Good morning and welcome to the Ionis Pharmaceuticals First Quarter 2020 Financial Results Conference Call. [Operator Instructions]. At this time I would like to turn the call over to Wade Walke Vice President 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. Additional 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 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 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 continue with growth in global markets despite some impact, new patient starts and maintenance dosing from COVID-19.

And 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 so much to do to bring this study to its planned completion for now, one very important step closer to providing a treatment for people living with this devastating disease. 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 with a million 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 to 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 expected to initiate the Phase 3 study of APOCIII-LRx in patients with SDS 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 continue 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 goal.

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, of which SPINRAZA was 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 invite and 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 1800 physicians are now using Akcea's genetic testing program with a growing number of patients being tested and diagnosed with AJPTR [ph].

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 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 U.S., including in southern Europe.

This 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 intend dissipate 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 in 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.

And we earned $50 million in R&D revenue from our cardiometabolic franchise. This included a $10 million milestone payments we earned 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 complimentary 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 be generally 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 priority 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 and C9-ALS. IONIS-C9Rx was recently granted fast-track designation in the U.S.

in addition to enabling an expedited regulatory path, fast track designation 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. On track to enter the clinic later this year. We're particularly excited about this medicine, our first medicine to enter development addressing the vast majority of patients with ALS.

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 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 and SMA patients of all ages.

And new data from an independent study published in Lancet Neurology demonstrated that teen and adult patients treated with SPINRAZA for 14 months achieve 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 fallacemia and central nuclear myopothy.

Additionally, we're particularly excited for the programs in our growing Ionis owned neurological disease pipeline, including our programs for Alexander, Lafora, and prion disease, which continued 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 just granted fast-track designation underscoring the significant value of this medicine may bring to millions of patients worldwide with an established Lp(a) driven cardiovascular disease with no effective therapeutic options.

Importantly, the Phase 3 horizon cardiovascular outcome study of AKCEA-APO(a)-LRx is progressing with our partner Novartis. And as of today Novartis expects no significant impact from COVID-19 on study timelines. And earlier this year, we reported positive top line results from Phase 2 proof-of-concept studies AKCEA-APOCIII-LRx and vupanorsen.

Both medicines which are part of our growing and advancing LICA pipeline, achieving their primary endpoint, demonstrating robust triglyceride lowering and substantial reductions in additional key cardiovascular risk factors with favorable safety and tolerability profiles.

And 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.

And in response to COVID-19, we briefly paused new patient enrollment in both studies in an effort to protect these patients, which are at high risk for COVID-19 related complications. It was also important 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 restriction eased. Importantly, we do not expect this free 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 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 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. And we still are planning 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 call. .

Thanks, Richard. Today, Ionis is stronger than ever. We are reaffirming our 2020 financial guidance, and we've remained well capitalized for the 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 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 like medicines. We 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 in 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 open the call for Q&A..

We will now begin the question-and-answer session. [Operator instructions] 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 Iona.

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..

Thanks for the questions, Jim. So, I'll take -- as you suggested, I'll take the first one I'll start there. But I'll also pass it over to Onaiza to give her perspective who is on the call for Q&A. So, as we stated in our -- just now recent, in our call earlier.

We are prioritizing continuing to build and expand the Ionis owned pipeline and identifying and characterizing each of the medicines in that pipeline as to the value and the synergies they create, when bundled together in various ways. These are principally focused on rare diseases.

And we're identifying those opportunities in that growing pipeline that will bring the greatest value to Ionis and shareholders. And we're looking at various options on commercialization strategies this year. And we're hoping to present some of those strategies later this year towards the fall. With that Onaiza, please jump in and add to my comments..

Sure. Hi, Jim, how are you? Thanks for the question. So we're making just 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 even grow further in the future.

So it's in which portfolio, you can imagine the initial steps in the commercialization work have been on portfolio privatization.

And we're preparing a high level strategy which is laying 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.

And we remain excited about the mid-stage portfolio as well which include acromegaly, non-transfusion dependent beta thalassemia, and hereditary angioedema. So I really look forward to providing a high level commercial strategy for the Ionis owned portfolio later this fall more likely at the Investor Day.

We currently have plans and we can get a little bit deeper at that time..

Thanks, Onaiza.

Richard, 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. And so 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 weekly inhalation of the product.

And 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. And we'll also be including data in the rollout. .

