Good day, and welcome to Ionis Pharmaceuticals Q4 and Full Year 2019 Financial Results Conference Call. All participants will be in listen-only mode. [Operator Instructions] After today’s presentation, there will be an opportunity to ask questions. [Operator Instructions] Please note this event is being recorded. I would now like to turn the conference over to Wade Walke, Vice President, Investor Relations. Please go ahead.

Thank you, Sarah. 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 on the call. 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; Onaiza Cadoret, Chief Corporate Development and Commercial Officer; Beth Hougen, our Chief Financial Officer; and Richard Geary, Senior Vice President of Development. Additionally, Eric Swayze, our Senior Vice President of Research will join us for Q&A. I would now like to draw your attention to Slide 3 of the slides that we have for today’s call, which contains our forward-looking language statement. We'll be making forward-looking statements which are based on 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 Monia.

Thanks, Wade, and good morning everybody and thanks for joining us on today's call. I'm very excited to be speaking to you today in my new role as Ionis’ CEO. In 30 years, Ionis has achieved enormous success by delivering on our commitments to help patients with the greatest unmet medical needs. Today, we're building upon that success. In fact, I believe that today we have the resources and people to make Ionis among the most innovative, productive and highest achieving companies in our industry. So now to recap last year's achievements. 2019 was an exceptional year from a financial perspective, as Beth will discuss shortly, 2019 was especially strong. SPINRAZA's blockbuster performance continued and Biogen expects growth again this year. And the commercial launches of TEGSEDI and WAYLIVRA progressed with plans in place to expand to new markets soon. Together with exceptionally strong R&D revenue, we delivered over $1 billion in revenue and over $400 million in net income and ended the year with $2.5 billion of cash, outperforming even our improved 2019 financial guidance. Importantly, we achieved these exceptional financial results while investing in all areas of the business that we believe have the greatest potential for value creation. And already this year, we're building upon this momentum to achieve even more success. As Richard will discuss, in 2019 we achieved strategic successes broadly across our pipeline, including in our neurological and cardiometabolic disease franchises. We achieved our primary goal, advancing four medicines into Phase 3 studies. We achieved positive clinical proof-of-concept results for five medicines. We advanced five new medicines into Phase 1 and we advanced 10 new medicines into development, six of which are Ionis-owned. Also, last year, we continued to advance and broaden the scope of our technology. In addition to moving two of our…

Thank you, Brett, and good morning everyone. I'm quite excited to join Ionis at this transformative time for the company. As Brett said, we are in a unique position of strength. We have an expansive, deep and advancing pipeline with a growing number of late-stage medicines. Our technology is broadly applicable, enabling us to bring novel medicines to patients. And most importantly, we have a strong experienced team, who operate with scientific rigor and innovative mindset and are very committed to delivering transformational medicines to patients with severe unmet needs. I am excited to assume leadership of the company's corporate development and commercial efforts. Our goal to maximize the value of each medicine in our pipeline remains unchanged. Looking ahead, we plan to pursue this goal by identifying the optimal commercial strategy, pathway and organization for each of our medicines, while preserving our established culture of scientific innovation. We plan to develop our commercial capabilities, allowing us to bring medicines from our growing Ionis-owned pipeline to patients. In parallel, we will continue to establish strategic partnerships, develop and commercialize those medicines with a potential to address diseases with the largest patient populations such as our most recent collaboration with Pfizer for Akcea, angiopoietin-like 3 LICA. We also look forward to continuing to support Akcea as they pursue their strategic goals and through the potential addition of a new Ionis medicine to the Akcea pipeline later this year. I look forward to updating you on our commercial strategy as our work evolves throughout the year. And with that, I'll turn the call over to Beth.

