小核酸药物深度解析 20260105 摘要 小核酸药物已从罕见病扩展至代谢、心血管等慢性疾病领域，如 PCSK9 抑制剂 Inclisiran 销售额显著增长，国内企业也在新型降血脂药物方面 取得突破，主要得益于肝脏递送技术的进步。 小核酸药物通过靶向 mRNA，干扰基因表达上游，突破了传统小分子抑 制剂和蛋白抗体类药物仅能调控可成药靶点蛋白的局限性，成为新型竞 争赛道，具有强靶向特异性、高效长效作用机制以及序列预测能力等优 势。 siRNA 技术通过 GalNAc 等肝脏递送技术实现高效、高选择性传输，诺 华与 OncLive 合作开发的 siRNA 产品 Inclisiran 在 2024 年销售额达 7.5 亿美元，预计 2025 年全年销售将超过 10 亿美元，标志着小分子药 物从罕见病向代谢性慢病转变。 近年来，小核酸领域涌现多项重要合作，如博望与诺华达成 42 亿美元 合作协议，麦维生物通过 siRNA 靶向双靶点达成 BD 出海协议，表明小 核酸赛道备受关注，临床早期管线产品价值凸显。 Q&A 小核酸药物市场的现状和未来发展趋势如何？ 近期小核酸药物市场热度持续提升。2024 年和 2025 年 ...

Investment Rating - The report maintains a "Buy" rating for the small nucleic acid sector, anticipating significant catalysts by 2026 [5]. Core Views - The report emphasizes three main investment themes for 2026: innovation, international expansion, and turnaround opportunities. It suggests focusing on innovative drugs, biotech companies that have gone global, and supply chain strategies [2][21]. - The small nucleic acid therapy market is expected to experience substantial growth, with FDA-approved drugs like Inclisiran and Vutrisiran projected to reach sales of $754 million and $971 million respectively by 2024 [3][16]. Summary by Sections 1. Small Nucleic Acid Market Outlook - The report highlights the commercial growth potential of small nucleic acid therapies, with significant sales forecasts for drugs like Inclisiran and Vutrisiran, and a projected market size of $30 billion for Novartis's xRNA therapies [3][16]. - The business development (BD) trend for siRNA therapies is improving, with notable deals such as a $4.165 billion agreement with Novartis [3][20]. - Clinical catalysts are expected, with Arrowhead's ARO-DIMER-PA set to announce trial results in H2 2026 [4][20]. - Increased capital recognition is noted, with companies like Rebio Biotech preparing for IPOs, indicating a positive market sentiment [4][20]. 2. Market Review and Trends - The report reviews the recent performance of the pharmaceutical sector, noting a 1.04% decline in the A-share pharmaceutical index, underperforming compared to the ChiNext and CSI 300 indices [24][28]. - The overall trading volume in the pharmaceutical sector was 423.35 billion yuan, accounting for 4.38% of the total market, below the historical average of 7.13% [43][24]. - The report identifies the best-performing sub-sector as medical services II, while the worst was pharmaceutical commerce II [35][38]. 3. Investment Recommendations - The report recommends focusing on high-quality siRNA companies in China, such as Frontier Biotech, Yuyuan Pharmaceutical, and others, as they are positioned for rapid development in the small nucleic acid space [7][21]. - It suggests monitoring the clinical progress of various siRNA drugs in development, particularly those targeting metabolic diseases [22][21].

Group 1 - The core viewpoint of the article highlights the positive impact of the Federal Reserve's interest rate cut on the Hong Kong stock market, particularly in the biotechnology sector, which is expected to see valuation recovery due to improved liquidity conditions [1][2] - The article discusses the ongoing optimization of the policy environment in the pharmaceutical industry, emphasizing the shift from price competition to value competition, supported by innovative payment models and regulatory measures [1][2] - The introduction of the Hang Seng Biotechnology Index futures is seen as a significant step in enhancing the investment ecosystem for the biotechnology sector, attracting long-term capital and stabilizing market expectations [3] Group 2 - The biotechnology sector is positioned for structural allocation opportunities due to its current low valuation levels and favorable policy support, with significant inflows from southbound capital [4] - The article notes that small nucleic acid drugs are emerging as a core area for innovation, with recent breakthroughs in delivery technology expanding their therapeutic applications [2] - The performance of leading biopharmaceutical companies and the increase in overseas collaborations indicate a strengthening of the industry's fundamentals and confidence [1][2]

China Healthcare Expert call takeaways: Small nucleic acid drugs Overview of small nucleic acid drugs in China On 28 November, we hosted a call with an expert with experience in small nucleic acid drug research and CRO services, to discuss: 1) the market potential and clinical applications of RNA drugs; 2) the latest trends of R&D for siRNA/ASO drugs domestically and globally; and 3) comparisons on delivery systems and patents. The expert was optimistic on the future clinical potential, especially on substi ...

