Good morning and welcome to the Ionis Pharmaceuticals First Quarter 2020 Financial Results Conference Call. At this time, I would like to turn the call over to Wade Walke, Vice President of Investor Relations, to lead off the call. Please begin.

Thank you, Allyssa. 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 have also posted slides on our website to 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. Additionally, Onaiza Cadoret, Chief Corporate Development and Commercial Officer, and Eric Swayze, Executive Vice President of Research, will join us for Q&A. I would like to draw your attention to slide three which contains our forward-looking language statement. We'll 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 details. And with that, I'll turn the call over to Brett.

Thanks, Wade. Good morning and thank you for joining us on today's call. Our strong performance in the first quarter reflects the sustainability of our business and the unwavering commitment of our team. Ionis was established to deliver transformational medicines to patients in need, which remains the foundation for everything we do. I'm proud of our dedicated employees who are going above and beyond to serve the patients who depend on our medicines. Because of the dedication of our organization, we've continued executing on our goals, and have already achieved many successes across our business while effectively managing our response to the pandemic. We are approaching the rest of 2020 from a position of strength given our operational momentum and strong balance sheet. We remain on track to achieve our goals of advancing our late-stage pipeline towards potential near-term approvals, advancing our Ionis-owned pipeline, broadening the reach of our technology and building our commercial capabilities. Moreover, we are reaffirming our financial guidance for this year. Now to briefly recap our recent achievements, we are pleased with the continued growth of our commercial medicine. SPINRAZA's strong performance continues with growth in global markets despite some impact on new patient starts and maintenance dosing from COVID-19. Both TEGSEDI and WAYLIVRA maintain consistent quarterly growth with new country launches underway. Our pipeline has also continued to deliver many important successes. Enrollment in the Phase 3 GENERATION HD1 study of tominersen in patients with Huntington's disease is now complete. While there's much to do to bring this study to its planned completion, we are one very important step closer to providing a treatment for people living with this devastating disease. The Phase 3 program for AKCEA-APO(a)-LRx continues to advance. Importantly, this medicine recently received Fast Track designation in the US, reflecting the significant unmet need that exists for a million patients with APO(a)-driven cardiovascular disease with no approved treatment options. Additionally, earlier this year we and Akcea reported positive top-line results from Phase 2 proof-of-concept studies of AKCEA-APOCIII-LRx and Akcea, angiopoietin-like 3 LRx, which we will now refer to as the nusinersen. We plan to present full data from both studies later this year. We and our partners have over 40 clinical studies underway at sites around the world. While some of our studies have experienced limited disruptions, primarily in countries most impacted by COVID-19, we remain confident that the mitigation strategies we deployed early in the pandemic should minimize the impact on our clinical studies and business operations. Looking ahead, we're continuing to invest in our strategic priorities and remain on track to achieve our 2020 objectives. We and Akcea expect to initiate the Phase 3 study of APOCIII-LRx in patients with FCS, bringing us to a total of six Phase 3 studies with biomedicine. We're on track to re-file the NDA for WAYLIVRA in the US. And we plan to report additional clinical proof-of-concept results from several programs this year. We are well-positioned to achieve our goal of delivering 10 or more NDAs through 2025. I'll now turn the call over to Beth to review our financial performance, followed by Richard who will discuss our pipeline progress. And then I'll open up the call for questions after some brief closing remarks. Now to you, Beth.

