Financial Data and Key Metrics Changes - Ionis Pharmaceuticals reported a revenue increase of 34% year-over-year, reaching $944 million in 2025, with commercial products contributing $436 million and R&D collaborations $508 million [30][31] - The company exceeded its financial guidance across all metrics, driven by strong execution and disciplined financial management [30][32] - Non-GAAP operating expenses increased modestly year-over-year, primarily due to investments related to the U.S. launch of TRYNGOLZA and DAWNZERA [32][39] Business Line Data and Key Metrics Changes - TRYNGOLZA generated $108 million in product sales in 2025, with a 56% increase in Q4 revenues compared to Q3 [19][31] - DAWNZERA achieved $8 million in product sales from its initial months of launch, with strong participation in a free trial program leading to 100% conversion to paid therapy [31][36] - Olezarsen is projected to exceed $2 billion in peak annual revenue, reflecting strong prescriber demand and positive Phase 3 data [24][66] Market Data and Key Metrics Changes - The payer mix for TRYNGOLZA is approximately 60% commercial and 40% government, with broad access for both clinically diagnosed and genetically confirmed patients [22][31] - The company anticipates a meaningful decline in TRYNGOLZA revenues throughout 2026 ahead of the sHTG launch, followed by accelerating growth post-approval [35][48] Company Strategy and Development Direction - Ionis is focused on maximizing the potential of its marketed medicines while preparing for multiple upcoming launches, including Olezarsen for sHTG and Zilganersen for Alexander disease [29][39] - The company aims to achieve cash flow breakeven by 2028, supported by a diversified revenue stream and disciplined investment strategy [30][39] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the company's ability to deliver transformational medicines and create shareholder value, citing strong commercial momentum and an advancing pipeline [41][43] - The company is actively engaging with payers to ensure broad access for its products while balancing long-term value realization [48][56] Other Important Information - Ionis received breakthrough therapy designation from the FDA for Olezarsen, which is currently under review [17][72] - The company is preparing for the anticipated U.S. approval of high-dose Spinraza, with a PDUFA date set for April 3rd [18] Q&A Session Summary Question: Guidance on sHTG sales and pricing dynamics - Management clarified that current guidance assumes standard review for Olezarsen, with sales from the sHTG patient population expected in Q4 [46][47] - Discussions with payers are ongoing to ensure broad access for TRYNGOLZA prior to the sHTG launch, with a meaningful decline in revenues anticipated until then [48][49] Question: Reimbursement in FCS and pricing dynamics - The company reported no significant impact from competitors on TRYNGOLZA demand, with strong patient access maintained [56][59] Question: Peak revenue for Olezarsen - Management expressed increased confidence in the $2 billion peak revenue estimate for Olezarsen, driven by strong demand trends and positive Phase 3 data [63][66] Question: FDA interactions regarding sHTG filing - Management indicated that interactions with the FDA have been positive, and they believe Olezarsen deserves priority review designation [72][73] Question: European sites for Angelman syndrome program - The company is awaiting approval to open European sites for the Angelman syndrome program and plans to do so once approval is received [81][82]

