Q1 2020 Earnings Call

Good morning, and welcome to the I honest Pharmaceuticals first quarter 2020, <unk> financial results Conference call.

Operator: Good morning, and welcome to the Ionis Pharmaceuticals first quarter 2020 financial results conference call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Wade Walke, Vice President, Investor Relations, to lead the call off. Please begin.

As a reminder, this call is being recorded at this time I would like to turn the call over to Wade Walke, Vice President Investor Relations to lead the call up please begin.

Thank you Melissa.

Wade Walke: Thank you, Alyssa. Before we begin, I encourage everyone to go to the investor section of the Ionis website to find the press release and related financial tables, including a reconciliation of the GAAP and non-GAAP financial measures that we will discuss today. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We've also posted slides on our website that accompany our discussion today. With me on today's call are Brett Monia, Chief Executive Officer, Beth Hougen, Chief Financial Officer, and Richard Geary, Executive Vice President of Development. Additionally, Onaiza Cadoret, Chief Corporate Development and Commercial Officer, and Eric Swayze, Executive Vice President of Research, will join us for Q&A.

Before we begin I encourage everyone to go to the investors section to be honest website to find the press release related financial tables, including a reconciliation of the GAAP and non-GAAP financial measures that we will discuss today.

We believe non-GAAP financial results better represent the economics of our business, how we manage our business.

Posted slides on the website that accompany our discussion today.

With me on todays call my breath on young Chief Executive Officer.

Okay, Chief Financial Officer, Richard Gary Executive Vice President development. Additionally, laser Cadorette, Chief corporate development commercial officer, and Eric Swayze Executive Vice President of research will join Us for Q1 day.

Wade Walke: I would like to draw your attention to slide 3, which contains our forward-looking language statement. We will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail. And with that, I'll turn the call over to Brett.

I'd like to draw your attention to slide three which contains our forward looking language statement.

We'll be making forward looking 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 are actually see filings for additional detail.

With that I'll turn the call over to Brett.

Thanks weight.

Brett P. Monia: Thanks, Wade. Good morning, and thank you for joining us on today's call. Our strong performance in the first quarter reflects the sustainability of our business and the unwavering commitment of our team. Ionis was established to deliver transformational medicines to patients in need, which remains the foundation for everything we do. I'm proud of our dedicated employees who are going above and beyond to serve the patients who depend on our medicine. Because of the dedication of our organization, we have 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. 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.

Good morning, 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.

When it was established skilled labor 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 renewed executing on our goals and have already achieved many successes across our business, while effectively managing our response.

Okay.

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 and advancing our late stage pipeline towards potential near term approval.

Same thing or I always on pipeline broadening 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 were pleased with the continued growth our commercial medicines.

Brett P. Monia: So now to briefly recap our recent achievements. We are pleased with the continued growth of our commercial medicine business. Spenraza's strong performance continued with growth in global markets despite some impact on new patient starts and maintenance dosing from COVID-19, and both Tec-Ceti and Whey Liver maintained consistent quarterly growth with new country launches underway. Our pipeline has also continued to deliver many important successes. Enrollment in the Phase III Generation HD1 Study of Tominersen in patients with Huntington's Disease has now been completed.

The strong performance continued growth in global markets. Despite some impact new patient starts and maintenance dosing from covert 19 in both Texadian, we'd never maintained consistent quarterly growth with new country launches underway.

Our pipeline has also continued to deliver many important successes enrollment in the phase three generation HD. One study of intercept in patients with Huntingtons disease is now complete.

Brett P. Monia: While there is still much to do to bring this study to its planned completion, we are now one very important step closer to providing a treatment for people living with this devastating disease. The Phase 3 program for Axia Apo Little A LRX continues to advance. Importantly, this medicine recently received fast-track designation in the U.S., reflecting the significant unmet need that exists for the millions of patients with LP little a driven cardiovascular disease with no approved treatment options. Additionally, earlier this year, we in AXSIA reported positive top-line results from Phase II proof-of-concept studies of AXSIA ApoC-3-LRX and AXSIA Angiopoietin-like 3-LR We and our partners have over 40 clinical studies underway at sites around the globe.

Well, there's still much to do to bring this study to its planned completion. We're now one very important step closer to providing a treatment for people living with this devastating disease.

Phase three program for Akcea April Little a lrx continues to be batch importantly, this medicine recently received fast track designation in U.S., reflecting the significant unmet need that exist for the millions H LP literally driven cardiovascular disease, but no approved treatment options.

Additionally earlier this year, we in axiom recorded positive topline results from phase two proof of concept studies, a vaccine able to see three lrx next year, Angiopoietin like three or X, which we'll now referred to as Norcen.

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 globe.

Brett P. Monia: While some of our studies have experienced limited disruptions, primarily in countries most impacted by COVID-19, we remain confident that the mitigation strategies we deployed early in the pandemic should minimize the impact on our clinical studies and business operations. We are looking ahead. We are continuing to invest in our strategic priorities and remain on track to achieve our 2020 objectives. We in AXSIA expect to initiate the Phase III study of ApoC3-LRX in patients with FCS, bringing us to a total of six Phase III studies with five medicines. We're on track to refile the MDA for Ridley Livera in the U.S., 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. And now, Beth. Thank you, Brett.

Well some of our studies have experienced limited disruptions primarily in countries. Most impacted by covered 19, we remain confident that mitigation strategies. We deployed early in the pandemic should minimize the impact to our clinical studies and business operations.

Looking ahead, we are continuing to invest in our strategic priorities and remain on track to achieve our 2020 objectives.

Your next you expect to initiate phase three study that people see three lrx impatience Fcs, bringing us to a total of six phase three studies, we fight medicines.

We're on track Refile Dnbi gay for with liver in the U.S. and we plan to report additional clinical proof of concept result from several programs this year.

We are well positioned to achieve our goal of delivering 10 or more and da's through 2025.

I'll now turn the call over the back to review our financial performance, followed by Richard will discuss our pipeline progress and then open up.

Call for questions. After some brief closing remarks.

Now to you bet.

Thank you Brett.

Elizabeth L. Hougen: 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 investments at the end of March. Over the last several years, we have consistently strengthened our financial position and constructed a balance sheet that is sustainable and will enable us to achieve our near and longer-term goals. Moreover, the prudent debt refinancing we undertook late last year resulted in a favorable debt maturity schedule while substantially reducing our cash interest expense and potential future dilution.

We entered the cobot 19 pandemic in a position of substantial financial strength.

Our first quarter financial results were in line with our projection, 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 priority.

Importantly, we remain well capitalized with $2.4 billion 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 calls.

Moreover, the prudent debt refinancing we undertook late last year resulted in a favorable debt maturity schedule, while substantially reducing our cash interest expense.

Potential future dilution.

Our commercial revenue increased nearly 25% over the first quarter up 29 team, which spinraza was the largest component.

Elizabeth L. Hougen: Our commercial revenue increased nearly 25% over the first quarter of 2019, of which Spinraza was the largest component. On SpinRod's strong first quarter performance, we earned $66 million in 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 U.S., growth was driven primarily by adult patients initiating Spinraza treatment. Outside the U.S., growth was reported in all major regions.

Spinraza strong first quarter performance, we earned $66 million royalty revenue.

An increase of approximately 10% compared to the same period last year.

At the end of March they were nearly 11000 patient spinraza treatment worldwide.

In the U.S. growth was driven primarily by adult patients initiating the treatment.

Outside the U.S. growth was reported in all major beach.

Importantly, because of the significant number of untreated patients and established and emerging market.

Elizabeth L. Hougen: Importantly, because of the significant number of untreated patients in established and emerging markets, we in Biogen continue to see potential for further growth. Product sales of Tecsteady and Waylibra also continued to grow in the first quarter, more than doubling compared to Q1 2019. Today, Tec-Citi is commercially available in 12 countries. In the US, over 1,800 physicians are now using AXIA's genetic testing program, with a growing number of patients being tested and diagnosed with HATTR. Many physicians and patients are choosing Tegceti due to its subcutaneous at-home administration, which is particularly attractive in the current COVID-19 environment.

We have buys and continue to see potential for further growth.

Right and they also takes study and way Liberal also continued to grow in the first quarter more than doubling compared to Q1 2019.

Good day Texadian commercially available in 12 countries.

In the U.S. over 18 on dispositions are now using axiom genetic testing program with a growing number of patients being tested and diagnosed but AJ TTR.

Many physicians and patients are choosing chegg study due to its subcutaneous at home administration, which is particularly attractive in the current coping nineteena buyer.

Additionally, axiom market access efforts have continued to translate into broad takes Eddie coverage.

Good in long term coverage secured for 75% of U.S. patients with commercial insurance.

Elizabeth L. Hougen: Additionally, Axia's market access efforts have continued to translate into broad tech-savvy coverage, including long-term coverage secured for 75% of U.S. patients with commercial insurance. Additionally, Axia has made progress expanding tech city access outside the U.S., including in Southern Europe. This is important because of the large endemic TTR amyloidosis patient population throughout this region.

I see it has made progress expanding take steady access outside the U.S., including in southern Europe.

Important because of the words endemic TTR amyloidosis patient population throughout this region.

I see it has also made progress in obtaining pricing and reimbursement and additional countries. Most recently in Spain and Austria.

