更新于：2024-12-05

Exon 44 Skipping Oligonucleotide(Entrada Therapeutics)

更新于：2024-12-05

概要

研发状态

概要

基本信息

药物类型

ASO

别名

a DMD exon 44 skipping PMO and a proprietary cyclic peptide, EEV, that is designed to enable robust muscle tissue uptake, high cellular internalization and endosomal escape of oligonucleotide therapeutics、exon skipping oligonucleotide、ENTR-601-44

靶点

Nucleic acids

作用机制

Nucleic acids抑制剂(核酸抑制剂)

治疗领域

神经系统疾病遗传病与畸形皮肤和肌肉骨骼疾病+ [1]

在研适应症

杜氏肌营养不良症

非在研适应症-

原研机构

Entrada Therapeutics, Inc.

在研机构

Entrada Therapeutics, Inc.

非在研机构-

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评孤儿药 (美国)

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关联

项与 Exon 44 Skipping Oligonucleotide(Entrada Therapeutics) 相关的临床试验

ISRCTN36174912 / Completed临床1期

Phase 1 Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate Safety, Tolerability, and Pharmacokinetics of a Single Intravenous Infusion of Ascending Doses of ENTR-601-44 in Healthy Male Volunteers

开始日期2023-08-23

申办/合作机构

Entrada Therapeutics, Inc.

100 项与 Exon 44 Skipping Oligonucleotide(Entrada Therapeutics) 相关的临床结果

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100 项与 Exon 44 Skipping Oligonucleotide(Entrada Therapeutics) 相关的转化医学

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100 项与 Exon 44 Skipping Oligonucleotide(Entrada Therapeutics) 相关的专利（医药）

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项与 Exon 44 Skipping Oligonucleotide(Entrada Therapeutics) 相关的文献（医药）

2021-08-01·Journal of molecular neuroscience : MN3区 · 医学

Parkinson Disease-Modification Encompassing Rotenone and 6-Hydroxydopamine Neurotoxicity by the Microtubule-Protecting Drug Candidate SKIP

3区 · 医学

Article

作者: Seroogy, Kim B ; Ivashko-Pachima, Yanina ; Gozes, Illana ; Sharabi, Yehonatan

Encompassing live cell imaging and morphometrics at the microscopical level, we showed here, for the first time, protection of neuronal-like cells by the novel drug candidate, SKIP, against the Parkinson's disease-related neurotoxin, rotenone. Mechanistically, rotenone disrupted microtubule dynamics, which SKIP partially repaired through microtubule end-binding proteins, coupled with increasing neurite branch length. Given the previous association of rotenone toxicity with increased dopaminergic cell death hallmarking Parkinson's disease, we chose an established rat model of 6-hydroxydopamine (6-OHDA) toxicity to initially evaluate SKIP in vivo. SKIP pretreatment showed protection against nigral dopaminergic cell degeneration and improved motor behavior in the forelimb asymmetry test. With Parkinson's disease being a major neurodegenerative disorder, afflicting millions of people globally, and with disease modification challenges, SKIP may hold promise for future therapeutic development.

2016-10-01·Molecular psychiatry1区 · 医学

Sexual divergence in microtubule function: the novel intranasal microtubule targeting SKIP normalizes axonal transport and enhances memory

1区 · 医学

Article

作者: Hacohen-Kleiman, G ; Amram, N ; Giladi, E ; Katz, J ; Pasmanik-Chor, M ; Malishkevich, A ; Lagoudaki, R ; Touloumi, O ; Yeheskel, A ; Sragovich, S ; Grigoriadis, N C ; Jouroukhin, Y ; Gozes, I

Activity-dependent neuroprotective protein (ADNP), essential for brain formation, is a frequent autism spectrum disorder (ASD)-mutated gene. ADNP associates with microtubule end-binding proteins (EBs) through its SxIP motif, to regulate dendritic spine formation and brain plasticity. Here, we reveal SKIP, a novel four-amino-acid peptide representing an EB-binding site, as a replacement therapy in an outbred Adnp-deficient mouse model. We discovered, for the first time, axonal transport deficits in Adnp(+/-) mice (measured by manganese-enhanced magnetic resonance imaging), with significant male-female differences. RNA sequencing evaluations showed major age, sex and genotype differences. Function enrichment and focus on major gene expression changes further implicated channel/transporter function and the cytoskeleton. In particular, a significant maturation change (1 month-five months) was observed in beta1 tubulin (Tubb1) mRNA, only in Adnp(+/+) males, and sex-dependent increase in calcium channel mRNA (Cacna1e) in Adnp(+/+) males compared with females. At the protein level, the Adnp(+/-) mice exhibited impaired hippocampal expression of the calcium channel (voltage-dependent calcium channel, Cacnb1) as well as other key ASD-linked genes including the serotonin transporter (Slc6a4), and the autophagy regulator, BECN1 (Beclin1), in a sex-dependent manner. Intranasal SKIP treatment normalized social memory in 8- to 9-month-old Adnp(+/-)-treated mice to placebo-control levels, while protecting axonal transport and ameliorating changes in ASD-like gene expression. The control, all d-amino analog D-SKIP, did not mimic SKIP activity. SKIP presents a novel prototype for potential ASD drug development, a prevalent unmet medical need.

