IONIS PHARMACEUTICALS INC

FOR THE 2024 ANNUAL MEETING OF STOCKHOLDERS

To Be Held on June 6, 2024

QUESTIONS AND ANSWERS ABOUT THESE PROXY MATERIALS AND VOTING

Why did I receive a Notice Regarding the Availability of Proxy Materials on the Internet?

The Board of Directors (the “Board”) of Ionis Pharmaceuticals, Inc. (the “Company”) is soliciting your proxy to vote at the 2024 Annual Meeting of Stockholders, including at any adjournments or postponements of the meeting. We are distributing our Notice of Annual Meeting and Proxy Materials (the “Notice”) by mail using the Notice and Access procedures established by the United States Securities and Exchange Commission (the “SEC”). The Notice is important because it contains a control number and instructions that will allow you to access our proxy materials and vote electronically through the Internet or to request printed proxy materials so you may vote by telephone or mail. Your vote is very important. Whether or not you plan to attend the meeting, please be sure to vote your shares as soon as possible to ensure your representation at the meeting. All stockholders will have the ability to access the proxy materials on the website referred to in the Notice or request to receive a printed set of the proxy materials. You can find instructions on how to access the proxy materials over the Internet or to request a printed copy in the Notice.

We intend to mail the Notice on April 26, 2024 to all stockholders of record entitled to vote at the Annual Meeting.

Will I receive any other proxy materials by mail?

We may send you a proxy card, along with a second Notice, on or after May 7, 2024.

Where and when is the Annual Meeting?

The Annual Meeting will be held on Thursday, June 6, 2024, at 2:00 p.m. Pacific Time. The Annual Meeting will be held in a virtual meeting format only, via live webcast on the Internet, with no physical in-person meeting. To participate, vote or submit questions during the Annual Meeting via live webcast, please visitwww.virtualshareholdermeeting.com/IONS2024.

If you cannot attend, please note that we will make a webcast of the presentation that follows the Annual Meeting available on the day of the meeting and for a limited time following the meeting atwww.ionispharma.com.1

If you plan to attend the virtual meeting and prefer to vote online, you may still do so even if you have already returned your proxy.

How do I attend the Annual Meeting?

We will be hosting the Annual Meeting via live webcast on the Internet. You will not be able to attend the Annual Meeting in person. All stockholders at the close of business on April 8, 2024 can listen to and participate in the Annual Meeting live via the internet atwww.virtualshareholdermeeting.com/IONS2024. The webcast will begin at 2:00 p.m. Pacific Time on June 6, 2024. Stockholders may vote and submit questions while connected to the Annual Meeting on the Internet. A summary of the information you need to attend the Annual Meeting online is provided below.

What do I need in order to be able to participate in the Annual Meeting online?

You will need the 16-digit control number included on your Notice of Internet Availability of Proxy Materials, proxy card or voting instruction form that accompanied your proxy materials to be able to vote your shares or submit questions during the virtual Annual Meeting. Instructions on how to connect and participate in the Annual Meeting via the internet, including how to demonstrate proof of stock ownership, are posted atwww.virtualshareholdermeeting.com/IONS2024.

1 Any information that is included on or linked to our website is not part of this Proxy Statement or any registration statement or report that incorporates this Proxy Statement by reference.

What if I have technical difficulties or trouble accessing the live webcast of the Annual Meeting?

If you encounter any difficulties accessing the live webcast of the Annual Meeting or during the Annual Meeting, please call the telephone number that is listed atwww.virtualshareholdermeeting.com/IONS2024 for assistance. If you misplace the 16-digit control number that is required to enter the Annual Meeting webcast and are a stockholder of record, operators providing assistance at this telephone number will be able to provide it to you. However, if you need your 16-digit control number and hold your shares in an account at a brokerage firm, bank, dealer, or other similar organization, you must contact that organization to obtain your 16-digit control number prior to the Annual Meeting.

Who can attend and vote at the Annual Meeting?

Only stockholders at the close of business on April 8, 2024 may attend and vote at the Annual Meeting. On this record date, there were 145,845,852 shares of common stock outstanding and entitled to vote.