In Latin America PTC Therapeutics is working just think your pricing in Brazil, and expand tech savvy access in that region.

Elizabeth L. Hougen: Axia 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 tech-study access in that region. We anticipate that expansion into new countries will help drive tech city growth this year. Now, turning to Wade Libra.

We anticipate that expansion into new countries will help drive any growth this year.

Now turning to weigh that Brian.

We live right is now on the market in Austria, Germany, and France, or the H. you are reimbursed early access program.

This year axiom plans to watch and additional your country and teaching PTC therapeutics is working toward their goal a filing for marketing authorization in Brazil, It's yeah.

I see it has a strong foundation in place for take study I went live right, which we believe supports growth as both medicines expand into new markets.

Elizabeth L. Hougen: Waylibera is now on the market in Austria, Germany, and France through the ATU, a reimbursed early access program. This year, Axia plans to launch Waylibera in additional EU countries, and PTC Therapeutics is working toward their goal of filing for marketing authorization in Brazil this year. Axia has a strong foundation in place for TIC-CITI and Welibra, which we believe supports growth as both medicines expand into new markets and broader access is achieved this year. Furthermore, 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 medicine... In Q1, we earned $49 million in revenue from numerous partnered medicines as they advanced.

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 its one of our many strengths.

And one that is particularly valuable during these uncertain times.

In addition to revenue from our three commercial medicine in Q1, we earned $49 million that revenue from numerous partner [laughter] They advance.

We are in more than $25 million in R&D revenues for advancing better [laughter], our neurological disease franchise, including Ionis Ttrx for Alzheimer's disease, and several other programs under our Biogen collaboration.

And we earned $15 million in R&D revenue from our cardio metabolic franchise.

This included a $10 million milestone payment mirroring what astrazenecas advanced eye on by three to 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 XT eight Oh, my gosh, L.R. <unk> last year.

We expect growth in revenue this year to be driven by continued significant commercial revenue and R&D revenues from numerous program.

Elizabeth L. Hougen: We earned more than $25 million in R&D revenue for advancing medicines within our neurological disease franchise, including Ionis MAP-TRX for Alzheimer's disease and several other programs under our Biogen collaboration. And we earned $15 million in R&D revenue from our cardiometabolic franchise, which included a $10 million milestone payment we earned when AstraZeneca advanced Ion 532 for the treatment of kidney disease.

Our first quarter non-GAAP operating expenses increased nearly 20% to $153 million compared to the same period last year.

The increase is driven by our investments in the global watches tech savvy and way Libra.

Phase three program for Akcea TTR like Uh Huh.

And our I O <unk> and <unk>.

As the year goes on we also expect when Baskin technologies that could broaden the reach of our technology as we did late last year. When we made strategic investment income income commentary technology.

Elizabeth L. Hougen: 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 XEA 808-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 was driven by our investments in the global launches of Tixeti and Waylibra. The Phase III program for Axia, TTR, Leica, RS, and our Ionis-owned pipeline.

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 that and as such are included in our full year operating expense guidance.

With these results we ended the first quarter nearing breakeven, but the net loss of $15 million I did not get paid.

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 dollar 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 increased as the year progressive inline with our guide.

Elizabeth L. Hougen: As the year goes on, we also expect to invest in technologies that could broaden the reach of our technology, as we did late last year when we made strategic investments in complementary technologies. 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 nearing break-even with a net loss of $15 million on a non-gap basis.

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 cousins 19 pandemic environment.

With that I'll turn the call over to Richard just provide an update on her but.

Thank you Beth.

While managing the challenges presented by Cobot 19, we'd have continued to achieve significant advancements across our pipeline of over 40 medicines in development.

As mentioned previously Roche completed enrollment and the global generation H.C., one phase three study for Tomlinson our.

Richard S. Geary: 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 strengths, we have the resources to execute on our near and longer-term strategic priorities, even in the challenging COVID-19 pandemic environment. And with that, I'll turn the call over to Richard to provide an update on our pipeline.

Our medicine in development for the treatment of Huntingtons disease rapid enrollment in this study reflects the profound commitment of huntingtons disease patients and caregivers to help us find an effective treatment for this devastating disease.

We're especially pleased that Roche recently confirmed this program remains on track.

Essential for data and 2022.

Biogen continued to advance clinical studies with two of our medicines.

Addressing two genetic forms of Ayloush phase three study of Jefferson inside one L. S and the phase two study of I want to see nine Rx and see nine Payless I own a scene I Rx was recently granted fast track designation in the U.S. In addition to enabling an expedited regulatory.

Fast track designation underscores a substantial benefit that's medicine. They delivered to these patients with the most common inherited warmer they alas who have no approved therapeutic option.

Richard S. Geary: 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 III Study for Tumminericin, a medicine in the 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. Meanwhile, Biogen continued to advance clinical studies with two of our medicines, addressing two genetic forms of ALS. Phase 3 Study of Doverson in SOD1-ALS and phase 2 study of Ionis C9-RX in C9-ALS

We had biogen have also expanded rls franchise to include eye on five for one or.

For the treatment of patients with sporadic kls.

On track to enter the clinic later this year, we're particularly excited about this medicine first medicine to enter development addressing the vast majority of patients with having a less.

Turning our attention to Spinraza the body of evidence supporting the durable efficacy and well established safety profile Spinraza also continues to grow.

The first patient was treated in devote phase two three study with a higher doses spinraza based on the well validated safety profile Spinraza. This patients. This study has the potential to demonstrate even greater efficacy and SMB patients of all ages.

And new data from an independent study published in Lancet neurology.

Demonstrated that hanging in adult patients treated with Spinraza 14 months, a cheap clinically meaningful improvements in Hammersmith scores with a continued favorable safety profile.

Richard S. Geary: Ionis C9-Rx 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 at Biogen have also expanded our ALS franchise to include ION541 for the treatment of patients with sporadic ALS, and it is on track to enter the clinic later this year.

Also during the first quarter, we and our partners initiated phase two proof of concept studies for three medicines addressing a diverse range of neurological and rare diseases, including a regulatory hereditary angioedema.

Let's see Mia and central nuclear Myopically.

Additionally, we're particularly excited for the programs in our growing eye on its own neurological disease pipeline, including our programs for Alexander Alexander Afoura and plan disease.

Which continued to move closer to their first by trials.

Richard S. Geary: We're particularly excited about this medicine, as it is our first medicine to enter development and address 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. For example, 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 in SMA patients of all ages, and new data from an independent study published in Lancet Neurology demonstrated that teen and adult patients treated with Spinaraza for 14 months achieved clinically meaningful improvements in Hammersmith scores with a continued favorable safety profile.

Our cardio metabolic pipeline continues to be a significant area focus for us addressing diseases, ranging from rare two very large and including both partner and I honestly don't mess.

Akcea able to light Lrx was granted fast track designation underscoring the significant value of this medicine neighboring to millions of patients worldwide with establish a established lpa driven cardiovascular disease have no effect of therapeutic options.

Importantly, the phase three horizon cardiovascular outcome study of Akcea April than like Lrx is progressing with our partner Novartis and as of today Novartis expects no significant impact from Covance 19 on studied timelines.

And earlier this year, we reported positive topline results from phase two proof of concept studies of the ixia able to see three lrx and Boop analgesia.

Both medicines, which are part of our growing in advancing like a pipeline.

Richard S. Geary: Also during the first quarter, we and our partners initiated Phase II proof-of-concept studies for three medicines addressing a diverse range of neurological and rare diseases, including hereditary angioedema, beta thalassemia, and centronuclear myopathy. Additionally, we're particularly excited for the programs in our growing Ionis-Owned Neurological Disease Pipeline, including our programs for Alexander, Lephora, and Prion Disease, which continue to move closer to their first clinical trial. Our cardiometabolic pipeline continues to be a significant area of focus for us, addressing diseases ranging from rare to very large, and including both partnered and ionosome medicines. Axia Apovalay LRX was granted fast-track designation underscoring the significant value of this medicine, may bring millions of patients worldwide with established LPA-driven cardiovascular disease who have no effective therapeutic, Importantly, the Phase III Horizon Cardiovascular Outcomes Study of Xea apolulea LRX is progressing with our partner Novartis, and as of today, Novartis expects no significant impact from COVID-19 on study timeline.

Using their primary endpoint, demonstrating robust triglyceride lowering and substantial reductions in additional key cardiovascular risk factors like 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 one development addressing very broad cardio metabolic diseases, including eye on Fivethree to targeting April L. One or the treatment of kidney disease, and ROI I honestly and like a medicine I on two to four targeting de get too for the treatment of Nash.

Enrollment is progressing in the phase three studies of Akcea TTR Lrx neurology transform in patients with GTR polyneuropathy and cardiac to transform in patients with TTR cardiomyopathy.

In response to covert 19, we briefly cost new patient enrollment in both studies.

Effort to protect these patients which are at high risk for Kobin 19 related complications was also important for us to preserve data integrity. At this early stage studies. However, enrollment has resumed in both studies sites come back online as local and regional restrictions east.

Importantly, we do not expect as freight costs significantly impact timelines. These studies cobot 19 presented us with a number of challenges, which we believe we are managing well.

