编者按：寡核苷酸疗法正成为罕见病治疗的重要突破方向。当前，全球范围内已有十多款寡核苷酸疗法获监管机构批准治疗罕见病，此外还有上百项寡核苷 酸疗法管线在针对罕见病适应症进行临床研究，未来有望造福更多患者。为帮助合作伙伴更高效地推动寡核苷酸药物从实验室走向临床，药明康德化学业务 旗下WuXi TIDES平台围绕寡核苷酸、多肽及其相关化学偶联药物建立了一体化解决方案，覆盖定制合成、共价偶联、工艺开发和CMC等关键环节，赋能创 新项目加速进入临床阶段。本文将回顾2025年寡核苷酸新药在罕见病领域取得的部分新进展。 再如，3月，赛诺菲（Sanofi）与Alnylam联合开发的siRNA疗法Qfitlia（fitusiran）获FDA批准上市，用于预防或减少12岁以上血友病A和血友病B患者的出血 事件，无论患者体内是否含有凝血因子VIII或IX的抑制物。该药通过降低抗凝血酶水平，从而促进凝血酶生成，重新平衡止血功能并预防出血，为血友病患 者提供了长效预防新选择。 寡核苷酸药物是全球新药开发的重要热点，正为众多曾被视为"不治之症"的罕见病带来新的治疗希望。 近年来，该领域研发进展持续加速。公开资料显示，全球已有十多款罕见病 ...

Industry Overview - The drug and biotech sector regained momentum in the latter part of 2025 after a weak first half, setting the stage for a strong year for select stocks [1] - Improved policy clarity following drug pricing agreements with the Trump administration reduced uncertainty, while a rebound in mergers and acquisitions revived investor appetite for risk [1] - Innovation accelerated across high-growth areas such as obesity, gene therapy, inflammation, and neuroscience, with the FDA approving 43 novel therapies as of December 22, 2025 [2] Company Highlights Ionis Pharmaceuticals - Ionis Pharmaceuticals' shares surged 127.6% in 2025, significantly outperforming the industry growth of 5% [5][6] - The company advanced its wholly-owned portfolio, highlighted by the FDA approval of Tryngolza for familial chylomicronemia syndrome, generating $57.4 million in sales in the first nine months of 2025 [9] - Ionis is evaluating Tryngolza in late-stage studies for severe hypertriglyceridemia, with plans to file for FDA label expansion soon [10] - The FDA approved Ionis' second drug, Dawnzera, for hereditary angioedema, with a regulatory filing in the EU expected in early 2026 [11] Structure Therapeutics - Structure Therapeutics' shares surged 127.2% in the past year, compared to the industry's 15.6% growth [13] - The stock rally was driven by positive data from the ACCESS clinical program for aleniglipron, showing up to 15.3% placebo-adjusted weight loss [15][16] - The company plans to initiate phase III development for aleniglipron in mid-2026 and is also developing other candidates for obesity treatment [18] Monopar Therapeutics - Monopar Therapeutics' shares rallied 185.9% in the past year, significantly outperforming the industry [20] - The stock price increase was fueled by positive expectations regarding its lead candidate ALXN-1840 for Wilson disease, following a licensing agreement with AstraZeneca [22] - Monopar plans to submit a regulatory filing with the FDA in early 2026 based on favorable long-term data for ALXN-1840 [26] Kodiak Sciences - Kodiak Sciences' shares rallied 181.1% in the past year, contrasting with the industry's 15.7% decline [27] - The stock's performance reflects growing investor confidence in its late-stage pipeline assets, particularly tarcocimab and KSI-501 [29] - Kodiak plans to submit a regulatory filing for tarcocimab for multiple indications, with top-line data from pivotal studies expected in 2026 [31][33]

Core Points - Ionis Pharmaceuticals has received Breakthrough Therapy designation from the U.S. FDA for zilganersen, aimed at treating Alexander disease, a rare and often fatal neurological condition [1][2] - The company plans to submit a new drug application (NDA) in Q1 2026 [1][3] Company Overview - Ionis Pharmaceuticals is recognized for its innovative approach in developing treatments for serious diseases, including neurological conditions [3][9] - The company has a strong pipeline, including marketed medicines and investigational therapies, positioning it for revenue growth and value creation [3][9] Zilganersen Study Details - The pivotal study for zilganersen involved 54 participants aged 1.5 to 53 years across 13 sites in eight countries, primarily focusing on children due to the early onset of Alexander disease [4][5] - The study demonstrated a statistically significant improvement in gait speed, with a mean difference of 33.3% (p=0.0412) at week 61 for the 50 mg dose compared to control [2][5] Alexander Disease (AxD) Insights - Alexander disease affects approximately 1 in 1 to 3 million people globally and is characterized by progressive neurological deterioration, leading to loss of mobility and independence [7] - There are currently no approved disease-modifying treatments for Alexander disease, highlighting the significance of zilganersen's potential [7][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 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 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]

Core Insights - Ionis Pharmaceuticals, Inc. (NASDAQ:IONS) is recognized as one of the top biotech stocks to invest in, with Leerink Partners maintaining an Outperform rating and increasing the price target from $63 to $68 following positive results for its Alexander disease therapy, zilganersen [1]. Group 1: Company Performance - The 10-meter walk test (10MWT) indicated that Zilganersen demonstrated a statistically significant improvement in stabilizing gait speed, along with steady gains across key secondary endpoints [2]. - Ionis Pharmaceuticals focuses on developing medications for serious medical conditions, particularly in the cardiovascular and neurological disorder sectors [3]. Group 2: Future Outlook - Detailed results from the Zilganersen trial are expected to be presented at an upcoming medical conference, while open-label extension data will provide further insights into the treatment's impact on life expectancy and disease progression in the future [3].

