Q4 2021 Ionis Pharmaceuticals Inc Earnings Call

Operator: Good morning, and welcome to the Ionis Pharmaceuticals fourth quarter and full year 2021 financial results conference call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Jennifer Cappuzello, Investor Relations, to lead off the call. Please begin.

Good morning, and welcome to the Ion Us Pharmaceuticals fourth quarter and full year 2021 financial results Conference call.

As a reminder, this call's being recorded.

At this time I would like to turn the call over to Jennifer.

Hello, Investor Relations to lead off the call. Please begin.

Jennifer Cappuzello: Thank you, Anthony. Before we begin, I encourage everyone to go to the investor section of the Ionis website to view the press release and related financial tables we will be discussing today, including a reconciliation of GAAP to non-GAAP financials. We believe non-gap financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website to accompany today's call. With me this morning are Brett Monia, Chief Executive Officer; Beth Hougen, Chief Financial Officer; and Richard Geary, Executive Vice President of Development.

Thank you Anthony.

Let me begin I encourage everyone to go to the investors section on its website and the press release and related financial table.

Right.

Including a reconciliation of GAAP to non-GAAP financials.

We believe non-GAAP financial results better represent the economics.

And how we manage our business.

We have also posted slides on our website, which will accompany today's call.

With me. This morning are <unk>, Chief Executive Officer, Beth Hougen, Chief Financial Officer, Richard Gary Executive Vice President.

Jennifer Cappuzello: And joining us for Q&A are Eric Swayze, Executive Vice President of Research, and Onaiza Cadoret, Chief Product Strategy and Operations Officer. I would like to draw your attention to slide three, which contains our forward-looking statement. During this call, we will be making forward-looking language 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 contained in our SEC filings for additional details. And with that, I'll turn the call over to Brett.

And joining us for Q&A.

Eric Swayze.

Second of Vice President of research, and then Theres, a cat or a chief product strategy and operations officer.

I would like to draw your attention to slide three which contains our forward looking statements.

During this call we will be making forward looking language statements. They are based on our current expectations and beliefs.

These statements are subject to certain risks and uncertainties and our actual results may differ materially.

Courage you to consult the risk factors contained in our SEC filings for additional detail.

And with that I'll turn the call over to Brett.

Brett Monia: Thanks, Jennifer. Good morning, everyone, and thanks for joining us on today's call. We made substantial progress last year toward achieving our vision of becoming a leading fully integrated biotechnology company. We're building our commercial pipeline, advancing and expanding our technology, and moving toward delivering an abundance of new medicines to the market, which together we expect will drive substantial future growth. At our Investor Day late last year, we introduced our go-to-market strategies for our near-term commercial opportunities at Blomtersen, Olosarsen, and Donnie DeLorsen.

Thanks, Jennifer and good morning, everyone and thanks for joining us for today's call.

Brett Monia: And through our strategic collaboration with AstraZeneca to jointly develop and commercialize Eplantersin, which we announced late last year, we bolstered our commercial organization and accelerated preparations for our near-term product launches while also positioning Eplantersin to win in the competitive TTR amyloidosis market. The clinical development of Evwantera Sinola-Sarsen and Donna Dolores also continued to progress well.

We made substantial progress last year toward achieving our vision of becoming a leading fully integrated biotechnology company.

We're building, our commercial pipeline advancing and expanding our technology and moving towards delivering an abundance of new medicines to the market, which together, we expect will drive substantial future growth.

At our Investor Day late last year, we introduced our go to market strategies for our near term commercial opportunities at once.

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And through our strategic collaboration with Astrazeneca to jointly develop and commercialize that one person, which we announced late last year.

Bolstered our commercial organization and accelerated preparations for our near term product launches, while also positioning <unk> to win in the competitive GTR amyloidosis Martin.

The clinical development of <unk> and dawn of doors and also continue to progress well.

Brett Monia: The Phase III Neurotransform study of aflatorcin in patients with TTR polyneuropathy completed enrollment in 2021 and remains on track for data around mid-year, followed by regulatory filing by the end of the year, assuming positive data. And the Phase III Cardiotransform study in patients with TTR cardiomyopathy is also progressing well, with data on track for 2024. We expanded our phase 3 pipeline late last year when we initiated the core severe hypertriglyceridemia study for Olazarsan.

The phase III neuro <unk> transform study of the church in patients with Polyneuropathy completed enrollment in 2021 and remains on track for data around midyear, followed by regulatory filing by the end of the year assuming positive data.

And the phase III cardio transform study in patients with cardiomyopathy is also progressing well with data on track for 2024.

We expanded our phase III pipeline late last year, when we initiated the core severe hypertension Dyslipidemia study for <unk>.

Brett Monia: This was an important step as it expands the Olazarsan phase 3 program beyond FCS to potentially address the more than 3 million patients with severely elevated triglycerides. Importantly, with first mover advantage, we have the potential to deliver a first-in-class medicine to this broad patient population. We plan to report data from our Olizarsin program in patients with FCS next year and in patients with severe hypertriglyceridemia the following year in 2024.

This was an important step as it expands deal absorption phase III program beyond the Fcs to potentially address.

To potentially address the more than 3 million patients with severely elevated triglycerides.

Importantly, with first mover advantage, we have the potential to deliver a first in class medicine to this broad patient population.

We plan to report data from our <unk> program in patients with FCS next year and in patients with severe hypertrophic triglycerides EMEA. The following year in 2024.

Brett Monia: We also initiated the Phase 3 OASIS-HAE study of Donaghue-Larsen inpatients with hereditary angioedema late last year, putting it on track for data also in 2020. Donna Dolorsan has demonstrated a potential best-in-class profile in studies to date.

We also initiated the phase III <unk>.

Study abdominal divorce and in patients with hereditary angioedema.

Last year, putting it on track for data also in 2024.

<unk> has demonstrated a potential best in class profile in studies to date.

Brett Monia: And given the continuing unmet medical need for more effective HAE prophylactic treatments, we see Donna Dilorsan as a very compelling opportunity for Ionis. Additionally, this year, we plan to report additional data from the Phase 2 study for Donald Doloresan and the ongoing Open Label Extension, further demonstrating Donald Doloresan's highly favorable profile based on studies to date. Now looking more broadly at our late and mid-stage programs, beginning with programs from our leading cardiovascular disease franchise. The Phase 3 Healthy Little A Horizons Study of Pella-Carson continues to progress well.

Given the continuing unmet medical need for more effective E prophylactic treatments.

<unk> is a very compelling opportunity for ion is.

This year, we plan to report additional data from the Phase III study for them to worsen in the ongoing open label extension further demonstrating Don Volitions highly favorable profile based on studies to date.

Now looking more broadly.

In mid stage programs, beginning with programs from our leading cardiovascular disease franchise.

The phase III LP Little a horizon study a pellet Carson continues to progress well.

Brett Monia: Novartis reached 50% enrollment last summer, and the study remains on track for data in 2025. Coming up this year, we look forward to several Phase 2B data readouts, including three from our cardiovascular franchise, beginning with data from the Ategian study of ION449, our PCSK9 glycomedicine with AstraZeneca in patients with dyslipidemia at ACC in April.

Novartis reached 50% enrollment last summer and study remains on track for data in 2025.

Coming up this year, we look forward to several phase two b data readouts, including three from our cardiovascular franchise.

Beginning with data from the adhesion study of IL 449, Rpc's canine like a medicine with Astrazeneca in patients with Dyslipidemia at ACC in April .

Brett Monia: Later this year, we expect data for Fesimericin, our Factor 11-like medicine, to bear in patients with end-stage renal disease, and Phase 2B data for Ionis AGT-LRX in patients with treatment-resistant hypertension. Moving to our neurological disease franchise, we further strengthened our leadership position in SMA by advancing a follow-on program to Spinraza with Biogen for the treatment of SMA, which has the potential to We're also pleased that Biogen continues to actively engage with regulatory authorities working towards a potential path forward for TOFRSYN inpatients with SOD1 ALS while continuing to evaluate the data from the Phase 3 Valor Study and the Open Label Extension.

Later this year, we expect data for as a medicine or factor 11, like a medicine with bear in patients with end stage renal disease and phase <unk> data for I own. This agg L. Rx in patients with treatment resistant hypertension.

Moving to our neurological disease franchise, we further strengthened our leadership position in SMA by advancing a follow on program to spin rosin with Biogen for the treatment of SMA, which has the potential to reduce dosing frequency.

We're also pleased that Biogen continues to actively engage with regulatory authorities working towards the potential path forward for <unk> in patients with sod one AOS, while continuing to evaluate the data from the phase III Valor study and the open label extension.

Brett Monia: The other programs in our ALS franchise also continue to progress well, and this includes our C9 ALS program, which is on track for data in the first half of this year. We are also pleased that, based on the findings from the Generation HD1 study, Roche has identified a path forward for Taminersen in patients with Huntington's, with plans to initiate a new phase two study in younger patients with less disease burden.

The other programs in our <unk> franchise also continues to progress well and this includes our <unk> program, which is on track for data in the first half of this year.

We're also pleased that based on the findings from the generation HD. One study Roche has identified a path forward for Tim Anderson in patients with Huntington's disease with plans to initiate a new phase III study in younger patients with less disease burden.

Brett Monia: We look forward to additional updates from Roche later in the year. And in addition to the Spinraza follow-on, we made other important technology advancements throughout last year, including advancements in microchemistry and in the potential identification of a new backbone chemistry, as we highlighted at our investor day in December. Importantly, we achieved all these pipelines and technological advances while strengthening our overall financial position and substantially exceeding our 2021 financial guidance. And looking ahead, we expect 2022 to be a busy year with a steady cadence of key catalysts that will keep moving us closer to our goal of becoming a leading fully integrated biotechnology company.

Look forward to additional updates from Roche later later in the year.

And in addition to the spin Rozzer follow on we made other important technology advancements throughout last year, including advancements in chemistries and into potential identification of a new backbone chemistry as we highlighted at our Investor day in December .

Importantly, we achieved all of these pipeline and technology advances, while strengthening our overall financial position and substantially exceeding our 2021 financial guidance.

Looking ahead, we expect 2022 to be a busy year with a steady cadence of key catalysts.

That will keep moving us closer to our goal of becoming a leading fully integrated biotechnology company.

Brett Monia: And with that, I'll turn the call over to Beth to review our 2021 financial results and our 2022 financial guidance, and Richard will discuss our recent key pipeline achievements and highlight pipeline catalysts for the year ahead. After Richard, I'll wrap up our prepared remarks before taking your questions.

And with that I will turn the call over to Beth to review, our 2021 financial results and our 2022 financial guidance.

And Richard will discuss our recent key pipeline achievements and highlight pipeline catalysts for the year ahead.

After Richard I'll wrap up our prepared remarks before taking your questions now over to Beth. Thank.

Beth Hougen: Thank you, Brett. I'm pleased to report we ended 2021 with a non-GAAP net income of $116 million based on revenues of more than $800 million and non-GAAP operating expenses of $695 million. These results significantly exceeded our 2021 revised guidance. Additionally, we remain well capitalized with 2021 year-end cash and investments of $2.1 billion. The key element of our strong financial foundation is our ability to consistently generate substantial revenue from numerous diverse sources. In 2021, we earned more than $340 million in revenue from our marketed products, with the majority coming from Spinraza. Spinraza's global sales were $1.9 billion in 2021, from which we earned more than $265 million in royalty revenue. Benraza global sales were down 7% year-over-year, primarily due to increased competition in the U.S.

Thank you Matt I am pleased to report we ended 2021 with non-GAAP net income of $116 million based on revenues of more than $800 million and non-GAAP operating expenses of $695 million.

