Core Findings - Ionis Pharmaceuticals reported results from the Phase 3 CORE and CORE2 studies of olezarsen for severe hypertriglyceridemia (sHTG), achieving a statistically significant placebo-adjusted mean reduction in fasting triglyceride levels of up to 72% at six months, sustained through 12 months [2][5] - Olezarsen demonstrated an 85% reduction in acute pancreatitis events, with 86% of treated patients achieving triglyceride levels below 500 mg/dL, the risk threshold for acute pancreatitis [3][6] Study Details - Nearly 1,100 patients were enrolled in the CORE and CORE2 studies, marking the largest pivotal program ever conducted in sHTG, with participants required to be on standard-of-care lipid-lowering therapy [5] - The studies showed favorable safety and tolerability for olezarsen, with significant reductions in secondary endpoints including apoC-III, remnant cholesterol, and non-HDL-C [4][7] Future Plans - Ionis is set to submit a supplemental new drug application for both the 50 mg and 80 mg doses to the FDA by the end of the year, with an ongoing open-label extension study where over 90% of patients from CORE and CORE2 chose to continue [8] Efficacy Metrics - In terms of triglyceride levels, 89% and 88% of patients on olezarsen 50 mg and 80 mg, respectively, achieved levels below 880 mg/dL, while 34% and 54% achieved normal triglyceride levels below 150 mg/dL [9] - The number needed to treat (NNT) analysis indicates that treating 20 patients with olezarsen is estimated to prevent one acute pancreatitis event over one year, and treating four patients in the highest risk group is estimated to prevent one event over one year [9]

Group 1 - U.S. stock futures are higher, with Nasdaq futures gaining approximately 1.5% [1] - Monday.Com Ltd is expected to report quarterly earnings of 88 cents per share, an increase from 85 cents per share year-over-year [2] - The consensus estimate for monday.com's quarterly revenue is $312.26 million, up from $251 million a year earlier [2] Group 2 - Monday.Com shares fell 2.6% to $184.70 in pre-market trading [2] - Metsera Inc shares dipped 15% to $70.68 in pre-market trading following Pfizer's $10 billion acquisition deal [4] - Ionis Pharmaceuticals Inc declined 11.5% to $65.00 after disclosing results from pivotal Phase 3 studies [4] - Other companies such as UniQure NV, Oscar Health Inc, Centene Corp, and Immunovant Inc also experienced declines in pre-market trading [4]

Group 1 - U.S. stock futures are higher, with Nasdaq futures gaining approximately 1.5% on Monday [1] - Monday.Com Ltd is expected to report quarterly earnings of 88 cents per share, an increase from 85 cents per share in the previous year [2] - The consensus estimate for monday.com's quarterly revenue is $312.26 million, up from $251 million a year earlier [2] Group 2 - Monday.Com shares fell 2.6% to $184.70 in pre-market trading [2] - Metsera Inc shares dipped 15% to $70.68 after Pfizer secured a $10 billion deal to acquire the company [4] - Ionis Pharmaceuticals Inc declined 11.5% to $65.00 following the disclosure of pivotal Phase 3 study results [4] - Other companies such as UniQure NV, Oscar Health Inc, Centene Corp, and Immunovant Inc also experienced declines in pre-market trading [4]

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]

Core Insights - Ionis Pharmaceuticals, Inc. (IONS) has released very positive trial data from phase-3 studies in their pipeline drugs, resulting in a significant share price increase of approximately 80% since the news broke [1] Company Overview - Ionis Pharmaceuticals is focused on developing transformative technologies in the pharmaceutical industry, particularly in the area of RNA-targeted therapeutics [1] Investment Perspective - The investment philosophy highlighted emphasizes the importance of patient investing and the accumulation of high-quality assets, while also considering high-risk, high-reward opportunities [1] - The approach to investing includes a commitment to companies that aim to make a positive impact on the world [1]

