Fibrogenesis

2024年1月31日，FibroBiologics以Direct Listing（直接上市）的方式上市。公司不发行新股，不从上市中获得任何融资。FibroBiologics曾在美国最大的股权众筹平台之一startengine创下历史上增长最快的生物技术公司纪录，筹集金额超100万美元。FibroBiologics总部位于得克萨斯州，在2021年从FibroGenesis中分拆出来，是一家基于成纤维细胞的细胞疗法公司。目前，公司药物管线还未推进至商业化进程，因此未有盈利，2023年净亏损1648.5万美元。但据FibroBiologics财报数据，公司的现有资本至少能为2025年2月28日之前的运营提供资金。 2023和2022年财务报表（图源：FibroBiologics官网）押注成纤维细胞，已获和待批专利超250项英国科学家约翰·格登和日本科学家山中伸弥因发现成熟细胞可以被重新编程为多功能的干细胞iPS（即诱导多功能干细胞）而获2012年诺贝尔生理学或医学奖，此后围绕干细胞的实验和研究便不断增多。实验室中的突破性进展促成了干细胞的首次人体试验，公司创始人Pete O'Heeron遂将目光转向与间充质干细胞一样具有多向分化潜能的成纤维细胞，并开始围绕这一“新”细胞进行研究。Pete具有扎实的医疗与管理学术基础，他在德克萨斯州立大学获得医疗保健管理学士学位，在休斯顿清湖大学获得医疗保健管理硕士学位，并在芝加哥大学获得兼并与收购高级管理证书。在医疗技术和生物技术开发领域，Pete“摸爬滚打”超25年，拥有300多项已获专利和待批专利。据FibroBiologics官网，在创立FibroBiologics之前，Pete曾创办一家名为Advanced Medical Technologies的业务投资集团，投资医疗治疗领域具有潜力的早期项目。此外，他还创立过医疗器械系统开发公司NeoSurg Technologies（2006年出售给Cooper Surgical）。正是这些经历，促使他在生物制剂、先进手术器械和医疗战略咨询等方面都具有个人独到的见解，并能将其融入公司的战略布局和管理之中。他广集人才，和团队一起不断推动独有技术和产品的商业化进程，公司目前拥有250多项已获和待批专利。Pete O'Heeron（图源：FibroBiologics官网）成纤维细胞：干细胞的挑战者，易获取、易分离、易培养人体内只有两种细胞类型可以再生组织和器官，那便是干细胞和成纤维细胞。成纤维细胞数量大大超过干细胞，而且没有干细胞在来源、分离和培养方面的限制，似乎是更好的细胞来源。成纤维细胞是结缔组织的主要细胞类型，可以产生并维持细胞外基质，保证组织和器官结构的完整性。除了在伤口愈合的组织重塑和增殖阶段使细胞外基质沉积外，还在免疫调节中发挥重要作用。 成纤维细胞示意图（图源：FibroBiologics官网）具体而言，成纤维细胞较干细胞而言的优势在于：● 易获取手术中产生的多余组织可作为异源成纤维细胞的主要来源，患者的一次皮肤穿孔就能为大多数临床应用提供充足的自体成纤维细胞来源。● 易分离成纤维细胞的平均倍增时间（16-24小时）明显更短，而且可稳定传代15次，因此从组织中分离成纤维细胞更简单直接。● 易培养成纤维细胞的扩增和维持对培养基的要求没有干细胞严格。成纤维细胞不需要干细胞所需的高成本添加剂，这就降低了批量生产高质量和稳定成纤维细胞的复杂性和成本。据FibroBiologics官网，在应用方面，成纤维细胞的再生和免疫调节功能甚至比干细胞更有效和强大。成纤维细胞更容易分化成多种不同类型的细胞，包括软骨细胞、脂肪细胞、心肌细胞、肝细胞、骨细胞、上皮细胞和内皮细胞，是临床组织再生应用的理想候选细胞。此外，成纤维细胞更易于维护，在冷链运输物流中不易受损，是干细胞的经济实用的替代品。 干细胞和成纤维细胞对比图（图源：FibroBiologics官网）三条管线同时推进，最快已进入临床1/2期随着FibroBiologics的临床工作进入人体试验阶段，研究人员在大量实验中发现，成纤维细胞参与人体许多生物过程，在治疗领域极具潜力。FibroBiologics专有的成纤维细胞平台是开发治疗慢性疾病（包括退化性椎间盘疾病、多发性硬化症、伤口愈合、癌症）的生物疗法和抗衰老延寿应用（如胸腺内陷逆转和脾脏内陷逆转）的基础。FibroBiologics目前有三款在研管线，进展较快的包括CYMS101和CybroCell™。目前，CYMS101已处于1/2期临床研究阶段，CybroCell™已完成临床前试验，正在提交IND。 药物管线图（图源：FibroBiologics官网）● CYMS101：针对多发性硬化症（MS）MS是一种由T细胞介导的针对髓鞘的自身免疫性疾病。针对MS，FDA目前已经批准了奥瑞珠单抗（Ocrelizumab）、阿仑单抗（Alemtuzumab）、Teriflunomide(Aubagio)等。这些药物可以降低MS的复发率、减轻复发的症状严重程度以及延缓其进展，但具有一定的副作用。目前，仍然未出现无副作用或副作用极小的药物获批。目前，用于自身免疫病治疗主要包含三类细胞：间充质干细胞（MSCs）、调节性T细胞（Treg）、髓源性抑制细胞（MDSCs），利用成纤维细胞的少之又少，而CYMS101就是少数用于治疗MS的异体成纤维细胞疗法。为了解成纤维细胞治疗MS的潜力，FibroBiologics在实验性自身免疫性脑脊髓炎（EAE）多发性硬化症动物模型中对耐受性成纤维细胞进行了体外和体内临床前研究。研究结果表明，耐受性成纤维细胞可以抑制致病性T细胞活化，刺激T调节（Treg）细胞扩增，抑制树突状细胞（DC）成熟，刺激少突胶质细胞扩增和髓鞘蛋白表达。在MS的EAE模型中，使用成纤维细胞的疾病抑制效果明显优于脂肪或骨髓间充质干细胞。此外，与脂肪和骨髓间充质干细胞相比，耐受性成纤维细胞的免疫调节功能也更加强大。在使用CYMS101完成动物实验后，FibroBiologics获批在墨西哥使用成纤维细胞成分对多发性硬化症患者进行临床研究，现已完成第一阶段研究。该研究在五名参与者中进行，研究的主要目标是评估安全性，次要目标是评估疗效，进而确定成纤维细胞在少突胶质细胞扩增中的作用模式。FibroBiologics预计提交2期临床试验的IND申请，并表示可能会寻求战略伙伴，合作开发CYMS101的3期临床试验。● CybroCell™：针对椎间盘退行性病变（DDD）DDD又称椎间盘（IVD）退化，是一种与脊柱中一个或多个椎间盘进行性和不可逆退化有关的疾病，大多数患者会出现慢性下背痛的病症。目前，通常利用间充质干细胞（MSCs）治疗DDD。而FibroBiologics打破了常规的治疗方法，采用CybroCell™——一种基于成纤维细胞的通用供体细胞产品。FibroBiologics已在DDD临床前模型中证明了其安全性和有效性，并获得美国食品药品监督管理局的IND批准，在获得其主细胞库批准的情况下，可以在美国进行CybroCell治疗退行性椎间盘疾病的1/2期研究。除上述管线外，FibroBiologics还正处于开发CYWC628（基于异体成纤维细胞的伤口愈合疗法）的临床前研究阶段。其研究重点在于利用成纤维细胞和成纤维细胞衍生细胞来治疗糖尿病小鼠和大鼠的伤口，预计最早于2024年向美国食品及药物管理局（FDA）提交伤口愈合IND申请。在“银发”时代放抗衰老“长线”，国内集中于干细胞技术路线此外，FibroBiologics还具有处于早期研发阶段的抗衰老和治疗肿瘤的项目。 早期研发阶段药物管线图（图源：FibroBiologics官网）随着年龄的增长，胸腺的功能会下降，这一过程被称为胸腺内陷。胸腺内陷过程会促进调节性T细胞（Treg）的生成，从而导致对病原体感染、肿瘤和自身免疫性疾病的易感性增加[1]。而CYTER915利用胸腺成纤维细胞与胸腺其他细胞的相互作用促使胸腺内陷逆转，恢复胸腺功能，进而抑制衰老对免疫系统的影响。通过细胞疗法，可以改善和延长胸腺的寿命，达到抗衰老的目标。今年1月，国家统计局发布数据显示，2023年末中国60岁及以上人口超2.9亿人。国家卫健委预计2035年左右，60岁及以上老年人口将突破4亿，在总人口中的占比将超过30%，进入重度老龄化阶段。