Forazapadin

编者按：9月是肌营养不良公共意识月（Muscular Dystrophy Awareness Month），杜氏肌营养不良症（DMD）的治疗不仅是一场医药攻坚战，也折射出寡核苷酸等创新疗法的技术演进。吗啉代反义寡核苷酸（PMO）是治疗DMD的重要模式，相关偶联技术，如多肽-PMO偶联物（PPMO）、抗体-寡核苷酸偶联物（AOC）的发展正在进一步突破递送瓶颈。为满足行业日益增长的研发需求，药明康德旗下WuXi TIDES平台为包括PMO、PPMO在内的各类寡核苷酸疗法提供从药物发现到商业化生产的一体化CRDMO服务，助力全球合作伙伴加速将创新疗法带给患者。 肌肉，是核酸药物难以抵达的组织之一。DMD在这一问题上极具代表性，正在成为新一代递送技术聚焦的关键疾病之一，多家公司把DMD项目作为其技术平台应用的首发管线。而跨越DMD壁垒后，这些疗法也能为其他神经肌肉疾病、心血管代谢性疾病等患者带来曙光。 DMD是一种致命的罕见肌肉萎缩疾病，由编码抗肌萎缩蛋白（dystrophin）的基因发生变异而引起。全球每年新增确诊DMD患儿约2万名，患者预期寿命很少超过40岁。 目前已经有8款DMD疗法获得美国FDA批准，其中5款针对DMD的根本病因，包括采用PMO技术的4款疗法。然而，PMO向骨骼肌和心肌组织的递送仍然有限[1]，这推动了研发策略的更新。根据公开资料，当下全球约有50款临床在研DMD候选疗法，其中约1/4为寡核苷酸疗法。以环状多肽为载体的新一代PPMO，以及AOC，正凭借亮眼的临床数据带来希冀。 PPMO再升级 当前获批多款DMD疗法为PMO。PMO是一类基于天然RNA框架而重构的分子，其碱基与吗啉环通过磷酰二胺键相连接，而非天然RNA中的核糖环与磷酸二酯键。这让PMO能与特定mRNA前体结合，且在生物体内不易被降解。在DMD中，PMO通过结合编码抗肌萎缩蛋白的mRNA前体，改变剪接过程，跳过突变的外显子，从而生成具有大部分功能的截短抗肌萎缩蛋白。 然而，PMO面临不易被肌肉细胞吸收、内体逃逸效率有限的局限。将PMO与细胞穿透肽（CPP）偶联的PPMO应运而生。CPP能拉着载荷穿透细胞膜，提升药物的组织渗透率。但传统PPMO多采用线性CPP，其阳离子特性较强，容易在肾脏中蓄积并引发安全性挑战。 环状肽为PPMO带来了新的可能。Entrada Therapeutics探索的正是这一路径。该公司开发了一种基于环状细胞穿透肽的内体逃逸载体（EEV）递送平台，EEV的环状结构确保了其刚性和稳定性，能够绕过细胞的天然清除系统，直达致病靶点释放药物[2]。EEV已在临床前模型中显示可改善PMO向骨骼肌和心肌的递送，且现有临床数据显示肾功能安全性良好。 今年5月，Entrada Therapeutics公布ENTR-601-44在DMD患者中的1/2期临床研究ELEVATE-44-201首个队列结果。该药物是针对外显子44跳跃的在研EEV-PMO，研究观察到良好的安全耐受性，接受治疗的患者肾功能指标均在正常范围内，抗肌萎缩蛋白水平在4.00%的基线水平上增加了2.36个百分点，“起身速率”这一功能性指标显著改善[3]。同样基于EEV-PMO技术，ENTR-601-45针对外显子45跳跃，第一组患者已在今年6月进入2期研究阶段[4-5]，另有两款候选药物也在临床前阶段展现潜力[2]。 AOC新路径下，两款疗法冲刺上市 实现PMO组织选择性递送的另一个策略，是将其与识别特定受体的抗体偶联，形成AOC。 在DMD领域，Avidity Biosciences（已被诺华收购）与Dyne Therapeutics等公司近期取得突破，两家公司均采用靶向转铁蛋白受体1（TfR1）的抗体或抗体结合片段来递送PMO。临床数据显示，抗体偶联策略显著提升了肌肉中抗肌萎缩蛋白的表达水平，相较非偶联反义寡核苷酸（ASO）呈现数量级提升。 今年第二季度，诺华已向美国FDA递交delpacibart zotadirsen（del-zota）的生物制品许可申请（BLA），以寻求加速批准用于适合外显子44跳跃治疗的DMD患者[6]。在1/2期临床试验EXPLORE44和开放标签扩展研究EXPLORE44-OLE中，DMD患者在1年治疗期间，关键功能指标相比疾病自然史数据有所改善，Del-zota总体安全可耐受[7]。 今年7月，Dyne Therapeutics宣布美国FDA已受理z-rostudirsen的BLA，用于适合接受外显子51跳跃治疗的DMD患者[8]。此次BLA主要基于1/2期DELIVER试验注册扩展队列的数据，DMD患者接受治疗6个月后，经校正的抗肌萎缩蛋白平均表达水平达到正常水平的5.46%，约为基线7倍。研究还在多项功能终点中观察到改善信号，以及良好的安全耐受性。 图片来源：123RF 偶联时代的寡核苷酸疗法研发挑战 在以DMD治疗为代表的mRNA前体剪接调控、外显子跳跃新药策略中，无论是搭载环状多肽的新型PPMO，还是AOC，核心载荷依然是PMO。PMO相关疗法的开发需要极复杂的工艺技术，其独特的骨架意味着难以直接平移常规核酸合成工艺，合成效率极具挑战。此外，伴随着偶联和高度修饰带来的化学复杂性，杂质谱也变得更加难以预测[9]。“高质量、公斤级”的PMO及其偶联物规模化生产于产业而言相对稀缺。 从序列设计到开发生产的一体化能力对于提升研发效率与成功率至关重要。扎根化学领域20余年，药明康德的深厚积淀也为开发新一代PMO等寡核苷酸疗法构筑了系统能力，旗下WuXi TIDES平台专注于为全球合作伙伴提供寡核苷酸、多肽药物及相关化学偶联物（“TIDES”药物）的一体化、端到端的CRDMO服务。 WuXi TIDES平台可支持寡核苷酸与多肽、脂质、小分子、毒素等组件的偶联，依托覆盖PMO单体、PMO、多肽、PPMO偶联至制剂开发的全链条整合技术能力，打造出业内稀缺的真正一站式PMO/PPMO开发平台。WuXi TIDES的高负载固相PMO合成工艺可实现50%以上的产率、75%以上的粗纯度和高于90%的最终产品纯度，且可支持大规模生产。 WuXi TIDES目前有超过10个研发和生产基地，多个基地可同时提供寡核苷酸和多肽的相关服务，为全球合作伙伴提供灵活的选择。与此同时，这样的能力和布局尤为适合寡核苷酸和多肽偶联物的开发和生产，尤其是PPMO。例如，常州基地集中了PMO、多肽与PPMO从临床前到商业化阶段的原料药工艺开发和生产服务能力，便于高效进行技术和物料衔接，降低风险，为合作伙伴加速项目进程。截至2026年上半年，WuXi TIDES团队正在赋能全球超20个PMO/PPMO管线开发。 多类疗法丰富治疗蓝图 除了偶联递送PMO，其他多类疗法今年在DMD领域也多有令人鼓舞的进展。 有的公司对寡核苷酸进行不同的骨架修饰以改善递送。Wave Life Sciences旗下ASO疗法WVE-N531采用包括磷酰胍（PN）在内的骨架化学修饰，针对外显子53跳跃治疗。WVE-N531已在2期临床试验中获得积极结果[10]。 在细胞和基因疗法领域，Capricor Therapeutics计划以上肢功能改善作为核心证据，继续与美国FDA沟通细胞疗法deramiocel的获批前景[11]；REGENXBIO的在研基因疗法RGX-202在关键性3期研究中取得积极结果，第12周时，93%的参与者达到>10%的微抗肌萎缩蛋白表达水平[12]；Genethon的候选基因疗法GNT0004治疗DMD的2年长期疗效结果积极，多个指标上的临床疗效持续维持，安全性良好[13]。 