Ionis reports third quarter 2023 financial results Olezarsen Phase 3 data showed significant triglyceride lowering, substantial reductions in acute pancreatitis attacks and favorable safety and tolerability in patients w

Ionis reports third quarter 2023 financial results

Olezarsen Phase 3 data showed significant triglyceride lowering, substantial reductions in acute pancreatitis attacks and

favorable safety and tolerability in patients with FCS; on track for regulatory filings in early 2024

Eplontersen marketing applications accepted for review in the EU and Canada; potential U.S. approval in December 2023

On track to achieve 2023 financial guidance

CARLSBAD, Calif., November 2, 2023 - Ionis Pharmaceuticals, Inc. (Nasdaq:

IONS) (the "Company"), today reported financial results for the third quarter of 2023.

"We continue to successfully execute on our strategy to deliver a steady cadence of potentially transformational medicines to patients," said Brett P. Monia, Ph.D.,

chief executive officer of Ionis. "Eplontersen is on track for its first potential approval in the U.S. and is under regulatory review in the EU and Canada. We believe the positive efficacy and safety data coupled with an attractive

self-administration dosing profile positions eplontersen to be the preferred therapy in the largely underserved hereditary ATTR polyneuropathy population. We reported positive data from the olezarsen Phase 3 Balance study in patients with familial

chylomicronemia syndrome, showing statistically significant triglyceride lowering, substantial reductions in acute pancreatitis attacks and favorable safety and tolerability,

positioning olezarsen to be our first independent commercial launch. We also made additional progress across our wholly owned and partnered pipeline, and further expanded our rich Phase 3 pipeline with the advance of zilganersen for patients with

Alexander disease into Phase 3 development. Looking ahead, we expect to continue our positive momentum with the potential approval and launch of eplontersen and the Phase 3 data readout of donidalorsen in hereditary angioedema."

Third Quarter 2023 Summary Financial Results:

Financial Highlights

Near-Term Commercial Opportunities and Late-Stage Pipeline Highlights

Partnered Program Highlights

Third Quarter 2023 Financial Results

"Our year-to-date financial results keep us on track to achieve our 2023 guidance as we execute on a strategy to unlock next-level value," said Elizabeth L. Hougen,

chief financial officer of Ionis. "Our strong financial foundation includes more than $2B in cash, significant royalty revenue with SPINRAZA, and substantial and sustained R&D revenue from multiple partners. We are well positioned to continue

investing in our key priorities to drive future positive cash flow, including advancing our go-to-market activities, growing our wholly owned pipeline and optimizing new cutting-edge technologies for future medicines. We look forward to the

potential U.S. eplontersen ATTRv-PN approval next month followed closely by launch. Together with our partner, AstraZeneca, we believe we are well positioned to identify new

patients to further grow the market and become the treatment of choice for this population that remains largely underserved by current therapies."

Ionis' revenue was comprised of the following:

Commercial revenue for the three and nine months ended September 30, 2023 included $67 million and $179 million from SPINRAZA royalties, respectively, which were

essentially flat compared to the same periods last year reflecting SPINRAZA's resilience against emerging competition. Ionis' commercial revenue in the three and nine months ended September 30, 2023 also included royalties from the U.S. launch of

R&D revenue decreased for the three months ended September 30, 2023 and increased for the nine months ended September 30, 2023 compared to the same periods last

year due to the timing of certain partner payments, including the $35 million license fee for IONIS-FB-LRx that Ionis earned from Roche in the three months ended September 30, 2022.

Ionis' operating expenses increased in the three and nine months ended September 30, 2023 compared to the same periods in 2022, consistent with expectations. As Ionis

advanced its robust pipeline, study costs increased compared to the same periods in 2022 as most of the Company's Phase 3 studies are either fully enrolled or approaching full enrollment,

resulting in higher R&D expenses year over year. Ionis' SG&A expenses also increased year over year primarily due to launch preparation activities for eplontersen, olezarsen and donidalorsen.

As of September 30, 2023, Ionis' cash, cash equivalents and short-term investments increased to $2.2 billion compared to $2.0 billion at December 31, 2022 primarily

due to the $500 million Ionis received from Royalty Pharma in January 2023. Ionis' working capital also increased over the same period primarily due to the Company's higher cash and short-term investments balance. In the first quarter of 2023, the Company recorded a long-term liability for future royalties due to Royalty Pharma. In June 2023, Ionis issued $575 million of senior convertible notes due in June 2028 with an interest rate of 1.75%. The Company used the majority of the proceeds to repurchase $504 million of

its 0.125% convertible notes.

Management will host a conference call and webcast to discuss Ionis' third quarter 2023 results at 11:30 a.m. Eastern time on Thursday, November 2, 2023. 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 2023 earnings slides

About Ionis Pharmaceuticals, Inc.

For more than 30 years, Ionis has been a leader in RNA-targeted therapy, pioneering new markets and changing standards of care. Ionis currently has four marketed

medicines and a promising late-stage pipeline highlighted by cardiovascular and neurological franchises. Our scientific innovation began and continues with the knowledge that sick people depend on us, which fuels our vision to become the leader in

genetic medicine, utilizing a multi-platform approach to discover, develop and deliver life-transforming therapies.

Ionis' Forward-looking Statement

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

(tofersen), SPINRAZA (nusinersen), TEGSEDI (inotersen), WAYLIVRA (volanesorsen), eplontersen, olezarsen, donidalorsen, zilganersen, ulefnersen, pelacarsen, bepirovirsen, IONIS-FB-LRx, 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 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, 2022, 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. QALSODYTM is a trademark of Biogen. SPINRAZA is a

registered trademark of Biogen.

Ionis Investor Contact:

D. Wade Walke, Ph.D.

info@ionisph.com 760-603-2331

Ionis Media Contact:

ionis_ca@ionisph.com 760-603-4679

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

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. 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

Key 2023 Value Driving Events(1)