstrating the potential for dosing flexibility as a self-administered once per month or once every 2 months treatment option. And importantly, over this extended time period, we continued to observe a favorable safety and tolerability profile. And just this morning, we announced our results from our 2-year open-label extension study, further reinforced donidalorsen's competitive profile. We look forward to presenting these new 2-year OLE data at a medical conference later this year. We also announced today that enrollment in our Phase III OASIS-HAE study is now complete, keeping us right on track for data in this study in the first half of next year. Furthermore, our SWITCH study evaluating the safety and efficacy of donidalorsen in patients who have switched from other HAE prophylactic treatments is continuing to progress well. Turning attention now to our neurological disease franchise, we continue to lead the field with RNA-targeted medicines for neurological diseases as further demonstrated by the approval of QALSODY patients with SOD1-ALS. Coming behind QALSODY, we have 12 medicines in clinical development for both severe rare diseases and broad neurological disease indications. No other company has the breadth and depth of experience that we do in developing RNA-targeted drugs for neurological diseases. And we continue to innovate in this space. Today, we're implementing less frequent dosing regimens, including quarterly, semiannual and potentially annual dosing, and we continue to expand our neuro pipeline with new drugs expected to enter clinical development later this year and next year. The recent approval of QALSODY represents a landmark accomplishment for the ALS community and for Ionis and our partner, Biogen, as the first product ever approved for the treatment of a genetic cause of ALS. QALSODY's approval was based on the reduction in plasma neurofilament light chain, or NfL, a marker of neuronal damage that directly correlates with disease progression in ALS patients. QALSODY's approval was also strongly supported by the 12-month integrated clinical results from the Phase III VALOR study and the open-label extension. In the integrated results, QALSODY showed trends towards slowing decline in measures of clinical function, respiratory function and muscle strength in patients in the earlier treatment group. Additionally, QALSODY demonstrated a favorable safety profile. QALSODY is now launched in the U.S. and is under review in Europe for potential market approval with the regulatory action expected later this year. In the ongoing Phase III ATLAS study of QALSODY in presymptomatic SOD1-ALS patients is also progressing well. QALSODY is our first anticipated success in ALS. Today, we have 2 additional clinical programs targeting different causes of ALS. ION541, also known as BIIB105, is in Phase II development with Biogen for nongenetic ALS. And we have ION363, now known as olefnerson, which Ionis is developing for a genetic cause of ALS that involve mutations in the FUS gene. The Phase III study is enrolling well with data expected in 2025. We're also quite encouraged by recently reported data from the Phase Ib study of IONIS-MAPTRx in patients with mild Alzheimer's disease. MAPTRx is designed to reduce tau protein production and aggregation, which is strongly associated with progression of dementia in patients with Alzheimer's disease. Results from the Phase Ib study in early AD patients treated for up to 100 weeks showed a rapid, substantial and sustained reduction in tau pathology, as measured by both tau levels in CSF and tau PET imaging. In fact, MAPTRx is the first drug to date to demonstrate this magnitude of reduction in tau pathology, which was demonstrated across all relevant brain regions and patients in this study. Biogen is advancing the Phase II CELIA study of MAPTRx in patients with early AD, evaluating both quarterly and semiannual dosing regimens. With the potential for semiannual dosing, our MAPT drug is just another example of advances we're making with our technology to further enhance the profile of our drugs to treat severe neurological diseases. Turning attention to our late-stage partner programs, all of which are on track and performing well. Our partner, Novartis is advancing pelacarsen for LP(a)-driven cardiovascular disease in Lp(a)HORIZON cardiovascular outcome trial. This study completed enrollment last year with more than 8,000 patients, putting it on track for data and potential regulatory submission in 2025. We also expanded our late-stage Phase III pipeline this year to 8 drugs advancing in 10 separate indications when GSK initiated the Phase III study of bepirovirsen in chronic HPV and Roche initiated the Phase III study of IONIS-FB-LRx in IgA nephropathy. And our expanding late-stage pipeline sets us up for a steady and growing cadence of data readouts this year, next year and for many years to come, increasing the potential for a substantial number of new Ionis medicines to reach the market. And here is how we see our pipeline advancing to the market over the next several years. Today, with the addition of QALSODY, we have 4 medicines on the market. And later this year, we look forward