Financial Data and Key Metrics Changes - Ionis generated $944 million in revenue for 2025, representing a 34% increase year-over-year [29] - Revenue from commercial products was $436 million (46% of total revenue), while R&D collaborations contributed $508 million (54% of total revenue) [29] - Royalty revenues increased by 11% to $285 million, driven by contributions from Spinraza and Waylivra [31] Business Line Data and Key Metrics Changes - TRYNGOLZA generated $108 million in product sales for 2025, with a 56% increase in Q4 sales compared to Q3 [30] - DAWNZERA achieved $8 million in product sales from its initial months of launch [30] - Olezarsen is projected to exceed $2 billion in annual peak revenue based on positive phase 3 data and strong prescriber demand [23][30] Market Data and Key Metrics Changes - The U.S. market for severe hypertriglyceridemia (sHTG) includes over 1 million individuals at high risk, indicating a significant patient population for Olezarsen [21] - The current payer mix for TRYNGOLZA is approximately 60% commercial and 40% government, with broad access for both clinically diagnosed and genetically confirmed patients [19] Company Strategy and Development Direction - Ionis aims to achieve cash flow breakeven by 2028 while expanding its commercial portfolio through multiple launches [39] - The company is focused on maximizing the potential of its marketed medicines and preparing for additional launches, including Olezarsen for sHTG and Zilganersen for Alexander disease [27][39] - Ionis is committed to maintaining broad patient access while maximizing long-term value realization for its products [46] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the company's trajectory, highlighting strong commercial momentum and a robust pipeline of innovative therapies [39] - The anticipated approval of Olezarsen is expected to drive significant revenue growth in the fourth quarter of 2026 [32] - Management noted that the company is actively engaging with payers to ensure continued access for patients [46] Other Important Information - The company has a well-capitalized balance sheet with approximately $1.6 billion in cash and investments projected by year-end [37] - Ionis plans to provide detailed revenue guidance for TRYNGOLZA and DAWNZERA at the first quarter earnings call [33] Q&A Session Questions and Answers Question: Can you clarify your guidance regarding sHTG sales and pricing dynamics? - Management confirmed that guidance does not assume significant sHTG sales initially and anticipates a decline in TRYNGOLZA revenues ahead of the sHTG launch, with growth expected post-approval [44][46] Question: What is the reimbursement landscape for FCS and how does it compare to competitors? - Management indicated that there has been no meaningful impact from competitors on TRYNGOLZA demand, and they are focused on maximizing value while ensuring broad access [56][58] Question: What is the expected timeline for the GSK partnered HBV program? - Management stated that GSK plans to present data at EASL in May, with peak sales estimates around $2.5 billion, and Ionis expects to earn tiered royalties from this program [87] Question: How does the launch strategy for Zilganersen compare to other rare diseases? - Management highlighted strong community interest and a focused launch strategy for Zilganersen, with a modest-sized team targeting major leukodystrophy centers [94]

Brett Monia, Ph.D. Chief Executive Officer Holly Kordasiewicz, Ph.D. Chief Development Officer YE:2025 Business Update and Financial Results February 25, 2026 Nasdaq: IONS 1 On Today's Earnings Call Beth Hougen Chief Financial Officer Eugene Schneider, M.D. Chief Clinical Development Officer 2 Eric Swayze, Ph.D. Executive Vice President, Research Forward-Looking Statements This presentation includes forward-looking statements regarding our business, financial guidance and the therapeutic and commercial pote ...

Product Sales and Revenue Growth - Ionis Pharmaceuticals achieved preliminary U.S. net product sales of $105 million for TRYNGOLZA® (olezarsen) in 2025, exceeding expectations as the first FDA-approved treatment for familial chylomicronemia syndrome (FCS) [4] - The company has increased the annual peak net sales guidance for olezarsen to over $2 billion for severe hypertriglyceridemia (sHTG) based on strong product profile and positive Phase 3 data [8] - Ionis anticipates five Phase 3 readouts and four NDA submissions in 2026, contributing to accelerating revenue growth and aiming for cash flow breakeven by 2028 [3] Clinical Trials and Regulatory Submissions - Positive topline results were announced for the pivotal Phase 3 program of bepirovirsen in chronic hepatitis B, with regulatory submissions planned in 2026 [11] - The launch of DAWNZERA™ (donidalorsen) for hereditary angioedema is expected to gain momentum, with EMA approval anticipated in Q1 2026 [11] - The company plans to submit an NDA for zilganersen for Alexander disease in Q1 2026, marking its first anticipated launch from the neurology portfolio [11] - Ionis expects to complete enrollment for the Phase 3 REVEAL study of ION582 for Angelman syndrome in 2026, with data expected in 2027 [11] - Results from the Phase 3 Lp(a) HORIZON cardiovascular outcomes study of pelacarsen are expected in H1 2026, with a planned NDA submission [11] - The company is preparing for multiple Phase 2 data readouts, including IONIS-MAPTRx in Alzheimer's disease [11] Future Outlook and Strategic Positioning - Ionis is well-positioned for continued momentum and substantial value creation in 2026 with two new independent launches and several pivotal data readouts [1]

Core Points - Ionis Pharmaceuticals, Inc. announced a change in the start time for its fourth quarter and full year 2025 financial results webcast, moving it from 11:30 a.m. Eastern Time to 8:30 a.m. Eastern Time on February 25 [1] Company Information - The date of the financial results call remains unchanged, and the webcast can be accessed online [1]