2013-04-01·Neurochemical research3区 · 医学

Spatiotemporal Expression of SKIP After Rat Sciatic Nerve Crush

3区 · 医学

Article

作者: Xiaolong Deng ; Haixiang Wei ; Xinghai Cheng ; Youhua Wang ; Hai Wen ; Dong Lou ; Yajuan Wu ; Long Long ; Hailei Chen ; Hao Wu ; Jiao Yang

Ski-interacting protein (SKIP) is a highly conserved protein from yeast to Human. As an essential spliceosomal component and transcriptional co-regulator it plays an important role in preinitiation, splicing and polyadenylation. SKIP can also combine with Ski to overcome the G1 arrest and the growth-suppressive activities of pRb. Furthermore SKIP has the capacity to augment TGF-β dependent transcription. While the distribution and function of SKIP in peripheral nervous system lesion and regeneration remain unclear. Here, we investigated the spatiotemporal expression of SKIP in an acute sciatic nerve crush model in adult rats. Western Blot analysis revealed that SKIP was expressed in normal sciatic nerves. It gradually increased, reached a peak at 1 week after crush, and then returned to the normal level at 4 weeks. Besides, we observed that up-regulation of SKIP was approximately in parallel with Proliferating cell nuclear antigen (PCNA), and numerous Schwann cells (SCs) expressing SKIP were PCNA and Ki-67 positive. Collectively, we hypothesized peripheral nerve crush induced up-regulation of SKIP in the sciatic nerve, which was associated with SCs proliferation.

项与 Exon 44 Skipping Oligonucleotide(Entrada Therapeutics) 相关的新闻（医药）

2024-10-09

·GlobeNewswire-Health Care

Entrada Therapeutics Presents New Data Supporting its Expanding Duchenne Franchise at the 29th Annual Congress of the World Muscle Society

