DYNE-251

关注并星标CPHI制药在线【今日直播报名】就药物研发而言，创新就是一切。ADC的热度还未散去，其"胞兄"AOC就已走向台前。抗体寡核苷酸偶联物（AOC）是指利用抗体将治疗性寡核苷酸递送至特定细胞或组织，从而减少治疗患者疾病所需的药物量以及解决不可靶向和寡核苷酸递送问题。       寡核苷酸与靶向配体的偶联还可以改善寡核苷酸的药代动力学特性并扩大其应用范围。与传统寡核苷酸疗法相比，AOC增强了药物的生物分布和改善递送，还有助于减少寡核苷酸类药物可能造成的血小板减少的毒性。目前这一赛道的布局药企主要集中在海外，包括Avidity Biosciences，Dyne Therapeutics等。从企业的管线布局上，可以了解AOC药物的研发近况。       Avidity Biosciences       Avidity Biosciences成立于2013年，位于美国加利福尼亚州，是AOC先驱。Avidity 的AOC平台技术通过实验及跟踪数据，建立了具有自主研发的AOC平台，该平台整合了寡核苷酸疗法、RNA过程调控、抗体工程和共轭以及先进的给药技术，以期将寡核苷酸输送到目标组织。目前，公司在研管线中有三款产品处于临床阶段：AOC1001、AOC1020、AOC1044。       AOC1001是第一个进入临床的AOC药物，用于治疗 1 型肌营养不良症 (DM1)。AOC1001由靶向转铁蛋白受体1（TfR1）的单抗、连接子、靶向强直性肌营养不良蛋白激酶（DMPK）mRNA的siRNA组成。       在I/II 期临床中，AOC 1001实现了将RNA递送到肌肉组织的目标，所有患者的致病基因DMPK都有所下降，下降的平均幅度为45%。FDA和欧盟均已授予AOC1001用于治疗DM1的孤儿药资格认定，且FDA已授予其快速通道资格。       AOC1020是一款由TfR1抗体与靶向DUX4 mRNA的siRNA偶联而成的AOC药物，被开发用于治疗面肩肱型肌营养不良症（FSHD）。FSHD是一种临床上常见的遗传性肌肉疾病之一，由骨骼肌中DUX4基因的异常表达引起，通过一系列下游事件导致骨骼肌萎缩和肌肉功能受损，目前还没有相应治疗药物获批。       临床前数据显示，AOC1020可抑制DUX4 mRNA的表达，从而降低DUX4蛋白水平，减少下游基因表达。目前AOC1020正在进行I/II期临床研究。       AOC1044用于治疗44号外显子跳跃突变的杜氏肌营养不良症（DMD），这是一种罕见的遗传性疾病，因负责生成肌营养不良蛋白的基因发生突变引起。AOC 1044旨在向骨骼肌和心脏组织提供磷酸二酰胺吗啉低聚物（PMO），从而恢复DMD基因的阅读框架，并使较小但仍有功能的肌营养不良蛋白得以产生。目前，AOC 1044正在针对DMD44患者进行I/II 期临床试验评估。       Dyne Therapeutics       Dyne Therapeutics 成立于2018年，总部位于马萨诸塞州。Dyne Therapeutics凭借其专有的FORCE平台开发AOC药物，可以实现向肌肉组织靶向给药、延长给药间隔时间、可重复给药、可针对疾病的遗传基础阻止或逆转疾病的发展。       同Avidity 一样，Dyne公司的研发管线聚焦于三大罕见肌肉疾病：DM1、DMD、FSHD。公司在研产品主要有三款：DYNE-101、DYNE-251、DYNE-301。       DYNE-101由专有的 Fab 与反义寡核苷酸 (ASO) 连接组成。旨在通过降低细胞核中突变DMPK RNA的水平，解决DM1的遗传基础问题。在非人灵长类动物中，DYNE-101显示出良好的安全性，并通过显著减少野生型DMPK RNA证明了其增强的肌肉分布。       2023年5月，EMA授予DYNE-101孤儿药资格认定。目前，DYNE-101正在进行I/II期全球多中心临床研究。       DYNE-251 由专有的Fab与PMO连接组成。在临床前研究中，DYNE-251在mxd小鼠模型中使基因发生跳跃的能力持久，诱导骨骼肌和心肌中的肌营养不良蛋白表达从而减少肌肉损伤、增加肌肉功能。       2022年，FDA授予DYNE-251快速通道资格，用于治疗适合外显子51跳跃突变的DMD。目前，DYNE-251正在I/II期DELIVER全球临床试验中进行评估。       DYNE-301由专有的Fab与ASO连接组成，旨在通过减少肌肉组织中DUX4的表达来解决FSHD的遗传基础。Dyne获得的概念验证数据显示，DYNE-301能降低FSHD患者DUX4生物标志物的表达。       除以上两家公司外，布局AOC赛道的海外药企还有Tallc Therapeutics、Denali Therapeutics等。Tallc 公司主要聚焦于肿瘤适应症，其技术平台可提供有效的Toll样受体（TLR9）激动剂（T-CpG），通过选择T-CpG偶联合适的细胞靶点和抗体，激活局部肿瘤微环境中或全身的特异性免疫细胞群。Denali 公司专注于神经退行性疾病，公司开发了专有的转运载体技术平台，能够使治疗用生物大分子更有效地穿过血脑屏障，包括抗体、蛋白质和寡核苷酸，从而将这些生物大分子传递到大脑。       国内布局AOC领域的药企较少，迦进生物在这一领域一枝独秀。公司专注于以偶联方式实现小核酸的肝外递送，将罕见病、肿瘤、中枢神经系统疾病作为首要布局方向。公司核心产品CGB1001已经在临床前动物实验中取得了积极的数据，适应症为1型肌强直性营养不良。       AOC疗法通过将成熟的单克隆抗体技术与寡核苷酸疗法的精确性和有效性相结合，进入以前无法治疗的组织和细胞类型，从而为当前缺乏有效治疗手段的各种严重疾病提供潜在的治疗选择。与当下热门的ADC、双抗相比，AOC赛道竞争压力小，市场前景广阔，值得押注。       主要参考资料：       1、Avidity biosciences receives FDA Orphan Drug Designation for AOC 1044 for treatment of Duchenne Muscular Dystrophy in people with mutations amenable.       2、Kalina Paunovska, et al. Drug delivery systems for RNA therapeutics. Nat Rev Genet. 2022 May;23(5):265-280. doi: 10.1038/s41576-021-00439-4.       3、https://www.biospace.com/article/releases/avidity-biosciences-receives-fda-orphan-drug-designation-for-aoc-1020-for-the-treatment-of-facioscapulohumeral-muscular-dystrophy/.【智药研习社近期直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

- Positive Initial Clinical Data from ACHIEVE Trial in DM1 Patients and DELIVER Trial in DMD Patients Demonstrated Proof-of-Concept, Validating the Promise of the FORCE™ Platform and Targeted Delivery to Muscle - - Strengthened Balance Sheet with $345 Million Public Offering Extending Projected Cash Runway Through 2025 - WALTHAM, Mass., March 05, 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 reported financial results for the fourth quarter and full year 2023 and recent business highlights. “We’ve had an exciting start to 2024 highlighted by Dyne’s first clinical data demonstrating proof-of-concept in our DM1 and DMD programs that validated the promise of the FORCE™ platform in developing targeted therapeutics for people living with rare muscle diseases. We were thrilled to see dose-dependent results in our ACHIEVE trial in DM1 as well as meaningful