Core Insights - Ionis Pharmaceuticals will host a live webcast on February 25, 2026, to discuss its fourth quarter and full year 2025 financial results and key program progress [1] - The company has a strong pipeline in neurology, cardiometabolic diseases, and other high-need areas, emphasizing its leadership in RNA-targeted medicines and gene editing [1] - Ionis achieved significant milestones in 2025, including two independent product launches and anticipates continued momentum and value creation in 2026 [1] Financial Results Webcast - The webcast is scheduled for February 25, 2026, at 11:30 a.m. Eastern Time [1] - A replay of the webcast will be available for a limited time [1] Company Achievements - Ionis has successfully executed its first two independent launches in 2025, marking a defining year for the company [1] - The company will provide a business update at the 44th Annual J.P. Morgan Healthcare Conference on January 13, 2026 [1] Product Approvals and Collaborations - The European Commission approved DAWNZERA™ (donidalorsen) for the prevention of hereditary angioedema in adults and adolescents aged 12 years and older [1] - Partner GSK announced positive topline results from Phase 3 studies for bepirovirsen, an investigational treatment for chronic hepatitis B, involving over 1,800 patients across 29 countries [1]

Core Insights - The small nucleic acid drug sector is experiencing a significant surge, marking the beginning of a golden era driven by technological breakthroughs and capital enthusiasm [2][11][22] Industry Developments - On January 5, 2026, Sanofi's APOC3 siRNA drug Plozasiran was approved for domestic market use to treat hyperlipidemia [1] - On January 9, 2026, Rebio Biotech, known as "China's first small nucleic acid stock," successfully listed on the Hong Kong Stock Exchange, with its stock price soaring by 40% on the first day, leading to a market capitalization exceeding 13 billion HKD [1] - China National Pharmaceutical Group announced a 1.2 billion CNY acquisition of Hegia Biotech, securing the world's first clinically validated liver-targeted delivery platform capable of annual dosing [1] Market Trends - The global small nucleic acid drug market has seen nearly 100 business development (BD) collaborations in the past three years, with transaction numbers and amounts increasing annually, reaching over 30 BD deals in 2025 totaling nearly 30 billion USD [4][9] - Notable transactions in 2025 included Novartis acquiring Avidity Biosciences for 12 billion USD and multiple other significant deals involving RNA therapies [7][9] Clinical Advancements - Ionis's APOC3 ASO drug Olezarsen showed promising results in reducing triglyceride levels by up to 72% in patients with severe hypertriglyceridemia, leading to an increase in peak annual sales forecast from 1.5 billion USD to 2.5 billion USD [12] - GSK's ASO therapy Bepirovirsen is expected to be the first drug to achieve functional cure for chronic hepatitis B, with a peak annual sales potential of 2 billion USD [12] Emerging Opportunities - The small nucleic acid drugs are expanding into various therapeutic areas, including obesity and kidney diseases, with promising results from clinical trials demonstrating significant weight loss and metabolic health improvements [13][15] - The number of small nucleic acid drugs in development globally has surpassed 1,200, with siRNA and ASO therapies being the most prominent [17] Strategic Collaborations - Domestic companies are increasingly recognized for their innovative value in small nucleic acid drugs, with active BD transactions, including significant collaborations by Rebio Biotech and other firms [18][21] - Companies like Saintin Biotech are forming strategic partnerships with major pharmaceutical firms to advance their small nucleic acid drug pipelines [19] Conclusion - The convergence of technological advancements, capital influx, and successful clinical outcomes is propelling small nucleic acid drugs into a pivotal position within the pharmaceutical industry, with China poised to become a global innovation hub [22]

