DYNE-101

- Presentations Will Feature Recent Clinical Data From DYNE-251 and DYNE-101 as Well as Preclinical Data in FSHD and Pompe Disease - WALTHAM, Mass., Oct. 09, 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 that previously reported clinical and preclinical data across its pipeline will be featured in poster presentations at the 29th Annual Congress of the World Muscle Society, held virtually and in Prague, Czech Republic, October 8-12, 2024. The presentations highlight the promise of the FORCE™ platform to deliver targeted therapeutics to address neuromuscular diseases. “The full breadth and versatility of our FORCE platform is on display at this year’s World Muscle Society Congress, with presentations covering both of our co-lead clinical programs in DM1 and DMD, along with preclinical work in FSHD and Pompe disease,” said John Cox, president and chief executive officer of Dyne. “We’ve observed targeted delivery with the FORCE platform showing broad distribution to key tissues like skeletal, cardiac, smooth muscle and the CNS – which has the potential to transform the lives of individuals living with these diseases.” Poster Highlights The Phase 1/2 DELIVER trial evaluating DYNE-251 in males with Duchenne muscular dystrophy (DMD) mutations amenable to exon 51 skipping includes 6-month biomarker and functional data from patients enrolled in the 20 mg/kg (approximate PMO dose) cohort and 12-month functional data from the 10 mg/kg cohort. DYNE-251 demonstrated dose dependent exon skipping and dystrophin expression and improvement in multiple functional endpoints in both cohorts. Patients treated with 20 mg/kg of DYNE-251 Q4W had a mean absolute dystrophin expression of 3.7% of normal (unadjusted for muscle content) and when adjusting for muscle content, it reached 8.7%. Importantly, treatment with DYNE-251 resulted in meaningful improvements in Stride Velocity 95th Centile (SV95C), a digital objective outcome measure of ambulatory performance in a patient’s normal daily environment. The change from baseline in SV95C met the published minimal clinically important difference as defined by the European Medicines Agency (0.1 m/sec) at 6 months for both the 10 and 20 mg/kg cohorts (approximately 0.2 m/sec change from baseline for both cohorts).The Phase 1/2 ACHIEVE trial evaluating DYNE-101 in adult participants with myotonic dystrophy type 1 (DM1) includes 12-month data from the 1.8 mg/kg Q4W (approximate ASO dose) cohort, 6-month data from the 3.4 mg/kg Q4W cohort, and 3-month data from the 5.4 mg/kg Q8W cohort. DYNE-101 demonstrated robust muscle delivery and dose-dependent, consistent splicing correction while also showing improvement in myotonia, muscle strength, and timed function tests and in the Myotonic Dystrophy Type 1 Activity and Participation Scale (DM1-ACTIVc) and the Myotonic Dystrophy Health Index (MDHI) patient reported outcomes. Patients in the 5.4 mg/kg Q8W cohort had a 27% mean splicing correction from baseline across a broad, 22-gene panel at 3 months, with all participants demonstrating splicing correction.Both DYNE-251 and DYNE-101 have demonstrated favorable safety profiles. 1 2Preclinical data for DYNE-302 in facioscapulohumeral muscular dystrophy (FSHD), demonstrated robust and durable DUX4 suppression and functional benefit in an innovative hTfR1/iFLExD mouse model developed by Dyne. In hTfR1/iFLExD mice, a single intravenous dose of DYNE-302 resulted in dose-dependent and robust reduction of the DUX4 transcriptome (D4T) that lasted up to three months, with benefit on muscle structure and function.Preclinical data in a Pompe disease model demonstrated the potential of the FORCE platform to deliver enzyme replacement therapy to cardiac and skeletal muscle and the central nervous system (CNS), potentially expanding the modularity of the platform beyond oligonucleotides. Presentation Information Title: Initial Data from the DELIVER Trial of DYNE-251 in Males with DMD Mutations Amenable to Exon 51 SkippingDate/Time: October 9, 2024, 2:30 p.m. CEST/8:30 a.m. ETPresenter: Liesbeth De Waele, M.D., Ph.D., Pediatric Neurologist at University Hospital Leuven, Belgium Title: Initial Data from the ACHIEVE Trial of DYNE-101 in Adults with Myotonic Dystrophy Type 1 (DM1)Date/Time: October 9, 2024, 2:30 p.m. CEST/8:30 a.m. ETPresenter: Joost Kools, M.D., Neuromuscular Department at Radboud University Medical Center, Netherlands Title: The FORCE™ Platform Achieves Robust and Durable DUX4 Suppression and Improves Muscle Function in Facioscapulohumeral Muscular Dystrophy Mouse ModelDate/Time: October 9, 2024, 5:15 p.m. CEST/11:15 a.m. ETPresenter: Tyler Picariello, Ph.D., Director, Neuromuscular Research, Dyne Therapeutics Title: The FORCE™ Platform Enables Tfr1-mediated Delivery of Enzyme Replacement Therapy to Muscle and Central Nervous System, Resolving Pompe Pathology in MiceDate/Time: October 11, 2024, 3:45 p.m. CEST/ 9:45 a.m. ETPresenter: Tyler Picariello, Ph.D., Director, Neuromuscular Research, Dyne Therapeutics The presentations will be available in the Scientific Publications & Presentations section of Dyne’s website following the session. Additionally, a symposium titled “Potential of the FORCE™ Platform to Address Unmet Needs in Rare Neuromuscular Diseases” will be held on October 10 at 8:15 a.m. CEST/ 2:15 a.m. ET. About the FORCE™ Platform The proprietary FORCE™ platform drives Dyne’s efforts to develop targeted, modern oligonucleotide innovative therapeutics with the potential to be life-transforming for patients with serious muscle diseases. Dyne designed the FORCE platform using its deep knowledge of muscle biology and oligonucleotide therapeutics to overcome the current limitations in delivery to muscle tissue with the goal of stopping or reversing disease progression. The FORCE platform leverages the importance of transferrin receptor 1 (TfR1) in muscle biology as the foundation for its novel approach. TfR1, which is highly expressed on the surface of muscle cells, is required for iron transport into muscle cells. Dyne links therapeutic payloads to its TfR1-binding fragment antibody (Fab) to develop targeted therapeutics for muscle diseases. 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 preclinical programs 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 potential of DYNE-101, DYNE-251 and DYNE-302, expectations regarding the timing and outcome of interactions with global regulatory authorities, 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. Safety data as of August 21, 2024Safety data as of August 20, 2024 Contacts: InvestorsAmy Reillyareilly@dyne-tx.com 857-341-1203 MediaStacy Nartkersnartker@dyne-tx.com 781-317-1938

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/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%