Summary of Key Points from the Conference Call on Small Nucleic Acid Drugs Industry Overview - The discussion centers around the small nucleic acid drug industry, highlighting its advantages over traditional drug platforms and the potential for various applications in treating diseases. Core Insights and Arguments 1. **Efficacy and Mechanism**: Small nucleic acid drugs can reduce protein expression levels by over 80%-90%, significantly outperforming small molecule and antibody drugs, which only lower activity or clear existing proteins [2][5][8] 2. **Long-lasting Effects**: Some small nucleic acid therapies require administration only once every six months, showcasing their long-lasting effects and low resistance development [2][5] 3. **Delivery Technologies**: The Golang liver delivery technology is currently the mainstream method but is limited to liver applications. New strategies involving peptide and antibody modifications aim to expand delivery beyond the liver [3][4] 4. **Multi-target Strategies**: The potential of multi-target strategies in drug development is significant, as demonstrated by Novartis' Inclisiran, which generated $790 million in revenue in the first three quarters of the year [5][8] 5. **Emerging Markets**: There is a growing market for small nucleic acid drugs in obesity treatment, with drugs like GPS-75 showing promise in altering the current weight loss market dynamics [9][20] 6. **Rare Diseases and CNS Applications**: Small nucleic acid drugs show potential in treating rare diseases and central nervous system disorders, with Novartis' acquisition of RVDP technology indicating strong confidence in muscle disease treatments [8][11] 7. **Challenges in Delivery**: The complexity of delivery systems poses significant barriers to entry for new companies, as effective delivery tools are crucial for the success of small nucleic acid therapies [12][22] 8. **Chemical Modifications**: Chemical modifications are essential for enhancing the stability and bioavailability of small nucleic acids, although current methods do not create significant barriers to entry [13][14] 9. **Market Potential**: The market for small nucleic acid drugs in treating cardiovascular diseases is substantial, as indicated by the $12 billion acquisition of a muscle treatment drug by Novartis [10][22] Other Important Insights 1. **Clinical Trials and Data**: Ongoing clinical trials, such as Wave 007, are showing promising results in weight loss applications, indicating a trend towards combining small nucleic acid drugs with existing therapies like GLP-1 [20][21] 2. **Regulatory and Safety Considerations**: The design of small nucleic acid sequences must consider potential off-target effects, necessitating thorough testing to ensure safety [18][25] 3. **Domestic Innovations**: Domestic companies like Shengyin, Bowang, and Ruibo are making significant strides in small nucleic acid research, with collaborations and innovations that enhance their market positions [28] This summary encapsulates the key points discussed in the conference call, providing a comprehensive overview of the small nucleic acid drug industry, its current state, and future potential.

Core Insights - The small nucleic acid drug market is entering a high-growth phase, driven by advancements in delivery technologies like GalNAc, which have enabled commercialization of liver-targeted drugs and expansion into common disease areas such as cardiovascular and central nervous system disorders [1][2]. Group 1: Industry Overview - Small nucleic acid drugs represent the third major class of drugs, including ASO and siRNA, with strong targeting capabilities and long-lasting effects, providing breakthroughs for traditionally non-druggable targets [1]. - The global small nucleic acid drug market is projected to grow from approximately $6.2 billion in 2024 to $46.7 billion by 2033, with a compound annual growth rate (CAGR) of 25% [2]. - The industry is characterized by a "one strong, many strong" structure, with leading companies like Alnylam, Ionis, and Arrowhead at the forefront of technology and pipeline development [2]. Group 2: Company Performance - Alnylam has established itself as the global leader in the siRNA field, leveraging its pioneering GalNAc liver-targeting delivery technology, which has set industry benchmarks [3]. - Since entering the commercialization phase in 2018, Alnylam has seen significant revenue growth, with total revenue reaching $2.617 billion in the first three quarters of 2025, a 58% year-on-year increase, and product net revenue of $1.992 billion, up 67% [3]. - The company continues to enhance its platform technology and expand its pipeline, with multiple cardiovascular, CNS, and rare disease drugs in clinical stages, which are expected to broaden its therapeutic indications [3]. Group 3: Investment Opportunities - Companies with leading advantages in small nucleic acid drug platform technologies and differentiated competitive positioning in target layouts are recommended for investment consideration, including Yuyuan Pharmaceutical, Fuyuan Pharmaceutical, Frontier Biotech, Shiyao Group, and Hengrui Medicine [4].