也有研究者尝试不依赖抗肌萎缩蛋白的治疗路径。Satellos Bioscience正在开发的新型口服小分子SAT-3247靶向AAK1蛋白以促进骨骼肌再生，AAK1是人体肌肉修复和再生的关键因子，在DMD中存在功能紊乱。今年7月公布的早期临床研究TRAILHEAD数据显示，在4名21~28岁成人患者中，观察到SAT-3247治疗后肌肉脂肪分数降低、总用力增加、肌力稳定、肌酸激酶水平降低，以及与此前数据一致的安全耐受性特征[14]。 对于DMD患者而言，这些复杂的创新疗法设计，最终都指向同一个目标——让失去力量的肌肉，保留多一些功能，让被疾病压缩的人生，留下多一些可能。随着治疗的边界被一次次拓宽，更多创新疗法有望改写DMD患者的命运。而今天为DMD所寻找的答案，也可能成为明天通向更多疾病解法的道路。药明康德也将持续强化在寡核苷酸等新分子领域的平台能力，助力全球合作伙伴加速创新疗法的开发，共同推动DMD及更多治疗领域的突破性进展。 How Next‑Generation Conjugation Is Reshaping DMD Oligonucleotide Therapies September is Muscular Dystrophy Awareness Month. The treatment of Duchenne muscular dystrophy (DMD) illustrates both the urgent need for effective therapies and the evolving technologies behind oligonucleotide drug development. Phosphorodiamidate morpholino oligomers (PMOs) are a key modality for DMD, and conjugated therapies such as peptide-conjugated PMOs (PPMOs) and antibody–oligonucleotide conjugates (AOCs) have improved the delivery of PMOs to muscle tissue in recent studies. To meet rising industry demand, WuXi TIDES offers integrated CRDMO services from discovery through development to commercial manufacturing for oligonucleotide therapeutics, including PMOs and PPMOs, helping clients accelerate the development of innovative therapies and bring them to patients. Muscle is relatively difficult to target with nucleic acid drugs. DMD exemplifies this challenge and has become an important focus of research into new delivery technologies. Several companies have chosen DMD as the lead indication for their delivery platforms, and successful muscle delivery platforms could be adapted for other neuromuscular and cardiac indications. DMD is a rare muscle-wasting disease caused by mutations in the gene encoding dystrophin. About 20,000 new DMD diagnoses occur worldwide each year, and most patients do not live beyond their 40s. To date, eight DMD therapies have been approved by the U.S. FDA, five of which target the underlying genetic defect, and these include four therapies based on PMO technology. Still, PMO delivery to skeletal and cardiac muscle remains limited, which has driven new development strategies. Publicly available data show roughly 50 clinical-stage DMD candidates globally, with about one-quarter based on oligonucleotides. Next-generation cyclic-peptide PPMOs and AOCs are generating promising clinical data. PPMOs Advance Through Cyclic Peptide Designs Several currently approved DMD therapies are based on PMOs. PMOs are synthetic molecules based on an RNA framework. Their bases are linked to morpholine rings via phosphorodiamidate bonds rather than the ribose–phosphate bonds of natural RNA. This structure enables PMOs to bind target pre-mRNA and resist degradation in vivo. In DMD, PMOs bind dystrophin pre-mRNA to skip mutated exons and modify splicing, producing truncated dystrophin proteins that retain partial function. PMOs nonetheless have poor uptake into muscle cells and limited endosomal escape. Peptide-conjugated PMOs (PPMOs) were developed to address these delivery challenges. Cell-penetrating peptides (CPPs) can carry cargo across membranes and increase tissue penetration. However, many early PPMOs used linear CPPs with strong cationic properties, which can promote renal accumulation and raise safety concerns. Cyclic peptides offer a new route. Entrada Therapeutics is pursuing this approach. The company has developed a cyclic CPP-based endosomal escape vehicle (EEV) delivery platform. The EEV’s cyclic structure ensures rigidity and stability and helps it evade cellular clearance to reach disease-causing targets. In preclinical models, EEV improved PMO delivery to skeletal and cardiac muscle, and early clinical data indicate an acceptable renal safety profile. In May 2026, Entrada announced topline results from cohort 1 of the DMD patients treated with ENTR-601-44 in the Phase 1/2 ELEVATE-44-201 study. ENTR-601-44 is an EEV‑PPMO designed for exon 44 skipping. The trial showed favorable safety and tolerability, and the renal function in treated patients remained within normal limits. Treated participants showed a 2.36% increase in dystrophin levels over a 4% baseline expression. The functional measure time to rise velocity also improved versus placebo. ENTR-601-45, an EEV‑PMO designed to induce exon 45 skipping, entered Phase 2 in June, and two additional candidates are progressing in preclinical studies. AOCs Chart a New Path, with Two Therapies Now Under FDA Review Another strategy to achieve tissue‑selective delivery of PMOs is to conjugate them to antibodies that recognize specific receptors, forming AOCs. In DMD, Avidity Biosciences and Dyne Therapeutics have recently made notable progress. Both companies use antibodies targeting transferrin receptor 1 (TfR1) to deliver PMOs into muscle. Clinical data showed marked increases in muscle dystrophin when treated by AOC versus unconjugated PMOs. In Q2 2026, Avidity submitted a Biologics License Application (BLA) to the U.S. FDA for delpacibart zotadirsen (del‑zota), seeking accelerated approval for DMD patients amenable to exon 44 skipping. In the Phase 1/2 EXPLORE44 study and its open-label extension, del-zota treatment was associated with improvements in key functional outcomes compared to natural history data, and del-zota demonstrated an acceptable safety and tolerability profile. In July 2026, the U.S. FDA accepted Dyne’s BLA for z‑rostudirsen for patients eligible for exon 51 skipping. The BLA is primarily supported by data from the registrational expansion cohort of the Phase 1/2 DELIVER trial. After six months of treatment, the adjusted mean dystrophin expression reached 5.46% of normal levels, a 7-fold increase from baseline. Signals of improvement across multiple functional endpoints were also observed, along with favorable safety and tolerability. Image source: 123RF An Integrated Platform for Conjugated Oligonucleotides Exon skipping strategies typically use PMO backbones, delivered via PPMOs or AOCs. Developing PMO-based therapies demands highly complex processes because