有需求就有市场空间，根据艾媒咨询发布的《2022—2023年全球与中国抗衰老行业发展及消费者需求研究报告》，预测到2025年时，全球抗衰老市场规模将突破3000亿美元。在细胞治疗领域，布局成纤维细胞的企业较少，更多还是集中在干细胞。《“十四五”生物经济发展规划》中也提到，要发展基因诊疗、干细胞治疗、免疫细胞治疗等新技术，对开展临床应用的干细胞治疗、细胞免疫治疗、医疗新技术科学开展临床评价等。在动脉橙不完全统计的临床管线中，过半的管线集中于头部企业中，主要集中在肌肉骨骼疾病和血液系统疾病治疗。目前，全球范围内从事干细胞治疗研发的头部代表企业有Athersys、Mesoblast、Gamida Cell、Cynata等。其中Cardio3、BrainStorm Cell Therapeutics和Cynata的几款自研产品都已进入临床三期阶段，获批上市在即。2023年4月，FDA批准Gamida Cell公司的细胞疗法Omisirge（omidubicel）上市。同时，以辉瑞、武田、拜尔等为代表的知名跨国企业陆续通过并购、合作、授权引进等多种交易形式布局该赛道。反观国内，干细胞治疗发展起步较晚，上市公司寥寥。 中国干细胞疗法上市公司图谱（图源：动脉橙数据库）衰老固然难以避免，但可以降速；慢性病难以根治，但也可以延缓其发展进程。与干细胞同样具有分化潜能的成纤维细胞或将代表细胞疗法成为最有潜力治疗慢性疾病的“良方”和抗衰老延寿应用的下一个“风口”。* 参考文献：[1]Wang, W., et al., Thymic Function Associated With Cancer Development, Relapse, and Antitumor Immunity – A Mini-Review. Front Immunol, 2020. 11: p. 773.近期推荐声明：动脉网所刊载内容之知识产权为动脉网及相关权利人专属所有或持有。未经许可，禁止进行转载、摘编、复制及建立镜像等任何使用。动脉网，未来医疗服务平台

─Chemomab to Host Conference Call for Investors Today, November 11 at 8:00 am ET─ TEL AVIV, Israel, Nov. 11, 2022 /PRNewswire/ -- Chemomab Therapeutics, Ltd. (Nasdaq: CMMB), a clinical-stage biotechnology company focused on the discovery and development of innovative therapeutics for fibrotic and inflammatory diseases with high unmet need, today announced financial and operating results for the third quarter ended September 30, 2022 and provided a corporate update. "We continued to make good progress in advancing our clinical programs for CM-101 during the third quarter," said Dale Pfost, PhD, Chief Executive Officer of Chemomab. "We have been preparing to report the results of our liver fibrosis biomarker trial in NASH patients in the coming weeks, while continuing to implement the expansion of our Phase 2 trial in primary sclerosing cholangitis, or PSC. Activities included opening additional clinical sites in the U.S. and Europe and filing regulatory submissions for the dose-finding cohorts and open label extension we are adding. We also are ramping up recruitment activities with patients and physicians to ensure enrollment is on-track. Importantly, during the quarter we wrapped up the design process for our upcoming Phase 2 trial in systemic sclerosis, or SSc. We are very pleased with the design, which was developed with input from a number of systemic sclerosis experts. In this trial we seek to confirm the critical role of CCL24 in SSc, and to generate data that can establish biological and clinical proof of concept for CM-101. The study should also enable us to identify the optimal patient population for CM-101 and to inform the selection of appropriate endpoints for subsequent trials. We anticipate launching the new trial around year-end and enrolling the first patients early in 2023." Dr. Pfost continued, "In support of our ongoing efforts to educate the scientific and medical communities about the critical role of CCL24 and CM-101 in fibro-inflammatory diseases, our researchers made presentations at important scientific meetings during the quarter. A poster at the recent AASLD Liver Meeting presented new preclinical data supporting the key role of CCL24 in the pathophysiology of PSC and showing how CM-101 can interfere with these disease processes. A featured presentation at the Anti-Fibrosis Drug Development Summit highlighted how Chemomab has used biomarkers as a strategic translational tool to inform and de-risk our drug development programs. A third presentation at an international conference on lung health unveiled new clinical data from an investigator-initiated open