These results significantly exceeded our 2021 revised guidance.

Further we remain well capitalized with 2021 year end cash and investments of $2 $1 billion.

The key element of our strong financial foundation is our ability to consistently generate substantial revenue for numerous diversified.

In 2021, we earned more than $340 million in revenue from our marketed products.

With the majority coming from Spain.

The massive global sales were $1 9 billion for 2021 from which we earned more than $265 million in royalty revenue.

<unk> global sales were down 7% year over year, primarily due to increased competition in the US However, we were encouraged that discontinuation decreased compared to Q3.

Beth Hougen: However, we were encouraged that discontinuations decreased compared to Q3. And in the rest of the world, Benraza sales increased year-over-year, primarily due to an increase in sales volume, particularly in Latin America and certain other markets. IGEN is continuing to evaluate Spinraza in the ASCEND, DEVOTE, and RESPONSE studies. These post-marketing studies are an important element of Viage's ongoing work to further inform SMA treatment and address the remaining unmet needs of SMA patients of all ages. With the substantial and growing body of evidence supporting SINRAZA's proven profile, we continue to see a bright future for SINRAZA. Tegceti and Wiliwra generated more than $55 million of revenue this year.

And then the rest of the world and lots of sales increase year over year, primarily from an increase in sales volume, particularly in Latin America and certain other markets.

Biogen is continuing to evaluate its been rather India and devote and respond to study these.

These post marketing studies are an important element of Biogen ongoing work to further inform SMA treatment and address the remaining unmet need that many patients about Egypt.

But the substantial and growing body of evidence supporting and Ross has proven profile, we continue to see a bright future for Scott.

Thanks, Eddie and we live Brad generated more than $55 million of revenue. This year as a reminder, we completed the transition of our commercial operations for these medicines.

Beth Hougen: As a reminder, we completed the transition of our commercial operation for these medicines to Sobe over the course of 2021. Therefore, our 2021 revenue was a mix of product sales and distribution fees based on product sales. We are pleased that both medicines will continue to expand into new markets throughout 2021 through the efforts of our partners, SOBE and PTC. Last year, we earned R&D revenue of more than $465 million, representing nearly 60% of our total revenue.

So the over the course of 2021.

Therefore, our 2021 revenue was a mix of product sales and distribution fees based on right now.

We are pleased that both medicines continue to expand into new markets throughout 2021 through the efforts of our partners Tobey and PTC.

Last year, we earned R&D revenue of more than $465 million, representing nearly 60% of our total revenue.

Beth Hougen: Most of our R&D revenue came from a number of different partners, as together we advanced nearly 20 programs. The $200 million upfront payment we earned from our affluent person collaboration with AstraZeneca was an important contributor to our total revenue. Revenue from our strategic collaboration with BiGEN was also an important contributor to our total revenue.

Most of our R&D revenue came from a number of different partners as together, we advance nearly 20 program.

The $200 million upfront payment, we earned from our Ethicon Trust and collaboration with Astrazeneca was an important contributor to our total revenue.

Revenue from our strategic collaboration with Biogen was also an important contributor to our total revenue.

Beth Hougen: We earned more than $160 million from Biogen for advancing numerous neurological programs, including the $60 million license fee for our SMA follow-on. We have a large and growing pipeline of programs advancing under our Biogen collaboration, all with the potential to generate substantial revenue and cash flows as they advance. We reported non-GAAP operating expenses of $695 million, which was a 9% increase compared with 2020.

We earned more than $160 million from Biogen for advancing numerous neurological program.

Including the $60 million licensee licensee for SMA follow on medicine.

We have a large and growing pipeline of programs advancing under our Biogen collaboration all with the potential to generate substantial revenue and cash flows as they advance.

We reported non-GAAP operating expenses of $695 million, which was a 9% increase compared with 2020.

Beth Hougen: R&D expenses increased by 33%, driven in large part by the six phase three studies we are currently conducting. As these programs continue to advance, we anticipate our R&D expenses will continue to increase. Last year, we also invested in internal and external technological advances. Of note, we obtained exclusive rights to Bicycle Therapeutics' innovative peptide technology. This, together with our internal efforts and other external partnerships, positions us to meaningfully expand our drug discovery capabilities and deliver many more transformational medicines to the market. Our SG&A expenses decreased by 37% compared with 2020, driven by the substantial savings we realized from the Axia integration and Sobe transaction.

R&D expenses increased by 33% driven in large part by the SEC.

Phase III studies, we are currently conducting.

As these programs continue to advance we anticipate our R&D.

The increase.

Last year, we also invested in internal and external technology advancement.

Of note, we obtained exclusive rights to bicycle therapeutics innovative peptide technology.

This together with our internal efforts and other external partnerships.

<unk> us to meaningfully expand our drug discovery capability and deliver many more transformational medicines to the market.

Our SG&A expenses decreased by 37% compared with 2020, driven by the substantial savings we realized from the integration and cerave transaction.

Beth Hougen: And, as planned, we are reinvesting these savings, as I will describe next. Now, turning to our 2022 financial guidance. We are projecting to earn more than $575 million in revenue, incur operating expenses in the range of $825 to $850 million, and end 2022 with a net loss of less than $275 million, all on a non-GAAP basis. Additionally, we are projecting to end 2022 with a healthy cash balance of approximately $1.7 billion. Our long history of financial responsibility has served us well.

And as planned we are reinvesting these savings as I will describe now.

Now turning to our 2022 financial guidance.

We are projecting to earn more than $575 million in rebate.

Incur operating expenses in the range of $825 million to $850 million.

And in 2022 with a net loss of less than $275 million on a non-GAAP basis.

Additionally, we are projecting to end 2022, with a healthy cash balance of approximately $1 7 billion.

Our long history of financial responsibility has served us well.

Beth Hougen: At a time when we need to increase our spending, we have the substantial financial resources to underwrite these investments necessary to achieve our goal of becoming a leading, fully integrated biotech company. Our 2022 guidance reflects our continued ability to generate significant revenue and make those necessary investments to realize our goal while remaining well-capitalized with a healthy cash balance. Importantly, our 2022 guidance demonstrates our commitment to advancing our near-term commercial opportunities, building our Ionis-owned pipeline, and ensuring our platform remains a key competitive advantage.

At a time when we need to increase their spending we have the substantial financial resources to underwrite these investments necessary to achieve our goal of becoming a leading fully integrated biotech company.

Our 2022 guidance reflects our continued ability to generate significant revenue and make those necessary investments to realize our goals, while remaining well capitalized with a healthy cash balance.

Importantly, our 2022 guidance demonstrates our commitment to advancing our near term commercial opportunity Bill.

Building, our I own its own pipeline and ensuring our platform remains a key competitive advantage.

Beth Hougen: Before I go into more detail on each of the elements of our 2022 Financial Guidance, I would first like to spend a few minutes explaining how we will reflect the cost sharing provisions of our Appalachian collaboration with AstraZeneca in our financials. Under our Eplen-Turson Agreement, AstraZeneca is responsible for 55% of the global phase 3 program costs, including internal and external costs as well as CMC costs. We are leading and conducting the ongoing global phase three program.

Before I go into more detail on each of the elements of our tonnage 22 financial guidance.

Beth Hougen: For that reason, we will recognize the 55% reimbursement we received from AstraZeneca as revenue in the same period we recognize the related development expenses. Our R&D expenses will continue to include the development expenses we are incurring for Appalachian Tourism.

I would first like to spend a few minutes explaining how we will reflect the cost sharing provisions of our Apple interest in collaboration with Astrazeneca in our financials.

Under our <unk> agreement Astrazeneca is responsible for 55% of the global Phase III program costs.

Including internal and external costs as well as CMC costs.

We are leading and conducting the ongoing global phase III program.

For that reason, we will recognize the 55% reimbursement we received from Astrazeneca as revenue in the same period, we recognize the related development expenses.

Our R&D expenses will continue to include the development expenses, we are incurring gravlin person.

Beth Hougen: AstraZeneca is also responsible for a large majority of the U.S. medical affairs costs. Since we and AstraZeneca are sharing responsibility for medical affairs activities in the United States, Our R&D expenses will include 100% of Ionis's Incurred Medical Affairs expenses net of any cost sharing payments we receive from AstraZeneca. AstraZeneca is also responsible for a large majority of the U.S. commercial costs for appleters. Because we in AstraZeneca are also sharing responsibility for commercialization activities in the United States, our SG&A expenses will include 100% of Ionis' incurred Eplantersan commercialization expenses.

Astrazeneca is also responsible for a large majority of the U S Medical affairs costs.

Since we and Astrazeneca are sharing responsibility for medical affairs activities in the United States.

Our R&D expenses will include 100% of I own it's incurred medical affairs expenses.

Net of any cost sharing payments we received from Astrazeneca.

Astrazeneca is also responsible for a large majority of the U S commercial costs for a blood test that.

We and Astrazeneca are also sharing responsibility for commercialization activities in the United States.

Our SG&A expenses will include 100% of violence is incurred a blood test and commercialization expenses net of any cost sharing payment we received from Astrazeneca.

Beth Hougen: Net of any cost-sharing payments we receive from AstraZeneca. As a reminder, AstraZeneca is solely responsible for costs associated with bringing Eplantersan to market outside the United States. Importantly, these cost-sharing payments provide us with substantial resources to scale our capabilities for the U.S. launch of Apple's first, in addition to our upcoming planned launches for Ola Darsan and Donita Larson. Beginning with our Q1 earnings, we plan to provide a table of our expenses and the cost-sharing payments we receive from AstraZeneca each quarter. Now I would like to provide a bit more color on our 2022 financial guide. We are projecting another year of generating revenue from multiple diverse sources.

As a reminder, astrazeneca is only responsible for costs associated with bringing up on tourists into market outside the United States.

Importantly, these cost sharing payments provide us with substantial resources to scale our capabilities for the U S launch of <unk> and.

In addition to our upcoming planned launches for all the documents and the need to learn.

Beginning with our Q1 earnings we plan to provide a table of our expenses and the cost sharing payments, we received from Astrazeneca each quarter.

Now I would like to provide a bit more color on our 2022 financial guidance.

We are projecting another year of generating revenue from multiple diverse sources.

Beth Hougen: We have a substantial and sustainable base of commercial revenue with Spinraza Royalties as the cornerstone. We also have a substantial and sustainable base of revenue from our partnership that we expect will contribute meaningfully to our 2022 revenue. Year over year, the composition of our R&D revenue from our partnerships may shift, but the sustainability of that revenue is constant. As we have always done, our R&D revenue is probabilized based primarily on the anticipated timing of the many different milestone payments we expect to achieve as we advance our partner program.

We have a substantial and sustainable base of commercial revenue.

I'd, rather royalties as the cornerstone.

We also have a substantial and sustainable base of revenue from our partnership that we expect will contribute meaningfully to our 2022 revenue.

Year over year, the composition of our R&D revenue from our partnerships may ship.

This inability of that revenue is.

As we have always done our R&D revenue is probable line based primarily on the anticipated timing of the many different milestone payments, we expect to achieve as we advance our partner programs.

Beth Hougen: Additionally, our R&D revenue will also include the reimbursements we will receive from AstraZeneca for Appalach-Tursyn collaboration, as I mentioned a few moments ago. Importantly, through our multiple streams of revenue, we can fund a large portion of our operating expenses.

Additionally, our R&D revenue will also include the reimbursement we will receive from Astrazeneca for Aflac person collaboration as I mentioned, a few moments ago.

Importantly through our multiple streams of revenue, we can fund a large portion of our operating expenses.

