OTX-2002

导读：新冠疫苗巨头之一——Moderna（莫德纳）的发展离不开Flagship Pioneering（旗舰先锋）这家独特眼光的投资公司的大力支持。Moderna的突然崛起也让Flagship再次走进大家的视野。 Flagship Pioneering是一家生物技术投资公司，以鼓励创新项目的落地和转化。自2000年成立以来，Flagship通过旗下的Flagship Labs部门发起并孵化了超过100家科技企业，包含20多家上市企业。 Flagship具有特色的投资和运营模式，分为四个阶段： nExplorations（探索阶段）：Flagship团队人员就各种前沿技术提出科学假设，并不断的优化迭代，直至产生突破性的想法和技术； nProtoCos（原型公司）：有前景的设想会在Flagship Labs立项，并赋予一个FL/LS编号，也是他们后期成立初创公司的“雏形”； nNewCo（初创型企业）：当设想被验证成功，Flagship会为其投资，该项目将会作为初创公司成立； nGrowthCo（成长型企业）：随着项目的开展，公司逐渐成长，吸引到外部投资者或合作伙伴。 目前，Flagship孵化的企业包括mRNA技术、核酸递送技术和AI药物开发技术。本期文章，菌菌将关注于mRNA领域，盘点顶级风投Flagship孵化的mRNA企业。 01 Moderna：mRNA疫苗/药物 2010年，麻省理工学院（MIT）化学工程学院教授Bob Langer向Flagship的创始人兼首席执行官（CEO）Noubar Afeyan介绍了“mRNA成药”的设想，由此成立了一家概念验证阶段的合资公司，代号为LS18，意为Afeyan创立的生命科学（Life Science）领域的第18家公司。 随后，LS18被重新命名为Moderna（名称来源于modified RNA），他们的核心技术为使用修饰mRNA在体内表达蛋白，潜在应用领域包括传染病和肿瘤免疫疗法等。 自2014年以来，Moderna成立了多家合资公司，分别聚焦于不同的疾病领域，如专注于mRNA肿瘤疗法的Onkaido Therapeutics、专注于传染病mRNA疫苗的Valera、专注于罕见病mRNA疗法的Elpidera、个性化肿瘤治疗的Caperna。Moderna还通过收购日本OriCiro Genomics获得了无细胞合成DNA的技术。 截止目前，Moderna已将2个mRNA热门管线推至上市，包括新冠疫苗Spikevax（mRNA-1273）和RSV疫苗mRESVIA（mRNA-1345），将有效减轻呼吸道疾病带来的社会负担。此外，Moderna多个管线处于后期临床阶段（2期至3期），包括流感疫苗（mRNA-1010、mRNA-1020、mRNA-1030、mRNA-1011、mRNA-1018）、巨细胞病毒CMV疫苗（mRNA-1647）、单纯疱疹病毒HSV疫苗（mRNA-1608）、带状疱疹VZV疫苗（mRNA-1468）、诺如病毒疫苗（mRNA-1403、mRNA-1405）、莱姆病疫苗（mRNA-1975、mRNA-1982）、寨卡病毒疫苗（mRNA-1893）、癌症疫苗（mRNA-4157、mRNA-4359）、蛋白替代疗法（mRNA-3927、mRNA-3705）等。 表1 Moderna临床2-3期管线汇总 02 Sail：环状mRNA疫苗/药物 Sail Biomedicines成立于2023年，由Falgship孵化的两家公司（环状mRNA公司Laronde与纳米颗粒递送 & AI平台型公司Senda）合并而成。 Sail的环状RNA平台依托于原Laronde公司，这一环状RNA平台被命名为Endless RNA（eRNA），最初由Avak Kahvejian博士团队开发。他们的研究起始于天然环状长链非编码RNA（lncRNA）的发现，随后专注于工程化改造的环状RNA和可编码环状mRNA。2021年，Laronde吸引到4.4亿美元的融资，包括Flagship Pioneering以及其他公共和私人投资者。 原Senda公司的最初研究方向为利用微生物组与人的互作实现疾病治疗，公司同时积累了丰富的AI经验。在一轮关键的融资后，Senda的研究转向了天然纳米颗粒的开发，用于RNA等药物的定向递送。 Sail的成立旨在整合平台资源，借助可编程的endless RNA（eRNA）技术、纳米颗粒和新兴独家AI技术，以释放环状mRNA药物的广泛潜力。 2024年1月份，Sail公开了他们近期的管线开发计划： 其一是疟疾预防和治疗，他们将基于创新型Endless RNA（eRNA）平台开发疟疾疫苗、以及编码单克隆抗体的eRNA药物。该项目获得了比尔和梅琳达·盖茨基金会的资助。 其二是囊性纤维化（CF）治疗，他们设计了一种编码功能性全长囊性纤维化跨膜传导调节因子（CFTR）的eRNA。早期研究数据显示，eRNA介导产生的CFTR蛋白表达水平和持续时间比线性mRNA更高、更长。该项研究由囊性纤维化基金会（CF Foundation）资助。 环状RNA专利方面，Flagship/Sail在circRNA结构设计、递送方案和circRNA应用等多个方面均有布局。 表2 Flagship/Sail在circRNA领域的专利组合布局 03 Omega：mRNA表观遗传疗法 Omega Therapeutics成立于2017年，是由Flagship孵化的一家临床阶段药物研发公司。Omega公司开创性地将mRNA用于靶基因的表观遗传调控，有望用于治疗或治愈多种疾病。 基于mRNA的OEC表观基因组控制子（OMEGA Epigenomic Controllers）是Omega公司的核心技术。OEC是一种模块化、可编程的mRNA疗法，其中mRNA编码一种由DNA结合域和表观遗传效应子蛋白组成的融合蛋白。该效应子能够通过多种表观遗传机制来控制基因表达的各种调节因子，例如 DNA 甲基化/去甲基化和控制染色质状态的机制（例如组蛋白修饰、乙酰化等）。 OTX-2002是Omega公司的代表性管线之一，利用mRNA表达靶向MYC基因的两个表观遗传控制子，目标适应症是肝细胞癌（HCC）。Omega此前公布了OTX-2002的临床前数据，揭示了OTX-2002在多种体外和体内模型中的作用机制和抗肿瘤活性。OTX-2002被FDA授予孤儿药称号，目前在开展1/2期临床研究。 图1 Omega公司OEC表观基因组控制子的结构特征 04 Tessera：mRNA基因编辑疗法 Tessera Therapeutics是由Flagship投资的另一家生物技术公司，此前已完成超5亿美元的融资。Tessera的技术特色在于一种新型基因治疗平台——“Gene Writing”（基因编写），利用该平台能够实现任何基因的删除或插入，具备治愈遗传病的潜力。结合脂质纳米颗粒（LNP）这一新型递送系统，Tessera正在探究该平台用于体内基因编写、体内基因重编写和体外基因编写的应用潜力。 2024年，Tessera在多个学术会议上公开了最新研究成果。借助T细胞靶向性LNP，他们将基于RNA的基因编写器直接递送至体内，并且在体内生成CAR-T细胞。造血干细胞（HSC）靶向的LNP能够将靶向镰状细胞突变的RNA基因编写器递送至体内，完成了RNA基因编写器治疗镰状细胞病（SCD）的体内概念验证。Tessera的另一研究项目是一种肝脏单基因遗传病——α-1抗胰蛋白酶缺乏症（AATD），Tessera平台优化后的RNA基因编写器成功校正了肝细胞中的基因组DNA。目前该项目已完成非人灵长类动物（NHP）的体内概念验证。 05 Repertoire：mRNA自免耐受疫苗 与Sail的成立类似，Repertoire也是由两家初创生物技术公司合并而成——Cogen Immune Medicine和Torque Therapeutics。其中Cogen专注于开发T细胞和免疫分析技术，随后衍生得到DECODE平台；而Torque聚焦于新型细胞免疫疗法。 Repertoire的成立，建立了一个T细胞受体（TCR）表位发现平台“DECODE”以及基于mRNA-LNP平台，专注于开发自身免疫性疾病的替代疗法。 2024年4月份，Repertoire宣布与百时美施贵宝（BMS）达成战略合作协议，开发针对自身免疫性疾病的耐受疫苗（Tolerizing vaccine）。耐受疫苗由编码抗原表位的mRNA和编码免疫调节因子的mRNA组成。耐受疫苗的作用机制是：通过触发机体内抗原特异性调节性T细胞的扩增，从而抑制免疫反应，恢复体内平衡，直接解决自身免疫疾病的真正驱动因素。耐受疫苗的成功有望在低给药频率下实现持久的效应，将改变自身免疫性疾病的管理模式。 06 结语 总体而言，Flagship Pioneering投资模式无疑鼓励了前沿性生物科技的成果转化，其孵化的mRNA创新企业均具备特色的技术风格。Moderna基于修饰mRNA，深耕于mRNA疫苗和蛋白替代疗法；Sail搭建了mRNA的2.0版本——环状RNA平台，将基于这一更稳定的结构释放RNA疗法的广阔潜力；Omega、Tessera和Repertoire则将mRNA-LNP技术应用于更前沿的基因疗法或细胞免疫疗法，期待改善遗传性疾病和自身免疫疾病的治疗模式。 识别微信二维码，添加生物制品圈小编，符合条件者即可加入 生物制品微信群！ 请注明：姓名+研究方向！ 版 权 声 明 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