Thank you, Brett. We entered the COVID-19 pandemic in a position of substantial financial strength. Our first quarter financial results were in line with our projections, enabling us to reaffirm our 2020 financial guidance, including ending this year meaningfully profitable. During the first quarter, we earned revenue from multiple sources and continued to invest in our strategic priorities. Importantly, we remain well capitalized, with $2.4 billion of cash and investment at the end of March. Over the last several years, we have consistently strengthened our financial position and constructed a balance sheet that is sustainable and will enable us to achieve our near and longer-term goals. Moreover, the prudent debt refinancing we undertook late last year resulted in a favorable debt maturity schedule while substantially reducing our cash interest expense and potential future dilution. Our commercial revenue increased nearly 25% over the first quarter of 2019, with SPINRAZA being the largest component. On SPINRAZA's strong first quarter performance, we earned $66 million of royalty revenue, an increase of approximately 10% compared to the same period last year. At the end of March, there were nearly 11,000 patients on SPINRAZA treatment worldwide. In the US, growth was driven primarily by adult patients initiating SPINRAZA treatment. Outside the US, growth was reported in all major regions. Importantly, because of the significant number of untreated patients in established and emerging markets, we continue to see potential for further growth. Product sales of TEGSEDI and WAYLIVRA also continued to grow in the first quarter, more than doubling compared to Q1 2019. Today, TEGSEDI is commercially available in 12 countries. In the US, over 1,800 physicians are now using Akcea's genetic testing program, with a growing number of patients being tested and diagnosed. Many physicians and patients are choosing TEGSEDI, due to its subcutaneous at-home administration, which is particularly attractive in the current COVID-19 environment. Additionally, Akcea's market access efforts have continued to translate into broad TEGSEDI coverage, including long-term coverage secured for 75% of US patients with commercial insurance. Akcea has made progress expanding TEGSEDI access outside the US, including in Southern Europe, which is important because of the large pandemic TTR amyloidosis patient population throughout this region. Akcea has also made progress in obtaining pricing and reimbursement in additional countries, most recently in Spain and Austria. In Latin America, PTC Therapeutics is working to secure pricing in Brazil and expand TEGSEDI access in that region. We anticipate that expansion into new countries will help drive TEGSEDI growth this year. Now turning to WAYLIVRA. WAYLIVRA is now on the market in Austria, Germany, and France through the ATU, a reimbursed early access program. This year, Akcea plans to launch in additional EU countries, and PTC Therapeutics is working towards their goal of filing for marketing authorization in Brazil this year. Akcea has a strong foundation in place for TEGSEDI and WAYLIVRA, which we believe supports growth as both medicines expand into new markets and broader access is achieved this year. We do not rely on a single product or partner for our revenue. The fact that we generate revenue from multiple sources is one of our many strengths, and one that is particularly valuable during these uncertain times. In addition to revenue from our three commercial medicines, in Q1 we earned $49 million of revenue from numerous partnered medicines as they advance. We earned more than $25 million in R&D revenue for advancing medicines within our neurological disease franchise, including IONIS-MAPTRx for Alzheimer's disease and several other programs under our Biogen collaboration. Additionally, we earned $50 million in R&D revenue from our cardiometabolic franchise, which included a $10 million milestone payment when AstraZeneca advanced ION-532 for the treatment of kidney disease. As we expected, Q1 R&D revenue was lower than the same period last year, given the $150 million we earned from Novartis when they licensed AKCEA-APO(a)-LRx last year. We expect growth in revenue this year to be driven by continued significant commercial revenue and R&D revenues from numerous programs. Our first quarter non-GAAP operating expenses increased nearly 20% to $153 million compared to the same period last year. This increase is driven by our investments in the global launches of TEGSEDI and WAYLIVRA, the Phase 3 program for Akcea's TTR LICA Rx, and our Ionis-owned pipeline. As the year goes on, we also expect to invest in technologies that could broaden the reach of our technology, as we did late last year when we made strategic investments in complementary technology. Our operating expenses in Q1 were lower than the fourth quarter of last year, principally because of these investments. These types of investments are an important objective for us this year, and as such are included in our full-year operating expense guidance. With these results, we ended the first quarter nearly breakeven with a net loss of $50 million on a non-GAAP basis. Our first quarter results and projections for the rest of this year enable us to reaffirm our 2020 financial guidance, including revenues in excess of $700 million and meaningful profitability. We project Q2 will generally be in line with Q1, with revenues increasing in Q3 and Q4. We also expect our non-GAAP operating expenses to increase as the year progresses in line with our guidance. Looking ahead to the remainder of 2020, we remain well-capitalized with a strong balance sheet and $2.4 billion in cash and investments. Enabled by our financial strength, we have the resources to execute on our near and longer-term strategic priorities even in the challenging COVID-19 pandemic environment. And with that, I’ll turn the call over to Richard, to provide an update on our pipeline.