Thank you, Onaiza. 2019 was an exceptional year, including financially. We significantly exceeded our 2019 financial guidance driven by revenue of more than $1.1 billion, nearly double compared to 2018. We earned over $350 million in commercial revenue and over $770 million in R&D revenue, including nearly $400 million for licensing Akcea-APO(a)-LRx and Akcea-ANGPTL3-LRx. Our revenues resulted in substantial non-GAAP operating income and net income of over $510 million and over $400 million respectively. We also achieved substantial operating income and net income on a GAAP basis. We achieved these exceptional results while further strengthening our balance sheet. We increased our cash balance to $2.5 billion and we refinanced a significant portion of our convertible debt, which enabled us to extend the maturity for most of our debt to 2024, achieved a one eight percent interest rate, which reduced our annual cash interest expense by approximately 40% and significantly increased our effective conversion price, which may reduce future dilution. Over the last several months, we also returned value to shareholders by repurchasing 2 million shares of our common stock through a stock repurchase program we implemented late last year. The refinancing of our debt and our share repurchase program underscores the confidence we have in the future of the company and our commitment to creating near and longer term value for shareholders. And because of our significant financial resources, we were able to execute these transactions while continuing to invest aggressively across our business. Now turning to our commercial revenue. SPINRAZA generated over $2 billion in worldwide net sales in 2019 resulting in nearly $300 million in royalty revenue to Ionis, an increase of more than 20% compared to 2018. At the end of last year, there were more than 10,000 patients on SPINRAZA treatment worldwide. Biogen achieved this important…

Thank you, Beth. As Brett mentioned, 2019 was a year full of important achievements. We made significant progress with our rapidly growing Neurological Disease Franchise. For example, IONIS-HTTRx for people with Huntington's disease and tofersen for people with SOD1-ALS entered Phase 3 studies last year and are progressing on schedule. We recently completed enrollment in our Phase 2 proof-of-concept study of IONIS-MAPTRx in patients with early Alzheimer's disease several months ahead of schedule. Biogen has expressed their enthusiasm for this program as an important part of their already robust Alzheimer's disease pipeline. And in fact, late last year, Biogen licensed IONIS-MAPTRx significantly earlier than anticipated, supported by encouraging blinded interim data from the ongoing study. Additionally, Biogen recently initiated a study of our medicine targeting LRRK2 most common genetic cause of Parkinson's disease. This is an exciting study which includes patients with both familial Parkinson's associated with LRRK2 mutations as well as patients with the sporadic form of the disease. Together these populations represent over three million patients worldwide. Also earlier this year we and Biogen advanced our program for the treatment of Angelman syndrome into development. We are particularly excited with the progress we're making with our pipeline of Ionis-owned medicines addressing neurological diseases. Patient enrollment is now underway in our Phase 3 NEURO-TTR transform study of AKCEA-TTR-LRx in patients with hereditary TTR amyloid polyneuropathy. Our Ionis-owned medicine for the treatment of Alexander disease was recently granted orphan drug status by the EMA, recognizing the significant need for therapeutic options for patients with this devastating and fatal genetic disease. We also added several additional Ionis-owned neurological disease medicines into development last year, including treatments for Lafora and prion disease. Turning to the recent advancements in our cardiometabolic franchise, enrollment is now underway and the Horizon Phase 3 cardiovascular outcome…

Thanks Richard. Before we end today, I'd like to remind everyone that this Saturday, February 29 is Rare Disease Day and in recognition of this important day, please join me in thanking the patients, families, and advocates who have been our partners in developing medicines to transform the lives of patients in need. I'd like to invite everyone to follow Ionis on Twitter and LinkedIn to learn more about how Ionis is raising awareness for the millions of people worldwide living with a broad range of diseases, including thousands of identified rare diseases, most without adequate treatment options. Today we're at a unique place in the history of Ionis. Our pipeline is broader and more mature than ever before with numerous programs nearing key value inflection points. This year we plan to use our financial strength to invest aggressively in all areas that have the greatest potential to create value for patients and shareholders, including growing and advancing our Ionis-owned pipeline. Further developing our commercial strategies and capabilities to ensure we maximize the value of each of our medicines, expanding the reach of our technology by, for example, optimizing different routes of drug administration and discovering new LICA strategies and identifying and increasing investments in complementary technologies that will also expand the reach of our antisense platform. And with that, I'd like to now open the call for Q&A.

[Operator Instructions] Our first question comes from Jason Gerberry with Bank of America. Please go ahead.

Hey thanks for taking my questions. So, I guess just on ANGPTL3 I was hoping, have you guys had a chance to discuss the recent data with Pfizer and any commentary that you can provide on that program and how you're thinking about the profile relative to some recent interim data from Arrowhead? Second question is just on Huntington's ahead of tomorrow some extension data from the earlier study. If you can set the table for what we could expect and the importance of those updates just in terms of understanding the broader safety profile of HTT ASO.