Established clinical proof-of-mechanism and validation of epigenomic controllers as potential new class of medicines from completed Phase 1 MYCHELANGELO™ I trial for c-MYC in HCC; Company exploring strategic partnership opportunities for Phase 2 development of OTX-2002Company is focusing capital resources on three prioritized programs that reflect Omega’s unique value proposition to enable precision epigenomic control for potential therapeutic advantages versus existing modalitiesBoard has appointed Kaan Certel, Ph.D., as Omega’s President and Chief Executive Officer, and Jennifer Nelson, Ph.D., as Chief Scientific OfficerCompany is pursuing strategic partnership opportunities to support development of new and existing pipeline programs; collaboration with Novo Nordisk for development of an epigenomic controller for obesity continues to advance CAMBRIDGE, Mass., Nov. 14, 2024 (GLOBE NEWSWIRE) -- Omega Therapeutics, Inc. (Nasdaq: OMGA) (“Omega”), a biotechnology company pioneering the development of a new class of programmable epigenomic medicines, today announced financial results for the quarter ended September 30, 2024 and multiple strategic and leadership updates, including the appointment of Kaan Certel, Ph.D., an industry veteran with extensive experience in corporate strategy and business development, as Chief Executive Officer. Dr. Certel succeeds Mahesh Karande as CEO, who has decided to leave Omega for personal reasons. In addition, the Company shared updated clinical data from the Phase 1 MYCHELANGELO™ I clinical trial and a strategic prioritization of its pipeline to focus resources on programs in which the Company believes epigenomic controllers have the potential to demonstrate therapeutic advantages over existing modalities, address significant unmet needs and unlock rapid value creation. “Kaan Certel has demonstrated outstanding business and scientific leadership as our Chief Business Officer since joining Omega earlier this year. We are excited to welcome him to his new role as Omega’s Chief Executive Officer,” said Chris Schade, Chairman of the Board of Directors of Omega Therapeutics. “His deep scientific expertise and strong track record of driving strategic partnerships will be invaluable as we advance our pipeline of impactful programs and expand our business development efforts. On behalf of the entire board, I want to extend our sincere gratitude to Mahesh for his efforts in establishing a strong foundation for Omega and advancing epigenomic controllers to clinical proof-of-mechanism.” “I am excited to work with the board and our team to build on the progress Omega has made harnessing the power of epigenomic controllers. The compelling data that we have generated both clinically and pre-clinically gives us greater confidence in the potential of programmable epigenomic medicines to address a broad range of diseases,” said Kaan Certel, Ph.D., President and Chief Executive Officer of Omega Therapeutics. “The industry-first data from our recently completed, first-in-human clinical trial provide clear proof-of-mechanism, having demonstrated highly specific, on-target engagement with the intended epigenomic state change. We believe these data validate epigenomic controllers as a potential new class of medicines. In parallel, we have deepened our