Good morning, and welcome to Ionis Pharmaceuticals Second Quarter 2021 Financial Results Conference Call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Dave Nakasone, Investor Relations to lead off the call. Please begin.

Thank you, Debbie. Before we begin, I encourage everyone to go to the Investors section of the Ionis website to find the press release and related financial tables including a reconciliation of the GAAP to non-GAAP financial measures that we will discuss today. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We've also posted slides on our website that accompany our discussion today. With me on today's call are Brett Monia, Chief Executive Officer; Beth Hougen, Chief Financial Officer; and Richard Geary, Executive Vice President of Development. And joining us for Q&A, Onaiza Cadoret-Manier, Chief Corporate Development and Commercial Officer; and Eric Swayze, Executive Vice President of Research. I would like to draw your attention to Slide 3, which contains our forward-looking language statement. We will be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail. With that, I'll turn the call over to Brett.

Thanks, Dave. Good morning, and thank you for joining us on today's call. Last year, when I took on my new role as CEO of Ionis, I moved forward with the plan intended to bring substantially greater success to Ionis and substantially greater value for all stakeholders. This plan was to leverage our well-established foundation of scientific innovation by focusing on three strategic objectives: First, to evolve our business model to include the commercialization of products of our own. This includes building the necessary capabilities to prepare for multiple Ionis commercial launches. Second, to expand our drug discovery capabilities through new initiatives to enhance our technology. And third, to significantly advance and grow our late-stage pipeline to ensure a substantial increase in the number of new products reaching the market in the near and longer term. So now let's see how we're progressing against these three strategic goals for this year. The Ionis wholly-owned pipeline is advancing on track and growing significantly. Last week, we reached full enrollment in the NEURO-TTRansform study of eplontersen for the treatment of patients with polyneuropathy. With this study now fully enrolled and on track for data by mid-2022, this medicine is one important step closer to reaching the market. We are also developing eplontersen for the treatment of cardiomyopathy in the Phase III CARDIO-TTRansform study, which continues to enroll well. Our Phase III study involving our APOCIII LICA medicine in patients with FCS is enrolling on schedule. And our second Phase III study for APOCIII LICA is on track to begin later this year in patients with severe hypertriglyceridemia, a much larger patient population. Our Phase III study for ION363 in patients with the genetic form of ALS due to mutations in the FUS gene is also progressing well. Furthermore, we look forward to initiating a Phase III study for our PKK LICA medicine in patients with hereditary angioedema late this year or early next year. And as our wholly-owned pipeline advances, we're also making great progress in building out our commercial capabilities and our strategy. Our acquisition of Akcea was a key step in advancing our commercial strategy in building these capabilities. We have now completed the integration of Akcea within Ionis. And we're pleased with the progress being made in our Sobi partnership for the distribution of TEGSEDI and WAYLIVRA in Europe and North America. As a reminder, we established this partnership to continue providing these important medicines to patients while we focus on eplontersen and APOCIII LICA. We've also made significant additional progress this year against our strategic objective to expand the reach of our drug discovery capabilities through new investments to enhance our technology. Our efforts include broadening our internal technology initiatives as well as in-licensing new technologies. We recently announced a new partnership with Bicycle Therapeutics for exclusive access to Bicycle's proprietary platform chemistry for oligonucleotide drugs focused primarily on targeted delivery to skeletal and cardiac muscle. This collaboration complements our significant internal efforts as well as the progress we're making under our Arrow Therapeutics and Genuity Sciences collaborations, all of which potentially enables us to significantly expand the reach of our technology. And lastly, we're making great progress this year in achieving our third strategic objective to have 12 or more marketed products in 2026. In addition to completing enrollment in the eplontersen NEURO-TTRansform study, we also recently achieved key Phase III milestones with tofersen and pelacarsen. All three of these significant milestones move these programs closer to reaching the market and highlight the excellent progress we're making across our late-stage pipeline. Biogen completed the placebo-controlled treatment portion of the Phase III VALOR study of tofersen, and they expect to report findings by this fall. They are now offering tofersen to SOD1-ALS patients on an individual compassionate use basis. If the Phase III VALOR results are successful, tofersen could become the first ever disease-modifying therapy for a genetic cause of ALS and our next commercial product. This week, we announced the achievement of a key enrollment milestone in the Lp(a) HORIZON Phase III study for pelacarsen in patients with LP(a)-driven cardiovascular disease. We have now achieved enrollment of nearly 4,000 patients in this cardiovascular outcome trial, representing 50% of our target enrollment goal for the study. This achievement, along with the substantial progress we're making across all of our mid- and late-stage LICA programs, demonstrates the consistently attractive profile of all our LICA medicines in development today. In wrapping up my opening comments, we are very pleased with the progress we're making to achieve all our strategic objectives. We've made great progress this year, and we are looking forward to an exciting second half of the year as we focus further on executing our strategy and achieving the goals that lie ahead. Importantly, we are well positioned for growth with the people and the financial strength to achieve all of this and more. With that, I'll now turn the call over to Beth to review our financial results. Then Richard will discuss recent pipeline updates and preview key pipeline catalysts expected for the remainder of the year. After Richard, I'll wrap up our prepared remarks before taking your questions. Now over to Beth.