– Additional positive data from the Company’s completed Phase 1 clinical trial evaluating ENTR-601-44 reinforces its safety profile and supports the planned Q4 2024 global regulatory filings for a Phase 2 clinical trial – – Preclinical data presented for the first time, showing exon skipping and dystrophin production for ENTR-601-45, supports the planned Q4 2024 regulatory filings for a global direct-to-patient Phase 2 clinical trial – BOSTON, Oct. 09, 2024 (GLOBE NEWSWIRE) -- Entrada Therapeutics, Inc. (Nasdaq: TRDA) is a clinical-stage biopharmaceutical company aiming to transform the lives of patients by establishing a new class of medicines that engage intracellular targets long considered inaccessible. Today the Company announced the presentation of clinical and preclinical data in support of its expanding Duchenne clinical franchise at the 29th Annual Congress of the World Muscle Society in Prague, Czechia from October 8-12, 2024. “We are excited to present these data which support the advancement of our Duchenne franchise. Adding to our previously reported positive data from our Phase 1 ENTR-601-44-101 trial, we are presenting further safety data demonstrating that there were no adverse findings or clinically relevant changes to any biomarkers of renal toxicity measured at the highest dose tested during the study. We are also pleased to present new data from preclinical studies of ENTR-601-45, showing compelling in vivo dystrophin production and functional improvement,” said Natarajan Sethuraman, PhD, President of R&D at Entrada Therapeutics. Dr. Sethuraman continued, “We are on track to submit regulatory applications this quarter to initiate separate global Phase 2 clinical trials for ENTR-601-44 and ENTR-601-45 in patients with Duchenne who are exon 44 skipping and exon 45 skipping amenable, respectively. In addition, we plan to submit regulatory applications in 2025 to initiate a global Phase 2 clinical trial for our third Duchenne candidate, ENTR-601-50, in patients who are exon 50 skipping amenable.” The posters will be presented during Poster Session 2 (DMD Treatments, 5:15-6:15 pm CET) and will be available on the Scientific Presentations page of the Company’s website. Poster presented by Natarajan Sethuraman, PhD, President of R&D of Entrada Therapeutics: Therapeutic Potential of ENTR-601-44, an Endosomal Escape Vehicle (EEV™)–Oligonucleotide Conjugate for the Treatment of Exon 44 Skip-Amenable Duchenne Muscular Dystrophy Highlights of the poster presentation include: Study ENTR-601-44-101 met all study objectives in healthy male volunteers with no adverse events related to ENTR-601-44 administration.Newly presented data include urine PK data, kidney function assessments and additional safety details. The data demonstrate that there were no adverse findings or clinically relevant changes to any biomarkers of renal toxicity at the highest dose tested (6 mg/kg) during the study.Dose dependent increases of the final metabolite were observed.Statistically significant differences in exon skipping between the 6 mg/kg and placebo administrations were also observed. These results demonstrate, for the first time, that the EEV platform can safely and effectively deliver oligonucleotide therapeutics to skeletal muscle with significant target engagement in human volunteers. Poster presented by Sweta Girgenrath, PhD, Vice President, Head of Cardiovascular and Neuromuscular Therapeutic Areas of Entrada Therapeutics: Exon 45 Skipping and Dystrophin Production with ENTR-601-45 in Preclinical Models of Duchenne Muscular Dystrophy Highlights of the poster presentation include data presented for the first time: ENTR-601-45 produced robust dose-dependent exon skipping and dystrophin restoration in both in vitro and in vivo models of exon 45 skip–amenable DMD.Improved skeletal muscle function in an exon 45 skip-amenable DMD mouse model suggests that ENTR-601-45 is capable of producing functional dystrophin protein in vivo.At the highest dose of ENTR-601-45 examined, dystrophin production and muscle function were similar to healthy control mice. These results show the therapeutic potential of ENTR-601-45 and support further study in patients with DMD amenable to exon 45 skipping. About Entrada TherapeuticsEntrada Therapeutics is a clinical-stage biopharmaceutical company aiming to transform the lives of patients by establishing a new class of medicines that engage intracellular targets that have long been considered inaccessible. The Company’s Endosomal Escape Vehicle (EEV™)-therapeutics are designed to enable the efficient intracellular delivery of a wide range of therapeutics into a variety of organs and tissues, resulting in an improved therapeutic index. Through this proprietary, versatile and modular approach, Entrada is advancing a robust development portfolio of RNA-, antibody- and enzyme-based programs for the potential treatment of neuromuscular, ocular, metabolic and immunological diseases, among others. The Company’s lead oligonucleotide programs are in development for the potential treatment of people living with Duchenne who are exon 44, 45 and 50 skipping amenable. Entrada has partnered to develop a clinical-stage program, VX-670, for myotonic dystrophy type 1. For more information about Entrada, please visit our website, www.entradatx.com, and follow us on LinkedIn. Forward-Looking StatementsThis 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 Entrada’s strategy, future operations, prospects and plans, objectives of management, the validation and differentiation of Entrada’s approach and its ability to provide a potential treatment for patients, expectations regarding significant accumulation of exon skipping and dystrophin production in patients, expectations regarding improvement in functional outcomes for patients after multiple doses of ENTR-601-44, expectations regarding the importance of endosomal escape to therapeutic index optimization, expectations regarding the timing of regulatory filings for the planned Phase 2 clinical trials for ENTR-601-44 and ENTR-601-45 in the fourth quarter of 2024, and ENTR-601-50 in 2025, the ability to recruit for and complete a global Phase 2 trial for ENTR-601-44, ENTR-601-45 and ENTR-601-50, the potential of Entrada’s EEV product candidates, including the potential for ENTR-601-44 to be a transformative treatment option, and EEV platform, and the continued development and advancement of ENTR-601-44, ENTR-601-45 and ENTR-601-50 for the treatment of Duchenne and the partnered product VX-670 for the treatment of myotonic dystrophy type 1, 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. Entrada 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 conduct of research activities and the initiation and completion of preclinical studies and clinical trials; uncertainties as to the availability and timing of results from preclinical and clinical studies; the timing of and Entrada’s ability to submit and obtain regulatory clearance and initiate clinical trials; whether results from preclinical studies will be predictive of the results of later preclinical studies and clinical trials; whether preliminary clinical data will be predictive of final clinical data; whether Entrada’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 Entrada’s filings with the Securities and Exchange Commission (SEC), including the Company’s most recent Form 10-K and in subsequent filings Entrada may make with the SEC. In addition, the forward-looking statements included in this press release represent Entrada’s views as of the date of this press release. Entrada anticipates that subsequent events and developments will cause its views to change. However, while Entrada 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 Entrada’s views as of any date subsequent to the date of this press release. Investor and Media ContactCaileigh DoughertyHead of Investor Relations & Corporate Communicationscdougherty@entradatx.com