Richard S. Geary: And earlier this year, we reported positive top-line results from Phase 2 Proof of Concept Studies of Xea ApoC 3 LRX and Buprenor, 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 venues. We also advanced new medicines into Phase I development, addressing very broad cardiometabolic diseases, including Ion 532 targeting ApoL1 for the treatment of kidney disease, and our Ionis-owned Leica medicine, Ion 224, targeting DGAT2 for the treatment of NAS. Enrollment is progressing in the Phase III studies of Xea-TTR-LRX, Neuro-T-TRANSFORM in patients with TTR polyneuropathy, and Cardio-T-TRANSFORM in patients with TTR cardiomyopathy.

We're continuing to monitor each program and are ready to respond if needed has the pandemic evolves.

Our dedicated team has successfully adapted to the current environment, enabling us continue advancing our pipeline and remain on track to achieve our top 2020 priorities. We plan to initiate phase three study of Akcea April C. L. Rx in patients with EPS, yes.

We remain on track to re file the NDA for way Libra and the less this year.

Yeah.

And we continue to expect clinical proof of concept data for at least for more programs. This year.

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.

Thanks Richard.

Today, I honestly is stronger than ever.

We are reaffirming our 2020 financial guidance and we remain well capitalized with a strong balance sheet.

Our strength and sustainability or enabling us to continue delivering value to patients and shareholders, while effectively managing the challenges presented or the Cobiz 19 endemic.

Richard S. Geary: In response to COVID-19, we briefly paused new patient enrollment in both studies in an effort to protect these patients, who are at high risk for COVID-19-related complications. It was also 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 restrictions allow.

Already this year, we continued to deliver strong performance from our commercial medicine.

We've made significant progress in advancing all of our phase three programs all of which remain on track.

Preparations are well underway to initiate another phase three program this year and to refile, we liver for approval in the U.S.

We reported positive data from two phase two like medicines, we initiated numerous phase one and phase two studies and we're on track to move five or more new programs into development. This year.

Brett P. Monia: Importantly, we do not expect this free pause to significantly impact the timelines of these studies. COVID-19 presented us with a number of challenges which we believe we are managing well. We are continuing to monitor each program and are ready to respond if needed as the pandemic evolves. Our dedicated team has successfully adapted to the current environment, enabling us to continue advancing our pipeline and remain on track to achieve our top 2020 priorities. We plan to initiate a Phase 3 study of Axia ApoC3 LRX in patients with FCS. We remain on track to re-file the NDA for Waylibra in the U.S. this year, and we continue to expect clinical proof of concept data for at least four more programs this year. And we are still 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 the call.

None of this would be possible without the dedication resilience and strength of our employees.

Hi, I'm incredibly proud of how the eye and his team has responded to overcome challenges posed by Cobas 90.

Because of our employees for continuing to execute effectively on our mission to deliver transformational medicines to patients need.

As we continue to invest in our strategic priorities, including building in advancing the eye on its own pipeline and developing our commercial capabilities. We remain on track to achieve our short and longer term strategic goals, including delivering new drug application for 10 or more of our medicines through 2025, we.

We have tremendous momentum as we look towards the rest of this year and 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 like open the call for today.

Well now begin the question and answer session to ask a question. You May proceed Star then one on your touched on some if you are using a speakerphone. Please pick up their handsets before passing the keys. So let's try your question. Please press Star then too.

Brett P. Monia: Thanks, Richard. Today, Ionis is stronger than ever. We are reaffirming our 2020 financial guidance, and we remain well capitalized with a strong balance sheet. Our strength and sustainability are enabling us to continue delivering value to patients and shareholders while effectively managing the challenges presented by the COVID-19 pandemic. Already this year, we have continued to deliver strong performance from our commercial medicine, and we have made significant progress in advancing all of our Phase III programs. All of which remain on track.

First question today comes from Kim Birch, No Wells Fargo. Please go ahead.

Hi, guys. Congrats on all the progress and work through the corporate 19 situation a few questions I guess number one Brett if we could get may be updated thoughts on internal commercialization versus the affiliate model and maybe some framework that will need to may be working on to establish a commercial model and I own.

Yes.

And then for Richard just on but see a program be the pulmonary program.

Should we expect data by year end in CF patients and what what should we look for there.

Operator: Preparations are well underway to initiate another phase three program this year and to refile Way Liver for approval in the U.S. We reported positive data from two Phase II Lyca medicines. We initiated numerous Phase I and Phase II studies, and we're 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're continuing to execute effectively on our mission to deliver transformational medicines to patients in need. As we continue to invest in our strategic priorities, including building and advancing the Ionis-owned pipeline and developing our commercial capabilities, we will remain on track to achieve our short and longer-term strategic goals, including delivering new drug applications for 10 or more of our medicines through 2025. We have tremendous momentum as we look towards the rest of this year and beyond. I'm excited about the future that we're creating and look forward to reporting on additional successes throughout this year and beyond. And with that, I'd like to open the call for Q&A.

And then maybe just one final one for back just in terms R&D revenues is that something we should consider remaining stable overtime 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 as you suggested I'll take the first one I'll start there, but also toss it over to an age that to give her perspective on who's on the call for doing that so.

As we stated in our.

Now recently in our in our call earlier, we are prioritize you continuing to build expand the eye on its own pipeline and identifying and characterizing each of the medicines in that pipeline as to the value.

And the synergies they they create when.

Bundled together in various ways that you'd are principally focused on rare diseases.

And we're identifying those opportunities in a growing pipeline that will bring the greatest value draw your own as I'm sure I'm looking at various options on commercialization strategies. This year, we're hoping to present.

Some of that strategy later this year towards the pool with that on AIDS that please jump in and at that to my comments.

Sure Hi, Jim how are you.

The question, so we're making good progress right and developing our commercial strategy.

Jim Birchnoff: We will now begin the question-and-answer session. To ask a question, you may press star, then 1 on your touch-tone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star, then 2. The first question today comes from Jim Birchnoff of Wells Fargo. Please go ahead.

Brett just said the eye and it sounds like one is large and we're making cuts you didn't best friends, we certainly expect it even grow further on future. So we put for which hopefully you can imagine the initial steps into commercialization work had been on portfolio prioritization and look for paying a high level of strategies such as she laying out how our innovative products deliver on the high unmet need in them.

Brett P. Monia: Yeah, 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 a commercial model at Ionis. And then for Richard, just on the CF program, the pulmonary program: should we expect data by year-end in CF patients, and what should we look for there? And then maybe just one final one for Beth, just in terms of R&D revenues, is that something we should consider remaining stable over time, or is there any reason to think that it could increase or decrease? Thanks.

Market what are strategic positioning is identifying where we have customer facing synergies.

Yeah as a result.

Yeah on its own Europe portfolio, we talked a lot I'm continues to be a priority.

And we remain excited about the mid stage portfolio as well it looks like crude medically non transfusion dependent beta thalassemia and hereditary angioedema.

So has a little part to providing high level commercial strategy for the I honestly oil later this fall more likely at the Investor Day. We currently have problems that we can get deeper at that time.

Thanks, Sundays, Richard but talk about our unique program.

So the next program is moving forward apt at a pace that we expect will complete enrollment this summer and so we do expect cystic fibrosis.

Brett P. Monia: Thanks for the questions, Jim. So, I'll take, as you suggested, I'll take the first one and I'll start there, but I'll also toss it over to Onaiza to give her perspective, who's on the call for Q&A.

Portion of that study be able to report out later this year.

What should we expect yeah. This is a relatively short term exposure of six weeks weekly of installation of the product.

Onaiza Cadoret: So, as we stated in our call earlier, we are prioritizing and continuing to build and expand the Ionis pipeline and identifying and characterizing each of the medicines in that pipeline as to the value and the synergies they create when bundled together. 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 through Commercialization Strategies this year. And we're hoping to present some of those strategies later this year, towards the fall. With that said, Onaiza, please jump in and add to my comments.

And we expect safety and some efficacy based on.

The target engagement. So that's that's essentially what we'll we'll know by the end of this we have all up fully completed phase one trial in normal volunteers that is shown excellent safety and Tolerability and will also be including data from the rollout and.

When we roll that out Jim I suspect will also be able to talk about additional potential phase two studies that are.

And planning phase right now for our Enac inhibitor, we're not going to develop that drug only first year, but actually there's quite a few other opportunities in the pulmonary front that we're quite excited about.

Onaiza Cadoret: Yeah, sure. Hi Jim, how are you?

Onaiza Cadoret: Thanks for the question. So we're making just good progress, right, in developing our commercial strategy. As Brett just said, the Ionis own pipeline is large, and we're making continued investments, and we certainly expect it to even grow further in the future. So with such a rich portfolio, you can imagine the initial steps in the commercialization work has been on portfolio prioritization. And we're preparing a high level strategy, such as, you know, laying out how our innovative products deliver on the high end met need in the market, what our strategic positioning is, and identifying where we have customer facing synergies. You know, as a result... The Ionis Onuro 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 One portfolio later this fall, more likely at the Investor Day we currently have planned, and we can get a little bit deeper at that time.

Got it.

She was the 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 you know as I mentioned earlier that the Q2 is likely going to look like Q1 in terms of grabbing is our revenues from R&D partnership tend to be more back.

Cambodia's this year, so I would expect to see revenue growth in Q3, and and also in Q4.