Beth Hougen: This year, we will be advancing more late-stage development programs than ever before. This includes the six Phase III studies and two open-label extension studies we are currently conducting. We also plan to initiate new studies supporting our Phase III programs, including additional open-label extension studies. Our R&D expenses will include increased spending for CMC activities and medical affairs activities to support Appalachians Olaf Olisarsson and Janita Larson. While a large percentage of our R&D expense relates to our late-stage medicine, we also will invest in our early and mid-stage pipeline to position us to deliver an abundance of new marketed products going forward.

This year, we will be advancing more late stage development programs than ever before.

This includes the six phase three studies and two open label extension studies, we are currently conducting.

We also plan to initiate new studies supporting our phase III program, including additional open label extension study.

Our R&D expenses will include increased and for CMC activities and medical affairs activities to support Epsilon, Tristan I'll, let Dr. Anthony to worsen.

While a large percentage of our R&D expense related to our late stage medicines. We also will invest in our early and mid stage pipeline to position us to deliver an abundance of new marketed products going forward.

Beth Hougen: And we expect to continue to expand and diversify our technology, ensuring we remain innovative and competitive. As a result of these investments, we expect our R&D expenses to increase approximately 25% to 30% this year compared to last year.

And we expect to continue to expand and diversify our technology, ensuring we remain innovative and competitive.

As a result of these investments we expect our R&D expenses to increase approximately 25% to 30% this year compared to last year.

Beth Hougen: We are also investing in our commercial readiness efforts to prepare to bring Eplantursen, Olazarsen, and Donatalorsen to the market. With the cost-sharing payments we will receive from AstraZeneca, along with realizing a full year of savings from our SOBE transaction and the integration of Axia, we expect our SG&A expenses this year to be in line with last year's.

We're also investing in our commercial readiness efforts to prepare to bring up one Tristan OLED <unk> and the need to listen to the market.

With the cost sharing payments, we will receive from Astrazeneca.

Along with realizing a full year of savings from our <unk> transaction and the integration of vaccines.

We expect our SG&A expenses this year to be in line with last year.

Beth Hougen: Our financial strength has been an enduring quality of Ionis for many years, with $2.1 billion in cash and a substantial and sustainable base of commercial and R&D revenue. Our solid financial foundation enables us to invest as needed to drive significant future growth. In doing so, we expect to deliver substantial value for the patients who rely on us and our shareholders. And with that, I'll turn the call over to Richard. Well, thank you, Beth.

Our financial strength has been an enduring quality of Iona for many years.

With $2 $1 billion of cash and a substantial and sustainable base of commercial and R&D revenues.

Our solid financial foundation enables us to invest as needed to drive significant future growth.

In doing so we expect to deliver substantial value for the patients who rely on us and our shareholders.

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

Richard Geary: We certainly achieved many pipeline advancements in 2021, with several key pipeline updates taking place even since our last call. We now have six medicines in our Rich Phase III pipeline for eight indications, including our three near-term commercial opportunities, Eflontersan, Olisarsan, and Donidolorsan, which alone address five separate indications. As both Brett and Beth mentioned, we're jointly developing and preparing to commercialize F1 tercin with AstraZeneca. In our collaboration, we are continuing to lead and oversee the Global Phase III studies, which continue to progress well and remain on track. We were pleased that eflanthirazine was granted the orphan drug designation by the FDA, underscoring the significant unmet need that remains for patients with TTR amyloidosis.

Well, thank you Beth.

We certainly achieved many pipeline advancements in 2021 with several key pipeline updates taking place even since our last call.

We now have six medicines in our rich phase III pipeline for eight indications, including our three near term commercial opportunities upon tourism, although <unk> and <unk>.

Which alone address five separate indications.

As both breadth and depth mentioned.

Equally developing and preparing to commercialize a bunker issue with Astrazeneca.

Under our collaboration we are continuing to lead and oversee the global phase III studies, which continued to progress well and remain on track.

We were pleased that <unk> was granted orphan drug designation by the FDA underscoring the significant unmet need that remains for patients with GTR amyloidosis.

Richard Geary: This sets us up nicely for our planned data readout of the Phase 3 Neuro T-Transform study in patients with TTR polyneuropathy and planned filing for regulatory approval in the second half of this year, assuming positive data. For Osarsen, we have a broad development program designed to fully realize its potential to address a range of patients at risk for triglyceride-driven disease who today have limited treatment options. The BALANCE-SCS study, our first phase 3 study of Olofsarsen, remains on track for data next year.

This sets us up nicely for our planned data readout.

The phase III neuro <unk> transform study in patients with <unk> Polyneuropathy and planned filing for regulatory approval in the second half of this year.

Positive data.

Yeah.

<unk>, we have a broad development program designed to fully realize its potential to address a range of patients at risk for triglyceride driven disease.

Today have limited treatment options.

Balance FCS study, our first phase III study of <unk>.

It remains on track for data next year.

Richard Geary: And recently, we initiated a second phase three study of olfsarsen, our core study in patients with severe hypertriglyceridemia with triglycerides over 500 milligram per deciliter. Severe Hydroglycemia represents a substantial opportunity with more than 3 million patients in the U.S. alone. Data from a Phase 2 study of olisarcin in patients with moderate hypertriglyceridemia at high risk for or with established cardiovascular disease were also recently published in the European Heart Journal. The data showed that treatment with olisarcin resulted in substantially reduced ApoC3, triglycerides, and atherogenic lipoproteins.

And recently, we initiated a second phase III study of all the stars in our core study in patients with severe hypertrichosis demeo with triglycerides over 500 milligram per deciliter.

Severe high triglycerides are.

Ah represents a substantial opportunity with more than 3 million patients in the U S law.

Data from the Phase II study of <unk> in patients with moderate hi, Patrick hyper triglycerides EMEA at high risk for or with established cardiovascular disease.

We're also recently published in the European Heart Journal.

The data showed that treatment with <unk>.

Results in substantially reduced debt by three triglycerides and atherogenic proteins.

Richard Geary: Importantly, more than 90% of those treated with the monthly 50 milligram dose achieved fasting triglyceride levels within the normal range. As a reminder, in addition to the 50 milligram monthly dose, we are also evaluating an 80 milligram monthly dose in both our core and balance phase three studies, which we expect to provide even greater triglyceride reduction. We've also made significant progress with our Denis Larson development program for the treatment of hereditary angioedema. We initiated the phase three OASIS-HAE study of Dunne-Larsen, with data expected in 2024.

Importantly, more than 90% of those treated with monthly 50 milligram dose achieved fasting triglyceride levels within the normal range. As a reminder, in addition to 50 milligram monthly.

We are also evaluating an 80 milligram monthly dose in both our core and balanced phase III study, which we expect to provide even greater triglyceride reduction.

We've also made significant progress with our Denise Morrison development program.

For the treatment of hereditary angioedema, we initiated the phase III Oasis HIV study is done the Larson with data expected in 2024.

Richard Geary: We also presented positive phase two results at the ACAAI annual meeting, demonstrating rapid and sustained reductions in HAE attacks with mean reductions of up to 97 percent with a favorable safety and tolerability profile, leading us to believe that the needle or arsen could be a best in class prophylactic treatment for patients with HAE. Now to review our recent progress from our leading cardiovascular and neurological disease franchise, starting with cardio at AHA in November, our partner AstraZeneca presented new data from a multiple ascending dose study of ION449 targeting PCSK9 in patients with dyslipidemia on stable statin therapy.

We also presented positive phase II results at the AC.

<unk> annual meeting demonstrating rapid and sustained reductions in HAE attacks.

Mean reductions excuse me of up to 97% with a favorable safety and Tolerability profile.

Leading us to believe that the needle horse and could be a best in class prophylactic treatment for patients with HIV.

Richard Geary: In the study, ION449 demonstrated robust and sustained reductions in PCSK9 and LDL-C, with mean PCSK9 reductions of up to 95% and LDL-C reductions of up to 73% and favorable safety and tolerability. Coming up at ACC in April, we look forward to data from a Phase 2B adhesion study of ION449 in patients with dyslipidemia. We expect safety and efficacy data from adhesion, which was conducted in a similar patient population, dyslipidemia patients on moderate or high-intensity stem therapy, to be highly consistent with the previously reported med study and to continue to support the potential for this medicine to be best-in-class for LDL-C production.

Now to review, our recent progress from our leading cardiovascular and neurological disease franchise, starting with cardio at IHA in November our partner Astrazeneca presented new data from our multiple ascending dose study of ion for 49 targeting <unk> canine in patients with <unk>.

This EMEA on a stable statin therapy.

In this study ion for nine demonstrated robust and sustained reductions in tcf's canine and ldlc.

With named Pcs canine reductions of up to 95%.

And LDL C reductions of up to 73% and favorable safety and Tolerability.

Coming up at ACC in April we look forward to data from phase <unk>.

Fusion study of ion for four nine in patients with Dyslipidemia, we expect safety and efficacy data from adhesion, which was conducted similar patient population.

The demerger of patients on moderate or high intensity statin therapy to be highly consistent with the previously reported Mad study and to continue to support the potential for this medicine to be best in class for Ldlc reduction.

Richard Geary: We also had several recent achievements in our leading neurological disease franchise. Early this year, we announced the advancement of Ion 306, our follow-on treatment to Spinraza, further enhancing our leadership position in SMA. This significant technology advancement is based on novel Ionis chemistry that includes enhanced potency and duration of action.

We also had several recent achievements and our leading neurological disease franchise early this year, we announced the advancement of ion 306 are.

Our follow on treatment to spin roster further enhancing our leadership position in SMA.

This significant technology advancement is based on novel <unk> chemistry that includes enhanced potency and duration of action and based on our preclinical data, we believe ion three or six offers the potential to substantially extended dosing intervals.

Richard Geary: And based on our preclinical data, we believe Ion 306 offers the potential to substantially extend dosing interval. We have also recently initiated a phase 1, 2 study in patients with Angelman syndrome, a rare genetic neuromuscular disease that presents in early childhood, resulting in profound developmental delays and frequent and severe seizures. We at Niogen remain encouraged by the data from the Phase III Valor study of Toversen in patients with SOD1 ALS, which showed signs of reduced disease progression across multiple secondary and exploratory.

We also recently initiated a phase one two study in patients with Angelman syndrome, a rare genetic neuromuscular disease.

Presents an early childhood, resulting in profound developmental delays and frequent and severe seizures.

We and Biogen remain encouraged by the data from the Phase III <unk> study October seven in patients with sod one AOS.

Which showed signs of reduced disease progression across multiple secondary and exploratory endpoints.

Richard Geary: Biogen continues to analyze results from the Phase III study and collect new data from the ongoing Open Label Extension study. And importantly, Biogen remains actively engaged with regulators to determine the next steps for this medicine. And in addition, the ATLAS pre-symptomatic study continues to enroll patients. We're also pleased that Roche has identified a potential path forward for telomeres. Findings from the post-hoc analysis of the phase 3 generation HD1 study show that dominersin may benefit younger adult Huntington's disease patients with less disease burden.

Biogen continues to analyze results from the phase III study and collect new data from the ongoing open label extension study and importantly, Biogen remains actively engaged with regulators to determine the next steps for this medicine.

And in addition, the Atlas III symptomatic study continues to enroll patients.

We're also pleased that Roche has identified a potential path forward for <unk>.

Richard Geary: Based on these findings, Roche plans to initiate a new phase 2 study in this patient population. We're encouraged by this important step for pulmonary function and look forward to seeing additional data from the post hoc analysis and learning more about the design of the phase 2 study from Roche later this year. Now turning to 2022.