to the approval of eplontersen in its first indication, ATTR polyneuropathy, followed by the potential approvals of olezarsen for FCS and donidalorsen for HAE. Following quickly after these, we anticipate our next approved medicines will address much larger indications. These include olezarsen for its second indication, sHTG, eplontersen for its second indication, ATTR cardiomyopathy, pelacarsen with Novartis for LP(a)-driven cardiovascular disease and bepirovirsen with GSK for chronic HPV. Of course, there will be more to follow from our mid-stage pipeline, setting us up for substantial sustainable revenue growth for many years to come. Furthermore, we continue to scientifically innovate and our innovation will enable us to continue advancing our technological capabilities in oligonucleotide therapeutics. We believe the advancements we've made and continue to make with our technology will further enhance the competitive profile of the drugs we advance into clinical development in both the near term and in the longer term. Our most recent technology achievement was to advance our first Bicycle conjugated medicine into preclinical development. It uses a muscle-targeting ligand to deliver an oligo drug to heart tissue for the treatment of heart failure. The Bicycle ligand we're using finds the transferrin receptor designed to deliver oligonucleotide drugs to skeletal and cardiac muscle. This technology is designed to provide a therapeutic profile for muscle targeting similar to those of our current LICA drugs that are targeting the liver. We look forward to providing more details about this program and other Bicycle conjugated medicines as these programs advance in development. Our advancements in technology don't stop here. Beyond using our extensive expertise to enhance the profiles of our neurological disease drugs, we've also made important advancements that we believe will enhance the profiles of our systemic subcu drugs, including using our novel MsPA backbone chemistry to extend dosing intervals. Of course, all the great progress we're making our strategic priorities would not be possible without a commitment to responsible management of our financial resources. As we advance eplontersen, olezarsen and donidalorsen to the market, we expect our investments to increase as we advance our large Phase III programs for these drugs and build our commercial capabilities to ensure successful commercial launches. We have taken several steps to bolster our balance sheet to ensure we maintain the financial strength to successfully bring these medicines to the market. We believe our strong financial foundation positions us well to bring a steady stream of important new products to the market and drive value for all stakeholders. Looking ahead to the rest of this year, we anticipate a number of key events still to come, including regulatory decisions and late-stage pipeline achievements. These include: a QALSODY regulatory action for SOD1-ALS in Europe; our first potential approval for eplontersen for ATTR polyneuropathy in the U.S. in December, along with submissions for regulatory approval in additional countries; completion of enrollment in the eplontersen Phase III CARDIO-TTRansform study in ATTR cardiomyopathy midyear; data from the olezarsen Phase III FCS BALANCE study in the second half of the year; and longer-term safety and efficacy data from the donidalorsen Phase II open-label extension study in HAE patients treated for 2 years, also coming in the second half of this year. We will keep you updated on our progress on these events and more throughout the rest of the year. As we continue to innovate in the advancement of our pipeline and our technology, we remain committed to thoughtful corporate responsibility across all aspects of our business. We believe that doing the right things for our patients, our employees, the environment and our communities matches perfectly with our core principles and our culture. So to wrap up, Ionis is doing extremely well today. Over the last couple of years, we persevered through some significant changes. We've endured some challenges with a few disappointments but have emerged well positioned to achieve all our strategic goals and realize our vision to be the leader in genetic medicine. We are continuing to deliver on all 4 of our key strategic priorities, which positions us for accelerated growth across the business. We have numerous attractive near-term product opportunities that are rapidly approaching the market. Our rich late-stage pipeline is advancing and expanding, setting us up for numerous new product opportunities for years to come. We are now a fully integrated biotech company, and our R&D and commercial organizations are working hand-in-hand to achieve commercial success on par with the R&D excellence Ionis has always been known for. And we're making great strides in expanding our leadership position in genetic medicine by further enhancing our platform capabilities. We look forward to sharing our progress as we build on our recent achievements and accomplish all our important objectives. We'll now move into the question-and-answer portion of our webcast. [Operator Instructions]