Thank you, Brett. Our financial results for the first half of this year reflect our commitment to invest in driving future growth. We earned nearly $240 million in revenue and recognized $312 million in non-GAAP operating expenses, resulting in a non-GAAP net loss of $81 million. These results were in line with our expectations and reflect the multiple steps we have already taken this year in support of our strategic objectives. We've completed the integration of Akcea, entered distribution arrangements with Sobi, and restructured our commercial operations. In our first quarter earnings call, we projected realizing substantial savings from the Akcea and Sobi transaction. I'm pleased to say we are on track to realize more than $50 million of savings this year. We are putting these savings to work by reinvesting them to drive future growth. That means investing in three key areas: advancing and expanding our wholly-owned pipeline, building our commercial capabilities, and enhancing our technology. I'll provide more details about the investments we've made so far this year when I talk about our operating expenses. But first, I'll provide additional details on our revenue. In the first half of this year, SPINRAZA continued its blockbuster performance, achieving over $1 billion in global sales. We earned over $130 million in royalty revenue, virtually all falling to our bottom line profit. Based on SPINRAZA's net sales, we reached the highest royalty tier in the second quarter. We are pleased with Biogen's continued efforts to build upon SPINRAZA's proven profile of long-term safety and efficacy in SMA patients of all ages. Biogen recently reported new data reinforcing the potential for improved outcomes in patients treated with a higher dose of SPINRAZA, which is being evaluated in the DEVOTE study. In the RESPOND study, Biogen is continuing to evaluate SPINRAZA's potential to benefit patients previously treated with gene therapy. Together with the substantial and growing body of evidence supporting SPINRAZA's proven profile and over 60,000 SMA patients, we believe SPINRAZA will continue to be the market-leading treatment for SMA patients of all ages. In the first half of this year, TEGSEDI and WAYLIVRA generated revenues of $31 million. Additionally, we completed the transition of our commercial operations to Sobi and recognized our first full quarter of TEGSEDI and WAYLIVRA revenues from distribution fees based on net sales. As a reminder, we included this shift in revenue in our 2021 revenue guidance. We also earned nearly $70 million in R&D revenues in the first half, including $10 million from Biogen for advancing ION541, which is in development for patients with ALS with no known genetic history of the disease. More than 85% of our R&D revenue was from medicines in our leading cardiometabolic and neurology franchises. Our R&D revenues included revenue from numerous partners, as together we advanced more than 10 programs. Our ability to generate revenue from numerous diverse sources is a key element of our financial strength. We reported non-GAAP operating expenses of $312 million in the first half of this year, a slight increase compared to last year, and in line with our expectations. R&D expenses increased by 20% compared to last year, driven primarily by the eplontersen and APOCIII LICA Phase III study and costs associated with our wholly-owned programs. We also incurred expenses associated with our Genuity collaboration to identify novel targets. These increases reflect two of our key areas of investment: our wholly-owned pipeline and our technology. SG&A expenses decreased by approximately 25% compared to last year due to cost efficiencies realized from integrating Akcea and restructuring our commercial operations. Based on our first half results and our projections for increased R&D revenues from our advancing partnered programs in the second half of this year, we are reaffirming our 2021 revenue guidance of more than $600 million. Already in the third quarter, we have earned a $25 million milestone payment from Novartis for achieving 50% enrollment in the Phase III study of pelacarsen. We expect our operating expenses to continue to increase in the second half of this year as we advance our ongoing Phase III studies for eplontersen, IONIS APOCIII LICA, and our FUS-ALS medicine. Our operating expenses will also increase as we get the Phase III study underway for APOCIII LICA in patients with severe high triglycerides and potentially start the Phase III study for PKK LICA. Additionally, we are investing to enhance our technology, ensuring that our platform remains innovative and competitive. As Brett mentioned, we recently entered into a license agreement with Bicycle Therapeutics for a $45 million upfront payment. We did not include this license fee in our original financial guidance, and for that reason alone, we are revising our 2021 operating expense and net loss guidance. We now project operating expenses in the range of $710 million to $750 million and a net loss of less than $110 million, assuming the low end of expenses, all on a non-GAAP basis. Because of our projected increase in R&D revenue in the second half of this year, we expect our net loss will be lower in the second half of this year compared to the first half. With the important steps we have already taken this year and more than $2 billion of cash and investments, we believe we are well positioned for accelerated growth. We look forward to continuing to invest in our pipeline and technology and to moving more medicines towards the market to achieve our goal of 12 or more marketed products in 2026. With that, I'll turn the call over to Richard.