the PMO backbone does not map directly to standard oligonucleotide synthesis methods, posing significant challenges for synthetic efficiency. Moreover, the added chemical complexity of conjugation and extensive modifications makes impurity profiles harder to predict. Kilogram scale, regulatory grade PMO and conjugate manufacturing capacity remains limited across the industry. Integrated capabilities from sequence design through development and manufacturing are critical to improving R&D efficiency and success rates. Building on two decades of experience in chemistry, WuXi AppTec has established systematic capabilities for the development of next‑generation PMOs and other oligonucleotide therapies. The WuXi TIDES platform focuses on providing integrated, end‑to‑end CRDMO services for oligonucleotides, peptides, and related synthetic conjugated drugs. WuXi TIDES supports conjugation of oligonucleotides to peptides, lipids, small molecules and toxins. With fully integrated capabilities from PMO monomers, PMOs, and peptides to PPMO conjugation and formulation development, WuXi TIDES delivers a truly one-stop PMO/PPMO development platform that is rarely available in the industry. WuXi TIDES’s high‑loading solid‑phase PMO synthesis process can achieve yields of more than 50%, crude purity above 75%, and final product purity exceeding 90%, while supporting large‑scale manufacturing.  The WuXi TIDES team currently operates more than 10 R&D and manufacturing sites. Multiple sites can simultaneously provide both oligonucleotide and peptide services, offering global partners flexible options. This footprint and capability are particularly well-suited for the development and manufacturing of oligonucleotide‑peptide conjugates, especially PPMOs. For example, the Changzhou site houses capabilities in PMO, peptide, and PPMO drug substance process development and manufacturing from preclinical through commercial stages, facilitating efficient process and material handoffs and accelerating projects for partners. As of H1 2026, the WuXi TIDES team is supporting development of more than 20 PMO/PPMO molecules. A Broader Therapeutic Landscape Beyond conjugated PMOs, a range of other approaches delivered encouraging DMD updates this year. Some companies modify the oligonucleotide backbone to improve delivery. Wave Life Sciences’ ASO WVE‑N531 incorporates phosphoryl guanidine (PN) backbone chemistry and is designed to induce exon 53 skipping. The company has reported positive Phase 2 results. In the field of cell and gene therapy, Capricor Therapeutics is continuing discussions with the FDA regarding the potential approval of deramiocel, with improvements in upper-limb function serving as key supporting evidence. REGENXBIO’s gene therapy RGX‑202 produced positive results in a Phase 3 study, with 93% of participants reaching >10% microdystrophin expression at week 12; and Genethon reported positive two‑year durability data for its candidate GNT0004, with sustained clinical signals and an acceptable safety profile. Non-dystrophin-based strategies