Right. Jason, thanks for the question. So starting with Angiopoietin-like 3, we've partnered that program prior to the unblinding of the Phase 2 data last year. And we and Pfizer were thrilled with the outcome, the Phase 2 results from that study. We achieved our primary endpoints, very high statistical significance and number of secondary endpoints positioning this drug very well for later stage development. And certainly Ionis and Akcea and Pfizer have gone through the data and are continuing to go through the data in quite extensive detail and forging the path forward next steps for this medicine to later stage developments. And we plan on sharing this data in detail in the second half of this year at a medical meeting to be determined. But short to say we're very excited as is Pfizer and Akcea about the Phase 2 results. We view them as being quite very, very positive. I don't really like to comment on other people's programs. I'm not very close to those programs. I focus more on exclusively really on Ionis programs. But we like our medicine and we believe we have the first and best-in-class medicine for targeting Angiopoietin-like 3. As far as Huntington's, the Huntington's program remains on track. It is of course targeting the root cause of Huntington's disease. The Phase 3 program is on track to deliver results in 2022 on schedule. And that's the basic message from the CHDI presentation that you'll hear about tomorrow. There's a lot of other presentations at the meeting too, but quite simply the messages that we have the premier program for targeting potentially targeting Huntington's – for targeting Huntington's disease that'll potentially bring this medicine to patients in the near future. Roche is very excited about the program and the message is that the Phase 3 study remains on track.

Thank you.

Our next question comes from Jim Birchenough with Wells Fargo. Please go ahead.

Hi guys. Congrats on all the progress and the broadening pipeline. A couple of questions, I guess just on capital allocation with $2.5 billion in cash, could you talk about your priorities for capital allocation and whether we should expect additional share repurchases? Also wanted to just touch on if you could, the revenue guidance for greater than $700 million, which is below the $1.1 billion from last year. But I guess if we back up the $400 million one-time payment, it's suggesting growth beyond that. So if you could comment on that, I guess the final bit is with the coronavirus, just wondering if you could comment on your exposure for your supply chain to Asia, what kind of cushion you have, if there is any exposure. Thanks.

Hi Jim. It's Beth. Thank you for your questions. So I'll start. I'll start off with capital allocation. And as Brett has laid out our priorities are to continue to invest aggressively across the business to focus on Ionis-owned pipeline to advance our technology, to invest in complementary technologies to broaden the reach of our technology. And with the addition of Onaiza on our leadership team, we are now defining further our commercialization strategy and building capabilities. And so that will also be an area of investment for the company. So I see first and foremost our investments and our capital being allocated to those areas of significant value creation for the company. In terms of share repurchase certainly with our stock where it is today, we believe it's a very attractive investment opportunity. And so that's something we'll be considering into the future. And we have a portion of our 1% notes that are coming due in about a year and a half or so. And then we'll be looking at what the appropriate actions are for addressing those notes as we go for it.

Thanks Beth. And with respect to coronavirus, Jim, at Ionis, we take great pride in preparing for potential crises before they were happening. We've been focused on this potential epidemic and talking about how we're going to protect our employees, our clinical trials as well as our supply chain. And we don't see any hiccups along the way. I'll ask Richard to comment on how we manage our supply chain with respect to the question.

Yes. Specifically on supply chain, of course, all of our API, we're not dependent on China for supply, which may be one of the questions. Certainly all of our clinical supplies are manufactured right here. And then the drug supply chains that supply our drugs are all also not only multiple pack up opportunities but also not dependent on China.

Our next question comes from Esther Rajavelu with Openheimer. Please go ahead.

Thank you for taking my question. Just a couple quick ones from me. How much of your 2020 guidance is driven by SPINRAZA versus other sources? And then I have a quick follow up.

Hi Esther, it's Beth. Good morning. So, as you can imagine SPINRAZA was a significant portion of our commercial revenues in 2019 and we and Biogen continue to see growth for SPINRAZA frankly in the U.S. and outside the United States. So, I would expect to continue to see SPINRAZA being a significant portion of our commercial revenues as the year unfolds. And then adding to that, of course we have TEGSEDI and WAYLIVRA as they expand into new countries in Europe in particular. And then we have a very substantial base of R&D revenues anchored by significant amortization of upfront and milestone payments and then built on by with licensing fees and milestone payments as our partner programs in development continue to advance.

