Vosoritide

摘要：大肠杆菌凭借重组 DNA 技术成为生物制药领域的核心工具，从首个重组胰岛素的生产至今，已在激素、酶、疫苗、抗体等多个领域展现重要价值。尽管存在翻译后修饰不足和毒性等局限，但其低成本、高产量和成熟的生产体系使其仍是首选宿主。本文系统梳理了大肠杆菌生产的各类生物药物，包括已获批的激素、酶、肽类、疫苗及融合蛋白等，并探讨其临床应用、优势与未来发展方向，展现其在生物制药产业中的关键地位与潜力。一、引言大肠杆菌在重组 DNA 技术的推动下，成为生物制药的重要宿主。自 1980 年代首个重组胰岛素获批以来，其凭借快速生长、低成本和高产量等优势，广泛应用于多种生物药物生产。尽管面临复杂蛋白折叠困难和缺乏糖基化修饰等挑战，但其在激素、酶、疫苗等领域的成果显著，已成为全球生物制药产业的基石之一（参考图 1: General method for producing recombinant biopharmaceuticals in Escherichia coli，了解大肠杆菌生产重组生物药物的通用流程）。二、大肠杆菌生产的生物药物类型2.1激素类药物大肠杆菌是生产重组激素的主力，涵盖胰岛素、生长激素、干扰素等。例如，首个重组人胰岛素Humulin由礼来公司开发，1982 年获 FDA 批准，彻底改变糖尿病治疗模式。随后，长效胰岛素类似物Lantus、生长激素Sogroya等相继问世，显著提升患者生活质量（表1: Approved recombinant hormones produced in Escherichia coli and their mechanism of action列出了主要激素药物及其作用机制）。干扰素 α-2b（Intron A）则用于肝炎、癌症治疗，其改良型Besremi对真性红细胞增多症疗效显著。2.2酶类药物酶类药物在代谢疾病和癌症治疗中至关重要。Krystexxa（聚乙二醇化尿酸酶）用于慢性痛风，通过降解尿酸缓解症状；Voraxaze（葡糖羧肽酶）可快速清除化疗药物甲氨蝶呤，降低肾损伤风险；Asparlas（聚乙二醇天冬酰胺酶）则用于白血病治疗，延长患者生存期（表2: Approved recombinant enzymes produced in Escherichia coli and their mechanism of action详细展示了相关酶类药物）。2.3肽类药物肽类药物在心血管和代谢疾病中应用广泛。Natrecor（奈西立肽）用于急性心力衰竭，通过扩张血管改善症状；Voxzogo（vosoritide）针对软骨发育不全，通过调节信号通路促进骨骼生长；Oxervate（神经生长因子）则用于治疗神经萎缩性角膜炎，修复角膜损伤（表3: Approved recombinant peptides produced in Escherichia coli and their mechanism of action列举了代表性肽类药物）。2.4疫苗类药物大肠杆菌在疫苗生产中表现突出，尤其在病毒样颗粒（VLP）疫苗领域。Hecolin是首个基于大肠杆菌的戊肝疫苗，在中国获批上市；Cecolin（HPV 疫苗）有效预防生殖器病变；兽用疫苗如Strangvac（马链球菌疫苗）和Leucogen（猫白血病疫苗）也展现重要价值（表4: Approved recombinant vaccines produced in Escherichia coli总结了人用及兽用疫苗）。2.5融合蛋白与抗体片段融合蛋白和抗体片段是癌症与免疫疾病的关键疗法。Lucentis（雷珠单抗）靶向 VEGF，用于湿性黄斑变性；Kimmtrak（ Tebentafusp）通过双特异性结合 T 细胞和肿瘤抗原，治疗转移性葡萄膜黑色素瘤；Cimzia（ certolizumab pegol）作为 TNF-α 抑制剂，有效缓解类风湿关节炎（表5: Approved recombinant antibodies and fusion proteins produced in Escherichia coli列出了主要抗体及融合蛋白药物）。2.6其他生物药物包括粒细胞集落刺激因子Neupogen（治疗中性粒细胞减少症）、瘦素类似物Myalept（治疗脂肪营养不良）等，均通过大肠杆菌生产，满足罕见病和免疫疾病治疗需求。三、大肠杆菌的优势与挑战优势：遗传背景清晰：便于基因操作和表达系统优化，如利用已知的克隆技术和表达载体高效生产目标蛋白。生产成本低：培养基简单（仅需基础营养物质），适合大规模发酵，例如 mRNA 新冠疫苗的低成本生产模式可复制至其他生物药。生产周期短：生长繁殖速度快，可在短时间内实现蛋白大量表达，如重组胰岛素从基因设计到生产仅需数周。挑战：翻译后修饰局限：无法进行复杂糖基化、二硫键形成等修饰，影响部分蛋白（如全长单克隆抗体）的功能，需依赖哺乳动物细胞补位（参考表5中部分抗体需哺乳动物细胞生产的限制）。内毒素风险：细胞壁成分可能引发免疫反应，需额外纯化工艺去除内毒素，增加生产成本（如疫苗生产中的严格纯化流程）。蛋白折叠问题：复杂蛋白易形成包涵体，需优化表达条件或采用共表达伴侣蛋白辅助折叠（如图1中纯化步骤的重要性）。四、未来发展方向技术优化：通过基因工程改造大肠杆菌，引入糖基化通路或共表达折叠辅助因子，提升复杂蛋白生产能力。例如，利用合成生物学技术构建 “设计型” 大肠杆菌，实现更接近天然蛋白的修饰。联合疗法拓展：大肠杆菌生产的疫苗与免疫检查点抑制剂（ICIs）联用，如mRNA 肿瘤疫苗 + PD-1 单抗的协同效应，已在黑色素瘤等适应症中展现潜力（参考前文KEYNOTE-942 研究数据）。兽用与罕见病药物：针对动物传染病（如马链球菌疫苗Strangvac）和罕见病（如脂肪营养不良药物Myalept），开发高性价比的大肠杆菌生产药物，填补市场空白。可持续生产：探索无血清培养基和连续生产工艺，降低环境负担，符合绿色制药趋势。五、结论大肠杆菌凭借低成本、高可及性和成熟的工业化体系，在生物制药领域占据不可替代的地位。尽管面临修饰能力有限等挑战，但其在激素、酶、疫苗等领域的成功案例（如表1-5中多款 FDA/EMA 批准药物）及技术优化潜力，使其持续成为创新药物开发的核心平台。未来，随着合成生物学和联合疗法的突破，大肠杆菌将进一步推动生物制药向高效、经济、普惠方向发展。识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！请注明：姓名+研究方向！本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

New data in children under 5 years with achondroplasia showed treatment with VOXZOGO was associated with improvement in tibial bowing, a common cause of pain and impaired function Data from the largest retrospective, multi-year observational study of more than 600 children and adults with hypochondroplasia found significantly higher rates of comorbidities, surgeries and overall doctor visits SAN RAFAEL, Calif., May 12, 2025 /PRNewswire/ -- BioMarin Pharmaceutical Inc. (Nasdaq: BMRN) today announced new data from studies of VOXZOGO® (vosoritide), demonstrating meaningful impact on tibial bowing in children with achondroplasia and investigational early efficacy results in other skeletal conditions. The data were presented at the 2025 Joint Congress of the European Society for Paediatric Endocrinology (ESPE) and the European Society of Endocrinology (ESE) in Copenhagen, Denmark and will be shared at the Pediatric Endocrine Society Annual Meeting (PES) in National Harbor, Maryland. VOXZOGO Demonstrated Positive Impact on Tibial Bowing An analysis of data presented at PES from the VOXZOGO Phase 2 CANOPY clinical studies in younger children assessed