Q4 2020 Ionis Pharmaceuticals Inc Earnings Call

[music].

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

Good morning, and welcome to I honest pharmaceuticals fourth quarter and full year 2020 financial results Conference call. As a reminder, this call is being recorded at this time I would like to turn the call over to Wade Walke, Vice President of Investor Relations to lead off the call. Please begin.

Wade Walke: Thank you, Tom. Before we begin, I encourage everyone to go to the Investors section of the Ionis website to find the press release and related financial tables, including a reconciliation of the GAAP to non-GAAP financial measures that we will discuss today. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website that accompany our discussion today. With me on today's call are Brett Monia, Chief Executive Officer; Beth Haugen, Chief Financial Officer; and Richard Geary, Executive Vice President of Development.

Thank you John before we begin I encourage everyone to go to the investors section of the on this website to find the press release from related financial tables, including a reconciliation of GAAP to non-GAAP financial measures that we will discuss today.

We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We also have posted slides on our website that accompany our discussion today.

With me on today's call are Brett <unk>, Chief Executive Officer, Beth Hougen, Chief Financial Officer, Richard Geary Executive Vice President of development and joining us for Q&A on as a category Chief corporate development, and commercial officer, and Eric Swayze Executive Vice President of research.

Wade Walke: And joining us for Q&A are Onaiza Cadoret, Chief Corporate Development and Commercial Officer, and Eric Swayze, Executive Vice President. I would like to draw your attention to slide 3, which contains our forward-looking language. We will be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional details. And with that, I'll turn the call over to Brett.

I would like to draw your attention to slide three which contains our forward looking language statement, we will be making forward looking statements, which are based on our current expectations or beliefs.

Statements are subject to certain risks and uncertainties and our actual results may differ materially I encourage you to consult the risk factors discussed in our SEC filings for additional details.

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

Brett P. Monia: Thanks, Wade. Good morning, and thank you for joining us on today's call. Last year marked a new beginning for Ionis; with new leadership in place, we laid out a bold new vision for the business and took important steps towards realizing our goal of having 12 or more medicines on the market in 2026. Key to our new vision is our strategy to maximize the value of each medicine in our wholly owned portfolio. Today, our focus is primarily on commercializing our rare neurological and cardiometabolic disease medicine.

Thanks, Wayne Good morning, and thank you for joining us on today's call.

Last year marked a new beginning per eye on his new leadership in place we laid out a bold new vision for the business and took important steps towards realizing our goal of having 12 or more medicines on the market in 2026.

Key to our new vision is our strategy to maximize the value of each medicine in our wholly owned portfolio today.

Today, our focus is primarily on commercializing our rare neurological and cardio metabolic disease medicines.

Brett P. Monia: For those opportunities outside these core areas, we will set a course forward that maximizes the value of each medicine, which may include Ionis commercialization or partnership. Last year, we accelerated our commercial strategy by acquiring Axia. This transaction also enabled us to strengthen our organization and to recognize the full value of Axia's rich product portfolio. Furthermore, our distribution agreement with Sobe made it possible for us to restructure our European operations, which further streamlined our business. We were able to unlock substantial resources through these transactions, which we are investing in the business in the following three key areas. First,

But those opportunities outside your core areas, we will set a course for that maximizes the value of each medicine.

May include eye on its commercialization or partnering.

Last year, we accelerated our commercial strategy by acquiring <unk>. This transaction also enabled us to strengthen our organization and to recognize the full value from <unk> rich product portfolio.

Further our distribution agreement with <unk> made it possible for us to restructure our European operations, which further streamlined our business.

We were able to unlock substantial resources in these transactions, which we are investing in the business in the following three key areas first we are advancing and expanding our wholly owned pipeline.

Brett P. Monia: We're advancing and expanding our wholly owned pipeline. Second, we're building our commercial capabilities in support of our rich pipeline as we prepare to launch prioritized medicines from the Ionis-Holyon pipeline, and third, we're broadening the reach of our technology through investments in medicinal chemistry, human genomics, validation of new routes of delivery, and through other means. We believe investing in these three key areas provides the greatest potential to drive future growth and to achieve our goal of 12 or more medicines on the market in 2026.

Second we're building our commercial capabilities in support of our rich pipeline as we prepare to launch prioritize medicines from the ion is hold on pipeline.

And third we're broadening the reach of our technology through investments in medicinal chemistry, human genomics validation of new routes of delivery and through other means.

We believe investing in these three key areas provides the greatest potential to drive future growth and to achieve our goal of 12 or more medicines on the market in 2026.

Okay.

Brett P. Monia: Last year, we made substantial progress towards achieving this goal, with numerous significant advances across our rich late and mid-stage pipeline. We now have six phase three studies underway, including three studies with polio medicine. We also have a prolific mid-stage pipeline of medicines advancing towards phase 3 development, many of which are expected to reach pivotal trials in the near term. With so many programs in mid to later stages of development, together with our historically high rate of clinical success, today we are in the enviable position of delivering a steady cadence of base-free data readouts for many years to come.

Last year, we made substantial progress towards achieving this goal with numerous significant advances across our rich late and mid stage pipeline.

We now have six phase III studies underway from three studies.

Volume holding on medicines, we also have a prolific mid stage pipeline of medicines advancing towards phase III development.

Many of which are expected to reach pivotal trials in the near term.

With so many programs in mid to later stages of development together with our historically high rate.

Success today, we are in the enviable position of delivering a steady cadence of phase III data readouts for many years to come.

Brett P. Monia: And we're especially excited about the upcoming phase 3 readout of the Valor study for Toprazin in patients with SOG1 ALS, with data expected in the second half of this year. Positive results from this study would put us one step closer to providing the first ever disease-modifying therapy for ALS.

And we're especially excited about the upcoming phase III readout on the Valor study from <unk> in patients with sovereign AOS with data expected in the second half of this year.

Positive results from this study will put us one step closer to providing the first ever disease modifying therapy for AOS and importantly positive results, but also provide for the first time tangible clinical evidence that treatment as possible for patients with AOS, providing hope for all patients.

Brett P. Monia: And importantly, positive Tilkerson results would also provide for the first time tangible clinical evidence that treatment is possible for patients with ALS, providing hope for all patients suffering from this devastating disease, and more broadly, Topherson's success once again demonstrates the power of our Anixin's technology to pioneer new markets and deliver transformational medicines to patients, in addition to advancing our pipeline. We're also expanding the utility of our technology, having now demonstrated proof of concept for aerosol delivery of antisense medicines to the lung.

Offering from this devastating disease.

Yes.

And more broadly tell for some success once again demonstrate the power of our antisense technology to pioneer new markets and deliver transformational medicines to patients.

In addition to advancing our pipeline.

We're also expanding the utility of our technology, having now demonstrated proof of concept for aerosol delivery manifest medicines alone.

Brett P. Monia: Based on these results, we're well on our way to building a new pulmonary disease franchise with the potential to treat conditions such as cystic fibrosis, COPD, IPF, and asthma. We've only scratched the surface of the unique capabilities of our antibiotics platform. With the medicines advancing in our pipeline today, we have the potential to continuously pioneer new markets in areas of significant unmet medical need and change the standards of care for diseases needing better treatment options for many years to come. As we begin the year in 2020, we could not have imagined the challenges society would face from the global COVID-19 pandemic.

Based on these results, we're well on our way in building the new pulmonary disease franchise with the potential to treat conditions, such as cystic fibrosis, COPD IPF and asthma.

We've only scratched the surface of the unique capabilities of our antisense platform.

The medicines advancing in our pipeline today, we have the potential to continuously pioneer new markets in areas of significant unmet medical need and change the standard of care for diseases needing better treatment options for many years to come.

As we begin as we began the year in 2020, we of course could not have imagined the challenges society with face from the global COVID-19 pandemic.

Brett P. Monia: Because of the dedication of our employees and the strength of our technology and our business, we were able to successfully manage the evolving pandemic and achieve our key goals for 2020. This includes achieving our 2020 financial guidance while advancing our pipeline and our technology. As Beth will describe in more detail, we plan to put our substantial financial resources to work even more this year by increasing our investments in our medicines and our technology.

Because of the dedication of our employees and strength of our technology and our business, we were able to successfully manage the evolving pandemic and achieve our key goals for 2020.

This includes achieving our 2020 financial guidance, while advancing our pipeline and our technology.

As Jeff will describe in more detail, we plan to put our substantial financial resources to work even more this year by increasing our investments in our medicines and our technology.

Brett P. Monia: We believe this has the greatest potential to drive future revenue and earnings growth. And with that, I'd like to turn the call over to Beth to review our 2020 financial results and our 2021 financial guidance, which is focused on maximizing the value of our wholly owned pipeline. Then Richard will discuss our key recent pipeline achievements and highlight important areas of focus for this year. After Richard, I'll wrap up. I'll make some remarks before taking your questions. Now, over to Beth.

We believe this has the greatest potential to drive future revenue and earnings growth.

And with that I'd like to turn the call over to Beth to review, our 2020 financial results and our 2021 financial guidance, which is focused on maximizing the value of our wholly owned pipeline.

Then Richard will discuss our key recent pipeline achievements and highlight important areas of focus for this year.

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

Elizabeth L. Hougen: Thank you, Brett. I'm pleased to say that we exceeded our 2020 guidance with revenues in excess of $700 million and net income of $111 million on a non-gap basis. We achieved these results while continuing to invest heavily in our rich pipeline with a focus on our wholly owned medicine. And we're particularly pleased with these results given the challenging global pandemic environment.

Thank you Brad.

I'm pleased to say that we exceeded our 2020 guidance with revenues in excess of $700 million.

And net income of $111 million on a non-GAAP basis.

We achieved these results while continuing to invest heavily in our rich pipeline with a focus on our wholly owned medicine.

And we're particularly pleased with these results given the challenging global pandemic environment.

Elizabeth L. Hougen: In the fourth quarter of 2020, we took important steps toward our goal of creating a stronger, more efficient company when we acquired Axia and moved our European operations to a distribution model. Together, these transactions unlocked substantial cost savings that we plan to reinvest to drive future revenue growth. I'll talk more about that in a few minutes, but first, I'll walk through our 2020 financial highlights, beginning with revenue. Last year, about 50% of our total revenue came from our marketed products, with the majority coming from Spinraza.

In the fourth quarter of 2020, we took important steps toward our goal of creating a stronger more efficient company. When we acquired axiom and moved our European operations distribution model.

Together these transactions unlocked substantial cost savings that we plan to reinvest to drive future revenue growth.

I'll talk more about that in a few minutes, but first I'll walk through our 2020 financial highlights beginning with revenue.

Last year about 50% of our total revenue came from our marketed products with the majority coming from <unk>.

Elizabeth L. Hougen: Most of the remaining 50% of our revenue came from eight different partners as together we advanced more than 20 programs. Our ability to generate revenue from numerous diverse sources is a key element of our financial strength. Finraza continued its blockbuster performance last year, generating over $2 billion in global sales. We earned $286 million in royalty revenue as a result, and virtually all of that revenue falls to our bottom line as a profit. Biogen remains committed to enhancing patient outcomes and reinforcing the proven efficacy and safety profile of Finraza in SMA patients of all ages. The RESPOND study and the DEVOTE study are two examples of this commitment.

Most of the remaining 50% of our revenue came from eight different partners together, we advanced more than 20 programs.

Our ability to generate revenue from numerous diverse sourcing is a key element of our financial strength.

And Ross It continued its blockbuster performance last year generating over $2 billion in global sales.

Earned $286 million in royalty revenue as a result, and virtually all of that revenue.

Bottom line as profit.

<unk> remains committed to enhancing patient outcomes and reinforcing the proven efficacy and safety profile and riser in SMA patients of all ages.

The response, Debbie and the devote study are two examples of this commitment.

Elizabeth L. Hougen: The response study, which is now underway, is evaluating Spinraza's potential benefit in SMA patients who have experienced a suboptimal response to gene therapy. And the DEVOTE study, which is evaluating the potential to deliver even greater benefits with higher doses of Spinraza compared to the currently approved dose, is now enrolling patients in the pivotal blinded cohort. Given Spinraza's robust efficacy and safety profile established in SMA patients of all ages, Srinivasan continues to be a foundation of care for the treatment of these patients.

The response study, which is now underway is evaluating the massive potential benefit in SMA patients who have.

<unk>.

Optimal response to gene therapy.

And the devote study, which is evaluating the potential to deliver even greater benefit with higher doses of <unk> compared to the currently approved dose is now enrolling patients in the pivotal blinded cohort.

Given <unk> robust efficacy and safety profile established in SMA patients of all ages.

<unk> continues to be a foundation of care for the.

Treatment of these patients and.

Elizabeth L. Hougen: And with over 11,000 patients on treatment at the end of last year and over 60,000 SMA patients in markets where Biogen has a commercial presence, we believe SINRAS' future remains bright. Tegceti and Waylivra had combined product sales of $70 million, an increase of more than 65% compared to 2019, as these medicines launched into new markets and new patients began treatment in existing markets. PigCity has demonstrated consistent quarterly growth since launch, driven by new patient growth in established markets such as the U.S. and in new markets across Europe. Last year, we achieved pricing and reimbursement in numerous new countries. Bringing the markets in which Tech Study is commercially available to 15.

And with over 11000 patients on treatment at the end of last year.

50000.

SMA patients in markets, where Biogen has a commercial person we beliefs on ross's future remains bright.