And when we roll that out, Jim, I suspect we will also be able to talk about additional potential Phase 2 studies that are in planning Phase right now for our ENaC inhibitor. We're not planning to develop that drug only for CF, but actually, there's 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. So as you know, R&D revenues tend to be lumpy and this year is no exception. What I would anticipate is that -- as I mentioned earlier that Q2 is likely going to look like Q1, in terms of revenues. Our revenues from R&D partnerships tend to be more backend loaded this year.

So I would expect to see revenue growth in Q3 and also in Q4, primarily, from our R&D revenues and of course the commercial revenues, I expect to grow quarter-over-quarter for the remainder of this year..

Great. Thanks for taking the questions guys..

Thanks, Jim. 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 readout 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. So just to back up a half step, as a reminder, our objective this year was to read out on six clinical proof-of-concept studies this year.

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 in FCS. 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 a program is also another program that we're expected to have a readout on later this year. In addition, we have an exciting program in hypertension. Angiotensin again is an exciting program where we have multiple phased programs ongoing. And 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 246 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.

And of course, we also have the ongoing study in which we're evaluating with AstraZeneca. Our program determining whether evaluating the an oral formulation for an undisclosed target that is in clinical testing now, which we hope to readout 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 by that. .

Maybe just a quick follow up on AKE. I guess this is the goal, standard of care injectables that have launched for prevention are achieving pretty high reductions in terms of attack rate.

So do you think you could improve upon that or is the goal to extend treatment duration with the LICA?.

So you're absolutely right. The AKE landscape is quite competitive. And patients have received substantial benefit in the reduction in attack rates with the current approved medicine. Our objective is to do as good as that or better with our mechanism of action blocking the kallikrein pathway.

And as you may have seen some of our Phase 1 data, we're really having a very potent molecule. We're having a large impact greater than 90% reductions in kallikrein.

We think we can beat it, potentially, but we also have going for us is the convenience of a very infrequent low volume injectable, subcutaneous injectable with the potential if we crack commercially viable oral bioavailability in the ongoing studies to move that drug into an oral formulation as well, which would be a significant advantage from a convenience standpoint.

So it is a competitive environment. And we think we are hopeful that we can compete. The other thing I'll just add to that is we are exploring additional potential indications for our kallikrein inhibitor. And plans are coming together to move on those. And we're hoping to share some of our thoughts on this later this year maybe 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 if this sporadic population is within the broader TRS umbrella? Then I have a couple follow ups after that. .

Sure Keith. So 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 and which is due read out Phase 2 data next year and our Phase 3 data for tofersen SOD1-ALS also due read out next year.

This is our first of several sporadic ALS target drugs that we're planning to bring forward in not too distant future, this is the first. It's 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.

And as you know, the sporadic population represents the majority, the vast majority of patients with ALS. I believe that it's somewhere north of 75% patients with ALS are sporadic variety. And Ataxin 2 no reason to believe that it couldn't get to perform well and address the majority of that majority, quite simply.

So it's really the majority of patients with ALS that is this drug potential treatment. .

Got it. I think you kind of bridged into my second question. My second question was how heterogeneous sclerosis formed? And it sounds like you planning to do multiple studies for that population.

Are you experimenting different mechanisms to address all the different mechanisms that could cause ALS? And I think you set up the [indiscernible] address plenty of it, are we thinking about maybe like 80%, 90% of it, depending upon the [indiscernible] that will be great? Thanks. .

It's hard to say how much of the sporadic population Ataxin 2 would address. Our hope -- and there's no reason to believe that we couldn't target the vast majority of that sporadic population as I mentioned.

We have a very exciting research program with Biogen in which we're evaluating multiple mechanisms, multiple targets in animal models for ALS, sporadic ALS. Maybe, Eric, you could add a little more color on the alternative types of mechanisms for addressing and how we're going about doing this..

Yeah. So as Brett mentioned the Ataxin compound, I mean, I think we really have to figure that out in clinical trials and find out exactly which patient populations respond the best for the preclinical work, which has been published by the way is very exciting and very strong.

And as Brett mentioned, 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.

And so we're looking at all sorts of different pathways and trying to figure out, which drugs or the combination of drugs are best for -- moving forward to treat the condition. So it's a very broad deep program. And 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 plant advanced 105 in a clinical year.

Can you talk about when we could possibly expect data next?.

You're referring to the sporadic?.

Yes. The sporadic. Yes..

Yes. Well, just starting this year, so I wouldn't expect data till 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. And I'm certainly glad to be hear the team at Ionis is managing things so well in this pandemic.