Stockholder of Record: Shares Registered in Your Name

If on April 8, 2024 your shares were registered directly in your name with our transfer agent, Equiniti Trust Company, then you are a stockholder of record. As a stockholder of record, you may vote online at the virtual meeting or vote by proxy over the telephone, by mail, or the Internet as instructed under the section below titled “How do I vote?” Whether or not you plan to attend the meeting, we urge you to fill out and return the proxy card or vote over the telephone or Internet to ensure your vote is counted.

Beneficial Owner: Shares Registered in the Name of a Broker or Bank

If on April 8, 2024 you did not own shares in your name, but rather in an account at a brokerage firm, bank, dealer or other similar organization, then you are the beneficial owner of shares held in “street name” and that organization is forwarding the Notice to you. The organization holding your account is the stockholder of record for purposes of voting at the Annual Meeting. As a beneficial owner, you may direct your broker or other agent regarding how to vote the shares in your account. If your shares are registered in the name of a broker or other nominee, your nominee may be participating in a program provided through Broadridge Financial Solutions, Inc. (“Broadridge”) that also allows you to vote by telephone or through the Internet. If so, the voting form your nominee sends you will provide telephone and Internet instructions. You are also invited to attend the virtual Annual Meeting via live webcast.

PLEASE NOTE, HOWEVER, THAT IF A BROKER, BANK OR OTHER NOMINEE HOLDS YOUR SHARES OF RECORD AND YOU WISH TO VOTE AT THE MEETING, YOU MUST OBTAIN A PROXY ISSUED IN YOUR NAME FROM THE BROKER, BANK OR OTHER NOMINEE.

What am I voting on?

The following matters are scheduled for a vote:

What if another matter is properly brought before the meeting?

The Board knows of no other matters that will be presented for consideration at the Annual Meeting. If any other matters are properly brought before the meeting, the persons named in the accompanying proxy intend to vote on those matters in accordance with their best judgment.

How do I vote?

You may vote in one of the following ways:

The procedures for voting are fairly simple:

For Shares Registered in Your Name:

If you are a stockholder of record, you may go towww.proxyvote.com to vote your shares through the Internet up until 11:59 p.m. Eastern Time on June 5, 2024. The votes represented by your proxy will be displayed on the computer screen and you will be prompted to submit or revise your votes as desired.

To vote your shares by telephone, you must first request that we send proxy materials to you by following the instructions included in your Notice. Once you have received your proxy materials, you may vote using a touch-tone telephone by calling 1-800-690-6903 up until 11:59 p.m. Eastern Time on June 5, 2024 and following the recorded instructions. Please have your proxy card available at the time you vote.

To vote using the proxy card, simply complete, sign and date the proxy card that may be delivered to you and return it promptly in the envelope provided. If we receive your signed proxy card before the Annual Meeting, we will vote your shares as you direct.

For Shares Registered in the Name of a Broker or Bank:

If your broker or bank holds your shares in “street name,” you will need to obtain a proxy form from the institution that holds your shares and follow the instructions included on that form regarding how to instruct your broker to vote your shares. If you do not give instructions to your broker, your broker can vote your shares with respect to “discretionary” items, but not with respect to “non-discretionary” items. Discretionary items are proposals considered routine under the rules of the New York Stock Exchange (“NYSE”) on which a broker may vote shares held in street name in the absence of your voting instructions. While Ionis is listed with the Nasdaq Stock Market (“Nasdaq”), NYSE rules affect how brokers licensed by the NYSE can vote in a director election of any company, including companies listed with Nasdaq. The proposal to ratify Ernst & Young LLP as independent auditors is a discretionary item. Proposals 1 through 3 regarding (1) the election of Directors, (2) an advisory vote on our executive compensation, and (3) approval of an amendment of the Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan to increase the aggregate number of shares of common stock authorized for issuance under such plan by 3,300,000 shares to an aggregate of 38,500,000 shares and to prohibit certain share recycling on full value awards are non-discretionary items. If you do not give your broker instructions for a non-discretionary item your broker cannot vote your shares, which will result in what is commonly referred to as a “broker non-vote.” Broker non-votes will have no effect.