Core Insights - The European Commission has approved Dawnzera (donidalorsen) for preventing recurrent attacks of hereditary angioedema (HAE) in adults and adolescents aged 12 years and older [1] Group 1: Approval and Market Impact - The approval was anticipated following a positive opinion from the Committee for Medicinal Products for Human Use of the European Medicines Agency in November [2] - Dawnzera was previously approved by the FDA in the United States in August last year for HAE prophylaxis [2] - Ionis is set to receive a $15 million milestone payment from Otsuka Pharmaceutical following the EU approval and can earn tiered royalties of up to 30% on net product sales [3] - Ionis shares increased by approximately 2.5% in response to the EU approval, with a notable 130.5% rise over the past year compared to the industry's 3.3% decline [3] Group 2: Clinical Data and Efficacy - The EU approval of Dawnzera was supported by data from phase III OASIS-HAE and OASISplus studies, demonstrating significant efficacy and safety [4] - The OASISplus study indicated a 94% overall reduction in the mean monthly attack rate at one year for patients treated with Dawnzera [4] Group 3: Product Details - Dawnzera is an RNA-targeted preventive therapy designed to reduce plasma prekallikrein production, which triggers HAE attacks [8] - It is administered via subcutaneous injections with long dosing intervals of four to eight weeks, making it the first and only RNA-targeted therapy for HAE globally [8]

Core Viewpoint - The article emphasizes the positive outlook for Ionis Pharmaceuticals (IONS) following recent approvals and upcoming catalysts that are expected to drive strong upside potential for the company [1]. Group 1 - The author has been focusing on Ionis for over five years, particularly in the healthcare sector, and shares insights from decades of investment experience [1]. - The article is the 13th in a series discussing Ionis, indicating a sustained interest and analysis of the company's performance and prospects [1]. Group 2 - The author expresses a beneficial long position in Ionis shares, indicating confidence in the company's future performance [2]. - There is a mention of potential trading activity in Ionis shares within the next 72 hours, suggesting ongoing engagement with the stock [2].

Core Insights - The small nucleic acid drug sector in China is entering a "capital year" in 2026, with increasing market interest and significant transactions, such as the successful IPO of Rebio and the acquisition of Hegia Biotech by China National Pharmaceutical Group for 1.2 billion yuan [1] - The global small nucleic acid drug market is characterized by a "three strong" dominance, with Alnylam, Ionis, and Sarepta leading the industry due to their technological barriers and commercialization advantages [1][5] - The market for small nucleic acid drugs is projected to grow from $5.247 billion in 2024 to $46.7 billion by 2033, with a compound annual growth rate (CAGR) of 25% [10] Market Dynamics - In 2024, global sales of small nucleic acid drugs reached $5.247 billion, with Ionis and Biogen's Spinraza leading at $1.573 billion, followed by Alnylam's Amvuttra at $0.971 billion and Sarepta's DMD treatments at $0.967 billion [2] - The current landscape features two main technological routes: Antisense Oligonucleotides (ASO) and small interfering RNA (siRNA), each with distinct mechanisms and advantages [4][7] - Alnylam has established itself as a leader in RNAi therapy, with a high clinical conversion rate of 64.3%, significantly above the industry average of 5.7% [7] Competitive Landscape - Ionis focuses on ASO technology, having launched the first ASO drug in 1998 and currently holding nine of the twelve approved ASO drugs globally, including the top-selling Spinraza [7][8] - Sarepta has specialized in muscle diseases, particularly DMD, with four approved drugs and a revenue growth of over 50% in 2024, reaching $1.9 billion [9] - The competitive landscape is evolving, with multinational corporations (MNCs) increasingly entering the market through acquisitions and collaborations, reflecting a growing interest in the sector [16][19] Emerging Opportunities - The market is entering a commercialization phase, with potential blockbuster products needed to transition from niche to mainstream [10] - Alnylam's Amvuttra and Novartis's Leqvio are identified as strong candidates for future blockbuster status, with Amvuttra projected to exceed $2 billion in sales by 2025 [12][13] - New products like Arrowhead's Plozasiran and Alnylam's Zilebesiran are expected to broaden the treatment landscape, moving from rare diseases to more common conditions [15] Strategic Movements - MNCs are actively pursuing partnerships and acquisitions to enhance their presence in the small nucleic acid space, with notable transactions in 2025 exceeding $36.473 billion [16][18] - Companies like Novartis are building comprehensive pipelines across various therapeutic areas, including cardiovascular and rare diseases, to strengthen their competitive position [18] - Chinese biotech firms are emerging as significant players, leveraging unique delivery technologies and cost advantages, leading to increased collaborations with MNCs [19][20]