the impact of treatment on tibial bowing, an orthopedic complication and significant cause of pain in children with achondroplasia. Children who received VOXZOGO had a significant reduction in the magnitude of tibial bowing compared to children who received placebo. Furthermore, the researchers found that this improvement was sustained in children who received treatment for several years. "Outcomes beyond height have long been prioritized by the dwarfism community," said Michael Hughes, Chair, Little People of America's (LPA) Biotech Industry Liaison Committee. "Tibial bowing can be a source of pain and surgical intervention for some children with achondroplasia, and this research reflects an encouraging shift toward addressing a meaningful outcome to the community." "In children with achondroplasia, tibial bowing can be painful and often requires surgical intervention," said Klane White, M.D., pediatric orthopedic surgeon and Rose Brown Endowed Chair of Pediatric Orthopedics at Children's Hospital Colorado. "Through my clinical practice, I have observed meaningful improvements that early treatment initiation with VOXZOGO has offered children with achondroplasia, including in proportionality, quality of life and now tibial bowing, which have the potential to improve physical well-being for these children into adulthood." The latest results from the VOXZOGO Phase 3 clinical trial reporting the longest follow-up to date demonstrated that continuous and early treatment was associated with sustained increases in annualized growth velocity (AGV). For the first time, it was possible to model potential final height gain for children with achondroplasia if they were treated early and continuously from 6 months until final adult height (FAH). Modeling indicated that VOXZOGO treatment could result in a height increase of 21.7 centimeters (cm) (95% Cl, 18.7-24.6) in girls and 26.4 cm (95% Cl, 22.9-29.8) in boys compared to untreated children. These data were presented today at ESPE as an oral presentation and add to the totality of evidence demonstrating that early and continuous treatment with VOXZOGO maximizes clinical benefits for children with achondroplasia. Hypochondroplasia Associated with Significant Increase in Comorbidities Researchers also presented data shedding light on the comorbidities associated with hypochondroplasia, a genetically defined form of skeletal dysplasia for which VOXZOGO is currently being evaluated in clinical trials. In more than 600 adults and children with hypochondroplasia who were studied using real-world electronic health primary care medical record data in England, comorbidity event rates were more common compared to people without hypochondroplasia. The condition was also associated with an increase in doctor visits, surgeries and orthopedic interventions. "This research is critical to shaping a deeper understanding of hypochondroplasia and underscores the importance of early diagnosis, which allows physicians to begin working with children and their families as soon as possible," said Greg Friberg, M.D., Executive Vice President and Chief Research & Development Officer at BioMarin. "We remain committed to developing new options for skeletal conditions, such as hypochondroplasia and Turner syndrome, and these early data continue to inform our clinical trials." In a prospective, single-center Phase 2 open-label clinical study in girls with Turner syndrome, researchers found that treatment with VOXZOGO was associated with a promising increase in AGV at 6 months compared to their baseline AGV. Importantly, AGV was increased even in children who were previously treated with human growth hormone and discontinued due to suboptimal results prior to enrollment in this study. VOXZOGO was also well-tolerated with safety results consistent with its known profile in achondroplasia. BioMarin continues to advance development across its CANOPY clinical program for VOXZOGO in hypochondroplasia, idiopathic