Thank you, Beth. As Brett described earlier, we are certainly pleased with the excellent performance across our pipeline in the first half of this year. With the achievement of key Phase III catalysts with tofersen, eplontersen, and pelacarsen, these medicines are now closer to reaching the market. These catalysts also position us well to deliver our regular cadence of Phase III data readouts, beginning with tofersen, expected by this fall. Tofersen is now one step closer to becoming the first genetically targeted therapy for the treatment of ALS and to becoming Ionis' next commercial product. Biogen recently began offering tofersen to SOD1-ALS patients on an individual compassionate use basis with plans to broaden this access once the data are reported. Biogen is also conducting the ATLAS study to investigate tofersen's potential to prevent or delay disease onset in presymptomatic SOD1-ALS patients. The rationale for ATLAS is similar to SPINRAZA's NURTURE study, which has enabled infants who began treatment prior to SMA symptom onset to develop more like non-SMA children. After tofersen, the next program on track to read out is the NEURO-TTRansform study of eplontersen for the treatment of TTR polyneuropathy. With enrollment in this study now complete, we expect data by the middle of next year. As a result, we are positioned to file for marketing authorization for eplontersen in patients with TTR polyneuropathy by the end of next year, assuming the data are positive. Up next, we expect the balance study of IONIS APOCIII LICA in patients with FCS to read out in 2023. We're on track to initiate a second Phase III study of IONIS APOCIII LICA in patients with severe high triglycerides in the second half of this year, which positions this program for data in 2024. Also in 2024, we anticipate Phase III data from the LPA HORIZON outcome study of pelacarsen, the CARDIO-TTRansform study of eplontersen, and the pivotal study in patients with FUS-ALS. In addition to our deep late-stage pipeline, we have a large mid-stage pipeline that we expect to continue to support additional Phase III starts. Many of these mid-stage programs have readout data recently or have upcoming data readouts that, if positive, position these medicines to move into the next stage of development. Data we presented at the AAIC last week demonstrated that monthly and quarterly dosing with Ionis MAPTRx achieved substantial, durable, and dose-dependent reductions in all forms of CSF tau with generally favorable safety and tolerability in Alzheimer's disease patients. Based on these results, Biogen plans to advance Ionis MAPTRx into a larger Phase II study to more fully test our antisense medicine as a treatment for Alzheimer's disease. Coming up in the second half of this year, we expect data from the vupanorsen Phase IIb study in patients with dyslipidemia and cardiovascular disease. We look forward to starting our Phase I/II study of ION582 for the treatment of patients with Angelman syndrome. Later this year, we anticipate reporting additional data from the Phase II study of Ionis PKK LICA in patients with hereditary angioedema. We also look forward to initiating our Phase III study with this medicine, which is on track late this year or early next year. Our partner, Bayer, is continuing to make good progress in the Phase IIb study of IONIS Factor XI LRx in patients with end-stage renal disease, putting this study on track for data in the first half of next year. As the year unfolds, we look forward to providing future updates as the pipeline continues to advance and we achieve additional catalysts from across the pipeline, which, together, move us closer to achieving our goal of 12 or more marketed medicines in 2026. With that, I'll turn the call over to Brett to close this portion of our call.

