Ionis reports fourth quarter and full year 2020 financial results and recent business achievements Achieved 2020 financial guidance 2021 guidance reflects increased investments in wholly owned pipeline to drive future re

Ionis reports fourth quarter and full year 2020 financial results and recent business achievements

Achieved 2020 financial guidance

2021 guidance reflects increased investments in wholly owned pipeline to drive future revenue growth

Webcast today, February 24, 2021, at 9:00 a.m. Eastern Time

CARLSBAD, Calif., February 24, 2021 - Ionis Pharmaceuticals, Inc. (Nasdaq: IONS)

today reported its financial results for the fourth quarter of 2020 and recent business highlights.

"Last year, we laid out a bold new vision for the Company and took important steps towards our goal of becoming one of the most successful biotechnology companies. Key

to our vision is our strategy to maximize the value of our pipeline by commercializing our wholly owned medicines. Our acquisition of Akcea was an important step in building our commercial capabilities while enabling us to further strengthen our

organization," said Brett P. Monia, Ph.D., chief executive officer at Ionis. "Last year, we also advanced our late-stage pipeline and expanded the utility of our technology. Looking ahead, we expect data from multiple wholly owned programs in the

first half of this year, followed by Phase 3 tofersen data in patients with SOD1-ALS in the second half. These key upcoming catalysts, together with our recent pipeline and technology achievements, position us well to have 12 or more products on the

market in 2026. Importantly, we continue to have the financial strength to expand investment in our wholly owned pipeline and commercial capabilities to drive meaningful and

increasing value for patients and shareholders."

2020 Summary Financial Results

2020 Marketed Products Highlights

Q4 2020 and Recent Pipeline Highlights

Upcoming 2021 Pipeline Catalysts

(2) Timing of partnered program catalysts based on partners' most recent publicly available disclosures

2020 Financial Results and 2021 Financial Guidance

"We achieved our 2020 financial guidance, even in the challenging COVID-19 pandemic environment. Moreover, in 2020 we made significant progress toward our goal of

creating a stronger, more efficient company focused primarily on advancing our wholly owned medicines to the market. We acquired Akcea enabling us to retain full value from its rich portfolio. We also restructured our European operations. Together,

these transactions unlocked substantial cost savings that we plan to reinvest to drive future revenue growth," said Elizabeth L. Hougen, chief financial officer of Ionis. "Our 2021 guidance reflects our new strategy to maximize the value of our

wholly owned pipeline, focused primarily on commercializing our rare neurological and cardiometabolic disease programs. Our guidance also reflects the investments we are making in three key areas of our business - advancing and expanding our wholly

owned pipeline, building commercial capabilities in support of our rich pipeline and broadening the reach of our technology. We can increase our investments in these areas while only modestly increasing our expenses because of the significant cost

savings we realized from acquiring Akcea and restructuring our European operations. Importantly, with nearly $2 billion of cash at the end of last year, we remain well capitalized with the substantial financial resources to achieve our goals."

2021 Financial Guidance

Ionis' full year 2021 financial guidance consists of the following components (on a non-GAAP basis)(1):

Ionis' revenue was comprised of the following (amounts in millions):

Financial Impacts of Akcea Acquisition and Restructured European Operations

In the fourth quarter of 2020, the Company's non-GAAP amounts exclude the following expenses related to the Akcea acquisition and restructured European operations

because the costs are not part of its normal ongoing operating activities. Refer to the detailed reconciliation of non-GAAP and GAAP measures, which is provided later in this release. (Amounts in millions):

As a result of the Akcea acquisition, Ionis and Akcea began reporting their federal taxes on a consolidated basis in the fourth quarter of 2020. The Company recorded a

valuation allowance against all Ionis' federal net deferred tax assets in the fourth quarter of 2020, due largely to Akcea's history of losses and the expected impact of this on Ionis' consolidated federal taxable income. The Company now maintains a

valuation allowance against all its consolidated federal and state net deferred tax assets.

Ionis' operating expenses for the year ended December 31, 2020 increased compared to 2019 driven by the Company's investments in advancing the Phase 3 programs for

IONIS-TTR-LRx, IONIS-APOCIII-LRx and other medicines in its wholly owned pipeline. Additionally, the Company incurred approximately $90 million in costs

related to the Akcea acquisition and restructured European operations on a GAAP basis. The costs consisted of $31 million of severance, retention and other costs and $59 million of non-cash stock-based compensation expense for the acceleration of

Akcea equity awards.

Net Loss Attributable to Noncontrolling Interest in Akcea

Prior to completing its acquisition of Akcea in October 2020, Ionis owned approximately 76 percent of Akcea. The line titled "Net loss attributable to noncontrolling

interest in Akcea" on Ionis' statement of operations reflects the portion of Akcea's net income or loss attributable to the other owners of Akcea's common stock. From mid-October 2020 through December 31, 2020, Ionis did not recognize any

noncontrolling interest in Akcea on its statement of operations because it owned 100 percent of Akcea. Beginning in 2021, the Company will no longer have an adjustment for noncontrolling interest in Akcea.