临床1期临床2期寡核苷酸

2024-09-29

·药明康德

从无药可医到多款疗法获批，DMD疗法的下一步走向何方？

▎药明康德内容团队编辑在近日举办的2024药明康德投资者开放日上，药明康德联席首席执行官陈民章博士对化学业务平台能力、规模及业务增长驱动力进行了精彩分享。其中，药明康德在开发包括吗啉代反义寡核苷酸（PMO）和多肽-PMO偶联物（PPMO）在内的寡核苷酸药物方面的能力，有望为大量罕见病患者带来福音。9月恰逢肌肉萎缩症公共意识月（Muscular Dystrophy Awareness Month），在今天这篇文章中，药明康德内容团队将以杜氏肌营养不良症（DMD）为引子，介绍PMO/PPMO疗法如何为DMD患者，乃至更多罕见病患者带来了新希望。 DMD是一种致命的罕见肌肉萎缩疾病，由于编码抗肌萎缩蛋白（dystrophin）的基因发生变异，导致肌肉逐渐无力萎缩。全球范围内，大约每3500-5000名男性新生儿中就有1名DMD患儿，每年有2万名儿童确诊DMD。患者的预期寿命很少超过40岁。可喜的是，在科学家和药物研发人员的共同努力下，自2016年以来，已经有8款DMD疗法获得美国FDA的批准，其中5款创新疗法针对DMD疾病的根本原因。 ▲FDA批准治疗DMD的药物（数据来源：公开资料，药明康德内容团队制图，截至2024年9月19日）针对DMD疾病根源的新治疗模式既然DMD的产生源于抗肌萎缩蛋白的缺失，那么提高抗肌萎缩蛋白的表达，就有望恢复肌肉细胞的功能，减少肌肉细胞的损伤。已有5款利用这个作用机制的创新疗法获得了FDA的批准。其中最主要的一类是寡核苷酸疗法，包括Sarepta Therapeutics公司的Amondys 45，Vyondys 53，和Exondys 51，以及Nippon Shinyaku公司的Viltepso。它们作用机制类似，通过让寡核苷酸药物与编码抗肌萎缩蛋白的mRNA前体结合，改变mRNA前体的剪接过程，跳过携带基因突变的DMD外显子，从而生成具有大部分抗肌萎缩蛋白功能的截短蛋白。 ▲以Viltepso（又名NS-065）为例展示的寡核苷酸疗法作用机制（图片来源：Nippon Shinyaku公司官网）另一类则是基因疗法，比如罗氏与Sarepta Therapeutics联合开发的基因疗法Elevidys（delandistrogene moxeparvovec，SRP-9001）将表达微抗肌萎缩蛋白（micro-dystrophin）的转基因包装在腺相关病毒（AAV）载体中，通过单次静脉注射，使得患者肌肉生成具有部分抗肌萎缩蛋白功能的重组蛋白。与基因疗法相比，寡核苷酸疗法生成的抗肌萎缩蛋白保存了野生型蛋白中更多的结构域，能够更好地模拟野生型蛋白的功能。并且，通过改变寡核苷酸疗法的序列，可以迅速使用这一治疗模式靶向其它基因或者突变。因此，这一药物类型得到了产业相当多的关注。目前，所有4款获批的寡核苷酸疗法均采用了PMO技术，PMOs是一类基于RNA天然框架设计的合成分子。尽管PMOs含有与RNA相同的核酸碱基，它们却与六边型的吗啉环相连接，而不是与RNA中的五边型的核糖环相连。此外，这些吗啉环通过磷酰二胺键连接，而不是RNA中的磷酸二酯键。这种结构使PMOs能够与特定的mRNA前体序列结合，同时在生物体内不容易被降解。 ▲PMO结构示意图（图片来源：参考资料[1]）值得一提的是，药明康德化学业务平台的新分子板块（WuXi TIDES）于2018年布局，在多肽和寡核苷酸等新分子的开发和生产方面不断精进平台能力。以PMO为例，这类分子类型合成、生产极为复杂，药明康德基于大量知识经验的积累和洞见，不断优化工艺、内部整合流程提供一体化服务，在3年内将PMO类药物活性成分（API）成本降低60%，让这类药物成为一种可行的治疗模式。任何一种疗法都有其优势与局限，PMO疗法也不例外：它们的组织渗透能力不强，不容易被肌肉细胞吸收。即便被细胞摄取后，也很容易在溶酶体中被降解。如何提高寡核苷酸疗法的组织特异性递送，在提高疗效的同时降低剂量，并且扩展适用的疾病范围，成为这一领域的重要研发方向。现有疗法的局限性，也促使更多生物技术公司继续加大投入，开发新一代的DMD疗法，以更好地造福病患。偶联技术提高寡核苷酸疗法递送效率和表达水平为了提升PMO疗法的临床效果，各个公司处于临床阶段的寡核苷酸药物纷纷在药物合成工艺上进行了创新。其中一种方式便是将寡核苷酸与细胞穿透肽（CPP）相偶联，形成称之为PPMO的新一代PMO疗法。CPP由少于30个氨基酸组成，具有两亲性或阳离子性，能够携带大分子生物载荷穿透细胞膜，从而增加寡核苷酸的细胞和组织渗透性，这使药物在低剂量时便具有增强的疗效。此外，临床前实验结果也显示，PPMO疗法能够促进抗肌萎缩蛋白的持续生产，并可靶向横膈肌与心肌，且能以更高的效率递送至目标组织。目前，几款PPMO疗法已进入临床试验阶段。其中Sarepta Therapeutics开发的SRP-5051（vesleteplirsen）旨在与抗肌萎缩蛋白的mRNA前体外显子51结合，促使mRNA在处理过程中跳过该外显子，从而生成缩短但功能保留的抗肌萎缩蛋白。