Thank you. And for WAYLIVRA, the resubmission of the marketing authorization in the U.S. what do you need to complete to be able to re-file this year?

Yes, great question. This is Richard. Nothing to complete except for writing up the results, so all of this, all of the expanded studies in open-label as well as expanded access are being added to the filing and bring us to about a three fold increase in exposure in patients and as well as additional safety data, which is very supportive.

So that's, we should expect that to happen sooner than later in the year then based on what you're saying?

I think we're guiding to a timing, but certainly we are expecting to file this year.

Okay, thank you.

Our next question comes from Paul Matteis was Stifel. Please go ahead.

Hey, thanks for taking the question. This is Nate on for Paul. Firstly for the LRRK2 Phase 1/2, can you review the study structure and specifically beyond safety and PK/PD are you or what exploratory markers of efficacy are you collecting and then I have a follow up?

Eric, we haven't disclosed much on the details of the LRRK2.

I don't believe we've disclosed things beyond that we're treating both genetic patients with LRRK2 mutations as well as the general population for sporadic. And of course it's a first in human study, so the primary endpoint is safety, but you can imagine there's lots of secondary biomarkers and exploratory endpoints that we'll look at.

Yes. More will come out on that study as the program matures Nate.

Well, maybe a second pipeline question on the C9ORF program. Are we thinking about this in the right way? That's primarily going to be addressing the gain of function aspects and if that's correct, are you worried at all about the loss of function aspects of C9ORF. And secondly, would you consider moving from ALS into C9ORF FTD as well?

So yes. Good questions both. Yes. You are thinking about it correctly that we are addressing predominantly the gain of function aspects of the C9ORF72 gene, which is causal for C9ORF72-ALS and FTD. An important thing about our drug is, is it is targeted such that it only decreases the mutant form of C9ORF72 by the location in which we target the gene. So, we don't expect to decrease all, C9ORF72 function is in fact there, there was an important component of that to safety or disease. However, I would emphasize that much of the preclinical data really suggests that it is a gain of function disease pathogenesis process. So, I think that medicine is another one that's like many of ours that's directly on target and on mechanism. And as you point out or C9ORF72 is also implicated in FTD and with Biogen we're actively considering how to move that drug forward in both ALS and FTD.

Yes. And I'll just expand on that a little bit, Nate by reminding you and others how we're attacking ALS with Biogen, our SOD1 program of course is in Phase 3 for another genetic form of ALS, SOD1 related ALS, in addition to C9ORF as a second one. And recently we added a third medicine into the Ionis Biogen pipeline for sporadic forms of ALS and much broader non-genetic forms of ALS. So we're doing a full core press on all forms of ALS and I think there will even be more coming.

Great to hear. Thanks guys.

Our next question comes from Chad Messer with Needham and Company. Please go ahead.

Great, thanks. Thanks for taking my questions. Maybe we can just start with the TTR Phase 3 program now that you've got those two studies up and running. Can you maybe set some expectations for enrollment timing? You guys have some experience enrolling rolling trials in the space. And is it your sense that it's easier or harder to enroll now that there are commercially available options for these patients?

Appreciate the question, Chad. Thank you. Yes, we're very excited. Ionis with Akcea, we're now underway in two Phase 3 studies for both the cardiomyopathy, the larger population, which includes both hereditary and wild-type and the polyneuropathy patient population, a separate Phase 3 where we're targeting essentially the same label as TEGSEDI. stabilizers: So, the work that folks like Pfizer are doing to identify patients and get them on to tafamidis, I believe will help our enrollment and the speed of our enrollment as well as just the disease awareness, the great work that we’re doing to make people aware of this disease. Hereditary polyneuropathy is certainly going to be a challenge to enroll. There's no question about that. There are multiple drugs approved for this rare patient population with TTR amyloidosis and there are other clinical trials in progress as well. However, with the great work that Akcea is doing to identify patients and investigators and the work they're doing with AKCEA CONNECT as well as our strong relationships with investigators from our NEURO-TTR Phase 3 study. We're confident we'll be able to roll this study on track and we're feeling good about it. The other advantage to the neuropathy study is of course, is the fact that it's an open label study. So patients will not be on placebo. We're going to be comparing the results of that study to a historical control, which of course will help enrollment as well as the fact that the sample size is significantly smaller than our Phase 3 NEURO-TTR study. So there will be challenges for polyneuropathy, but I think we can manage them.