So we got several questions come in. I'll start with the first one. The Phase III eplontersen data look great. Now that you have these results in hand, how do you see this drug differentiating from the competition?

Thanks. Great question. We are really enthusiastic, excited about the eplontersen, and we agree that the Phase III data in polyneuropathy does look great. We also believe that this is a great market opportunity estimated beyond $10 billion or so for both polyneuropathy as well as cardiomyopathy. And we believe that we have a very, very competitive profile to have a significant impact to deliver eplontersen to a large number of patients once we get this drug potentially launched. I'd like to hand it over to Onaiza Cadoret to talk a little bit about how we feel eplontersen will compete in the market, some of the advantages of the drug and how it differentiates.

Sure, I'd be happy to. So we're preparing very actively for a co-commercialization launch with AstraZeneca. It's a really great collaboration where you're bringing the strength of both the commercial depth and the scale of AZ with our great deal of expertise in amyloidosis for well over a decade and our rare disease expertise together. We think this is very complementary and that is our go-to-market approach is to really leverage the both -- best of both companies and what they bring. As Brett said in his opening remarks that we're very, very pleased with the data that we got on polyneuropathy at week 66 as well as our interim data at week 35. What we like about it is that it's very, very consistent from the 35 week to the 66 week. We showed a great substantial sustained reductions in TTR that we were able to maintain throughout the full period. That bodes really well for the durability of TTR reductions we're going to see in our clinical profile. And we see that in our mNIS+7, which is one of the second co-primary clinical endpoints that we have and then Norfolk Quality of Life. We really like the Norfolk Quality of Life continuing to decline. We actually haven't seen it later yet at our week 66. We do believe this is going to be really important clinically to physicians. This is the tool that they use to assess the progress and the symptoms of the patients, and our responder analysis from baseline looks excellent where we show patients not just halting their disease progression but showing improvement in both mNIS+7 as well as in Norfolk Quality of Life. We believe these are really strong clinical areas that we're going to continue to pursue in the marketplace. And then on the nonclinical side, we do have a self-administration subcu at-home auto-injector with very low volume. We believe this continues to become another differentiator for us as this empowers patients to take control of their disease and also for physicians to have the ease of seeing their patients not always in the office for an administration by a health care professional as well. So all in all, we're very excited for launch, and the teams are really getting into place for launch readiness.

Thank you, Onaiza. Next question.

What drugs do you think are most underappreciated in your pipeline?

Good question. So obviously, eplontersen and donidalorsen for our near-term commercial opportunities get a great deal of attention and deservedly so. These are great-looking drugs that are, we think, are rapidly approaching the market. But I would have to say, and I think my team would agree, that a triglyceride drug, a drug to manage severely elevated triglycerides, olezarsen, which is in Phase III development for 2 indications, as I highlighted earlier, a rare genetic cause of severely elevated triglycerides, FCS and then the much broader, larger indication, sHTG are all on track. And again, the FCS Phase III data is expected to readout soon in the second half of this year. And we expect to be first to market for this indication. It's not that well appreciated. I do believe that there's some confusion as to how -- what the unmet need is in patients for severely elevated triglycerides. We've done a great deal of market research, working on KOLs, investigators, patient communities. And we are really excited about this patient -- this market opportunity. And again, I'd like to turn it over to Onaiza to talk a little bit about what her views are on olezarsen and how we see this drug impacting the patient community and the market once it reaches the market.

Yes. There are 2 indications, as Brett just said. With the BALANCE study reading out in the second half of this year, you can imagine that our teams are getting ready to launch in the rare disease FCS patient population. This is really genetically associated with really high levels of triglycerides over -- ranges of over 2,000. And then we read into the severe hypertriglyceridemia indication, which is for all patients who are elevated over 500. The 500 is a really important marker in the sense that it really leads to this risk that's associated with it for risk for acute pancreatitis. And one of the areas that we've really learned is from physicians that there's a huge unmet need here, that are already in the medical guidelines that these patients need to be treated to get them well below their high trigs of thousands, into the 500 or below level. But what we hear from the marketplace is that we understand this, particularly our 2 specialties of endocrinologists and cardiologists, but we just really don't have any great tools at our disposal to do that. Yes, there are fibrates and niacin and other standard of care available such as Vascepa. But those are really taking your triglycerides down at like a very low range that's not going to get these patients down to that 500 or below level. And we've seen very powerful reductions in our Phase II trials. We're in Phase IIIs and a severe population, looking at 2 doses, and we expect to see magnitudes of triglyceride reduction at maybe 3x the standard of care. So very excited about this. This is, again, one of those underappreciated programs in our pipeline.

And we're going to work very hard in the second half of the year to really shine a light on olezarsen as the FCS Phase III data, our first step towards severely elevated triglycerides, managing patients with severe elevated triglyceride as our first Phase III data reads out. So stay tuned for that. Next question, Wade.

Yes. We've had a couple of questions on our commercialization plans for our drugs that we're going to commercialize outside of the U.S. Is there more on that?

