NNC0268-0965

一、已上市药物深度解析：技术突破与研究启示1.1 药品成功的要素解析1.2市场动态与竞争格局（1）依从性经济效应：诺和诺德的口服索马鲁肽（Rybelsus®）在2023年的销售额高达34.2亿美元[4]，其出色表现使得注射剂型的市占率下降了12%，这充分证明了口服剂型在市场上的强大颠覆力。口服剂型由于其使用便捷性，能显著提高患者的用药依从性，从而在市场竞争中脱颖而出。（2）技术迭代第一代（1990s）：采用粗放型酶替代技术，如胰酶肠溶片，但其生物利用度极低，小于1%。这种早期技术在药物的有效吸收和利用方面存在明显不足。第二代（2010s）：通过将肽类药物与吸收增强剂相结合，如索马鲁肽，使得生物利用度提升至0.8-1.4%。这一阶段的技术进步在一定程度上改善了药物的吸收情况。第三代（2025）：目前在研项目中，有65%采用了AI设计纳米载体以及工程菌原位表达等前沿技术[5]。这些新技术有望进一步提高药物的疗效和生物利用度。二、在研药物技术的创新与产业化挑战2.1 在研药物信息2.2技术转化的难点（1）载体工艺困境脂质体：在包裹胰岛素时，包封率小于60%，且在长期储存过程中稳定性差，6个月的泄漏率大于40%。这严重影响了药物的储存和使用效果。PLGA微粒：存在明显的突释效应，在前30分钟内释放量大于50%，同时其酸性降解产物可能引发局部炎症反应。这些问题限制了PLGA微粒在药物递送中的应用。金属有机框架（MOFs）：虽然载药量可达35%，但其细胞毒性尚未明确，例如Zr-MOFs。在应用前需要对其安全性进行深入研究。（2）跨学科协作缺口材料科学与药效学的参数冲突：以壳聚糖为例，其最佳分子量为20kDa时有利于粘附，但却会抑制细胞旁路转运。这体现了材料科学与药效学在参数选择上存在的矛盾，需要跨学科团队共同解决。GMP生产标准尚未统一：对于纳米制剂，批次间粒径差异需控制在<10%，但目前行业内GMP生产标准尚未完全统一，这给纳米制剂的大规模生产带来了困难。三、未来开发战略：技术融合与临床转化3.1 跨学科技术矩阵构建合成生物学：开发动态调控回路，如光控表达系统（Blue-Light Inducible），能够实现对药物剂量的精准调节，提高药物治疗的安全性和有效性。材料科学：研究仿生粘液穿透材料，例如在PEG化硅纳米粒表面嫁接粘蛋白抗体（Anti - MUC2），有助于药物更好地穿透肠道粘液层，提高吸收效率[10]。人工智能：利用AlphaFold-M预测蛋白-载体结合能，将ΔG≤-50kJ/mol作为优选组合的标准，从而筛选出最佳的蛋白-载体搭配，降低研发过程中的试错成本[11]。临床医学：构建患者分层模型，基于SNP分析（如GH1基因型）定制个性化给药方案，实现精准医疗。3.2风险效益平衡策略（1）短期优先项（1-3年）开发局部作用药物：例如专注于开发肠道IL-12抗体治疗克罗恩病等局部作用药物，这类药物能够规避全身暴露风险，同时满足特定疾病的治疗需求。采用GRAS级辅料：选用GRAS级辅料（如壳聚糖、柠檬酸等），可以加速IND审批进程，缩短药物研发周期。（2）长期技术储备（5+年）外泌体-纳米杂化载体：利用CD47“别吃我”信号延长循环半衰期，提高药物在体内的稳定性和有效性。器官芯片预筛选：构建肠道-肝脏共培养模型，用于预测药物的首过效应，为药物研发提供更准确的前期评估。3.3 监管科学新动向FDA举措：FDA在2024年启动了“Oral Biologics Real-World Evidence”计划，允许使用电子药丸（如 Proteus Digital Health）收集药物吸收数据，这为口服生物制剂的研发和审批提供了新的途径和数据支持。EMA要求：EMA要求口服蛋白药物需进行肠道免疫耐受性评估，以调节性T细胞占比大于5%为标准，确保药物在肠道内的安全性和耐受性[12]。四、行业竞争格局与投资热点4.1 企业技术布局分析4.2 学术机构突破性研究麻省理工学院：成功开发肠道原位合成支架，该支架由水凝胶负载tRNA-氨酰化酶构成，能够实现口服mRNA翻译。相关研究成果发表于《Nature》2023年第618卷第1026页，为口服药物的研发开辟了新的思路。洛桑联邦理工学院：基于CRISPR-dCas9技术构建工程菌动态反馈系统，能够精准调控蛋白表达量。相关研究成果发表于《Cell》2024年第187卷，为细菌载体药物的开发提供了重要技术支持。结语口服蛋白/多肽类药物正处于从传统“剂型改良”向“生物工程技术革命”的重大转移阶段。在未来5年，随着微针胶囊（如Rani公司的技术）、细菌载体（如Synlogic公司的技术）等平台技术逐渐成熟，会有越来越多的口服蛋白/多肽类药物实现商业化。然而，需要警惕技术泡沫风险，目前仅有37%的纳米递送项目能够进入II期临床。在激烈的竞争环境中，能够深度融合AI预测技术（降低研发试错成本）、精准匹配临床需求（如针对儿童患者等特定群体）、并构建坚实专利护城河（如开发新型靶向配体）的创新主体，将更有可能在这场技术变革中取得成功。参考文献[1] FDA. Bioavailability and Bioequivalence Studies for Orally Administered Drug Products: General Considerations [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2023 Mar.[2] Buckley ST, et al. Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. Sci Transl Med. 2018;10(467):eaar7047.[3] Hua S, et al. Enzyme stabilization by non-crystalline saccharide glasses. Int J Pharm. 2021;592:120045.[4] Novo Nordisk A/S. Annual Report 2023: Driving Change in Diabetes Care [Internet]. Bagsværd (Denmark); 2024 Feb [cited 2024 Jun].[5] Mitragotri S, et al. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat Rev Drug Discov. 2022;21(7):511-533.[6] Banerjee A, et al. Ionic liquid-mediated transdermal delivery of peptide drugs. Sci Adv. 2021;7(11):eabd5654.[7] Van Roy M, et al. The preclinical pharmacology of the high affinity anti-IL-6R Nanobody® ALX-0061 supports its clinical development in rheumatoid arthritis. mAbs. 2020;12(1):1783119.[8] Isabella VM, et al. Development of a synthetic live bacterial therapeutic for the human metabolic disease phenylketonuria. Cell Host Microbe. 2023;31(2):189-203.[9] Seres Therapeutics, Inc. SER-287 Phase 1b Study in Mild-to-Moderate Ulcerative Colitis [Internet]. Cambridge (MA); 2023 Jul [cited 2024 Jun].[10] Zhao Z, et al. Bioinspired mucopenetrating nanoparticles for enhanced oral insulin delivery. Adv Mater. 2023;35(18):e2211163.[11] Jumper J, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596(7873):583-589.[12] EMA. Guideline on quality requirements for drug-device combinations [Internet]. Amsterdam: European Medicines Agency; 2023 Nov [cited 2024 Jun]. EMA/CHMP/QWP/185401/2023.[13] Rani Therapeutics Holdings, Inc. Form 10-K Annual Report [Internet]. San Jose (CA): U.S. Securities and Exchange Commission; 2024 Mar [cited 2024 Jun].药事纵横投稿须知：稿费已上调，欢迎投稿

