Summary of Ionis Pharmaceuticals 2025 Investor Day Company Overview - **Company**: Ionis Pharmaceuticals (NasdaqGS:IONS) - **Event**: 2025 Investor Day held on October 07, 2025 - **Objective**: To update stakeholders on the progress in transforming the lives of patients with severe unmet medical needs through innovative medicines and technology [1][2] Key Industry Insights - **Focus Areas**: Neurology and cardiometabolic diseases, both of which have high unmet medical needs [16] - **Pipeline**: Ionis has a robust pipeline with 10 medicines in late-stage development, aiming for continuous Phase III data readouts [14][18] Core Points and Arguments - **Commercial Strategy**: Ionis has transitioned to a fully integrated biotechnology company with its first two independent commercial launches, aiming for positive cash flow and growing revenue [6][10][20] - **Recent Achievements**: - Six positive Phase III data readouts in the last two years, leading to four approved medicines [14] - Launch of Trangolza for Familial Chylomicronemia Syndrome (FCS) and Donzera for hereditary angioedema [22][26] - **Future Launches**: Anticipation of three more FDA-approved medicines in the upcoming year, including olazarsen for severe hypertriglyceridemia [20][21] Financial Strategy - **Path to Cash Flow**: Ionis is focused on achieving positive cash flow in the near term through its independent launches and pipeline advancements [6][39] - **Investment in Research**: Successful launches will allow reinvestment into research and development, enhancing the pipeline further [38] Pipeline Highlights - **Neurology**: - SPINRAZA and CALSADI are breakthrough treatments for spinal muscular atrophy and ALS, respectively [16] - Eleven medicines in the neurology pipeline, including treatments for dementia and rare pediatric neurological diseases [17] - **Cardiometabolic**: - Olazarsen is positioned for FDA approval next year, targeting severe hypertriglyceridemia, with significant clinical data showing a 72% mean placebo-adjusted reduction in triglycerides [24][25] - Other candidates include pelicarcin for Lp-driven cardiovascular disease and eplontirsen for ATTR cardiomyopathy [17][38] Clinical Insights - **Triglyceride Disorders**: - FCS is a severe genetic disorder with high triglyceride levels leading to acute pancreatitis; Ionis's Trangolza is the first FDA-approved treatment for this condition [22][61] - Olazarsen has shown an 85% reduction in acute pancreatitis events, marking a significant breakthrough in treatment [25][66] - **Patient Impact**: Positive feedback from patients and healthcare providers regarding the efficacy and tolerability of new treatments [23][28] Research and Development - **Innovative Technologies**: Ionis is expanding its drug discovery capabilities, focusing on new platforms and targeted delivery systems to enhance treatment efficacy [40][41] - **Future Directions**: Plans to initiate new clinical studies in various therapeutic areas, including neuromuscular diseases and cardiac conditions [43][44] Conclusion - **Outlook**: Ionis Pharmaceuticals is well-positioned for future growth with a strong pipeline, innovative treatments, and a clear path to financial self-sufficiency, aiming to deliver transformative medicines for patients with severe diseases [45][46]

Financial Data and Key Metrics Changes - The company has achieved two FDA approvals for wholly owned products in the last twelve months, with commercial launches underway [3][5] - The first independent launch for familial chylomicronemia syndrome, Trangolza, is off to a strong start, and the approval of Donzara for hereditary angioedema has also been secured [5][6] - The company has increased its guidance for the FCS market to $70 million to $80 million for the first year of launch [34] Business Line Data and Key Metrics Changes - The drug olazarsen demonstrated a 72% mean reduction in triglycerides and an 85% reduction in acute pancreatitis events in a recent Phase III trial [6][15] - The severe hypertriglyceridemia (SHTG) market is estimated to have over three million affected individuals in the U.S., with a focus on high-risk patients [21][22] Market Data and Key Metrics Changes - The company is targeting high-risk patients with triglyceride levels above 880 mg/dL, which accounts for about one million individuals in the U.S. [22][24] - The competitive landscape includes drugs like Aerohaz, pravasiran, and GLP-1 analogs, with the company emphasizing its first-mover advantage and unprecedented efficacy [27][30] Company Strategy and Development Direction - The company plans to submit a supplemental NDA for olazarsen by the end of the year and aims to present full data at a medical congress [17][19] - The strategy includes focusing on high-risk