are also being pursued. Satellos Bioscience is developing the oral small molecule SAT‑3247, an AAK1 inhibitor designed to promote skeletal muscle regeneration. AAK1 is implicated in muscle repair and is dysregulated in DMD. Early study data in four adults (ages 21–28) showed reduced muscle fat fraction, increased effort, stable strength, lower creatine kinase and a favorable safety profile. Collectively, these approaches for DMD share a single aim: preserve more muscle function and expand life’s possibilities. As therapeutic boundaries shift, more innovations may change the course of DMD and open paths for other diseases. WuXi AppTec will continue strengthening its platform capabilities in oligonucleotides and related emerging therapeutic modalities to help global partners accelerate development and advance treatments for DMD and beyond. Key Takeaways: Technical advances such as cyclic-peptide PPMOs (EEV platforms) and TfR1-targeted AOCs are improving PMO delivery to muscle and producing measurable dystrophin increases in clinical studies. Manufacturing PMOs and conjugates remains complex, signaling growing demand for specialized capacity for oligonucleotide conjugates. WuXi AppTec’s WuXi TIDES platform provides integrated CRDMO services for PMO, PPMO and AOC development, supporting clients from discovery through commercial manufacturing. As of 2026, WuXi AppTec’s high-loading solid-phase PMO processes achieve >50% yields and >90% final purity. WuXi TIDES’ global footprint and end-to-end capabilities position it to accelerate conjugate oligonucleotide programs, including dozens of delivered PPMO projects. 参考资料： [1] Stenler S, et al., (2026). Timing matters: Exon skipping therapy is most effective when initiated early in a mouse model of Duchenne muscular dystrophy. Mol Ther Nucleic Acids, DOI: 10.1016/j.omtn.2026.103017 [2] Entrada Therapeutics. Retrieved September 4, 2026, from https://www.entradatx.com [3] Entrada Therapeutics Announces Positive Topline Results from Cohort 1 of Participants with Duchenne Muscular Dystrophy Treated with ENTR-601-44 in Phase 1/2 ELEVATE-44-201 Study. Retrieved September 4, 2026, from https://ir.entradatx.com/news-releases/news-release-details/entrada-therapeutics-announces-positive-topline-results-cohort-1 [4] Entrada Therapeutics Receives Authorization in the European Union to Initiate ELEVATE-45-201, a Phase 1/2 Multiple Ascending Dose Clinical Study of ENTR-601-45 in Patients Living with Duchenne Muscular Dystrophy Amenable to Exon 45 Skipping. Retrieved September 4, 2026, from https://ir.entradatx.com/news-releases/news-release-details/entrada-therapeutics-receives-authorization-european-union [5] Independent Safety Data Monitoring Committee Recommends Initiation of Cohort 2 at the Increased Dose of 10 mg/kg in Entrada Therapeutics’ ELEVATE-45-201 Study. Retrieved September 4, 2026, from https://ir.entradatx.com/news-releases/news-release-details/independent-safety-data-monitoring-committee-recommends [6] Novartis delivered sales growth in Q2 and further advanced the pipeline; Full-year