Core Insights - The pharmaceutical industry is experiencing a structural change driven by the growth cycles of major products, with significant opportunities emerging in innovative drugs, medical devices, and consumer healthcare [3][6][31] - The demand for pharmaceuticals is expected to improve in 2026, supported by policies encouraging innovation and a recovery in domestic consumption [3][7] - The supply side of the pharmaceutical industry is characterized by high entry barriers due to patent protections and government regulations, which helps maintain a stable competitive environment [4][5] Group 1: Industry Trends - The aging population, urbanization, and changing disease patterns are making the pharmaceutical industry a perpetual growth sector [3] - The global pharmaceutical market has seen rapid expansion from 2009 to 2019, followed by a surge in demand due to COVID-19, and is now entering a phase of recovery and growth [3][6] - The Chinese pharmaceutical industry is expected to gradually produce world-class companies, with increasing recognition of Chinese innovative drug assets by multinational corporations (MNCs) [4][5] Group 2: Investment Opportunities - Opportunities in innovative drugs are highlighted, particularly in oncology, metabolic diseases, and autoimmune diseases, with a focus on next-generation therapies and precision medicine [6][31] - The demand for innovative drugs is expected to remain strong, with policies improving medical insurance payments and the upcoming launch of commercial insurance drug catalogs [7][31] - The medical device sector is anticipated to recover, with a focus on domestic demand and international expansion, particularly in areas with low domestic production rates [7][8] Group 3: Company Performance - Major pharmaceutical companies like Eli Lilly, AbbVie, and AstraZeneca are experiencing significant growth driven by key products, with Eli Lilly's Tirzepatide generating $24.8 billion in sales [12][15] - The report identifies specific companies such as Hengrui Medicine, Hansoh Pharmaceutical, and BeiGene as outperformers in the market, with strong pipelines and global competitiveness [7][8] - The report emphasizes the importance of mergers and acquisitions (M&A) and business development (BD) strategies for MNCs, with China becoming a significant source of projects for top global pharmaceutical companies [22][24]

Investment Rating - The report suggests a positive investment opportunity in the small nucleic acid drug industry, highlighting its unique advantages and potential for growth [2]. Core Insights - Small nucleic acid drugs possess unique advantages such as broad target accessibility, strong specificity, high development efficiency, and prolonged dosing intervals, which significantly enhance patient compliance and open up potential clinical demand [2]. - Recent technological breakthroughs in small nucleic acid drug design have addressed challenges such as vascular degradation, immune activation, and delivery difficulties, leading to successful market approvals and showcasing excellent efficacy and safety [2]. - The global market for RNAi therapies is projected to grow from $12 million in 2018 to $25 billion by 2030, with a CAGR of 449.2%, indicating a rapid expansion phase for small nucleic acid drugs [2]. - Major multinational corporations (MNCs) are increasingly investing in the small nucleic acid field, with significant collaborations and development projects emerging, particularly in China [2]. - The report emphasizes the limited number of approved small nucleic acid products, suggesting that Chinese companies have the potential to capture a significant share of the global market [2]. Summary by Sections 1. Introduction and Core Technology of Small Nucleic Acid Drugs - Small nucleic acid drugs are defined as short-chain nucleic acids composed of dozens of nucleotides, targeting RNA to regulate protein expression [10]. - The report outlines the unique characteristics of small nucleic acid drugs, including their ability to target a wide range of disease-related genes and their potential to become a third major class of therapeutics after small molecules and antibody drugs [19]. 2. Market Overview of Small Nucleic Acid Drugs - The small nucleic acid drug market is experiencing rapid growth, with the global market size expected to reach $52.47 billion in 2024, reflecting an 18% year-on-year increase [50]. - The report forecasts that the RNAi therapy market in China will grow from approximately $4 million in 2022 to over $300 million by 2025, with a CAGR exceeding 300% [50]. 3. Disease Areas for Small Nucleic Acid Drugs - The report identifies genetic rare diseases as the most common indication for approved small nucleic acid drugs, with 16 out of 22 approved products targeting this area [51][52]. 4. Leading Overseas Companies in Small Nucleic Acid - The report highlights several leading companies in the small nucleic acid space, including Alnylam, Ionis, and Arrowhead, which are at the forefront of innovation and development [2]. 5. Recommended Companies to Watch - The report suggests monitoring companies with proprietary technology platforms and innovative pipeline layouts, such as Yuyuan Pharmaceutical, Rejuve Biotech, and others, as potential investment opportunities [2].