patients and building a commercial team to support the launch of olazarsen [24][26] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the safety and efficacy of olazarsen, citing favorable results from previous studies [32] - The company anticipates a strong market reception for Donzara, with early feedback indicating positive sentiment from the HAE community [39][40] Other Important Information - The company is conducting the largest study ever in TTR cardiomyopathy, with results expected in the second half of next year [50][52] - The LP(a) study is also on track, with expectations for significant reductions in cardiovascular risk factors [55][56] Q&A Session Summary Question: What is the company's view on the commercial opportunity for olazarsen? - The company highlighted the significant unmet medical need in the SHTG market, with a focus on high-risk patients who have previously experienced acute pancreatitis [21][22] Question: How does the company plan to position itself against competitors? - The company emphasized its first-mover advantage and the unprecedented efficacy of olazarsen, setting a high bar for competitors [28][30] Question: What are the expectations for the launch of Donzara? - Management indicated that the launch is off to a strong start, with positive early feedback from the patient community and healthcare providers [39][40] Question: What is the anticipated market share for Donzara? - The company expects Donzara to be a $500 million plus drug, with a significant portion of patients switching from existing treatments [46] Question: How is the company preparing for the upcoming regulatory submissions? - The company is focused on gathering data and engaging with payers to demonstrate the value of olazarsen before announcing pricing [36][37]

Financial Data and Key Metrics Changes - In Q2 2025, Ionis Pharmaceuticals reported revenue of $452 million, a twofold increase year over year, and $584 million for the first half of 2025, representing a nearly 70% increase compared to the prior year [30][31] - Non-GAAP net income for the quarter was $154 million, reflecting strong financial performance [31] - The company raised its 2025 revenue guidance by $100 million, now expecting between $825 million and $850 million in revenue for the year [34] Business Line Data and Key Metrics Changes - The launch of Trincolza generated $19 million in net product sales for Q2, marking a threefold increase quarter over quarter [10][32] - Royalty revenues increased by approximately 10% to $70 million in Q2, supported by contributions from SPINRAZA and WAYNUA [32] - Ionis anticipates $75 million to $80 million in Trincolza product sales for the full year [34] Market Data and Key Metrics Changes - The coverage mix for Trincolza patients is approximately 60% commercial and 40% government, with over 90% of patients paying $0 out of pocket since launch [12] - The company is targeting over 3,000 physicians and has reached more than 30,000 healthcare providers through its marketing efforts [14] Company Strategy and Development Direction - Ionis is focused on expanding its pipeline with multiple upcoming launches, including Donavolorsen for hereditary angioedema, which is expected to receive FDA approval soon [7][9] - The company aims to leverage its first-mover advantage in both familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (SHTG) markets [15][71] - Ionis plans to continue investing in its late-stage programs while maintaining disciplined capital management [35] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the continued commercial success of Trincolza and the upcoming launch of Donavolorsen, highlighting the strong therapeutic profiles and unmet needs these products address [5][9] - The company anticipates a steady cadence of independent and partnered launches over the next few years, contributing to sustained revenue growth and positive cash flow [37] Other Important Information - Ionis is preparing for an innovation day on October 7 to highlight its pipeline and advancements in drug discovery [38] - The company is also set to initiate a quiet period starting July 31, which will be lifted upon data announcement from the CORE and CORE II studies [39] Q&A Session Summary Question: How is the TRINGOZA FCS launch progressing? - The company reported strong execution with a threefold increase in Q2 sales, effective patient identification efforts, and favorable reimbursement trends [41][43] Question: What triglyceride lowering is expected in the upcoming SHTG readout? - The company expects a reduction of 58% to 62% in triglyceride levels, which is considered clinically meaningful for physicians [48][49] Question: What is the status of Donavolorsen's launch preparations? - The company confirmed that everything is in place for the launch following the expected FDA approval on August 21 [50][54] Question: How does the company view competition in the market? - Management believes that patients are willing to switch to Donavolorsen due to its strong profile and ease of use compared to existing treatments [78] Question: What is the expected acute pancreatitis (AP) event rate in the CORE and CORE II studies? - The company confirmed that there will be more AP events in the CORE and CORE II studies combined than in the FCS BALANCE study, but specific numbers were not disclosed [64][104]

