Here are a few analogies to describe Ionis Pharmaceuticals:

• Ionis Pharmaceuticals is like Moderna or BioNTech for chronic diseases, using advanced RNA technology to develop a wide range of treatments, with several already approved.
• Ionis Pharmaceuticals is like Vertex Pharmaceuticals, but specializing in RNA-targeted drugs for a diverse range of rare and challenging conditions.

• SPINRAZA: A treatment for spinal muscular atrophy (SMA) in pediatric and adult patients.
• TEGSEDI: An injection for the treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.
• WAYLIVRA: A treatment for familial chylomicronemia syndrome and familial partial lipodystrophy.

• AstraZeneca (AZN)
• GlaxoSmithKline plc (GSK)
• Johnson & Johnson (JNJ) (parent company of Janssen Biotech, Inc.)
• Bayer AG (BAYRY)
• Novartis AG (NVS)
• Pfizer, Inc. (PFE)
• Biogen Inc. (BIIB)
• Flamingo Therapeutics, Inc. (private company)
• Roche (RHHBY)

Brett P. Monia, Ph.D. Chief Executive Officer

Dr. Monia is the Chief Executive Officer, a member of the board of directors, and a founding scientist of Ionis Pharmaceuticals. He was appointed CEO in January 2020. Dr. Monia co-founded Ionis Pharmaceuticals (originally Isis Pharmaceuticals) in 1989 and has over 35 years of experience with the company. His contributions at Ionis include extensive research into RNA-targeting modalities and he is an inventor on over 100 issued patents and has published more than 200 scientific manuscripts. He previously held roles such as Chief Operating Officer and Senior Vice President of Translational Medicine. Dr. Monia also serves on the board of directors of Cognition Therapeutics and Flamingo Therapeutics.

Elizabeth L. Hougen Executive Vice President, Chief Financial Officer

Ms. Hougen serves as the Executive Vice President and Chief Financial Officer of Ionis Pharmaceuticals. She joined Ionis in May 2000 as Vice President, Finance, and was appointed Chief Accounting Officer in January 2007, and Chief Financial Officer in January 2013. Ms. Hougen has over 25 years of finance and business experience, primarily within the life sciences industry. Before joining Ionis, she was the Chief Financial Officer for Molecular Biosystems, Inc., a public biotechnology company.

Stanley T. Crooke, M.D., Ph.D. Founder and Executive Chairman

Dr. Crooke is the Founder of Ionis Pharmaceuticals, which was established as Isis Pharmaceuticals in 1989. He previously served as the Chief Executive Officer before transitioning to his current role as Executive Chairman of the Board of Directors. Prior to founding Ionis, Dr. Crooke was a research leader at GlaxoSmithKline.

C. Frank Bennett, Ph.D. Executive Vice President, Chief Scientific Officer

Dr. Bennett is the Executive Vice President and Chief Scientific Officer at Ionis Pharmaceuticals.

Joseph T. Baroldi Executive Vice President, Chief Business Officer

Mr. Baroldi serves as the Executive Vice President and Chief Business Officer, responsible for leading Ionis' business development and alliance management activities. He brings over two decades of industry experience, having previously served as Chief Operating Officer at Avidity Biosciences, where he played a key role in their initial public offering and team development.

The key risks for Ionis Pharmaceuticals (IONS) are primarily centered around the inherent challenges of drug development and commercialization within the highly competitive biopharmaceutical industry, as well as its strategic business model.

1. Clinical Trial and Regulatory Failure: As a biotechnology company with a vast pipeline of RNA-targeted therapeutics, Ionis Pharmaceuticals faces significant risks associated with the rigorous process of drug discovery, development, and regulatory approval. The success of its numerous investigational medicines, targeting a wide range of diseases from neurological disorders to cardiometabolic conditions, is contingent upon favorable outcomes in preclinical studies and clinical trials, followed by regulatory clearances. Any delays in trials, unexpected safety concerns, or failure to demonstrate efficacy could lead to the abandonment of promising programs, negatively impacting future revenue and growth prospects. For instance, the early termination of the Hero study for an Alzheimer's disease candidate illustrates the potential for setbacks in their development pipeline.

2. Competition and Loss of Market Exclusivity: Ionis operates in a highly competitive landscape where numerous companies are vying for market share, particularly in the rapidly evolving RNA-targeted therapy space. This intense competition can lead to pricing pressures and challenges in gaining and maintaining market access for both its approved drugs and future products. For example, their established drug SPINRAZA faces competition in the spinal muscular atrophy (SMA) market, contributing to declining royalty revenues. Similarly, drugs like WAINUA compete directly with products from rivals such as Alnylam Pharmaceuticals in indications like transthyretin-mediated amyloidosis. The eventual expiry of patents for its commercialized medicines also poses a risk, opening the door to generic or biosimilar competition and potentially reducing profitability.

3. Reliance on Collaborative Agreements: Ionis Pharmaceuticals heavily leverages strategic partnerships with larger pharmaceutical companies for the late-stage development and commercialization of many of its drug candidates. While this model helps mitigate the substantial costs and risks associated with building a global commercial infrastructure, it also introduces a dependency on these partners. The termination or unfavorable renegotiation of these collaboration agreements could significantly impact Ionis' financial results, which can already be "lumpy and difficult to predict" due to the timing of partner payments. A past example includes Bayer's decision to discontinue the clinical development of fesomersen, leading to its return to Ionis.