Yes. And then just on the polyneuropathy study that has an interim, is that meant to be something you could file on or are you just trying to get, an earlier sense for efficacy?

We will look at the interim analysis data at eight months and make decisions based on the data. Those will be data driven decisions, want to remind you that at eight months in our NEURO-TTR TEGSEDI Phase 3 trial, we saw a high statistical significance with TEGSEDI as well as that, of course at the end of the study at 15 months. So we have a very nice comparison at our interim analysis at eight months in the TTR LICA study that we'll be able to compare it to historical controls and we want to get this medicine to patients as does Akcea as rapidly as possible and if the data supports it and off we go.

All right. Great. Thanks. Very helpful.

My pleasure.

Our next question comes from Vincent Chen with Bernstein. Please go ahead.

Great. Thank you very much for taking the questions, a couple from me. So the first one on Huntington's just sort of following up on the earlier, what should we be looking for in the updated data tomorrow? I guess in your view we'll get some data updated data on the safety, the biomarkers including neurofilament light chain. What does a good outcome look like in terms of the updated safety and biomarker data, including neurofilament? And then a second question on a somewhat different topic, I was just wondering, if you could provide any color on the relative mix of product sales in terms of I guess WAYLIVRA versus TEGSEDI and then for TEGSEDI U.S. versus O-U.S.

Eric, would you like to touch on the biomarker data

Yes, I mean, I don't really want to get ahead of our partners Roche, who is presenting the data tomorrow, but really what's being presented should be thought of as an extension of the data that they've already presented. And I'd also note that the safety profile it has been presented of the drug is outstanding. The Phase 3 trials as Brett mentioned, is on track and is scheduled to read out in 2022 and we're very pleased with the progress of the drug and pleased with the way Roche is advancing it.

Yes. The way I see it, Vincent is the key message is the fact that the Phase 3 trial is on track as Eric said and as I said earlier. And Roche is very excited about the program. The bi-monthly dosing is looking excellent and it's moving forward on pace. We will be issuing on Friday a sort of a roundup, a short summary of all the presentations on our Huntington drug. So we can capture it, we'll post that to our website and we'll also distribute it to our analysts. Beth, would you take the division of TEGSEDI with…

Sure. So the – as you can imagine since WAYLIVRA was just launched late in 2019 and in Germany, really only the vast majority of the revenue in 2019 was TEGSEDI. And we were pleased to see steady progress quarter-over-quarter, with quarter-over-quarter growth in 2019. We think that sets an important and strong foundation for continued growth this year. And we look forward to moving WAYLIVRA and TEGSEDI into new countries this year. In terms of the mix between U.S. and an ex-U.S. that information that we and Akcea are not sharing at this point.

Great. Thank you very much.

Thanks.

Our next question comes from Ellie Merle with Cantor Fitzgerald. Please go ahead.

Hey, guys. Thanks so much for taking. Just on the oral program now that you're committing to 2024 proof-of-concept data. Can you walk us through what exactly we'll get in this readout? And I guess what specifically would constitute from your perspective proof-of-concept for oral delivery? Are there specific levels of protein knockdown relative to the Sub-Q that you're running in parallel that you'd be looking for? Or just can you sort of walk through what in your perspective would constitute proof-of-concept for oral?