Thank you, Beth. While managing the challenges presented by COVID-19, we have continued to achieve significant advancements across our pipeline of over 40 medicines in development. As mentioned previously, Roche completed enrollment in the global GENERATION HD1 Phase 3 study for tominersen, our medicine in development for the treatment of Huntington's disease. The rapid enrollment in this study reflects the profound commitment of Huntington's disease patients and caregivers to help us find an effective treatment for this devastating disease. We are especially pleased that Roche recently confirmed that this program remains on track with the potential for data in 2022. Biogen continued to advance clinical studies with two of our medicines addressing two genetic forms of ALS. The Phase 3 study of tofersen in SOD1-ALS and the Phase 2 study of IONIS-C9Rx in C9-ALS. IONIS-C9Rx was recently granted fast track designation in the U.S., which underscores the substantial benefit this medicine may deliver to these patients with the most common inherited form of ALS who have no approved therapeutic options. We and Biogen have also expanded our ALS franchise to include ION541 for the treatment of patients with sporadic ALS, which is on track to enter the clinic later this year. We're particularly excited about this medicine, our first to enter development addressing the vast majority of ALS patients. Turning our attention to SPINRAZA, the body of evidence supporting the durable efficacy and well-established safety profile of SPINRAZA also continues to grow. The first patient was treated in the DEVOTE Phase 2/3 study with a higher dose of SPINRAZA. Based on the well-validated safety profile of SPINRAZA, this study has the potential to demonstrate even greater efficacy in SMA patients of all ages. New data from an independent study published in Lancet Neurology demonstrated that teen and adult patients treated with SPINRAZA for 14 months achieved clinically meaningful improvements in Hammersmith scores with a continued favorable safety profile. Also during the first quarter, we and our partners initiated Phase 2 proof-of-concept studies for three medicines addressing a diverse range of neurological and rare diseases, including hereditary angioedema, beta-thalassemia, and central nuclear myopathy. Additionally, we're particularly excited about the programs in our growing Ionis-owned neurological disease pipeline, including our programs for Alexander, Lafora, and prion disease, which continue to move closer to their first set of trials. Our cardio-metabolic pipeline continues to be a significant area of focus for us, addressing diseases ranging from rare to very large, and including both partner and Ionis-owned medicine. AKCEA-APO(a)-LRx was just granted fast-track designation, underscoring the significant value this medicine may bring to millions of patients worldwide with established Lp(a)-driven cardiovascular disease and no effective therapeutic options. Importantly, the Phase 3 horizon cardiovascular outcome study of AKCEA-APO(a)-LRx is progressing with our partner Novartis. As of today, Novartis expects no significant impact from COVID-19 on study timelines. Earlier this year, we reported positive top-line results from Phase 2 proof-of-concept studies AKCEA-APOCIII-LRx and vupanorsen, both of which are part of our growing and advancing LICA pipeline, achieving their primary endpoint and demonstrating robust triglyceride lowering and substantial reductions in additional key cardiovascular risk factors with favorable safety and tolerability profiles. This year, we look forward to presenting the full data from these studies at a medical conference or other venue. We also advanced new medicines into Phase 1 development, addressing very broad cardiometabolic diseases, including ION532 targeting APOL-1 for the treatment of kidney disease and Ionis-owned LICA medicine ION224 targeting DGAT2 for the treatment of NASH. Enrollment is progressing in the Phase 3 studies of AKCEA-TTR-LRx NEURO-TTRansform in patients with TTR Polyneuropathy and CARDIO-TTRansform in patients with TTR cardiomyopathy. In response to COVID-19, we briefly paused new patient enrollment in both studies in an effort to protect these patients, who are at high risk for COVID-19-related complications. It was also essential for us to preserve data integrity at this early stage in the studies. However, enrollment has resumed in both studies, as sites have come back online as local and regional restrictions eased. Importantly, we do not expect this brief pause to significantly impact the timeline of these studies. COVID-19 presented us with a number of challenges, which we believe we are managing well. We're continuing to monitor each program and are ready to respond if needed as the pandemic evolves. Our dedicated team has successfully adapted to the current environment, enabling us to continue advancing our pipeline and remain on track to achieve our top 2020 priorities. We plan to initiate the Phase 3 study of AKCEA-APOCIII-LRx in patients with FCS. We remain on track to re-file the NDA for WAYLIVRA in the US this year and we continue to expect clinical proof-of-concept data for at least four more programs this year. We still plan to add another five or more new medicines to our pipeline. And with that, I'll turn the call back over to Brett to close this portion of the call.

Thanks, Richard. Today, Ionis is stronger than ever. We are reaffirming our 2020 financial guidance, and we've remained well-capitalized with a strong balance sheet. Our strength and sustainability are enabling us to continue delivering value to patients and shareholders while effectively managing the challenges presented by the COVID-19 pandemic. Already this year, we've continued to deliver strong performance from our commercial medicines. We've made significant progress in advancing all of our Phase 3 programs, all of which remain on track. Preparations are well underway to initiate another Phase 3 program this year and to re-file WAYLIVRA for approval in the US. We reported positive data from two Phase 2 medicines, initiated numerous Phase 1 and Phase 2 studies and are on track to move five or more new programs into development this year. None of this would be possible without the dedication, resilience, and strength of our employees. I am incredibly proud of how the Ionis team has responded to overcome the challenges posed by COVID-19. Because of our employees, we are continuing to execute effectively on our mission to deliver transformational medicines to patients in need. As we continue to invest in our strategic priorities, including building and advancing the Ionis-owned pipeline and developing our commercial capabilities, we remain on track to achieve our short and longer-term strategic goals, including delivering new drug applications for 10 or more of our medicines through 2025. We have tremendous momentum as we look towards the rest of this year and beyond. I'm excited about the future that we're creating and look forward to reporting on additional successes throughout this year and beyond. And with that, I'd like to open the call for Q&A.

We will now begin the question-and-answer session. The first question today comes from Jim Birchenough of Wells Fargo. Please go ahead.

Hi, guys, congrats on all the progress and your work through the COVID-19 situation. A few questions. I guess number one, Brett, if we could get maybe updated thoughts on internal commercialization versus the affiliate model and maybe some framework that Onaiza may be working on to establish your commercial model at Ionis. And then for Richard, just on the CF program, the pulmonary program, should we expect data by year-end in CF patients and what should we look for there? And then maybe just one final one for Beth, just in terms of R&D revenues, is that something we should consider remaining stable over time or is there any reason to think that that could increase or decrease? Thanks.

Thank you for the questions, Jim. I'll start with the first one and then I'll turn it over to Onaiza for her insights. As we mentioned in our recent call, we are focused on continuing to develop and enhance the Ionis-owned pipeline while identifying and assessing the value and synergies of each of the medicines within that pipeline. Our primary focus is on rare diseases. We are exploring opportunities within that growing pipeline that will deliver maximum value for Ionis and our shareholders. This year, we are evaluating different commercialization strategies and plan to present some of those strategies later in the fall. Onaiza, feel free to add to my remarks.