Core Insights - Ionis Pharmaceuticals announced positive topline results from a pivotal phase III study for its investigational RNA-targeted therapy zilganersen, aimed at treating Alexander disease (AxD) [1][4] Group 1: Study Results - The study met its primary endpoint, showing that patients receiving a 50 mg dose of zilganersen achieved a statistically significant 33.3% stabilization in gait speed compared to the control group, measured by the 10-Meter Walk Test (10MWT) [2] - Treatment with zilganersen demonstrated a favorable safety and tolerability profile, with consistent benefits observed across key secondary endpoints, indicating evidence of slowed disease progression [3][9] Group 2: Regulatory and Market Implications - Ionis plans to submit a regulatory filing with the FDA for zilganersen in Q1 2026, marking it as the first investigational medicine to show a positive disease-modifying impact in AxD [6][4] - If approved, zilganersen will join Ionis' portfolio as the third wholly-owned drug, alongside Tryngolza and Dawnzera, which were approved in the last 12 months [7] Group 3: Financial Performance and Strategy - Year-to-date, Ionis shares have increased nearly 76%, significantly outperforming the industry growth of 12% [8] - Ionis has established collaborations with major pharmaceutical companies, providing funds through license fees and milestone payments to support the development of its wholly-owned pipeline [10] - The company earns commercial revenues from royalties on Spinraza and Qalsody, with ongoing partnerships for other drug developments [11][12]

Group 1 - Ionis Pharmaceuticals has reported positive results from a pivotal study of its experimental medicine, zilganersen, aimed at treating Alexander disease, a rare neurological disorder [5] - The study demonstrated that a 50 mg dose of zilganersen significantly improved outcomes for patients suffering from Alexander disease [5]

Core Insights - Ionis Pharmaceuticals reported second-quarter 2025 adjusted earnings per share (EPS) of 86 cents, significantly exceeding the Zacks Consensus Estimate of 27 cents, compared to an adjusted loss of 24 cents in the same period last year [1] - Total revenues reached $452 million, doubling year-over-year and surpassing the Zacks Consensus Estimate of $271 million [2] Revenue Streams - Ionis has licensed Spinraza to Biogen, which is responsible for its commercialization, and receives royalties from its sales. Spinraza is approved for treating spinal muscular atrophy globally [3] - Ionis also earns royalties from Biogen's Qalsody, approved for treating amyotrophic lateral sclerosis with SOD1 mutations, launched in the U.S. in 2023 and in the EU in May 2024 [3] - The FDA approved Wainua (eplontersen) for treating hereditary transthyretin-mediated amyloid polyneuropathy in December 2023, co-marketed with AstraZeneca in the U.S. [4] - Following Wainua's U.S. launch, Ionis began receiving royalties from AstraZeneca, which are included in commercial revenues [5] Commercial Revenue Performance - Commercial revenues rose 43% year-over-year to $103 million, driven by Tryngolza product sales and Wainua royalties, exceeding the Zacks Consensus Estimate of $88 million [7] - Tryngolza contributed $19 million in sales, up from $6 million in the previous quarter, indicating strong launch momentum [8] - Spinraza royalties totaled $54 million, down 5% year-over-year, with sales of $393 million, reflecting an 8% decline compared to the previous year [8] - Wainua royalty revenues amounted to $10 million, with sales of $44 million recorded by AstraZeneca [9] R&D Revenue Growth - R&D revenues surged 128% year-over-year to $349 million, driven by a $280 million upfront payment for out-licensing rights for a rare blood cancer drug to Ono Pharmaceutical [12] - Collaborative agreement revenues totaled $337 million, compared to $141 million in the year-ago quarter [13] Cost and Guidance Updates - Adjusted operating costs rose 8% year-over-year to $282 million, with SG&A costs increasing 42% to support commercialization efforts [14] - Ionis raised its 2025 revenue outlook to $825-$850 million, up from the previous guidance of $725-$750 million, reflecting strong uptake for Tryngolza [15] - The adjusted operating loss is now expected to be between $300-$325 million, down from previous guidance of less than $375 million [18] Updates on Wholly-Owned Candidates - Tryngolza is being evaluated in three late-stage studies for severe hypertriglyceridemia, with positive data from the ESSENCE study [20] - Donidalorsen is under FDA review for hereditary angioedema, with a decision expected next month [21] - Zilganersen is in a late-stage study for Alexander disease, with data expected in 2025 [22] Partnered Candidates Developments - AstraZeneca and Ionis are developing Wainua for ATTR-CM, with data from the phase III CARDIO-TTRANSform study expected in the second half of 2026 [23] - Novartis is developing pelacarsen for elevated Lp(a)-driven cardiovascular disease, with data expected this year [24] - AstraZeneca initiated a phase IIb study on opemalirsen for APOL1-mediated kidney disease, triggering a $30 million milestone payment to Ionis [25]