Sure. Thanks for the question, Ellie. So yes, we're very excited about the clinical trial and progress evaluating the potential for commercially viable oral delivery with our partner AstraZeneca. And as you mentioned, the plan is to have data readout from that study, second half of this year. What does proof-of-concept mean aside from poor safety and tolerability is the bioavailability, pharmacokinetics port that we expect to achieve that will – that was predicted based on our extensive preclinical data that would support commercially viable oral dosing. More than that, we have the ability to assess the effects on target reduction of biomarker reduction in the clinical trial is designed with that in mind with that intense and we'll have crisp data readouts on all of them in that – once that data reads out. The other aspect of – in this topic that I'd like to expand on, if you will, is that we're not sitting still on the development of formulations to further increase and enhance oral bioavailability. We actually have active work research ongoing at Ionis where we are already making substantial significant improvements in the potential for oral delivery even beyond that of the formulation we have in our clinical study right now. So, we're continuing to make advancements in an oral delivery and we're hoping to even bring those on in the future. Further, where we've identified a number of Ionis-owned products that we're planning to bring into the development as an oral pill soon after right behind the Ionis AZ collaboration. So this isn't – there was many original quarter if you will in the oral front and we're feeling pretty good that we're going to have success in making oral commercially viable for our platform.

Got it. Thanks very much for the color and just one quick follow-up if I may just for Brett. I mean, it seems like you have a lot of programs in development. You have many, you know, readouts this year. I think in your size you called out that you have four proof-of-concept readouts this year. I guess, which program or which datasets are you most excited about?

Well, it's hard to pick one. I mean for the pipeline of more than 40 drugs, all of which have the potential to be transformative in nature, it really is. And if we went around the table here, we'd probably get six different choices. But – and then in the shorter term, well, we have the rare disease buckets. We have the broad disease populations, right. And it's hard to not include Lp(a) in a choice, in a selection for drugs. I mean, this is such a large patient population. We're so far ahead of any form of competition. The Phase 3 study with Novartis is progressing extremely well and the commercial opportunity – and the opportunity for patients is so enormous. So you got to include that one. On the other hand, in our rare disease bucket, I have to – I gravitate towards ALS. I mean, there are no treatments for this terrible neurodegenerative disease. And Ionis with Biogen is, as I said earlier, used the analogy of a full-court press on all forms of ALS, which we are doing now. Our SOD1 program is due to readout for the first of multiple ALS drugs. As a reminder that drug showed really remarkable – provided really remarkable evidence of efficacy in the short three months study in patients with SOD1-ALS. And now, the Phase 3 is going to readout next year. As Eric referred earlier, we have a C9 program. That's also a Phase 2 program that’s due readout next year. And now we have a drug for sporadic ALS. So I would lean towards those two programs, but I could take all day talking about our pipeline. There are lots and lots of drugs there to be very excited about.

Got it. Thanks so much for that color.

Sure. Our next question comes from Tyler Van Buren with Piper Sandler. Please go ahead.

Hi, guys. Good morning. Just had a brief follow up on your comments on capital allocation earlier you mentioned potential complementary technologies that you're looking at. So I just want to get your updated thoughts or interest in tissues, specific technologies. There's some emerging out there tissue specific RNA technologies and one example is antibody conjugates. So I just want to get your thoughts there.

So thanks, Tyler. We're very thrilled to be in a position of such strong – of such a strong financial position that allows us to invest in technologies that complement our antisense platform and expand the reach of our antisense platform and do even more than that. We're investing in genomics to identify novel targets for to continue to replenish the pipeline as new drugs reach commercialization, novel targets that are genetically linked. We're working with companies and academic collaborators to identity – to work on pathways that lead to selection of novel targets as well. And we're working internally and with – externally with cloud through collaborations with new LICA technologies. Just late last year, we completed a partnership with a genomics company to identify novel targets and with another company to identify novel strategies, LICA strategies to expand the reach of antisense to newer organ systems, new cell types. We're making great progress. Antibody conjugates and their derivatives are just one aspect of the types of strategies we're taking. I view that as one tool in a toolbox of approaches with LICA is that we have and what we're developing – we're working on ourselves. So they have the potential to work, but I believe that we have many different strategies that are showing promise to getting into cell types that are less sensitive to antisense today.

Great. Thank you.

Our next question comes from Jessica Fye with J.P. Morgan. Please go ahead.

Hey, guys. Good afternoon. Thanks for taking my question. Smelling up on one of the earlier questions about angiopoietin-like 3. Can you just talk a little bit about how you see that product positioned relative to ApoC-III LICA? Is the ApoC-III LICA really going to focus on the indications that you've previously discussed for WAYLIVRA?