Take steady and we've never had combined product sales of $70 million, an increase of more than 65% compared to 2019 as these medicines launched into new markets and new patients began treatment in existing markets.

Take study has demonstrated consistent quarterly growth since launch driven by new patient growth in established markets such as the U S and in new markets across Europe.

Last year, we achieved pricing and reimbursement and numerous new country.

Bringing the market, which is steady and commercially available.

Elizabeth L. Hougen: Notably, we began generating revenue in countries across Southern Europe, including Portugal, which is strategically important because of its large endemic HATTR patient population. We began recognizing revenue in Canada, and we continue to expand into Latin America. Patients in Brazil and Argentina are being treated with TXETI under a named patient program administered by our partner PPC.

Notably we began generating revenue in countries across southern Europe, including Portugal, which is strategically important because of its large endemic ACP PR patient population.

We began recognizing revenue in Canada, and we continue to expand into Latin America.

Patients in Brazil, and Argentina are being treated with Chegg study under a named patient program administered by our partner <unk>.

In its first full year of commercial sales, we deliver achieved important successes despite the pandemic.

Elizabeth L. Hougen: In its first full year of commercial sales, Waylivre achieved important successes despite the pandemic. Through the efforts of our European team, we achieved pricing and reimbursement in six major European markets. Coelibra is under review for marketing authorization in Brazil through PTC, and we are optimistic about a potential approval this year.

Through the efforts of our European team, we achieved pricing and reimbursement in six major European market.

Whenever it is under review for marketing authorization in Brazil through PTC, and we are optimistic about our potential approval this year.

Elizabeth L. Hougen: PTC is continuing its efforts to expand access in other Latin American markets as well. During 2020, we earned R&D revenues of approximately $365 million, slightly above our annual average of $350 million. Approximately 80% of our R&D revenue is from medicines in our leading cardiometabolic and neurology franchises, with more than $165 million from our cardiometabolic franchise and over $125 million from our neurology franchise. Additionally, we earned nearly $50 million from Alvin Island last year.

<unk> is continuing continuing its efforts to expand access in other Latin American markets as well.

During 2020, we earned RMB revenues of approximately $365 million slightly above our annual average of $350 million.

Approximately 80% of our R&D revenues from medicines, and our leading cardio metabolic and neurology franchise net.

It's more than $165 million from our cardio metabolic franchise and over $125 million from our neurology franchise.

Additionally, we earned nearly $50 million from outlined on last year.

This included $41 million in Sublicense revenue, we earned in the fourth quarter, then we obtained favorable award and our arbitration from <unk>.

Elizabeth L. Hougen: This included $41 million in sub-licensed fees revenue we earned in the fourth quarter when we obtained a favorable award in our arbitration proceedings. As 2020 once again demonstrated, our ability to consistently earn revenue from multiple sources is a key pillar of our financial strength. As we projected in our 2020 guidance, our non-GAAP operating expenses increased compared to 2019. The increase was driven by growth of just over 10% in non-GAAP R&D expenses related to advancing our Phase III programs for TTR-LiCA and APOC-III-LiCA, plus our Holy Oak Medicine. Our SG&A expenses on a non-gap basis were slightly lower year over year, primarily due to reduced travel and related expenses due to the pandemic.

As 2020, once again demonstrated our ability to consistently earn revenue from multiple sources is a key pillar of our financial strength.

As we projected in our 2020 guidance on our non-GAAP operating expenses increased compared to 2019.

The increase was driven by growth of just over 10% and non-GAAP R&D expenses related to advancing our phase III program for <unk>.

And agency <unk>.

On our wholly on Madison.

Our SG&A expenses on a non-GAAP basis were slightly lower year over year, primarily from reduced travel and related expenses due to the pandemic.

We exceeded our net income guidance of meaningfully profitable with net income of $111 million on a non-GAAP basis, and we ended 2020 with nearly $2 billion in cash, enabling us to increase our investments across our business.

Elizabeth L. Hougen: We exceeded our net income guidance of meaningfully profitable with net income of $111 million on a non-gap basis, and we ended 2020 with nearly $2 billion in cash, enabling us to increase our investments across our business. As a result of our AXSEA and SOBE transactions. We recognized approximately $400 million of related expenses in Q4 last year. Importantly, most of these expenses were non-cash and non-recurring. We excluded these expenses from the non-GAAP results I just reviewed with you because they do not reflect our normal ongoing operation. These expenses were comprised of $31 million of severance and retention costs.

As a result of our axiom and <unk> transaction, we recognized approximately $400 million of related expenses in Q4 last year.

Importantly, most of these expenses were noncash and nonrecurring.

We excluded these expenses from our non-GAAP results I just reviewed with you because they do not reflect our normal ongoing operations.

Is expenses were comprised of $31 million of severance and retention costs.

$59 million of noncash stock based compensation expense and $312 million and a non cash adjustment of our valuation allowance for our federal deferred tax asset.

I'd like to just take a couple of minutes to provide some additional information about the adjustment to our valuation allowance.

Since <unk> IPO, we have been required to report our federal taxes as two separate companies.

Elizabeth L. Hougen: $59 million of non-cash stock-based compensation expense and $312 million in a non-cash adjustment of our valuation allowance for our Federal Deferred Tax Act. I'd like to just take a couple minutes to provide some additional information about the adjustments to our valuation allowance. Since Axia's IPO, we've been required to report our federal taxes as two separate companies. That meant that Xeus operating losses and R&D tax credits were not available to reduce Ionis' taxable income during that time.

That meant that XD is operating losses, and R&D tax credits were not available to reduce I honesty taxable income during that time.

As a result of the acquisition, we were able to reconsolidation of two companies for federal tax purposes.

And you'll know combined equity as expected losses on <unk> taxable income was <unk>.

Belting and tax losses for the next few years as we make significant investments to drive future revenue growth from our rich pipeline.

Elizabeth L. Hougen: As a result of the acquisition, we were able to reconsolidate the two companies for federal tax purposes, and we will now combine Axia's expected losses with Ionis's taxable income, resulting in tax losses for the next few years as we make significant investments to drive future revenue growth from our rich pipeline. Additionally, this means that pre-acquisition federal tax assets of nearly $300 million are now available to us to reduce our consolidated taxable income in the future. However, because we anticipate consolidated tax losses in the near term, we are required to establish a valuation allowance against these deferred tax assets.

Additionally, this means at pre acquisition federal tax assets of nearly $300 million are now available to us to reduce our consolidated taxable income in the future.

However, because we anticipate consolidated tax losses in the near term we are required to establish a valuation allowance against the deferred tax assets.

So while it's a large number it's important to note that this is a non cash adjustment based on technical accounting guidance.

And reflects the substantial tax benefits, we have available track to reduce our consolidated taxable income in the future.

Elizabeth L. Hougen: So while it's a large number, it's important to note that this is a non-cash adjustment based on technical accounting guidance and reflects the substantial tax benefits we have available to us to reduce our consolidated taxable income in the future. Now I'd like to provide some color on the financial benefits from our Axia acquisition and the restructuring of our European operations. Last year, we put our strong balance sheet to work when we reacquired Axia.

Now I'd like to provide some color on the financial benefits from our <unk> acquisition on the restructuring of our European operations.

Last year, we put our strong balance sheet to work and we reacquired ixia.

The acquisition provided us with significant financial benefits.

We retain the full value of XD as rich portfolio, which we expect to drive considerable revenue growth in the future.

Second we are realizing significant cost savings from the efficiencies we are achieving by operating as a single company.

Elizabeth L. Hougen: The acquisition provided us with significant financial benefits. First, we retain the full value of Axios' rich portfolio, which we expect to drive considerable revenue growth in the future. Second, we are realizing significant cost savings from the efficiencies we are achieving by operating as a single company. Third, we gained full access to XE's substantial cash balance of nearly $400 million at the time of the acquisition, enabling us to freely use it to maximize the value of our medicine, and fourth, we gain access to the nearly $300 million of XCS deferred tax assets I discussed a few moments ago.

Third we gained full access to see a substantial cash balance of nearly $400 million at the time of the acquisition, enabling us to freely used it to maximize the value of our medicines and.

And fourth we gain access to the nearly $300 million of vaccine.

He is deferred tax asset I discussed a few moments ago.

We are also realizing significant financial benefits from our <unk> transaction.

Restructuring, our European operations improved our bottomline by enabling us to distribute take steady and we live in a more cost effective manner by leveraging <unk> commercial infrastructure and reach across Europe.

Elizabeth L. Hougen: We are also realizing significant financial benefits from our SOBE transactions. Restructuring our European operations improves our bottom line by enabling us to distribute Tegceti and Weylivra in a more cost-effective manner by leveraging SoBi's commercial infrastructure and reach across Europe. As a result, we expect to realize substantial savings. In aggregate, we expect to realize more than $50 million of savings in 2021.

As a result, we expect to realize substantial savings.

In aggregate, we expect to realize more than $50 million of savings in 2021.

And we are putting these substantial savings to work on.

Investing them in other value driving areas of our business.

Now turning to our 2021 financial guidance.

We are projecting to earn more than 600 million EBITDA.

Afternoon, Inc.

Operating expenses in the range of 675 million to $725 million and in 2021 with a net loss of less than $75 million, assuming the low end of expenses.

Elizabeth L. Hougen: And we are putting these substantial savings to work by reinvesting them in other value-driving areas of our business. Now, turning to our 2021 financial guidance. We are projecting to earn more than $600 million in revenue, incur operating expenses in the range of $675 million to $725 million, and end 2021 with a net loss of less than $75 million, assuming the low end of expenses, all on a non-GAAP basis. Our 2021 guidance reflects our new strategy to maximize the value of our wholly owned medicine, focused primarily on commercializing our rare neurological and cardiometabolic disease programs.

On a non-GAAP basis.

Our 2021 guidance reflects our new strategy to maximize the value of our wholly owned medicine.

Focused primarily on commercializing, our rare neurological and cardio metabolic disease program.

Our guidance also reflects the shift in revenue per check Betty and way liver in Europe from product revenue to royalty rates.

As I mentioned, a few moments ago, our restructured European operations will provide us with substantial savings, which we are redeploying to achieve our growth objectives.

As we've always done our R&D revenue is probably is based primarily on the anticipated timing of the many different milestone payments, we anticipate achieving as we advance partnered programs.

Elizabeth L. Hougen: Our guidance also reflects the shift in revenue for Tixeti and Waylibra in Europe from product revenue to royalty revenue. As I mentioned a few moments ago, our restructured European operations will provide us with substantial savings, which we are redeploying to achieve our growth objectives.

As of this approach we have.

Have upside opportunity.

Particularly since we expect our R&D revenues to be higher in the second half of the year compared to the first half.

We expect our operating expenses to increase as we invest in driving future growth.

Elizabeth L. Hougen: As we've always done, our R&D revenue is probabilized based primarily on the anticipated timing of the many different milestone payments we anticipate achieving as we advance partnered programs. Because of this approach, we have upside opportunities, particularly since we expect our R&D revenues to be higher in the second half of this year compared to the first. We expect our operating expenses to increase as we invest in driving future growth. That means investing our resources in three key areas.

That means investing our resources in three key areas.

Advancing and expanding our wholly owned pipeline.

Building, our commercial capabilities and broadening the reach of our technology.

Our investments in our pipeline are focused on advancing our ongoing phase III studies for <unk> and <unk>.

Starting a new phase III study for <unk> in a larger patient population.

Advancing eye on 36, three in patients with ALS and the phase III development.

Continuing to progress our multiple mid stage programs.

Elizabeth L. Hougen: Advancing and Expanding Our Wholly Owned Pipeline, Building Our Commercial Capabilities, and Broadening the Reach of Our Technology. Our investments in our pipeline are focused on advancing our ongoing Phase 3 studies for TTR-Like and ApoC-3-Like, and starting a new phase 3 study for APOC3 Leica in a larger patient population. Advancing ION363 in patients with FUS ALS into Phase 3 development and continuing to progress our multiple mid-stage programs.

We are also investing in building our commercial capabilities.

With <unk>, we acquired a strong commercial foundation and we continue to build on that foundation.

Specifically, we have established a new products strategy strategy team, which is focused on go to market strategy and indication optimization ahead of launching our wholly owned benefit.

And we are investing to broaden the reach of our technology, ensuring our platform remains innovative and competitive.

We expect our R&D expenses to increase approximately 25% to 35% in 2021 compared to last year.

Elizabeth L. Hougen: We are also investing in building our commercial capability. With Axia, we acquired a strong commercial foundation, and we continue to build on that foundation. Specifically, we have established a new product strategy team, which is focused on go-to-market strategies and indication optimization ahead of launching our wholly-owned benefits. And we are investing to broaden the reach of our technology, ensuring our platform remains innovative and competitive. We expect our R&D expenses to increase approximately 25 to 35% in 2021 compared to last year.

And because most of our synergies are within SG&A, we expect our SG&A expenses to decrease.

We can increase our investments as I. Just described we are projecting a modest net loss this year because of our multiple sources of revenue on.

On a significant cost savings, we realized from acquiring <unk> and restructuring our European operations.

Our capital allocation strategy is focused on investing internally for growth.

We strongly believe this is the best use of our capital we are confident that investing in our medicine can grow future revenues at double digit rates as we bring more and more new medicines to the market and achieve our goal of 12 or more marketed products in 2020 from <unk>.