label study assessing CM-101 in COVID patients with acute lung injury. It showed that CM-101 administration was well tolerated and was associated with decreases in inflammatory and fibrogenic biomarkers that are also relevant in other fibro-inflammatory diseases like systemic sclerosis. This is an excellent example of the types of data we also hope to see in the liver fibrosis biomarker study that we are looking forward to reporting later this year." Clinical Update Phase 2 Liver Fibrosis Trial in NASH patients Chemomab has concluded the treatment phase of its randomized, placebo-controlled Phase 2 liver fibrosis trial in NASH patients. Preparations for a planned topline read-out continued in the third quarter. The main study outcome is safety and tolerability, with secondary outcomes including a variety of biomarkers associated with inflammation and fibrosis. These may provide useful insights in support of the overall CM-101 clinical development program and should also generate the pharmacokinetic and tolerability data needed to inform next steps in the development of the current subcutaneous formulation of CM-101. The company is on-track to report study results before year-end. Phase 2 Trial in Primary Sclerosing Cholangitis patients The company has been adding additional clinical sites, along with an open label extension and a dose finding component intended to inform selection of the optimal dose of CM-101 to advance in later development. Global regulatory filings supporting these changes are proceeding, with a number of new sites in Europe and the U.S. now open. An interim Drug Monitoring Committee safety review of the current PSC cohort is targeted for later this year. Additionally, a number of outreach and education initiatives have been implemented to support ongoing patient recruitment. Phase 2 Trial in Systemic Sclerosis patients Chemomab has completed the design of its upcoming Phase 2 trial in systemic sclerosis. The company aims to establish biological proof of concept for clinically relevant aspects of this complex disease, focusing on CM-101's potential activity in modifying the skin, lung and vascular pathophysiology observed in SSc patients. To that end, we will enrich the study with SSc patients who have higher levels of CCL24 and may therefore be more likely to respond to neutralization of this critical chemokine. Key design elements include the following: The trial is a randomized, double-blind, placebo-controlled study that will enroll sixty (60) SSc patients. To be eligible for the study, patients must manifest two key characteristics: the presence of clinically active disease, either dermatologic or pulmonary, and high serum levels of circulating CCL24. Forty (40) patients will be randomized to treatment with CM-101 and twenty (20) will be randomized to placebo. Of the 40 patients on active treatment, approximately half will have limited SSc, and half will have diffuse cutaneous disease. The study includes a 24-week double blind period during which patients assigned to active treatment will receive CM-101 at a dose of 10 mg/kg, via intravenous infusion, every three weeks. Following the double-blind period, patients will enter a 24-week open label treatment period, where all patients will receive CM-101 at a dose of 20 mg/kg via intravenous infusion every three weeks. All patients enrolled will undergo a skin biopsy at baseline and again after the double-blind treatment period, along with multiple clinical