Like to maybe start with a liver in the refilling, 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. So 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 that we received on when we were in the U.S. And we are confidence that for approval for WAYLIVRA in the U.S.

has grown as we've continued to collect and evaluate that data. Our confidence grew even more based on our meetings with the FDA to talk about refiling for WAYLIVRA. We feel good about the discussion we have had with them. And those discussions have been very supportive and productive. So we’re excited.

What we’re doing now is putting the data, packaging it up 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 have met with our pre-resubmission meeting and then encouraged to resubmit that the data is there. And so we’re just putting that package together. .

Okay, great. Thanks.

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

Certainly we have so much experience in FCS Chad as you know from our elaborate experience and we will use all of that information to build on our Phase 3 study design for APOCIII LICA.

Richard?.

So a couple of things as we were moving 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 will enrich for patients for those who have ongoing and consistent pancreatitis. So that will 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 maybe hard to convincingly beat in a trial unless it was a really large one. .

Yes. You're absolutely right, Chad. The efficacy that SPINRAZA has demonstrated in all forms of SMA that's a very high bar, not only for our DEVOTE study, but also for all of us. But there -- but we do believe that going to higher doses, as does Biogen, has the potential to show even greater efficacy.

I mean, as an example in between maintenance dosing, sometimes patients will start to feel some symptoms start returning towards the end of a maintenance dose. That's just one example.

The patients that we get to later in their disease, we have a potential before later they have more diseases progressed, before they've gone on SPINRAZA we have the potential to show even greater efficacy in those patients, for example. And then there's others and there's other ways to show greater efficacy.

So, based on the pristine safety that SPINRAZA has demonstrated, we have the luxury of going to a significantly substantially higher dose in our DEVOTE study. And that study, as you know, is under way. So, it does have a high bar of efficacy. But we do believe that there's the opportunity to show you greater efficacy.

And I'll just add also to, if I can expand on your question, Chad. We're also working, making great progress with Biogen on a follow on drug, potential follow on drug for SMA.

Follow-on test SPINRAZA based on a new chemical entity that we think our objective is and we're feeling pretty good that we'll be able to get to by annual dosing or maybe even annual dosing with an intratumoral administered medicine. So we're defending the SMA franchise Ionis and Biogen.

And we're excited about not only positive but the higher dose as well as fall-on medicine. .

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

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 which we've had a minimal impact on the progress we're making on our clinical trials. Similar story for bio partners, where we have always been in remaining close contact with our partners and have been meeting with them even more frequently once this crisis occurred.

And we're seeing substantial impacts on any of our pipeline, our partner pipeline programs take in certainly nothing meaning. And as Richard mentioned in earlier the Phase 3 programs ultimately with Novartis and the cardiovascular outcome trial start one Phase 3 program with Biogen and the Huntington program are all on track to readout on time.

So, our partners are managing the situation quite well..

Thank you. And then you've always been in an enviable cash position recently.

And do you have any updated thoughts on capital deployment in this current environment?.

Yes, sure. I'll comment on that. And I'll ask Beth to make some comments too. So, we are in a very envious position. We're very proud of the strong financial position we are in. And we will continue to invest in all of the areas priorities that we planned on investing in last year and as we talked about earlier this year.

And that includes investing in our pipeline and investing in 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 commercial value of the medicines we bring to the finish line through Phase 3, as Onaiza touched on earlier during this Q&A. And we continue to invest as we did earlier this year.

I'm going to continue to do so in new technologies, technologies that complement what we're doing in antisense to continue to ensure that our leadership position in RNA therapeutics is not only maintained but it's extended.

Genomics collaborations to continue to populate the pipeline with novel genetically linked targets for drug discovery LICA chemistries, new LICA chemistries that we're collaborating with a new partner there and we continue to look for other collaborations as well.

And brand new technologies that we continue to survey and pursue and look at potentially diversify our platform into new areas. .

Great. All right. More specifically, maybe if you could comment.

Can you hear me?.

Yes, I can. .

No worry.

Just more specifically maybe on that, if you can comment on share repurchases and what your thinking is for the remainder of the year?.

Hi, Esther it is Beth. So 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 very 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 that Brett was describing is really a better use of cash today. So we don't have any specific plans.

But that being said, we'll 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 kind of what drives this, if it's completed enrolling or if it's still enrolling and close to completion? And then in terms of the specific data that we could expect to get in terms of the oral, I guess, what and have you and AstraZeneca worked out in terms of what you actually would disclosed.

If this data comes out in 2020, it would be sort of levels of protein reduction, things like that in terms of what we should look for in the release? Thanks..

