Ionis Pharmaceuticals, Inc. Common Stock

Innovation and product development · Intellectual property protection and infringement

If we cannot protect our patent rights or our other proprietary rights, others may compete more effectively against us. Our success depends to a significant degree upon whether we can continue to develop, secure and maintain intellectual property rights to proprietary products and services.

Market position and competition · Patent expiration and generic competition

For example, Biogen has in the past disclosed that SPINRAZA revenue decreased in part due to lower pricing in the U.S. and certain rest-of-world markets. SPINRAZA faces competition from both a gene therapy product and an oral product for the treatment of SMA.

Customer and revenue · Customer concentration and key customer dependence

If the market does not accept our medicines, including our commercial medicines and our medicines in development, we are not likely to generate substantial revenues or become consistently profitable. The degree of market acceptance for our medicines depends upon several factors.

Customer and revenue · Reimbursement and pricing pressure healthcare or insurance

If government or other third-party payers fail to provide adequate coverage and payment rates for our medicines, including our commercial medicines and our medicines in development, or if healthcare reform measures increase our costs, decrease our sales, or negatively impact reimbursement for our products, our revenue will be limited.

Customer and revenue · Changing customer preferences and behavior

The degree of market acceptance for our medicines, including our commercial medicines and our medicines in development, depends upon several factors, including the establishment and demonstration in the medical and patient community of the efficacy and safety of our medicines, public perception regarding our medicines and their potential advantages over competing products.

Strategic execution · Joint venture and partnership risks

We depend on our collaborations with Biogen for the development and commercialization of SPINRAZA and QALSODY. We are relying on Biogen to obtain additional regulatory approvals for SPINRAZA and QALSODY, generate additional clinical data for SPINRAZA and QALSODY, manufacture SPINRAZA and QALSODY, and successfully commercialize SPINRAZA and QALSODY.

Market position and competition · Competitive pressure and market share loss

If we or our partners fail to compete effectively, our medicines, including our commercial medicines and our medicines in development, will not generate significant revenues. The biotechnology and pharmaceutical industries are highly competitive and subject to significant and rapid technological change.

Corporate governance · Internal controls and risk management

Our business is subject to changing regulations for corporate governance and public disclosure that has increased both our costs and the risk of noncompliance. Each year we are required to evaluate our internal control systems to allow management to report on our internal controls as required by Section 404 of the Sarbanes-Oxley Act.

Industry regulation · Safety and environmental regulations

Because we use biological materials, hazardous materials, chemicals and radioactive compounds, if we do not comply with laws regulating the protection of the environment and health and human safety, our business could be adversely affected.

Industry regulation · Regulatory compliance and changes

Our medicines could be subject to regulatory limitations following approval. Following approval of a medicine, we and our partners must comply with comprehensive government regulations regarding the manufacture, marketing and distribution of medicines.

Tax and financial reporting · Tax compliance and changes in tax law

Our ability to use our net operating loss carryovers and certain other tax attributes may be limited. Under Sections 382 and 383 of the Code, if a corporation undergoes an 'ownership change,' the corporation's ability to use its pre-change NOL carryforwards and other pre-change tax attributes to offset its post-change income or taxes may be limited.

Legal and litigation · Intellectual property disputes

Intellectual property litigation could be expensive and prevent us from pursuing our programs. If a third party claims that our medicines or technology infringe its patents or other intellectual property rights, we may have to discontinue an important product or product line.

Natural and catastrophic events · Climate change and environmental impact

The potential impacts of climate change may also include increased operating costs associated with additional regulatory requirements and investments in reducing energy, water use and greenhouse gas emissions.

Natural and catastrophic events · Pandemic and public health crises

Our business could be adversely affected by health epidemics in regions where we or our partners are commercializing our medicines, have concentrations of clinical trial sites or other business operations. For example, enrollment in some of our clinical trials was delayed due to the COVID-19 pandemic.

Economic and market conditions · Credit market conditions

Negative conditions in the global credit markets and financial services and other industries may adversely affect our business, financial condition or stock price. The global credit and financial markets have experienced extreme volatility and disruptions recently.

Natural and catastrophic events · Natural disasters and extreme weather

Our business may be adversely affected by health epidemics, climate change, extreme weather events, fires, earthquakes, war, civil or political unrest, terrorism or disruptions of the U.S. government. In recent years, extreme weather events and changing weather patterns have become more common.

Cybersecurity and data protection · Third party data security and vendors

Our current, past and prospective business partners face similar risks and any security breaches of their systems (or those of third parties upon which they rely) could adversely affect our security posture.

Digital transformation and innovation · Artificial intelligence and automation

We use artificial intelligence in certain aspects of our business, and challenges with properly managing its use could adversely affect our business. Our competitors or other third parties may incorporate AI into their businesses more quickly or more successfully than us, which could impair our ability to compete effectively.

Human capital and workforce · Talent acquisition and retention

The loss of key personnel, or the inability to attract and retain highly skilled personnel, could make it more difficult to run our business and reduce our likelihood of success. We are dependent on the principal members of our management, scientific and commercial staff.

Project and contract management · Project execution and delivery risks

If the results of clinical testing indicate that any of our medicines are not suitable for commercial use, we may need to abandon one or more of our drug development programs. Drug discovery and drug development have inherent risks and the historical failure rate for drugs is high.