Sure. Hi, Jim, how are you? Thanks for the question. So we're making good progress in developing our commercial strategy. As Brett just said, the Ionis-owned pipeline is large and we're making investments. We certainly expect to continue to grow in the future. So, as part of that portfolio prioritization, the initial steps in the commercialization work have been focused on portfolio prioritization. We're preparing a high-level strategy that lays out how our innovative products deliver on the high unmet need in the market, what our strategic positioning is, and identifying where we have customer-facing synergies. As a result, the Ionis-owned portfolio we talked about last time continues to be a priority. We remain excited about the mid-stage portfolio as well, which includes acromegaly, non-transfusion dependent beta-thalassemia, and hereditary angioedema. I really look forward to providing a high-level commercial strategy for the Ionis-owned portfolio later this fall, likely at the Investor Day. We currently have plans and we can get a little bit deeper at that time.

Thanks, Onaiza. Richard, do you want to talk about our ENaC program a little bit?

Yes. So the ENaC program is moving forward at a pace that we expect will complete enrollment this summer. We do expect the cystic fibrosis portion of that study to be able to report out later this year. What should we expect is a relatively short-term exposure of six weeks of weekly inhalation of the product. We expect safety and some efficacy based on the target engagement. So that's essentially what we'll know by the end of this. We have a fully completed Phase 1 trial in normal volunteers that has shown excellent safety and tolerability. We will also be including data in the rollout.

When we roll that out, Jim, I suspect we will also be able to talk about additional Phase 2 studies that are in planning phase right now for our ENaC inhibitor. We're not planning to develop that drug solely for CF, but actually, there are quite a few other opportunities in the pulmonary front that we're quite excited about. Beth, you want to take Jim's other question?

Sure, absolutely. Hi, Jim. As you know, R&D revenues can be unpredictable, and this year is no different. I expect that, as I mentioned earlier, the second quarter will likely resemble the first quarter in terms of revenues. Our R&D partnership revenues are more likely to be loaded towards the end of the year. Therefore, I anticipate revenue growth in the third and fourth quarters, mainly from our R&D revenues; and of course, I also expect commercial revenues to increase quarter-over-quarter for the rest of this year.

Great, thanks for taking the questions, guys.

Thanks, Jim. I appreciate the questions.

The next question comes from Tyler Van Buren of Piper Sandler. Please go ahead.

Hi, guys. Good morning. Thanks for taking the question. I guess with respect to the four or more proof-of-concept results that we should expect these upcoming catalysts. I know you mentioned some of them. But could you just review at least those four for us? And maybe specifically highlight the one or two that you're most excited about? And what you'd need to see in order to achieve proof-of-concept?

Sure, happy to, Tyler. Thanks. Just to back up half a step, as a reminder, our objective this year was to read out on six clinical proof-of-concept studies. We already have two in the bag with two very successful Phase 2 outcomes; with angiopoietin-like 3 LICA, which is now licensed and partnered with Pfizer, and our APOCIII LICA which is running a Phase 3 study to initiate later this year. We have a number of opportunities for clinical readouts this year, and we're on track to achieve those six clinical readouts this year. We're expecting to read out on our acromegaly program growth hormone receptor, which is in patients on SFAs who are not controlled, looking at endpoints such as IGF-1. Hereditary angioedema from our PKK LICA program is another program that we're expecting to have a readout on later this year. In addition, we have an exciting program in hypertension. Angiotensin is an exciting program where we have multiple phased programs ongoing. We're hoping to share some of that data later this year as well. In addition, there's the potential for some data coming from our beta-thalassemia program; it remains to be seen if they'll be ready to go this year or not, or whether they'll go into next year. But in addition, the ENaC program for pulmonary diseases that Richard already mentioned. Of course, we also have the ongoing study in which we're evaluating with AstraZeneca our program determining whether evaluating the oral formulation for an undisclosed target that is in clinical testing now, which we hope to read out later this year as well and present data on our partner. So, quite a rich set of pipeline updates coming in the second half of this year that we're really excited about.

Maybe just a quick follow-up on AKE. I guess this is the goal, standard of care injectables that have launched for prevention and are achieving pretty high reductions in terms of attack rate. Do you think you could improve upon that or is the goal to extend treatment duration with the LICA?

You're absolutely right. The AKE landscape is quite competitive. Patients have received substantial benefit in the reduction in attack rates with the current approved medicine. Our objective is to perform as well, if not better, with our mechanism of action blocking the kallikrein pathway. As you may have seen, in some of our Phase 1 data, we're developing a very potent molecule which has shown to have a large impact of greater than 90% reductions in kallikrein. We think we can do better but also we have the convenience of a very infrequent low-volume injectable, subcutaneous formulation, with the potential for a commercially viable oral bioavailability in ongoing studies. This would be a significant advantage from a convenience standpoint. It is a competitive environment, and we are hopeful that we can compete. The other thing I'll just add is that we are exploring additional potential indications for our kallikrein inhibitor, and plans are coming together to move on those. We're hoping to share some of our thoughts on this later this year, possibly at Investor Day.