Elizabeth L. Hougen: And because most of our synergies are within SG&A, we expect our SG&A expenses to decrease. We can increase our investments, as I just described, while projecting a modest net loss this year because of our multiple sources of revenue and the significant cost savings we realized from acquiring Exia and restructuring our European operations. Our capital allocation strategy is focused on investing internally for growth. I strongly believe this is the best use of our capital.

Now I'll turn the call over to Richard.

Thank you Beth.

We made important progress across our portfolio in 2020, including moving many of our wholly owned programs closer to market.

We're pleased with the performance of our phase III assets with several key achievements last year, the phase III studies of <unk>.

For Huntington's disease, and <unk> for Shaoguan AOS achieved full enrollment.

We initiated phase III studies with two of our rare wholly owned cardio metabolic disease programs <unk> for patients with TCR cardiomyopathy enabled C III <unk> for patients with Fcs.

Elizabeth L. Hougen: We are confident that investing in our medicines can grow future revenues at double-digit rates as we bring more and more new medicines to the market and achieve our goal of 12 or more marketed products in 2026. And with that, I'll turn the call over to Richard.

And importantly, all six of our phase III studies continue to progress well.

We also made substantial progress with our mid stage programs, including reporting positive data from <unk> studies.

Richard S. Geary: Thank you, Beth. We made important progress across our portfolio in 2020, including moving.

And as you are saving more than 10, new phase II studies and expanding the reach of our technology by demonstrating our ability to safely deliver antisense medicines by aerosol to the alone.

Richard S. Geary: Moving many of our

Transcription Service: Transcription by Transcription Outsourcing, LLC. We're pleased with the performance of our Phase 3 assets, with several key achievements last year. The Phase 3 studies of Tominursin for Huntington's disease and Tofursin for SOD1 ALS achieved full enrollment. Additionally, we initiated phase 3 studies with two of our rare wholly-owned cardiometabolic disease programs, TTR-LRX, for patients with GTR cardiomyopathy, and ApoC3-LRAC, for patients with FCS. And importantly, all six of our phase three studies continue to progress well.

We are well positioned for a very busy year of catalysts. The first significant of which is the phase III data for the valor study of <unk> in patients with <unk> on the Nols.

AOS as a disease, particularly of importance for us because antisense technology is ideally suited to address the root causes of ALS, we have leveraged our platform to develop medicines to treat all forms of this disease today with four medicines in development, we believe we could true.

Transcription Service: We also made substantial progress with our mid-stage programs, including reporting positive data from six studies, initiating more than 10 new phase two studies, and expanding the reach of our technology by demonstrating our ability to safely deliver antisense medicines by aerosol to the lungs. We are well positioned for a very busy year of CATLAS, the first significant of which is the Phase 3 data for the VALOR study of Topherson in patients with SOT1 ALS. ALS is a disease particularly of importance for us. Because antisense technology is ideally suited to address the root causes of ALS, we have leveraged our platform to develop medicines to treat all forms of this disease.

<unk> have a surround.

<unk> has the potential to become the first disease modifying treatment for AOS, which we believe will fundamentally change the treatment landscape.

Positive Tophus and data.

It also gives us greater confidence for our programs for the treatment of other forms of ALS.

We believe <unk> may also have the potential to slow progression or even delay the onset of disease and pre symptomatic sod one AOS patients similar to the profound effects demonstrated by pre symptomatic SMA patient treated with spin Lazar before symptom onset.

Biogen plans to initiate the Atlas study this year.

Richard S. Geary: Today, with four medicines in development, we believe we could truly have ALS around. Toperson has the potential to become the first disease-modifying treatment for ALS, which we believe will fundamentally change the ALS treatment landscape. Positive Cochresan data would also give us greater confidence for our programs for the treatment of other forms of ALS. We believe Topherson may also have the potential to slow progression or even delay the onset of disease in pre-symptomatic SOD1 ALS patients. Similar to the profound effects demonstrated by pre-symptomatic SMA patients treated with Spinraza before symptom onset.

To address this question and hopefully demonstrate a similarly profound benefit from <unk> and pre symptomatic ALS patients.

Our next day AOS program to enter development is ion 363 for the treatment of fuss AOS.

Which we plan to move directly into a pivotal study.

<unk> shortly.

<unk> is a devastating rapidly progressive form of ALS caused by mutations in the <unk> gene. So we are pleased to be moving so rapidly to evaluate this medicine.

In patients with such a clear unmet medical need and importantly, ion three <unk> three <unk> first wholly owned AOS medicine to enter the clinic.

Richard S. Geary: Biogen plans to initiate the ATLAS study this year, to address this question and hopefully demonstrate a similarly profound benefit for Toverson in pre-symptomatic ALS. Our next ALS program to be developed is ION363 for the treatment of FUS ALS, which we plan to move directly into a pivotal study shortly. Plus ALS is a devastating, rapidly progressive form of ALS caused by mutations in the FUS gene.

In addition to these exciting AOS catalysts, we have a busy agenda from programs across our wholly owned portfolio.

Coming up on the first half of this year, we look forward the multiple catalysts, including key data.

Readouts and study initiations.

We plan to report top line phase III data from PKK L Rx and <unk> <unk> for the treatment of HIV and acromegaly, respectively. We also plan to present more detailed data from our enact to five Rx and <unk> programs.

Richard S. Geary: So we are pleased to be moving so rapidly to evaluate this medicine in patients with such a clear unmet medical need, and importantly, ION363 is Ionis' first wholly owned ALS medicine to enter the clinic. In addition to these exciting ALS catalysts, we have a busy agenda from programs across our wholly owned portfolio. Coming up in the first half of this year, we look forward to multiple catalysts, including key data readouts and study initiations.

At upcoming scientific meetings, taking place in May at.

At the American Thoracic Society meeting, we plan to present phase two data for <unk>, two five Rx in patients with cystic fibrosis.

And at the American College of Cardiology Conference, we plan to present phase two data for <unk> in patients with resistant hypertension. Each of these medicines has the potential to change the standard of care for these indications. Additionally, these medicines have the potential to address additional indications.

Richard S. Geary: We plan to report top-line Phase 2 data from PKK-LRX and GHR-LRX for the treatment of HAE and acromegaly, respectively. We also plan to present more detailed data from our ENAC 2.5 Rx and AGT LRx programs at upcoming scientific meetings taking place in May. At the American Thoracic Society meeting, we plan to present phase 2 data for ENAC 2.5 Rx in patients with cystic fibrosis, and at the American College of Cardiology Conference, we plan to present phase two data for AGT-LRX in patients with resistant hypertension.

Representing further opportunities for growth.

Looking at upcoming study initiations, we are very close to starting a phase II study for eye on $3 73 in patients with Alexander disease.

Together with ion $3 63 for patients with phosphate Alas.

These programs represent significant advancements among our wholly owned neurological disease medicines.

We plan to advance <unk> into a larger phase <unk> study and resistant hypertension patients on three or more anti hypertensive medications are population representative of real world patients. This study is expected to get underway. So we.

Richard S. Geary: Each of these medicines has the potential to change the standard of care for these indications. Additionally, these medicines have the potential to address additional conditions, representing Further Opportunities for Growth. Looking at upcoming study initiations, we are very close to starting a phase two study for Ion 373 in patients with Alexandria, together with Ion 363 for patients with fossaile asthma. These programs represent significant advancements among our wholly owned neurological disease medicines. We plan to advance GT-LRX into a larger Phase IIb study in resistant hypertension patients on three or more antihypertensive medications, a population representative of real-world patients.

We also plan to study <unk> in patients with heart failure in a phase III study expected to start mid year.

And also in the first half we look forward to advancing eye on two to four are wholly owned medicines targeting to get to and our most advanced medicine in development for Nash into a phase <unk> study.

Looking to the second half of this year, we expect even more key value driving events, we plan to further expand our pulmonary disease franchise based on our growing body of.

The data supporting aerosol delivery on antisense medicines to the lung in addition to continuing to advance our phase III study in patients with COPD, we look forward to advancing our cystic fibrosis development program with the initiation of a larger phase <unk> study of <unk> two five Rx in cystic fibrosis.

Richard S. Geary: This study is expected to get underway soon. We also plan to study AGT-LRX in patients with heart failure in a Phase II study expected to start mid-year. And also in the first half of this year, we look forward to advancing ION224, our wholly owned medicine targeting DGET2, and our most advanced medicine in development for NASH, into a Phase IIb study. Looking to the second half of this year, we expect even more key value-driving events.

As patients not amenable to <unk> modulators.

Biogen recently offered on early preview of our Alzheimers disease program, noting that map T. Rx demonstrated durable time and dose dependent reductions in CSF Tau protein and was generally well tolerated in the phase one two study in Alzheimer's disease patients.

Richard S. Geary: We plan to further expand our pulmonary disease franchise based on our growing body of data supporting aerosol delivery and antisense medicines to the lung. In addition to continuing to advance our phase two study in patients with COPD, we look forward to advancing our cystic fibrosis development program with the initiation of a larger phase two B study of ENAC 2.5 Rx in cystic fibrosis patients not amenable to CFTR modulator. Biogen recently offered an early preview of our Alzheimer's disease program, noting that MAP-T-RX demonstrated durable time and dose-dependent reductions in CSF-Tau protein and was generally well-tolerated in the Phase I-II study in Alzheimer's disease patients.

Yes.

With Biogen, we look forward to reporting these results later this year.

And as I mentioned, we of course look forward to data from Phase III Valor study October so on the inpatients with sub on AOS later in the second half.

In addition in the first half of this year, we plan to host a series of disease focused educational webinars with invited experts who will discuss current.

Treatment options and needs for patients with cystic fibrosis, hereditary angioedema and acromegaly, we look forward to hosting these webinars prior to topline data reports for each of these programs around the middle of the year, we plan to wrap up the series with an investor focused webcast to talk specifically about.

Richard S. Geary: With Biogen, we look forward to reporting these results later this year. And, as I mentioned, we, of course, look forward to data from the Phase 3 VALOR study of dopers in inpatients with SAG-1 ALS later in the second half. In addition, in the first half of this year, we plan to host a series of disease-focused educational webinars with invited experts who will discuss current treatment options and needs for patients with cystic fibrosis, hereditary angioedema, and acromegaly. We look forward to hosting these webinars prior to top-line data reports for each of these programs.

Data from these programs in the context of the unmet market need.

Importantly, with our pipeline progress to date and our key anticipated data catalysts this year.

We are well positioned for a steady cadence of phase III data for years to come these.

These data support our goal of 12 or more medicines on the market in 2026, including potentially six or more wholly owned medicines.

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

Richard S. Geary: Around the middle of the year, we plan to wrap up this series with an investor-focused webcast to talk specifically about data from these programs in the context of unmet market needs. Importantly, with our pipeline progress to date and our key anticipated data catalysts this year, we are well positioned for a steady cadence of Phase 3 data for years to come. These data support our goal of 12 or more medicines on the market in 2026, including potentially six or more polio medicines. And with that, I'll turn the call back over to Brett to close this portion of the call. Thanks, Richard.

Thanks Richard.

This is an exciting time for eye on as we expect to accelerate our next stage of growth and deliver a growing number of new transformational medicines to patients in need.

We have the potential to bring three new medicines to market by 2023 and looking further ahead.

We are well on our way to achieving our goal of 12 or more medicines on the market in 2026 over half from our wholly owned pipeline.

In support of our new vision to commercialize our wholly owned medicines, we're making significant investments to aggressively advance. These programs forward and also as part of our strategy as the wholly owned pipeline develops we're setting our plans to determine the best path forward for each asset to maximize value to patients and to shareholders.

Brett P. Monia: This is an exciting time for Ionis as we expect to accelerate our next stage of growth and deliver a growing number of new transformational medicines to patients in need. We have the potential to bring three new medicines to market by 2023, and looking further ahead, we're well on our way to achieving our goal of 12 or more medicines on the market in 2026, more than half from our Holy One Pipe.

And from across our entire pipeline forward to a continuous flow of phase three data readouts for many years to come.

In addition to investing in our wholly owned pipeline, we're investing in building, our commercial capabilities and implementing our plans to commercialize our own medicines, advancing our technology and potentially expanding with new technologies that complement our antisense platform.

We believe these investments will provide substantial returns, including double digit revenue growth.

Brett P. Monia: In support of our new vision to commercialize our wholly-owned medicines, we're making significant investments to aggressively advance these programs forward. And also, as part of our strategy, as the wholly-owned pipeline develops, we're setting our plans to determine the best path forward for each asset to maximize value to patients and to shareholders. And across our entire pipeline, we look forward to a continuous flow of phase three data readouts for many years to come.

And this growth will be driven a successful phase three programs enter the market generating more value from the wholly owned programs we commercialized.

And from those programs partner today, and those we retained longer before we partner in the future.

Before we close this portion of the call I wanted to take a moment to recognize rare disease day, which has been celebrated around the world. This week.

For many years I own. This is dedicated to continuously dedicated substantial resources to serve patients suffering from rare diseases, such as SMA and ALS.

Brett P. Monia: In addition to investing in our wholly owned pipeline, we're investing in building our commercial capabilities and implementing our plans to commercialize our own medicines, advancing our technology, and potentially expanding it with new technologies that complement our antisense platform. We believe these investments will provide substantial returns, including double-digit revenue growth.

We're proud to say that in the case of SMA. We at Aon has pioneered a new market and brought the first disease modifying medicine to.

These patients many of whom are with us today because of spin loans.

And in the case of AOS in just a few short months, we again have the potential to deliver the first disease modifying medicine to treat AOS.

We're proud of these achievements, but we're only at the beginning.

Yes.