Core Insights - Ionis Pharmaceuticals, Inc. (IONS) has released highly positive phase-3 trial data for its pipeline drugs, resulting in an approximate 80% increase in share price since the announcement [1] Company Overview - Ionis Pharmaceuticals is focused on developing transformative technologies in the pharmaceutical industry, aiming to create high-quality assets that contribute positively to society [1] Investment Perspective - The investment philosophy highlighted emphasizes the importance of patient investing, combining steady accumulation of quality assets with high-risk, high-reward opportunities [1] - The approach includes learning from others and adapting investment strategies based on insights gained from various sources [1]

Core Insights - Ionis Pharmaceuticals reported a narrower adjusted loss per share of 61 cents for Q3 2025, significantly better than the Zacks Consensus Estimate of a loss of $1.15, and improved from a loss of 72 cents in the same period last year [1][7] - Total revenues reached $157 million, exceeding the Zacks Consensus Estimate of approximately $130 million, marking a 17% increase year-over-year [2][7] - The company raised its 2025 revenue guidance to between $875 million and $900 million, up from the previous estimate of $825 million to $850 million, reflecting strong drug uptake [14][15] Financial Performance - Adjusted operating costs increased by 14% year-over-year to $286 million, with SG&A costs rising 71% to support commercialization efforts [13] - Commercial revenues surged 53% year-over-year to $116 million, driven by strong sales of Tryngolza and higher royalties from Wainua [9][10] - R&D revenues declined by 29% year-over-year to $41 million, but still surpassed the Zacks Consensus Estimate of $25 million [12] Product and Pipeline Updates - Tryngolza, launched in December 2024, contributed $32 million in sales, while Wainua royalties amounted to $13 million, reflecting a strong market presence [10][11] - Positive results from phase III studies for Tryngolza indicate its potential for label expansion, with an FDA filing planned before the end of 2025 [17][18] - Ionis is also advancing other candidates in its pipeline, including zilganersen for Alexander's disease and ION582 for Angelman syndrome, with regulatory filings expected in the near future [19] Stock Performance - Year-to-date, Ionis shares have increased by 106%, significantly outperforming the industry growth of 8% [3]

Financial Performance - Total revenue for the three months ended September 30, 2025, was $156.7 million, an increase of 17.0% compared to $133.8 million for the same period in 2024[14] - Product sales for the three months ended September 30, 2025, were $31.8 million, compared to $0 for the same period in 2024[14] - Royalty revenue increased to $75.7 million for the three months ended September 30, 2025, from $66.8 million in the same period of 2024, representing a growth of 13.3%[14] - Net loss for the three months ended September 30, 2025, was $128.6 million, compared to a net loss of $140.5 million for the same period in 2024, reflecting a decrease of 8.5%[15] - Total revenue for the nine months ended September 30, 2025, was $740,381, an increase of 54.7% compared to $478,562 in the same period of 2024[41] - The consolidated net loss for the nine months ended September 30, 2025, was $152.0 million, a decrease of 56.6% from a net loss of $349.5 million for the same period in 2024[111] Assets and Liabilities - Total assets as of September 30, 2025, were $3.03 billion, a slight increase from $3.00 billion as of December 31, 2024[12] - Total liabilities as of September 30, 2025, were $2.42 billion, compared to $2.42 billion as of December 31, 2024, indicating stability in the company's financial obligations[12] - Stockholders' equity increased to $618.0 million as of September 30, 2025, from $588.4 million as of December 31, 2024, marking a growth of 5.4%[12] - Total current assets as of September 30, 2025, were $2.52 billion, a slight decrease from $2.62 billion as of December 31, 2024[12] Cash Flow and Investments - Cash and cash equivalents as of September 30, 2025, were $338.3 million, an increase from $242.1 million as of December 31, 2024[12] - Net cash used in operating activities for the nine months ended September 30, 2025, was $130,874 thousand, down from $384,808 thousand in 2024, indicating a 66% reduction[21] - The company reported a net cash provided by investing activities of $141,729 thousand for the nine months ended September 30, 2025, contrasting with a net cash used of $202,240 thousand in 2024[21] Research and Development - Research and development expenses for the nine months ended September 30, 2025, were $636.0 million, slightly down from $656.0 million for the same period in 2024[14] - Research and development revenue for the nine months ended September 30, 2025, was $445.858 million, significantly up from $271.202 million in the same period of 2024, marking a 64.3% increase[14] - The company recognized $278 million in R&D revenue for the license of sapablursen to Ono, completing the performance obligation upon delivery of the license[65] Collaborations and Revenue Sources - The collaboration with AstraZeneca generated $27.1 million in revenue for the three months ended September 30, 2025, representing 17% of total revenue, compared to 15% in the same period of 2024[62] - The company received a $200 million upfront payment from AstraZeneca in 2021 for the WAINUA collaboration, with total revenue from this collaboration exceeding $960 million through September 30, 2025[60] - Revenue from the relationship with Ono for the three months ended September 30, 2025, was $2,979,000, representing 2% of total revenue, while for the nine months, it was $282,979,000, accounting for 38% of total revenue[66] Stock and Equity - The company issued 3,229 thousand shares of common stock in connection with employee stock plans, generating $84,787 thousand in net proceeds[21] - The total unrecognized estimated stock-based compensation expense related to non-vested stock options, RSUs, and PRSUs was $138.3 million as of September 30, 2025[81] - The weighted-average grant date fair value of stock options granted to employees for the nine months ended September 30, 2025, was $17.21 per share, compared to $24.73 per share in 2024[84] Securities and Investments - The total available-for-sale debt securities amounted to $1,983,725,000 as of September 30, 2025, with an amortized cost of $1,980,492,000[74] - The company recorded a net unrealized loss of $2.0 million related to publicly traded equity securities in the nine months ended September 30, 2025[77] - The company invests in debt securities with strong credit ratings, maintaining an investment grade rating at or above A-1, P-1, or F-1[71] Other Financial Metrics - The company reported a basic and diluted net loss per share of $0.80 for the three months ended September 30, 2025, compared to $0.95 for the same period in 2024[14] - Total operating expenses for the three months ended September 30, 2025, were $316.901 million, up from $282.470 million in the same quarter of 2024, representing a 12.2% increase[14] - The company recorded a nominal income tax expense for the three and nine months ended September 30, 2025, compared to an income tax benefit of $3.6 million and $3.5 million for the same periods in 2024[88]