Thank you, Richard. In the first half of the year, we continued to successfully advance all our key strategic objectives. We have made great progress in evolving our business model, building our commercial capabilities, and preparing for multiple Ionis commercial launches. We've made significant progress in advancing our technology to expand our drug discovery capabilities. With the progress we've made across our pipeline, including achieving key Phase III milestones that move tofersen, eplontersen, and pelacarsen closer to the market, we are very well positioned to achieve our goal of delivering a substantial number of new products to the market in the near and the long term. The second half of the year is shaping up to be even more successful with several new key clinical trial initiations and clinical readouts, including results of the Phase III VALOR study in patients with SOD1-ALS by this fall. Importantly, we have the resources and people we need to invest in all our strategic priorities, positioning us for accelerated growth and helping to ensure great success for Ionis for many years to come. With that, I'll now open the call up for questions.

The first question comes from Jason Gerberry with Bank of America.

A couple for me. Just maybe can you help set the expectation into the Phase IIb for vupanorsen. Just sort of curious, the high unmet need subgroup of patients with more severe triglyceride levels. Just wondering your thoughts in terms of the ability to read across from this study to that patient population. And then I guess, just secondarily, have you given any thought to Huntington's disease and potentially next steps to revisiting that as a category? Just curious your latest thoughts on Huntington's.

Sure, Jason, thanks for the question. So for vupanorsen, the Phase IIb study, which Pfizer has said that they plan to have top line data announced this year. As a reminder, this is in patients with high non-HDL cholesterol and high triglycerides. This is the patient population that if they move to Phase III, which is the plan that they're targeting for a Phase III program. The unmet medical need for elevated cholesterol combined with high triglycerides, mixed dyslipidemias, is very significant, encompassing a very large patient population, and one that positions vupanorsen to target mixed dyslipidemia quite nicely. We’re also, in addition to vupanorsen, very excited about our APOCIII LICA drug that we're moving to Phase III for severe high triglycerides as well. We think that this mechanism is the best-in-class strategy for patients suffering purely from high-triglyceride-related diseases, which affects millions of people. I raised that because it’s important to realize that vupanorsen and our APOCIII LICA medicine are targeting very large patient populations and distinct populations that don’t have some overlap but are quite distinct for that. And I can touch on Huntington. But first, I'd like to just see if Richard wanted to add anything to what I said.

No. I think you've covered it well, Brett.

Okay. Thank you, Richard. As far as Huntington, as Roche said, Jason, they continue to analyze all the data, and they've promised an update on the results of the study as they go through more data as well as the next steps by the end of the year. We're working very closely with Roche on this. So stay tuned for the second half of the year for an update.