Of course rare disease day is about the patients and families living with rare diseases, where our strong partnerships with these brave people. We are confident that we will continue to provide transformational medicines for more patients for many years to come.

Brett P. Monia: And this growth will be driven as successful phase three programs enter the market, generating more value from the wholly-owned programs we commercialize and from those programs we partner today and those we retain longer before we partner in the future. Before we close this portion of the call, I want to take a moment to recognize Rare Disease Day, which is being celebrated around the world this week. For many years, Ionis has dedicated and continues to dedicate substantial resources to serve patients suffering from rare diseases such as SMA and ALS.

With that in mind. Please join me in recognizing celebrating his dedication and accomplishments of the brave patients suffering from devastating rare diseases as well as the families who care for them.

And with that I'll open the call for questions.

We will now begin the question and answer session to ask a question you May Press Star then one on your Touchtone phone. If you are using a speakerphone. Please pick up your handset before pressing the keys.

If at any time. Your question has been addressed and you would like to withdraw your question. Please press Star and then two.

Brett P. Monia: We're proud to say that in the case of SMA, we at Ionis pioneered a new market and brought the first disease-modifying medicine to these patients, many of whom are with us today because of spinal onset. And in the case of ALS, in just a few short months, we again have the potential to deliver the first disease-modifying medicine to treat ALS. We're proud of these achievements, but we're only at the beginning. Of course, Rare Disease Day is about the patients and families living with rare diseases.

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

And the first question comes from Yaron Werber with Cowen. Please go ahead.

Great. Thanks, so much for taking my progress from and really nice progress.

Two questions from majors, who your housekeeping and then a question more about the pipeline just on.

In terms of the comp line your guidance for more than 600 revenues group.

Can you give us a little bit of a sense. How are you looking at spin around growth.

We're expecting it to be kind of flattish on the growing segments or are you expecting a little growth.

Operator: Through our strong partnerships with these brave people, we're confident that we will continue to provide transformational medicines for more patients for many years to come. With that in mind, please join me in recognizing and celebrating the dedication and accomplishments of the brave patients suffering from devastating rare diseases, as well as the families who care for them. And with that, I'll open the call for questions. We will now begin the question and answer session. To ask a question, you may press star, then one on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing star.

Greenough collaborative revenues you mentioned on a go to ramp on the second half, but anything you can guide US there and then a quick question on net two five.

Technology, I mean, we're going to get data shortly the study is fully characterized.

And you're noting that you refer to phase two do now which is new this year.

Can you just remind us.

Are we mostly going to be looking at expression in the CF patients who are we going to be able to also look at some carnival.

Pulmonary function. After if you want or is this credit is too small of a phase two thank you.

Sharing on good.

Turning on.

So thinking about our topline guidance.

This year.

When you think about the commercial revenue stream really the only impact to commercial revenue is.

Yaron Benjamin Werber: If at any time your question has been addressed and you would like to withdraw your question, please press star and then. At this time, we will pause momentarily to assemble our roster. And the first question comes from Yaron Werber with Cowan. Please go ahead. Great, thanks so much for taking my progress, and really nice progress. Two questions, Beth, maybe just for you, housekeeping, and then a question more about the pipeline. Just on, in terms of the top line, your guidance for more than 600 million in revenues, can you give us a little bit of a sense of what it is? How are you looking at Spinoza?

Is that the transition from <unk> steady and we live rep from.

On.

From a product sales on top line in Europe to royalty revenue in Europe.

We continue to think that <unk> has a very bright future as I mentioned.

We see the.

The opportunity to continue to expand the numbers of patients on treatment.

Primarily outside of the United States, but I think the strong efficacy has been rather that's been well established in more than 11000 patients for seven plus years.

Elizabeth L. Hougen: Are you kind of expecting it to be kind of flattish in the growing segments? Or are you expecting a little growth and, I know the collaborative revenues you mentioned are going to ramp up more in the second half, but anything you can guide us there. And then a quick question on ENIX 2.5 technology. I mean, it sounds like we're going to get data shortly. The study is fully dosed to Phase IIa, and you're noting that you'll start a Phase IIb now, which is new in CF this year.

For many of those patients.

Bodes well for <unk> future and so we're not anticipating.

On a negative impact at all on the top line with regard to NASDAQ.

And then on R&D revenues.

As we always do we probably rise there's many many milestone opportunities we have over the course of the year.

And by doing that we know that.

We have lots of opportunity to overachieve on our top line.

Elizabeth L. Hougen: Can you just remind us, are we mostly going to be looking at expression in the CF patients, or are we going to be able to also look at some kind of pulmonary function like FEV1, or is the study just too small, the Phase IIa? Thank you.

As the year progresses, and we achieved those milestone events and the payments that go with them. So starting here in February.

We'd like to.

Make sure that we have guidance that we can achieve.

Elizabeth L. Hougen: Sure Yaron, good morning. So thinking about our top line guidance for this year, when you think about the commercial revenue stream, you know, really the only impact on commercial revenue is the transition for Tech City and Winn-Libre from a product sales top line in Europe to royalty revenue in Europe. You know, we continue to think that Spinraza has a very bright future, as I mentioned. We see the opportunity to continue to expand the numbers of patients on treatment, primarily outside of the United States.

<unk> consistently in the past, we have outperformed that guidance and.

And we certainly have those opportunities this year as well.

Thanks, Doug.

And to address.

I'm sorry was there a follow up I was just going to ask Beth just remind us if you don't mind with sobey.

The royalty and milestone agreements on what you've disclosed so we'll make sure everybody gets this correct on the models. Thank you.

Yes, sure we haven't disclosed the actual royalty percentage.

But think about it.

In the general range of.

Royalties associated with a drug that we share in many of the <unk>.

Elizabeth L. Hougen: I think the strong efficacy of Spinraza that's been, you know, well established in more than 11,000 patients for, you know, seven plus years for many of those patients really bodes well for Spinraza's future. And so, we're not anticipating, you know, a negative impact at all on the top line with regard to Spinraza.

Post marketing activities. So we're continue to.

See supply drug and handle the distribution we continue to.

On to manage safety, we continue to be actively involved with kols in this setting the global strategy.

And working very closely with Zalviso think about it really as a as a relationship in which we share in the the opportunities for topline growth.

Okay.

And then.

Elizabeth L. Hougen: And then on R&D revenues, you know, as we always do, we probabilize the many, many milestone opportunities we have over the course of the year. And by doing that, you know, we know that we have lots of opportunity to overachieve on our top line as the year progresses and we achieve those milestone events and the payments that go with them. So, you know, starting here in February, we like to make sure that we have guidance that we can achieve, but consistently in the past, we have outperformed that guidance, and we certainly have those opportunities this year as well.

To address your questions Yaron on <unk>, So as a reminder, last year we.

<unk> demonstrated that.

Presented data on.

Demonstrating robust reductions.

<unk> levels in the lung of normal volunteers following aerosol weekly delivery with excellent safety and Tolerability this year at the <unk>.

<unk> meeting in May we plan to present.

Our first data in patients with cystic fibrosis.

And in our Phase II study, which is complete now and we will share the results from that study.

In that study indeed.

Eric E. Swayze: Thanks, guys. And to address EPR, I'm sorry, was there a follow-up? I was just going to ask Beth, just remind us, if you don't mind, about SOBE, the royalty and milestone agreement and what you've disclosed, so we'll make sure everybody gets this right in the models. Thank you.

Because this is our first experience and patient safety and Tolerability ability will be very important to demonstrating and we're looking forward to share on those results. In addition, as you said it's a small study is also a short study I think it's three months or so on duration, but.

But we will we will be presenting data on lung function.

Elizabeth L. Hougen: Yep, sure. We haven't disclosed the actual royalty percentage, but think about it in the general range of royalties associated with a drug that we share in many of the post-marketing activities. So we continue to supply the drug and handle the distribution. We continue to, you know, manage safety. We continue to be actively involved in KOLs and in setting the global strategy and working very closely with Sobeys. So think about it really as a relationship in which we share in the opportunity for top-line growth.

And we're very much looking forward to sharing to presenting that data.

Yes this year.

So stay tuned for that.

And then in addition, just as a reminder, <unk> is the first of several drugs moving into development for pulmonary diseases with delivered by aerosol, we're starting planning to start another clinical trial this year.

To coincide with the index studies and also the EBIT. We also have a phase II study for <unk> in COPD that's ongoing.

And then more coming behind.

Clinical start this year so.

We're very much looking forward to building this franchise out from pulmonary diseases.

The next question from Vivek.

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

Eric E. Swayze: And then to address your questions, Yaron, on ENAC, so as a reminder, last year, we demonstrated and presented data demonstrating robust reductions of ENAC levels in the lung of normal volunteers following aerosol weekly delivery with excellent safety and tolerability. This year, at the ATS meeting in May, we plan to present our first data in patients with cystic fibrosis and in our phase two study, which is complete now. And we'll share the results of that study.

Hey, this is Alexandra Paul Thanks for taking the question.

I was just curious about this new program for the.

<unk> product and what the rationale is for that mechanism of action and weather development. There is pending anything in hypertension.

You plan to go on that direction, regardless of how the hypertension program goes thanks.

Do I take that sure.

Happy to so as.

You know rasp inhibitors have been used in heart failure.

Eric E. Swayze: In that study, indeed, and because this is our first experience with patients, safety and tolerability will be very important to demonstrate, and we're looking forward to sharing those results. In addition, as you said, it's a small study. It's also a short study. I think it's three months or so in duration.

Our preclinical work certainly points to a robust effect.

By targeting angiotensin engine in heart failure models.

In addition to that.

The idea here.

It was certainly not a new one.

The design of the study and half from patients allows us in a population where a lot is known.

Eric E. Swayze: But we will be presenting data on lung function, and we're very much looking forward to sharing and presenting that data at AGS this year, so stay tuned for that. And then, just as a reminder, ENAC is the first of several drugs moving into development for pulmonary diseases delivered by aerosol. We're planning to start another clinical trial this year to coincide with the ENAC studies and also the ENAC phase two study for ENAC and COPD that's ongoing. And then more coming behind the clinical start this year.

About heart failure, and the effects of <unk> inhibitors.

As well as safety in that regard will allow us to do a strong proof of concept study, it's powered to get us a bit more information now moving on Biomarkers, but also on functional output. So we're excited about getting.

Our first look in heart failure in humans with with reduced.

With the reduced effect.

Yes.

And as a reminder, Alex again, we're planning to present much.

Richard S. Geary: So we're very much looking forward to building this franchise out for pulmonary disease. The next question comes from Paul Mattheis with Stiefel. Please go ahead. Hey, this is Alexander Paul.

A much more detailed data full dataset from.

From our phase II study in patients with refractory hypertension.

<unk>.

Great. Thank you.

Youre welcome.

The next question comes from Jim <unk> with Wells Fargo. Please go ahead. Please go ahead.

Richard S. Geary: Thanks for taking the question. I was just curious about this new HFREF program for the AGT product and what the rationale is for that mechanism of action and whether development there is pending anything in hypertension or if you plan to go in that direction, regardless of how the hypertension program goes. Thanks. Richard, would you like to take that? Sure. Happy to.

Hey, guys. Congrats on all the progress terrific stuff, maybe on the financials and then a pipeline question on the financials just.

That is the spin rozzer royalty outlook contemplate some COVID-19 recovery and less spacing out of interest equal injections, just interested on how youre thinking about that and then remind us. If you are at the point with PTC.

Richard S. Geary: So, as you know, brass inhibitors have been used in heart failure. And our preclinical work certainly points to a robust effect by targeting angiotensinogen in heart failure models. In addition to that, the idea here... is certainly not a new one, but the design of the study in the half-rep patients allows us to study a population where a lot is known about heart failure and the effects of RAS inhibitors, as well as safety in that regard, will allow us to do a strong proof-of-concept study. It's designed to get us a bit more information, not only on biomarkers but also on functional output.

Where you've reached the sales threshold, where youre participating in some of the upside from Latin America for Chegg study and way liver.

Sure Hi, Tim.

So it's been rather.

I think we and Biogen certainly anticipate Pat on the Covid environment is going to ease over the course of this year.

And as Biogen noted in their year end earnings call, a few weeks ago and Theyre already seen patients move back to enlarge the from a competitive products primarily because.

Richard S. Geary: So we're excited about getting, you know, our first look at heart failure in humans with reduced extremities, with the reduced effect. And as a reminder, Alex, again, we're planning to present much more detailed data, the full data set for our phase two study in patients with refractory hypertension at ACC. Great, thank you. The next question comes from Jim Birchall, at Wells Fargo.

They are seeing.

On the need for the efficacy that's been Rozzer on Florida.

And so the fact that that's already started in the fourth quarter and we anticipate that to continue on throughout this year into.

And to be aided by the fact that the <unk>.

Pandemic is starting to in certainly in the U S and around the world as well.

Jonathan Birchall: Please go ahead. Hey, guys, congrats on all the progress. Terrific stuff. Maybe on the financials and a pipeline question on the financials. Just Beth, does the Spinraza Royalty Outlook contemplate some COVID recovery and less spacing out of intrathecal injections? It's just interesting how you're thinking about that. And then remind us if you're at the point.

From PTC, we were we hit that point, where we started the clock on the on the 12 months and so we would anticipate.

That we may be able to see some some contribution from PTC sales in Latin America. This year, but it will be late this year.

Great. That's helpful. And then maybe on the pipeline and per Richard just on <unk> could you speak about the.