assessments of skin, vascular and pulmonary function. The primary outcome measure for the trial will be demonstration of the safety and tolerability of treatment with CM-101. All other outcome measures will be principally assessed as changes from baseline to the end of the double-blind treatment period. The secondary outcome measures of the trial are focused on highly relevant and informative biological read-outs. Key secondary outcomes include: Evaluation of multiple serum-based biological markers that are known to be associated with different manifestations of SSc including: Inflammatory cytokines (such a CCL2, IL6 and CXCL10) Vascular and growth factor-related biomarkers (such as VEGF and PDGF) Pulmonary-related biomarkers (such as KL-6, SPD and CCL18), and Fibrogenesis and extracellular matrix biomarkers (collagens, MMPs and ELF score). Inflammatory, fibrotic and target expression markers in skin biopsies, including but not limited to CCL24 and CCR3 expression levels. Pharmacokinetics and target engagement of CM-101. Monitoring for the presence of any potential anti-drug antibodies during the study. Exploratory biological outcomes assessments will include immune cell phenotyping, assessments of neutrophil function, and ex-vivo biological assays. Exploratory clinical outcomes will include evaluation of: Vascular involvement, using nail fold capillaroscopy, vascular imaging and digital ulcer burden Skin involvement using modified Rodnan scoring Pulmonary disease involvement using pulmonary function tests, and Multiple patient-reported outcome measures. The data collected should also enable us to evaluate global effects of intervention with CM-101 using the revised CRISS scale. We intend to conduct this study at multiple sites in the U.S., the E.U. and Israel. We are currently finalizing the required regulatory documents and we intend to file an Investigational New Drug application with the U.S. Food and Drug Administration in the coming weeks. Recent Highlights At the American Association for the Study of Liver Disease (AASLD) Liver Meeting® 2022, Chemomab presented a poster, CCL24 Blockade Attenuates Biliary Inflammation by Interfering with Monocyte and Neutrophil Recruitment, that reinforces the key role of CCL24 in the pathophysiology of primary sclerosing cholangitis. Using two in-vivo models for immune cell trafficking, Chemomab researchers demonstrated that CCL24 plays a critical role in the recruitment and migration of monocytes and neutrophils, which are major players in PSC pathophysiology. Chemomab's CM-101, a first-in-class CCL24 neutralizing monoclonal antibody, demonstrated an anti-inflammatory effect by interfering with migration of these cells to the damaged biliary area in an animal model of PSC. This study adds to the growing body of evidence validating CCL24 as a target for PSC and confirming the therapeutic potential of Chemomab's CCL24-neutralizing antibody. At the Union World Conference on Lung Health 2022, Chemomab CSO Adi Mor presented Treatment with CM-101 Reduced Inflammatory & Fibrotic Biomarkers in Patients with COVID-19-Derived Lung Damage, unveiling promising clinical data from an investigator-initiated open label clinical study showing that a single 10 mg/kg dose of CM-101 reduced biomarkers of lung inflammation and fibrogenesis in hospitalized COVID patients with serious lung involvement. Some of the mechanisms underlying lung inflammation resulting from COVID-19 infection are similar to those seen