short stature, Noonan syndrome, Turner syndrome and SHOX deficiency. In April, BioMarin completed enrollment in its pivotal Phase 3 study with VOXZOGO in hypochondroplasia, and the company is on track to share topline data in 2026, with potential launch in 2027. Below are key presentations for BioMarin and VOXZOGO at both meetings: ESPE and ESE Design of a Phase 2, Randomized, Controlled, Multicentre Study of Vosoritide Treatment in Children with Idiopathic Short Stature ePoster P647 Saturday, May 10 Design of a Randomized, Multicentre, Phase 2 Study of Vosoritide in Children with Turner Syndrome, Noonan Syndrome, or Short Stature Homeobox-Containing Gene (SHOX) Deficiency ePoster EP840 Saturday, May 10 The Medical Impact of Hypochondroplasia Among Children in England Between 1998 and 2019: A Matched Cohort Study Using Electronic Medical Records from the Clinical Practice Research Datalink ePoster P617 Saturday, May 10 The Medical Impact of Hypochondroplasia by Age Among Adults in England between 1998 and 2019: A Matched Cohort Study Using Electronic Medical Records from the Clinical Practice Research Datalink ePoster P603 Saturday, May 10 The Achondroplasia Roadmap ePoster EP202 Saturday, May 10 Long-Term Height Gain and Maintenance of Treatment Effect in Children with Achondroplasia Receiving Vosoritide Oral Presentation OC7.4 Monday, May 12, 3:05 – 3:15 p.m. Central European Summer Time (CEST) PES (all times in Eastern Daylight Time [EDT]) IGF-1 Values in Hypochondroplasia and Effects of Vosoritide Poster P9 Thursday, May 15, 6:30 – 8:30 p.m. Medical Impact of Hypochondroplasia Among Children and Adults in England: A 22-Year Retrospective Study Poster P42 Friday, May 16, 12:00 – 12:30 p.m. Vosoritide Improves Tibial Bowing in Infants and Toddlers with Achondroplasia Poster P28 Friday, May 16, 12:00 – 12:30 p.m. Preliminary Assessment of Vosoritide for Short Stature in Turner Syndrome: 6-Month Data from a Clinical Trial Poster P39 Saturday, May 17, 12:45 – 2:30 p.m. About Achondroplasia Achondroplasia, the most common form of skeletal dysplasia, is characterized by impaired bone growth caused by a change in the FGFR3 gene. Bone growth is regulated by multiple biological processes including signaling pathways through fibroblast growth factor (FGF, which slows bone growth) and C-type natriuretic peptide (CNP, which increases bone growth). In achondroplasia, these signals are out of balance, resulting in a slowing of endochondral ossification, and causing disproportionate short stature and disordered architecture in the long bones, spine, face and base of the skull. More than 80% of children with achondroplasia have parents of average stature and have the condition as a result of a spontaneous gene mutation. The worldwide incidence rate of achondroplasia is about one in 25,000 live births. VOXZOGO is being evaluated in children whose growth plates are still "open," typically those under 18 years of age. Approximately 25% of people with achondroplasia fall into this category. About VOXZOGO In children with achondroplasia, endochondral bone growth, an essential process by which bone tissue is created, is negatively regulated due to a gain of function mutation in FGFR3. VOXZOGO, a C-type natriuretic peptide (CNP) analog, acts as a positive regulator of the signaling pathway downstream of FGFR3 to promote endochondral bone growth. VOXZOGO is approved in the U.S., Japan and Australia to increase linear growth in children of all ages with achondroplasia with open epiphyses, and VOXZOGO is indicated in the EU for the treatment of achondroplasia in children 4 months of age and older whose epiphyses are not closed, as confirmed by appropriate genetic testing. In the U.S., this indication is approved under accelerated approval based on an improvement in annualized growth velocity. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trial(s). To fulfill this post-marketing requirement, BioMarin intends to use the ongoing open-label extension studies compared to available natural history. Patient Support Accessing VOXZOGO To reach a BioMarin RareConnections® Case Manager, please call, toll-free, 1-833-VOXZOGO (1-833-869-9646) or e-mail VOXZOGOSupport@biomarin-rareconnections.com. For more information about VOXZOGO, please visit www.voxzogo.com. For additional information regarding this product, please contact BioMarin Medical Information at medinfo@bmrn.com. VOXZOGO U.S. Important Safety Information What is VOXZOGO used for? VOXZOGO is a prescription medicine used to increase linear growth in children with achondroplasia and open growth plates (epiphyses). VOXZOGO is approved under accelerated approval based on an improvement in annualized growth velocity. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials. What is the most important safety information about VOXZOGO? VOXZOGO may cause serious side effects including a temporary decrease in blood pressure in some patients. To reduce the risk of a decrease in blood pressure and associated symptoms (dizziness, feeling tired, or nausea), patients should eat a meal and drink 8 to 10 ounces of fluid within 1 hour before receiving VOXZOGO. What are the most common side effects of VOXZOGO? The most common side effects of VOXZOGO include injection site reactions (including redness, itching, swelling, bruising, rash, hives, and injection site pain), high levels of blood alkaline phosphatase shown in blood tests, vomiting, joint pain, decreased blood pressure, and stomachache. These are not all the possible side effects of VOXZOGO. Ask your healthcare provider for medical advice about side effects, and about any side effects that bother the patient or that do not go away. How is VOXZOGO taken? VOXZOGO is taken daily as an injection given under the skin, administered by a caregiver after a healthcare provider determines the caregiver is able to administer VOXZOGO. Do not try to inject VOXZOGO until you have been shown the right way by your healthcare provider. VOXZOGO is supplied with Instructions for Use that describe the steps for preparing, injecting, and disposing VOXZOGO. Caregivers should review the Instructions for Use for guidance and any time they receive a refill of VOXZOGO in case any changes have been made. Inject VOXZOGO 1 time every day, at about the same time each day. If a dose of VOXZOGO is missed, it can be given within 12 hours from the missed dose. After 12 hours, skip the missed dose and administer the next daily dose as usual. The dose of VOXZOGO is based on body weight. Your healthcare provider will adjust the dose based on changes in weight following regular check-ups. Your healthcare provider will monitor the patient's growth and tell you when to stop taking VOXZOGO if they determine the patient is no longer able to grow. Stop administering VOXZOGO if instructed by your healthcare provider. What should you tell the doctor before or during taking VOXZOGO? Tell your doctor about all of the patient's medical conditions includingIf the patient has heart disease (cardiac or vascular disease), or if the patient is on blood pressure medicine (anti-hypertensive medicine). If the patient has kidney problems or renal impairment. If the patient is pregnant or plans to become pregnant. It is not known if VOXZOGO will harm the unborn baby. If the patient is breastfeeding or plans to breastfeed. It is not known if VOXZOGO passes into breast milk. Tell your doctor about all of the medicines the patient takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements. If the patient has heart disease (cardiac or vascular disease), or if the patient is on blood pressure medicine (anti-hypertensive medicine). If the patient has kidney problems or renal impairment. If the patient is pregnant or plans to become pregnant. It is not known if VOXZOGO will harm the unborn baby. If the patient is breastfeeding or plans to breastfeed. It is not known if VOXZOGO passes into breast milk. You may report side effects to BioMarin at 1-866-906-6100. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. Please see additional safety information in the full Prescribing Information and Patient Information. About BioMarin BioMarin is a global biotechnology company dedicated to translating the promise of genetic discovery into medicines that make a profound impact on the life of each patient. The San Rafael, California-based company, founded in 1997, has a proven track record of innovation with eight commercial therapies and a strong clinical and preclinical pipeline. Using a distinctive approach to drug discovery and development, BioMarin seeks to unleash the full potential of genetic science by pursuing category-defining medicines that offer new possibilities for people living with genetically defined conditions around the world. To learn more, please visit www.biomarin.com. Forward-Looking Statements This press release contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc. (BioMarin), including without limitation, statements about: data presented at the 2025 Joint Congress of the European Society for Paediatric Endocrinology (ESPE) and the European Society of Endocrinology (ESE) and data to be shared at the Pediatric Endocrine Society Annual Meeting (PES), including the oral and poster presentations; VOXZOGO's efficacy, safety and impact on children with achondroplasia, including the potential benefits of early treatment with VOXZOGO on height increase, proportionality, quality of life and tibial bowing and potential to improve physical well-being for children into adulthood; VOXZOGO's potential benefits, safety and impact on children with hypochondroplasia and Turner syndrome, including potential increase in annualized growth velocity (AGV); BioMarin's commitment to develop new options for skeletal conditions; and BioMarin's CANOPY clinical development program for achondroplasia, hypochondroplasia, idiopathic short stature, Noonan syndrome, Turner syndrome and SHOX deficiency, including BioMarin's plans and expectations to share topline data for its pivotal Phase 3 study with VOXZOGO in hypochondroplasia in 2026, with potential launch in 2027. These forward-looking statements are predictions and involve risks and uncertainties such that actual results may differ materially from these statements. These risks and uncertainties include, among others: results and timing of current and planned pre-clinical studies and clinical trials of VOXZOGO; any potential adverse events observed in the continuing monitoring of the patients in the clinical trials; the content and timing of decisions by the U.S. Food and Drug Administration, the European Medicines Agency, the European Commission and other regulatory authorities; and those factors detailed in BioMarin's filings with the Securities and Exchange Commission, including, without limitation, the factors contained under the caption "Risk Factors" in BioMarin's Quarterly Report on Form 10-Q for the quarter ended March 31, 2025, as such factors may be updated by any subsequent reports. Stockholders are urged not to place undue reliance on forward-looking statements, which speak only as of the date hereof. BioMarin is under no obligation, and expressly disclaims any obligation to update or alter any forward-looking statement, whether as a result of new information, future events or otherwise. BioMarin®, BioMarin RareConnections® and VOXZOGO® are registered trademarks of BioMarin Pharmaceutical Inc. Contacts: Investors Media Traci McCarty Andrew Villani BioMarin Pharmaceutical Inc. BioMarin Pharmaceutical Inc. (415) 455-7558 (628) 269-7393 View original content to download multimedia:https://www.prnewswire.com/news-releases/biomarin-presents-new-data-for-voxzogo-vosoritide-in-children-with-achondroplasia-and-other-skeletal-conditions-at-two-international-endocrinology-meetings-302451485.html SOURCE BioMarin Pharmaceutical Inc.