Yes. So as a reminder, as we've now -- we are now a fully integrated biotech company prepared for our first launch [ co-co ] with AstraZeneca, for eplontersen and then our first independent launch, olezarsen soon to follow donidalorsen. Our commercial strategy is a strategy in which we will focus on the U.S. market initially. Our independent launches, of course, will involve a field force that's commensurate with the market needs to ensure that we bring our drugs, olezarsen, donidalorsen to as many patients as possible. For eplontersen, of course, we're playing a very significant role in AstraZeneca in the [ co-co ] in the U.S. for eplontersen. But we also recognize that the diseases we're tackling have an unmet -- strong unmet medical need not just in the United States but globally. And we're preparing our plans to ensure that these transformational medicines reach as many patients as possible globally. And we plan to drive that strategy as we lay out our -- as we build our plans and finalize our plans for ex U.S. commercialization for our near-term commercial opportunities. And really, I'd like to leave it at that for now because we're still working on those plans, but they're coming together pretty well.

Great. There's clearly interest in our MsPA chemistry that you mentioned because we've had several questions about that. Can you give an update on where Ionis is with this new chemistry?

Yes. This is one of several technology science breakthroughs that we've made over the last couple of years here at Ionis. I highlighted too, as I recall in my opening statements, one, MsPA, the other, Bicycle muscle-targeting LICA chem platform. There's more coming. But MsPA is a very important advancement in the field of oligonucleotide therapeutics. It brings several advantages. What MsPA does is accomplish a goal that we and many, many others in this field have been trying to accomplish for a long time. And that is to be able to replace phosphatide backbone from a significant portion of our drugs. And that includes both ASOs, what some people refer to as ASOs for antisensing stranded oligonucleotides as well as for double-stranded RNAi molecules. We've been able to do that. MsPA now is in 2 medicines that are in preclinical development, and that means IND-enabling toxicology studies for 2 CNS indications. And we're hoping to reach clinical development for our first 2 MsPA molecules for those 2 CNS drugs next year. What is the MsPA -- and there is more coming. What does MsPA bring to the table for ASOs and siRNA? Well, first and most importantly, it stabilizes the gap, if you will, in Gapmers for RNase H dependent molecules, and it stabilizes other regions of the molecule such that it's providing our ability to dose semiannually, every twice a year, maybe even annually. Certainly, quarterly is easy for this backbone chemistry, and that applies to both CNS applications as well as subcutaneous applications. So we're well on our way with MsPA moving into development. What MsPA also provides is because we can reduce phosphatide content, and I think most of the folks out there that are familiar with this with oligonucleotides recognize that phosphatide can have pro-inflammatory activity when they are used at high doses and when they're used in tissues or organs or cell types that are particularly prone to pro-inflammatory, they're highly sensitive to pro-inflammatory activity like the lung. We think that MsPA, because of our ability to remove the phosphatide backbone is opening up doors such as pulmonary delivery. We're making great progress here with the MsPA backbone for that application, for CNS, as I mentioned, as well as for subcu drugs to not only reduce pro-inflammatory potential but to allow us to get to semiannual dosing. So we're well on our way here. It's a significant advancement in our technology. Stay tuned, and we look forward to providing further updates in the near future.

Great. Next question is about disconnect between the value of our stock today and what others see. So the question is this. Some investors and stakeholders would suggest there's a meaningful value disconnect between where the stock is today and how partners think about the value of the programs we have. Do you feel that, that's the case? And is there a deal to be done to capture that value disconnect?

Absolutely, we believe that. We believe that we are -- our stock is greatly undervalued. And importantly, what's probably more important is we're taking -- we take it very seriously here. We really want to deliver value for shareholders as well as, of course, for patients, for Ionis' employees, all the key stakeholders. And we're working very hard on driving the value through our stock price that Ionis deserves. As I mentioned in my opening comments, we had a few disappointments and challenges a couple of years ago in our pipeline. What's more important is the future, not the past. We are well on our way with the progress we're making, as highlighted today, as highlighted throughout this year, as highlighted last year from our pipeline, the technology advancements that we're making, our financial strength, the products that we're looking at reach the market in the near term and long term for rare diseases and long-term diseases. A deal is not going to -- in our view is not going to have a significant meaningful impact on our stock price certainly in a sustainable manner. Our job is to do the 3 things or 4 things that are key strategic imperatives, right? To deliver an abundance of medicines to the market in a continuous sustained manner; to advance the technology, to continue to advance technology and lengthen the distance between us and competitors in oligonucleotide therapeutics; thirdly is to build and launch products of our own full integration; and then fourth, of course, is to ensure that we have the financial strength to be able to invest in all of the things we need to do, invest in to ensure shareholder value. We're making great progress across all 4 of these strategic imperatives. And that's what's going to drive value and shareholder value stock price in the future. And I believe that you can see the momentum behind the stock as we've seen over, even last year and this year certainly, in a very tough market, Ionis, I think, is doing pretty well, not to our satisfaction but doing pretty well in the market, and we think that, that's just the beginning of a lot of momentum that's coming as we deliver more and more drugs to the market.