The next question is from Luca Issi with RBC.

Two quick ones on the pipeline. So maybe the first on TTR, Richard, can you expand a little bit more on the interim analysis that you're planning for TTR LICA in mid-2022 for polyneuropathy? It looks to me that the interim analysis is actually 8 months ahead of the primary endpoint. So wondering what gives you confidence that with such a short follow-up, you're going to be able to see a separation of the curves. And then the second question is on ENaC. Wondering if you can provide any update there. We've seen Arrowhead also running into safety issues there. So any thoughts on whether the safety issues that they have had are similar to the one that you saw? And maybe bigger picture if you can comment on what's next for the respiratory franchise.

Yes. Thanks. I'll take that eplontersen question for you first. Our confidence, of course, derives from the first polyneuropathy study we ran with TEGSEDI, which demonstrated its mechanism of action. We believe we have a much safer and well-tolerated drug with once monthly administration. At 8 months with TEGSEDI in that trial, we had statistically significant improvements in our endpoints. It was already separating from placebo quite nicely at that time point. So we believe that gives us the confidence we need in going into this interim analysis. In fact, it's quite high. The second question you had, I can't speak to what might be happening with the competition. We had a preclinical issue. We're working through that, and we're very confident that we'll be able to.

Yes, and if I can just add to what Richard said. Thank you, Richard, is on eplontersen, also what gives us great confidence not only is the fact that TEGSEDI showed statistically significant benefit in the same primary endpoints in the Phase III study that was conducted for that drug at 8 months. Eplontersen is showing even greater TTR reductions, we're at around 90% reductions based on the dose rising in Phase III with excellent safety and tolerability. As Richard mentioned, we're very confident in that outcome and we also have a - we're very comfortable with the regulatory path forward as well. And just to add on the pulmonary, we're making really good progress preclinically and looking at new designs, new molecules that can move the pulmonary program back into development in the future. So stay tuned for that. We'll talk more about that at maybe the end of the year or next year.

The next question is from Yaron Werber with Cowen.

Congrats to the team on the progress. This is Brendan on behalf of Yaron. Just a couple of quick ones from us. I know you mentioned that you're looking to initiate the Phase III HAE study by the end of the year or early next year. Could you just clarify what steps are left there? If you already have alignment with the FDA on the study design and it's mostly just logistics or if you're still finalizing the study? And then really quickly for Angelman, I wanted to see if we might get any preclinical data from that at any point this year and what you might be able to tell us about timing and maybe trial design for the Phase I/II?

Sure thing. I'll take the HAE and then I'll ask Eric to talk a little bit about what we presented and published on in the Angelman program after that. So for HAE, we're putting the final touches on the Phase III study design. We're having very good discussions with regulators. Really, it's mostly logistics, Brendan. We're getting drug made and preparing for the Phase III design, selecting our sites, moving forward for activation of sites. It's just blocking and tackling, honestly, at this point to get that study up and running. We're hoping it's a stretch goal to get it done and initiated by the end of the year. But certainly, we see it happening later than the first quarter of next year. When we share the full data set late in the second half of the year for our Phase II study, we also plan to share our development strategy, what our Phase III design looks like, and why we think it will position PKK LICA potentially as a best-in-class molecule for HAE. So stay tuned for that in the second half. We've got a lot of momentum going into the second half of the year and a lot of exciting news coming out, we think, in the second half. Eric, we published on Angelman.

Yes. We have. We were actually the first to elucidate the mechanism in collaboration with our academic colleagues that you can inhibit an antisense transcript and upregulate UBE3A, which is the deficient protein in Angelman syndrome. We spent a good amount of time trying to optimize the drug and find the ideal human development candidate. It took us a little longer than I had hoped, but we've got a great-looking molecule and are looking forward to getting that started in the first human study later this year. We took everything we learned about how to make great neurology drugs from our extensive experience and tried to make a molecule that we're hopeful will be best-in-class in this space and provide a great benefit to patients with Angelman.