Primarily from a from R&D revenues and of course that the commercial revenues.

Back to grow quarter over quarter for the remainder 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.

Hey, 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 this upcoming catalysts. I know you you mentioned some of them, but could you just review or at least those four for us and maybe specifically highlight the one or two that you were well read outs are you.

We're most excited about and what you'd need to see in order to achieve proof of concept.

Onaiza Cadoret: Thanks, Onaiza.

Richard S. Geary: Yeah, 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.

Sure happy to Tyler. Thanks, So just just the backup I have said 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 these outcomes with angiopoietin like three like a which is now licensing partner.

Richard S. Geary: What should we expect? This 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. We have a fully completed Phase 1 trial in normal volunteers that has shown excellent safety and tolerability, and we'll also be including that in the rollout.

Fines or and are able to see three like I'm trying to phase III study to initiate later this year in S., yes.

We have a number of opportunities for clinical Readouts this year.

And we're on track to achieve those six clinical Readouts. This year, Oh, we're expecting to read out on our economically program pro forma interceptor, a which is in patients on assays, who are not control yeah endpoints such as.

Richard S. Geary: And when we roll that out, Jim, I suspect we'll also be able to talk about additional potential Phase II studies that are in the planning phase right now for our ENAC inhibitor. We're not planning to develop that drug only for CF, but actually, there are quite a few other opportunities on the pulmonary front that we're quite excited about.

Hi, Jeff one.

Hereditary angioedema.

From our PKK like a program is also another program that we're expecting to have readout on later this year.

Eric E. Swayze: Uh, Beth, do you want to take... choose, uh...

In addition.

Elizabeth L. Hougen: Sure, absolutely. Hi Tim.

We have an exciting program in hypertension.

Endogenous antigen is a is an exciting program, where we have multiple phase two programs.

Elizabeth L. Hougen: 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, Q2 is likely going to look like Q1 in terms of revenues. Our revenues from R&D partnerships tend to be more back-end 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.

Ongoing.

And we're hoping to share some of that data later this year.

As well.

In addition, there's the potential for us some data coming out from our Bayes adults immune program Tempur six remains to be seen if there will be ready to go this year or not whether they'll go into next year.

But in addition, the Enac program or for pulmonary disease that Richard I already mentioned and.

Of course, we also have the ongoing study in which we're evaluating with Astrazeneca our program.

Jim Birchnoff: Great. Thanks for taking the questions, guys. Thanks, Jim. I appreciate the question.

Determining whether evaluating the from an oral formulation for undisclosed target.

Jim Birchnoff: Thanks Jim, I appreciate the questions.

It's in clinical testing now, which we hope to read out later this year as well present data with our partner.

Operator: The next.

Tyler Van Buren: Hey 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 as upcoming catalysts, I know you mentioned some of them, but could you just review those four for us and maybe specifically highlight the one or two that your readouts that you're most excited about and what you need to see in order to achieve proof-of-concept?

So quite a rich set of pipeline updates coming in second half of this year that we're really excited [laughter].

Maybe just a quick follow up on each or you are I.

I guess is the goal the standard of care Injectables that have launched for prevention or achieving pretty high reductions in terms of attack rates. So do you think you could improve upon that or or is the goal to kind of extend treatment duration looked like.

Brett P. Monia: 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 two outcomes with angiopoietin-like 3-lyca, which is now licensed and partnered with Pfizer, and our ApoC3 Leica, which we're planning a phase three 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 We're expecting to read out on our acromegaly program, growth hormone receptor, which is in patients on SSAs who are not controlled, looking at endpoints such as IGF-1. Hereditary Angioedema from our PKK LICA program is also another program that we're expecting to have a readout on later. In addition, we have an exciting program in hypertension.

So you're absolutely right the AG landscape is quite competitive.

And and patients are and I would have had ever seen substantial benefit and reduction in attack rates.

When the current approved medicines.

Our objective is to do as good as that or better with our with our mechanism.

Of action blocking the Kallikrein pathway.

And as you may have seen some of our phase one data I mean, we're really really having a very very potent molecule, we're having large impact greater than 90% reductions and pre kallikrein enormous.

We think we can be to potentially but we also have going for us is the convenience of I very infrequent or low volume injectable subcutaneous injectable with the potential if we cracked commercially viable oral bioavailability and ongoing studies to move that drug into.

Brett P. Monia: Angiotensinogen is an exciting program where we have multiple Phase II 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 out from our beta thalassemia program, 10-part 6. It remains to be seen if that will be ready to go this year or not, or whether that will 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 that we're evaluating with AstraZeneca. Our program is evaluating an oral formulation for an undisclosed target that is in clinical testing now, which we hope to read out later this year as well and present data on with our partners. So, quite a rich set of pipeline updates coming in the second half of this year that will really...

An oral formulation as well, which would be a significant advantage from a convenient 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 we and plans are coming together through to move on those and we're hopeful I'm, hoping to share some of our thoughts on this later this year, maybe at Investor day.

Very helpful. Thanks for taking the questions.

Right.

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

Hi, This is key encore, Jason Thanks for taking my questions I have to.

Brett P. Monia: Maybe just a quick follow-up on HAE. I guess the standard of care injectables that have been launched for prevention are achieving pretty high reductions in terms of attack rates. So do you think you could improve upon that, or is the goal to kind of extend treatment duration with the LICA?

A couple on topic when OPI for sporadic here as it gets the first one on that maybe can you talk about you know hobby, especially at the market opportunity for that will be it gets how lock. If this works sporadic population is what BNP brought a ers in.

Brett P. Monia: So, you're absolutely right, the HAE landscape is quite competitive, and patients have received a substantial benefit in the reduction in attack risk. Our objective is to do as good as that, or better, with our mechanism of action blocking the calicrime pathway, and as you may have seen some of our phase one data, we're really, we have a very potent molecule. We have a large impact, greater than 90 percent reductions in precalocrine levels. So, we think we can beat it, potentially. What we also have going for us is the convenience of a very infrequent, low-volume injectable, subcutaneous injectable, with the potential, if we achieve 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. It is a competitive environment, and we think we're hopeful that we can compete. The other thing I'll just add to that is we are exploring additional potential indications for our calocrine 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.

When applicable up a couple of follow up after that.

Sure change so.

We're very excited about our allies program as as you know there are multiple causes L.S. genetic and sporadic are to lead programs are targeting genetic she nine and or and which is due to read out phase two data next year and our phase three data.

Or overseeing someone LSW also do read out next year. This is our first of several sporadic LLS target drugs that were planning to bring forward and I'm not too distant future. This is the first it's targeting a tax and to the preclinical data looks very exciting and compelling and one of arc.

He objectives this years to get the clinical study started by engine.

And as you know the sporadic population represents the majority vast majority of patients with Airbus I believe it's somewhere north of 75% patients, but they are less urban sporadic variety.

And they Texan too there's no reason to believe that it couldn't into performed well address the majority of that majority quite simply so it's really or.

Tyler Van Buren: Very helpful. Thanks for taking the question.

Tyler Van Buren: Thanks, Folks.

Operator: The next

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

Brett P. Monia: Hi, this is Chi on behalf of Jason. Thanks for taking our questions.

Majority patients with air last this drug is central to treat.

Got it I think you'd kind Oh rich into my second question. My second question was how had working to get this that's bracket for and it sounds like you are planning to do multiple studies support Appalachian experimenting there from Maxim that sounds to address all the.

Brett P. Monia: I have a couple of questions on the BIP-105 for sporadic ARS. I guess the first one on that, maybe, can you talk about, you know, how you imagine the market opportunity for that would be, I guess, how large the sporadic population is within the broader ARS umbrella? And I have a couple of follow-up questions after that.

Brett P. Monia: Sure, Chi. 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 causes, C9, which is due to read out Phase 2 data next year, and our Phase 3 data for Toversen, SOD1 ALS, also due to read out next year. This is the first of several sporadic ALS target drugs that we're planning to bring forward in the not-too-distant future.

Differing Mac and that's something that could cost up sporadically I'll ask kind of I think you sat up de duplicate the taxi yet you cannot dress.

Yeah that Oh, we thinking about maybe like 80%, 90% of it because again sort of quantify that will be great. Thanks.

It's it's it's hard to say how much of the sporadic population apex into would address.

Brett P. Monia: Targeting Ataxin-2. The preclinical data looks very exciting and compelling, and one of our key objectives this year is to get the clinical study started with Biogen. As you know, the sporadic population represents the majority, the vast majority of patients with ALS. I believe that it's somewhere north of 75% of patients with ALS are of the sporadic variety. And Ataxin-2, there's no reason to believe that it couldn't, if it performed well, address the majority of that majority, quite simply. So it's really the majority of patients with ALS that this drug will help.

Our hope and has no reason to believe that we can 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 or rail that sporadic out west.

Maybe Eric you can you can at a little more color on the alternative types mechanisms for addressing and how we're going about 10 minutes.

Yeah, I mean so.

As Bret mentioned for your tax income I mean, I think we're really have to figure that out in clinical trials and find out exactly which patient populations respond the best but the preclinical work, which has been published by the way. It is very exciting very strong and as Bret mentioned, we have a very broad program with Biogen looking at all forms of they allowed us.