Findings from the post hoc analysis of the phase III generation HD one study.

So that <unk> may benefit younger adult Huntington's disease patients with less disease burden based on these findings Roche plans to initiate a new phase II study in this patient population.

We're encouraged by this important step fulfillment hersom and look forward to seeing additional data from the post hoc analysis and learning more about the design of the phase II study from Roche later this year.

Richard Geary: This year, we have a deep pipeline of mid and late stage medicines with at least nine mid and late stage data readouts highlighted by EplanTurk. We are planning for phase three data from the NeuroT Transform study mid-year. Our joint Ionis and AstraZeneca team is working diligently and collaboratively to prepare a file for regulatory approval in the second half of this year. And, of course, the teams are already preparing for the commercial launch of Implinter.

Now turning to 2022 this year, we have a deep pipeline of mid and late stage medicines with at least nine mid and late stage data readouts highlighted by up long term.

We are planning for the phase III data from the neuro <unk> transform study mid year are joined <unk> and Astrazeneca team are working diligently and collaboratively to prepare a file a regulatory approval in the second half of this year and of course the teams are already preparing.

For the commercial launch of <unk>.

Richard Geary: We also have the potential to further expand our Rich Phase 3 pipeline as we look forward to four Phase 2b data readouts this year alone. As I just mentioned, we look forward to Phase 2B data from our PCSK9 drug, ION449, at ACC in April. We expect GSK to report data from the Phase 2b be clear study of Bupiravirin in patients with chronic hepatitis B.

We also have the potential to further expand our rich phase III pipeline as we look forward to four phase II B data Readouts this year alone.

As I just mentioned, we look forward to phase <unk> data from our Pcs canine drug ion for four nine at ACC in April .

We expect GSK to report data from the phase to be clear.

Our study of <unk> in patients with chronic hepatitis D.

Richard Geary: We also expect Bayer to report data from the Phase 2b RETHINK-ESRD study of fesomersin in patients with end-stage renal disease, and we're planning to report data from our Phase 2B study of Ionis AGT-LRX in patients with treatment-resistant hypertension. In addition to our four Phase 2b data readouts, we also expect data from multiple Phase 2 studies this year, including Ionis C9 data in patients with C9 ALS, and Donita Larson data including additional results from the Phase 2 study and later data from the OLA or Open Label Extension Study.

We also expect Bayer to report data from the phase two B rethink ESR D study of <unk> in patients with end stage renal disease.

And we're planning to report data from from our.

Phase <unk> study of <unk> in patients with treatment resistant hypertension.

In addition to our four phase III data Readouts. We also expect data from multiple phase II studies this year, including <unk> nine data in patients with <unk>.

And Donegal orphan data, including additional results from Phase II study and later data from the OLED or open label extension study.

Richard Geary: We are also planning to initiate several key studies this year focused on our cardiovascular and neurology franchises to further advance and expand our rich pipeline. Furthermore, we anticipate making additional technological advancements, which we hope to share with you later this year. And with that, I'll turn the call back over to Brett to close this portion of the call.

We are also planning to initiate several key studies this year focused on our cardiovascular and neurology franchises to further advance and expand our rich pipeline.

Further we anticipate making additional technology advancements, which we hope to share with you later this year.

And with that I will turn the call back over to Brett to close this portion of the call.

Brett Monia: Thanks, Richard. With at least nine data readouts planned, including phase three data for epilontericin and a potential regulatory filing, we have an eventful and catalyst-rich year ahead. We remain focused on achieving our goal of becoming a leading fully integrated biotechnology company. To that end, our plans this year are focused on our three strategic priorities.

Thanks Richard.

With at least nine data readouts plans, including phase III data for <unk> and a potential regulatory filing we have an eventful and catalyst rich year ahead.

We remain focused on achieving our goal of becoming a leading fully integrated biotechnology company.

To that end our plans. This year are focused on our three strategic priorities building <unk> commercial pipeline and advancing our three near term commercial opportunities if one person <unk> worse.

Brett Monia: Building the Ionis commercial pipeline and advancing our three near-term commercial opportunities at Wantersen, Olazarsen, and Dorsey; continuing to build on the substantial progress we made last year by expanding and diversifying our technology; and thirdly, delivering an abundance of new medicines to the market in the near term and longer term, highlighted this year by the Phase III readout for eplantersin and hereditary TTR polyneuropathy These three strategic priorities are central to my commitment to driving substantial growth for Ionis.

Continuing to build on the substantial progress we made last year by expanding and diversifying our technology.

And thirdly, delivering an abundance of new medicines to the market in the near term and longer term highlighted this year by the phase III readout for <unk> in hereditary <unk> polyneuropathy and the potential filing for approval.

These three strategic priorities are central to my commitment to drive substantial growth for <unk>.

Brett Monia: As we have discussed this morning, we have made great progress across our business in support of this commitment, with even more exciting progress planned for this year. Before closing, I want to take a moment to speak about Rare Disease Day, which is Monday, February 28. And it's important to Ionis. There are approximately 7,000 rare diseases that affect more than 300 million people around the world.

As we have reviewed this morning, we've made great progress across our business in support of this commitment with even more exciting progress plans for this year.

Before closing I want to take a moment to speak about.

Rare disease day, which is Monday February 28, and.

And it's important to Aon.

There are approximately 7000 rare disease that affects more than 300 million people around the world.

Brett Monia: On Rare Disease Day, actually every day, the Ionis team honors the determination, resilience, and resolve of these patients and their loved ones by working tirelessly and with a sense of urgency to discover, develop, and deliver life-transforming treatments. And with that, I'm now open to call up for questions. Anthony.

On rare disease day, actually everyday and the owner's team honors the determination resilience and resolve these patients and their loved ones are.

We're working tirelessly and with a sense of urgency to discover develop and deliver life transforming treatment.

And with that.

I'll open the call up for questions.

Anthony.

Operator: We will now begin the question and answer session. To ask a question, you may press stars and 1 on your telephone keypad. If you're using a speakerphone, please lift your hands before pressing the keys.

We will now begin the question and answer session.

Perhaps a question EBIT for Star then one on your telephone keypad, if you're using a speakerphone. Please pick up your handset before pressing the keys.

To withdraw your question. Please press Star then two.

Operator: To withdraw your question, please press star then two. At this time, we will pause momentarily to assemble our roster. Our first question comes from Gary Mackman with BMO Capital Markets. You may now go ahead. Hi guys, thanks for taking my questions. First, the follow-on product Biogen license for SMA; describe it a bit more. How similar is this to Spinraza in terms of mechanism, and what have you been able to do to potentially extend the dosing intervals for it?

At this time, we will pause momentarily to assemble our roster.

Gary Mackman: And when do you think Biogen might enter the clinic with it? And then the second question is just, you know, talk about some of the progress you've been making on the commercial side, preparing for Eplanturcin, how collaborative the process has been so far with AstraZeneca, and any sense of how big the sales forces will be for both you and AstraZeneca to capitalize on the PN opportunity and then prepare for cardiomyopathy as well.

Our first question comes from Gary Nachman with BMO capital markets. You May now go ahead.

Hi, guys. Thanks for taking my questions first.

The follow on product Biogen licensed for SMA, describing a bit more how similar is it just been rather in terms of the mechanism.

Have you been able to do the potentially extended dosing intervals for it.

And when do you think biogen might enter the clinic with it.

And then the second question is just talk about some of the progress you've been making on the commercial side preparing for outbound tourists and how collaborative has that process been so far with astrazeneca.

And any sense of how big the sales forces will be for both you and astrazeneca to capitalize on the pn opportunity.

And then prepare for the cardiomyopathy as well.

Gary Mackman: Great. Great questions, Gary. I'm going to ask Eric Swayze, Head of Research, to talk a little about the mechanism and the Chemistry, and you have a few questions related to the SMA follow-on, and Onaiza Cadoret to talk a little bit about how the AZ co-development, co-commercialization partnership is going, which is going great. But Eric, why don't you kick it off?

Great.

Great questions, Gary I'm going to ask Eric Swayze head of research and talk little bit about the mechanism and the.

The chemistry.

Questions related in the SMA follow on in amazement cabaret to talk a little bit about how the co development co commercialization partnership is going well.

Great, but everybody in particular.

Brett Monia: Sure. Thanks, Brett. So the follow-on, BIP-115 or IM-306, it uses the same mechanism as Spenroza's, so it is a splicing modulation mechanism that promotes synthesis of SMN protein, just like Spenroza, and the objective of the program was to improve potency and extend the dosing interval, and the follow-on does both of those things. We use a different backbone chemistry, which we haven't disposed exactly what's in the molecule, but it's a new backbone chemistry that works particularly well in the splicing modulation mechanism, and it gives an improvement in potency of the molecule and extends the dosing frequency, so we've got great preclinical data on the compound and hope to really be able to extend the dosing regimen from Spenroza, and you asked about clinical trials, BIOGEN is working on their clinical program but hasn't given guidance on when they're going to start.

Sure. Thanks, Brett.

The follow on.

One five or <unk> 300.

<unk> uses the same mechanism.

So it is a splicing modulation mechanism.

Most synthesis of.

SMN protein.

Like spin Rosa and the objective of the program.

To improve potency and extend the dosing interval and the follow on those both of those things we use a different backbone chemistry, which we haven't disclosed exactly what's in the molecule, but its a new backbone chemistry that works, particularly well in this and the splicing modulation mechanism.

And it gives us an improvement in potency of the molecule.

Extensive dosing frequency, so <unk> got great preclinical data on the compound.

To really be able to extend the dosing regimen from spin Rosa.

And you asked about clinical trial starts Biogen is working on their clinical program, but hasnt give any guidance on when they're going to start that.

Brett Monia: And just to add to that, thanks Eric, the drug is ready for clinical development, so it's cleared for toxicology studies, and it's ready to go; they're just putting the final touches on clinical trial design and regulatory discussions, but stay tuned for that. As Eric said, they haven't disclosed timing for the start of that study. Onaiza, would you like to please talk a little bit about how the co-commercialization partnership is going with AstraZeneca and F1 sericin? Sure. I'm happy to oblige, Brett.

And just add to that thanks, Eric.

The drug is ready for clinical development. So it's cleared Dr. <unk> tox.

Tox studies and is ready to go to just putting the final touches on clinical trial design and regulatory discussions, but stay tuned for that as Eric said.

Disclose timing for the start of that study.

Okay. So would.

Would you like to talk a little bit about how the co commercialization.

Partnerships going with Astrazeneca and Influencers.

Eric Swayze: Thanks, Gary, for the question. The collaboration is just going seemingly well. AstraZeneca and, you know, Ionis are just really great partners. I think, you know, having been on a lot of co-promotes in the past, I think we're approaching this in absolutely the right way. We're leveraging each other's capabilities where there is strength and differentiation. So, in that sense, the mindset within which we're entering this is just a fabulous start. More tactically to your question, you know, Ionis will certainly be leading the areas where they have great expertise in the marketplace.

Sure I'm happy to Brad.

Thanks, Gary for the question. The collaboration is just going swimmingly, well astrazeneca and and.

Iron Mr. Just really great partners I think.

Having been in a lot of co promote in the past.

I think we're approaching this is absolutely the right way, we're leveraging each other's capabilities.

Where there is strength and differentiation.

Since the mindset within which we're entering this is just a fabulous start.

More tactically to your question.

This will be certainly, beating the areas, where they have great expertise in the marketplace. We know amyloidosis really well we've been in the marketplace.