Financial Data and Key Metrics Changes - In Q3 2025, the company generated $157 million in revenue, a 17% increase year-over-year, and for the first nine months, revenue totaled $740 million, reflecting a 55% increase compared to the prior year [23][24] - TRYNGOLZA product sales reached $32 million, representing a nearly 70% increase over the second quarter [23][24] - Royalty revenues increased by approximately 13% to $76 million in Q3, driven by contributions from SPINRAZA and WAINUA [24] - The company raised its 2025 financial guidance, now expecting total revenue between $875 million and $900 million, an increase of $50 million from prior guidance [25][26] Business Line Data and Key Metrics Changes - TRYNGOLZA, the FDA-approved treatment for familial chylomicronemia syndrome, continues to show strong momentum with significant sales growth [5][14] - DAWNZERA, approved for hereditary angioedema, has seen strong early adoption, with initial prescriptions being filled shortly after approval [19][20] - The company anticipates two additional independent launches next year, with olzarsen for severe hypertriglyceridemia and zilganersen for Alexander disease [6][10] Market Data and Key Metrics Changes - The U.S. prophylactic HAE market is well established, with approximately 20% of patients switching treatments annually, indicating a significant opportunity for DAWNZERA [20] - The severe hypertriglyceridemia (sHTG) patient population is estimated to exceed 1 million in the U.S., with many patients struggling to manage triglyceride levels with current treatments [16][17] Company Strategy and Development Direction - The company is focused on executing its commercial strategy for TRYNGOLZA and DAWNZERA while preparing for upcoming launches of olzarsen and zilganersen [22][27] - The company aims to achieve cash flow breakeven by 2028, driving long-term value creation [26][27] - The commercial team is expanding outreach to healthcare providers and enhancing patient identification efforts to maximize the potential of its therapies [15][17] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the continued success of TRYNGOLZA and DAWNZERA, highlighting the strong early feedback from physicians and patients [19][20] - The company is optimistic about the upcoming data presentations and regulatory submissions, which are expected to further validate its pipeline and market potential [9][11] - Management emphasized the importance of addressing unmet needs in serious diseases and the potential for multi-billion dollar revenue from its pipeline [7][10] Other Important Information - The company announced the retirement of Richard Geary, Chief Development Officer, recognizing his contributions over the past 30 years [28] - The company is preparing for a significant data presentation at the American Heart Association (AHA) conference, which is expected to highlight the efficacy of olzarsen [38][39] Q&A Session Summary Question: What is the expected launch curve for olzarsen in sHTG? - The company anticipates strong interest from healthcare providers and plans to target approximately 20,000 HCPs covering around 360,000 patients with sHTG [31][33] Question: Any concerns regarding acute pancreatitis events in olzarsen studies? - Management expressed confidence in the groundbreaking results and emphasized that the data will be presented at AHA, with no significant concerns noted [37][38] Question: What are the peak revenue expectations for olzarsen and DAWNZERA? - Peak sales for DAWNZERA are expected to exceed $500 million, while olzarsen is anticipated to surpass $1 billion [39][40] Question: What is the pricing strategy for olzarsen? - The company is still evaluating pricing and will announce final pricing upon approval of the sHTG indication [44][45] Question: How is the early adoption of DAWNZERA progressing? - Early adoption is strong, with both switching patients and newly diagnosed patients starting treatment [72] Question: What is the source of revenue growth for WAINUA? - The revenue growth is primarily driven by new patient identification and the product's performance in improving quality of life [73]