Financial Data and Key Metrics Changes - The company increased its 2025 financial guidance across all metrics, raising revenue expectations by more than 20% due to strong Q1 results and successful licensing transactions [29][34] - Revenue for Q1 2025 was $132 million, a 10% year-over-year increase, with over half coming from commercial products, which grew 28% compared to the same period last year [29][30] - Non-GAAP operating loss guidance improved by nearly 25% to less than $375 million, with an expected cash balance of $1.9 billion by year-end [37][38] Business Line Data and Key Metrics Changes - The first independent commercial launch, TrINGOLZA, generated over $6 million in product sales in its first full quarter, exceeding expectations [6][30] - SPINRAZA royalties contributed $48 million, reflecting a 25% year-over-year increase, while Waynua royalties were $9 million, with expectations for growth driven by strong U.S. demand [30][31] - The company anticipates additional product revenue from the upcoming launch of Donadolorsen for Hereditary Angioedema (HAE) [36][59] Market Data and Key Metrics Changes - The company is focused on expanding its market presence, particularly in the rare disease space, with significant unmet needs in conditions like familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (SHTG) [6][18] - The estimated patient population for FCS in the U.S. is around 3,000, while SHTG has a much larger addressable market of over 1 million patients [70][72] Company Strategy and Development Direction - The company is executing on strategic priorities, including multiple independent launches and partnerships to enhance its product pipeline and revenue potential [5][8] - The focus remains on disease education and patient identification to maximize the potential of TrINGOLZA and prepare for the launch of Donadolorsen [35][96] - The company is well-positioned to leverage its first-mover advantage in both FCS and SHTG markets, aiming for substantial revenue growth and positive cash flow [22][39] Management's Comments on Operating Environment and Future Outlook - Management acknowledged the evolving regulatory environment and potential disruptions due to new tariff policies but expressed confidence in the company's strategic execution [4][5] - The company is optimistic about achieving sustained revenue growth, with late-stage programs expected to deliver significant peak sales potential in the multibillion-dollar range [38][41] - Management emphasized the importance of ongoing patient identification efforts and payer engagement to ensure access to treatments [15][16] Other Important Information - The company completed licensing transactions for sapaglutzin and ex-U.S. commercialization rights for olazarcen, enhancing its financial outlook [33][34] - The company is actively engaging with payers to establish broad access for TrINGOLZA and Donadolorsen, with favorable coverage dynamics reported [12][13] Q&A Session Summary Question: Overlap between physician prescribers for FCS and SHTG - Management indicated significant overlap among cardiologists and endocrinologists treating both FCS and SHTG patients, which could facilitate the transition to SHTG treatment [48][49] Question: Preparation for Donadolorsen launch - The company is actively preparing for the launch of Donadolorsen, focusing on patient advocacy and physician education to facilitate transitions from existing therapies [59][60] Question: Impact of tariffs and FDA interactions - Management reported no significant impact from tariffs or changes in FDA interactions, with all programs on track [61][63] Question: Confidence in FCS patient estimates - The company expressed confidence in the estimated 3,000 FCS patients and is focused on increasing awareness and identification of these patients [68][70] Question: Channel stocking for TrINGOLZA - Management confirmed that TrINGOLZA sales are demand-driven, with no significant channel stocking observed [75][76] Question: Manufacturing footprint and tariff exposure - The company has a robust manufacturing supply chain in place and has not experienced any meaningful impacts from tariffs to date [78][79]