The first inpatient study, the Phase I/II study will be focused, obviously, on safety, tolerability, dose escalation, and dose selection based on biomarker readouts for a potentially follow-up Phase III study.

The next question is from Yanan Zhu with Wells Fargo.

Great. Congrats on the progress. A lot of things going on. I have one question on the technology platform front with regards to the Bicycle collaboration. So have you compared their bicyclic peptide approach targeting transferrin receptor with the approaches of using either monoclonal antibodies or antibody fabs? And also, given your prior experience with myotonic dystrophy in clinical studies, when you look at the data from your diligence, do you feel there is enough fold increase in muscle exposure compared with on-labeled antisense that gives you confidence that you could perhaps restart the myotonic dystrophy program and have an accelerated path? Yes. So that's the first question.

Thanks, Yanan. We're really excited about the advances we're making in targeted delivery across the board, including Bicycle. Eric - and the answer is yes, we've done comparative work prior to completing the Bicycle deal. Eric led that effort with his team. And so I'll turn it over to him to tell you why we're so excited about Bicycle and how we believe we differentiate from other approaches.

Yes. Sure. Thanks, Brett. We absolutely have compared it with other transferrin receptor ligands. We were involved in this space originally early on and then extensively looked at how monoclonal antibodies and fabs that target transferrin receptor-1 can deliver cargoes to the muscle. We definitely demonstrated that this can happen, and we're interested in trying to find better ligands that we thought would make better drugs in the end. That ultimately led us to Bicycle, which has these very unique bicyclic peptides that have been able to develop high ligands for multiple proteins and transferrin receptor-1 in particular. We absolutely compared the Bicycle oligo conjugates to the fabs and found them to be essentially identical in terms of potency based on the oligonucleotide that will be delivered. The key advantage here is the size. Monoclonal antibodies are big. Bicyclic peptides are small. There’s probably a 50 to 75-fold difference in weight. This translates directly to less total drug that would need to be administered if you scale it up to a human dose projection because all of those are reasonably small and the Bicycles are smaller. We think this will be a large advantage with this technology if we can make it work and hopefully make the best-in-class muscle and cardiac targeting antisense drugs. As to the programs, you alluded to DMPK and DM1. Yes, we needed more potency in that program. The bicyclic transferrin receptor-1 targeting technology provides that. We think it certainly has the potency enhancement to get us in the range of what we need clinically. Beyond that, we're not really prepared to comment on what targets will advance or the timing, but we have a whole host of neuromuscular and cardio - cardiac targets lined up that we think are great for this technology and are anxious to get it moving.

Great. And then a quick question on tau lowering or the MAPT program. You showed some very impressive reductions of tau. How should we think about this approach compared with, for example, an antibody approach targeting tau? And could there be a kind of biomarker path forward with this approach given the recent developments with a beta approach?

Yes. As for the path forward, Biogen said they plan to advance this into a larger Phase II study to more fully test the clinical outcomes and clinical benefits associated with tau lowering. So that’s the clinical strategy. In terms of comparing the antisense approach to an antibody approach, I really think there is no comparison. Tau is an intracellular protein known to accumulate and aggregate inside the cells. Our drugs work by turning off the translation and creation of tau protein by binding to integrated RNA. So we turn off all forms of tau, and that's what we demonstrated in the clinical trial, where all forms of tau are reduced. To reduce tau in the CSF by our mechanism, it has to be reduced inside the cell because that's where it comes from. Antibodies, however, are macro molecules with a small penetration into the CNS space. In the CSF, they bind to the tau protein and reduce it only there in the CSF. We don't think those antibodies can engage tau productively inside of a cell, which is what our drugs are doing, and we think that's where key pathology occurs with tau. We’re very encouraged about our drug. We think it's one of the key things to test the tau lowering hypothesis in AD. We're excited that Biogen is taking it forward to do exactly that.