Brett P. Monia: I think you kind of bridged into my second question. My second question was, how heterogeneous is the sporadic form? And it sounds like you are planning to do multiple studies for that population. Are you experimenting with different mechanisms to address all the different mechanisms that could cause sporadic ALS?

Genetic familial sporadic and all mechanisms that could potentially contribute to the genesis up of 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 certainly optimistic we'll have lots more programs coming for.

Eric E. Swayze: 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 and multiple targets in animal models for ALS and sporadic ALS. Maybe Eric, you can add a little more color on the alternative types of mechanisms we're addressing and how we're going about doing this. Yeah, I mean, as Brett mentioned, for the ataxin compound, I think we really have to figure that out in clinical trials and find out exactly which patient populations respond best. But the preclinical work, which has been published, by the way, is very exciting and very strong. And

Got it maybe just one final falloff from knee I believe the planet the events one O piping to claim that gets here.

And you can you talk about when we could possibly expect data next.

You're referring to the sporadic I missed the yeah sporadic program yet.

Well just starting this year, so I wouldn't mix I wouldn't expect data until next year at the earliest so okay I think that much.

Yep.

Thank you.

Next question comes from Chad Messer Needham and company. Please go ahead.

Great. Thanks for taking my questions and its certainly glad to hear the team at Ioannis is managing things. So so well through this a pandemic.

Like that maybe start with with we lived Brenda into Refiling can you sort of walk us through the the steps that are left is it.

Really just data collection are there any regulatory interactions that need to occur.

Thanks, Chad So we're very excited.

About refiling and liberal or the U.S. potential for potential approval.

Eric E. Swayze: And, as Brett mentioned, we have a very broad program with Biogen.

Eric E. Swayze: All of these companies have been looking at all forms of ALS, genetic, familial, sporadic, and all mechanisms.

For S., yes, or.

You know we've been with Akcea collecting a substantial amount of additional data since the original CRL that we're seeing I'm I'm waiting from U.S. and were and we have our confidence that for approval for way labor in the U.S. has grown as we've continued to collect and evaluate.

Eric E. Swayze: ...could potentially contribute to the pathogenesis of the disease. And so, we're looking at all sorts of different pathways.

Eric E. Swayze: and trying to figure out...

Eric E. Swayze: Drugs or a combination of drugs are best.

Eric E. Swayze: For moving forward to

Eric E. Swayze: 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 data.

Our confidence grew even more based on our meetings with the FDA to talk about Refiling remember, we feel good about the discussions we've had with them and and those discussions have been very supportive in productive so.

Chi: Got it. Maybe just one final follow-up from me. I believe the plan is to advance 105 in the clinical sphere. Can you talk about when we could possibly expect data next?

We're excited what we're doing now is.

Putting the data packaging it up and we're getting ready to re filed later this year.

Brett P. Monia: Are you referring to the sporadic program? Yeah, the sporadic program.

Brett P. Monia: Yeah, yeah.

Richard you want to add anything to that.

Brett P. Monia: Well, it's just starting this year, so I wouldn't expect data until next year at the earliest. Okay, thanks so much.

Only to affirm we have no more regulatory interactions we match with our pre pre resubmission meeting and many encourage to read resubmit. The data is there and so we're just putting that package together.

Chi: Thank you.

Operator: The next question comes from Tad Messer of Needham & Company. Please go ahead.

Okay, great. Thanks.

Tad Messer: Great, thanks for taking my questions, and I'm certainly glad to hear the team at Ionis is managing things so well through this pandemic. I'd like to maybe start with WayLibera and the refiling. Can you sort of walk us through the steps that are left?

And then just on the eight BOE see threed like the upcoming FCS study is is that pretty much should we assume it will look like approach or were there some where there's some lessons learned from having gone through all of this before.

Brett P. Monia: Is this really just data collection, or are there any regulatory interactions that need to occur?

Certainly we you know we have so much experience NFC, yes chat as you know runway labor experience and we will use all of that information to build.

Brett P. Monia: Thanks, Chad. So we're very excited about refiling Libra for the US for potential approval by SCS. You know, we've been with AXSIDA collecting a substantial amount of additional data since the original CRL that we received on labor in the US, and we have our confidence that the chances of approval for whey liver in the U.S. have grown as we continue to collect and evaluate that data. Our confidence grew even more based on our meetings with the FDA to talk about re-filing for whey liver. We feel good about the discussions we've 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 together, packaging it up, and we're getting ready to refile later this year. Richard, do you want to add anything?

On our phase three study design for variable seems to be like Richard.

So a couple of things as we were moving through the development of way Libra.

Akcea has has been hard at work developing a patient.

Reported outcome, which will be included in this study that was not included in the first studies. So that's one difference.

Hi, there will also be.

No real focus on prospectively on the pancreatitis and will enrich for patients.

Before.

Those who have oh ongoing and consistent.

Pancreatitis, so that will.

Another piece is a bit different.

Richard S. Geary: Only to affirm that we have no more regulatory interactions. We've met for our pre-resubmission meeting and have been encouraged to resubmit that the data is there. And so we're just putting that package together.

Otherwise it will look a lot like the French trial.

Okay, that's something well I'm hopeful and then maybe just one on one on Spinraza on that on the boat study.

Don't know how much additional share, but maybe talk us through what kind of efficacy dealt a <unk>, we could pop potentially expect there I mean, it it seems like the efficacy.

Tad Messer: Okay, great. Thanks. And then just on the APOC3 LICA, the upcoming FCS study, is that pretty much, should we assume, going to look like this approach, or were there some lessons learned from having gone through all of this before?

We already happened Spinraza, maybe maybe hard to convincingly beat in a in a trial unless it was really large ones.

Richard S. Geary: Certainly, we, you know, we have so much experience in FCS, Chad, as you know, from our own labor experience, and we will use all of that information to build on our phase three study design for able CTPs like Richard.

Yeah.

We're you're absolutely right Chad the efficacy that's been rods as demonstrated in all forms of estimate sepsis very high bar not only for.

Our devote study, but also for all our competitors.

Richard S. Geary: So a couple of things as we were moving through the development of WeyLibre. Axia 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 thing that is different. There will also be a real focus on, prospectively, pancreatitis and will enrich patients for those who have ongoing and consistent pancreatitis, so that will be another piece that is a bit different. Otherwise, it will look a lot like the APPROACH trial.

But there, but we do believe that I'm going to higher doses as as 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 repreve returning towards the end of a.

We ended the maintenance dose that's just one example.

Patient stack, we get too late later in their disease habit, we have the potential for you know later they have more diseases progressed [noise] before they cannot 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.

Tad Messer: Okay, thanks, helpful. And then maybe just one on Spinraza from 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 from Spinraza may be hard to convincingly beat in a trial unless it was, you know, a really large one.

You know based on the pristine safety Esperanza has demonstrated we have the luxury I'm going to Miss a significantly substantially higher dose in our thrown study in that study as you know it's under underway. So.

Brett P. Monia: Yeah, you're absolutely right, Chad. The efficacy that Spinraza has demonstrated in all forms of SMA sets a very high bar, not only for our dedicated study but also for all of our competitors. But we do believe that going to higher doses, as does Biogen, has the potential to show even greater effort. For example, in between maintenance doses, sometimes patients will start to feel some symptoms 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 the potential, you know, later they have more, their disease has progressed before they've gone on Spironaza, we have the potential to show even greater efficacy in those patients, for example. And then there are others.

It does have a high bar of efficacy and we do but we do believe that there's the opportunity to show you rhetoric and I'll just add also to the I can expand on your question Chad. We're also working making great progress with.

Hi, Jim on a follow on drug potential follow on drug for estimate.

On test Spinraza based on a new chemical entity that we think our objective is and we're feeling pretty good.

Well I guess is by annual dosing or maybe even annual dosing within intrathecal with an interest you administered.

Medicine so.

We're.

No we're defending the estimate franchise I understand biogen.

And we're excited about not only to rob's of but see higher dose as well as far as long as.

Okay, great. Thanks, All Oh pass the might appreciate all the ethics.

Brett P. Monia: And there's other ways to show greater efficacy. So, you know, based on the pristine safety that Spironaza 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 underway. It does have a high bar of efficacy, but we do believe that there's the opportunity to show even greater efficacy. And I'll just add, also, to 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, Spironza, 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 biannual dosing or maybe even annual dosing with an intrathecal, with an intrathecal administered [inaudible] We're, we're, um... You know, we're defending the SMA franchise, Ionis and Biogen, and we're excited about not only Temraza, but the higher dose as well as the follow-on medicine.

Thanks Jen.

The next question comes from Aster Ratchet that.

Oppenheimer. Please go ahead.

Hi, Good morning. Thank you for taking my question on can you maybe give us some color on your partner programs that maybe experiencing cobot 19 related delays at the magnitude of that as you think about if I sat with the ever since the second half and then I have another quick follow up.

And as as we.

Our and as we've stated with respect to the clinical programs were running which meant I've had a minimal impact on the progress we're making on our clinical trials.

Similar story for by our partners, where we are a I've always been remained close contact with our partners and have in meeting with them even more frequently when someone wants this crisis.

Occurred.

And we're not seeing substantial impacts on any of our pipeline apartment pipeline programs take and certainly nothing a meeting and as Richard mentioned in.

Tad Messer: Okay, great. Thanks. I'll pass the mic. Appreciate all the updates.