A number of brokers and banks are participating in a program provided by Broadridge that allows proxies to vote shares by means of the telephone and Internet. If your shares are held in an account with a broker or bank participating in the Broadridge program, you may vote your shares by telephone or through the Internet by having the voting form in hand and calling the number or going to the website indicated on the form and following the instructions.

What if I return a proxy card or otherwise vote but do not make specific choices?

If you return a signed and dated proxy card or otherwise vote without marking voting selections, one of the individuals named on your proxy card will vote your shares as follows:

If any other matter is properly presented at the meeting, one of the individuals named on your proxy card will vote your shares using his or her best judgment.

Who is paying for this proxy solicitation?

Our Board is soliciting your proxy to vote at the Annual Meeting. We will bear the entire cost of soliciting proxies, including preparing, assembling, making available on the Internet and printing and mailing this Proxy Statement, the proxy card and any additional information furnished to stockholders. We will furnish copies of solicitation materials to banks, brokerage houses, fiduciaries and custodians holding our common stock in “street name” on behalf of beneficial owners of such shares. We may reimburse persons representing beneficial owners of our common stock for their costs of forwarding solicitation materials to such beneficial owners. Our Directors, officers or other employees may supplement original solicitation of proxies by telephone, electronic mail, or personal solicitation. We will not pay our Directors, officers, or employees any additional compensation for soliciting proxies. However, please be aware that you must bear any costs associated with your Internet service, such as usage charges from Internet access providers or telephone companies.

What does it mean if I receive more than one Notice?

If you receive more than one Notice or proxy card, your shares are registered in more than one name or are registered in different accounts. Please complete, sign, date and return each separate proxy card or vote by telephone or through the Internet by following the instructions included with each Notice or proxy card to properly vote your shares.

Can I change my vote after submitting my proxy?

Yes. Once you have submitted your proxy by mail, Internet, or telephone, you may revoke it at any time before we exercise it at the Annual Meeting. You may revoke your proxy by any one of the following four ways:

If your shares are held by your broker, bank, or other agent, you should follow the instructions provided by your broker, bank, or other agent.

When are stockholder proposals due for next year’s Annual Meeting?

If you have a proposal that you would like us to include in our proxy materials for next year’s Annual Meeting of Stockholders, you must send the proposal to us in writing by no later than December 27, 2024 and comply with all applicable requirements of Rule 14a-8 promulgated under the Securities Exchange Act of 1934, as amended (“Rule 14a-8”). Stockholders wishing to submit proposals or Director nominations that are not to be included in such proxy materials for next year’s Annual Meeting of Stockholders pursuant to Rule 14a-8 must do so no later than the close of business on February 6, 2025, as required by our bylaws. Stockholders should also review our bylaws, which contain additional requirements with respect to advance notice of stockholder proposals and Director nominations. In addition to satisfying the foregoing requirements under our bylaws, stockholders who intend to solicit proxies in support of director nominees other than the Company’s nominees must also comply with the additional requirements of Rule 14a-19(b).

What is the quorum requirement?

A quorum of stockholders is necessary to hold a valid meeting. A quorum will be present at the meeting if at least a majority of the outstanding shares entitled to vote are represented at the meeting or by proxy. We will count your shares towards the quorum only if you submit a valid proxy vote (or one is submitted on your behalf by your broker, bank, or other nominee) or vote at the meeting. We will count abstentions and broker non-votes towards the quorum requirement.

If there is no quorum, either the chair of the meeting or the holders of a majority of shares present at the meeting or represented by proxy may adjourn the meeting to another date.

How are votes counted?

Each share of our common stock you own entitles you to one vote. Your Notice and proxy card indicates the number of shares of our common stock you owned at the close of business on April 8, 2024. The inspector of elections will count votes for the meeting and will separately count “For” and “Against” votes, abstentions, and, if applicable, broker non-votes for Proposals 1, 2, 3 and 4. Abstentions will have no effect on Proposal 1 and Proposal 3. Abstentions will count towards the vote total for Proposal 2 and Proposal 4 and will have the same effect as “Against” votes. Broker non-votes have no effect and the inspector of elections will not count them towards the vote total for Proposals 1, 2 and 3.

What are “broker non-votes”?