Very helpful. Thanks for taking the question.

The next question comes from Jason Gerberry of Bank of America. Please go ahead.

Hi, this is Keith on for Jason. Thanks for taking our question. I have a couple on the 105 for sporadic TRS. I guess the first one on that maybe can you talk about how efficient the market opportunity for that will be? I guess how large is the sporadic population within the broader TRS umbrella? Then I have a couple follow-ups after that.

Sure, Keith. We're very excited about our ALS program. As you know, there are multiple causes of ALS, both genetic and sporadic. Our two lead programs are targeting genetic C9, which is due to read out Phase 2 data next year, and our Phase 3 data for tofersen in SOD1-ALS is also due to read out next year. This is our first of several sporadic ALS target drugs we're planning to bring forward in the not-too-distant future. This is targeting Ataxin 2. The preclinical data looks very exciting and compelling, and one of our key objectives this year is to get the clinical study started with Biogen. As you know, the sporadic population represents the vast majority, the vast majority of patients with ALS. I believe that it's somewhere north of 75% of patients with ALS are the sporadic variety. Ataxin 2 has no reason to believe that it couldn't perform well and address a significant portion of that population.

Got it. I think you've kind of bridged into my second question. My second question was how heterogeneous is sclerosis formed? Are you planning multiple studies for that population? Are you evaluating different mechanisms to address all the different mechanisms that could cause ALS? If you could provide some insight into that, that would be great. Thanks.

It's difficult to determine how much of the sporadic population Ataxin 2 could impact. We're optimistic that we can target most of that sporadic population as previously mentioned. We have an exciting research collaboration with Biogen where we are exploring various mechanisms and targets in animal models for sporadic ALS. Eric, could you provide more details on the different mechanisms we are considering and our approach to this?

Yeah. As Brett mentioned, the Ataxin compound is very exciting, but we will really need to figure that out in clinical trials and find out which patient populations respond best. The preclinical work, which has been published by the way, is very strong. We have a very broad program with Biogen, looking at all forms of ALS, genetic, familial, sporadic, and all mechanisms that could potentially contribute to the pathogenesis of the disease. We're looking at all sorts of different pathways and trying to figure out which drugs or combination of drugs are best for moving forward to treat the condition. So it's a very broad, deep program. I'm certainly optimistic we'll have lots more programs coming forward.

Got it. Maybe just one final follow-up from me, I believe, the plan is to advance 105 into clinical trials this year. Can you talk about when we could possibly expect data next?

You're referring to the sporadic?

Yes, the sporadic.

Yes, starting this year, so I wouldn't expect data until next year at the earliest.

Okay. Thanks so much.

Thank you.

Your next question comes from Chad Messer of Needham and Company. Please go ahead.

Great. Thanks for taking my questions. I'm certainly glad to hear the team at Ionis is managing things well in this pandemic. I'd like to maybe start with a liver in the refiling, can you sort of walk us through the steps that are left? Is it really data collection or are there any regulatory interactions that need to occur?

Thanks, Chad. We're very excited about refiling and for the U.S. for potential approval for FCS. We've been with Akcea collecting a substantial amount of additional data to the original CRL we received when we were in the U.S. Our confidence about approval for WAYLIVRA in the U.S. has grown as we've continued to collect and evaluate that data. Our confidence has grown even more based on our meetings with the FDA to talk about refiling for WAYLIVRA. We feel good about the discussions we've had with them, and they have been very supportive and productive. What we’re doing now is putting the data together and we’re getting ready to file later this year. Richard, do you want to add anything to that?

Only to affirm, we have no more regulatory interactions. We've met with our pre-resubmission meeting and were encouraged to resubmit as the data is there. So we’re just putting that package together.

Okay, great. Thanks. And then just on the APOCIII LICA upcoming FCS study, is that pretty much, should we assume going to look like the approach or were there some lessons learned having gone through all of this before?

Certainly we have extensive experience in FCS. As you know, we're using all of that information to build on our Phase 3 study design for APOCIII LICA. Richard?

A couple of things as we move through the development of WAYLIVRA, Akcea has been hard at work developing a patient-reported outcome, which will be included in this study that was not included in the first study. So that's one difference. There will also be a real focus prospectively on the pancreatitis, and we'll enrich for patients who have ongoing and consistent pancreatitis. So that will be another piece that is a bit different. Otherwise, it will look a lot like the approach trial.

Okay. Thanks, and helpful. And then maybe just the one SPINRAZA on the DEVOTE study. I don't know how much of this you can share, but maybe talk us through what kind of efficacy delta we could potentially expect there. I mean, it seems like the efficacy that we already have with SPINRAZA may be hard to convincingly beat in a trial unless it was a really large one.

