Ionis reports second quarter 2024 financial results WAINUA TM U.S. launch progressing well; approved in Canada; EU approval decision expected this year Olezarsen PDUFA

Ionis reports second quarter 2024 financial results

WAINUATM U.S. launch progressing well; approved in Canada; EU approval decision expected this year

Olezarsen PDUFA December 19, 2024 for FCS

Positive Phase 3 donidalorsen data for HAE; preparing U.S. and EU regulatory submissions

On track to achieve 2024 financial guidance

CARLSBAD, Calif., August 1, 2024 - Ionis

Pharmaceuticals, Inc. (Nasdaq: IONS) (the "Company"), today reported financial results for the second quarter of 2024.

"Over the first half of this year, we continued to deliver on our goal to bring a steady cadence of medicines to people with serious diseases. The WAINUA launch for

hereditary ATTR polyneuropathy (ATTRv-PN) continues to progress well with AstraZeneca. QALSODY is now approved in the EU, expanding the number of patients who can benefit from the first approved

treatment for a genetic form of ALS. And we are well positioned for our first independent launch with olezarsen, which was accepted for Priority Review with a December FDA action date for people with familial chylomicronemia syndrome (FCS), a serious and rare disease with no approved treatments in the U.S. Additionally, we completed enrollment in our Phase 3 olezarsen program for the much larger severe hypertriglyceridemia (sHTG) patient population, keeping us on track for data in the second half of next year. And based on recent positive Phase 3 results, we believe donidalorsen, our second planned

independent U.S. launch, is positioned to be a preferred choice for people with hereditary angioedema (HAE)," said Brett P. Monia, Ph.D., chief executive officer of Ionis. "We also advanced our

next wave of potentially transformational medicines, including announcing plans to independently advance ION582 into a Phase 3 study next year, based on positive data in Angelman syndrome; this program is poised to become the cornerstone of our

robust wholly owned neurology pipeline. Our recent achievements, together with multiple upcoming catalysts, position Ionis to deliver next-level value for all stakeholders."

Second Quarter 2024 Summary Financial Results(1):

Financial Highlights

Recent Marketed Medicines Highlights

Recent Late-Stage Pipeline Highlights

Recent Other Pipeline Updates

Second Quarter 2024 Financial Results

"Ionis is at a critical inflection point. We have achieved important development and regulatory milestones for WAINUA, olezarsen and donidalorsen, all of which have

significant potential to help patients in need. In parallel, we continue to advance our next wave of potentially transformational medicines," said Elizabeth L. Hougen, chief financial officer of Ionis. "To drive next-level of value creation for all

stakeholders, we remain focused on strategically investing our capital to fully unlock the potential of our promising near-and longer-term portfolio. Our investments are focused on go-to-market preparations for our upcoming planned olezarsen and

donidalorsen launches. And with our increased confidence in the potential of WAINUA and olezarsen to address broader patient populations, we are planning additional investments to scale our capabilities in line with the significant potential that

these important medicines represent. Additionally, we are investing in our next wave of medicines, including pre-commercialization activities and Phase 3 development for ION582 for Angelman syndrome, which we plan to start in the first half of next

year. We expect our investments today and in the years ahead will position Ionis for sustainable growth for years to come."

Ionis' revenue was comprised of the following:

Commercial revenue in the second quarter and first half of 2024 included a new source of royalty revenue with the launch of WAINUA in the U.S. in late January 2024.

Ionis' commercial revenue in the second quarter and first half of 2024 also included royalties from the net sales of QALSODY, which Biogen launched in the U.S. in the second quarter of 2023 and in the EU in the second quarter of 2024.

R&D revenue in the second quarter and first half of 2024 increased compared to the same periods last year primarily due to the amortization of upfront payments from

the new collaborations with Roche and Novartis that Ionis entered into during the second half of last year. In addition, license fees increased year over year as a result of new collaborations

Ionis entered into during the second quarter of 2024, including the expanded donidalorsen licensing agreement with Otsuka, which now includes the Asia-Pacific region in addition to Europe. These increases were partially offset by the decrease in

WAINUA joint development revenue, which decreased as development activities relating to ATTRv-PN wound down with the launch of WAINUA for this indication.

Ionis' operating expenses increased in the second quarter and first half of 2024 compared to the same periods in 2023, consistent with expectations. SG&A expenses

increased year over year primarily due to the launch of WAINUA in the U.S. and launch preparation activities for olezarsen and donidalorsen, including establishing the field team for olezarsen. R&D expenses decreased in the second quarter and

were essentially flat in the first half of 2024 compared to the same periods last year as several late-stage studies have ended.

As of June 30, 2024, Ionis' cash, cash equivalents and short-term investments decreased to $2.1 billion compared to $2.3 billion at December 31, 2023. The Company plans

to continue deploying its capital resources toward growth opportunities, and as previously guided, projects to end 2024 with $1.7 billion in cash, cash equivalents and short-term investments.

Ionis' working capital also decreased over the same period primarily due to the Company's lower cash and short-term investments balance. We expect to make increased strategic investments in the years ahead, with a focus on late-stage programs, wholly

owned assets, and our next wave of innovative medicines.

Management will host a conference call and webcast to discuss Ionis' second quarter 2024 results at 11:30 a.m. Eastern time on Thursday, August 1, 2024.

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 second quarter 2024 earnings slides click

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).

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

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.

About Ionis Pharmaceuticals, Inc.

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

and a leading pipeline in neurology, cardiology, and other 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, 2023, 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 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 2024 Value Driving Events(1)