Earlier or the phase three programs LP literally.

Operator: [inaudible]

Esther Rajavelu: 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 partner 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.

With Novartis cardiovascular outcome trial side, one phase three program with Biogen.

And I think in program are all on track to read out on time, So our partners or management situation quite well.

Awesome. Thank you and then you you know you and then you've always been an enviable cash position recently and do you have any updated thoughts on capital deployment and this kind of environment.

Yeah sure I'll comment on that.

I'll ask that to make some comments too. So we are in a very envious position. We're very proud of this strong financial position we're in.

Brett P. Monia: As we have stated with respect to the clinical programs we're running, which have had a minimal impact on the progress we're making in our clinical trials, a similar story by our partners. We have always been and remain in close contact with our partners and have been meeting with them even more frequently once this crisis occurred, and we're not seeing substantial impacts on any of our pipeline, our partner pipeline programs to date, and certainly nothing of meaning, and as Richard mentioned earlier, the phase three programs, LP Little A with Novartis and the Cardiovascular Outcome Trial, FOD1 phase three program with Biogen, and the Huntington Program are all on track So our partners are managing the situation quite well.

And we we will continue to invest in all of the areas priorities that we planned on investing in last year and as a as we've talked about earlier. This year that includes investing in our pipeline and investing in or later stage pipeline.

On this one later stage pipeline such as the Phase three program frequency three like a and of course, the TTR like a phase three studies.

And and our mid stage pipeline.

Well, we're also investing in or building of commercial capabilities and identifying berries options for maximizing commercial value of the medicines, we bring to the finish line through phase three as our needs or touched on earlier turns queuing day.

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

Brett P. Monia: Yeah, sure, I'll comment on that, and I'll... I'll ask Deb to make some comments too.

And we continue to invest as we as we did earlier this year and to continue to do so in new technologies technologies that complement what we're doing in antisense to continue.

Esther Rajavelu: So, we are in a very envious position. We're very proud of the strong financial position we're in, and we will continue to invest in all of the areas, the priorities that we planned on investing in last year and as we talked about early this year. That includes investing in our pipeline and investing in our later stage pipeline, Ionis on later stage pipeline, such as the phase three program for ApoC3 Leica, and, of course, the DTR Leica phase, and our mid-stage pipeline, as well. We're also investing in building up commercial capabilities and identifying various options for maximizing the commercial value of the medicines we bring to the finish line through phase three, as Onaiza touched on earlier during this Q&A. And we continue to invest, as we did earlier this year, and we plan to continue to do so in new technologies, technologies that complement what we're doing in Antifense to continue to ensure that our leadership position in RNA therapeutics is not only maintained but is extended. Genomics Collaborations to continue to... We'll populate the pipeline with novel genetically linked targets for drug discovery, Leica chemistries, new Leica 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, pursue, and look at to potentially diversify our platform.

To ensure.

Our leadership position in Arnie therapeutics, not only is maintaining but is extended.

Genomics collaborations to continue to.

Populate the pipeline with novel genetically linked targets for drug discovery.

Like.

Chemistries, new like the Chemistries that were collaborating with with.

[music] partner, there and we continue to but for other collaborations as well and brand new technologies that we consider survey and pursue and look at it potentially diversify our platform into new areas.

Yeah, Great [laughter].

Hi, most typically eastern if he can comment.

And I can can you hear me.

Yes, I get asked or sorry, I was happy.

[laughter], sorry, I didn't think there's more specifically maybe on that you can comment on share repurchases and what you're thinking is where that for the remainder thier.

I answer is that so you know as we as we think about our our cash position Tom I think right did a really nice job of outlining our priority, they're very clear, we're very clear internally about where we're going to investor capital when we think it.

Now share repurchases our view at this point is.

Particularly given the uncertainty of the current environment that holding onto our caching and having it available for some of these other opportunities that Brett was describing is you know really a better use of cash today. So we we don't have any specific plan, but that being said, we'll certainly keep at all.

Brett P. Monia: Sorry, more specifically, maybe if you could comment. Go ahead. Okay.

Elizabeth L. Hougen: Yes, I can.

Elizabeth L. Hougen: I'm sorry, I was... Oh, don't worry. I was just more specifically on that, if you could comment on Sherry's purchases and what you're thinking for the remainder of the year.

And then in mind.

Elizabeth L. Hougen: Hi Esther, it's Beth. So you know, 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, you know, 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.

Our next question comes from I Lean Merrell Cantor Fitzgerald. Please go ahead.

Okay. 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, I can you give us a little bit more color just in terms of kind of what drives that you know, it's completed and rolling or.

Still enrolling and close to completion and then in terms of this specific data we could expect to get in terms of the oral I guess, what have you and astrazeneca worked out in terms of what you would actually disclosed.

Esther Rajavelu: Awesome, thank you very much. Thank you. The next question comes from Ellie 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 it.

If that's you know data comes out in 2020, if we'd see start up in a level that you know protein production on things like that in terms of what we should look for in the early thanks.

Surely so.

Operator: in terms of what we should look for.

We're working very closely with H.C. and the number of programs and the Cardiometabolic space and putting this one [noise].

Ellie Merle: Sure, Ellie. We're working very closely with AZ on a number of programs in the cardiometabolic space, 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 along our way to achieving commercially viable oral delivery. And 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, 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 URO program, so it'll actually tell us a great deal about how the URO is stacking up and will stack up with continued development of the subcutaneous formula.

Our.

But we're looking to do is to complete a phase of the study that we think we'll provide ample proof of concept quite simply and so that we can you know we can make some calls on whether or not we think that we're well on our way in achieving commercial commercially viable oral delivery.

What you would expect.

What form that would come in the of course bioavailability PK that is predicting base our preclinical data.

As well as biomarker data so.

Tacked on Biomarkers that are reflective of targeting age and.

But it also.

We have a parallel program that's ongoing tomorrow with the same drugs, but administered subcutaneously and we'll also have data from that study we hope.

To compare side by side with the oil program. So it'll actually tell us a great deal about how the we're always stacking up and will stack up.

It's continued development to the subcutaneous formulation.

Ellie Merle: The main 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 availability is potency. These are Gen 2.5 glycomolecules 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 that we think we need. And our sub-Q data will be very important to show that what we've seen and predicted preclinically will translate to that level of potency. So it's both programs that are causing the...

The main one of the breakthroughs a there were number but one of the breakthroughs that really allowed us to get oral we think to where it is now protesting and potentially achieving commercially viable oral bioavailability is potency.

These are gen 2.5, like molecules and that are stable in the guy.

And and remain intact upon absorption Nick.

And and it's the potency that really allows us to get the bioavailability everything we need.

And our Subcu data it would be very important to show that what we've seen in predicting preclinically will translate to that level and see you. So it's both programs I think it'd be very important.

Brett P. Monia: Got it. Thanks. And then just in terms of, you know, thinking about COVID impacts on the TTR LICA phase three program, I guess, you know, if you could characterize sort of how enrollment is going in each of those phase threes and, you know, how COVID is potentially impacting the enrollment timelines and just sort of your latest expectations for when you could complete enrollment in these studies. And, you know, I know it's a competitive environment. So curious sort of the latest on what you're seeing with the timelines there. Thanks.

Got it thanks, and then just in terms of you know thinking about coal bed impacts on the TTR like of Phase three program. I guess, you know if you could characterize sort of Hollywood rone that it's going in each of those phase threes and you know how cold it is potentially impacting enrollment timelines and just sort of <unk> their latest expectations for when you pets.

Complete enrollment and these studies on you know and not that competitive environment.

So curious sort of that the latest sunlight, you're seeing like what the timelines there. Thanks.

So as Richard mentioned earlier.

Brett P. Monia: So, as Richard mentioned earlier, we did, so the enrollment is ongoing, and the programs are going well. Both the T-transform cardiomyopathy, the cardiomyopathy study, and the neuropathy study are both going well, and they're on track.

We did such that'd be roaming is ongoing and in the programs are going well both both the ER to transform card them up.

The current Napoli study that they're up he said here, both going going well and on track. We did put those studies very briefly and we did that based on requests by our sites that we're activating up and running because they have to assess their own situation there are being overloaded their hospitals and their sites.

Brett P. Monia: 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 were being overloaded at their hospitals and their sites. And they didn't know what to expect, you know, from COVID patients that they were having to manage. So, you know, we obviously appreciated their, you know, those challenges, and we were, you know, we paused the enrollment briefly until they assessed the situation. And then they told us that they're ready to go and reactivated, and we're enrolling again. We expect 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 while during this brief pause. So, we're not expecting a significant impact on timelines.

And they didn't know what to expect or you know from Cowen patients are having to manage so you know, we obviously or appreciated there you know that those challenges and and we were you know we parse the enrollment I briefly until they assess the situation and then they were they told us that was.

The ready to go and Maria and reactivated number rolling again, we don't expect significant impact on the timelines for either study going forward, we did implement a number of mitigation strategies.

As is and developed to catch up.

And we're doing and we did quite a bit remotely well during this brief pause so we're not expecting significant impact on timelines.

Ellie Merle: Got it. Thanks. Very helpful.

Got it thanks very helpful.

Thank you.

Ellie Merle: Thank you.

Operator: The next question comes from Yao Chen of Leibon College.