technical capabilities with a focus on upregulation and exquisite multiplexed control, which we believe may hold therapeutic advantages over existing modalities.” Dr. Certel continued, “Together with our new Chief Scientific Officer, Jennifer Nelson, Ph.D., we are focusing our pipeline on three programs with significant opportunities in obesity, regenerative medicine and metabolic indications that fully leverage our unique value proposition in epigenomic modulation. Going forward, we plan to focus our resources on these prioritized programs and on cultivating strategic partnerships to advance existing and new development candidates as a core component of our corporate strategy. We are actively engaged in ongoing dialogue with potential partners to further support and expand our pipeline in an accelerated and capital-efficient manner.” Prioritized Pipeline Omega is prioritizing select preclinical programs in three areas where precision epigenomic control offers clear potential therapeutic advantages over existing modalities, including trans-differentiation for cellular reprogramming and durable upregulation of gene expression of intracellular proteins or secreted proteins where naturally occurring protein production may offer advantages over traditional biologics. Program advancement will be disciplined and data-driven to maximize shareholder value, capital efficiency and strategic partnering opportunities. Obesity In collaboration with Novo Nordisk, Omega continues to advance the development of an epigenomic controller for obesity. This program leverages Omega’s platform capabilities in trans-differentiation to transition the epigenetic state of white adipose cells to metabolically active brown adipose cells, with the goal of enhancing metabolic activity as a part of a potential new treatment approach for obesity management. Regenerative Medicine HNF4A: Multiple liver diseases such as MASH (metabolic dysfunction-associated steatohepatitis) are characterized by fibrosis secondary to chronic inflammation. HNF4A is a nuclear receptor and master regulator of liver development and function. Upregulation of the HNF4A gene holds the potential to mitigate fibrosis and restore liver function. Omega has generated in vitro and in vivo data demonstrating the ability of epigenomic controllers to significantly upregulate HNF4A gene expression and reduce key measures of fibrosis. Metabolic FGF21: A hormone involved in multiple metabolic processes, FGF21 has been implicated in hyperlipidemia and obesity. Well established preclinical models have demonstrated clear translatability to clinical studies and provide an opportunity to rapidly advance candidates to clinical proof-of-concept studies. Upregulation of FGF21 through precision epigenomic control may offer a compelling approach to address multiple metabolic indications where upregulation of natural protein expression cannot be mimicked by existing modalities. Other Programs The Phase 1 MYCHELANGELO trial of OTX-2002 has been completed and the Company is engaged in discussions with potential partners to further advance clinical development into Phase 2 or may choose to resume development through internal efforts with additional funding.The OTX-2101 and CXCL1-8 programs have been deprioritized in order to focus resources and capital on the three selected programs described above. The Company is pursuing strategic partnership opportunities to advance these programs or may choose to resume development through internal efforts with additional funding. “Our prioritized pipeline leverages the differentiated capabilities of our platform and reflects the diverse potential applications