in chronic diseases that involve lung inflammation and fibrosis. The objective of the study was to assess the safety and activity of CM-101, including its impact on biomarkers related to lung inflammation and systemic sclerosis. CM-101 was well tolerated and demonstrated activity on these key biomarkers of inflammation and fibrogenesis that are relevant for systemic sclerosis and other fibro-inflammatory diseases. At the Sixth Anti-Fibrotic Drug Development Summit in Boston, Dr. Mor was a featured speaker, highlighting the growing use of inflammatory and fibrotic biomarkers to inform clinical trial design and de-risk drug development. In her presentation, Crossing the Divide: Leveraging Fibrosis-Inflammatory Biomarkers to Inform Clinical Trial Design, Dr. Mor showed how Chemomab has strategically used biomarkers throughout the drug discovery and development process as a key translational tool for competitive advantage, and how the company is continuing to use them today. Third Quarter 2022 Financial Highlights Cash Position: Cash and cash equivalents were $46.5 million as of September 30, 2022, compared to $51.8 million as of June 30, 2022. The Company currently expects its runway to last through year-end 2023. Research and Development (R&D) Expenses: R&D expenses were $5.4 million for the third quarter ended September 30, 2022, compared to $1.5 million for the same quarter in 2021. The increase in R&D expense year-over-year primarily reflects the increase in activities in support of the company's preclinical and clinical programs. General and Administrative (G&A) Expenses: G&A expenses were $2.9 million for the third quarter ended September 30, 2022, compared to $1.4 million for the same quarter in 2021. The increase was primarily due to increases in salaries and related benefits expenses mainly related to key additions to the senior management team, as well as an increase in non-cash share-based expenses. Net Loss: Net loss was $8.1 million, or a net loss of approximately $0.035 per basic and diluted share, for the third quarter ended September 30, 2022, compared to $3.0 million, or a net loss of approximately $0.013 per basic and diluted share, for the quarter ended September 30, 2021. The weighted average number of ordinary shares outstanding, basic and diluted were 228,773,418 (equal to 11,438,671 American Depository Shares) and 228,349,115 (equal to 11,417,456 American Depository Shares) for the quarters ended September 30, 2022, and September 30, 2021, respectively. For further details on Chemomab's financial results for the quarter ended September 30, 2022, refer to the Form 10-Q, which was filed with the SEC on November 10, 2022. Conference Call Chemomab management will host a conference call for investors today, Friday, November 11, 2022, beginning at 8:00 a.m. Eastern Time to discuss these results and answer questions. Shareholders and other interested parties may access the live webcast or replay at Webcast link or at Chemomab's website at , or by dialing +1 877-407-9208 (in the U.S.) or +1 201-493-6784 (outside the U.S. and in Israel) and entering passcode 13732524. Upon dialing in, please request the Chemomab conference call. A replay of the call will be available on Chemomab's website for 90 days at . About Chemomab Therapeutics Ltd. Chemomab is a clinical stage biotechnology company focusing on the discovery and development of innovative therapeutics for fibrotic and inflammatory diseases with high unmet need. Based