Financial Data and Key Metrics Changes - In Q3 2025, the company generated $157 million in revenue, a 17% increase year over year, and for the first nine months, revenue totaled $740 million, reflecting a 55% increase compared to the prior year [23][24] - The company raised its 2025 financial guidance, now expecting total revenue between $875 million and $900 million, an increase of $50 million from previous guidance [25][26] - Operating loss is anticipated to be between $275 million and $300 million for the full year, with a cash balance expected to exceed $2.1 billion [25][26] Business Line Data and Key Metrics Changes - Tringolsa reported $32 million in net product sales, a nearly 70% increase quarter over quarter [14][23] - Royalty revenues increased by approximately 13% to $76 million in Q3, driven by contributions from Spinraza and Waylivra [24] - Donzera's launch is showing strong early adoption, with initial prescriptions being filled shortly after approval [19][20] Market Data and Key Metrics Changes - The U.S. prophylactic HAE market is well established, with approximately 20% of patients switching treatments annually, indicating a significant opportunity for Donzera [20] - The severe hypertriglyceridemia (SHTG) market is estimated to have over 1 million high-risk patients in the U.S., with Olzarsen positioned to address unmet needs in this population [16][17] Company Strategy and Development Direction - The company is focused on executing its strategy with two independent launches underway and plans for two additional launches next year [27][22] - The advancing wholly owned late-stage pipeline and a robust partnered portfolio are expected to drive sustained growth [7][26] - The company aims to achieve cash flow breakeven by 2028, emphasizing long-term value creation [26] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the continued success of Tringolsa and the upcoming launches of Olzarsen and Zilganersen, highlighting the strong momentum across the business [5][27] - The management team is optimistic about the potential for multi-billion dollar revenue from the new product launches and the overall pipeline [7][25] Other Important Information - Richard Geary, Chief Development Officer, will retire at the end of the year, marking his last earnings call with the company [28] Q&A Session Summary Question: Thoughts on the launch curve for Olzarsen in SHTG - Management indicated strong interest from healthcare providers and plans to target approximately 20,000 HCPs covering around 360,000 patients [30][32] Question: Concerns regarding acute pancreatitis events in Olzarsen studies - Management reassured that the data is groundbreaking and that the acute pancreatitis outcomes will be detailed at the upcoming AHA presentation [36][38] Question: Peak revenue potential for Donzera and Olzarsen - Management expects peak sales for Donzera to exceed $500 million and for Olzarsen to exceed $1 billion [39] Question: Pricing strategy for Olzarsen - Management is still working on pricing and expects to provide more clarity next year [44][45] Question: Early prescriptions for Donzera - The launch is going well, with both switching patients and newly diagnosed patients contributing to early prescriptions [70][72]