Sure Ellie. So we're working very closely with AZ on a number of programs in the cardiometabolic space and including this one.

What we're looking to do is to complete a phase of the study that we think will provide ample proof of concept, quite simply so that we can make some calls on whether or not we think that we're well on our way in achieving commercially viable oral delivery. What you would expect -- what form that would come in would be of course bioavailability, PK.

That is predicted based on our preclinical data as well as biomarker data. So impact on biomarkers that are reflective of target engagement. But also, we have a parallel program that's ongoing to oral with the same drug, but administered subcutaneously. And we'll also have data from that study we hope to compare side by side with the oral program.

So it will actually tell us a great deal about how the oral is stacking up and will stack up with continued development with the subcutaneous formulation. The main -- one of the breakthroughs, there were a number.

But one of the breakthroughs that really allowed us to get oral we think to where it is now for testing and potentially achieving commercially viable oral bioavailability is potency. These are Gen 2.5 LICA molecules and that are stable in the gut and remain intact upon absorption in the gut.

And it's the potency that really allows us to get the bioavailability everything we need. And our subcu data will be very important to show that what we've seen in predicting preclinically will translate to that level of potency. So both programs that we think are very important..

Got it thanks. And then just in terms of thinking about COVID impacts on the TTR LICA Phase 3 programs, I guess. If you could characterize sort of how enrollment is going in each of those phase 3s and how COVID is potentially impacting enrollment timelines and just sort of your latest expectations for when you put complete enrollment in these studies.

And I know it's a competitive environment. So curious what is the latest on what you're seeing what the timeline there? Thanks..

So, as Richard mentioned earlier we did -- so the enrolment is ongoing and the programs are going well both the TTRansform cardiomyopathy, cardiomyopathy study and neuropathy study are both going well, and they're on track. We did pause those studies very briefly.

And we did that based on requests by our sites that were activated and up and running because they had to assess their own situation. They are being overloaded in their hospitals and their sites. And they didn't know what to expect from the COVID patients that they're having to manage. So, we obviously appreciated their challenges.

And of course the enrollment briefly until they assess the situation and then they told us that we're ready to go. And we're reactivated. And we're rolling again. We don't expect a significant impact on the timelines for either study going forward. We did implement a number of mitigation strategies as this developed to catch up.

And we're doing, we did quite a bit remotely during this brief pause. So we're 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 thanks for taking the questions. And impressed by your situation under COVID-19. Just two quick ones. The first one is ION-224 the DGAT2 program in NASH. Do you guys have any -- I know most of the DGAT2 was in 30 years stage development.

But what do you feel some of the strength you might have comparing to other programs in development? And then I have follow-up..

Sure, Yale. Thanks.

So one of the advantages we have is building on the really impressive Phase 2 data that 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 that let that triggered us to go back and identify and bring on bring forward the LICA version of that to allow us go to even lower doses and less frequent dosing administration.

As from a target standpoint, the advantage we have, I think are multiple. There are multiple aspects to that. 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 -- we've actually looked at all the targets in the triglyceride as they concluded that our DGAT2 was the most appropriate sensitive target for managing liver fat. The second advantage we have is specificity.

As small molecules have difficulty in specificity and isoforms such as DGAT1 and DGAT1 inhibit others get into some side effects that we've published on actually. DGAT2, our inhibitors very specific and we think that it will measure up very well against the competition for other agents that are targeting triglyceride pathway in November..

Okay, great. That's very helpful. And maybe the next question really follow up, the very first question really, is that you guys going to assess a lot of your rare disease pipeline in terms of their commercialization or pathway to go.

And as well as that yesterday in Akcea conference call, they were also probably anticipate or expect some of these programs may be moving to their pipeline.

So overall, how would you guys think about what to maintain on your own work, you might be moved to other parts of Akcea for their development as a general principle or thought?.

So we're having very productive discussions with Akcea on a potential asset to move into Akcea and their objective is this year. They of course have a very full agenda. This year to TEGSEDI, WAYLIVRA, the APOCIII LICA Phase 3 study in the re-filing with WAYLIVRA in the US.

So discussions have been very productive and we have whittled down to a few potential rare disease programs from the Ionis owned pipeline. And I think you'll hear more about that later this year from Akcea and Ionis. Certainly one area of priority for us at Ionis is our rare neurological disease pipeline. It's a pipeline that we're very excited about.