Elizabeth L. Hougen: Thank you for participating in some of the Upside from Latin America.

Transcription Service: Transcription by CastingWords

Elizabeth L. Hougen: takes fatty and whey liver.

Operator: [inaudible]

Elizabeth L. Hougen: Sure. Hi Jim.

The strength of supportive data, whether it's just the biologic rationale or any preclinical data and how that compares to the strength of support for sod. One AOS just trying to get a sense of how validating one may be for the other and then.

Elizabeth L. Hougen: So with Spinraza, you know, I think we and Biogen certainly anticipate that the COVID environment is going to ease over the course of this year. And as Biogen noted in their year-end earnings call a few weeks ago, they're already seeing patients move back to Spinraza from a competitive product, primarily because they're seeing, you know, the need for the efficacy that Spinraza affords. And so the fact that that has already started in the fourth quarter, and we anticipate that to continue throughout this year and be aided by the fact that the pandemic is starting to ease, certainly in the U.S. and around the world as well.

Part is just on your.

Chart of catalysts and milestones.

Huntington's update in terms of natural history study an open label extension is lifted sometime in 2021, and so just maybe if you could give us a sense of what you would expect to see in contrasting those two groups. Thanks.

Yes.

I'll give a high level and then I'll pass it over to.

My colleague Eric too.

I have a little bit.

Plus AOS of course is a monogenic.

Elizabeth L. Hougen: For PTC, we were, you know, we hit that point where we started the clock on the 12th month. And so we would anticipate that we may be able to see some contribution from PTC sales in Latin America this year, but it will be late this year.

Form and hereditary form of AOS.

And because there is a known causative.

Genetic component here that we can directly we can.

Can directly.

Target.

We believe that the phosphate ALS compounds, which we've shown is a very good drug for lowering.

Eric E. Swayze: Great, that's very helpful. And then maybe on the pipeline and, for Richard, just on FUS-1 ALS. I was just going to talk about the strength of supportive data, whether it's just the biological rationale or any preclinical data, and how that compares to the strength of support for SOD1 ALS, just trying to get a sense of how validating one may be for the other. And then a second part is just on... A Huntington's Update in terms of Natural History Study and Open Label Extension is scheduled sometime in 2021, and so just maybe to give us a sense of what you would expect to see in comparing those two groups.

Bus the bus genetic component.

Bodes well for us and allows us in fact with our conversations with regulatory to move directly into.

A study that is registrational and.

And I'll pass it over.

Over to Erik for any other comments.

Thanks Richard.

It's most of the REIT versus the known genetic cause of ALS much like sod one drive sub one AOS is known to be a perfect pathogenic protein, which accumulates on aggregates themselves and so it's similar to <unk> that we're reducing genetic cause and reducing the pathogenic protein and we do have preclinical data.

Eric E. Swayze: Thanks. Yeah, I'll give a high level and then I'll pass it over to my colleague, Eric, to flesh it out a little bit. Plus ALS, of course, is a monogenic form and hereditary form of ALS, and because there is a known causative genetic component here that we can directly, we can directly target, we believe that the FUS-ALS compound

This supports that reducing fast and provide a benefit so I do think it's similar to the <unk> program in that regard.

And then I think you asked about Huntington, what Roche is planning to present and I can just really refer you to their statements where there are continuing to plan to present some data from the open label study a natural history study at.

Eric E. Swayze: which we've shown is a very good drug for lowering FUS to FUS genetic component bodes well for us and allows us, in fact, with our conversations with regulatory authorities, to move directly into a study that is registration. And I'll pass it over to Eric for any other comments. Yeah, thanks, Richard. It's mostly right. FUS is a known genetic cause of ALS, much like SOD1 drives SOD1 ALS. It's known to be a pathogenic protein that accumulates and aggregates in cells.

Some point in 2021.

And then beyond that but we're really.

<unk> focused on the phase III study, which is progressing.

Scheduled first readout in 2022, which I think is the key definitive experiment for Huntington's disease.

Great. Thanks for taking the questions guys.

Thanks, Ken.

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

Hey, guys good morning.

Couple of questions.

On the financial side, you guys have.

<unk> been profitable over the last few years, so I guess based on the guidance this would be the first year.

Eric E. Swayze: And so it's similar to Toberson in that we're reducing a genetic cause and reducing a pathogenic protein. And we do have preclinical data that support that reducing FUS can provide a benefit. So I do think it's similar to the Toberson program in that regard. And then I think you asked about Huntington and what Grosch is planning to present. And I can just really refer you to their statements where they are planning to present some data from the Open Label Study and the Natural History Study at some point in 2021. And then beyond that, we're really focused on the Phase 3 study, which is progressing and scheduled for its readout in 2022, which I think is the key definitive experiment for Huntington.

Turning to net loss and obviously that's justified.

By having pushing our wholly owned programs moving forward, but should we expect kind of a modest net loss like this for the foreseeable future on the next several years.

Sure.

Continue to grow and then.

The second question on the pipeline is just related to.

The phase III programs, we have with <unk>.

Decent amount of clarity on the phase III programs, when we'll get those readouts when they could reach the market, but I guess as we look across.

The two of the four phase III readouts over the course of the first half.

Which one of those do you think could make it to market first store, which one or two.

When might that be.

Okay.

So thanks.

Thanks for the questions Tyler and good morning.

We have.

Jonathan Birchall: Great. Thanks for taking the questions, guys. Thanks, Kenny. The next question comes from Tyler Van Buren with Piper Sampson. Please go ahead. Hey guys, good morning. Just a couple questions. You know, on the financial side, you guys have been profitable over the last few years. So I guess, based on the guidance, this would be the first year you guys would be turning a net loss, and obviously that's justified by having, you know,

We're in a enviable position with a very strong balance sheet at Aon is to invest in all aspects of the pipeline and our commercial strategy and our technology.

To really maximize the value.

For Ireland is to grow our owners for the benefit of patients shareholders and the like.

And that's exactly what we're doing now as you know.

And we're going to continue to do that.

Two two.

To maximize.

Tyler Van Buren: The program is moving on.

Our upside in all possible ways, we're not really projecting right now what next year on year. After we will.

Operator: Should we expect a modest net loss like this for the foreseeable future in the next several years, or will it continue to grow? And then the second question on the pipeline is just related to...

Look like.

But we will continue to invest over the next few years of course, we also have the benefit of <unk>.

Brett P. Monia: We have a decent amount of clarity on the phase three programs when we'll get those readouts, when they could reach the market. But I guess as we look across, You know, the two or the four phase two readouts over the course of the first half, which one of those do you think could make it to market first, or which one or two, and when might that be? So thanks for the questions, Tyler, and good morning. We are in an enviable position with a very strong balance sheet at Ionis to invest in all aspects of the pipeline and our commercial strategy and our technology to really maximize the value for Ionis, to grow Ionis for the benefit of patients, shareholders, and the like.

Multiple sources of revenue as bedroom.

And her presentation as well as achieving reminds us all the time.

<unk> through R&D revenue partnerships as well as our commercial revenue and we expect our net net commercial products to be 12%.

And Peter you are like a polyneuropathy and.

Huntington potential.

Potentially those three medicines, reaching market in 2023, so you can see how the commercial revenue as well as the R&D revenue really offset arent those investments in the future too early to project on profitability for 2022.

But certainly we're going to be continuing to invest that's would you like to add anything to that no. I think that was I think that was extremely well said Brett.

Brett P. Monia: And that's exactly what we're doing now, as you know, and we're going to continue to do that to maximize, you know, our upside in all possible ways. We're not really projecting right now what next year or the year after will look like, but we will continue to invest over the next few years. Of course, we also have the benefit of multiple sources of revenue, as Beth will. I said in her presentation, as she reminds us of all the time, through R&D revenue, partnerships, as well as our commercial revenue, and we expect our next commercial product to be Toprazin and a TTR-like polyneuropathy, and Huntington, potentially those three medicines reaching the market in 2023, so you can see how the commercial revenue, as well as the R&D revenue, really offset those investments in the future. Too early to project Beth, would you like to add anything to that?

Maybe the only thing I will add is that.

We have a long history of financial discipline, and we will continue to exercise that discipline while.

Investing deeply in our wholly owned pipeline and our technology and really ensuring that our medicines.

Our prepared and ready to successfully launch when they get to market.

And as far as your Tyler.

Tyler on your question on.

Phase II, Readouts, which we have a lot coming on.

On the first after this year, we have three wholly owned rare disease programs hereditary angioedema.

Acromegaly as well as the <unk> cystic fibrosis program.

I think based on what we see as the next step for those programs and the size of the next.

Studies that would require them.

Elizabeth L. Hougen: No, I think that was, I think that was extremely well said, Brett. Maybe the only thing I would add is that, you know, we have a long history of financial discipline. And we will continue to exercise that discipline while investing deeply in our wholly owned pipeline and our technology and really ensuring that our medicines are prepared and ready to successfully launch when they get to market.

Allow them to be registered and improved I would have to say that.

The program with new Richard is the furthest along the pending positive data from the.

Study thats going to read out this year the first half of this year.

It is probably positioned well for two pivotal study would you say Richard sure I would say that the.

After the phase <unk> for cystic fibrosis, there would be positioning for phase III, but there is work to be done there.

Brett P. Monia: And as far as your, Tyler, your question on phase two readouts, which, you know, we have a lot coming, the first half of this year we have three wholly owned rare disease programs, hereditary angioedema, acromegaly, as well as the ENAC, Cystic Fibrosis Program. I think, you know, based on what we see as the next step for those programs and the size of the next studies that would require them, that would allow them to be registered and approved, I would have to say that the acromegaly program, when you, Richard, is the furthest along that pending positive data from the study that's going to read out this year, this first half of this year, is probably positioned well for, to move to a pivotal study, wouldn't you say, Richard? Sure. I would say that the.

And then for PKK Al you also on a position.

Depending on the results of this phase II study, but if if positive that too could move relatively quickly.

Thanks for taking the questions.

Thank you Kyle.

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

Congrats on all burgers from thank you very much for taking the question. Maybe just one quick question I was wondering if you had a little more experience dosing RNA into the CNS. How do you think about likely dosing regimen for this I noticed for example that the.

Firstly on that program is dosed I guess.

After the initial loading dose every every two months, which was kind of the.

At the midpoint of the doses you try to keep moving somewhat less frequent dosing then.

Richard S. Geary: After the Phase IIb for Cystic Fibrosis, there would be positioning for Phase III, but there's work to be done there. And then for PKKL, you're also in a position of depending on the results of this phase two study, but if they're positive, that too could move relatively quickly.

And then the follow on program, how do you think about that.

Dosing required to treat CNS diseases.

Eric loans, yes.

Yes sure.

Sure.

I mean.

We're always looking at extending our dosing regimen, and making them consistent with the duration of action of the drug.

And so on earlier programs.

Richard S. Geary: Right. Thanks for taking the question. Thank you, Tyler. The next question comes from Vincent Chen with Bernstein. Please go ahead.

We're working out how to dose the CNS and learning how to get the.

Drugs.

Book delivered in a way that they could reduce their targets understanding those relationships and as we learned more and more when we bid on it we're understanding how to extend the dosing regimen. So I would look for continued expansion and extension of our dosing regimens in the clinic is a key objective and we think the profile of the drug supports it and were working across all of our clinical programs to try and understand.

Vincent Chen: Congratulations on all the progress and thank you very much for taking the time to answer the question. Maybe just one quick question. I was wondering, now that you've had a little more experience dosing RNA into the CNS, how do you think about likely dosing regimens for this? I noticed, for example, that the FUS ALS program is dosed, I guess, after the initial loading dose every two months, which is kind of the midpoint of the doses you tried in some regions and somewhat less frequent dosing than the SOG1 program. How do you think about the dosing required to treat a CNS disease? Eric, do you want to jump in? Yeah, sure. Hi Vincent.

How we can best extend dosing because obviously extended dosing is much more convenient for patients and an example of that would be on the Huntington's program, where we work with Roche to get the every four month dosing into the phase III program.

That's ongoing and scheduled to read out on 2022, So we think thats on the benefit and we can transfer that and hopefully extended across all programs and.

And if I could just add to that.

If I could just add to that very quickly.

On.

Our strategy to enhance.

The durability and reduced dosing frequency is coming in two forms right.

Eric E. Swayze: I mean, we're always looking at extending our dosing regimen and making it consistent with the duration of action of the drug. And so in earlier programs, we were working out how to dose the CNS and learning how to get the drugs, the every four-month doses into the Phase 3 program that's ongoing and scheduled to read out in 2022. So we think that's a good benefit, and we can transfer that and, hopefully, extend it across more programs. And if I could just add to that...

We're learning how to select molecules.

More optimally that allows us to have a longer duration of effect and also through medicinal chemistry.

New Chemistries that are coming down on the pipe.

And then the last thing I would mention is.

As we and Biogen have said we've demonstrated.

Very durable reductions in town.

In our study with <unk> T in patients with mild Alzheimer's disease net data will be presented this year and I think it can be very telling how durable that is of the effects, we're seeing that molecule.

Brett P. Monia: If I could just add to that really quickly, then... You know, our strategy to enhance durability and reduce dosing frequency is coming in two forms, right? We're learning how to select molecules more optimally that allows us to have a longer duration of effect and also through medicinal chemistry. New chemistries that are coming down the pipe. And then, the last thing I would mention is, as we and Biogen have said, we have demonstrated very durable reductions in tau in our study with MAPT in patients with mild Alzheimer's disease, and that data will be presented this year.

