DYNE-101

来源：药渡 撰文：哥哈骎     编辑：维他命 1 抗体-寡核苷酸偶联物(AOC) 基于寡核苷酸的基因疗法因其在调控基因表达方面的独特优势，在过去几年中如火如荼地发展。寡核苷酸是长度在20到60个单位之间的短DNA或RNA寡聚体，可以以单链（ss）或双链（ds）寡聚体的形式自然存在。寡核苷酸药物的引入拓宽了疾病治疗的手段和边界，为许多疾病的治疗带来了新的希望。 然而，未修饰的寡核苷酸由于其高分子量、高亲水性和负电荷，以及体内稳定性低和非特异性积累问题，导致很难穿过细胞膜和血脑屏障。目前，主要批准的寡核苷酸药物递送系统是LNP递送系统和GalNAc递送系统，但两者都不能在肝外进行药物靶向递送。几十年来，将寡核苷酸递送至细胞一直是研究人员孜孜以求的目标。配体偶联、细胞穿透肽，纳米颗粒和外泌体都曾经是人们尝试的手段。 将寡核苷酸递送至肝外组织的一种新兴策略是将它们与单克隆抗体连接，以形成抗体-寡核苷酸偶联物（antibody–oligonucleotide conjugates, AOC）。AOC已经逐渐展现出了取代纳米颗粒作为递送寡核苷酸药物载体的趋势。虽然纳米粒子具有携带多个siRNA的能力，但依然面临巨大的工程挑战。AOC则借助着ADC的发展东风抟扶摇而上，成为新一代寡核苷酸药物递送机制。抗体已被证明是理想的递送剂，因为它们具有高特异性、长半衰期和低免疫原性。 ADC领域在过去十年中发展迅速，使人们对靶标选择、释放机制、有效载荷效力以及每个组分在整体活性概况中的作用有了更好的理解。随着越来越多的临床数据可用，人们对ADC的剂量水平和毒性管理有了更好的理解，从而提高了临床成功率。 AOC通常有三个部分组成：靶向靶点的单抗、寡核苷酸药物载荷，以及连接两者的接头（可裂解或不可裂解）。所以从大的领域来划分，AOC仍然隶属于ADC，只是其载荷不是传统意义上的小分子药物，而是寡核苷酸类分子。反义寡核苷酸（ASO）和小干扰RNA（siRNA）药物均可通过不同的机制消耗mRNA靶标。 siRNA和ASO的使用在过去十年中经历了高速的发展。抗体具有更长的半衰期、在细胞内选择性递送治疗药物的能力以及靶向特性，使其成为寡核苷酸靶向递送的理想合作伙伴。由于非选择性有效载荷，ADC具有全身毒性，但寡核苷酸的选择性可以凸显偶联物仅影响靶疾病细胞的能力。抗体-寡核苷酸偶联物将siRNA或ASO的高精度与抗体的递送率相结合，从而协同发挥了两种技术的优势。 AOC最初作为诊断工具得到应用，但最近逐渐发展为许多疾病的靶向治疗方法。随着寡核苷酸领域的成熟和选择性组织递送成为临床应用的重要挑战，AOC转变为潜在的单药疗法。在过去十年中，ADC和寡核苷酸领域在化学、偶联和分析方面都实现了明显的进步。 2 AOC代表：DYNE-101 DYNE-101是Dyne Therapeutics针对1型强直性肌营养不良（DM1）的寡核苷酸AOC，目前处于全球I/II期ACHIEVE临床试验。 DM1是一种罕见的进行性遗传疾病，会影响骨骼肌、心脏和平滑肌。它是一种单基因、常染色体显性遗传病。CTG重复序列的扩增导致有毒RNA在细胞核中聚集，形成核病灶并改变对正常细胞功能至关重要的多种蛋白质的剪接。这种改变的剪接或剪接病会导致广泛的症状。DM1患者通常会出现肌强直和主要肌肉群进行性无力，这会影响活动能力、呼吸、心脏功能、言语、消化和视力以及认知。据估计，DM1在美国影响超过40000人，在欧洲影响超过74000人，但目前还没有批准的疾病改善疗法。 图1. DYNE-101结构示意图，来源：Dyne Therapeutics DYNE-101是寡核苷酸为载荷的AOC候选药，由反义寡核苷酸（ASO）与抗体片段（Fab）偶联组成，抗体部分经过工程设计可以与在肌肉细胞上高度表达的转铁蛋白受体1（TfR1）结合，从而能够定向将载荷递送至骨骼肌、心脏肌和平滑肌（图1）。与单克隆抗体（mAb）相比，Fab具有显著的肌肉递送优势，包括增强组织渗透性、提高耐受性和降低免疫系统激活风险。DYNE-101可以实现靶向肌肉组织的递送，减少细胞核中的有毒DMPK RNA，释放剪接蛋白，允许正常的mRNA加工和正常蛋白质的翻译，并可能阻止或逆转疾病进展。DYNE-101已被FDA授予孤儿药资格。 在DYNE-101的I/II期ACHIEVE试验中，DYNE-101使用3个月时在5.4 mg/kg队列中的所有患者中显示出剂量依赖性的27%的平均剪接矫正。DYNE-101在肌强直、肌肉力量和定时功能测试中均有所改善。Dyne打算使用剪接校正来替代生物标志物，以加速DM1适应症在美国的批准。Dyne目前最大的竞争对手是Avidity Biosciences，后者的ADC候选药delpacibart etedesiran已经处于DM1的III期。 Dyne管线内还有另一款载荷为寡核苷酸的AOC候选药DYNE-251，针对杜氏肌营养不良症（DMD），处于I/II期DELIVER研究。接受DYNE-251治疗的患者的抗肌萎缩蛋白表达水平高于获批的Sarepta Therapeutics的DMD药物Exondys 51（eteplirsen）。然而，这些数据仅来自六名患者。Avidity同样拥有一款DMD的ADC药物AOC 1044，其I/II期研究EXPLORE44试验可能会在今年晚些时间读数。 3 AOC未来展望 AOC领域最初是一种诊断工具，但在过去10年中已成为一种新型治疗方式。该领域还处于起步阶段，需要更多的临床前以及临床研究。AOC的主要挑战包括分析表征、靶点和疾病选择、运输和体内稳定性。随着更多工具的出现，我们对AOC的知识和机理理解也将不断发展。以DYNE-101为代表的AOC临床研究已经证明了这一疗法潜在的有效性和安全性。 随着ASO和siRNA领域的进步，AOC的格局将在未来十年内迅速变化。新的寡核苷酸载荷将具有更高的稳定性和膜通透性，溶酶体逃逸将成为AOC可以利用的工具。接头技术的不断进步也将为AOC的精准靶向性提供有利支持。除此之外，仪器和分析方法的开发将有利于测量代谢物、PK和AOC表征。这些进步将对下一代AOC产生重大影响。 个性化疗法开发也将成为AOC未来的发展方向之一，其寡核苷酸序列可以针对一个组织中的特定遗传缺陷进行定制，癌症活检可能产生个性化的siRNA混合物，蛋白质可以被选择性抑制。AOC可能成为精准医疗的重要武器库，这些都证明AOC未来10年的发展值得期待。 参考文献： 1. Mullard, A. Antibody–oligonucleotide conjugates enter the clinic. Nature. 2022. 21. 6-8. 2. Dyne Therapeutics Announces New Clinical Data from ACHIEVE Trial of DYNE-101 in DM1 and DELIVER Trial of DYNE-251 in DMD Demonstrating Compelling Impact on Key Disease Biomarkers and Improvement in Multiple Functional Endpoints. Dyne Press Release. 20. 05. 2024. 3. Dugal-Tessier, J. et al. Antibody-Oligonucleotide Conjugates: A Twist to Antibody-Drug Conjugates. J. Clin. Med. 2021, 10, 838. https://doi-org.libproxy1.nus.edu.sg/10.3390/jcm10040838 专栏作者 哥哈骎 南开大学本科、硕士，德国比勒菲尔德大学博士。多肽化学、多肽API GMP生产专家、欧洲制药公司首席科学家； 拥有Lean Six Sigma黑带认证； 著有专著《Side Reactions in Peptide Synthesis》。 *声明：本文仅是介绍医药疾病领域研究进展或简述研究概况或分享医药相关讯息，并非也不会进行治疗或诊断方案推荐，也不对相关投资构成任何建议。内容如有疏漏，欢迎沟通指出！ 罕见遗传病新希望——基因治疗药物，让血友病、SMA等不再“无药可医” 一年长高11厘米！诺和诺德长效生长激素国内申报上市 《生物安全法案》通过引波澜：CXO板块集体受挫，药明康德跌超10%