Broker non-votes occur when a beneficial owner of shares held in “street name” does not give instructions to the broker or nominee holding the shares as to how to vote on matters deemed “non-routine.” If your broker holds your shares in “street name,” and you do not give instructions to your broker, your broker can vote your shares with respect to “discretionary” items, but not with respect to “non-discretionary” items. The proposal to ratify Ernst & Young LLP as independent auditors is a discretionary item. Proposals 1 through 3 regarding (1) the election of Directors, (2) an advisory vote on our executive compensation, and (3) approval of an amendment of the Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan to increase the aggregate number of shares of common stock authorized for issuance under such plan by 3,300,000 shares to an aggregate of 38,500,000 shares and to prohibit certain share recycling on full value awards are all non-discretionary items.

How many votes are needed to approve each proposal?

How can I find out the results of the voting at the Annual Meeting?

We will announce preliminary voting results at the Annual Meeting. In addition, we will publish final voting results in a current report on Form 8-K that we expect to file within four business days after the Annual Meeting. If final voting results are not available to us in time to file as part of a Form 8-K within four business days after the Annual Meeting, we intend to file a Form 8-K to publish preliminary results and, within four business days after we know the final results, file an additional Form 8-K to publish final results.

How can I elect to receive materials for future Annual Meetings electronically?

We are pleased to offer to our stockholders the benefits and convenience of electronic delivery of Annual Meeting materials, including:

We encourage you to conserve natural resources and to reduce printing and mailing costs by signing up for electronic delivery of our stockholder communications after you place your current vote atwww.proxyvote.com.

List of Shareholders

A list of stockholders entitled to vote at the Annual Meeting will be available for examination at our principal executive offices at the address listed above for a period of 10 days prior to the Annual Meeting, and will be available during the virtual Annual Meeting for examination atwww.virtualshareholdermeeting.com/IONS2024.

Corporate Responsibility and Environmental, Social and Governance (“ESG”) Initiatives

At Ionis, we work with a sense of urgency to discover, develop and deliver medicines to create a better future for people with serious diseases. We believe operating responsibly and sustainably creates long-term value for the Company and our stakeholders. We encourage you to view our 2023 Corporate Responsibility Report published on our website for more detailed information regarding our ESG initiatives. Nothing in the report or on our website shall be deemed incorporated by reference into this Proxy Statement.

Our approach to corporate responsibility strategy and disclosure is informed by our stakeholders and third-party frameworks such as the Sustainability Accounting Standards Board (SASB) Health Care – Biotechnology and Pharmaceuticals Standard and the Task Force on Climate Related Financial Disclosures (TCFD). In addition, our corporate responsibility strategy is aligned with the United Nations Sustainable Development Goals (UN SDGs), which represent the international community’s plan of action to address the most pressing challenges facing our world today. In 2023, we continued to evolve our corporate responsibility program, building on our foundation and further defining our strategic direction. We established the following three corporate responsibility strategic pillars and associated goals that we believe are most important to our business. These pillars guide our approach and provide a framework for reporting on our performance.

Corporate Responsibility Governance

Our corporate responsibility initiatives are driven by our Chief Executive Officer and executive-level Corporate Responsibility Steering Committee. The Corporate Responsibility Steering Committee consists of senior leaders in key functions across the company, including Legal, Finance, Investor Relations, Human Resources, Research and Development, Manufacturing, Commercial, Compliance and Corporate Affairs. In 2023, we expanded this committee to include a broader cross-section of senior leaders to ensure we continue to develop the right programs, policies and systems to oversee ethical and sustainable operations across our business.

Our Board of Directors, specifically the Nominating, Governance and Review Committee, has oversight of our overall corporate responsibility strategy and material ESG risks and opportunities as outlined in the Nominating, Governance and Review Committee’s charter. The Nominating, Governance and Review Committee receives updates at least once annually and is engaged on specific topics as needed.

Clinical Trials and Product Quality

We are committed to conducting our clinical trials in a safe and ethical manner. We have established a series of policies and procedures that govern the ethical conduct of clinical trials and we adhere to applicable standards set by the International Council for Harmonization of Technical Requirements for Pharmaceutical Human Use. We are also committed to complying with applicable laws, regulations, global standards and collective GxP guidelines as they pertain to patient safety, product quality and data integrity. Quality risk management is embedded in our quality management system, which outlines a systematic, proactive and objective approach to identify, assess, control, monitor and document risks. In addition, to enhance patient access and ensure diverse representation, we are developing initiatives aimed at better aligning the demographics of our clinical trial participants with those of the affected patient populations.