improvement in myotonia at the lowest dose, and in our DELIVER trial to exceed the level of dystrophin production reported for the standard of care for DMD exon 51 with a fraction of the dose. The strength of these data formed the foundation of the $345 million offering we completed in January 2024, which has extended our projected cash runway through 2025,” said Joshua Brumm, president and chief executive officer of Dyne. “In 2024, we are focused on leveraging the favorable safety profiles for both DYNE-101 and DYNE-251 and the adaptive nature of our ACHIEVE and DELIVER trials to optimize dose and dose regimen. We plan to provide an update from both trials in the second half of 2024, including reporting data from multiple, higher dose cohorts. We also continue to pursue expedited regulatory pathways as part of our commitment to move with a sense of urgency to deliver potentially transformative therapies for the DM1 and Duchenne communities.” Highlights from Clinical Programs Phase 1/2 ACHIEVE Trial of DYNE-101 in DM1 In January 2024, Dyne reported initial clinical data from the Phase 1/2 ACHIEVE trial of DYNE-101 in adult patients with myotonic dystrophy type 1 (DM1). The initial efficacy assessment was based on data from 32 patients enrolled in the randomized, placebo-controlled multiple ascending dose (MAD) portion of the trial, including 6-month data from the 1.8 mg/kg (approximate ASO dose) cohort and 3-month data from the 3.4 mg/kg Q4W cohort. DYNE-101 demonstrated a dose-dependent splicing correction as well as an increase in muscle delivery and DMPK knockdown. Patients treated with 1.8 mg/kg Q4W of DYNE-101 also experienced functional improvement in myotonia as measured by video hand opening time (vHOT) and overall improvement in the Myotonic Dystrophy Health Index (MDHI) patient reported outcome, including the fatigue subscale, suggesting potential benefit in the central nervous system.Safety and tolerability data were based on 45 patients enrolled through the 5.4 mg/kg Q8W cohort of the MAD portion. DYNE-101 demonstrated a favorable safety profile as of the data cutoff date1. The ACHIEVE trial is fully enrolled through the 5.4 mg/kg Q8W cohort and is currently enrolling participants in the 6.8 mg/kg Q8W cohort. Phase 1/2 DELIVER Trial of DYNE-251 in DMD In January 2024, Dyne reported initial clinical data from the Phase 1/2 DELIVER trial of DYNE-251 in Duchenne muscular dystrophy (DMD). The initial efficacy assessment was based on 6-month data from 6 male patients with DMD amenable to exon 51 skipping enrolled in the 5 mg/kg (approximate PMO dose) cohort of the randomized, placebo-controlled MAD portion of the trial. Once every 4-week administration of DYNE-251 reached levels of dystrophin expression, exon skipping and percent dystrophin positive fibers that exceeded levels reported in a clinical trial for the current weekly standard of care for DMD exon 51, eteplirsen, at 6 months2 with a 24-fold lower total PMO dose.Safety and tolerability data were based on 37 patients enrolled through the 20 mg/kg cohort of the MAD portion. DYNE-251 demonstrated a favorable safety profile as of the data cutoff date1. The DELIVER trial is fully enrolled through the 20 mg/kg Q4W cohort and is currently enrolling participants in the 40 mg/kg Q8W cohort. Other Business Highlights In January 2024, Dyne completed an underwritten public offering of 19,722,500 shares of its common stock at a public offering price of $17.50 per share, which included 2,572,500 shares issued upon the exercise in full by the underwriters of their option to purchase additional shares of common stock in the offering. The gross proceeds to Dyne from the offering were approximately $345.1 million, before deducting underwriting discounts and commissions and offering expenses payable by Dyne. Upcoming Events & Key 2024 Milestones Initial data from ACHIEVE and DELIVER reported in January 