- Initiating Registrational Cohorts with Update on Path to Registration by Year-End 2024 -- Virtual Investor Event Today at 8:00 a.m. ET - WALTHAM, Mass., Sept. 03, 2024 (GLOBE NEWSWIRE) -- Dyne Therapeutics, Inc. (Nasdaq: DYN), a clinical-stage muscle disease company focused on advancing innovative life-transforming therapeutics for people living with genetically driven diseases, today announced new clinical data from its ongoing Phase 1/2 DELIVER trial of DYNE-251 in patients with Duchenne muscular dystrophy (DMD) who are amenable to exon 51 skipping demonstrating unprecedented dystrophin expression and functional improvement in multiple cohorts. “We believe these data reinforce the opportunity to transform the treatment paradigm for individuals living with Duchenne. In DELIVER, DYNE-251 achieved the highest level of dystrophin expression reported for an exon 51 skipping therapy and improvement in multiple functional endpoints across multiple cohorts that continued with time on therapy,” said Wildon Farwell, M.D., MPH, chief medical officer of Dyne. “Our goal has always been to drive dystrophin levels that lead to functional benefit for patients – these data suggest that the distribution across cardiac, diaphragm and other skeletal muscles observed preclinically with the FORCE platform is translating in the clinic. Importantly, treatment with DYNE-251 resulted in meaningful improvements in SV95C, a digital outcome measure approved as a primary endpoint for Duchenne clinical trials in Europe. With these exciting data, we are moving quickly to initiate registrational cohorts in DELIVER, and we continue to pursue expedited approval pathways and plan to provide an update on our path to registration by the end of this year.” This assessment of the DELIVER trial evaluating DYNE-251 includes 6-month biomarker and functional data from 8 male patients enrolled in the 20 mg/kg (approximate PMO dose) cohort who were randomized to receive DYNE-251 or placebo once every four weeks, and 12-month functional data from 6 participants in the 10 mg/kg cohort.1 DYNE-251 demonstrated dose dependent exon skipping and dystrophin expression and improvement in multiple functional endpoints in both cohorts. Key findings include: Dystrophin expression: DYNE-251 demonstrated unprecedented dystrophin expression as measured by Western blot. Patients treated with 20 mg/kg of DYNE-251 Q4W had a mean absolute dystrophin expression of 3.71% of normal (unadjusted for muscle content), more than 10-fold higher than the 0.3% reported in a clinical trial of the weekly standard of care, eteplirsen.2 When adjusting for muscle content, the DYNE-251 treated group reached 8.72% mean absolute dystrophin, which is greater than levels reported by peptide conjugate