根据今年初公布的2期多剂量递增试验结果，接受该疗法的DMD患者产生了令人鼓舞的抗肌萎缩蛋白水平。 ▲抗体（左）与CPP（右）偶联寡核苷酸疗法示意图（图片来源：参考资料[5]）此外，PepGen公司通过其专有EDO平台开发的PPMO疗法PGN-EDO51也正在临床2期试验中，评估其在适合外显子51跳跃基因突变的DMD患者中的疗效与安全性。EDO平台的专有CPP可增强细胞摄取，并促使寡核苷酸在被溶酶体降解前成功逃逸。临床前研究表明，该疗法能够有效递送至多种肌肉组织，包括心肌、骨骼肌和平滑肌，展现出广泛的治疗潜力。同样为了应对溶酶体降解的挑战，Entrada Therapeutics开发了ENTR-601-44，这款疗法由该公司专有的内体逃逸载体（EEV）多肽与PMO偶联，旨在治疗适合接受外显子44跳跃疗法的DMD患者。今年6月发布的1期临床试验结果显示，与安慰剂组相比，接受ENTR-601-44治疗的患者，其外显子跳跃水平显著提高，具统计学意义。 ▲部分处于临床阶段的下一代DMD寡核苷酸疗法在研管线（数据来源：公开资料，药明康德内容团队制图，截至2024年9月19日） PMO、PPMO相关疗法的开发需要极复杂的工艺技术，而药明康德在化学业务上20年的丰富经验为开发这类新一代疗法打下坚实的基础。根据2024药明康德投资者开放日公开的信息，其团队具备PMO单体、PMO、多肽、PPMO偶联及制剂开发的综合能力，在PMO与PPMO疗法的开发上是唯一可以提供“一站式”解决方案的CDMO。投资者开放日上，我们还看到了一个具体的赋能案例：对于生产技术极为复杂的PPMO疗法，公司寡核苷酸、多肽、制剂、分析等6个团队平行推进、无缝衔接，将一款来自客户的在研疗法仅用11个月推进至IND。这也得益于药明康德在CMC一体化解决方案方面的专精与专长。截至目前，药明旗下负责PMO和PPMO生产的WuXi TIDES平台已为三款治疗DMD的PMO和PPMO疗法提供了研发赋能。值得一提的是，今年8月，PepGen公司首席执行官James McArthur在接受《波士顿商业杂志》采访时特地感谢了药明康德为其公司提供的赋能服务。这名行业老兵已经在产业里摸爬滚打了超过25年，他直言与药明康德的合作已经贯穿了他的多家公司。在先前的一家公司里，没有一家美国的供应商能在有限的时间里完成他们想要的工作，只有药明康德满足了他的要求。展望未来，考虑到寡核苷酸疗法的作用机制，此类疗法的治疗范围远不只是DMD，更多不同的罕见病患者有望从这种新分子疗法中受益。能为全球创新合作伙伴们赋能，药明康德倍感荣幸。我们也祝愿更多好药新药能够顺利问世，造福全球病患！ ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料： [1] Roberts et al, (2023). Therapeutic approaches for Duchenne muscular dystrophy. Nature Reviews Drug Discovery. https://doi.org/10.1038/s41573-023-00775-6 [2] MDA Kicks Off Muscular Dystrophy Awareness Month in September with ‘30 Days of Strength’ Campaign with Hundreds of Events to Advance Research and Care for the Neuromuscular Disease Community. Retrieved September 19, 2024, from https://www.mda.org/press-releases/2024/mda-kicks-off-muscular-dystrophy-awareness-month-in-september-with-30-days-of-strength-campaign-with-hundreds-of-events-to-advance-research-and-care-for-the-neuromuscular-disease-community [3] RNA Platform Leveraging RNA technology to treat rare disease. Retrieved September 19, 2024, from https://www.sarepta.com/science/rna-platform [4] Sarepta Therapeutics Corporate Presentation 2024. Retrieved September 19, 2024, from https://investorrelations.sarepta.com/static-files/54793bd6-09b6-4c68-8281-39e586071e88 [5] Roberts TC, Langer R, Wood MJA. Advances in oligonucleotide drug delivery. Nat Rev Drug Discov. 