of Omega’s technology. We are excited by the opportunity to demonstrate the power of precision epigenomic control in these select high-value programs and build on the clinical progress we have made,” said Jennifer Nelson, Ph.D., Chief Scientific Officer of Omega Therapeutics. “Our first-in-human study clearly demonstrated our ability to prospectively design an epigenomic controller capable of inducing prespecified changes in epigenetic signatures that alter gene expression with high specificity. Expanding on these results, we have an incredible opportunity to establish epigenomic controllers as a new class of medicines with unparalleled versatility.” Topline Data from Completed Phase 1 MYCHELANGELO™ Trial The Phase 1 monotherapy dose escalation portion of MYCHELANGELO I was designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of OTX-2002 in patients with relapsed or refractory hepatocellular carcinoma (HCC) and other solid tumor types known for association with the MYC oncogene. Twenty-four patients, including 19 with HCC, were enrolled across six dose cohorts (spanning 0.02 mg/kg to 0.3 mg/kg) and were treated with OTX-2002 intravenously once every two weeks. Topline data from the completed Phase 1 trial showed: Pharmacodynamics and pharmacokinetics: Highly specific on-target engagement with intended epigenetic changes at the target genomic loci, as evidenced by a robust increase in cell-free DNA MYC methylation signal following administration of study drug. The signal was dose dependent within the tolerated dose range. Pre-dose levels of MYC methylation were non-detectable. The increased methylation signal persisted throughout the two-week dosing interval and downregulation of MYC expression was observed.Predictable and consistent pharmacokinetics profile with rapid clearance, minimal variability observed within and between patients, and no accumulation observed with repeat administration. Safety and tolerability: At the recommended dose for expansion (0.12 mg/kg), OTX-2002 showed a favorable safety profile, with infusion-related reactions being the most common adverse event, generally consistent with the known profile of other FDA-approved LNP-delivered therapeutics. Preliminary clinical activity in HCC: The observed disease control rate (DCR) for response-evaluable HCC patients was 50%, with a best overall response of stable disease. This DCR is in-line with the historical benchmark range for completed Phase 1 trials for approved TKIs and PD-1 monotherapies in HCC (29-65%). The Company plans to present the Phase 1 dataset at an upcoming scientific conference. Corporate Updates The Board of Directors has appointed Kaan Certel, Ph.D., as Omega’s Chief Executive Officer, and Jennifer Nelson, Ph.D., as Chief Scientific Officer. Dr. Certel is a recognized leader with over 20 years of experience in the biopharmaceutical industry and academia with a track record of successfully driving strategic partnerships, corporate development, growth and innovation in the biopharmaceutical industry. He was previously Chief Business Officer at Omega and before that served as Chief Business Officer at BioCity Biopharma and Head of Oncology External Innovation at Sanofi.Dr. Nelson was Omega’s Senior Vice President of Research and, prior to that, was Vice President of Research at Flagship Pioneering, where she helped launch and develop bio-platform companies. She has previously served as Head of Vaccines at Laronde and played a leading role in advancing novel approaches to leveraging mRNA for therapeutic purposes at Moderna Therapeutics. An updated corporate presentation is available on the Investors section of the Company’s