Ionis reports third quarter financial results Advanced key priorities: initiated manufacturing infrastructure project to support growth Increased 2022 cash and investments guidance

Ionis reports third quarter financial results

Advanced key priorities: initiated manufacturing infrastructure project to support growth

Increased 2022 cash and investments guidance

CARLSBAD, Calif., November 9, 2022 - Ionis Pharmaceuticals, Inc. (Nasdaq: IONS)

(the "Company") today reported financial results for the third quarter of 2022. Financial results are summarized below:

Financial Highlights

Late-Stage Pipeline Highlights

Mid-Stage Pipeline Highlights

"We have made significant progress on our key priorities this year, building our commercial pipeline, delivering an abundance of new medicines to the market and

expanding and diversifying our technology. We delivered positive data from eight key programs, positioning us to potentially add two new marketed medicines to our portfolio and expand our rich Phase 3 pipeline to eight medicines next year.

Additionally, we have recently begun work on a manufacturing facility to support our pipeline growth," said Brett P. Monia, Ph.D., chief executive officer of Ionis. "As we advance

our near-term opportunities, including filing the NDA this year for eplontersen, and expanding our rich late-stage pipeline, we are well positioned to drive increasing value for all stakeholders."

Third Quarter 2022 Financial Results

Ionis' revenue was comprised of the following:

Total revenue for the three and nine months ended September 30, 2022 increased 20 percent and 18

percent compared to the same periods last year, respectively. The increase was driven by significant payments Ionis earned across multiple partnered programs. R&D revenue for the nine months ended September 30, 2022 included $85 million from

Biogen for advancing several neurology disease programs, $63 million from Roche for licensing and advancing IONIS-FB-LRx and $55 million from AstraZeneca for its share of the global Phase 3 development costs for eplontersen.

Commercial revenue for the three and nine months ended September 30, 2022 decreased 15 percent and 13 percent compared to the same periods last year, respectively.

SPINRAZA royalties for the three and nine months ended September 30, 2022 decreased 7 percent and 12 percent compared to the same periods last year, respectively. In the U.S., SPINRAZA sales were flat in the first nine months of 2022 compared to the

same period last year. Outside of the U.S. SPINRAZA royalties were lower due to lower SPINRAZA product sales primarily due to decreased pricing, foreign currency exchange and competition. TEGSEDI and WAYLIVRA revenue was also lower due to the shift

to distribution fees in 2021.

Ionis' non-GAAP operating expenses increased for the three and nine months ended September 30, 2022 compared to the same periods in 2021, in line with expectations. For

both periods, higher R&D expenses were driven by the expanded number of Phase 3 studies the Company is conducting, which doubled from three to six studies in 2021. SG&A expenses increased for the three months ended September 30, 2022 compared

to the same period last year driven by Ionis' go-to-market activities for eplontersen, donidalorsen and olezarsen. SG&A expenses were lower for the nine months ended September 30, 2022 compared to the same period last year largely due to the

substantial savings the Company achieved from integrating Akcea and restructuring its commercial operations in 2021.

As of September 30, 2022, Ionis had cash, cash equivalents and short-term investments of $2.0 billion, compared with $2.1 billion at December 31, 2021. Ionis' debt

obligations and working capital did not change significantly from December 31, 2021 to September 30, 2022.

In October 2022, Ionis entered into a sale and leaseback transaction for several of its real estate assets. Under the agreement, Ionis will receive net proceeds of

approximately $240 million plus full funding to expand the Company's R&D campus. The net proceeds reflect the Company's extinguishment of its mortgage debt for the related properties. Ionis' fourth quarter financial results will reflect the

impact this transaction.

2022 Financial Guidance

The Company reaffirmed its full year 2022 guidance for total revenue, operating expenses and net

loss, on a non-GAAP basis. The Company's 2022 operating expense guidance, compared to the prior year, includes increasing R&D expenses between 25% and 30% and consistent SG&A expenses. Ionis expects to recognize a substantial gain on the sale

of its real estate assets in the fourth quarter. The gain will not impact the Company's non-GAAP results since the sale was non-recurring and not part of the Company's normal business operations.