Onaiza Cadoret: We know amyloid doses really well. We've been in the marketplace, you know, with investigators and KOLs. We're really going to be leveraging that strength all the way through to field medical as well. So we'll be leading a lot of the medical affairs capabilities and having a field medical affairs team to launch at Blancherson. We're also going to be leaning on our great strength in rare diseases, patient services, and patient support and planning that collaboratively and leading that effort as well.

With investigators and Kols.

A decade, when you think about it and we're really going to be leveraging that strength all the way through.

Two field medical as well, leading a lot of the medical affairs capabilities.

And having a field medical affairs.

Two.

To launch at the long term.

Then.

Hmm.

We're also going to be leaning on our just great strength.

Rare diseases patient services and patient.

Patient support and planning that collaboratively and leading that effort as well. So that gives you a bit of color on the types of activities that I own. This will be leading we will obviously rely on the broad strength in heart failure.

Onaiza Cadoret: So that gives you a bit of color on the types of activities that Ionis will be leading. We will obviously rely on the broad strength in heart failure that AstraZeneca brings and just a great cardiovascular presence that they have in a variety of other ways. As to your question, the size of the team has just not been established yet. We just have more work to do on that front.

For that Astrazeneca, bringing great cardiovascular Hudson City.

Variety of other ways as to your question size of team just not been established yet.

Onaiza Cadoret: So happy to share that as we work along that path with AC. And then lastly, I would say we are certainly taking the capabilities that we're building for at Blancherson in this co-commercialization effort to really have an eye towards and a line of sight towards what we will be leveraging for Luzarsan and Donna Dolorsan, our next launches, which will be Ionis only. Thanks, Ines.

More work to do on that front, we're happy to share that as we work along that path with AC and then lastly, I would say we are certainly taking the capabilities that we're building for Epsilon person in the co commercialization effort to really have an eye towards in a line of sight towards what we will.

Leveraging for resources and Donna to loosen, our next launches, which will be I have it.

Uh huh.

Brett Monia: Okay, that's great, very helpful. Thanks. Thanks, Gary.

Excellent okay. Thank.

That's great very helpful. Thanks, guys.

Thanks, Gary.

Jessica Bai: Our next question comes from Jessica Bai with JPMorgan. You may now go ahead. Hey guys, good afternoon.

Our next question comes from Jessica Fye with Jpmorgan you May now go ahead.

Jessica Bai: Thanks for taking my questions. I had a couple. It looks like you're going to have two updates this year for the HAE program, one in the first half and one in the second half. Can you elaborate on what types of data we should expect you to share in each of those two updates? And then, second, what do you see as the benchmark for differentiated LDL lowering with ION449? Like what constitutes a meaningful difference relative to the closer ends?

Hey, guys.

Good I guess now afternoon, thanks for taking my questions.

Had a couple it looks like youre going to have to update this year for the <unk> program.

One in the first half one in the second half can you elaborate on what types of data we should expect your share in each of the two updates.

Then second what do you see as the benchmark for a differentiated LDL lowering with ion for 49.

What constitutes a meaningful difference relative to infer trends.

Jessica Bai: Good thing. Thanks, Jess. So, for Donna Dolores and the updates that are coming for NHAE, in the first half of this year, as you said, we're planning an update at a medical meeting, and there you're going to see more data from the Phase 2 controlled study, data like quality of life, for example, and other, you know, other data from deeper investigations into the results of that study. And I also, and then in the second half of the...

Sure thing Thanks Jess.

So.

Dawn <unk>.

The.

Updates.

They are coming for <unk>.

The first half of this year as you said, we are planning an update.

At a medical meeting and there youre going to see more data from the phase two controlled study data like quality of life for example, and other other data from.

Deeper investigations into the results of that study.

I also.

And then in the second half of it.

Brett Monia: In the second half of the year, we're planning to present at a medical meeting open-label extension data to demonstrate not only the robustness of the Phase 3 study to demonstrate the durability of the protection that these patients received and the long-term tolerability and safety, which, you know, we think will further support our position that this is the best in class molecule. And I would also look for a third update, which is publication. We're planning to publish the Phase II data in a journal somewhere, hopefully soon, so there'll be a further update on that. With respect to ION449 differentiation, it's really straightforward.

Second half of the year.

Planning to present at a medical meeting.

Open label extension data.

Demonstrate not only.

To go beyond the robustness of the phase III study to demonstrate the durability.

The protection that these patients have received in the long term tolerability and safety.

Think will further support our position that this is the best in class molecule.

I would also look for a third update which is the publication planning.

Planning to publish.

The phase II data.

In a journal sometime hopefully soon.

Yes.

Further update on that.

With respect to <unk> hundred 90 differentiation, it's really straightforward.

Brett Monia: There's a need for better drugs that lower PCSK9 and LDL-C better than the current drugs that are out there, whether they are monoclonal antibodies or, Are there other drugs, siRNA? to get patients that have a risk of cardiovascular disease despite... So it's a better lowering agent. It's a better PCSK9 inhibitor and, consequently, a better LDL-C lowering effect from that better potency and efficacy we see. And that's based on the phase one data in patients with, on statins with high cholesterol that Richard talked about, and his talk earlier, but also the Phase 2B data that will present the APC. So it really does look like a best-in-class molecule. And, of course, the more you lower your LDL-C, the greater cardiovascular risk reduction is achieved. So that's really the key differentiator there.

There is a need for better.

Drugs that lower Dcs canine and ldlc better than current drugs that are out there whether they are monoclonal antibodies or.

Are there other drugs.

Hey.

To get patients that are have risk of cardiovascular disease.

Despite these treatments so it's a better it's a better lowering agent, it's a better <unk> inhibitor.

And consequently, a better ldlc lowering.

From from that.

Better potency and efficacy, we see and Thats based on the phase one data.

Yeah.

In patients with <unk>.

Stands with high cholesterol that Richard talked about.

In his talk earlier, but also the phase II data, though.

So it really does look like a best in class molecule and of course.

The more you lower LDL C at a greater rate.

Cardiovascular risk reduction.

That's really the key differentiator there.

Thank you.

Operator: Thank you. Our next question comes from Joseph Stringer with Needham Inco. You may now go ahead.

Our next question comes from Joseph Stringer with Needham <unk> Co. You May now go ahead.

Joseph Stringer: Thanks for taking our questions. Just on one of the Phase 2B readouts with the ADT program and hypertension, just given the competitive landscape and different modalities, what are you looking for in terms of clinically meaningful changes in blood pressure? And again, what would constitute sort of a competitive profile in this indication? Richard, do you want to take that?

Hi, good afternoon, thanks for taking our question.

On one of the phase <unk> readout.

With the.

ADT program in hypertension.

Just given the competitive landscape in different modalities.

What are you looking for in terms of clinically meaningful changes in blood pressure and again.

What would constitute sort of.

Our competitive profile in this.

Indication thank you.

Richard Geary: Yeah, happy to take that. Thanks. So, great question. What we expect to see with this molecule is robust systolic reduction in blood pressure. Really, anything more than five is something you would like to see in a blood pressure or lowering.

So joining Richard you want to take that.

Yeah happy to take that.

Thanks.

So great question, what we.

Expect to see with this molecule is robust systolic reduction in blood pressure.

Really anything more than five is something you would you would like to see in.

Blood pressure lowering but for these patients who are.

Richard Geary: But for these patients who are resistant to lowering, and they're on multiple medications for their blood pressure lowering, Getting them to essentially lower blood pressure and control, and we're thinking around 10 millimeters of mercury reduction in systolic would be a real winner, and Best in Class to be able to add on to medications that are not bringing these patients to control. We're excited about it, and the trial is going well, and we expect it to be read out this year. Great, thanks for taking our questions. Our next question comes from Paul Matisse with FIFO. You may now go ahead. Hi there, Thanks for taking our question. This is Alex on for Paul.

Resistant to lowering than they are on multiple medications for their blood pressure Laurie.

<unk>.

Getting them to essentially.

Our lower blood pressure.

And control and we're thinking.

Around 10 millimeters of Mercury reduction in systolic would be a real winner.

Best in class to be able to add on to.

Medications that are not bringing these patients to control but.

So we're excited about it and the trial is going well and we expect it will readout this year.

Great. Thanks for taking my question.

Our next question comes from Paul Matisse with Stifel. You May now go ahead.

Operator: Just one on the upcoming C9 readout in the first half. Curious if you could talk a little bit more about biomarkers beyond target engagement that we might see. I guess I'm curious if you expect to disclose any NFL data, and if so, do we know anything about NFL natural history in this population? I know it's a little bit less known here than say SOT1, so I'd be curious if you could elaborate more. Thanks. Yeah,

Hi, there. Thanks for taking our question. This is Alex on for Paul I was just one on the upcoming readout.

Read out in the first half.

Curious if you could talk a little bit more about biomarkers beyond target engagement that we might see I guess I'm curious if you expect to disclose any NFL data and if so.

Do we know anything about NFL natural history in this population I know, it's a little bit less known here than they thought one so curious if you could elaborate more thanks.

Yes.

Alex: Sure thing, Alex. So, you know, we're excited by the fact that the study is wrapping up, and Biden is going to release the C9 phase 2 data and potentially next steps as well for that program. That study is, of course, focused on selecting a dose potentially for a future study, potentially a phase 3 study in C9 ALS. So, aside from safety and tolerability, of course, which are very important for a person-patient study, it is very important to select a dose based on target engagement, C9 peptide reductions in those patients, and to correlate those reductions with how that translates to reductions, you know We will certainly be looking at secondary, you know, tertiary endpoints, characterizing all the classic endpoints you would expect to see, but that's really not the main focus of the study. That would include the NFL, certainly.

Sure thing Alex so.

<unk>.

We're excited by the fact.

Study is wrapping up and Baidu is going to dispose of as benign phase II data.

And so the next steps as well for that program.

<unk>.

That study is of course focused on selecting a dose essentially for for future study potentially phase III study in C&I.

So.

Aside from safety and Tolerability of course, which is very important for a first in patient study.

Very important is to select the dose based on target engagement.

<unk>.

<unk> peptide reductions.

Those patients and correlate those reductions with what we have.

That translates to reductions.

And the relevant ranges of the CNS, the spinal cord branch them based on preclinical data.

We will certainly be looking as secondary.

Tertiary.

Endpoints and characterizing the classic endpoints, you would expect to see but that's really not the main focus of the study.

That would include NFL certainly that would include.

Vital.

<unk> that would include.

AOS functional rating scale, but thats really not the objective. The objective has been selected those achieved in productions and target that we want to achieve between safety and Tolerability, especially Peru.

Brett Monia: That would include vital capacity and, you know, an ALS functional rating scale. But that's really not the objective of the study. The objective is to select those to achieve the reductions in target that we want to achieve with good safety and tolerability and position to improve, potentially in a phase three study. All right, thank you.

Essentially a phase III study.

Alright, thank you.

Operator: Ionis Pharmaceuticals Inc., Our next question comes from Joss Shimmer with Evercore ISI. You may now go ahead. Thanks for taking the time.

Our next question comes from Jos <unk> with Evercore ISI.

You May now go ahead.

Alright, Thanks for taking the question first for the Nexgen MSP a background in technology. When do you expect this will be in the clinic and how do you plan to prioritize targets.

Joss Shimmer: First, for the next gen, MSPA backbone technology. When do you expect this to be in the clinic, and how do you plan to prioritize targets? Visiting Validated Terrible, Scholar Generation Productors, going to be deployed more for now and then. Kelly, or relatedly, there's been a fair amount of evolution in your portfolio. I'll probably go with you, and NeuroDataSets and ALI. How are you now thinking about which program?