The next question comes from Yale Jen laid on company. Please go ahead.

Yao Chen: Good morning, and thanks for taking the questions and impressed by your situation under COVID-19. Just two quick ones. The first one is ION224, the DGAC-II programs in NASH. Do you guys have any... I know most of DGAC-II was in earlier stage development, but what do you feel are some of the strengths you might have compared to other programs in development? And then I have a follow-up.

Oh, good morning, and thanks for taking the questions and a impressed by your situation under to if you like Nike Inc. Oh, just two quick ones.

The first one is the island I'll I'll into 24, the de got to programs in Nash.

You guys have any I know most of the do you get to was in earlier stage development, but what do you feel to sum up the string you might have a.

<unk> comparing to other programs, India about them.

And then I'll follow up.

Sure, yes, thanks I.

Brett P. Monia: Sure. Yeah.

Brett P. Monia: Thanks. One of the advantages we have is building on the really impressive phase two data that we generated in patients with NAFLD, fatty liver disease, with the non-likelihood, where we had high statistical significance reductions in liver fat with excellent safety and tolerability. That triggered us to go back and identify and bring forward the Leica version of that to allow us to go to even lower doses, less frequent dosing administration. As from a target standpoint, the advantage we have, I think, is 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.

So one of the advantage we have is building on the really precedence phase two data that was that we generated in patients with NAFLD fatty liver disease with non like <unk>, which we had high statistical significant reductions liver fat with excellent safety and tolerability that but that.

Triggered us to go back and identifying and bring on bring forward. The like a version of that will allow us to go to even lower dose is less frequent dosing administration.

That's from a target standpoint, or the advantage we have I think our multiple there are multiple aspects to that one is that the in fact, if you get too is the rate limiting enzyme in the triglycerides because this pathway in liver, we've demonstrated that we've actually examine.

Brett P. Monia: We've actually examined, and we've actually looked at all the targets in the triglyceride synthesis pathway and concluded that our DGAT2 was the most appropriate, sensitive target for managing liver fat. The second advantage we have is specificity. As you know, small molecules have difficulty with specificity against isoforms, such as DGAT1. You do not want to inhibit DGAT1. Otherwise, you get into some side effects that we've published on, actually. DGAT2, our inhibitor, is very specific, and we think that it will measure up very well against competition for other agents that are targeting triglyceride impact.

We've actually looked at all the targets in the triggers right to stop and concluded that are do you get to was the most.

Appropriate sensitive target for managing liver fat.

The second advantage, we have is specificity.

As you know small molecules.

Difficulty in specificity its isoforms such as do you get one did you got one in ever do you get one.

Of as you've got interest and side effects that Weve published on actually you got to our inhibitors very specific and we think that it'll measure up very well against competition for other agents that are targeting.

Triglyceride backwards in November.

Yao Chen: Okay, great. That's very helpful.

Okay, Great that's very helpful maybe well.

Brett P. Monia: Maybe the next question really is a follow-up to the very first question, really, is that you guys are going to assess a lot of your rare disease pipeline in terms of their sort of commercialization or pathway to go. And as well as that, on Yesterday's conference call with IKEA, they were also probably anticipating or expecting some of these programs may be moving into their pipeline. So overall, how would you guys think about what to maintain on your own, what you may be moved to IKEA? I can see how it's good for their development. So the general principle of thought.

The next question video to fall off the very first question Rudy.

<unk> that are you guys going to assess lot of Youre ready. These pipeline in terms of their sort of commercialization all pathway to go and as well that the yesterday and echoes the conference call. They were also probably anticipate all expecting some of these programs may be moving to there.

Oh the pipeline. So overall Hollywood Hollywood you guys think about what to me they maintain Oh, what you might be moved too.

Other party.

Yes.

Ah yes.

Yes full for their development to the general principle, that's all.

Brett P. Monia: So, we're having very productive discussions with AXSIA on a potential asset to move into AXSIA, and their objective is this year. They, of course, have a very full agenda this year, too, with TXETI, Waylivera, the ABLC-3-lycophase-3 study, and the refiling of Waylivera in the U.S. Our discussions have been very productive, and we have a little bit down to a few potential rare disease programs from the ionosome pipeline, and I think you'll hear more about that later this year It's a pipeline that we're very excited about. Prion, Alexander's, Leflora, as Richard mentioned earlier, more are coming and expanding. And that's certainly a high priority for Ionis to prioritize at least some of those for ourselves. So I think you'll be hearing more about that later this year as well.

Sure so.

We're having very productive discussions with akcea.

On put a potential asset to move into Akcea ER and their objectives. This year.

Of course had a very full agenda. This year two weeks anyway liver the embassy three like a phase three study the re filing of we live.

In the U.S., so, but though our our discussions have been very productive and we have moved down to a few potential rare disease programs from the eye on its own pipeline and I think you'll you'll hear more about that later this year from axiom and I own is certainly one area.

Yeah, a priority for us I own. This is our NERC are rare neurological disease pipeline cuts and it's a pipeline.

We're very excited about prion Alexander's before as Richard mentioned earlier, more coming and expanding and that's certainly a high priority for I own. This too prioritize for some of those for ourselves. So I think you'll be hearing more about that later and later this year as well.

Yao Chen: Okay, great. Thanks a lot. And again, congrats on the progress. Thanks.

Including at our Investor Day.

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

Thanks, Yeah.

Your next question comes from Palmetto teased US Stifel. Please go ahead.

Operator: The next question comes from Paul Mattheis of Schiphol. Please go ahead.

Paul Andrew Matteis: Hi, this is Alex on behalf of Paul. We just have a couple questions from us. Thanks for taking the questions 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 is another large market indication. What are your thoughts as they stand 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 APOL1 program with AstraZeneca. Thanks.

Hi, This is Alex on for Paul I, just a couple of questions from my thanks for taking the questions here I guess, the first one kind of related to this hole on the way that you're thinking about partnerships just curious how you're thinking about your AG T program. Given it is another large market indication what are your thoughts as they stand today on a continuing.

Developing on your own or are looking for partners moving forward and then secondarily I was hoping you could give us a little bit more background on your April one program with Astrazeneca Ah. Thanks.

Brett P. Monia: [inaudible] Happy to do so. Alex, our strategy on partnering for large, broad indications remains the same, except that, you know, we're not going to be taking on very large phase three studies of the type that an antihypertensive would entail, similar to when, as we did for Lp little A, we'll seek a partner at the appropriate time. With that said, we're in no rush. We're in no hurry.

Sure.

Me too so.

Alex our our strategy.

On partnering for large broad indications remains saying, except that is you know, we're not going to be taking on.

Very large phase three studies of the site type that anti hypertensive would entail similar.

As we've done for helping that away, we'll see can partner to appropriately.

With that said, we're in that rush or no hurry, we have the financial strength to be able to bring these these large indications through clinical proof of concept and as far as we need to take them to maximize the economics that comes through I own is ER franchise partner.

Brett P. Monia: 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 for any such partner in the future, and so you know 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? Oh, ABLE-01. Thank you.

Future.

And so you know.

We're window area partner in this program. We're excited about what we're seeing and we're looking forward to I'm sharing some of the results. The this study. These studies later this year.

And what was the second one Oh able and thank you Oh, yeah. If oil is very exciting. It's a it's a program that we initiated at Ioannis a number of years ago. It's a it's a it's a target as and so it's a genetic linked to.

Brett P. Monia: Yeah, ABLE-01 is very exciting. It's a program that we initiated at Ionis a number of years ago. It's a target that has 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 published on this target, I forget where, but we published on it about a year or so ago. Some very exciting data and models of ApoL1 that we've, 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 highlighted it in their own earnings call, so they're excited.

Kidney disease, or SGS and other kidney diseases, we we didn't enter into our cardio metabolic collaboration after we did a lot of work you're at I. onus on this target we published on this target I forget where but we published on about a year.

Or so ago, some very exciting models people not one that weve kidney disease that we develop.

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

Brett P. Monia: Great, thanks.

Great. Thanks.

Next question comes from Jessica Fye JP Morgan. Please go ahead.

Operator: The next question comes from Jessica Fye of J.P. Morgan. Please go ahead.

Jessica Fye: Hey guys, good afternoon. Thanks for taking my question. Um, my question is on the Acromegaly program heading into

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 associates either from a mechanistic perspective or the target patient population. Thank you.

Jessica Fye: This product will differentiate itself from competitors, namely the SSAs.

Richard S. Geary: Thank you for joining us.

Richard S. Geary: Richard, would you like to take this one?

Richard S. Geary: Sure, I'd be happy to. So the program, the proof of concept study, is in patients who have uncontrolled IGF-1 on 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 therapy. So I think what you'll want to see is IGF-1 control with the addition of our acrometallic GHR, like a program. It also has a much improved tolerability profile for this compound, and we are also initiating monotherapy studies 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 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.

Richard would you like exactly sure I'd be happy too. So the the program. The proof of concept study is in patients who are uncontrolled I'd F. One on.

The some added some asked analogs and and so I'm quite a number it turns out.

As much as 40, 50% of these patients don't get.

Well control on their current therapies.

So I think what you want to see is I T F. One.

Control.

With with the addition of our ACRA metallurgy THR Lika program. It's also a much improved tolerability profile for this compound and we are also initiating.