Prion, Alexander, Lafora as Richard mentioned earlier, more coming. And expanding and that's certainly a high priority for Ionis to prioritize for at least some of those for ourselves. So I think you'll be hearing more about that later this year as well, 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 kind of related to this whole 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? And then secondarily, I was hoping you could give us a little bit more background on your APOCI program with AstraZeneca? Thanks..

Sure. So, Alex our strategy on partnering for large broad indications remains same, except we're not going to be taking on very large Phase 3 studies of this type that an antihypertensive would entail. Some other way as we've done for Lp(a) will seek a partner at the appropriate time. With that said, we're in no rush, we're in no hurry.

We have the financial strength to be able to bring these large indications through clinical proof of concept. And as far as we need to take them to maximize the economics that comes to Ionis brings such partners in the future. And so, we're in no hurry to partner in 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. And what was the second one? APOCI was very exciting. It's a program that we initiated at Ionis a number of years ago. It's a target that it's a genetic link to kidney disease FSGS and other kidney diseases.

We did enter into our cardiometabolic collaboration after we did a lot of work here at Ionis on this target. We've published on this target. Actually a player, but we published on it about a year or so ago. It's a very exciting data models, people are wanted to meet kidney disease that we developed.

That trial is in humans now and is in clinical testing. So we're hoping that AZ will have more to say about that program later this year or early next year. They certainly highlight it in their own earnings calls. They're excited about it..

Great, thanks..

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

Hi, guys. Good afternoon. Thanks for taking my question. Question is 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..

Richard, would you like to take that one?.

Sure. Be happy to. So the program, the proof-of-concept study is in patients who are uncontrolled IGF-1 on the somatostatin analogs. And so quite a number it turns out as much as 40%, 50% of these patients, don't get full control on their current therapies.

So, I think what you want to see is IGF-1 control with the addition of our acromegaly GHR LICA program. Also a much improved tolerability profile for this compound. And we are also initiating monotherapy studies in this in patients, who are not on SSRLs or are weaned off and come on to this program.

So, the program is 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. And I would just say that we've done some initial work on kind of the product profile in early on in addition to the IGF-1 control. We're also seeing there's an unmet need on just breakthrough symptoms.

And we believe like with our product, we can actually offer both and along with the monthly dosing that is the turning out to be applied to differentiating profile..

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. So first, I just wanted to touch on the oral ASO candidate again. The timing of that first clinical data disclosure are going to be controlled by AstraZeneca.

What is that a joint decision between the two companies? And secondly, a broader question about the opportunity for oral ASOs.

How do you think of an ideal therapeutic indication or end markets for oral ASOs? How does this compare to the way you think about the targets for your conventionally administered drugs?.

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 advantage of progress we're making an oral for our other programs.

We're already moving out of 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.

And the focus really is on areas where oral would provide a significant, either competitive advantage or convenience advantage for patients, your chronic lung diseases, where patients are going to be on therapy for long periods of time.

Diseases where, it could be a severe disease, but patients are generally asymptomatic until they have an event of some sort will be particularly well suited for an orally administered agent. And in areas where we're competing, with other technologies or other medicines where we think oral can event provided 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 just follow up on the Roche Huntington’s data release. But 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. .

So, 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 is that open label extension study is completed and they're evaluating the data.

Now along with the natural history study, which has not completed yet, which will complete this year or early next year and then they'll share that data alongside the oral data next year. That's what to expect for next year. .

Got it. And then can you go into maybe a little more detail about the C&M2 program for intranuclear myopathy. You indicated the Phase 1/2 started.

Can you give us with the trial design and timelines for that data and maybe just how you look at the indication?.

So, this is with our partner Dynacare. C&M2 is the target. And it's for the treatment of all forms of central nuclear myopathies. They published with us a joint publication, some very exciting preclinical data models of C&M. This is a muscle target. And based on that data, we watched into clinical development.

The study design is in older patients with C&M. And these patients have had a long natural history lately of a substantial amount of natural history data for each of these patients that are entering studies. So there's a lot of information to go off from that study and it is open label. So all patients are getting the drug.

Then the goal is to move into infants next year, which is more spirit 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?.

So 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 that 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 it's 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 win, more aggressive steps should be taken for that part of the business? Thanks..

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

Sure. Hi, Josh. So 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.

As you know, it's really 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 and reaffirmed our guidance again this year to be meaningfully profitable. And so we are obviously committed to that.

And we're also committed to working with Akcea and their new management team, with Damien and Kyle today, their Chief Commercial Officers 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 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.

And we look forward to updating you on our progress as the year unfolds. So take care everybody, and we'll talk soon. Bye now..

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