You'll be revisiting validated targets, such as <unk> with a third generation product or it's going to be deployed more for novel target tissues and then.

Separately or.

<unk>, there's been a fair amount of evolution in your portfolio, including with some of that in there.

Zero dataset and ALS.

How are you now thinking about which programs you are likely to advance to commercialization on your own.

Eric Swayze: You're likely to advance to commercialization on your own, for that strategy. Historically, you've been in CNS focused and heavy like that. Eric, can I take the MSPA? Yeah, I'll take the MSPA, but not the commercial.

That strategy at least historically, you've been CNS focused in heavy is that still the case.

Yeah.

Eric I think the MCA.

I'll take the MSP wins, but not the commercial.

Yeah.

Eric Swayze: So the MSPA backbone is currently in consideration for every new drug we're making. So we haven't given exact timing on when it would enter the clinic, and a little bit on how it performs with all the other chemistries we have. But we're actively competing with every modality and every chemical technology we have at our disposal to make the best possible drug. And that's again, and that's in all therapeutic areas and all platforms.

So the MSP backbone is currently in consideration for every new drug we're making.

So we haven't given exact timing on when it would entering the clinic.

On how it performs with all the other chemistries, we have but we're.

We're actively competing with every modality in every chemical technology, we have at our disposal to make the best possible drug.

And that's against and Thats in all therapeutic areas.

All platforms.

Yeah.

Eric Swayze: And if I could just expand on that a little bit, Eric, so this chemistry, we also expect, we also expect... Other chemistry. And we're looking to allow us to open up tissues that we may have had some trouble with in the past.

And if I could just expand on that a little bit.

Right.

So this chemistry, we also expect we also.

Brett Monia: As Eric presented at Investor Day last year, we believe we have a molecule that can greatly reduce pro-inflammatory effects in tissues where that can be a problem, for example, lung. We're hoping that that could be a path forward there. We're not committing to that yet, but certainly that's a possibility.

Other chemistries.

And we're looking to.

Allow us to open up tissues that we may have had some trouble with in the past.

Presented at Investor Day last year.

We believe we have a molecule that can greatly reduce pro inflammatory effects in tissues, where that can be a problem for example, pulmonary.

We're hoping that that could be a path forward there without committing to that yet, but certainly you got to.

Brett Monia: We also like the durability that this chemistry gives us, which really allows us to dose very infrequently, at least based on preclinical data so far, you know, using the subcarb route. So it's offering a lot, a lot of different aspects for the overall profile. And yeah, we're planning to move the first molecule into development this year, but that means, you know, initiating the top studies and then clinical development thereafter. With regard to the Portfolio and Neuro-Polyome pipeline, of course, we have our Phase 3 Fos-ALS study that's progressing nicely. We're rolling out that study. We're planning to bring that to the market ourselves.

Stability, we also like the durability that this chemistry gives us which really.

Allows us those very infrequently at least based on preclinical data so far do.

Do you think so.

Ralph So it's offering a lot a lot of different aspects.

Overall profile and yes, we are planning to move it in first molecule into development. This year, but that means initiated tox studies and in clinical development thereafter.

Yeah.

Regard to the portfolio of neuro wholly owned pipeline of course, we have our phase III study that's progressing nicely. We're rolling out study, we're planning to bring that to the market ourselves.

Brett Monia: Really, and then we have two other drugs in development right now that are wholly owned by Ionis as well. One is our GFAP study in Alexander's disease, which is in a phase 2, 3 study. And then thirdly, a drug, a study that we're planning to initiate this year in first, in carriers, in patients with prion disease. And we're really looking forward to the second half of this year to talk more about that program. We think it's a very exciting program.

Really and then we have two other drugs in development right now that are wholly owned by owners as well one is our G fast studying Alexander's disease, which is in a phase two three study.

And.

And then thirdly, a drug with a study that we're planning to initiate this year.

And carriers.

<unk>.

Isn't prion disease, and we're really looking forward in the second half of this year to talk more about that program.

Brett Monia: We think we have a very novel path forward for potential approval from a regulatory standpoint. We think we have a great drug based on our preclinical data. Behind that is a rich pipeline of neurodrugs, targets of which we haven't disclosed yet, but it's growing. And we do believe that following our near-term commercial opportunities, you've heard about it, Edward Olsarsson, and Don Dolorson are really looking towards our neuropipeline as being the follow-on of real movers for our commercial pipeline in the future. And we're going to talk more about that this year.

And we think it's a very exciting program. We think we have a very novel.

Forward for potential approval from regulatory standpoint, where do we have a great drug based on our preclinical data.

Behind that is a rich pipeline of neuro drugs targets of which we haven't disclosed yet, but its growing and we do believe that following our near term commercial opportunities heard about <unk>.

We're really looking towards our neuro pipeline as being a follow on.

Real movers for our commercial pipeline in the future and we're going to talk more about that this year.

Okay.

Yanan Zhu: Our next question comes from Yanan Zhu with Wells Fargo. You may now go ahead. Thank you and congrats on the progress. I have a question regarding Aplon-Turson's study in cardiomyopathy. I am certainly looking forward to the mid-year polyneuropathy data, but if we look a little further ahead for the cardiomyopathy opportunity, I think one of the features of the trial's design is that there's no path for patients on sephamidus, and therefore it may be a more real-world mix of patients.

Our next question comes from Vietnam, Xu with Wells Fargo. You May now go ahead.

Thank you and congrats on the progress.

I have a question regarding Epsilon persons.

<unk> in cardiomyopathy, certainly looking forward to the midyear polyneuropathy data.

But if we look a little further ahead for the cardiomyopathy.

Opportunity I think one of the feature of the <unk>.

<unk> designed it that there is no path for patients onto <unk> and therefore, it may be a more real world mix of patients.

Yanan Zhu: In contrast to a competitor's trial. So the question I have is, wouldn't the increased proportion of sephamidus patients in both arms affect the delta between the two arms? And do you have a statistical measure to address that, and is there a hierarchical testing that may allow you to look at sephamidus patients versus patients who are not, those two subgroups separately? And if you may also elaborate, how did this trial design allow you to have a better claim in the marketplace? I think you highlighted that, but could you elaborate exactly how that could support a differentiated claim?

In contrast to our competitors trial.

So the question I have is.

Wouldn't.

The increased proportion of fabulous patients in both arms.

Does that affect the delta.

Between.

The two arms and do you have.

Statistical measure too.

To address that and is there a hierarchical.

Testing that may allow you to look at parameters patients versus patients who are not those two.

Separately and if you may.

So elaborate how is this trial design allow you to have a better.

Claim.

In a marketplace I think you highlighted that but could you elaborate how exactly how.

That could support a differentiated claims thank you.

Richard Geary: Thank you. Thanks, Ian. And Richard, maybe you can address the first part on the cardiomyopathy design and the usage of and Management of Nutritaminous Uses in the Study and How the Study is Powered at a High Level. And then Onaiza, you talked a little bit about why this is relevant in a real-world setting and why we're so enthusiastic about the trial design. Yeah, so the trial design is one that we're really excited about because it does allow us to actually benefit from a real-world experience and the expectations of the world that we're going to enter upon approval if all goes well.

Thanks, Kevin and Richard you can address the first part of it.

Cardiomyopathy design and the usage of.

And management of Ducommun is Houston study and other studies.

Powered at a high level.

Can you talk a little bit about why this is relevant real world setting why we're so.

Enthusiastic about the trial design.

Yes. So the trial design is is one that we're really.

Excited about.

Because it does allow us to actually.

The benefit from a real world experience.

And the expectation of the world that we're going to enter.

Upon.

Approval.

All goes well.

Richard Geary: And so the study, which is larger than any of the other cardiomyopathy studies in this indication, allows for typhamatous use. It's actually powered, and this may not be well understood, but the study was powered, based on the assumption that everyone in the control group was on FAMAS, so already benefiting from a defamitist background.

And so the study which is larger than any of the other.

Cardiomyopathy studies in this indication.

Allowance for <unk> use.

It's actually powered and this may not be well understood.

Study was powered.

Based on the assumption that everyone in the control group.

It was on to families and.

So already benefiting from a defamatory background.

Onaiza Cadoret: In reality, you know, we've selected countries that have tefamidus available, like the United States, and other countries that do not. So it will be a mix, which will allow us to do a statistical analysis not only looking at those on defamators but also looking at naive patients that are not on tablets. So it provides a broad spectrum look and a real nice benefit in terms of the design of the study. So that's the design and the reason that we're excited about it.

In reality.

Selected countries that have <unk> available like the United States and other countries that do not so it will be a mix, which will allow us to do a statistical analysis not only looking at those on to <unk>.

But also looking at naive patients that are not on tablets.

So it provides a broad spectrum look and.

A real nice benefit.

In terms of the design of the study.

So that's the design and the reason that we're excited about it.

Onaiza Cadoret: I'm going to pass it over to Onaiza to speak about why this is so important. Yes, thank you, Richard. So, I would say our customers are very excited about the design as well. I think we're skating, you know, to where the puck will be in the future.

Pass it over to an ASR.

So why this is so important.

Onaiza Cadoret: And, you know, particularly in large geographies, such as the US, there will be a lot of patients who will be on taphometes because, you know, the patients are getting diagnosed, and they're being treated, which is all great. So, we have the ability, with the largest clinical trial now, to generate the evidence and data for both sets of patients. There will be patients who will be naive to stabilizers, and there will be patients who will already be on stabilizers.

Yes, Thank you Richard.

So I would say our customers are very excited about the design as well I think where we're sitting.

To where the puck will be in the future and we.

Push it too literally.

In large geographies such as the U S. It will be a lot of patients who will be on parameters because.

Patients are getting diagnosed and theyre treating which is great.

So we have the ability with the largest clinical trial now to generate the evidence data for both.

There'll be patients who'll be naive.

Stabilizers and there will be patients who will be on stabilizers.

Onaiza Cadoret: And the ability to actually come in and give physicians a data set on how to evaluate a patient who's currently on background therapy and what that incremental then benefit looks like in cardiovascular risk reduction above that will be extremely important. And they will be requiring that data to make that decision for the patient. So we will have the data, the evidence, and, you know, as all things go in terms of our ability to, you know, get these from a label perspective, we certainly are working towards the very, you know, likely outcome that we will be able to have that and put those into claims, as you had asked.

And the ability to actually come in and give physicians a data on how to evaluate a patient who's currently in background candidates what that.

Incremental then benefit looks like.

The cardiovascular risk reduction about that will be extremely.

Extremely important and they will be requiring that data to make that decision for the patient.

Onaiza Cadoret: So these will be the two generated claims. I'll also add, this is also great data. I think it's important not just for healthcare professionals but also for patients because they want to know if I add on another treatment, what does that look like? If I'm not on any treatment, you know, is epilonterstin the best treatment to go on?

We will have the data the evidence and you know as all things go in terms of our ability to.

Yeah from a label perspective, we certainly are working towards.

The very end.

Likely outcome that we will be able to have that in.

The claim as you head out. So these will be the key generated claims that were looking forward to I'll also add this is also a great data not just for us.

Onaiza Cadoret: So we will have those data sets with them. And, very importantly, you always have to check on reimbursement and access. And we've done that for our U.S. payers to really see if there were a combination used, how they would actually think about reimbursement for that, and, very fortunately, and with a very patient mindset because these patients are very sick, they came at it at the same place and said, "We would cover both stabilizers and silencers together, as long as you have the data and evidence to generate that, and physicians were actually making that Ionis Pharmaceuticals Inc. Ionis Pharmaceuticals Inc., Thank you for the very detailed cover letter. I appreciate it.