Have you gained any insight into I guess.

Using the Huntington's data, where you do now have some patients who have been treated on every four months.

Dosing I guess the open label extension of the initial generation 81 patients have you gained incrementals were a PK PD insights into into sort of what I guess feasibility of longer dosing and is there a reason why first dose more frequently.

And then I guess, what youre doing on Huntington's as a matter of when for example are you trying to knock it down further just kind of curious what the thinking is there.

Well for some of the diseases like ALS there.

A very aggressive diseases, and so you want to get enough drug on board quickly to make a difference and reduce the protein quickly because the patients are progressing fairly rapidly and so that's been some of the thinking in AOS Huntington is a much slower progressing disease. So you can take some time to get the drug to steady state and get the dial and the level of target.

Brett P. Monia: And I think it's going to be very telling how durable that is, the effects we're seeing with that molecule. Have you gained any insight into, I guess, using the Huntington data, where you do now have some patients who have been treated with every four months doses, and I guess the open-label extension of the initial generation AC1 patients, have you gained incremental sort of PKPD insights into sort of the feasibility of longer dosing, and is there a reason why Fuss is dosed more frequently than, I guess, what you're doing at Huntington Well, for some of the diseases, like ALS, they're very aggressive diseases.

<unk> that we want.

And I.

I really think that some of it is a matter of that you say understanding with PK PD of the drug and it takes time and some good human clinical experimentation to get that and really understand how our growth are working in the CNS with.

Humans as opposed to preclinical species and so in addition to what Brett said in terms of optimizing chemistries and understanding how to design. The drugs. There is also just optimizing our dosing regimen and understanding how our existing DUC drugs work and Thats, what we did along with Roche and some of the experiments that led us to an extended interval.

Eric E. Swayze: And so you want to get enough drug on board quickly to make a difference and reduce the protein quickly because the patients are progressing fairly rapidly. And so that's been some of the thinking in ALS. Huntington's is a much slower progressing disease, and so you can take some time to get the drug to steady state and dial in the level of target reduction that we want. And I really think that some of it is a matter of, as you say, understanding the PKPD of the drug, and it takes time and some good human clinical experimentation to get that and really understand how our drugs are working in the CNS of humans, as opposed to preclinicals.

Great. Thank you very much for the year.

And congrats again on Broadway.

Thank you.

The next question comes from Joel Beatty with Citi. Please go ahead.

Hi, Congrats on the progress could you tell us more about the phase III trial, that's ongoing for <unk> in COPD.

And maybe the first part of the question is when could we see data from that trial and then the second part is how predictive is your cystic fibrosis clinical data in predicting efficacy for COPD.

Eric E. Swayze: And so, in addition to what Brett said in terms of optimizing the chemistries and understanding how to design the drugs, there's also just optimizing our dosing regimen and understanding how our existing drugs work. And that's what we did along with Roche in some of the hunting experiments that led us to the extended intervention.

Richard.

Good day.

So.

With our phase one phase two a experience.

Vincent Chen: Great. Thank you very much for the discussion. And congratulations again on the program. Thank you. The next question comes from Joel. Please go ahead.

With the <unk> molecule, we were able to look at a broad spectrum.

Genetic modifications.

And that led us to move into COPD because in addition to.

Joel: Hi, congrats on

Operator: Could you tell us more about the Phase 2 trial that's ongoing for ENAC and COPD? And I mean, the first part of that question is, when will we see data from that trial? And the second part is, how predictive is your cystic fibrosis clinical data in predicting efficacy for COPD? Richard.

On the <unk>.

Target gene going down we saw other important genes.

I don't think we've disclosed at this point, but there'll be more information coming out.

In regard to what else we saw in that that early work that led us to move fairly rapidly into a COPD trials COPD trial.

Richard S. Geary: Yeah, so with our phase one, phase two, A experience with the ENAC molecule, we were able to look at a broad spectrum of genetic modifications. And that led us to move into COPD because, in addition to the ENAC target gene going down, we saw other important genes. I don't think we've disclosed this at this point, but there will be more information coming out in regard to what else we saw in that early work that led us to move fairly rapidly into a COPD trial. The COPD trial likely reporting out, I don't know what we've put out publicly, probably early next year as well as phase 2B also would be next year. In 2022,

Likely reporting out.

I don't know what we've put out publicly probably early next year.

As well as the.

On the phase two B also would be next year.

2022.

And Joe Thats, a study in COPD patients nearly 200 patients.

For little over three months or so of treatment, which day primary change will be F&B. One so we'll be looking at real clinical.

Ciao function outcomes in COPD.

COPD study.

Yes.

Eric E. Swayze: And Joel, that's a study of COPD patients, nearly 200 patients for a little over three months or so of treatment, where the primary change will be FEV1. So we're looking at real clinical function outcomes in that COPD study. And just to add, if you think about ENAC inhibition as a way to rehydrate the lung, there's a strong rationale for using it in COPD, just like in cystic fibrosis, because you can restore the hydration balance by inhibiting ENAC.

And just to add if you think about <unk> inhibition as a way to rehydrate alone and so there is a strong rationale for using it in COPD just like in cystic fibrosis, because you can restore the hydration balance by anybody either.

Great. Thank you for all that.

Yeah.

Thank you Joe.

Okay.

The next question question comes from Yale Jen with Laidlaw <unk> Company. Please go ahead.

Good morning, and thanks for taking questions on <unk>.

Joel: Great, thank you for all that. Thank you, Joe. The next question comes from Yale Gen, with Laidlaw and Company. Please go ahead. Good morning, and thanks for taking the time.

On the progress.

My first question is in terms of Rd.

Our revenue sort of anticipation for the 'twenty to 'twenty one are you guys.

Yale Gen: Good morning.

Wade Walke: My first question is that in terms of RD revenue anticipation for 2021, are you guys not including any possible ownership, and that's why you have the current projection, or is that part of things already sort of included?

Not including any possible partnership and Thats why you have the current projection or that's part of it already.

Included.

Okay.

Elizabeth L. Hougen: Yale, sorry, could you repeat your question? I didn't quite hear you.

Sorry could you repeat your question I didn't quite hear you.

So the R&D.

Yale Gen: For the R&D revenue of 2021, are you guys not including any revenues from potential new partners, or just, and that's what the current estimate is?

Revenue of 2021.

Sure.

Not including any revenues from potential new partners.

And Thats, what the current estimate.

Elizabeth L. Hougen: Great question. So, I want to reiterate that our top-line guidance really reflects the new strategy to, you know, hold on to our drugs longer, partner if we do partner, you know, later in development, and to, you know, really advance a broad pipeline of homeopathic medicines to the market, primarily in neuro and cardio. So really, as we think about our R&D revenue, based on amortizations from prior upfronts and milestones, as well as a whole host of potential milestones and licensing fees across our current partner programs in drugs and later

B.

Great question, so I want to reiterate that.

Our top line guidance.

Really reflects the new strategy too.

Uh huh.

Hold on franchise longer partner, if we do partner later in development and two two.

Really.

<unk>.

Broad pipeline of wholly owned medicine to the market.

Primarily in your own car yet.

So really as we think about our R&D revenue.

It's.

Based off of amortization from.

Prior Upfronts and milestones.

As well as.

And a whole host of potential milestones.

And licensing fees across our current partnered programs in.

And drugs in later stage research programs.

Elizabeth L. Hougen: Okay, that's very helpful.

Okay. That's very helpful. Maybe just one question for Brad which is that you mentioned that you also contemplate particular, new technology that will complement curran.

Brett P. Monia: Next question for Brett, which is that you mentioned that you also contemplate potential new technology to complement the current technology you have; what likely would be an idea technology that may be fitting into the bill? So thanks, Yael.

Okay.

Youll have.

What's likely to be an ideal technology that may be fitting into that bill.

So.

Brett P. Monia: Think about the technology investments that we're making in two ways, or in two buckets, if you will. The first are technologies or investments in technology that will expand the reach of our current technology. So, new chemistries, new drugs that open up new tissues like muscle. Cardiac Tissue, Immune Cells, Cancer Cells; we're working on that with partners, as well as heavy investments internally. New Routes of Delivery is another example of that to expand the scope of our technology, like we do with pulmonary and before that intrathecal, and we're doing more. Genomics is a third, where, you know, everybody knows, genomically linked, the best targets from a validation standpoint prior to you validating a target with a drug. And we're investing in that. We have lots of hits.

Thanks Yale.

Think about the technology investments that we're making in two way or into two buckets. If you will the first our technologies and our investments in technology there.

Spend the reach of our current technology FSS.

<unk>, new Chemistries, new like Chemistries that open up new tissues like muscle cardiac tissue.

Immune cells cancer cells, we're working on that with.

Both with partners.

As well as heavy investments internally.

New routes of delivery is another example of that to expand the scope of our technology, if I could do a pulmonary and before that interest vehicle and we're doing more.

Genomics is a third where everybody knows genomic we linked targets are.

Best targets from a validation standpoint prior to your validating a target with the drug.

And we are investing in that we have lots of hits, we have a lot of genomic.

Brett P. Monia: We have a lot of genomic targets that we're very excited about that are very novel. And these are through partnerships, as well as work we're doing with our functional genomics group internally. That's bucket one.

Targets that we're very excited about that are very novel.

And these are true partnerships as well as work, we're doing with our functional genomics group internally.

That's bucket one bucket two is what I think you were really asking about which is new platforms, new complementary technologies outside of emphasis and I really can't provide.

Brett P. Monia: Bucket two is what I think you were really asking about, which is new platforms, new complementary technologies outside of antisense. And I really can't provide much detail there, except that we are investing in reviewing and conducting proof of concept studies and doing work in various areas to do things, to invest in technologies that can do things maybe more effectively, more efficiently, that antisense has less success in doing. So technologies, for example, that can more effectively regulate the expression of change. Of course, we can do that with our technology. Spinraza is the best

Much detail there except that we are investing in.

Reviewing and <unk>.

Conducting proof of concept studies in doing work in various areas to do things to invest in technologies that can do things, maybe more more effectively more efficiently.

As you will have less success in doing so technologies for example that can more effectively up regulate the expression of genes of course, we can do that with our technologies can rise as the.

Brett P. Monia: Perfect example of that, but it's less robust to be able to do that, and technologies that do that will help us complement. And that's a little further out, but we're working on it, and we're working on it very seriously. So stay tuned. Okay, great. Thanks a lot.

Perfect example of that but.

It's less robust to be able to do that and technologies that do that will help us complement.

The things, we can do to expand our reach from <unk> and Thats, a little further out but we're working on it and we're working on it very.

Seriously so stay tuned.

Okay, great. Thanks, a lot.

Brett P. Monia: The plot, again, congrats. Thank you.

Okay and good growth.

Operator: Thanks. The next question comes from Luca Issi with RBC. Please go ahead.

Thank you.

The next question comes from Luca <unk> with RBC. Please go ahead.

Luca Issi: Oh, terrific. Thanks so much for taking my questions. Congratulations on all the progress. I have two, one on HAE and one on AGT.

Terrific. Thanks, so much for taking my questions. Congrats on a on the progress on two one on each day and one on <unk>. So on <unk> I think there was some interesting back and forth on the editorial or the New England Journal Medicine, a couple of weeks ago.

Brett P. Monia: So on HAE, I think there was some interesting back and forth in the editorial of the New England Journal of Medicine a couple weeks ago, where essentially the debate was around inhibiting liver PKK versus inhibiting plasma calocrine, which is what Teixeira was doing, and whether maybe knocking down liver PKK is less preferable than what Teixeira was doing. So I'm wondering if you have any thoughts on that, and maybe, bigger picture, if you can offer any color on how we should think about the upcoming Phase 2 data.

We're essentially the debate was around inhibiting liver PKK versus hany, beating plasma <unk> credit, which is what <unk> was doing and whether maybe on knocking down liver PKK is less preferable to what <unk> was doing so I'm wondering if you have any thoughts on that and maybe bigger picture. If you can offer any color on how should we think about the upcoming.

<unk> phase II data and then on HGTV I know you have two molecules in development at this point I'm wondering if you can comment on how youre thinking about the relative prioritization of one versus the other given on again, one is theyre running phase II versus the other just enter phase one healthy volunteer so any color there would be helpful. Thank you.

Brett P. Monia: And then on AGT, I know you have two molecules in development at this point. I'm wondering if you can comment on how you're thinking about the relative prioritizations of one versus the other, given, again, one is already in Phase 2 versus the other just entered Phase 1 in Healthy Volunteers. So any call there will be helpful. Thank you. Thanks, Luca.

Thanks, Luca maybe I'll take a stab at the day question that you can fill in and then take the ADT.

Richard S. Geary: Maybe I'll take a stab at the H-A-E question that you can fill in and then take the H-E-T question, the two molecules. So, you know, by far, the vast majority of it is derived from the hepatocyte, the liver, whether it's in the plasma or what's elsewhere or what's in tissues. We are blocking precalocrine with our mechanism of action that essentially prevents the production of precalocrine into the plasma as well as the metabolite of precalocrine, calocrine, the active molecule that leads to bradykinin production and hereditary angioedema attacks.

The two molecules so.

Yes.

By far the vast majority of Calvert Brian.

Is derived from the hepatic site deliver.

Whether it's in the plasma or elsewhere.

Elsewhere or whats on tissues.

We are blocking <unk>.

With our mechanism of action that essentially prevents the production of pre Calgary on into the plasma as well as the.