website at https://ir.omegatherapeutics.com/. Third Quarter 2024 Financial Results As of September 30, 2024, the Company had cash and cash equivalents totaling $30.4 million, which is expected to fund operations into Q2 2025. Research and development (R&D) expenses for the third quarter of 2024 were $12.8 million, compared to $16.5 million for the third quarter of 2023. The $3.7 million decrease in R&D expenses was primarily driven by a decrease in personnel-related expenses. General and administrative (G&A) expenses for the third quarter of 2024 were $6.2 million, compared to $7.2 million for the third quarter of 2023. The $1.0 million decrease in G&A expenses was primarily driven by a decrease in personnel-related expenses and consulting and professional fees. Net loss for the third quarter of 2024 was $16.4 million, compared to $22.2 million for the third quarter of 2023. The decrease in net loss was driven predominantly by the decrease in R&D and G&A expenses. About Omega Therapeutics Omega Therapeutics is a biotechnology company pioneering the development of a new class of programmable epigenomic medicines to treat or cure a broad range of diseases. By pre-transcriptionally modulating gene expression, Omega’s approach enables precision epigenomic control of nearly all human genes, without altering native nucleic acid sequences. Founded in 2017 by Flagship Pioneering following breakthrough research by world-renowned experts in the field of epigenetics, Omega is led by a seasoned and accomplished leadership team with a track record of innovation and operational excellence. The Company is committed to revolutionizing genomic medicine and has a pipeline of therapeutic candidates derived from its OMEGA platform. For more information, visit omegatherapeutics.com, or follow us on X and LinkedIn. About the OMEGA Platform The OMEGA platform leverages the Company’s deep understanding of gene regulation, genomic architecture and epigenetic mechanisms to design a potential new class of programmable epigenomic medicines that precisely target and modulate gene expression at the pre-transcriptional level. Combining world-class data science capabilities with rational drug design and customized delivery, the OMEGA platform enables control of fundamental epigenetic processes and reprogramming of cellular physiology to address the root cause of disease. Omega’s modular and programmable mRNA medicines, called epigenomic controllers, target specific genomic loci within insulated genomic domains with high specificity to durably tune single or multiple genes to treat and cure diseases through unprecedented precision epigenomic control. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including, without limitation, statements regarding: potential strategic partnership opportunities; our prioritization of certain preclinical programs and platform efforts; the potential of the OMEGA platform to engineer programmable epigenomic mRNA therapeutics that successfully regulate gene expression by targeting insulated genomic domains; expectations regarding our recent leadership changes and the potential of our product candidates and programs; expectations regarding our pipeline, including the advancement of multiple preclinical development programs in obesity, regenerative medicine and metabolic conditions; potential partnership opportunities; our anticipated cash runway into the second quarter of 2025; and our participation in upcoming events and presentations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: the novel technology on which our product candidates are based makes it difficult to predict the time and cost of preclinical