PMOs in clinical development.3Function: Meaningful improvements in multiple functional endpoints were observed in both the 20 mg/kg and 10 mg/kg DYNE-251 Q4W groups, including North Star Ambulatory Assessment (NSAA), Stride Velocity 95th Centile (SV95C), 10-Meter Walk/Run Time (10-MWR), Time to Rise from Floor. The 10 mg/kg cohort showed continued improvement in all reported measures from 6 months to 12 months.1 SV95C is a digital objective outcome measure of ambulatory performance in patients’ normal daily environment and is approved as a primary endpoint for Duchenne clinical trials in Europe. The change from baseline observed in both the 10 mg/kg and 20 mg/kg cohorts of DELIVER met the published minimal clinically important difference (MCID) as defined by the European Medicines Agency. Safety and Tolerability: Safety and tolerability data are based on 54 participants enrolled in the DELIVER trial. DYNE-251 demonstrated a favorable safety profile and the majority of treatment emergent adverse events were mild or moderate.4 No related serious treatment emergent adverse events have been identified other than in two participants at the 40 mg/kg dose level with events potentially related to study drug and both participants have recovered. Approximately 675 doses have been administered to date in the DELIVER trial, representing over 50 patient-years of follow-up. Key Milestones for DELIVER and ACHIEVE Trials Based on these data and regulatory interactions, Dyne is initiating registrational cohorts in the DELIVER trial and plans to provide an update on the path to registration by the end of 2024.Dyne is also executing its ongoing Phase 1/2 ACHIEVE clinical trial of DYNE-101 in myotonic dystrophy type 1. The safety profile of DYNE-101 continues to be favorable and includes safety data up to the 6.8 mg/kg Q8W cohort.5 The company continues to engage with global regulators, including the U.S. Food and Drug Administration, and plans to provide an update on the path to registration for DYNE-101, including additional clinical data, by the end of 2024. Virtual Investor Event Dyne will host a video webcast event to discuss these DELIVER data today, September 3, 2024, at 8:00 a.m. ET and a replay will be accessible for 90 days following the presentation. An accompanying slide presentation for the event and an updated corporate presentation will also be available. To access these presentations and register for the live webcast and replay, please visit the Investors & Media section of Dyne’s website at https://investors.dyne-tx.com/news-and-events/events-and-presentations and the live event may also be accessed here. About the DELIVER Trial DELIVER is a Phase 1/2 global clinical trial evaluating DYNE-251, consisting of a 24-week multiple ascending dose (MAD) randomized placebo-controlled period, a 24-week open-label extension and a 96-week long-term extension. The trial, which is designed to be registrational, is enrolling ambulant and non-ambulant males with Duchenne muscular dystrophy (DMD) who are ages 4 to 16 and have mutations amenable to exon 51 skipping. The primary endpoints are safety, tolerability and change from