Next question is about a couple of programs in our pipeline. Can you give an update on the angiotensinogen and Factor XI programs, our plans for Phase III for these drugs? And whether or not you think fesomersen can compete with Bayer's Factor XI small molecule drug?

Yes. So this will be pretty brief. So AGT for angiotensinogen is -- we've been saying and we'll continue to say, this is our plan is that this is a program that we believe is best suited for a partner with resources that can fully develop in a very, very large Phase III program and for commercialization. It doesn't sit well in where we are today as a fully integrated biotech at our stage. So we're looking to partner it, but I can also tell you that we're looking to provide an update on our Phase II study for AGT in patients with hypertension in the second half of this year. That will be primarily a safety tolerability study with target engagement in patients with hypertension. It's not powered for blood pressure control, but we're going to provide an update at a medical meeting in the second half of this year. As far as fesomersen goes, fesomersen Factor XI prophylactic for thrombosis, we had, with our partner, Bayer, as a reminder, great Phase IIb data in patients with end-stage renal disease who are prone for thrombosis and bleeding. The results were everything we could have hoped they would be. However, Bayer returned the program to us because they have competing programs internally that they've developed, and they chose to focus on their internal small molecule versus our antisense. Similar to AGT, we believe that fesomersen is best in the hands of a partner that has the resources that can fully -- to take advantage and achieve all the value that we think fesomersen has to offer. So we're looking to partner that program. We're not looking to move it into Phase III. And I can't really say much more about how those conversations are going at this point. But we look forward to providing an update as soon as we can.

The next question is about our DMPK program. Will you be using a partner LICA or in-house developed LICA for our DMPK drug delivery to muscle and CNS? If you're targeting DMPK in CNS, will you be using a LICA to deliver the drug?

So myotonic dystrophy, it's an insightful question. Myotonic dystrophy is not just the peripheral disease, it's also a central disease, CNS, right, that affects these patients. A lot of the work that's out there today, clinical development is really focused on the peripheral manifestations, the neuromuscular manifestations of the disease. We're working on both today. For muscle, I kind of just alluded to it a couple of questions ago. One of the other technology advancements we've made recently, really significant advancement is using new targeted delivery strategies, what we call LICA to muscle, skeletal muscle, cardiac myocytes for drug discovery in muscle tissue using our in-licensed Bicycle technology that we -- the partnership that we established in 2021. It's going great, it really is. We've now advanced our first Bicycle LICA medicine into preclinical development, IND-enabling tox studies, that is, gearing up to manufacture it and put it into tox studies and hopefully, clinical development next year. It actually is targeting a cardiac target for heart failure. Can't go further than that and that this is a competitive space but we look forward to sharing more details there. As far as DMPK goes, we know DMPK very well. We were first to develop the oligonucleotide therapeutic, of course, against this target for the peripheral manifestations of the disease, myotonic dystrophy. We're working with multiple platforms with both partners as well as ourselves to identify an optimal molecule using muscle-targeting LICA strategy for peripheral DMPK -- or peripheral manifestations of myotonic dystrophy. For CNS, we continue to make great advancements, as I tried to highlight in my opening comments, MsPA backbone chemistry, other chemistries that are allowing us to do all kinds of things that are, I think, are very impressive with respect to target engagement, efficacy as well as in frequent delivery. Again, our MAPT drug is being tested in Phase II development in AD semiannually now, dosing every 2 months as well as quarterly. We think that, that's going to be the norm. That's going to be -- obviously the norm for our drugs that we bring forward in CNS going forward using our chemistries and our general know-how. As far as LICA in the CNS, we continue to explore all kinds of approaches to further enhance our delivery to different cell types in the CNS. But our drugs distribute really well and we know a lot about this. And it's actually more of the medicinal chemistry and less about targeted delivery in the CNS that we're really interested in. And if I could just maybe take this a step further. We're also very excited about penetrating the blood-brain barrier potentially for CNS diseases. That is during intravenous or a subcutaneous administration, route of administration. Here is where LICA is helping us and really showing great progress in our preclinical -- research studies, targeting using a LICA approach, similar to what we're using for Bicycle in muscle, a similar but not identical approach for crossing the blood-brain barrier. I'm very, very pleased with the confidence -- with the progress we're making in preclinical models and showing the penetration to cross the blood-brain barrier, target engagement, distribution and so on. And that itself could potentially open up a whole another area for drug development in CNS diseases based on differential distribution of oligonucleotide drugs when you're coming from the vascular system versus the CSF. So stay tuned for that. We're looking forward to providing an update our CNS and our technology later this year.