2024 will be featured in oral presentations at the Muscular Dystrophy Association (MDA) Clinical and Scientific Conference on March 6, 2024. Dyne anticipates reporting data from multiple, higher dose cohorts from both the ACHIEVE and the DELIVER trials in the second half of 2024 with the goal of initiating registrational cohorts by the end of 2024. Fourth Quarter and Full Year 2023 Financial Results Cash position: Cash, cash equivalents and marketable securities were $123.1 million as of December 31, 2023. In January 2024, the Company completed an underwritten public offering of 19,722,500 shares of its common stock for net proceeds of approximately $323.9 million. The Company expects that its cash, cash equivalents and marketable securities as of December 31, 2023, together with the net proceeds from the January 2024 underwritten public offering, will be sufficient to fund its operations through 2025. Research and development (R&D) expenses: R&D expenses were $58.8 million and $33.2 million for the quarters ended December 31, 2023 and 2022, respectively. R&D expenses were $210.8 million and $142.8 million for the years ended December 31, 2023 and 2022, respectively. General and administrative (G&A) expenses: G&A expenses were $8.8 million and $7.0 million for the quarters ended December 31, 2023 and 2022, respectively. G&A expenses were $31.4 million and $28.2 million for the years ended December 31, 2023 and 2022, respectively. Net loss: Net loss for the quarter ended December 31, 2023 was $66.6 million, or $1.09 per basic and diluted share. This compares with a net loss of $38.8 million, or $0.74 per basic and diluted share, for the quarter ended December 31, 2022. Net loss for the year ended December 31, 2023 was $235.9 million, or $3.95 per basic and diluted share. This compares with a net loss of $168.1 million, or $3.23 per basic and diluted share, for the year ended December 31, 2022. 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 trial design of the DYNE-101 and DYNE-251 clinical trials, the anticipated timelines for reporting data from the DYNE-101 and DYNE-251 clinical trials and initiating registrational cohorts, plans to optimize dose and dose regimen for DYNE-101 and DYNE-251 and the sufficiency of Dyne’s cash resources for the period anticipated, 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 initiate and 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; whether Dyne’s cash resources will be sufficient to fund the Company’s 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-K 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. Safety data as of December 6, 20232. 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 Dyne Therapeutics, Inc. Condensed Consolidated Statement of Operations (in thousands, except share and per share data) Three Months Ended Year Ended December 31, December 31, 2023 2022 2023 2022 Operating expenses: Research and development$58,843 $33,191 $210,762 $142,760 General and administrative 8,846 6,955 31,400 28,202 Total operating expenses 67,689 40,146 242,162 170,962 Loss from operations (67,689) (40,146) (242,162) (170,962)Other (expense) income, net 1,050 1,319 6,225 2,863 Net loss$(66,639) $(38,827) $(235,937) $(168,099)Net loss per share, basic and diluted$(1.09) $(0.74) $(3.95) $(3.23)Weighted average common shares outstanding, basic and diluted 61,393,409 52,817,413 59,683,851 51,976,343 Dyne Therapeutics, Inc. Condensed Consolidated Balance Sheet Data (in thousands) December 31, 2023 2022 Assets Cash, cash equivalents and marketable securities $123,100 $256,012 Other assets 41,982 50,313 Total Assets $165,082 $306,325 Liabilities and Stockholders’ Equity Liabilities 73,790 53,961 Stockholders' equity 91,292 252,364 Total liabilities and stockholders' equity $165,082 $306,325 Contacts: InvestorsAmy Reillyareilly@dyne-tx.com 857-341-1203 MediaStacy Nartkersnartker@dyne-tx.com 781-317-1938