Yes, you're absolutely right. The efficacy that SPINRAZA has demonstrated in all forms of SMA is a very high bar, not only for our DEVOTE study, but for all of us. However, we do believe that going to higher doses, as does Biogen, has the potential to show even greater efficacy. For instance, in between maintenance dosing, sometimes patients will start to feel some symptoms returning towards the end of a maintenance dose. This is just one example. The patients we get to later in their disease may have more disease progression before going on SPINRAZA. We have the potential to show even greater efficacy in those patients, for example. There are other ways to show greater efficacy as well. So based on the pristine safety that SPINRAZA has demonstrated, we have the luxury of going to a significantly higher dose in our DEVOTE study. This study is underway. So, it does have a high bar of efficacy, but we do believe there's an opportunity to show greater efficacy. I'll also expand on your question, if I can. We're also working with Biogen on a follow-on drug, a potential follow-on drug for SMA, based on a new chemical entity that we feel pretty good will allow us to make a biannual or possibly even annual dosing with an intratumoral administered medicine. So, we're reinforcing the SMA franchise with Ionis and Biogen. We're excited about both the positive high-dose results as well as the follow-on medicine.

Great. Thanks, I’ll pass the mic. Appreciate all the insights.

Thanks, Chad.

The next question comes from Esther Rajavelu of Oppenheimer. Please go ahead.

Good morning. Thank you for taking my question. Can you maybe give us some color on your partnered programs that may be experiencing COVID-19 related delays, the magnitude of that, as you think about the first half of the year versus the second half? And then I have another quick follow-up.

As we've stated, with respect to the clinical programs we're running, we've had minimal impact on the progress we're making on our clinical trials. A similar story applies to our bio partners, where we have always been in close contact with them and have been meeting even more frequently since the crisis began. We're not seeing substantial impacts on any of our pipeline or partner pipeline programs, taking in certainly nothing meaningful. As Richard mentioned earlier, the Phase 3 programs with Novartis and the cardiovascular outcome trial, as well as the Phase 3 program with Biogen, and the Huntington program are all on track to readout on time. Our partners are managing the situation quite well.

Thank you. You've always been in an enviable cash position recently. Do you have any updated thoughts on capital deployment in this current environment?

Yes, sure. I'll comment on that. I'll ask Beth to make some comments too. We're very proud of the strong financial position we are in. We will continue to invest in all of the areas and priorities we've planned on investing in last year and as we talked about earlier this year. That includes investing in our pipeline, our later-stage pipeline, the Ionis-owned later-stage pipeline, such as the Phase 3 program for APOCIII LICA and of course TTR LICA Phase 3 studies, and our mid-stage pipeline as well. We're also investing in building up the commercial capabilities and identifying various options for maximizing the commercial value of the medicines we bring to the finish line through Phase 3, as Onaiza touched on earlier during this Q&A. Additionally, we continue to invest as we did earlier this year and plan to continue to do so in new technologies; technologies that complement what we're doing in antisense to ensure that our leadership position in RNA therapeutics is not only maintained but extended. Genomics collaborations will continue to populate the pipeline with novel genetically linked targets for drug discovery, LICA chemistries, new LICA chemistries that we're collaborating with new partners, and we continue to look for other collaborations as well. We also explore brand new technologies that we continue to survey and pursue, looking at potentially diversifying our platform into new areas.

Great. All right. More specifically, maybe if you could comment on share repurchases and what your thinking is for the remainder of the year?

Hi, Esther, it's Beth. As we think about our cash position, I think Brett did a really nice job of outlining our priorities. They're very clear; we're clear internally about where we're going to invest our capital. When we think about share repurchases, our view at this point is particularly given the uncertainty of the current environment, that holding on to our cash and having it available for some of these other opportunities Brett was describing is really a better use of cash today. We don't have any specific plans, but we will certainly keep it always in mind.

Awesome, thank you very much.

Thanks.

The next question comes from Eliana Merle of Cantor Fitzgerald. Please go ahead.

Hey guys, thanks so much for taking the question. Just in terms of the oral program. I know you mentioned that you're still hoping to get data in 2020. Can you give us a little bit more color just in terms of what drives this, if it's completed enrolling or if it's still enrolling and close to completion? In terms of what specific data we could expect to get in terms of the oral, I guess, what have you and AstraZeneca worked out in terms of what you would disclose?

Sure, Ellie. We're collaborating closely with AZ on several initiatives in the cardiometabolic area, including this one. Our goal is to complete a phase of the study that we believe will provide sufficient proof of concept, which will help us determine if we are progressing towards achieving commercially viable oral delivery. You can expect this in the form of bioavailability and pharmacokinetics predicted from our preclinical data, as well as biomarker information. The effect on biomarkers that indicate target engagement is also significant. We have a concurrent program using the same drug delivered subcutaneously, and we aim to compare the two approaches directly. This comparison will provide valuable insights on how the oral formulation is performing as we continue developing the subcutaneous version. The key advancement that enables us to pursue oral delivery is potency. These are Gen 2.5 LICA molecules that are stable in the gut and remain intact during absorption. The potency enables us to achieve the necessary bioavailability and other requirements for the drug. Our subcutaneous data will be crucial to demonstrate that our preclinical predictions translate to this level of potency. We believe both programs are very important.