The metabolite of free Gallacher on Calvert price the active molecule that leads to <unk>.

Production in hereditary angioedema attacks. So we're doing we're actually we feel that our mechanism our approach.

Richard S. Geary: So we're doing, we actually feel that our mechanism, our approach is superior to an approach targeting calocrine because we prevent the molecule from ever being made. We don't have to clean it up after it's been made.

It's superior to an approach targeting <unk>, because we prevent the module from ever being made we don't have to mop. It up average been made.

And we think that this is the.

Brett P. Monia: And we think that this is potentially a superior approach to prophylactic treatment of hereditary angioedema. And we're really looking forward to the New England Journal data you referred to is very encouraging, and we look forward to presenting that phase two data in the first half of this year. Richard, if you want to add to that, please do, or jump into HR. No, I think you covered that nicely. So I'll jump into AGT for just a minute.

Particularly as the superior superior approach to prophylactic treatment.

Our regulatory angioedema.

So we're really looking forward.

New England Journal data you referred to is very encouraging and we look forward to presenting phase.

Phase two data this first half of this year.

Richard on add to that please do or jump into agg.

No I think you've covered that nicely.

So I'll jump into agg for just a minute we have two molecules one that is a phase <unk> ready and one that is not yet in the clinic.

Richard S. Geary: We have two molecules, one that is in phase two ready, and one that is not yet in the clinic, or has just started in the clinic, I should say. Our phase one study for ION904 has started. And so we're moving forward with the 2.5-lica now. But I think to remember is that the 2.5 Leica is, based on all of our preclinical data, a significantly higher potency molecule. So we think of it in two ways.

Or has just started in the clinic I should say our phase one study for eye on 904 has started and so we're moving forward with the two five like on now.

The thing to remember is that the $2 five Leica is E Bay.

Based on all of our preclinical data significantly.

Higher potency molecule. So we think we think of it in two ways first and heart failure it would be highly.

Richard S. Geary: First, in heart failure, it would be highly, perhaps beneficial to have a molecule that we can administer very infrequently with a sub-Q approach. And in addition to that, the 2.5 Leica gives us the potential for oral. So it's really a play on really moving into the best, first, and best in class for that indication. And so we're moving that one forward quickly, and we'll have data along the way in the phase one trial to be able to read out exactly what that potency looks like in man, its potency, and its duration of action.

Perhaps.

Beneficial to have a molecule that we can administer.

Very infrequently with a sub Q approach.

And in addition to that the two five like it gives us a potential for oral <unk>. So it's really a a play on really moving into a best <unk>.

First and best in class.

For that indication and so we're moving that one forward quickly and we will have data along the way.

In the phase one trial to be able to read out exactly what that potency looks like in an mam potency and duration of action.

Richard S. Geary: So look for that. Thank you. The next question comes from Jessica Fye with J.P. Morgan; please go ahead. Good morning, this is Daniel for Jessica Fye, our question focusing on near-term readout and echomegaly given that good hormone receptors are found in multiple, Transcribed by https://otter.ai

So look for that.

Thank you.

Okay.

The next question comes from Jessica Fye with Jpmorgan. Please go ahead.

Good morning. This is Daniel from Jessica Fye, Thanks for taking our question.

Focusing on the near term readout in acromegaly.

Given that growth hormone receptors that are found in multiple tissues throughout the body DCF risks and targeting a liver specific call at home on recycling receptor expression alone.

Would you like on product.

Operator: [inaudible] So, I can take that. Okay.

And then when it reads on what should we expect with the top line data.

So.

Onaiza Cadoret: Yeah, thank you, Daniel. So, first of all, yes, we are targeting the liver, where the majority of the receptor, at least systemically, lies. And so the initial is, in addition to somatostatin analogs, which have already, you know, gathered up in addition to a majority of receptors. And now what we're doing is significantly reducing the activity in the liver. Again, I think, you know, wait for the data, but the top line data is going to be IGF1.

I can take that.

Yes, Thank you Daniel.

So.

First of all yes, we are targeting.

Liver, where the majority of the receptor.

At least systemically.

Our lives and and so the initial is in in addition to somatostatin analogs, which are already.

Gathered up.

Inhibition of majority of the receptors and now what we're doing is significantly reducing.

On the activity in the liver.

Again, I think wait for the data, but the topline data is going to be IGF one.

Onaiza Cadoret: And we'll also be looking at a, probably not the top line, but later, we'll be able to report out all of the information on quality of life, where we're seeing some exciting kind of results. So I think that's it.

And what are we looking at also a.

Probably not topline, but later, we'll be able to report out all of the information on quality of life, where we're seeing some.

Exciting kind of results so I think thats the.

Richard S. Geary: What you're going to be able to see as we move forward and why we think liver targeting is likely to be not only additive but potentially even as a single agent. We've started our single agent study. And I'll just add that liver is also the primary source of IGF-1, in addition to the growth hormone receptors in the pathocytes, which of course drives this disease.

What youre going to be able to see as we move forward and why we think.

Liver liver targeting is likely to be not only additive, but potentially even as the single agents. We've started our single agent study.

Yeah, and I'd just add to that deliver is also the primary source of IGF one and.

In addition to the growth hormone receptors.

Out of sites, which of course drives this disease.

Brett P. Monia: And, you know, what we're hoping to show is that patients who are poorly controlled on somatostatin analogs, that we can get a fair number of those patients, a good number of those patients under control. It's a normal idea for them, though, and that's what we're hoping to do. And we think this mechanism has, you know, the potential to do that. So we're looking forward to sharing those results. Thank you. The next question comes from Mani Foroohar with SVP.

And.

What we're hoping to show is that patients who are poorly controlled on somatostatin analogs.

But we can get a fair number of those patients the number of those patients under control to normal idea from that and that's we're hoping to do and we think this mechanism.

Okay.

The potential of index. So we're looking forward to share those results.

Okay. Thank you.

Okay.

Okay.

Okay.

The next question comes from money from <unk> with SVP Leerink. Please go ahead.

Mani Foroohar: Please go ahead. Thanks for taking the question, guys. We'll start with a specific one and then go to a more general one.

Hey, Thanks, taking my question guys.

The specific one and grow more General award.

Brett P. Monia: There's been a little discussion about the HAE opportunity on this call. Can you dig into more detail on where you see the opportunities, like commercially and clinically, in terms of frequency of administration, depth of attack reduction, where you see that opportunity, and how that would translate into a clinical trial design that could generate a label that could support a success in a pretty competitive market? And then the second question, more broadly, there's a lot of discussion around all of the therapeutics outside of the liver expanding into other areas of therapy.

There's a little discussion about the AJ opportunity on this call.

And in more detail on where you see the opportunities that commercially and clinically in terms of frequency of administration.

Depth of attack reduction on just where you see that opportunity on how that would translate into a clinical trial design that can generate a label that could support.

But could support a success on a pretty competitive market.

And then the second question more broadly on the lot of discussion around all of our therapeutics outside of the liver expanding into other.

Other areas of therapy.

Brett P. Monia: Most of our competing companies seem to be unaware of your success in CRS. As you think about producing data of effective knockdown and therapy in the lung and other indications, how should we think of other target tissues? How should we think about the tempo with which that could translate into an acceleration on the R&D partnership side as you sort of expand the aperture of potential target tissues in which you could find partnerships? So, Bonnie.

Dubai, a competitive competing companies who seem to be unaware of as deposits.

Yes.

As you think about producing data of effective knockdown on therapy in lung and other indications how should we think about other target tissues. How should we think about the tempo with which that could translate into an acceleration on the R&D partnership side as you sort of expand the aperture of potential target tissues that you defined.

And which you would find partnerships.

So thanks Ronny great.

Onaiza Cadoret: Great questions. So I'd like Onaiza, who's on the call, hasn't had a chance to speak up, to talk about the opportunity that we see in HAE. As you say, there are drugs out there already that treat this disease. But we think, we like the potential of our current model. But I'd like Onaiza to maybe speak to that.

Great questions.

So I'd like to on Asia.

On the call.

<unk> had a chance to speak up can you talk about the opportunity that we see <unk> as you say.

Yes.

There are drugs out there already that are treating this disease, but we think.

We like the potential of our current margin, but I'd like on Asia to.

Maybe speak to this.

Onaiza Cadoret: Sure, I'd be happy to. Hi money. So, as I think it's already been said, but I think it's worth it.

Sure I'd be happy to.

Hi, My name's Suez.

So as I think it's already been said, but I think it's worth reiterating is that we're really looking at treatment. That's designed to prevent the tax rather than simply kind of treat acute episodes on demand right.

Onaiza Cadoret: I think the name of the game is we're looking at a treatment that's designed to prevent attacks rather than simply kind of treat acute episodes on demand, right? And we expect an improved tolerability profile than existing therapies as well.

And we expect an improved tolerability profile than existing therapies as well I think the name of the game over here in this marketplace has really been about zero tax and as he said zero.

Onaiza Cadoret: The time spent over here in this marketplace has really been about...

Onaiza Cadoret: We've talked about zero tax. And, as you said, TAC Zero has done a nice job as they entered the market with that. But what we see as a continued opportunity from an efficacy perspective is the durability of response. We know that initially you can get down to zero tax, but can you actually maintain that zero tax over time?

<unk> done a nice job as they.

<unk> entered the market with that.

What we see as a continued opportunity from an efficacy perspective is the durability of response.

We know that initially you can get down to zero tax, but can you actually maintained is here on tax over time, and we really believe that the PK.

Onaiza Cadoret: We really believe that the PKK, again, the mechanism and what's already been described in the call will help us achieve that. Of course, we'll see that as the phase two data comes out. That is really where the competitive positioning of the product will be. Of course, we know that the current treatments on the marketplace have a more viscous, difficult to inject profile as well, and we'll certainly beat that profile as well. That's the way we're looking at it.

Again, the mechanism and what's already been described on the call.

<unk> will help us achieve that and of course, we will see that as the phase two data comes out but that is really where the positioning competitively on the products will be.

Then of course.

We knew that.

The current treatments on the marketplace have.

More of it is difficult to inject profile as well and we will certainly beat that profile as well that's why we're looking at it.

And.

Brett P. Monia: And so we're excited. We think our PKK Leica molecule has the potential to be the best in the class. We have to prove it, of course, with respect to reduction in attack rates, but we shall see. We're certainly getting great reductions in PKK, which is the cause of this disease. I mean, Bradykinin is, but PKK is the promoter of Bradykinin levels.

So we're excited we think the PKK like our molecule has potential to be the best in the class with a fruit of course.

With respect to reduction in attack rates, but we shall see.

We're certainly getting great reductions in PKK, which is the cause of this disease, I mean, Brady kind of hits, but teekay kuz promoter right kind of levels.

Brett P. Monia: Regarding other target tissues, Moni, there are a lot of questions in your question, so let me take a stab at it, and if I don't get it right, just follow up, but yes, our CNS platform, we've just begun to scratch the surface of new molecules, new drugs for devastating neurodegenerative diseases that are coming into our pipeline. Our pipeline's already very rich, and it's going to get richer with more and more neurodrugs as we continue to validate the platform, showing again and again robust reductions in target and CSF, as we did again this year with the TAO program, as we did in the past with Huntington and SAD1 and Spiroza, and more is coming. And as Eric referred to earlier, we're continuing to optimize delivery to the CNS with Lung is a potential new franchise.

Regarding other target tissues money.

There were a lot of questions.

In your question. So let me take a stab at it and if I don't get it right just follow up.

Yes, our CNS platform.

We've just begun to scratch the surface of new molecules, new drugs for devastating neurodegenerative diseases that are coming.

Into our pipeline our pipeline is already very rich and it's gonna get richer with more and more neuro drugs as we continued to validate the platform showing again and again robust reductions in target and CSS as we're doing again this year with Tau program as we've done in the past for Huntington and sub one and its profit.

And more is coming and as Eric referred to earlier, we're continuing to optimize delivery to the CNS with less frequent dosing and we continue to move forward with new molecules to do that.

Loans is a potential new franchise, we're very excited about this.

Brett P. Monia: We're very excited about this. You know, years ago, we had a lung program, and we showed we had evidence of activity, but it wasn't good enough. So we went back to the lab and developed new chemistries, Gen 2.5, which seems to be getting it done. We get great target engagement, excellent safety, and tolerability.

Years ago, we had a loan program and we showed evidence.

Evidence of activity, but it wasn't good enough and went back to the lab and develop new Chemistries Gen. Two five which seems to be getting it done.

Getting great target engagement excellent safety, and Tolerability and Thats, a new franchise that we're very excited about opening up new organs and tissues and then with respect to.

Brett P. Monia: And that's a new franchise that we're very excited about opening up new organs and tissues. And then, with respect to, you know, outside of new routes of delivery, we're continuing to look at new routes of delivery all the time. But outside of that are new chemistries to open up new organ systems and tissues. And, you know, we believe that we will be in development this year for a muscle, like a program.

Outside of new routes of delivery will continue with aircrafts delivered all the time.

But outside of that are.

New Chemistries to open up new organ systems, new tissues.

We believe that we will be in the <unk> and.

In development this year for a muscle like a program that's our plan that's our goal.

Brett P. Monia: That's our plan. That's our goal, and we can't provide more details on that at this time. But that's just one of several that we think are going to be coming for targeting muscle. And not just skeletal muscle but also heart failure, cardiac.

<unk>.

We cant provide more details on that at this time, but that's just one of several that we think are going to be coming for targeting muscle.

And not just skeletal muscle, but also heart failure cardiac tissue.