Health care professionals, but also for patients because they want to know if I add on another treatment and what does that look like if I'm not in any treatment.

Yes, Apple interest and the best people to pick out one so we will have those data sets with them and very importantly, you always have to check on reimbursement.

And we've done that for our U S peers to really see if they were combination use.

I actually think about reimbursement.

Reimbursing that and very Fortunately and very patient mindset. Because these patients are very sick. They they came at it at the same place instead.

We would we would cover.

Cover both.

Stabilizers and filings together as long as you have the data and evidence to generate that and physicians were actually making that choice. So we do see from all three perspective.

It's real world evidence in a clinical trial is going to be very very capable.

After the launch in Korea.

Got it. Thank you for the very detailed color appreciate it.

Operator: Thank you, Ian. Our next question comes from Jason Gerberry with Bank of America. You may now go ahead. Hey guys, thank you for taking my questions.

Thank you Ian.

Our next question comes from Jason <unk> with Bank of America, You May now go ahead.

Jason Gerberry: I guess just thinking ahead this year to the Eplen Thurston update, if you can speak to how you guys are thinking about the safety differentiation relative to TegCeti and just to have a more competitive product in the market, is it really, is there one of the two black box warnings and REMS monitoring components, either renal or thrombocytopenia, that is more important, or is it really the key to sort of develop a product Those safety considerations, and as we think about sort of TegCeti so far commercially, I know it doesn't get talked about a lot on these calls, but just, you know, what proportion of patients are currently contraindicated for TegCeti, and if you could just speak to the underlying kind of market share and volume trends, which are hard to tease out because of the revenue reporting changes, that' Sure, Jason.

Hey, guys. Thank you for taking my questions.

I guess just thinking ahead this year could be epsilon or some updates that you can speak to how you guys are thinking about the safety differentiation relative to take steady and just.

Have a more competitive product in the market is it really is there one of the two black box warnings and rems monitoring components, either renal or combo cytopenia that is more important or is it really is a key to sort of develop a product with a profile that distance itself from both of those safety considerations and as we think.

Sort of peg steady so far commercially I think I think you talked a lot on these calls, but just what proportion of patients are currently contraindicated for Chegg study and if you could just speak to the underlying kind of market share and volume trends, which are hard to tease out because of the revenue reporting changes that'd be helpful. Thanks.

Brett Monia: Yeah, we agree it's a rich year for our pipeline, our catalysts, a lot of catalysts coming up this year, including Eplan-Tursyn, Phase III readout by mid-year for polyneuropathy, You know, we don't expect any safety issues for epinephrine and polyneuropathy in the polyneuropathy readout at all. I mean and that's based on blinded data that's been continuously evaluated by our safety oversight committee and moving this drug forward each time it's been reviewed and are like a platform overall so you know to us which is more important, The need for renal monitoring, to move away from renal monitoring or platelet monitoring that is occurring with TXETI for eplantersin is not really that relevant because we don't expect any monitoring beyond what's normal for any drug that reaches the market today.

Sure Jason Yes, we agree with rich year for our for our pipeline our catalysts a lot of catalysts coming up this year, including up on person.

Bayes III readout by mid year.

For Polyneuropathy.

We don't expect.

Any.

50 issues.

For <unk>.

In Polyneuropathy in the Polyneuropathy readout at all.

And that's based on blinded data that has been continuously evaluated by our safety oversight Committee and moving this drug forward.

Or.

Each time, it's been reviewed.

And our like our platform overall.

<unk>.

To us which is more important.

The need for renal monitoring to move away from renal monitoring where platelet monitoring occurring.

Recurring with tech savvy for it but for <unk> <unk>.

Not really that relevant because we don't expect any monetary.

On what's normal for any drug.

Brett Monia: So we don't expect any platelet signals or renal signals, and that's the assumption going forward. And as far as patients that are not, you know, eligible for TXETI, I'd have to go back and look at that.

Today, So we don't expect.

Any platelet signals or renal signals and thats the assumption.

Going forward.

And as far as.

Patients that are not.

Hum.

Brett Monia: And then we can follow back with you on that. But you know, TXETI is approved. All patients with hereditary TTR, amyloidosis, and symptoms of polyneuropathy are eligible for TxETI, provided that they are tested first for certain renal and platelet parameters, and they're above a certain threshold, which I don't have that number exactly in front of me, but all patients are eligible for the drug, except that small population.

Eligible protect city I'd have to go back and look at that.

And then we can follow back with you on that.

<unk> is approved for.

For patients with hereditary <unk> amyloidosis and symptoms of Polyneuropathy periods. So all our bold patients are eligible for <unk>.

Steady provided that.

Or tested first for certain renal and platelet parameters and they are above a certain threshold, which I don't have that number exactly in front of me, but all patients are eligible for the drug.

Except that.

That small population, but.

Brett Monia: But eplantersin is where our focus is. Eplantersin has demonstrated TTR reductions in our phase one study that are highly competitive, not superior to what we've seen out there today. We think this has the potential to be a best-in-class product for TTR amyloidosis, hereditary TTR amyloidosis with polyneuropathy, as we do for eplantersin and cardiomyopathy. Our next question comes from Miles Minter with William Blair. You may now go ahead. Hi, this is Sarah. I'm from Miles.

Applications, where our focus is F. One person has demonstrated GTR reductions in our phase one study.

R.

Our highly competitive if not superior to what we've seen out there today. We think this has the potential as the best in class product for GTR amyloidosis.

Hereditary <unk> amyloidosis Polyneuropathy as we do for <unk> in cardiomyopathy.

Our next question comes from Myles Minter with William Blair You May now go ahead.

Beth Hougen: Thanks for taking the questions. Just to kind of follow up on our last question a bit. Can you comment on the kind of trajectory of the Tuxedi franchise moving forward? Sure, happy to.

Hi, This is Sarah on for Myles. Thank you for taking the question just to kind of follow up on that last question a bit can you comment on kind of the trajectory of the tech savvy franchise moving forward.

Beth Hougen: So, as I mentioned in our prepared remarks, Tech Study sales continued to expand into new countries last year, and we're pleased with the work that SOBE and TTC are doing. Obviously, I can't get ahead of what each of them have disclosed publicly, but we would expect to see continued support from SOBE and PTC in their respective areas for Tech Study going forward. And then, in terms of revenue, of course, this is our first full year of revenue from Tech Study, based on a distribution model.

Yes.

Sure happy to so as I mentioned.

In our prepared remarks.

<unk> sales.

Steady continue to expand into new countries last year, and we're pleased with the work that <unk> doing obviously I can't get ahead of what each of them have disclosed publicly.

But we would expect to see.

The continued support from <unk> and PTC in.

In their respective areas.

For tech steady going forward.

And then.

In terms of revenue of course this is our first full year of <unk>.

Revenue from Chegg study.

Beth Hougen: So you would expect to see our revenues actually decline year over year, or decrease year over year, because last year was a mix of product sales and distribution fees. So this year, you would expect to see that decrease. However, we also had substantial expense savings when we moved to the distribution model with the SOBI transactions for Tick-City and WayLiver, for that matter.

Based on a distribution model. So you would expect to see our revenues actually declined year over year decrease year over year, because last year was the mix of product sales and distribution fees.

So this year you would expect to see that decrease however, we also had substantial.

Thanks, David when we moved to the distribution model with Adobe transactions protect study and we lever for that matter. So.

Beth Hougen: So our overall P&L impact from that change is actually quite positive. And as I've said before, we're reinvesting those savings into our commercial opportunities, into the neuro pipeline, into the rest of our mid-stage pipeline, our technology, commercial capabilities, all of the things that we think are absolutely essential to build Ionis into the leading fully integrated biotech company. That's about it.

Our overall P&L impact from.

That change is actually quite positive and as I've said before we are we investing those savings into our commercial opportunities into the neuro pipeline into the rest of our mid stage pipeline, our technology commercial capability all of the things that we think are absolutely essential to build <unk> into the <unk>.

<unk>.

A fully integrated biotech company.

Got it thank you.

Yes, Sir.

Operator: Thank you. Our next question comes from Luca Issi with RBC. You may now go ahead. Well, great.

Our next question comes from Luca <unk> with RBC you May now go ahead.

Luca Issi: Thanks so much for taking my question. Maybe circling back on a prior question for TTR, polyneuropathy, maybe ask the question a little more directly. Great partnership with AstraZeneca, obviously, but a fairly competitive market. So maybe, Onaiza, how are you thinking about the market share split long-term between you and Alnalen, given that, obviously, they're ahead and they may be in a position to dose less frequently? And then maybe the second question, on AGT, can you just remind us the rationale for going after heart failure?

Oh, great. Thanks, so much for taking my question, maybe circling back on a prior question for TCR pulling neuropathy, maybe you asked the question a little more directly great partnership with Astrazeneca, obviously, but fairly competitive market. So <unk>. How are you thinking about the market share split long term between you and ill now.

Given that obviously, there I had them they may be in a position to dose less frequently.

And then maybe second question on <unk> can you just remind us the rationale for going after heart failure again, one of your competitors going after just a hypertension, but you have a trial for heart failure.

Onaiza Cadoret: Again, one of your competitors is going after just hypertension, but you have a trial for heart failure with reduced ejection fraction, so we'd love if you could remind us the rationale there. And then, maybe lastly, sounds like you're going to have some data with GSK for hepatitis B. I wonder if you can give us some color on that one. I forget if that trial is monotherapy or a combination with nukes or a combination with capsule inhibitors. So any color there would be great.

Reduced ejection fraction so would love if you can remind us the rationale there and then maybe lastly, it sounds like you're going to have some data with GSK for hepatitis B I Wonder if you could give us some color on that one I forget if that trial is monotherapy or combination with nukes or a combination with <unk>. So any color there would be great. Thanks, so much.

Hi, Nathan.

Onaiza Cadoret: Thanks so much. Onaiza? Yes, sure. I'll start. Thank you, Luca, since you already directed the question to me. Yeah, so, you know, for a blunt person in polyneuropathy, particularly as the first launch, you want to think about this as a systemic disease and that we will be in hereditary ATTR, so we will be looking at both the mixed phenotype as well as the pure polyneuropathy patient. So, think about it as a large market.

Yes.

Since you already directed the question to me.

Yes.

Sure.

One person in Polyneuropathy, particularly as the first launch and you want to think about this as a systemic disease.

And that we will be in hereditary <unk>. So we will be looking at both.

Both the mixed phenotype as well as the pure polyneuropathy patients. So think about it as a large market only 10% to 15% of those patients have been.

Onaiza Cadoret: Only 10 to 15% of those patients have been diagnosed and treated, so it's a big market for multiple players to share. We have – are expecting very strong data in terms of efficacy with both MNIST-7 and our Norfolk Quality of Life. Brett just went through what we expect on the safety profile.

Diagnosed and treated so a big market for sure.

Multiple players too sure.

Onaiza Cadoret: And then, you know, after those things are done, then you have to look at what's next in terms of hierarchy that's important to the market, be it physicians and patients. And here, I would say our product presentation of self-administration at home is a very key driver of choice. So, we do believe that that's going to be a really important feature of the product as well that will, in addition to efficacy and safety, be really important.

We have.

We're expecting very strong data in terms of efficacy.

And I don't know if the quality of life, Brett just went through what we expect for the safety profile and then after those things are done then you have to look at what's next in terms of hierarchy, that's important to the market.

Be it physicians and patients and here I would say, our our product presentation itself administration at home.

He is a very key driver of choice. So we do believe that that's going to be.

Feature of the product as well that will in addition to efficacy and safety really important.