Got it thanks. In terms of thinking about COVID impacts on the TTR LICA Phase 3 programs, could you characterize how enrollment is going in each of those Phase 3 studies and how COVID is potentially impacting enrollment timelines? What are your latest expectations for when you predict completion of these studies?

As Richard mentioned earlier, the enrollment is ongoing and the programs are going well; both the TTRansform cardiomyopathy study and neuropathy study are both going well and on track. We did pause those studies very briefly. That was based on requests by our activated sites who had to assess their situation, being overloaded in their hospitals managing COVID-19 patients. They didn't know what to expect from COVID, so we of course appreciated their challenges and we paused the enrollment until they assessed the situation. They told us that they were ready to go, and we reactivated and are rolling again. We do not expect a significant impact on the timelines for either study going forward. We implemented a number of mitigation strategies as this developed to catch up and did quite a bit remotely during this brief pause. So we are not expecting significant impact on timelines.

Got it. Thanks. Very helpful.

Thank you.

Next question comes from Yale Jen of Laidlaw and Company. Please go ahead.

Good morning, and thank you for the questions. I'm impressed with how you're handling the situation under COVID-19. I have two quick questions. The first is about ION-224, the DGAT2 program in NASH. Do you have any insights? I know most DGAT2 drugs are in a 30-year development stage, but what do you perceive as your strengths compared to other programs in development?

Sure, Yale. Thanks. One of the advantages we have is building on the really impressive Phase 2 data we generated in patients with NAFLD liver disease, with the non-LICA, which we had high statistical significance reductions in liver fat with excellent safety and tolerability, which led us to go back and identify and bring forward the LICA version of that to allow us to go to even lower doses and less frequent dosing administration. As from a target standpoint, the advantages we have are multiple. One is the fact that DGAT2 is the rate-limiting enzyme in the triglyceride synthesis pathway in the liver. We've demonstrated that. We've actually examined all the targets as they concluded that our DGAT2 was the most appropriate sensitive target for managing liver fat. The second advantage we believe we have is specificity, as small molecules have difficulty with specificity and isoforms such as DGAT1 and DGAT1 inhibitors; others can lead to side effects that we've published on actually. DGAT2, our inhibitors are very specific and we think that it will measure up very well against the competition for other agents targeting the triglyceride pathway in November.

Okay, great. That's very helpful. And maybe the next question really follows up on the very first question really, are you guys going to assess a lot of your rare disease pipeline in terms of their commercialization or pathway to market? I know that yesterday in Akcea's conference call, they were also anticipating or expecting some of these programs to move to their pipeline. So overall, how would you think about what to maintain on your own work versus potentially moving some of those other parts of Akcea for their development?

We're having very productive discussions with Akcea about potential assets to move into Akcea this year. They, of course, have a very full agenda this year with TEGSEDI, WAYLIVRA, the APOCIII LICA Phase 3 study in the re-filing of WAYLIVRA in the US. Discussions have been very productive and we've narrowed down to a few potential rare disease programs from the Ionis-owned pipeline. I think you'll hear more about that later this year from Akcea and Ionis. Certainly, getting our rare neurological disease pipeline is a priority for us at Ionis. It's a pipeline that we're very excited about, including programs for prion disease, Alexander, and Lafora, which Richard mentioned earlier. We have more coming and expanding; that's certainly a high priority for Ionis. You will be hearing more about that later this year, including at our Investor Day.

Okay, great. Thanks a lot, and again, congrats on the progress.

Thank you.

The next question comes from Paul Matteis of Stifel. Please go ahead.

Hi, this is Alex on for Paul. Just a couple of questions from us. Thanks for taking the question here. I guess the first one related to the way that you're thinking about partnerships, just curious how you're thinking about your AGT program, given it as another large market indication. What are your thoughts as it stands today on continuing development on your own or looking for partners moving forward?

Sure, Alex. Our strategy on partnering for large broad indications remains the same, except we're not going to take on very large Phase 3 studies that an antihypertensive would entail. Some other way as we've done for Lp(a) will seek a partner at the appropriate time. That said, we're in no rush and we have the financial strength to be able to bring these large indications through clinical proof of concept, far enough as it needs to go to maximize the economics that come to Ionis when we bring in partners in the future. So, we're not in a hurry to partner this program. We're excited about what we're seeing and we're looking forward to sharing some of the results of these studies later this year.

Great, thanks.

Next question comes from Jessica Fye of J.P. Morgan. Please go ahead.

Hi, guys. Good afternoon. Thanks for taking my question. I have a question on the acromegaly program heading into that proof-of-concept data later this year. How do you expect that product will differentiate from competitors, namely the SSAs, either from a mechanistic perspective or the target patient population? Thank you.