[noise] monotherapy studies in this and in patients who are not on SSR else or our weaned off and come onto this program. So the the program a staggered a bit with the monotherapy coming after they the add on but we're excited about.

What we're seeing and hope to have some some real data in the second after this year.

Yeah, I'm just symphony So I went and that was Craig and I would say that we've done some initial work on oncology the product profile in early on in addition to be idea when control. We're also seeing there's an unmet need on just stop breaks for sometime.

Onaiza Cadoret: Yeah, Jessica and Onaiza, that was...

Onaiza Cadoret: That was great, and I would just say that early on, in addition to the IGF-1 control, we're also seeing there's an unmet need for just breaks for symptoms, and we believe that with our product, we can actually offer both, and along with the monthly dosing, that is turning out to be quite a differentiating profile. Good, thank you.

And we believe like without how quick actually on for patent and along with the monthly does seem that is turning out to get quite a differentiated profile.

Great. Thank you.

Jessica Fye: Anything else, Jess?

Anyones guess.

Okay. That's it thank you.

Jessica Fye: That's it. Thank you. The next question comes from Manny Florohar of SVB Reerink. Please go ahead.

<unk>.

The next question comes from many of our a heart of SBB Leerink. Please go ahead.

Manny Florohar: Good afternoon, everyone. This is Rick on the call from NAMI.

Good afternoon, everyone. This is Rick on the call for money well, thanks for taking your questions.

Rick: Thanks for taking our questions. So first, I just wanted to touch on the oral ASO candidate again. Is the timing of that first clinical data disclosure going to be controlled by AstraZeneca, or is that a joint decision between the two companies? Secondly, there is a broader question about the opportunity for oral ASOs. How do you think of an ideal therapeutic indication or end market for oral ASOs, and how does this compare to the way you think about targets for your conventionally administered drugs?

So first I just wanted to touch on the oral is so candidate again. This is the timing of that first critical did you disclose you're going to be controlled by Astra Zeneca, where does that a joint decision between the two companies and the secondly.

Hi, My broader question about the opportunity for oral ensues huh.

So how do you think of an ideal therapeutic indication and market for oral is how does this compare to the way to think about targets for your conventionally administered drugs.

So the the decision on the timing to talk about the program is joined I own as an estrogenic 'em. We work very closely together on this program in our other cardiometabolic programs as for the.

Brett P. Monia: So, the decision on the timing to talk about the program is joint. Ionis and AstraZeneca work very closely together on this program and our other cardiometabolic programs. As for the focus, really, is on, you know,

You know [noise].

Potential.

To exploit take advantage of progress, we're making an oral further programs, we're ready moving other programs over programs that are non partnered that have gen 2.5, like a chemistry.

Brett P. Monia: There are areas where oral would provide a significant competitive advantage or convenience advantage for patients, such as chronic lung diseases where patients are going to be on therapy for long periods of time. Diseases where, you know, it could be a severe disease but patients are generally asymptomatic until they have an event of some sort will be, you know, particularly well-suited to an orally-administered agent, and in areas where we're competing with other technologies or other medicines where we think oral can provide a competitive advantage.

We're identifying gen 2.5, like like us for existing programs as potential problem loans and the focus really is on you know.

Areas, where oral would provide a significant either competitive advantage or convenience advantage for patients your chronic longs diseases, where patients are gonna be on on therapy for long periods of time.

Diseases, where you know the it could be a severe disease, but agents are generally asymptomatic until they have an event some store.

Will be particularly well suited for anoro either minister age.

And in areas, where I'm, we're competing.

ER with some with other technologies or other other other medicines, where we think we're open that provided a competitive advantage.

Rick: Great. That's it from us. Thank you.

Great that's it from us.

Okay. Thank you.

Operator: The next question is from Ritu Baral of Cowan. Please go ahead.

Next question is from Ritu Baral of Cowen. Please go ahead.

Ritu Baral: Hey guys, thanks for taking the question. I want to just follow up on the Roche Huntington data release. But I think you mentioned that they have said phase three data is in 2022. But I'm wondering about any interim data we could get in the meantime, whether it's an interim look at phase three or the phase one data for open label extension. Any timelines for that? And then I've got a follow-up.

I think also translates into question what can you just follow up.

Roche Huntington data really but I think you mentioned that they have some phase three data.

Only 22, but I'm wondering about <unk> interim data, we could get in the meantime, whether it's a an interim look into phase three where the sees when too.

Extension data.

Any timelines for that you know kind of fall.

Brett P. Monia: 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 has completed, and they're evaluating the data. Now, along with the Natural History study, which has not been completed yet, but will be completed this year or early next year, and then they'll share that data alongside the OLE data next year.

So roche's not indicated in any way that there would be an interim look at the phase three data before the phase three data readout, and which is expected to 2022.

Next year or they are planning to share the open label extension data from our phase one two study which is that an 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 is which will complete this year.

Early next year, and then they'll sure that data alongside the oil data next year. So that's why what to expect for next year.

Ritu Baral: Got it. And then I can can

Got it and then can you go into maybe little more detail about the PNM too.

Brett P. Monia: Can you go into a little more detail about the DNM2 program for central nuclear myopathy? You indicated that Phase 1-2 started. The trial design and the timelines for that data, and maybe just how you look at the indication.

Central nuclear Myopically you indicated the phase one two started can you give us.

The trial design and the timelines for that data and maybe just and how you look at the kitchen.

Brett P. Monia: So this is with our partner Dynacure. Dynamine II is the target. And it's for the treatment of all forms of central nuclear myopathies. They published with us, in a joint publication, some very exciting preclinical data and models of CNM. This is a muscle target, and based on that data, we launched into clinical development. The study design is in older patients with CNM, and these patients have had a long history, a natural history. We have a substantial amount of natural history data for each of these patients that are entering the study, so there's a lot of information to build off of in that study. And it's open label, so all patients are getting the drug. And then the goal is to move it to infants next year, which is the more severe form of CNM.

So this is with our partner Diagnocure.

I need to is the target and its for its for the treatment of all forms of central nuclear biographies, they publish with US a joint publication, some very exciting preclinical data models of see an M. This is a muscle target and based on that data.

We would watched into clinical development. The study design isn't is in older patients would see an M.

And these patients have had along a history natural history, where we have a substantial amount natural history data for each of these patients that are entering study. So there's a lot of information to build up in that study.

And its open label. So all patients are getting are getting to drug then the goal is to move into infants next year, which is more severe foreign cnf.

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

Is there a particular biomarker functional marker in these older fishing, that's a 2.2 announcements will pay attention to it.

Richard S. Geary: These will be measures of mobility and Quality of Life. Dynamin 2 is not measurable in the blood, but other biomarkers are under development by Dynacure.

No these would be measures of mobility and and quality of life, the dining and two is not measurable in blood.

The other biomarkers are on the development by dining furniture.

Ritu Baral: Got it. Thanks for taking the questions.

Got it thanks for taking the questions.

Operator: Thanks. Maybe one more question.

Thanks Richard.

Maybe one more question it we're going quite well.

Josh Schimmer: we're

Elizabeth L. Hougen: You're going quite long.

Elizabeth L. Hougen: And the last question today comes from Josh Schimmer of Evercore ISI. Please go ahead.

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

Josh Schimmer: Thanks for putting me in. Just on Axia, 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 and when more aggressive steps should be taken for that part of the business?

Thanks for fitting me in just on actually are the commercial performance has been below expectations from its still a drag on your ability to 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 and when more aggressive steps should be taken for that part of the business. Thanks.

Elizabeth L. Hougen: Thanks, Josh. I'll ask Beth to address that. Congratulations.

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

Elizabeth L. Hougen: Sure. Hey Josh.

Sure Hey, Josh.

Elizabeth L. Hougen: So, you know, as Ixia mentioned on the earnings call yesterday, and we reiterated, we see, you know, we see continued growth for both Tech City and Waylibra as they expand into new markets throughout Europe, as well as in Latin America with PTC. It's, you know, 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, you know, continuing to be sustainably profitable. We, you know, have a stated goal to be sustainably profitable, and we've been able to do that for 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 Ixia and their new management team, with Damien and Kyle Janay, their new commercial chief commercial officers, to build the Tech City and Waylibra franchises. So, stay tuned.

So so you know as as I see you mentioned on their earnings call yesterday, and we reiterated we see you know we see continued growth for both take city and we've ever as they expand into new markets I'm throughout Europe as well, it's in Latin America with PTC. Its you know as you know like it's really quite customary too.

Say that 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 you know we have.

I stated goal to be sustainably profitable and we've been able to hit at the last several years, then we affirmed 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 there.

New management team with aim in AD cloud today, then your commercial Oh, Chief commercial officer, just build the Texadian women are franchise, so less teaching.

Josh Schimmer: Thanks, Josh. Thanks, Beth. Okay, with that, I think we'll wrap it up.

Thank you.

Thanks, Thanks, Josh Thanks that okay with that I think we're wrapping up thanks, everybody again for joining us today I'm feeling really good where we are they own us confident we're taking the necessary steps on chart success. This year.

Brett P. Monia: 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 our continued 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 of yourselves, and we'll talk to you soon. Bye now.

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, we'll take care everybody and we'll talk soon bye now.

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

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