baseline in dystrophin levels as measured by Western blot. Secondary endpoints include measures of muscle function, exon skipping and pharmacokinetics. For more information on the DELIVER trial, visit https://www.clinicaltrials.gov/ (NCT05524883). About DYNE-251 DYNE-251 is an investigational therapeutic being evaluated in the Phase 1/2 global DELIVER clinical trial for people living with DMD who are amenable to exon 51 skipping. DYNE-251 consists of a phosphorodiamidate morpholino oligomer (PMO) conjugated to a fragment antibody (Fab) that binds to the transferrin receptor 1 (TfR1) which is highly expressed on muscle. It is designed to enable targeted muscle tissue delivery and promote exon skipping in the nucleus, allowing muscle cells to create a truncated, functional dystrophin protein, with the goal of stopping or reversing disease progression. DYNE-251 has been granted fast track, orphan drug and rare pediatric disease designations by the U.S. Food and Drug Administration for the treatment of DMD mutations amenable to exon 51 skipping. In addition to DYNE-251, Dyne is building a global DMD franchise and has preclinical programs targeting other exons, including 53, 45 and 44.  About Duchenne Muscular Dystrophy (DMD) DMD is a rare disease caused by mutations in the gene that encodes for dystrophin, a protein critical for the normal function of muscle cells. These mutations, the majority of which are deletions, result in the lack of dystrophin protein and progressive loss of muscle function. DMD occurs primarily in males and affects an estimated 12,000 to 15,000 individuals in the U.S. and 25,000 in Europe. Loss of strength and function typically first appears in pre-school age boys and worsens as they age. As the disease progresses, the severity of damage to skeletal and cardiac muscle often results in patients experiencing total loss of ambulation by their early teenage years and includes worsening cardiac and respiratory symptoms and loss of upper body function by the later teens. There is no cure for DMD and currently approved therapies provide limited benefit. About Dyne Therapeutics Dyne Therapeutics is a clinical-stage muscle disease company focused on advancing innovative life-transforming therapeutics for people living with genetically driven diseases. With its proprietary FORCE™ platform, Dyne is developing modern oligonucleotide therapeutics that are designed to overcome limitations in delivery to muscle tissue. Dyne has a broad pipeline for serious muscle diseases, including clinical programs for myotonic dystrophy type 1 (DM1) and Duchenne muscular dystrophy (DMD) and a preclinical program for facioscapulohumeral muscular dystrophy (FSHD). For more information, please visit https://www.dyne-tx.com/, and follow us on X, LinkedIn and Facebook. Forward-Looking Statements This press release contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this press release, including statements regarding Dyne’s strategy, future operations, prospects and plans, objectives of management, the potential of the FORCE platform, the anticipated timelines for reporting additional data from the ACHIEVE and DELIVER clinical