guidance reaffirmed. Retrieved September 4, 2026, from https://www.novartis.com/news/media-releases/novartis-delivered-sales-growth-q2-and-further-advanced-pipeline-full-year-guidance-reaffirmed [7] Del-zota treatment is associated with near normalization of CK levels and improvements in key functional outcomes at 1 year in participants with DMD44. Retrieved September 4, 2026, from https://www.mdaconference.org/abstract-library/del-zota-treatment-is-associated-with-near-normalization-of-ck-levels-and-improvements-in-key-functional-outcomes-at-1-year-in-participants-with-dmd44/ [8] Dyne Therapeutics Announces U.S. FDA Acceptance of Biologics License Application (BLA) for Z-Rostudirsen in Exon 51 Duchenne Muscular Dystrophy (DMD). Retrieved September 4, 2026, from https://www.globenewswire.com/news-release/2026/07/20/3329635/0/en/dyne-therapeutics-announces-u-s-fda-acceptance-of-biologics-license-application-bla-for-z-rostudirsen-in-exon-51-duchenne-muscular-dystrophy-dmd.html [9] Solve Industry Bottlenecks. Retrieved September 4, 2026, from https://oligos-cmc-analytical-development.com/industry-bottlenecks/ [10] 48-Week Data from the Phase 2 Open-Label FORWARD-53 Study of WVE-N531 in Boys with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping. Retrieved September 4, 2026, from https://www.mdaconference.org/abstract-library/48-week-data-from-the-phase-2-open-label-forward-53-study-of-wve-n531-in-boys-with-duchenne-muscular-dystrophy-amenable-to-exon-53-skipping/ [11] Capricor Therapeutics Reports Second Quarter 2026 Financial Results and Provides Corporate Update. Retrieved September 4, 2026 from https://www.capricor.com/investors/news-events/press-releases/detail/353/capricor-therapeutics-reports-second-quarter-2026-financial [12] REGENXBIO Announces Positive Topline Results from Pivotal Phase III AFFINITY DUCHENNE® Study of RGX-202. Retrieved September 4, 2026, from https://www.prnewswire.com/news-releases/regenxbio-announces-positive-topline-results-from-pivotal-phase-iii-affinity-duchenne-study-of-rgx-202-302771834.html [13] Gene Therapy for Duchenne Muscular Dystrophy: Genethon Confirms Two-Year Efficacy in Patients Treated with Its Drug Candidate GNT0004 at Therapeutic Dose in the First Phase of Its Clinical Trial. Retrieved September 4, 2026, from https://www.businesswire.com/news/home/20260311396921/en/Gene-Therapy-for-Duchenne-Muscular-Dystrophy-Genethon-Confirms-Two-Year-Efficacy-in-Patients-Treated-with-Its-Drug-Candidate-GNT0004-at-Therapeutic-Dose-in-the-First-Phase-of-Its-Clinical-Trial [14] Non-dystrophin-based strategies are also being pursued. Satellos Bioscience is developing oral small molecule SAT‑3247, an AAK1 inhibitor designed to promote skeletal muscle regeneration—AAK1 is implicated in muscle repair and is dysregulated in DMD. Early study data in four adults (ages 21–28) showed reduced muscle fat fraction, increased total force, stabilized strength, lower creatine kinase and a safety profile consistent with prior findings. 免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，传递医学新知