twiist™ expands compatibility offerings to become the first AID system compatible with Senseonics Eversense® 365 one-year CGM system twiist with Eversense 365 launch expected in Q3 MANCHESTER, N.H. and GERMANTOWN, Md., April 29, 2025 (GLOBE NEWSWIRE) -- Sequel Med Tech, LLC, a company developing state-of-the-art insulin delivery technologies, and Senseonics Holdings, Inc. (NYSE American: SENS), a medical technology company focused on the development and manufacturing of long-term, implantable CGM systems for people with diabetes, today announced their commercial development agreement to integrate Sequel’s twiist Automated Insulin Delivery (AID) System powered by Tidepool with Senseonics’ Eversense 365 CGM. Through this collaboration, the twiist™ AID System will become the first AID system compatible with the Senseonics Eversense 365, the world’s first and only one-year CGM system, offering people with type 1 diabetes a new level of flexibility and personalization in their diabetes management. The agreement between Sequel and Senseonics will provide individuals with type 1 diabetes the option of a one-year CGM that integrates with the twiist AID System. The integrated system aims to enhance diabetes management by offering people with diabetes more tools to manage care, which may lead to improved glucose control, increase convenience, and provide greater flexibility. “Sequel is committed to investing in innovations that empower people with diabetes with options in how they manage their diabetes,” said Sequel CEO and Co-Founder Alan Lotvin, M.D. “By partnering with Senseonics, a company pioneering long-duration CGM, we aim to deliver the flexibility people want to personalize their diabetes management on their terms.” “This collaboration with Sequel marks a significant step forward in transforming diabetes care,” said Tim Goodnow, PhD, President and CEO of Senseonics. “People with diabetes who choose the convenience and ease of our one-year CGM sensor have been waiting for a compatible AID system to enhance their diabetes management. The synergy of Eversense and twiist will provide people with diabetes our most recent innovations in advanced pump, algorithm, and sensor technologies to simplify diabetes management, providing users with an AID solution that unlocks the full experience of our year-long CGM technology.” Sequel remains committed to advancing diabetes technology and expanding partnerships to give people with diabetes more choice and flexibility in how they manage their diabetes. People living with type 1 diabetes who choose to use twiist will have the flexibility to select from two compatible CGM partners, the Senseonics Eversense 365 and Abbott’s FreeStyle Libre 3 Plus sensor, to best suit their individual needs for managing diabetes. In September 2024, Eversense 365 received FDA clearance as an integrated continuous glucose monitoring (iCGM) system for people with diabetes, paving the way for its use within an automated insulin delivery (AID) system. United by a shared commitment to simplifying diabetes management and improving quality of life, Senseonics and Sequel have begun work to integrate Senseonics’ newest generation one year sensor, Eversense 365, with twiist, Sequel’s state-of-the-art AID system. This expanded CGM compatibility between Eversense and twiist will mark a significant advancement—offering greater personalization, more choice, and the potential for improved outcomes for people living with diabetes. The integration is expected to be available in the third quarter of this year. About twiist The twiist AID System is the first insulin delivery system that directly measures the volume of insulin delivered with every micro-dose. Cleared for people ages six and up with type 1 diabetes, the twiist AID System offers the capability and flexibility to address each person’s individual dosing needs. The twiist Loop algorithm, based on the diabetes community-driven Tidepool Loop, allows the system to automatically adjust basal insulin delivery based on real-time sensor readings and predicted glucose levels. For more information about twiist, set to be commercially available in Q2 2025, please visit www.twiist.com. About Sequel Med Tech Headquartered in Manchester, N.H., Sequel Med Tech, LLC is developing the next generation of transformative drug-delivery advancements. Sequel’s approach is to look at disease management holistically to advance systems that make living with disease simpler and easier for all. Its FDA-cleared innovation, the twiist® Automated Insulin Delivery (AID) system, integrates novel technologies to reimagine insulin delivery and sets a new standard for drug delivery. Co-founded by visionary Dean Kamen, serial entrepreneur Pablo Legorreta, seasoned medical device executive Bill Doyle and