Thanks, Jess, and I appreciate the question. So, angiopoietin – first of all, of course, we're thrilled with the results from the Phase 2 studies that Ionis Akcea unblinded and presented top-line data on our announced top-line data for both programs. It was C-III LICA and angiopoietin-like 3 LICA, both at the primary end points, both are positioned very well for Phase 3 trials down the road. There is overlap in both of these medicines in the atherogenic lipids that they manage, that they control, triglycerides, remnant cholesterol, LDL-cholesterol effects on – positive effects on HDL, but there is also a significant enough difference between these two drugs that we believe as those our partner Pfizer for angiopoietin-like 3 and of course Akcea 2 that they differentiate significantly sufficiently well that they will have a different profile in patients with cardiovascular disease. I think that ApoC-III LICA is the most potent triglyceride lowering target drug out there today and angiopoietin-like 3 brings a number of other advantages such as effects on cholesterol in addition to just significant triglyceride lowering and positive effects on HDL. So, I think, they differentiate enough to be very important and meaningful additions to the cardiovascular – the treatment of cardiovascular disease in the future as is our partner Pfizer and Akcea.

Our next question comes from Mani Foroohar with SVB Leerink. Please go ahead.

Hey, good morning. This is Rick on the line for Mani. I have two questions for you. First, just broadly speaking about the opportunities set for the oral delivery of ASOs. Do you think that oral delivery could potentially be a good fit for any liver directed therapy? Or do you think the technology is best utilized in specific areas like cardiometabolic indication? And second, just given the increasing focus on your wholly-owned pipeline, could you give us a sense of how you're currently viewing the relationship with Akcea? Do you think it would make a sense at any point to think about bringing the remainder of Akcea back into the company? I'm really just looking for any commentary on how you view the relationship with Akcea evolving as more focus is based on your internal pipeline.

Sure thing. Thanks, Rick. So, the oral – the work – the progress we're making on oral delivery is successful, has the potential to reach all of our liver programs. That's what's really so exciting about it. It's not just this one particular clinical trial, but it's also the potential impact it'll have on any of our LICA liver like programs, including drugs on that target ApoC-III or angiopoietin-like 3 or Factor XI, TTR and so forth. And we're focused on that. And as I said in one of the questions earlier, we've already identified additional liver targets that we're moving forward to oral studies in the clinic. So, it does have a very broad reach is successful. And that's, I also mentioned, we're continuing to even improve on the current formulations, which are showing a lot of potential. We're changing gears. We're very excited about Akcea and we're committed to Akcea’s success. We’re confident they’re going to be very successful. Our fully owned – our wholly owned rare disease pipeline is growing and expanding and there's a lots of opportunities to bring these drugs to maximize the commercial value of each of these medicines in different ways and Akcea is certainly one of those options that are available. And as we mentioned earlier, we're already in negotiations discussions with Akcea about the potential addition of a new medicine or rare disease medicine in the pipeline later this year. As far as the future of Akcea, relationship with Ionis, that's the topic for discussion down the road right now. Akcea is doing well and they have a very full and exciting agenda or pipeline agenda, which is really an agenda that's comprised of both pipeline and getting WAYLIVRA approved in the U.S. and continuing progress with TEGSEDI and getting WAYLIVRA launched, but with ApoC-III LICA, now in their pipeline and planning to start Phase 3 in FCS later this year with TTR LICA having undergoing two Phase 3 studies already in progress. It's quite a lot on their plate. And we believe that they're on track to deliver on their strategic goal. So, that's what I have to say about that right now. I hope Rick that addresses your question.

Yes, it does. Thank you for taking our question.

The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.

All right, thanks. This is Ross on. Can you help us to understand the breakdown of product sales to TEGSEDI and WAYLIVRA and some of the gating factors for both of these launches here? Specifically, I'm looking for some additional color on your comment that the prescribing base for TEGSEDI grew about like 4% q-over-q. I'm just trying to think about what factors drove this significant uptake? And where are these physicians coming back? And then I have a follow up.