Onaiza Cadoret: And I'll say in our new normal of COVID, it's actually a great deal even more important where more virtual visits are being done by physicians, and there's just a preference for that. So, giving patients the control of self-administration at home continues to be a really big benefit. And we think that the monthly is certainly, you know, a very important kind of consideration, but it really didn't show up very, very strongly when we tested this in terms of, you know, monthly versus quarterly. Honestly, it was the self-administration that was driving more of the choice than, you know.

And I'll say in a new normal kind of Covid, it's actually a great deal even more important where more virtual visits are being done by type by physicians and their preference to that giving patients. The control of self administration at home continues to be a really big benefit and we think that that.

Monthly.

A very important.

Have a consideration, but it didn't show up very very strongly when we tested both in terms of monthly versus quarterly honestly. It was a self administration that was driving more of a choice.

The penetration, but wanted to give you that color you can calculate chairs based on that.

Onaiza Cadoret: I wanted to give you that color so you can calculate shares based on that and just think about what the product really offers. And hopefully, you'll get to be able to model that. But I wanted to make sure you had that. Great. And maybe I can take the heart failure question for angiotensinogen. So, first of all, angiotensinogen has shown some real benefits in some of the preclinical models for heart failure, and we moved into this heart failure initial study to look at the safety of shutting down or reducing angiotensinogen production in these patients.

And just think about what the product offers.

And hopefully you'll get.

To be able to model that but I wanted to make sure you have that person.

Okay, Great and then maybe I can take the heart failure question for <unk>.

First of all.

Andrew to incentives. In addition, some real benefit in some of the preclinical models for.

Heart failure, and we moved into this heart failure initial study to look at the safety of.

Shutting down or reducing angiotensin engine production in these patients.

Onaiza Cadoret: You know, one of the issues in heart failure is that you have to be very careful because of the renal issues as well as the possible benefit on the cardiac side. However, actual RAS inhibition or the ability to utilize those medications has been very limited in these patients. So they aren't getting what they need in terms of control both on blood pressure as well as their heart failure side effects.

One of the issues in heart failure is.

You have to be very careful.

Cause of the renal issues as well as.

The possible benefit on the cardiac side.

Actual ras inhibition or the ability to utilize those medications has been very limited in these patients so they arent getting.

What they need in terms of control.

Both on on blood pressure as well as their heart failure side effects and so.

Richard Geary: What we see with angiotensinogen is the opportunity to treat at the top of the RAS pathway with angiotensinogen without hitting the kidney, and so we're looking at safety as a primary as well as, of course, the lowering of blood pressure. So we're excited about the study, we're excited about that as a possible indication for angiotensinogen, and we'll learn more as we complete these early Thanks, Richard.

What we see with angiotensin adjourn has the opportunity to.

Treat at the top of the Ras pathway with angiotensin adjourn.

Without hitting the kidney and so we're looking at safety as a primary.

As well as of course, the lowering of angiotensin adjourn and control of blood pressure. So we're excited about the study we're excited about that as a possible indication for angiotensin agenda, and we'll learn more as we complete these early studies.

Eric Swayze: Eric, do you want to comment on the HPV travel time plus one new thing, what we might expect from that readout? Sure. So. That's basically it.

Thanks, Richard Eric do you want to comment on the HBV trial designs plus funds nukes.

But we might expect from that readout.

So.

Sure.

Oh.

Eric Swayze: So they've got the pure virucin drug on top of a standard of care, which is nucleoside inhibitors of the plum race and elone and the, ideas in phase two to see if we can get reduction of the S antigen protein and subsequent immunoclearance of the viral infection and try to achieve what we call a functional cure where the immune system can overcome the S antigen which is causing, kind of inhibiting the immune system's ability to cope with the virus and clear it. So that's the goal and, Some cool preclinical data that suggests that it might be possible and hopefully it'll be borne out in the phase two study. Thanks, sir. Fantastic.

That's.

Basically it so they've got the <unk> drug.

On top of standard of care, which is a nucleoside inhibitors of the polymerase and alone.

No.

Ideas in phase II to see if we can get reduction of the S antigen protein and subsequent clearance of the viral infection and trying to achieve what we call a functional cure werent immune system.

<unk> the S antigen, which is causing.

Kind of inhibiting the immune system's ability to cope with the virus.

So that's the goal.

And some preclinical data that suggests that it might be possible.

Be borne out in the phase II study.

Yeah. Thanks, Eric.

So much.

Thanks.

Eric Swayze: Thanks so much. Our next question comes from Yale Jen with Laidlaw and Co. You may now go ahead. Thanks for speaking to me about the questions. I've got two quick ones.

Our next question comes from Yale Jen with Laidlaw and call you May now go ahead.

Yale Jen: The first one is that, given that you have the AstraZeneca co-commercialization agreement, should we anticipate in terms of adding StealthSports, StealthSprap, to your commercial teams would be something maybe starting in 2024 or later? And the second one is that, to tag on the previous question in terms of Apple Purchasing in PN, besides the self-administrative advantage, is there any other sort of theoretical benefit you can think of comparing to the Tertarand at this moment?

Thanks for fitting me.

The question is that.

Two quick ones. The first one is that.

Given that you have to as Rosanna Mccollough co commercialization agreement should we anticipate in terms of adding sales force itself scrap.

To your commercial teams will be something maybe starting in 2024.

Or later.

Second one is just.

Just to add on the previous question in terms of.

Oh interesting.

In Pn.

Besides the self administrative administrative.

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Any other sort of theoretical benefit you can think of competing comparing to the.

Uh huh.

At this moment and thanks.

Yale Jen: And thanks. [inaudible] Onaiza Yes, yeah, I'd be happy to. So, for AstraZeneca in the collaboration, you know, we're still working out how we're going to divide up some of the customer-facing resources. But, you know, for your modeling purposes, I would just suggest that, you know, we have, and are likely going into this, we're going to be doing more of the non-sales customer-facing resources. So the larger part of the salespeople that will be required will be handled by AstraZeneca, and we will be handling more of the field medical, like nurse case managers and those types of things. So hopefully, that will help you calibrate in terms of size for them.

Yes, yes.

Be happy too so.

Astrazeneca in the collaboration.

Still working out how we're going to divide up the customer facing resources, but for your modeling purposes I would just suggest that.

We have.

Unlikely going into this that we're going to be doing more of the non sales customer facing resources. So the larger part of the sales people that will be required will be handled by astrazeneca and we will be handling more of the field medical like nurse case managers and those type of customer facing resources.

Onaiza Cadoret: And then, you know, I think for the differentiation, it's always a trifecta, right? You have to look at it from all the things that you offer to the physician, the patient, and the payer. And we really are very, very confident in the product profile, both for polyneuropathy and for cardiomyopathy, in terms of what this is going to offer in efficacy, in safety, in ease of administration, tolerability, and, you know, obviously, at-home dosing, as I just explained earlier as well. But it's really the whole package together that will drive the differentiation.

So hopefully that will help you calibrate in terms of size.

For that.

And then I think for the differentiation.

It's a choice at that rate you have to look at it from.

All the things that you offer to the physician the patient and and the payer and we really are very very confident in the product profile, both for Polyneuropathy and cardiomyopathy in terms of what this is going to offer an efficacy safety and ease of administration tolerability.

And.

Obviously at the at home dosing as I, just explained earlier as well, but it's really the whole package together that will drive the differentiation but.

Onaiza Cadoret: But we are very excited about both the polyneuropathy launch and then, you know, the cardiomyopathy with the differences in terms of our real world evidence trial that will really help us characterize the two sets of populations for typhamatous, and or alone, Nye Kitsamis as well. Our next question comes from Yaron Weber with Cowen. You may now go ahead. Hi, this is Brendan on for your own.

We are very excited about both the Polyneuropathy launch and then.

The cardiomyopathy with the with the differences in terms of our real world evidence trials that will really help us characterize the two sets of population for to come at us.

And or alone Nike took standard as well.

Okay.

Our next question comes from Yaron Werber with Cowen.

May now go ahead.

Yaron Werber: Thanks for taking the questions as well. First, I honestly just wanted to follow up on one of the earlier questions about the hep B infection readout at age two. You know, given the data we've seen in the last couple of years from competitors, I really just want to see where you think the bar is at this point in terms of antigen reduction. And then, actually, in acromegaly, I also wanted to see how enrollment here has been going given some of the difficulties in the combo study last year, and I guess how you're all thinking about potential next steps for the program. And I guess that we are moving forward with based on everything that you have so far. Thanks very much. You're welcome. Erik, why don't you take the first one, and I'll touch on that for you.

Hi, This is brendon on for your own thanks for taking the questions as well first on this I just wanted to follow up on one of the earlier questions about the Hep B infection readout in H two.

Given the data we've seen the last couple of years from competitors really just wanted to see where you think the bar is at this point in terms of S antigen reduction.

And then actually in Acromegaly I also wanted to see how enrollment has been going given some of the difficulties in the combo study last year and I guess, how you're all thinking about potential for the program and I guess that drug moving forward with based on everything so far thanks, so much.

Youre welcome Eric wanted to take the first one I'll touch on that for sure.

Eric Swayze: Yeah, sure. I mean, the bar is probably more than just S antigen reduction per se. The objective, as I said earlier, is to reduce S antigen enough and then combine that with the ability of the immune system to create what they call a functional clear and eradicate the virus.

The bar is probably more than just S antigen reduction per se that we objected to this earlier is to reduce S. Antigen enough and then combine that with the ability of the immune system to create what they call the functional clear the virus.

Eric Swayze: And so I don't think just S antigen reduction alone is enough. And in our Phase 2A trial that we reported on, published recently in Nature Medicine somewhere, there, we actually showed evidence that that could in fact happen and had some really impressive clearances of viral infection in patients. So that's what we're hoping to, what GSK is hoping to show in the larger... And for the acromegaly phase two monotherapy study, we're very confident this study will read out as planned this year. Enrollment is actually ahead of schedule and going very well, and we're looking forward to that readout. So no, no, no concerns, and no red flags there whatsoever.

And so I don't think just S antigen reduction alone is enough.

Our phase Iia trial that we reported about it.

Published recently in a tremendous and somewhere there we actually showed evidence that that could in fact happened and had some really impressive clearances.

Arnaud infection in patients. So that's what we're hoping to with Gsk's, hoping to show in the larger space.

And for.

The Acro Acromegaly phase II monotherapy study were very confident this study.

It will read out as planned this year enrollment is actually ahead of schedule.

Very well.

Looking forward to that readout. So no no no concerns no red flags, there whatsoever and I also want to remind you that.

Brett Monia: And I also want to remind you that we also have an update on the open-label extension from the acromegaly studies that we had data come out last year on in patients that are resistant to somatostatin analog. So we're going to have additional data beyond the monotherapy, but we're very confident enrollment went great in the monotherapy study and we're looking forward to that readout. And I think that pretty much wraps up the questions about where we are now.

We also have an update on the open label extension from the.

Hum.

Acromegaly studies that we.

Had data come out last year on and patients that are resistant to somatostatin analog. So we're going to have additional data beyond the monotherapy, but we're very confident that enrollment has gone right.

The monotherapy study.

We're looking forward to that readout.

And I think that pretty much wraps up the questions, where we are now so I'd like to thank everyone who joined.

Brett Monia: So I'd like to thank everyone who joined us and participated in the call today. I look forward to providing further updates on our progress throughout the year, and until then, thank you again and have a great day. The conference has now concluded. You may now disconnect. Thank you.

And as I stated on the call today by <unk>.

To providing further updates on our progress throughout the year and then thank you again.

Have a great day.

Yeah.

The conference has now concluded you may now disconnect.

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