The clear emerging threat for Ionis Pharmaceuticals is the rise of alternative therapeutic modalities and competing products in the disease areas where Ionis has commercialized drugs. For example, Ionis's SPINRAZA (for spinal muscular atrophy) faces significant competition from gene therapies and oral small molecule therapies that offer different administration routes (such as one-time administration versus chronic injection) and potentially different efficacy profiles. Similarly, Ionis's TEGSEDI (for hereditary transthyretin-mediated amyloidosis) faces competition from other RNA-based therapies and small molecule stabilizers. These alternative treatments and modalities present a direct challenge to the market share and revenue streams derived from Ionis's key commercial products.

Ionis Pharmaceuticals (IONS) develops and markets RNA-targeted therapeutics for various diseases. Here are the addressable market sizes for its main products:

SPINRAZA (for Spinal Muscular Atrophy - SMA)

• The global spinal muscular atrophy (SMA) treatment market was estimated at approximately USD 4.40 billion in 2024 and is projected to reach USD 13.09 billion by 2030.
• Another estimate indicates the global SMA market reached USD 3.0 billion in 2023 and is expected to reach USD 13.0 billion by 2034 across the seven major markets (7MM).
• The North American market held the largest share of the global SMA treatment market, accounting for 68.4% in 2024.
• Asia-Pacific is anticipated to be the fastest-growing region in the SMA treatment market.

TEGSEDI (for hereditary transthyretin-mediated amyloidosis - hATTR)

• The global transthyretin amyloidosis treatment market was valued at USD 5.9 billion in 2023 and is expected to reach USD 11.2 billion by 2032.
• Another projection estimates the global transthyretin amyloidosis treatment market size at USD 6,644.3 million in 2024, growing to USD 16,526.5 million by 2030.
• North America dominated this market with a revenue share of 47.8% in 2024.
• There are an estimated 50,000 patients with hATTR amyloidosis worldwide.

WAYLIVRA (for Familial Chylomicronemia Syndrome - FCS and Familial Partial Lipodystrophy - FPLD)

• For Familial Chylomicronemia Syndrome (FCS), the total market size in the seven major markets (7MM: United States, EU4, United Kingdom, and Japan) was approximately USD 15 million in 2022 and is projected to increase through 2034.
• The global FCS market is estimated to reach US$ 18.89 million by 2032.
• WAYLIVRA is approved for FCS in Europe.
• For Familial Partial Lipodystrophy (FPLD), which falls under the broader lipodystrophy market, the market size in the U.S. was approximately USD 77 million in 2021 across the 7MM.
• Germany accounted for the largest market size for lipodystrophy treatments among the EU4 countries, valued at approximately USD 94 million.
• WAYLIVRA has received regulatory approval for familial partial lipodystrophy in Brazil.

1. Launch and Expansion of New Independent Products: Ionis expects significant revenue growth from the independent launch and commercialization of new therapies. Olezarsen, for severe hypertriglyceridemia (sHTG), is particularly highlighted as a major independent launch in 2026, targeting a broad patient population. Another key independent launch anticipated in 2026 is zilganersen for Alexander disease, which marks the company's first neurology launch.
2. Growth of Recently Launched Therapies: Recently launched products such as DAWNZERA (donidalorsen) for hereditary angioedema and TRYNGOLZA are expected to continue their revenue ramp-up. DAWNZERA has shown strong initial participation and a high conversion rate to paid therapy, indicating promising future revenue growth. TRYNGOLZA also demonstrated substantial product sales growth in 2025.
3. Increasing Royalty Revenue from Commercial Products: The company anticipates continued and growing royalty revenue from its established commercial products, including SPINRAZA and WAINUA (eplontersen). WAINUA, in particular, is contributing a new stream of royalty revenue.
4. Milestone Payments from Partnered Programs: Ionis benefits from its robust partnered pipeline, which is projected to yield numerous milestone payments. Key partnered programs, such as pelacarsen (Lp(a) HORIZON trial) and eplontersen (CARDIO-TTRansform trial), are expected to have significant Phase 3 readouts in mid to late 2026, which can trigger substantial R&D revenue. The company has already reported earning significant milestone payments from collaborations in early 2026.

**Share Issuances**

• In September 2024, Ionis Pharmaceuticals conducted a public offering of 11,500,000 shares of its common stock, with expected gross proceeds of approximately $500.3 million.
• The company's shares outstanding increased to 0.15 billion in 2024, representing a 4.42% rise from 2023.
• Shares outstanding further grew to 0.160 billion by the quarter ending September 30, 2025, marking a 7.52% increase year-over-year.

**Inbound Investments**

• Ionis received a $280 million upfront payment in the second quarter of 2025 for granting Ono Pharmaceutical Co., Ltd. a global license for sapablursen.
• A significant portion of Ionis's $944 million total revenue in 2025 was generated from R&D collaborations.

**Capital Expenditures**

• Operating expenses in 2025 saw an increase due to investments made to support the launches of TRYNGOLZA, DAWNZERA, and WAINUA.
• For 2026, the company anticipates a modest increase in non-GAAP operating expenses as it invests in independent launches and advances its wholly-owned pipeline of innovative medicines.
• Research and development expenses are projected to remain consistent in 2026, with resources being reallocated to support drugs expected to drive future growth.