healthcare visionary Alan Lotvin, MD. Sequel is bringing the latest developments in science and technology to help drive more accessible drug delivery. For more information, visit sequelmedtech.com and twiist.com. About Eversense Eversense 365 is developed by Senseonics and brought to patients by Ascensia Diabetes Care, a subsidiary of PHC Holdings Corporation (TSE: 6523). As the only implantable CGM available, it offers patients a truly differentiated CGM experience, providing One Year of exceptionally accurate monitoring with minimal interruptions. It benefits endocrinologists and care teams by offering their patients confidence in decision-making, long-term peace of mind and enhanced quality of life with just one CGM. The unique approach also allows people to overcome common frustrations and interruptions experienced with traditional, short-term CGMs, so that patients can focus on managing their diabetes and not their CGM. The Eversense® Continuous Glucose Monitoring (CGM) Systems are indicated for continually measuring glucose levels for up to 365 days for Eversense® 365 and 180 days for Eversense® E3 in persons with diabetes age 18 and older. The systems are indicated for use to replace fingerstick blood glucose (BG) measurements for diabetes treatment decisions. Fingerstick BG measurements are still required for calibration primarily one time per week after day 13 for Eversense® 365 and one time per day after day 21 for Eversense® E3, and when symptoms do not match CGM information or when taking medications of the tetracycline class. The sensor insertion and removal procedures are performed by a health care provider. The Eversense CGM Systems are prescription devices; patients should talk to their health care provider to learn more. For important safety information, see www.eversensediabetes.com/safety-info/. A media kit for Eversense 365, including images, logos and further information, can be accessed at www.ascensia.com/media/eversense365-media-kit/. About Senseonics Senseonics Holdings, Inc. (“Senseonics”) is a medical technology company focused on the development and manufacturing of glucose monitoring products designed to transform lives in the global diabetes community with differentiated, long-term implantable glucose management technology. Senseonics’ CGM system Eversense® 365 includes a small sensor inserted completely under the skin that communicates with a smart transmitter worn over the sensor. The glucose data are automatically sent every 5 minutes to a mobile app on the user’s smartphone. Forward Looking Statements Any statements in this press release about the expectations regarding potential impact on people with diabetes’ and providers’ experience, benefits and outcomes, statements regarding the results, success and timeline for completion of the integration, and other statements containing the words “believe,” “expect,” “intend,” “may,” “projects,” “will,” “planned,” and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: uncertainties inherent in the new product launch and ongoing commercialization of Eversense 365, uncertainties inherent in the coordination with third parties and new partners, uncertainties inherent in the development of new technologies, uncertainties in insurer, regulatory and administrative processes and decisions, uncertainties in prescriber and patient decisions and responses to new technology or initiatives, and such other factors as are set forth in the risk factors detailed in Senseonics’ Annual Report on Form 10-K for the year ended December 31, 2023 and subsequent quarterly reports on Form 10-Q filed with the SEC under the heading “Risk Factors.” In addition, the forward-looking statements included in this press release represent Senseonics’ views as of the date hereof. Senseonics anticipates that subsequent events and developments will cause Senseonics’ views to change. However, while Senseonics may elect to update these forward-looking statements at some point in the future, Senseonics specifically disclaims any obligation to do so except as required by law. These forward-looking statements should not be relied upon as representing Senseonics’ views as of any date subsequent to the date hereof. Sequel Media ContactGreta GustafsonHighwire PRsequel.med.tech@highwirepr.com Senseonics Investor ContactJeremy FefferLifeSci Advisorsinvestors@senseonics.com