Questions related specific to LICA and the CNS is, is Ionis working on a LICA for CNS drugs? How close are you to having a LICA for the CNS ready for clinical trials? Will you be using a partnered or in-house created LICA?

Right now, for CNS, as I mentioned, we're really just -- we're really focused on crossing the blood-brain barrier with targeted delivery strategies using strategies similar to our muscle LICA strategies. In the CNS, I think we have it solved largely with our chemistries that are giving us great target engagement, 2 new -- 2 approved drugs now for neurodegenerative diseases, QALSODY, SPINRAZA and a third proof of concept now in the clinic in MAPT in Alzheimer's disease. I really think that our focus, I wouldn't rule it out, but our focus for CNS is really, today, is continuing to prove the platform that has delivered for us already in the CNS and then looking at blood-brain barrier using a LICA strategy.

The next question is about targeting the lung. Will you have a drug targeting lung and ready for clinical trials this year or next year? If so, do you have a LICA strategy for lung delivery?

No LICA strategy. We believe that -- well, we're making great progress in tackling inhaled delivery of oligonucleotide drugs to the lung for pulmonary diseases. MsPA backbone chemistry is a big help. It's really -- it has really, really, we think, has solved some of the issues that have held us back in the past. We're not there yet so I don't want to overpromise, but we're very -- the results we've generated to date for pulmonary delivery are very encouraging. We haven't put time lines on this yet. But again, if we can get to a technology update maybe in the second half of this year, we'll certainly include some of the work we're doing in pulmonary delivery possible. So stay tuned for that. We don't see the need for a LICA strategy for the lung. We're getting great update. We're getting great distribution. We're getting broad distribution across many different cell types in the lung. The real challenge because lung is such a sensitive organ for pro-inflammatory effects is to maximally reduce pro-inflammatory potential so that we can deliver at doses that are efficacious. That is what MsPA, we think, is bringing to the table. We still have some work to do there, so stay tuned.

All right. The next question is about the donidalorsen program. Does Ionis anticipate Q8-week dosing that's every 2 months dosing will be part of the label as a starting dose? Or will it be an option once patients have been attack-free on monthly dosing?

I'll pass it over to Onaiza to give her perspective.

Well, hope you guys get to see the wonderful news today in our -- in the durability of our data in our 2-year OLE, which is really -- continues to demonstrate really strong durability and sustained mean reduction in HAE attack rates of 96%. This is -- continues to be a potential best-in-class profile for us as we're looking forward to our Phase III results in the first half of 2024. We do have both doses in our Phase IIIs. One dose of the Phase IIIs, one at Q4 weeks and one at Q8 weeks. We did, as Brett actually went through it, like 3/4 of our patients who transitioned to bimonthly dosing and open-label extension, they remain attack-free. So really, it's going to be very data dependent in terms of what comes out of our Phase IIIs. But we do want to remind everybody that the standard of care right now is that every 2 weeks. So at the 4 weeks, we're going to beat the standard of care, both in efficacy and in dosing convenience. And we do believe that the 8-week could potentially provide a nice flexible option for patients.

The study -- the Phase III study is powered for both arms based on the Phase II data that we've generated and announced last year. So stay tuned for that. We're looking forward to the Phase III readout first half of next year.

The next question is about the -- our APOCIII program, olezarsen. How does Ionis plan to compete with Arrowhead and their plans for cardiovascular outcome trial they're planning to start next -- early next year? Will this give them a significant advantage when it comes to reimbursement, particularly in European markets?