The Company increased its full year 2022 cash and investments guidance to approximately $2.0 billion

from the previous guidance of $1.7 billion.

"Our strong year-to-date results, including year-over-year revenue growth of nearly 20 percent, keep us on track to meet our 2022 P&L guidance," said Elizabeth L.

Hougen, chief financial officer of Ionis. "Additionally, we recently bolstered our balance sheet when we unlocked net proceeds of approximately $240 million plus full funding to

expand our R&D campus by capitalizing on the favorable life sciences real estate market and monetizing several of our facilities through a sale and leaseback transaction. As a result, we are increasing our 2022 cash and short-term investment

guidance to approximately $2 billion."

Management will host a conference call and webcast to discuss Ionis' third quarter 2022 results at 11:30 a.m. Eastern time on Wednesday, November 9, 2022. Interested

parties may access the webcast here. A webcast replay will be available for a limited time at the same address. To access the Company's third quarter 2022 earnings slides

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 cardiovascular and neurological franchises. Our scientific innovation began and continues with the knowledge that

sick people depend on us, which fuels our vision of becoming a leading, fully integrated biotechnology company.

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), WAYLIVRA (volanesorsen), eplontersen, olezarsen, donidalorsen, ION363, pelacarsen, tofersen, Ionis' technologies and Ionis' other products in development. 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 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, 2021, and most recent Form 10-Q, which are on file with the Securities and Exchange Commission. 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" all refer to Ionis Pharmaceuticals and its subsidiaries.

Ionis Pharmaceuticals is a registered 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:

Ionis Pharmaceuticals Media Contact:

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, Loss From Operations, and Net Loss

*In October 2020, Ionis completed a merger transaction with Akcea such that following the completion of the merger Akcea became a wholly owned subsidiary of Ionis.

Additionally, in December 2020 and April 2021, Ionis restructured its European operations and its North American TEGSEDI operations, respectively, as a result of entering into distribution agreements with Sobi. The Company excluded the Akcea merger

and restructured commercial operation costs from its non-GAAP amounts for the applicable periods.

Reconciliation of GAAP to Non-GAAP Basis

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

adjusted from GAAP to exclude compensation expense related to equity awards and the related tax effects. Compensation expense related to equity awards are non-cash. In 2021 all non-GAAP amounts also excluded expenses related to the Akcea merger and

restructured commercial operations. Expenses related to the Akcea merger and restructured commercial operations included: severance costs, retention costs and other costs related

to commercial operations. 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.

Summary of the Financial Impacts of the Eplontersen Collaboration with AstraZeneca

For the Nine Months Ended, September 30, 2022

Ionis' financial results for the nine months ended September 30, 2022 reflected the cost-sharing provisions related to its collaboration with AstraZeneca to develop and

commercialize eplontersen for the treatment of ATTR. Under the terms of the collaboration agreement, AstraZeneca is paying 55 percent of the costs associated with the ongoing global Phase 3 development program. Because Ionis is leading and conducting

the Phase 3 development program, Ionis is recognizing the 55 percent of cost-share funding AstraZeneca is responsible for, net of Ionis' share of AstraZeneca's development expenses, as R&D revenue in the same period Ionis incurs the related

development expenses. For the nine months ended September 30, 2022 Ionis earned $55 million in joint development revenue under this collaboration.

Because AstraZeneca is responsible for the majority of the medical affairs and commercial costs in the U.S. and all costs associated with bringing eplontersen to market

outside the U.S., Ionis is recognizing cost-share funding it receives from AstraZeneca related to these activities as a reduction of its medical affairs (R&D expenses) and commercialization expenses (SG&A expenses). For the nine months ended

September 30, 2022 Ionis recognized $1.4 million and $1.5 million of medical affairs expenses and commercialization expenses for eplontersen, respectively, net of cost-share funding from AstraZeneca. Ionis expects its medical affairs and

commercialization expenses to increase as this collaboration progresses.

IONIS PHARMACEUTICALS, INC.

Condensed Consolidated Balance Sheets

2022 Pipeline Milestones(1)