PresentationAnd with that, thank you so much for joining us here today on a busy day. Brett, I'll turn it over to you.Hello, everyone, and welcome to Oppenheimer's 36th Annual Life Science Conference. I'm Jay Olson, one of the biotech analysts here at Oppenheimer, and it's a pleasure to welcome you to our discussion with Ionis. And it's an honor to introduce Brett Monia, the CEO, and the timing is perfect as the FDA has just accepted the sNDA filing for olezarsen to treat sHTG with a priority review, which ...

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 Insights - Ionis Pharmaceuticals reported an EPS of -$1.41, missing consensus estimates of around -$1.23, but exceeded revenue expectations with $203 million in total revenue [1][3] - The company has shown a pattern of revenue beats in recent quarters despite a year-over-year decline in Q4 total revenue [4] Financial Performance - Ionis reported a total revenue of $203 million for Q4 2025, which is an ~11% decline from $227 million in Q4 2024, but surpassed the Zacks Consensus Estimate by ~30% [3][4] - Commercial revenue grew approximately 64% to ~$141 million in Q4, driven by products like TRYNGOLZA, offsetting declines in royalties and R&D revenue [4] - The current ratio stands at approximately 2.79, indicating good short-term financial health despite ongoing unprofitability [2][5] Valuation Metrics - Ionis has a negative price-to-earnings (P/E) ratio of approximately -50, indicating current unprofitability [5] - The price-to-sales ratio is about 13, suggesting investors are willing to pay a premium for revenue amid pipeline expectations [5] - The enterprise value to sales ratio is also approximately 13, reflecting the company's valuation relative to revenue [5] Future Outlook - Ionis is focused on discovering and developing RNA-targeted therapeutics, with multiple independent launches planned for 2026 [2] - CEO Brett P. Monia emphasized the potential for continued success in 2026, highlighting upcoming launches such as olezarsen for sHTG and zilganersen for AxD [4]

Group 1 - The small nucleic acid drug industry is recommended to focus on three categories: clinical progress type (key targets with Phase III data + beneficiaries of medical insurance), technology platform type (extracellular delivery + multi-target technology companies), and international cooperation type (local companies endorsed by MNCs) to capture dual dividends from new drug launches and data readout windows [1] - Small nucleic acid drugs have become a core track in precision medicine due to their technological breakthroughs and therapeutic differentiation, covering thousands of rare and chronic disease-related targets [1] - The global market for small nucleic acid drugs is expected to grow from $2.7 billion in 2019 to $5.7 billion in 2024, with a CAGR of 16.2%, and projected to reach $20.6 billion by 2029, driven by the increase in chronic diseases and significant drug commercialization [2] Group 2 - The industry is entering a high growth phase, with over 50% of the 19 drugs currently on the market targeting rare diseases, while the proportion of chronic diseases is expected to gradually increase [2] - Key players in the industry include Alnylam and Ionis, which dominate the market with their technological barriers, while local companies like Reebio and Bowang Pharmaceutical are focusing on niche areas [2] - 2025 is anticipated to be a pivotal year for small nucleic acid drugs, with several key drugs expected to achieve significant sales milestones and clinical endpoints [3]

Core Insights - GSK shared data from two pivotal Phase 3 studies, B-Well 1 and B-Well 2, for bepirovirsen, an investigational treatment for chronic hepatitis B, involving over 1,800 patients [1] - The studies met their primary endpoint, showing a statistically significant and clinically meaningful functional cure rate for bepirovirsen compared to standard care alone [3] - If approved, bepirovirsen could become the first finite, six-month therapeutic option for chronic hepatitis B [5] Financial and Partnership Details - Ionis received an upfront payment, license fee, and development milestone payments from GSK, with potential additional payments of $150 million and tiered royalties of 10-12% on net sales of bepirovirsen [2] - The collaboration between Ionis and GSK began in 2019 when GSK licensed bepirovirsen from Ionis [1] Study Results and Future Plans - The B-Well studies demonstrated an acceptable safety and tolerability profile consistent with previous studies, with full results to be presented at a scientific congress and submitted for regulatory approvals in early 2026 [4] - The studies showed significantly higher functional cure rates in patients with baseline surface antigen levels ≤1000 IU/ml [3] Analyst Commentary - Analysts from William Blair noted that Ionis is well-positioned with five Phase 3 readouts expected in 2026, highlighting bepirovirsen as an underappreciated opportunity in the market [6] - The performance of Gilead Science's Vemlidy, projected to exceed $1 billion in revenue for fiscal 2025, suggests a growing market for hepatitis B treatments [6] Market Reaction - Following the announcement, Ionis Pharmaceuticals shares increased by 4.06% to $84.80, while GSK shares rose by 1.20% to $51.16 [8]

Investment Rating - The report indicates a positive investment outlook for the innovative drug sector, particularly focusing on RNA-targeted therapies for metabolic diseases [5][6]. Core Insights - The approval of the first APOC3 siRNA therapy for treating Familial Chylomicronemia Syndrome (FCS) marks a significant milestone in the RNA-targeted therapy landscape, showcasing the potential of these therapies in managing lipid disorders [17][28]. - RNA-targeted therapies, including small interfering RNA (siRNA) and antisense oligonucleotides (ASOs), are being developed to effectively lower triglyceride levels and improve patient compliance due to reduced dosing frequency [5][10]. - The report highlights ongoing clinical trials and the promising results of therapies like volanesorsen and olezarsen, which have shown significant reductions in triglyceride levels and lower incidence of acute pancreatitis in patients with FCS [17][28][34]. Summary by Sections Section 1: Focus on Innovative Drugs - The report emphasizes the rapid advancements in RNA-targeted therapies for metabolic diseases, particularly in the context of lipid management [5][6]. - Key developments include the approval of siRNA therapies that target APOC3 mRNA, which is crucial for regulating triglyceride levels in patients with FCS [10][17]. Section 2: Clinical Developments - The report details various therapies in clinical stages, including volanesorsen and olezarsen, which have received FDA approval and demonstrated efficacy in lowering triglyceride levels significantly [17][28]. - Clinical trial results indicate that patients treated with these therapies experienced substantial reductions in triglyceride levels compared to placebo groups, with olezarsen showing a 43.5% reduction at six months [28][34]. Section 3: Market Dynamics - The report outlines the competitive landscape, noting that several companies are advancing their RNA-targeted therapies through clinical trials, with a focus on improving patient outcomes and safety profiles [33][34]. - The potential market for these therapies is substantial, given the prevalence of metabolic diseases and the need for effective treatment options [5][6].