2020 Oct;19(10):673-694. doi: 10.1038/s41573-020-0075-7. Epub 2020 Aug 11. PMID: 32782413; PMCID: PMC7419031. [6] Avidity Biosciences Announces Positive AOC 1044 Data Demonstrated Significant Increase of 25% in Dystrophin Production and Reduction of Creatine Kinase Levels to Near Normal in People Living with Duchenne Muscular Dystrophy Amenable to Exon 44 Skipping in the Phase 1/2 EXPLORE44™ Trial. Retrieved September 22, 2024 from https://www.prnewswire.com/news-releases/avidity-biosciences-announces-positive-aoc-1044-data-demonstrated-significant-increase-of-25-in-dystrophin-production-and-reduction-of-creatine-kinase-levels-to-near-normal-in-people-living-with-duchenne-muscular-dystrophy-amenab-302218647.html [7] Sarepta Therapeutics Announces Positive Data from Part B of MOMENTUM, a Phase 2 Study of SRP-5051 in Patients with Duchenne Muscular Dystrophy Amenable to Skipping Exon 51. Retrieved September 22, 2024 from https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-positive-data-part-b-momentum [8] Advancing the Use of Peptide-Conjugated Oligonucleotides to Target Neuromuscular Disorders: Enhanced Delivery Oligonucleotides for DMD and DM1. Retrieved September 22, 2024 from https://investors.pepgen.com/static-files/ff601ea2-0a29-435f-82b1-c885924cfb94 [9] Watanabe N, Tone Y, Nagata T, Masuda S, Saito T, Motohashi N, Takagaki K, Aoki Y, Takeda S. Exon 44 skipping in Duchenne muscular dystrophy: NS-089/NCNP-02, a dual-targeting antisense oligonucleotide. Mol Ther Nucleic Acids. 2023 Sep 20;34:102034. doi: 10.1016/j.omtn.2023.102034. PMID: 37854955; PMCID: PMC10579524. [10] Myotonic Dystrophy Type 1 Program. Retrieved September 22, 2024 from https://www.entradatx.com/dm1 [11] Tsoumpra MK, Fukumoto S, Matsumoto T, Takeda S, Wood MJA, Aoki Y. Peptide-conjugate antisense based splice-correction for Duchenne muscular dystrophy and other neuromuscular diseases. EBioMedicine. 2019 Jul;45:630-645. doi: 10.1016/j.ebiom.2019.06.036. Epub 2019 Jun 27. PMID: 31257147; PMCID: PMC6642283. 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。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：本文来自药明康德内容团队，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，聚焦全球生物医药健康创新