Access and Affordability

We recognize that it is critical for the medicines we develop to be accessible and affordable for the patients who need them. Commercial market access activities for our currently-approved medicines are handled by the licensees of these medicines. Moving forward, we expect to independently commercialize our wholly owned medicines in the U.S. and we will work to provide equitable access to all patients regardless of their racial, ethnic or socioeconomic background or ability to pay. We also have an expanded access policy that outlines when we will consider providing access to an investigational medicine for an individual patient outside of a clinical trial.

Workplace Culture

With nearly 1,000 employees globally, we are dedicated to maintaining a culture in which everyone feels respected and valued and we are committed to providing ongoing opportunities for their career development, learning and personal growth. Our Culture Statement and Core Principles guide us in our mission to improve the lives of people living with serious diseases and motivate us to strive for the highest level of individual and organizational excellence.

Talent Recruitment and Career Development

We have a formal talent recruitment strategy and processes in place to support the fair and equitable recruitment of candidates. Whether we are hiring entry-level, mid-career or executive-level candidates, we look beyond a candidate’s academic qualifications to identify valuable experience and skills that we believe will add to our culture and organizational capacity. We also offer internships, postdoctoral fellowships and clinical fellowships to extend the reach of our talent pipeline. Beginning with onboarding, we aim to provide our employees with the tools and training necessary to succeed at every stage with Ionis. Our robust training and development program illustrated in the graphic below, referred to as “The Learning Continuum,” supports each employee on their career journey.

Diversity, Equity and Inclusion

Our diverse workforce represents a wide range of identities, backgrounds, perspectives and experiences. We strive to create an environment that values and amplifies different perspectives and where everyone feels empowered to contribute fully, which we know leads to better ideas and increased innovation. To expand and reinforce diversity, equity and inclusion (“DEI”) at Ionis, we enhanced our DEI strategy in 2023. The following elements of DEI help guide our efforts and measure change over time as we execute our programs:

Employee Resource Groups

We have nine employee-initiated and led inclusion networks, called Employee Resource Groups (“ERGs”), that allow employees to create community around common bonds or similar backgrounds. These ERGs foster a positive work environment and important social connections at work. Many of our ERGs are also active in our local communities, engaging with students and patients and collaborating with local non-profit organizations and other life sciences companies. Our ERGs include:

Social Impact and Community Engagement

Every year we provide support to various organizations that are making a difference in their communities. We seek sustainable partnerships and initiatives that encourage scientific innovation and help address unmet needs for people impacted by serious diseases and for local communities where we live and work. In 2023, we developed a formal social impact strategy to help amplify and focus our efforts. The strategy identified three priority areas: adaptive experiences; science, technology, engineering and math (STEM) education; and support for local communities. We are developing a multi-year plan to support these priorities, which will be rolled out later in 2024.

Environmental Sustainability

We are committed to conducting our operations in an environmentally responsible manner to protect our employees, the environment and the communities in which we operate. Ionis has an environmental management system (“EMS”) that serves as a systematic approach to managing and continuously improving our environmental performance across company operations. Our EMS establishes policies and procedures, outlines processes for identifying risk and implementing preventative measures, and sets performance standards to improve our environmental performance. In 2023, we made updates to our EMS to track and support compliance with local, state and federal mandates.

Governance and Integrity

We are guided by our Code of Ethics and Business Conduct (“Code”), which applies to all employees, including executive officers and all members of our Board. We are committed to upholding a comprehensive and rigorous ethics program, including anti-bribery and anti-corruption commitments, as detailed in our Code. We strive to create an environment in which employees feel comfortable speaking up. The Code addresses processes for reporting potential ethics and legal violations confidentially at Ionis. We encourage employees to raise concerns to any manager or supervisor, Human Resources, Legal or Compliance, or make an anonymous report to the Ionis Helpline, which is a confidential 24/7 helpline hosted through a third-party provider and accessible via phone or online with multiple language options.