DUX4

The acquisition enhances the portfolio of Aditxt in precision diagnostics and infectious disease treatment. Credit: Gorodenkoff / Shutterstock.com. Aditxt has announced a definitive agreement under which its subsidiary, Adivir, will acquire complete issued and outstanding Class A common shares of biopharmaceutical company Appili Therapeutics. The move enhances Aditxt’s portfolio and creates synergies with its existing programmes, particularly in precision diagnostics. Founded in 2015, Appili developed the Food and Drug Administration-approved LIKMEZ (ATI-1501). LIKMEZ is a reformulated version of the antibiotic metronidazole that improves patient experience and compliance by making the medication easier to swallow and better tasting. Appili licensed the manufacturing and commercialisation rights of the product in the US and other selected territories to Saptalis Pharmaceuticals. See Also: Forma Therapeutics gets grant for USP30 inhibitor compounds for medical use Dyne Therapeutics gets grant for muscle-targeting complex inhibiting DUX4 expression with oligonucleotide payload Appili is also advancing ATI-1701, a live attenuated vaccine for Francisella tularensis. The US Department of Defense has supported the ATI-1701 biodefence programme with $14m non-dilutive funding to progress the vaccine’s development. Another key asset in Appili’s portfolio is ATI-1801, a topical formulation for cutaneous leishmaniasis. The product, which contains paromomycin, offers a more patient-friendly treatment option for this painful and disfiguring disease. The acquisition will aid Aditxt in bolstering its portfolio and integrating precision diagnostics with tailored treatment strategies. The closure of the acquisition will occur in the third quarter of 2024. Aditxt co-founder, chairman and CEO Amro Albanna stated: “The acquisition of Appili would represent another step in Aditxt’s journey towards advancing promising innovations in health. “Our mission is to accelerate some of the most promising health innovations, like those developed by Appili, to reach their full potential and to have a lasting impact. “By integrating Appili’s proven expertise and diverse portfolio in the infectious disease and biodefence domain, Aditxt can substantially contribute to advancing public health solutions.”

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~

March 07, 2024 - Solid Biosciences Inc. (Nasdaq: SLDB), a life sciences company developing precision genetic medicines for neuromuscular and cardiac diseases, today announced a non-exclusive worldwide license and collaboration agreement with Armatus Bio for the use of Solid’s proprietary capsid AAV-SLB101 for the development and commercialization of Armatus’ vectorized RNAi candidate to treat Facioscapulohumeral muscular dystrophy (FSHD). The AAV-SLB101 capsid has been shown in preclinical studies to have enhanced biodistribution and improved expression in muscle cells. Under the terms of the agreement, Solid granted Armatus a non-exclusive worldwide license to utilize AAV-SLB101 for treatment of FSHD and will provide Armatus AAV-SLB101 plasmid material, preclinical data characterizing AAV-SLB101, and manufacturing and regulatory know-how to enable development. In return, Solid will receive an upfront payment, payments upon the achievement of certain development and sales milestones, and tiered royalties on net sales for any products incorporating AAV-SLB101. Armatus will be responsible for the development and commercialization of licensed products incorporating AAV-SLB101. “Our transaction with Armatus Bio is the first of what we intend to be a broad out-licensing of our capsid library to both companies and academic institutions. We designed AAV-SLB101 for enhanced biodistribution to skeletal muscle, which is intended to help improve the efficacy and reduce the toxicity of AAV-delivered gene therapies for muscular disorders,” said Bo Cumbo, President and Chief Executive Officer at Solid Biosciences. “AAV-SLB101 is the capsid for our next-generation Duchenne candidate, SGT-003, and we are excited to expand AAV-SLB101’s use to FSHD through this agreement with Armatus Bio.” Armatus is developing ARM-201, a potential best-in-class, single dose therapeutic used for the treatment of FSHD, a progressive genetic neuromuscular disorder caused by DUX4 overexpression. ARM-201’s proprietary miRNA payload seeks to reduce DUX4, and thus arrest muscle weakening and atrophy, prevent further degeneration, and ameliorate the amount of inflammation and oxidative stress caused by FSHD. “The use of Solid’s unique AAV-SLB101 capsid will help enable optimal patient dosing for our FSHD program. The preclinical data presented to date for AAV-SLB101 demonstrate increased muscle transduction while simultaneously reducing biodistribution in the liver. These data, combined with the data we have generated for ARM-201 give us high confidence in the potential to reduce total AAV dose levels compared to first generation capsids,” commented Brian Price, Ph.D., Chief Technology Officer at Armatus Bio. “Further, we are encouraged by the strong safety profile demonstrated by AAV-SLB101, which has a cleared IND as the capsid in Solid’s SGT-003 construct for the treatment of DMD. With this license in place, we are eager to advance our optimized ARM-201 construct as the lead candidate toward clinical evaluation.” AAV-SLB101 is a proprietary, rationally designed capsid developed for enhanced muscle tropism and reduced liver uptake. With a robust preclinical package in mice and nonhuman primates, AAV-SLB101 has demonstrated increased transduction speed, enhanced skeletal and cardiac muscle tropism, decreased liver biodistribution and improved efficiency when compared to first generation capsids. The incorporation of AAV-SLB101 into AAV delivered therapies has the potential to be a step forward in the treatment of neuromuscular and cardiac diseases. Solid Biosciences aims to license AAV-SLB101 broadly to both companies and academic institutions pursuing treatments for rare diseases. Solid Biosciences is a life sciences company focused on advancing a portfolio of gene therapy candidates for neuromuscular and cardiac programs, including SGT-003, for the treatment of Duchenne muscular dystrophy (Duchenne), SGT-501 for the treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT), AVB-401 for the treatment of BAG3-mediated dilated cardiomyopathy, AVB-202-TT for the treatment of Friedreich’s ataxia, and additional assets for the treatment of fatal cardiac diseases. Solid is advancing its diverse pipeline across rare neuromuscular and cardiac diseases, bringing together experts in science, technology, disease management, and care. Patient-focused and founded by those directly impacted, Solid’s mandate is to improve the daily lives of patients living with these devastating diseases. For more information, please visit www.solidbio.com. Armatus Bio is a privately held late preclinical stage biotechnology innovator leveraging vectorized RNAi to address urgent unmet medical needs in genetically-driven neurological diseases. Based in Columbus, Ohio, the company is led by a seasoned team with expertise in drug development and delivery, and partnered with world renowned experts in vector biology, genomics, and neurology. The content above comes from the network. if any infringement, please contact us to modify.