Sure. I'd be happy to. The proof-of-concept study is in patients who are uncontrolled IGF-1 with the somatostatin analogs, and so quite a number; it turns out as much as 40% to 50% of patients don't get full control on their current therapies. What you'd want to see is IGF-1 control with the addition of our acromegaly GHR LICA program. Also, we have a much improved tolerability profile for this compound. We're also initiating monotherapy studies in this population in patients who are not on SSRLs or who have weaned off and come onto this program. The program's staggered a bit with the monotherapy coming after the add-on, but we're excited about what we're seeing and hope to have some real data in the second half of this year.

Jess, it is Onaiza. That was great. I'd just say that we've done some initial work on the product profile early on, and in addition to the IGF-1 control, we're also seeing there's an unmet need on breakthrough symptoms, and we believe with our product, we can offer both along with the monthly dosing that is turning out to be applied to differentiation.

Great. Thank you.

Anything else, Jess?

That's it. Thank you.

The next question comes from Mani Foroohar of SVB Leerink. Please go ahead.

Good afternoon, everyone. This is Rick on the call from Mani. Thanks for taking our questions. First, I just wanted to touch on the oral ASO candidate again. The timing of that first clinical data disclosure is going to be controlled by AstraZeneca. Is that a joint decision between the two companies?

So, the decision on the timing to talk about the program is joint; Ionis and AstraZeneca. We work very closely together on this program and our other cardiometabolic programs. As for the potential to exploit the progress we're making in oral for our other programs, we're already moving those programs forward, programs that are non-partnered, that have Gen 2.5 LICA chemistry, or we're identifying Gen 2.5 LICAs for existing programs as potential follow-ons. The focus really is on areas where oral would provide significant competitive or convenience advantages for patients, like chronic lung diseases, where patients will be on therapy for long periods. Diseases could be severe but patients are generally asymptomatic until they have an event of some sort, which would be particularly well-suited for an orally-administered agent. In areas where we're competing with other technologies or medicines where we think oral can provide a competitive advantage.

Great. That's it from us.

Thank you.

The next question is from Ritu Baral of Cowen. Please go ahead.

Hey guys, thanks for taking the question. I want to follow up on the Roche Huntington’s data release. I think you mentioned that they had some Phase 3 data in 2022. But I'm wondering about any interim data we could get in the meantime, whether it's an interim look into Phase 3 or the Phase 1/2 open label extension data. Any timelines for that? And then I've got a follow-up.

Roche has not indicated in any way that there would be an interim look at the Phase 3 data before the Phase 3 data reads out, which is expected in 2022. Next year, they are planning to share the open label extension data from our Phase 1/2 study, which has been completed, and they're evaluating the data. They will share that data alongside the natural history study, which has not been completed yet but will complete this year or early next year.

Got it. Can you go into a little more detail about the C&M2 program for intranuclear myopathy? You indicated the Phase 1/2 started. Can you give us the trial design, timelines for that data, and maybe just how you look at the indication?

This is with our partner Dynacare. C&M2 is the target for the treatment of all forms of central nuclear myopathies. They've published with us a joint publication of some very exciting preclinical data models of C&M. This is a muscle target. Based on that data, we watched it move into clinical development. The study design is in older patients with C&M. These patients have had a long natural history with substantial amounts of data for those entering studies. So, there's a lot of information to consider. The study is open-label, allowing all patients to receive the drug. The goal is to move into infants next year, which is more a severe form of C&M.

Is there a particular biomarker or a functional marker in these older patients that the Phase 1/2 analysis will pay attention to?

These will be measures of mobility and quality of life. C&M2 is not measurable in the blood, but other biomarkers are under development by Dynacure.

Got it. Thanks for taking the question.

Thanks, Ritu. Maybe one more question; we're going quite long.

The last question today comes from Josh Schimmer of Evercore ISI. Please go ahead.

Thanks for feeding me in. Just on the Akcea, the commercial performance has been below expectations and is still a drag on your ability to achieve profitability. Do you think that's going to change meaningfully over the next 12 months? How are you thinking about mitigating the burn? And then deciding if we need to take more aggressive steps for that part of the business?

Thanks, Josh. I'll ask Beth to address that.

As Steve mentioned on their earnings call yesterday, and we reiterated, we see continued growth for both TEGSEDI and WAYLIVRA as they expand into new markets throughout Europe, as well as in Latin America with PTC. It's quite customary to invest ahead of revenue growth when you're launching new products and expanding into new markets, and that's what we're seeing right now. We are continuing to be sustainably profitable. We have a stated goal to be sustainably profitable, and we've been able to do that the last several years, reaffirming our guidance again this year to be meaningfully profitable. We're obviously committed to that, and we're also committed to working with Akcea and their new management team to build the TEGSEDI and WAYLIVRA franchises. So stay tuned.

Thank you.

Thanks, Josh. Thanks, Beth. Okay, with that, I think we’ll wrap it up. Thanks, everybody again for joining us today. We're feeling really good about where we are at Ionis. We're confident we're taking the necessary steps to ensure success this year. We have the financial strength to continue pursuing our short and long-term strategic priorities. We look forward to updating you on our progress as the year unfolds. Take care, everybody, and we'll talk soon. Bye now.

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