Summary of Ionis Pharmaceuticals Conference Call Company Overview - **Company**: Ionis Pharmaceuticals (NasdaqGS:IONS) - **Date of Conference**: November 13, 2025 - **Key Speakers**: Beth Hougen (CFO), Kyle Jenne (Chief Global Product Strategy Officer) Key Industry and Company Insights Commercial Performance - **Tryngolza**: Launched for FCS (Familial Chylomicronemia Syndrome) with sales guidance of **$85-$95 million** for the full year, exceeding expectations [2][10] - **Donidalorsen**: Recently approved for HAE (Hereditary Angioedema), showing strong early market enthusiasm [2][3] - **Olezarsen**: Phase three data indicates a potential billion-dollar opportunity for SHTG (Severe Hypertriglyceridemia) [3][4] Clinical Data Highlights - **Olezarsen Efficacy**: Achieved up to **72% placebo-adjusted reduction in triglycerides**, leading to an **85% reduction in acute pancreatitis risk** [7][8] - **Safety Profile**: Slight increases in liver enzymes and fat observed, but no clinical sequelae reported [9] - **Patient Population**: Targeting **3,000 high-risk SHTG prescribers** in the U.S. with a broader potential market of **3.4 million** SHTG patients [10][12] Market Strategy - **Targeting High-Risk Patients**: Focus on patients with a history of acute pancreatitis and those over 80 years old, with a strategy to reach **20,000 HCPs** [14][16] - **Regulatory Timeline**: Anticipating filing for sNDA by the end of the year, with a potential approval in **October next year** [18] Pricing Strategy - **Pricing Range**: Expected to be in the **$10,000-$20,000** range to maximize patient access and minimize payer restrictions [24] - **Market Demand**: HCPs indicate a strong need for therapies that lower triglycerides, regardless of historical events [20][21] HAE Market Insights - **Market Dynamics**: Approximately **75% of identified HAE patients** are on prophylactic therapy, indicating a switch market with **20% annual switching** due to efficacy, tolerability, and convenience [25][26] - **Donidalorsen Expectations**: Projected peak sales of **greater than $500 million**, with an initial consensus of **$8 million** for the end of the year [29][31] Financial Outlook - **Projected Peak Sales**: Anticipated annual peak sales of **$5 billion or more**, with **$3 billion** from wholly owned pipeline and **greater than $2 billion** in royalties from partnered programs [41][42] - **Break-even Target**: Aiming for positive cash flow break-even by **2028** [41][43] Additional Important Points - **Market Research**: Ongoing discussions with HCPs and payers to determine optimal pricing and market positioning [24][35] - **Competitive Landscape**: The TTR (Transthyretin Amyloidosis) market is expected to grow significantly, with projections exceeding **$20 billion** globally [33][34] This summary encapsulates the key points discussed during the conference call, highlighting Ionis Pharmaceuticals' current market position, product pipeline, and financial outlook.

Core Viewpoint - Ionis Pharmaceuticals is pricing a $700 million offering of 0.00% Convertible Senior Notes due 2030 to refinance its existing 2026 Convertible Notes, with proceeds aimed at repurchasing or repaying the 2026 notes before maturity [1][4]. Summary by Sections Offering Details - The offering consists of $700 million aggregate principal amount of Convertible Senior Notes due 2030, with an option for initial purchasers to buy an additional $70 million [1][3]. - The expected closing date for the sale of the notes is November 17, 2025, subject to customary closing conditions [1]. Financial Proceeds - Ionis estimates net proceeds from the offering to be approximately $682.8 million, or $751.2 million if the additional notes option is fully exercised [3]. - Approximately $267.6 million of the net proceeds will be used to repurchase $200 million of the 2026 Convertible Notes [4]. Conversion and Redemption Terms - The notes will not bear regular interest and will mature on December 1, 2030, unless converted, redeemed, or repurchased earlier [2]. - Holders can convert their notes under specific conditions before September 1, 2030, and at any time thereafter until maturity [5]. - The initial conversion rate is set at 10.1932 shares per $1,000 principal amount, equating to an initial conversion price of approximately $98.10 per share, representing a 35% premium over the last reported sale price of $72.67 [5]. Repurchase Transactions - Concurrently, Ionis is engaging in transactions to repurchase $200 million of the 2026 notes, which are not contingent upon the new offering [8]. - Hedged holders of the 2026 notes may unwind their hedge positions, potentially impacting the market price of Ionis' common stock [9]. Additional Information - The notes and any shares issued upon conversion have not been registered under the Securities Act and may not be offered or sold in the U.S. without registration or an exemption [10]. - Ionis has a history of innovation in RNA-targeted medicines and continues to advance its pipeline in various therapeutic areas [12].

Core Insights - The conference call is focused on discussing the detailed results of Phase III trials for olezarsen [1] Group 1 - The call is being led by Wade Walke, Senior Vice President of Investor Relations [1]

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]