Yes. So again, I'm going to ask Onaiza to talk a little bit about this disease -- this indication, the opportunity that we're pursuing and how it differentiates from what a drug would do to treat cardio -- to be tested in a cardiovascular outcome trial. I really don't want to get into partner or competitor profiles and comparisons. But I think it's worth talking a little bit about how our strategy differentiates from a strategy involving a cardiovascular outcome trial. So Onaiza, why don't you take it away?

Sure. So one of the things that's really important to know is where our Phase IIIs are being studied. And we have, again, 2 pivotal studies in the greater than 500 milligrams per deciliter in terms of triglycerides. And this is a different population than one where you would actually do a cardiovascular outcome study. Important to know that TG are packaged very differently. And in the greater than 500 population, they are not in that VLDL population. They're packaged in chylomicrons. Therefore, they are at greater risk for different things. And this is a population that is at greater risk for pancreatitis. And it is not the population that one would actually conduct a CV outcome study in. And so that is really kind of important baseline information to have as you think about the opportunity. This population is well over 3 million patients in the United States. We will have a substantial first-mover advantage, both for the FCS indication and very much so for the severe hypertriglyceride indication. We've done a fair amount of market research. Not only do we have a clear path with regulators on this in terms of where we talked to them at our end of Phase II in terms of design but also from a payer perspective and also from a clinician perspective. Payers actually recognize the unmet need here as well and know that this is really about triglyceride reduction and then showing some AP event reduction as well would be nice for them but really is triglyceride reduction. And then for clinicians, as I said earlier, both the ACC guidelines and the endocrine guidelines recommend getting TGs down below 2,000 to 500 level over here. Again, different population. And really, our study is designed to realize that opportunity over here, which continues to be a very blockbuster opportunity for us and for olezarsen.

Thanks, Onaiza. I think that that's a great answer, and it speaks to my -- one of the questions that was earlier asked about underappreciated assets, confusion on -- for triglyceride-lowering drugs. It's really very different patient populations. We're targeting a different patient population. And we think this is the right strategy, a strategy that will achieve approval based on triglyceride lowering. Of course, we will be collecting AP events and acute pancreatitis events during the course of the study, and we're looking forward to that data in both FCS and sHTG. And we have a great-looking drug based on our Phase II data and our experience in this space, and we're ahead. So we really like our -- we like our position for both FCS and sHTG with olezarsen.

Great. We have time for 1 more question, and it's a 2-part question. First is, what are the chances for an interim look in the eplontersen cardiomyopathy study? And the second part of the question is what's the likelihood for an interim look in the olezarsen sHTG Phase III study?

Sure. So as a reminder, we're planning to complete the enrollment in the eplontersen Phase III cardiomyopathy study soon around midyear, the largest study ever conducted in TTR cardiomyopathy by far. We think that, that has several many important advantages over other investigational medicines in development today. That study -- that data is due to -- we're expecting to read out in the 2025 time frame. We are not planning an interim analysis in the Phase III cardiomyopathy study. However, based on emerging data internally in our program as well that we monitor very carefully as well as data that externally that we're, of course, always paying attention to, we can always complete the study early. We can always end the study because we feel that we have achieved everything we can achieve in this study for a successful outcome. And when I say a successful outcome, I mean, more than just a p-value but a rich positive data set that will provide us a competitive advantage on the market. So we can stop the study earlier if we choose to but no interim analysis. And the same for sHTG. SHTG is for -- remember that there are -- there's a safety database that this is not a rare disease. Eplontersen is targeting a rare indication. For broad indications, you got to be really careful about interim analysis and taking alpha statistical penalties. And you also need to make sure that you have the safety database that you need to support an indication that's broad, right? Remember, we have 2 Phase III studies CORE and CORE 2 that are in progress for efficacy endpoints and then a much larger patient or a much larger study in parallel to round out the safety database that's necessary to bring this drug to market for a large indication. So we're not planning an interim analysis is sHTG without -- even without sHTG. Even without an interim analysis, we're well ahead of any competition that we can see that's out there today for investigational medicines that are in development. And as Onaiza has said, there are no effective treatments for FCS or sHTG that are on the market today. So thank you all for the questions. I'd like to thank everybody who joined us and participated in our call today. As we look ahead, we plan to continue our momentum by delivering on additional key commercial pipeline, technology advancements throughout the year. We look forward to providing updates on our progress throughout the year. And until then, thank you, again, and have a great day.