Net Income (Loss) Attributable to Ionis Common Stockholders

Ionis recognized a net loss attributable to Ionis' common stockholders for 2020 compared to net income in 2019 primarily due to higher revenue in 2019, including

approximately $400 million in license fees Ionis earned from Pfizer and Novartis. Also contributing to Ionis' net loss in 2020 was the non-cash adjustment of the valuation allowance Ionis recorded against its federal net deferred tax assets discussed

above. Additionally, Ionis' operating expenses increased in 2020 compared to the same period last year as described above.

Ionis ended 2020 with cash, cash equivalents and short-term investments of $1.9 billion, compared to $2.5 billion at December 31, 2019. In

October 2020, Ionis used approximately $545 million of its cash for the Akcea acquisition.

Today, at 9:00 a.m. Eastern Time, Ionis will conduct a live webcast to discuss this earnings release and related activities. Interested parties may access the webcast here.

A webcast replay will be available for a limited time at the same address.

About Ionis Pharmaceuticals, Inc.

For more than 30 years, Ionis has been the leader in RNA-targeted therapy, pioneering new markets and changing the standards of care with its novel

antisense technology. Ionis currently has three marketed medicines and a premier late-stage pipeline highlighted by industry-leading neurological and cardiometabolic franchises. Our scientific innovation began and continues with the knowledge that

sick people depend on us, which fuels our vision of becoming one of the most successful biotechnology companies.

Ionis' Forward-looking Statement

This press release includes forward-looking statements regarding Ionis' business, financial guidance and the therapeutic and commercial potential of SPINRAZA

(nusinersen), TEGSEDI (inotersen) and WAYLIVRA (volanesorsen) and Ionis' technologies and products in development, including the business of Akcea Therapeutics, Inc., Ionis' wholly owned subsidiary. Any statement describing Ionis' goals,

expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, including those related to the impact

COVID-19 could have on our business, and including but not limited to those related to our commercial products and the medicines in our pipeline, and particularly those inherent in the process of discovering, developing and commercializing medicines

that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. Ionis' forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its

results to differ materially from those expressed or implied by such forward-looking statements. Although Ionis' forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors

currently known by Ionis. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Ionis' programs are described in additional detail in Ionis' annual report on Form 10-K for the year ended

December 31, 2019, and the most recent Form 10-Q quarterly filing, which are on file with the SEC. Copies of these and other documents are available from the Company.

In this press release, unless the context requires otherwise, "Ionis," "Company," "we," "our," and "us" refers to Ionis Pharmaceuticals and its subsidiaries.

Ionis Pharmaceuticals is a trademark of Ionis Pharmaceuticals, Inc. Akcea Therapeutics is a registered trademark of Akcea Therapeutics, Inc. TEGSEDI

is a registered trademark of Akcea Therapeutics, Inc. WAYLIVRA is a registered trademark of Akcea Therapeutics, Inc. SPINRAZA is a registered trademark of Biogen.

Ionis Pharmaceuticals Investor Contact:

D. Wade Walke, Ph.D.

Vice President, Investor Relations

Ionis Pharmaceuticals Media Contact:

Vice President, Marketing and Communications

IONIS PHARMACEUTICALS, INC.

SELECTED FINANCIAL INFORMATION

Condensed Consolidated Statements of Operations

(In Millions, Except Per Share Data)

IONIS PHARMACEUTICALS, INC.

Reconciliation of GAAP to Non-GAAP Basis:

Condensed Consolidated Operating Expenses, Income (Loss) From Operations, and Net Income (Loss)

Reconciliation of GAAP to Non-GAAP Basis

As illustrated in the Selected Financial Information in this press release, non-GAAP operating expenses, non-GAAP income (loss) from operations, and non-GAAP net income

(loss) attributable to Ionis Pharmaceuticals, Inc. common shareholders were adjusted from GAAP to exclude compensation expense related to equity awards and costs related to the Akcea acquisition and restructured European operations and the related

tax effects. Compensation expense related to equity awards are non-cash. Costs related to the Akcea acquisition and restructured European operations include: severance costs, retention costs, other costs, non-cash stock-based compensation expense for

the acceleration of Akcea equity awards and non-cash income tax expense as a result of establishing a valuation allowance for Ionis' federal net deferred tax assets. Ionis has regularly reported non-GAAP measures for operating results as non-GAAP

results. These measures are provided as supplementary information and are not a substitute for financial measures calculated in accordance with GAAP. Ionis reports these non-GAAP results to better enable financial statement users to assess and

compare its historical performance and project its future operating results and cash flows. Further, the presentation of Ionis' non-GAAP results is consistent with how Ionis' management internally evaluates the performance of its operations.

IONIS PHARMACEUTICALS, INC.

Condensed Consolidated Balance Sheets