寡核苷酸信使RNA基因疗法临床研究核酸药物

2024-08-13

·GlobeNewswire-Health Care

Entrada Therapeutics Reports Second Quarter 2024 Financial Results

– Generated positive data from the Phase 1 clinical trial of ENTR-601-44 for DMD, including dose-dependent plasma and muscle concentration, and exon skipping – – Planning underway for separate global Phase 2 clinical trials for ENTR-601-44 and ENTR-601-45 with regulatory filings anticipated in Q4 2024 – – Completed $100 million registered direct offering led by a U.S.-based healthcare focused investor, two global mutual funds and Janus Henderson Investors, a global asset management firm – – Cash runway expected into 2027 with $470 million in cash, cash equivalents, and marketable securities as of June 30, 2024 – BOSTON, Aug. 13, 2024 (GLOBE NEWSWIRE) -- Entrada Therapeutics, Inc. (Nasdaq: TRDA) is a clinical-stage biopharmaceutical company aiming to transform the lives of patients by establishing a new class of medicines that engage intracellular targets long considered inaccessible. The Company today reported financial results for the second quarter ended June 30, 2024, and highlighted recent business updates. “In the last quarter, Entrada delivered compelling Phase 1 clinical data from our Duchenne program ENTR-601-44, demonstrating the translation of our nonclinical studies to healthy volunteers. We remain on track to advance separate Phase 2 clinical trials across multiple Duchenne programs, including those targeting exon 44, exon 45 and exon 50,” said Dipal Doshi, Chief Executive Officer at Entrada Therapeutics. “With the completion of a successful financing that extends our cash runway into 2027, we are positioned to advance our Duchenne portfolio while expanding into other disease areas that could benefit from our differentiated approach to intracellular delivery.” Recent Corporate Highlights In June, Entrada announced positive preliminary data from its Phase 1 clinical trial of ENTR-601-44-101 for Duchenne muscular dystrophy (DMD). The study has since been completed with no drug-related adverse findings noted. ENTR-601-44 was generally well-tolerated in healthy volunteers with no serious adverse events, no drug-related adverse events and no clinically significant changes or trends noted in vital signs, electrocardiograms, physical exams or laboratory assessments observed in the trial. The product candidate demonstrated a strong dose-dependent response, significant plasma concentration, muscle concentration and exon skipping, at levels that suggest the potential for a clinically meaningful starting dose in planned upcoming patient trials. Data will be featured in a poster presentation at the 29th Annual Congress of the World Muscle Society, taking place in Prague, Czechia from October 8-12, 2024.Planning is underway for separate global Phase 2 clinical trials for ENTR-601-44 and ENTR-601-45 with regulatory filings anticipated in Q4 2024. The Company also plans to submit regulatory applications in 2025 to initiate a global Phase 2 clinical trial for its third Duchenne candidate, ENTR-601-50, in patients who are exon 50 skipping amenable.The Company completed a $100 million registered direct offering in June 2024. The proceeds from the offering resulted in the extension of the Company’s cash runway into 2027.Vertex Pharmaceuticals announced that they continue to enroll and dose patients in the global Phase 1/2 clinical trial for VX-670 in people with DM1 and expect to complete the single ascending dose (SAD) portion of the study by the end of 2024. Following completion of the SAD portion of the trial, Vertex will move into the multiple ascending dose portion, where both the safety and efficacy of VX-670 will be evaluated. Upcoming Investor Conferences The Company will present at the H.C. Wainwright 25th Annual Global Investment Conference in New York, NY on September 9, 2024. Second Quarter 2024 Financial Results Cash Position: Cash, cash equivalents and marketable securities were $469.7 million as of June 30, 2024, compared to $352.0 million as of December 31, 2023. The increase was primarily a result of the $100 million registered direct offering completed in June of 2024 and the receipt of the $75 million payment for the clinical advancement milestone for VX-670 that was achieved in March of 2024. Based on current operating plans, the Company believes that its cash, cash equivalents and marketable securities as of June 30, 2024 will be sufficient to fund its operations into 2027. Collaboration Revenue: Collaboration revenue was $94.7 million for the second quarter of 2024, compared to $18.2 million for the same period in 2023. The increase was primarily a result of additional VX-670 research activities performed during the second quarter of 2024 and an increase in the total transaction price related to the clinical advancement milestone that was achieved in March of 2024. Research & Development (R&D) Expenses: R&D expenses were $32.0 million for the second quarter of 2024, compared to $26.3 million for the same period in 2023. The increase was primarily driven by additional research activities performed for VX-670 and additional preclinical costs incurred related to ENTR-601-50, as well as higher personnel costs (including non-cash, stock-based compensation). General & Administrative (G&A) Expenses: G&A expenses were $9.2 million for the second quarter of 2024, compared to $8.2 million for the same period in 2023. The increase was primarily due to higher personnel costs (including non-cash, stock-based compensation). Net Income (Loss): Net income was $55.0 million for the second quarter of 2024, compared to a net loss of $(25.9) million for the same period in 2023. About Entrada Therapeutics Entrada Therapeutics is a clinical-stage biopharmaceutical company aiming to transform the lives of patients by establishing a new class of medicines that engage intracellular targets that have long been considered inaccessible. The Company’s Endosomal Escape Vehicle (EEV™)-therapeutics are designed to enable the efficient intracellular delivery of a wide range of therapeutics into a variety of organs and tissues, resulting in an improved therapeutic index. Through this proprietary, versatile and modular approach, Entrada is advancing a robust development portfolio of RNA-, antibody- and enzyme-based programs for the potential treatment of neuromuscular, ocular, metabolic and immunological diseases, among others. The Company’s lead oligonucleotide programs are in development for the potential treatment of people living with Duchenne who are exon 44, 45 and 50 skipping amenable. Entrada has partnered to develop a clinical-stage program, VX-670, for myotonic dystrophy type 1. For more information about Entrada, please visit our website, www.entradatx.com, and follow us on LinkedIn. 