Brett P. Monia: And we're very encouraged by the work we've done so far, the data we've generated. And more are coming, too. And, you know, we've also talked about our pancreatic data cell program. We've done work with AstraZeneca. We're doing our work ourselves.

And we're very we're very encouraged by what we are.

On the work we've done so far the data, we've generated and more and more are coming to end.

We've also talked about our pancreatic beta cell program with some work with Astrazeneca during our work ourselves and we have other life is coming.

Brett P. Monia: And we have other life coming for new cell types and tissues, and we're very encouraged by the data we've generated so far. And with respect to partnerships, I'm not sure if you meant bringing, you know, partnering out licensing or in licensing. But I'll assume you mean in licensing.

For new cell types and tissues that we're very encouraged by the data we've generated so far and with respect to partnerships I'm not sure. If you meant.

On.

Bringing partnering out licensing or in licensing, but let's see.

You mean in licensing we've already established partnerships in with.

Brett P. Monia: We've already established partnerships with companies and invested our capital to broaden our scope in like chemistries. And we're planning, hoping to do more of that so that we're going to take advantage of partnerships to expand our platform and to complement all the great work we're doing here at Ionis under our roof in our medicinal chemistry program.

With companies investing our.

Our capital to broaden our scope and Leica Chemistries and we're planning hoping to do more of that.

So that will.

Trying to take advantage of partnerships too.

To expand our <unk> platform to complement.

All the great work, we're doing here at Aon is under our roof and our medicinal chemistry.

Program I hope that answered your question.

Mani Foroohar: I hope that answered your question. Yeah, that's helpful. One of the things I think what I was thinking about is...

Yes, that's helpful. One of the I think what I was thinking about it.

Brett P. Monia: If you look at consensus estimates looking out forward, they don't contemplate acceleration in your R&D revenue from expansion into a broader universe of outlicensing opportunities for you. I was thinking, should we think about other opportunities, should you prove out delivery in the lung, delivery in the muscle, serially, and other tissue types? Should we be thinking about this changing the top line, sort of a tager, as it were, of growth in R&D? Should we think of this as more of a step function, as one of your smaller RNAi competitors has discussed it?

If you look at consensus estimates looking out forward they don't contemplate.

Acceleration in your R&D revenue.

From expansion into a broader point.

From a broader universe from out licensing opportunities for you.

How should we think about.

Other opportunities should you prove out delivery in lung delivery and muscle cereal. The other day another tissue types should we be thinking should we think about this changing the topline CAGR as it were of growth of R&D should we think of this as more of a step function as one of your smaller RNA or competitors, who discussed the gist.

Brett P. Monia: Just how do you think about the size and the speed with which you guys could... and I'm going to ask them to capitalize on the potential expansion of R&D revenue if you're attacking different tissue types. That was more of my question.

How do you think about the size and the speed with which you guys could.

Capitalize on potential expansion on R&D revenue, if you're if you're attacking different tissue types because that was more on my question.

Mani Foroohar: Well, expanding the scope of the platform certainly will drive even more interest from other companies wanting to partner with us to take advantage of all the great progress we're making. I mean, there's so much interest already in what we're doing today, and then there's also tremendous interest in working with us to develop these technologies. You know, we're working with AstraZeneca on new chemistries and new routes of delivery. We're working with Biogen on new chemistries to maximize delivery to muscle as well as the CNS.

Expanding the scope of the platform certainly will drive even more interest by.

Other companies wanting to partner with us to take advantage of all the great progress, we're making there.

So much interest already in what we're doing today and then Theres also tremendous interest.

In working with us to develop these technologies.

We're working with Astrazeneca on new Chemistries and new routes of delivery, we are working with Biogen.

On new Chemistries.

To maximize delivery to muscle as well as CNS.

Brett P. Monia: And there will certainly be interest as we expand this scope by other companies that will want to take advantage of this in the future. And, sure, we'll be doing more partnerships in the future. But as we emphasized earlier in the call today, we're going to be very selective in the partnerships we do, not just for the R&D revenue that you referred to, although that's nice. It's really to bring strategic value to the company, you know, to really expand the scope of our technology and to really, you know, strengthen our leadership position in this space.

And there will certainly be interest as we expanded scope by other companies.

On that we'll want to take advantage of this in the future and.

Sure, we'll be doing more partnerships in the future.

But as we emphasized in the.

Earlier on the call today, we're going be very selective.

And the partnerships we do.

Not just for the R&D revenue that you referred to of all Thats nice.

It's really to bring strategic value to the company.

On the to really expand the scope of our technology and.

So really.

Strengthen our leadership position in this space. So I do think the partnerships based on advancements, we're making in tech and the technology that you referred to are.

Mani Foroohar: So, you know, I do think that partnerships based on the advancements we're making in the technology that you referred to are likely in the future. I also think that partnerships for some of the broader indications that we're working on are possible, too, even without those, you know, within the existing pipeline. So lots of potential for partnerships down the road, lots of interest. And we will be selective, and we'll not just do partnerships for the sake of financial return but also for, Unknown Speaker. Great, that's really helpful. Thanks.

Likely in the future I also think that partnerships for some of the broader indications that we're working on are possible too.

Without those.

Within the existing pipeline, so lots of potential for partnerships down the road lots of interest and we will be selective and will not just do partnerships for the stake.

Financial return, but also for strategic value.

Great that's very helpful. Thanks.

Jason Gerberry: Thank you. The next question comes from Jason Gerberry with Bank of America. Please go ahead. Oh, hi, this is Chiang for Jason. Thanks for taking questions. I guess the first one is on Huntington.

Thank you.

Yeah.

The next question comes from Jason <unk> with Bank of America. Please go ahead.

Oh, Hi, this is chi on for Jason Thanks for taking the question.

Yes, the first one on the Huntington.

Chiang: Can you outline some of the things you've been looking at with your natural history cohort and open label data that are going to be presenting sometime this year? What can get you comfortable with the ability to show improvement in functional endpoints and safety, ultimately? I'm curious how important it is to see your matching natural history cohort deteriorating over a 15-month observation period. I guess the second question on HAE is, just to confirm, to generate competitive data and to compete in the space, is the thought that you will need to generate longer-term follow-up data beyond the typical six-month trial to prove better maintenance of ECTAP reduction benefits? Thank you. Um, Eric, would you like to talk about the Huntington? OLE, and I'll take the HA.

Can you outline some of the things you have been looking at what you're on.

Natural history cohort on open label data that kind of big percentage, sometimes here what can get you comfortable in our ability to show improvement on functional endpoints.

We ultimately can.

Here is how important it is to see you are matching that with history cohort is deteriorating over a 15 month observation period.

I guess the second question on <unk> just to confirm.

Generally competitive data and to compete in the space.

Thought that you would need to generate longer term follow up data beyond the typical six month trial to prove that a maintenance of a tax deduction benefit. Thank you.

Okay.

Eric would you like to talk about the Huntington.

OLED and on pace.

Eric E. Swayze: Yeah, so we touched on this a little bit earlier in the call. And again, Roche has stated that sometime this year, they're going to discuss some data from the OLE and natural history studies. And beyond that, I really can't comment.

Yes, so we touched on this a little bit earlier on the call.

Again Roche has stated that sometime this year theyre going to discuss some data from the early and natural history studies.

And.

Let's see what they present and beyond that I really can't comment, but I do think that the key endpoint and the key thing to focus on is the ongoing phase III, that's scheduled to read out in 2022.

Eric E. Swayze: But I do think that the key endpoint and the key thing to focus on is the ongoing phase three that's scheduled to read out in 2022. Huntington's a slowly progressing disease, and the study's designed to give the drug the time to lower mutant Huntington, which we know it does, and have a disease benefit and really test the hypothesis that lowering mutant Huntington will have a disease benefit. So that, to me, is the key experiment.

I think in terms of slowly progressing disease and the study is powered to give it.

To give the drug at the time to lower mutant Huntington, which we know it does and how the disease benefit and really test the hypothesis that lowering mutant Huntington will make it to see the benefits. So that to me is the key experiment.

And regarding the <unk> question.

Brett P. Monia: And regarding the HAE question, the phase two study, as we said, we'll read out and present top line data at least the first half of this year in patients with respiratory angioedema. We're looking at frequency of attack rates over about a three month period of time. There's a wealth of data published with existing therapies on attack rates that we will, you know, we'll compare to. We'll look at it, and we'll ask ourselves whether or not we're competing, whether or not we're competitive, or potentially even superior in reducing attack rates.

The phase III study.

Said will readout and we will present topline data at least the first half of this year in patients with <unk>.

Terry Angioedema, we're looking at.

Frequency of attack rates.

And over about a three month period of time, there's a wealth of data published with existing therapies.

On attack rates.

That we book.

Well compared to what we will look at it and we will ask ourselves on will answer.

Ask ourselves, whether or not were competing with competitive or potentially even superior in Turkey and producing tech ridge.

Brett P. Monia: And based on the data, we have to review the data, we'll decide on the next steps. We obviously have already had various options in place based on the data outcome, but I would not rule out this program, as Richard mentioned earlier, could move to a pivotal study based on the phase two data that comes out in the first half of this year. We have to look at the data, and then we have to decide what the best phase three strategy is.

And based on the data with these data we will decide on next steps.

We obviously have already has been.

<unk> options in place based on the data outcome, but.

But I would not rule out this program as Richard mentioned earlier come into a pivotal study based on the phase II data that comes out first half of this year, we have to we have to look at the data and then we have to.

Side, what the best Phase III strategy would be.

Brett P. Monia: One other piece of information to add to that, Brad, is that we have moved all eligible patients into an open label extension that allows us to continue to monitor attack rates. So we have an open label extension for the Phase 2 program that is ongoing, and has already started. Many of these patients have been in the open label extension for many months, so that is where we're going to get long-term data very quickly.

One other piece of information to add to that.

Perhaps.

Is is that we have moved all eligible patients into an open label extension that allows us to continue to monitor Tac rates.

On the long term. So we have an open label extension for the Phase II program.

That is ongoing has already started many of these patients have been in the open label extension for many months.

So that that is where we're going to get.

Long term data.

Brett P. Monia: Yeah, and I will just add to the need, I think you said, beyond six months. So if you take a look at the real world data and how patients are doing currently, you start seeing excursions from their therapy as early as three months. And then, you know, more substantial declines between that three to six month period. So, we don't think that, you know, we would need data well beyond that period to demonstrate.

Very quickly.

Yes, and I will just add to the need I think you said beyond six months. So if you take a look on the real world data on how patients are doing currently you strict exclusions from their therapies as early as three months.

And then a more substantial declines between that three to six month period. So.

Don't think that we.

We would need data well beyond that period to demonstrate it.

Salveen Richter: Next slide, please. The next question comes from Salveen Richter with Goldman Sachs. Please go ahead. Hi, thank you so much for taking our question. This is Sonia on behalf of Salveen. A few quick questions from us. I was wondering, could you give us the status on your

Yes.

Thanks Denise.

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

Yes.

Hi, Thank you so much for taking on our question. This is Sonya on for Celgene. A few quick questions from US I was wondering could you.

Give us a status on Europe prion disease asset and when you can expect data there I think there were thinking your trial initiation sometime midyear and then also on the muscle like that.

Operator: [inaudible]

Sonia: If you could give us some... color on what indications you would potentially go into? That would be really helpful, thank you.

You gave us on.

Color on what indication do you potentially go into that would be really helpful. Thank you.

Eric E. Swayze: Eric, would you like to run with that? So I'll start with muscle strength. We're not really prepared to discuss exactly what indications we're going into at this time with the muscle program, but we're very, very excited about what we're doing in terms of being able to target the muscle. There are lots of opportunities there across various spaces of neuromuscular disease. And as for the pre-M program, I can't provide too much color on timing, but

Alright, so our growth there.

So I'll start with musselwhite.

Not really prepared to discuss exactly what indications we're going into it.

At this time on the muscle program, but.

We're very very excited about what we're doing in terms of being able to target the muscle.

There is lots of opportunities there.

And they're across various spaces of book neuromuscular disease.

And as for the for the pre owned program I can't provide too much color on timing, but.

Eric E. Swayze: We have identified several candidate molecules and are working as hard as we can to rapidly get the best candidate forward and move it to patients. Thank you. Thank you, Sean. This concludes our question and answer session. I would now like to turn the conference back over to Brett Monia for any closing remarks. Well, thank you, everybody, for joining us on today's call, and thank you for all the questions in the Q&A session.

We are identified several candidate molecules on working as hard as we can as.

Rapidly get the best candidate forward or moving to patients.

Thank you.

Thank you sung.

This concludes our question and answer session.

I would now like to turn the conference back over to Brett ammonia for any closing remarks.

Well. Thank you everybody for joining us on today's call and thank you for all the questions.

And the Q&A session, obviously youre at Aon is we're very excited.

Eric E. Swayze: Obviously, here at Ionis, we're very excited about the future, the present, and the future of the company, and we're very much looking forward to providing additional updates on the great progress we're making at Ionis throughout the remainder of the year. So, thank you again for joining us, and have a great day. This concludes our conference. Thank you for attending today's presentation.

The future the <unk>.

Present, and the future of the company.

We'll look forward book very much looking forward to providing.

Additional updates on the progress of the great progress, we're making on eye on us.

Throughout the remainder of the year. So thank you again for joining and have a great day.

Yes.

This concludes our conference. Thank you for attending today's presentation you may now disconnect.

Yes.

[music].