Ionis reports first quarter 2025 financial results - Encouraging start to first independent launch with TRYNGOLZA TM - - On track for second independent launch with donidalorsen PDUFA

Ionis reports first quarter 2025 financial results

- Encouraging start to first

independent launch with TRYNGOLZATM -

- On track for second

independent launch with donidalorsen PDUFA August 21, 2025 -

- Increasing 2025 financial

guidance by more than 20% -

CARLSBAD, Calif., April 30, 2025 - Ionis

Pharmaceuticals, Inc. (Nasdaq: IONS) (the "Company") today reported financial results for the first quarter ended March 31, 2025.

"With an encouraging start to the TRYNGOLZA launch for familial chylomicronemia syndrome, the first of four independent launches expected over the next two years,

Ionis' new chapter as a fully integrated, commercial-stage biotechnology company is well underway," said Brett P. Monia, Ph.D., chief executive officer, Ionis. "We look forward to continued momentum this year, including our second independent

launch for donidalorsen in hereditary angioedema and Phase 3 results for olezarsen for severe hypertriglyceridemia in the third quarter. We also continue to advance our next wave of wholly owned neurology medicines, including ION582 for Angelman

syndrome, which is on track to start Phase 3 development shortly. Our advancing pipeline of transformational medicines, together with strong commercial and financial execution, position Ionis to deliver increasing value for all stakeholders."

First Quarter 2025 Summary Financial Results(1):

Recent Financial Highlights

Recent Highlights - Marketed Medicines

Recent Highlights - Late-Stage Wholly Owned Pipeline

Recent Highlights - Partnered Pipeline

First Quarter 2025 Financial Results

"We are increasing our 2025 financial guidance including raising revenue guidance by more than 20 percent due to our strong first quarter results and recent successful

licensing transactions. We are also substantially improving our operating loss and cash guidance and now expect to end the year with approximately $1.9 billion in cash. Our strong financial

position and commitment to drive operating leverage position Ionis to advance our strategic priorities and successfully navigate the dynamic macroeconomic environment," said Elizabeth L. Hougen, chief financial officer, Ionis. "Our first quarter

results reflected encouraging early performance in the TRYNGOLZA launch, adding product revenue to our P&L for the first time. Moving forward, the three additional independent launches anticipated over the next couple of years position Ionis to

deliver substantial and growing product revenue. This product revenue coupled with anticipated increasing royalty revenue from multiple partner launches and disciplined investment, position Ionis to achieve sustained positive cash flow."

Ionis' revenue was comprised of the following:

Commercial revenue for the first quarter of 2025 increased 28% compared to the same period in 2024, driven in part by revenue from U.S. product sales from the launch

of TRYNGOLZA. Higher royalty revenues from SPINRAZA, WAINUA and QALSODY also contributed to the year over year increase.

The remainder of the Company's revenue came from programs under its R&D collaborations, reflecting the value that Ionis' pipeline and technology continues to

SG&A expenses increased in the first quarter of 2025 compared to the same period in 2024 primarily due to the launches of WAINUA and TRYNGOLZA, and advancing

launch preparation activities for donidalorsen. This increase was partially offset by a decrease in R&D expenses as several late-stage studies ended. Overall, this led to a slight increase in total operating expenses.

As of March 31, 2025, Ionis' cash, cash equivalents and short-term investments were $2.1 billion, compared to $2.3 billion at December 31,

2024. Ionis' working capital decreased over the same period primarily due to the Company's lower cash and short-term investments balance. Ionis generated $280 million from the global license of sapablursen in the second quarter.

Management will host a conference call and webcast to discuss Ionis' first quarter 2025 results at 11:30 a.m. Eastern time on Wednesday, April 30, 2025. 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 first quarter 2025 earnings slides click here.

Ionis' Marketed Medicines

INDICATION for TRYNGOLZA (olezarsen)

TRYNGOLZA (olezarsen) was approved by the U.S. Food and Drug Administration as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia

IMPORTANT SAFETY INFORMATION

TRYNGOLZA is contraindicated in patients with a history of serious hypersensitivity to TRYNGOLZA or any of the excipients in TRYNGOLZA. Hypersensitivity reactions

requiring medical treatment have occurred.

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions

Hypersensitivity reactions (including symptoms of bronchospasm, diffuse erythema, facial swelling, urticaria, chills and myalgias) have been reported in patients treated

with TRYNGOLZA. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to promptly seek medical attention and discontinue use of TRYNGOLZA if hypersensitivity reactions occur.

The most common adverse reactions (incidence >5% of TRYNGOLZA-treated patients and >3% higher frequency than placebo) were injection site reactions, decreased

platelet count and arthralgia.

Please see full Prescribing Information for TRYNGOLZA.

INDICATION for WAINUA (eplontersen)

WAINUA injection, for subcutaneous use, 45 mg is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

IMPORTANT SAFETY INFORMATION for WAINUA (eplontersen)

WARNINGS AND PRECAUTIONS

Reduced Serum Vitamin A Levels and Recommended Supplementation WAINUA leads to a decrease in serum vitamin A levels. Supplement with recommended daily allowance of vitamin A. Refer patient to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occur.

Most common adverse reactions ( 9% in WAINUA-treated patients) were vitamin A decreased (15%) and vomiting (9%).

Please see link to U.S. Full Prescribing Information for WAINUA.

For more information about SPINRAZA and QALSODY, visit https://www.spinraza.com/ and https://www.qalsody.com/, respectively. QALSODY is approved under accelerated approval based on reduction in plasma neurofilament light chain (NfL) observed in patients treated with QALSODY.

Continued approval may be contingent upon verification of clinical benefit in confirmatory trial(s).

About Ionis Pharmaceuticals, Inc.

For three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has six marketed medicines and a leading

pipeline in neurology, cardiology and select areas of high patient need. As the pioneer in RNA-targeted medicines, Ionis continues to drive innovation in RNA therapies in addition to advancing new approaches in gene editing. A deep understanding of

disease biology and industry-leading technology propels our work, coupled with a passion and urgency to deliver life-changing advances for patients. To learn more about Ionis, visit Ionis.com

Ionis' Forward-looking Statement

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

medicines, additional medicines in development and technologies. 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. Except as required by law, we undertake no

obligation to update any forward-looking statements for any reason. 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, 2024, 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. TRYNGOLZATM 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

and QALSODY are registered trademarks of Biogen. WAINUATM is a registered trademark of the AstraZeneca group of companies.

Ionis Investor Contact:

D. Wade Walke, Ph.D.

Ionis 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

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 2025 and 2026 Value Driving Events(1)