The next question is from Paul Matteis with Stifel.

This is Alex on for Paul. Actually, a follow-up on MAPT. I was wondering if you could comment on the relative ASO doses versus in tominersen Phase III? And then secondarily, curious if there are any biomarkers or VMRI measures in this study and if you could comment on that or if you expect that this would get published or presented in the future.

Sure. The doses weren't disclosed in that poster. We are working on getting our Phase I data published, so stay tuned for that. We believe this is a strong oligonucleotide. We've been working hard on making advances in how we design and identify oligos and subtle tweaks to the chemistry and the design of the compounds. We've been able to make them more potent over the years. Our PK/PD modelers have done a fantastic job predicting the human doses. We think this represents one of the better molecules we've made, performing as expected. We hope to share more data in a publication soon.

Can you just say whether or not there were biomarker data taken in this study? Or is that something that was only measured as baseline to screen these patients in?

We had a range of biomarkers and outcomes in the study. I can't comment beyond what we reported in terms of MAPT.

The next question is from Esther Rajavelu with UBS.

On FUS-ALS, can you help us understand some of the trial design considerations for this Phase II that you're starting to enroll compared to tofersen? And then I have a follow-up on another topic.

Sure. This is FUS. Yes. The design and the regimen are similar, so it is a Phase III registrational study. It’s moving directly from what has been an open label single patient or a few patients being treated to a full registration with all health authority input with the design, etc. In terms of where we are with FUS, we're very confident that the design we put together will support this again as a very good drug moving into Phase III. We’re excited that the program has started and that patients are enrolling.

To add, Esther, the primary endpoint is the same as for tofersen. There’s a direct link there, the ALS functional rating scale. Obviously, we have the ability to measure target engagement in patients like we did with the tofersen study. This study is longer than the 6-month tofersen study; it will be about 250, almost a year of treatment.

Is it the longer duration of treatment that is specific to this patient phenotype? Or what's the thought behind that?

ALS is a rapidly progressing neurodegenerative disease, but certain forms of ALS are more rapidly progressing than others. FUS is a sort of your normal progressing patient population for ALS, which necessitates a longer study design.

Got it. Okay. And then a quick follow-up on the transferrin receptor question that was asked earlier. You referred to cardiac indications, but can you help us clarify whether you’re referring to cardiometabolic indications or more tied to the structural issues in the heart?

We're focused on diseases like heart failure. We're targeting cardiac myocytes directly, not metabolic conditions. We're going after well-validated targets based on genetics as well as validated targets based on preclinical data targeting directly cardiac myocytes. So different forms of heart failure are our primary focus there.

The next question is from David Lebowitz with Morgan Stanley.

When you look forward to the Slide 1 readout, could you just run us through what we could expect to see in that readout and what you think needs to be achieved to exceed regulatory thresholds? That would be very helpful.

Sure, David. This is a randomized, placebo-controlled 6-month trial comparing tofersen to placebo, primarily focused on the ALS functional rating scale. The aim is to demonstrate a statistically significant clinical benefit to patients on the drug versus placebo. There will also be extended long-term data from that study as well. We do not believe that SOD1 reductions alone will be sufficient for approval. There is enormous outcry from the ALS community for this drug. This is a very active patient community that has sought out access to it for a long time, particularly in light of the lack of treatments for this severe neurodegenerative disease. I believe that regulators will be open-minded about trying to deliver a drug like this to patients as rapidly as possible. Thank you, David. I think that's our last question. With that, I’d like to thank everybody who joined us on our call today. We have a lot of momentum going into the second half of the year. As the year unfolds, we're looking forward to providing further updates as we continue to execute on all of our goals. Until then, thanks for joining us today, and have a great day.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.