Core Viewpoint - Maiwei Biotech has signed exclusive licensing and preferred stock purchase agreements with Kalexo Bio, Inc. for the 2MW7141 project, which could yield up to $1 billion in upfront and milestone payments, along with low single-digit royalties [1][2]. Group 1: Company Overview - Maiwei Biotech's stock price increased by over 10% following the announcement, reaching a peak increase of 13.21% [1]. - The company is focused on developing dual-target small nucleic acid drugs, with 2MW7141 aimed at managing dyslipidemia and preventing high-risk cardiovascular events [2][5]. - The 2MW7141 project is currently in the CMC (Chemistry, Manufacturing, and Controls) development stage, and specific drug targets have not been disclosed due to confidentiality [1][5]. Group 2: Partnership Details - The agreement with Kalexo allows for exclusive global development, production, and commercialization rights for the 2MW7141 project [2]. - Kalexo, established in December 2023, is an innovative drug company created by AditumBio, which focuses on accelerating new drug development through capital and expertise [2][3]. - The potential total transaction value for the partnership is higher than previous collaborations, with Maiwei Biotech receiving an upfront payment of $12 million and milestone payments contributing to the total of up to $1 billion [3]. Group 3: Industry Context - The cardiovascular disease sector is highly competitive, with major pharmaceutical companies actively pursuing small nucleic acid therapies [5]. - Existing therapies, while effective, still leave room for improvement in reducing disease indicators, which the dual-target approach of 2MW7141 aims to address [5]. - Recent collaborations in the industry, such as the one between Boehringer Ingelheim and Novartis, highlight the trend of strategic partnerships focusing on early-stage projects in the small nucleic acid space [5][6].

Summary of Codexis Conference Call Company Overview - Codexis specializes in protein engineering and biocatalysis, providing solutions for small molecule medicines like Januvia and Paxlovid [4][4] - The company is now focusing on enzymatic synthesis of oligonucleotides, particularly in the siRNA therapeutics space [4][4] Industry Insights - The siRNA therapeutics market is expected to grow significantly, with demand projected to increase from 100 kilos in 2023 to at least 10 metric tons by the end of the decade [8][8] - Recent announcements from companies like Novartis and CureVac indicate a growing demand, with CureVac projecting a need for 25 metric tons per year, which exceeds current phosphoramidite chemistry capabilities [9][9] - Codexis estimates that the demand could reach 50 metric tons or more as the market expands into preventive medicines and larger indications [9][9] Technical Challenges and Solutions - Current chemical synthesis methods for siRNA are inefficient, expensive, and labor-intensive, requiring significant raw materials and infrastructure [6][6] - Codexis offers a range of solutions from ligation of shortmers to end-to-end enzymatic synthesis, which can improve yield and reduce costs [10][10][12][12] - The company is engaged with multiple customers, including one drug moving into phase 3 trials, demonstrating the feasibility and scalability of their platform [11][11] Customer Engagement and Market Strategy - Codexis has seen a significant increase in customer engagement, with a progression from one contract in 2024 to multiple contracts signed in 2023 [21][21] - The company aims to partner with biotech firms that have strong management teams, funding, and potential for large indications [21][21] - Codexis is focused on long-term partnerships, with revenue growth expected as customers move through clinical development stages [28][28][30][30] Competitive Landscape - Codexis positions itself against established companies like Novartis and Alnylam, which have existing supply chains for their drugs [26][26] - The company believes its enzymatic process offers a faster and more cost-effective solution for scaling production compared to traditional methods [26][26] Future Developments - Codexis plans to showcase its capabilities at upcoming conferences, including the ability to produce GMP drugs at required clinical trial quantities [39][39] - The company is also exploring advancements in chiral control for molecules, which could lead to more potent and safer therapeutics [40][40][41][41] Financial Position - As of the last quarter, Codexis reported over $60 million in cash, sufficient to establish its GMP facility and support future growth [42][42] Conclusion - Codexis is well-positioned in the growing siRNA therapeutics market, with innovative solutions to address current production challenges and a strong pipeline of potential partnerships and revenue growth opportunities [43][43]