trials and initiating registrational cohorts, expectations regarding the timing and outcome of interactions with global regulatory authorities and the availability of accelerated approval pathways for DYNE-101 and DYNE-251, and plans to provide future updates on pipeline programs, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “objective,” “ongoing,” “plan,” “predict,” “project,” “potential,” “should,” or “would,” or the negative of these terms, or other comparable terminology are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Dyne may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various important factors, including: uncertainties inherent in the identification and development of product candidates, including the initiation and completion of preclinical studies and clinical trials; uncertainties as to the availability and timing of results from preclinical studies and clinical trials; the timing of and Dyne’s ability to enroll patients in clinical trials; whether results from preclinical studies and initial data from early clinical trials will be predictive of the final results of the clinical trials or future trials; uncertainties as to the FDA’s and other regulatory authorities’ interpretation of the data from Dyne's clinical trials and acceptance of Dyne's clinical programs and the regulatory approval process; whether Dyne’s cash resources will be sufficient to fund its foreseeable and unforeseeable operating expenses and capital expenditure requirements; as well as the risks and uncertainties identified in Dyne’s filings with the Securities and Exchange Commission (SEC), including the Company’s most recent Form 10-Q and in subsequent filings Dyne may make with the SEC. In addition, the forward-looking statements included in this press release represent Dyne’s views as of the date of this press release. Dyne anticipates that subsequent events and developments will cause its views to change. However, while Dyne may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as representing Dyne’s views as of any date subsequent to the date of this press release. 1.During the OLE period, all participants in 10 mg/kg cohort were dose escalated to 20 mg/kg Q4W regimen.2.No head-to-head trials have been conducted comparing DYNE-251 to eteplirsen. Eteplirsen data may not be directly comparable due to differences in trial protocols, dosing regimens and patient populations. Accordingly, these cross-trial comparisons may not be reliable. Eteplirsen data from J Neuromuscul Dis. 2021; 8(6): 989–1001.3.No head-to-head trials have been conducted comparing DYNE-251 to SRP-5051. SRP-5051 data may not be directly comparable due to differences in trial protocols, dosing regimens, methodologies for calculating muscle content adjusted dystrophin and patient populations. Accordingly, these cross-trial comparisons may not be reliable. SRP-5051 data from Clinical Update: MOMENTUM (Study SRP-5051-201, Part B) Jan. 29, 2024.4.DYNE-251 safety data as of August 21, 2024.5.DYNE-101 safety data as of August 20, 2024. Contacts: InvestorsAmy Reillyareilly@dyne-tx.com 857-341-1203 MediaStacy Nartkersnartker@dyne-tx.com781-317-1938