on the unique and pivotal role of the soluble protein CCL24 in promoting fibrosis and inflammation, Chemomab developed CM-101, a monoclonal antibody designed to bind and block CCL24 activity. CM-101 has demonstrated the potential to treat multiple severe and life-threatening fibrotic and inflammatory diseases. It is currently in Phase 2 trials for primary sclerosing cholangitis and liver fibrosis, with a Phase 2 trial in systemic sclerosis expected to open around year-end, with first patients enrolled in early 2023. For more information on Chemomab, visit chemomab.com. Forward Looking Statements This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act. These forward-looking statements include, among other things, statements regarding the clinical development pathway for CM-101; the future operations of Chemomab and its ability to successfully initiate and complete clinical trials and achieve regulatory milestones; the nature, strategy and focus of Chemomab; the development and commercial potential and potential benefits of any product candidates of Chemomab; and that the product candidates have the potential to address high unmet needs of patients with serious fibrosis-related diseases and conditions. Any statements contained in this communication that are not statements of historical fact may be deemed to be forward-looking statements. These forward-looking statements are based upon Chemomab's current expectations. Forward-looking statements involve risks and uncertainties. Because such statements deal with future events and are based on Chemomab's current expectations, they are subject to various risks and uncertainties and actual results, performance or achievements of Chemomab could differ materially from those described in or implied by the statements in this presentation, including: the uncertain and time-consuming regulatory approval process; risks related to Chemomab's ability to correctly manage its operating expenses and its expenses; Chemomab's plans to develop and commercialize its product candidates, focusing on CM-101; the timing of initiation of Chemomab's planned clinical trials; the timing of the availability of data from Chemomab's clinical trials; the timing of any planned investigational new drug application or new drug application; Chemomab's plans to research, develop and commercialize its current and future product candidates; the clinical utility, potential benefits and market acceptance of Chemomab's product candidates; Chemomab's commercialization, marketing and manufacturing capabilities and strategy; Chemomab's ability to protect its intellectual property position; and the requirement for additional capital to continue to advance these product candidates, which may not be available on favorable terms or at all. Additional risks and uncertainties relating to Chemomab's and its business can be found under the caption "Risk Factors" and elsewhere in Chemomab's filings and reports with the SEC. Chemomab expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in Chemomab's expectations with regard thereto or any change in events, conditions or circumstances on which any such statements are based. Contacts: Media: Chemomab Therapeutics: Barbara Lindheim Consulting Vice President Investor & Public Relations, Strategic Communications Phone: +1 917-355-9234 [email protected] Investor Relations: Irina Koffler LifeSci Advisors, LLC Phone: +1 917-734-7387 [email protected] SOURCE Chemomab Therapeutics, Ltd.