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 Entrada’s strategy, future operations, prospects and plans, objectives of management, the validation and differentiation of Entrada’s approach and its ability to provide a potential treatment for patients, the translatability of the data from the Phase 1 clinical trial for ENTR-601-44 to future clinical trials for ENTR-601-44, expectations regarding the ability of Entrada’s preclinical studies and clinical trials to demonstrate safety and efficacy of its therapeutic candidates, and other positive results, expectations regarding the starting dose for Entrada’s planned Phase 2 clinical trial for ENTR-601-44, expectations regarding the timing of regulatory filings for the planned Phase 2 clinical trials for ENTR-601-44 and ENTR-601-45 in the fourth quarter of 2024, and ENTR-601-50 in 2025, the ability to recruit for and complete global Phase 2 clinical trials for ENTR-601-44, ENTR-601-45 and ENTR-601-50, the potential of Entrada’s EEV product candidates, including the potential for ENTR-601-44 to be a transformative treatment option, and EEV platform, and the continued development and advancement of ENTR-601-44, ENTR-601-45 and ENTR-601-50 for the treatment of DMD and the partnered product candidate VX-670 for the treatment of myotonic dystrophy type 1, expectations regarding the progress and success of Entrada’s collaboration with Vertex, including express and implied statements regarding any future payments Entrada may receive under the Vertex Agreement, the ability to continue to expand and develop additional therapeutic programs, including further exon skipping programs, the potential therapeutic benefits of its EEV candidates and the ability to advance EEV-therapeutic candidates in indications beyond neuromuscular disease, and the sufficiency of its cash resources into 2027, 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. Entrada 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 conduct of research activities and the initiation and completion of preclinical studies and clinical trials; uncertainties as to the availability and timing of results from preclinical and clinical studies; the timing of and Entrada’s ability to submit and obtain regulatory clearance and initiate clinical trials; whether results from preclinical studies or clinical trials will be predictive of the results of later preclinical studies and clinical trials; whether Entrada’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 Entrada’s filings with the Securities and Exchange Commission (SEC), including the Company’s most recent Form 10-K and in subsequent filings Entrada may make with the SEC. In addition, the forward-looking statements included in this press release represent Entrada’s views as of the date of this press release. Entrada anticipates that subsequent events and developments will cause its views to change. However, while Entrada 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 Entrada’s views as of any date subsequent to the date of this press release. ENTRADA THERAPEUTICS, INC.Condensed Consolidated Statements of Operations (Unaudited)(In thousands, except share and per share amounts) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 Collaboration revenue 94,694 18,170 153,814 43,430 Operating expenses: Research and development 32,035 26,300 60,643 49,402 General and administrative 9,236 8,169 18,635 16,107 Total operating expenses 41,271 34,469 79,278 65,509 Income (loss) from operations 53,423 (16,299) 74,536 (22,079)Other income: Interest and other income 4,366 4,218 8,580 6,875 Total other income 4,366 4,218 8,580 6,875 Income (loss) before provision for income taxes 57,789 (12,081) 83,116 (15,204)Provision for income taxes (2,758) (13,847) (4,589) (17,398)Net income (loss) 55,031 (25,928) 78,527 (32,602)Net income (loss) per share, basic$ 1.61 $ (0.78) $ 2.32 $ (0.99)Net income (loss) per share, diluted$ 1.55 $ (0.78) $ 2.23 $ (0.99)Weighted‑average common shares outstanding, basic 34,180,549 33,163,320 33,838,811 32,770,989 Weighted‑average common shares outstanding, diluted 35,507,029 33,163,320 35,148,221 32,770,989 ENTRADA THERAPEUTICS, INC.Condensed Consolidated Balance Sheet Data (Unaudited)(In thousands) March 31, 2024 December 31, 2023 Cash, cash equivalents and marketable securities$ 469,746 $ 351,969Total assets 581,963 469,192Total liabilities 152,038 226,832Total stockholders’ equity 429,925 242,360 Investor and Media ContactCaileigh DoughertyHead of Investor Relations & Corporate Communicationscdougherty@entradatx.com

临床1期财报临床2期临床结果

100 项与 Exon 44 Skipping Oligonucleotide(Entrada Therapeutics) 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
杜氏肌营养不良症	临床1期	英国	Entrada Therapeutics, Inc.	2023-09-22

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ENTR-601-44-101 (Company_Website) 人工标引	临床1期	杜氏肌营养不良症	32	ENTR-601-44	製製繭築鏇鏇膚遞鹽築(憲繭壓窪鹽簾憲齋淵簾) = None 遞製鏇壓繭廠積網獵構 (壓觸獵積鏇簾選鹹鬱顧 ) 更多	积极	2024-06-24
MDA2023	N/A	-	3	Casimersen	衊鹹選餘憲淵觸網築顧(夢製膚選齋鏇憲蓋糧製) = Autism spectrum disorder precluded meaningful functional assessment in one ambulatory subject 淵簾繭鹹壓鹹憲鹽鏇選 (衊願選衊選夢繭醖鬱糧 ) 更多	积极	2023-03-19
MDA2023	N/A	-	3	Golodirsen		积极	2023-03-19