Hi, it's Beth. So, the breakdown of TEGSEDI and WAYLIVRA, as I said, is primarily TEGSEDI because WAYLIVRA was launched in Germany late in 2019. And there right now Akcea is expanding WAYLIVRA out across additional countries in Europe. But they started with Germany and that's a relatively small patient population in Germany with Akcea. And so a small, very small portion of the product revenues in 2019 were WAYLIVRA, so the vast majority were TEGSEDI. In terms of the growth in prescribing physicians, a lot of that is a function of the work that the Akcea team is doing with their genetic testing program, getting out not only into academic centers, but also into the community settings, expanding the number of physicians that are utilizing the Akcea genetic testing program to identify patients, who could be potential patients for TEGSEDI. And then getting those physicians on board and getting those identified patients onboard with TEGSEDI. So I think that's where a lot of the growth is coming from and we're looking forward to the continued success of that program and other programs that that Akcea is engaged in right now to grow TEGSEDI revenues this year and also frankly to grow WAYLIVRA revenues working with similar programs.

Thanks, Beth. Got it, got it. That's really helpful there. And then just finally, how should we be thinking about, rest of plans likely market entry later this year and the impact of SPINRAZA use?

Well, I'll start. Sure. SPINRAZA continues to be the global foundation of care for all forms of SMA, Ross, and as Beth mentioned earlier Biogen is expecting continued growth of SPINRAZA despite the potential for additional competition down the road. And it's setting a very – SPINRAZA has set a very high bar on efficacy and safety that competitors are going to have to meet to be a significant competitors for the SMA population. It's hard to comment on competition when so little data has actually been presented. And so, I really don't want to comment on the potential for other drugs in this space like risdiplam. Suffice to say that we're very confident that SPINRAZA will continue to perform very well for all forms of SMA this year and for years to come.

Got it. Thanks for taking the questions.

Sure.

Our next question comes from Yale Jen with Laidlaw and Company. Please go ahead.

Thanks for taking the questions. Just the one that’s a little bit linked on the previous one, which is that you guys are going to file – refile WAYLIVRA later this year as well as you're going to start a pivotal study for ApoC-III LICA in FCS. So is there any connection or the relationship or expectation of those two events?

Hi, Yale. Thanks for the question. Those two events are not linked in any way. We're having very productive Ionis Akcea discussions with the FDA on WAYLIVRA. And as Richard indicated, we're – we now are in an envious – a fortunate position of having a lot more data to make the case that this important medicine should be approved in the U.S. and planning to refile later this year. And no way this is linked to ApoC-III LICA. We obviously have a lot of patients. It's – obviously, it’s the same patient population, which is the point of your question, but in no way are these filings the one for potential approval in the U.S. with the start-up of Phase 3 trial in any way linked together. These are moving forward independently and we don't see any impact that WAYLIVRA could have on the urgency that we have to get the Phase 3 study with ApoC-III LICA moving.

Okay, great. And maybe just quick follow-ups, which is that how much stocks repurchasing at this point still left?

We have fully executed on the stock repurchase program, the initial program that our board approved. So that is wrapped up right now. And as I said earlier with where our stock is trading right now, we think it's a great investment, so we may be looking to expand that into the future.

Okay, great. Thanks a lot. I appreciate it.

Thank you, Yale.

Our next question comes from Gena Wang with Barclays. Please go ahead. Ms. Wang, your line is open.

Oh, sorry. I got my line muted. Thank you very much for taking my questions. So I just ask one question regarding the SOD1 data expectation. Brett, do you have any thoughts, you know, what you would consider as a very impressive data or meaningful data?

Thanks, Gena. And Sarah, this will be the last question. We're running long, long time. So as I mentioned earlier, we're very excited about the SOD1-ALS program. If you recall, the Phase 2 study was three months in which the clinical endpoints that we’re – some of the clinical end points that were looked at in the study that really made everyone so excited about where the ALS functional rating scale and respiration – improvements in respiratory function in that trial. And as I mentioned earlier, the results were remarkable, really stunningly positive. And that was only three months. Biogen executed a very efficient Phase 3 program, which they basically added a new cohort to the ongoing Phase 2 study, so that they can start that study very quickly. And the way to simply think about it is that the end points are essentially the same as they were in the Phase 2 study. We're just looking toward even greater efficacy than we saw at three months.

Great. Thank you.

Thank you.

So thank you again everybody for joining us today. We're obviously very excited for this year and we look forward to updating you on our progress as the year unfolds and wish everybody a great day. Thank you very much.

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