and clinical development and subsequently obtaining regulatory approval, if at all; the substantial development and regulatory risks associated with epigenomic controllers due to the novel and unprecedented nature of this new category of medicines; our limited operating history; the incurrence of significant losses and the fact that we expect to continue to incur significant additional losses for the foreseeable future; our need for substantial additional financing; volatility in capital markets and general economic conditions; our investments in research and development efforts that further enhance the OMEGA platform, and their impact on our results; uncertainty regarding preclinical development, especially for a new class of medicines such as epigenomic controllers; potential delays in and unforeseen costs arising from our clinical trials; the fact that our product candidates may be associated with serious adverse events, undesirable side effects or have other properties that could halt their regulatory development, prevent their regulatory approval, limit their commercial potential, or result in significant negative consequences; difficulties manufacturing the novel technology on which our epigenomic controller candidates are based; our ability to adapt to rapid and significant technological change; our reliance on third parties for the manufacture of materials; our ability to successfully acquire and establish our own manufacturing facilities and infrastructure; our reliance on a limited number of suppliers for lipid excipients used in our product candidates; our ability to advance our product candidates to clinical development; and our ability to obtain, maintain, enforce and adequately protect our intellectual property rights. These and other important factors discussed under the caption “Risk Factors” in our Quarterly Report on Form 10-Q for the quarter ended September 30, 2024, and our other filings with the SEC, could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management’s estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change. Omega Therapeutics, Inc.Consolidated statements of operations and comprehensive loss(Unaudited, In thousands except share and per share data) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 Collaboration revenue$2,612 $831 $7,106 $2,105 Operating expenses: Research and development 12,807 16,506 41,162 61,638 General and administrative 6,225 7,228 19,395 20,029 Total operating expenses 19,032 23,734 60,557 81,667 Loss from operations (16,420) (22,903) (53,451) (79,562)Other income (expense), net: Interest income, net 14 684 644 2,323 Other income (expense), net (38) (29) (71) 25 Total other income (expense), net (24) 655 573 2,348 Net loss$(16,444) $(22,248) $(52,878) $(77,214)Net loss per common stock attributable to common stockholders, basic and diluted$(0.30) $(0.40) $(0.96) $(1.44)Weighted-average common stock used in net loss per share attributable to common stockholders, basic and diluted 55,155,583 55,140,058 55,153,699 53,629,468 Comprehensive loss: Net loss$(16,444) $(22,248) $(52,878) $(77,214)Other comprehensive income (loss): Unrealized gain on marketable securities — 85 14 393 Comprehensive loss$(16,444) $(22,163) $(52,864) $(76,821) Omega Therapeutics, Inc.Condensed Consolidated Balance Sheets(Unaudited, In thousands) September 30, December 31, 2024 2023 Assets Cash and cash equivalents$30,377 $68,443 Marketable securities — 4,986 Other assets 122,350 130,937 Total assets$152,727 $204,366 Liabilities and stockholders’ equity Liabilities$141,184 $146,350 Stockholders’ equity 11,543 58,016 Total liabilities and stockholders’ equity$152,727 $204,366