Summary of Ionis Pharmaceuticals FY Conference Call Company Overview - **Company**: Ionis Pharmaceuticals (NasdaqGS:IONS) - **Event**: FY Conference Call on February 26, 2026 - **Key Speaker**: Brett Monia, CEO Core Industry and Company Insights - **FDA Acceptance**: The FDA accepted the supplemental NDA for olezarsen to treat severe hypertriglyceridemia (sHTG) with priority review status, setting a PDUFA date of June 30, 2026, which positions the company for a launch in late June or early July [2][3] - **Transformational Year**: 2025 was described as a pivotal year for Ionis, marking its transition to a fully integrated commercial-stage biotechnology company with successful independent launches of TRYNGOLZA for familial chylomicronemia syndrome (FCS) and DAWNZERA for hereditary angioedema (HAE) [3][4] - **Revenue Growth**: The company aims to achieve cash flow break-even by 2028, with expectations of accelerating revenue growth driven by its innovative pipeline [4][5] Product Pipeline and Launch Strategy - **Pipeline Success**: Ionis has had six positive Phase 3 readouts and four approved medicines in the last two and a half years, with 11 medicines in late-stage development [6][7] - **Upcoming Launches**: Expected product approvals and launches in 2026 include: - Olezarsen for sHTG - Zilganersen for Alexander disease - Bepirovirsen for chronic HBV [7][8] - **Market Focus**: Initial launch strategy for sHTG will prioritize patients with a history of acute pancreatitis and those with triglyceride levels above 880, as these patients are at the highest risk [29][30] Financial Projections - **Revenue Guidance**: The acceptance of the priority review for olezarsen is expected to improve revenue guidance, with updates to be provided in the Q1 earnings call [32] - **Peak Product Revenue**: The company anticipates over $4 billion in potential annual peak product revenue from its own medicines, with an additional $2 billion from partnered medicines, totaling over $6 billion in revenue [20][21] Neurology Portfolio - **Zilganersen Launch**: Zilganersen is positioned as Ionis' first independent launch in neurology, with positive Phase 3 data reported and an NDA submitted [19][36] - **Future Developments**: The company is also working on the Angelman syndrome program, which has received Breakthrough Therapy designation and is expected to complete enrollment in its Phase III study this year [20][39] Competitive Landscape and Innovation - **DAWNZERA's Competitive Edge**: DAWNZERA is noted for its compelling product profile, offering better efficacy, tolerability, and convenience compared to existing treatments for HAE [11][12] - **Follow-On Programs**: Ionis is exploring follow-on programs for its existing products to enhance dosing convenience and efficacy [33][34] Conclusion - **Outlook**: Ionis Pharmaceuticals is positioned for a transformative year in 2026, with multiple product launches and a strong pipeline that addresses significant unmet medical needs in cardiometabolic and neurological diseases [21][42]

Core Findings - Olezarsen demonstrated a placebo-adjusted mean reduction in fasting triglyceride levels of up to 72% at six months, with reductions sustained through 12 months [2][4][11] - 86% of patients treated with olezarsen achieved triglyceride levels below 500 mg/dL, which is below the risk threshold for acute pancreatitis [2][4][5] - Olezarsen is the first investigational treatment for severe hypertriglyceridemia (sHTG) to significantly reduce acute pancreatitis events, showing an 85% reduction in such events [2][5][7] Study Details - The CORE and CORE2 studies involved nearly 1,100 patients, making it the largest pivotal program for sHTG [4][11] - Participants were required to be on standard lipid-lowering therapy and had baseline triglyceride levels of at least 500 mg/dL [11][14] - The studies met their primary endpoint across doses, with significant reductions in triglyceride levels observed [4][11] Safety and Tolerability - Olezarsen exhibited a favorable safety profile, with adverse events balanced across treatment arms [7][8] - Serious adverse events were less frequent in the olezarsen group compared to placebo [7][8] - The most common treatment-emergent events were mild injection site reactions [7][8] Future Prospects - Ionis Pharmaceuticals plans to submit a supplemental new drug application for olezarsen to the FDA by the end of the year [9] - An open-label extension study of olezarsen for sHTG is ongoing, with over 90% of patients from the CORE and CORE2 studies opting to continue [9][10] - Olezarsen is expected to be one of two independent launches for Ionis in 2026, targeting a larger patient population at risk of acute pancreatitis [7][9]