Chemomab Ltd.

昨日（1月3日），以色列制药公司Chemomab宣布该公司的CCL24单抗CM-101在IIa期临床中达到了其在非酒精性脂肪性肝炎(NASH)中的安全性和耐受性的主要终点，并实现了一系列肝纤维化生物标志物的次要终点。 次要终点包括ProC-3、ProC-4、ProC-18、TIMP-1和ELF等肝纤维化相关生物标志物改善，治疗第20周60%的患者至少有3个生物标志物改善，而对照组这一比例为0。此外，非盲数据还显示，与安慰剂治疗的患者相比，CM-101治疗组的患者具有更高的纤维化基线水平。 虽然说，此次临床用的并不是此前Resmetirom那样采用了FDA肝活检的金标准，而是通过FibroScan的非侵入性弹性成像方法评估肝纤维化程度，不过从机理上来看CM-101这一CCL24单抗似乎在一些纤维化和炎症疾病具有普遍适用性。从Chemomab公司的管线来看也可以应证这一点。 CM-101的作用机理 C基序趋化因子配体24 (CCL24或嗜酸性粒细胞趋化因子-2)是一种趋化因子，主要通过C-C基序趋化因子受体3 (CCR3)复合物促进细胞运输并调节炎症和纤维化活性。已知趋化因子由活化的T细胞、单核细胞、上皮细胞和内皮细胞以及活化的成纤维细胞表达。 CCL24诱导ccr3表达细胞趋化和激活，包括免疫细胞和成纤维细胞，且能刺激人类肺成纤维细胞增殖和胶原合成，并被发现与特发性肺纤维化的进展有关。CM-101目前已经在多个炎症相关临床前模型中证明了有效性，其中包括系统性硬化症，肝纤维化模型，动脉粥样硬化模型，类风湿性关节炎和脑脊髓炎。 特别是在肝纤维化中，CCL24及其受体CCR3在NAFLD和NASH患者的肝脏和外周血细胞中显著表达。CCL24和CCR3在NASH患者肝脏的实质和非实质细胞中广泛表达，并且不仅仅由免疫细胞表达。使用实验性MCD诱导的NASH模型Ccl24敲除小鼠更表明，相比于WT（野生型小鼠）对照，在没有CCL24的情况下，疾病参数的强烈衰减表明，CCL24-CCR3轴可能在调节肝脏损伤中涉及的炎性纤维化轴中具有重要作用。 更深入的研究则进一步揭示了其具体机制，根据CCR3和α-SMA在肝成纤维细胞上的共定位，人LX2细胞表达CCR3，从而使这些细胞能够感知和应答CCL24。CCL24能够诱导肝成纤维细胞等细胞的活化。而研究人员开发的CCL24封闭抗体CM-101则能够通过降低运动性、α-SMA表达和前胶原1分泌来阻断CCL24诱导的活化。这些结果表明，CM-101治疗可以减轻肝星状细胞激活，从而潜在地减轻在实验模型中和最终在患者中看到的纤维化损伤。 还能治疗新冠病毒导致的严重肺损伤！？ 由新冠病毒感染肺部引起的肺部炎症的一些潜在机制类似于在涉及肺部炎症和纤维化的慢性疾病中看到的机制，在去年9月时，Chemomab公司公布了在16名患有严重呼吸系统疾病的成年新冠肺炎患者中施用CM-101的初步疗效。 对这种急性疾病患者群体施用CM-101被发现是安全且耐受性良好的。CM-101暴露和目标参与情况类似于Chemomab研究人员在以前的CM-101临床研究中看到的情况。重要的是，在用CM-101治疗后，观察到肺部炎症、纤维形成和嗜中性粒细胞活性的血清生物标记物快速减少。 Chemomab方面认为这项研究证实并扩展了CM-101的安全性和耐受性，并证明了与肺部炎症和纤维化相关的生物标志物的临床相关变化。研究人员相信这些结果增加了表明CM-101具有减轻肺部炎症和纤维化的潜力的数据，进一步加强了用该药物治疗系统性硬化症患者的理论基础。 小编总结 从具体市场看好程度来看，CM-101虽然在盘前上涨了63%，但随后立即回落，相比于样本量巨大，全部采用了金标准肝活检的Resmetirom不可相提并论。总的来说，CM-101的临床也只是处于起步阶段展示了一些初步的临床数据，想要验证有效性可能还有较长的路要走。不过有介于其在各个纤维化疾病的普遍性适用可能性，这可能使得这一靶点引来更多Followers。 参考来源：Segal-Salto M, Barashi N, Katav A, Edelshtein V, Aharon A, Hashmueli S, George J, Maor Y, Pinzani M, Haberman D, Hall A, Friedman S, Mor A. A blocking monoclonal antibody to CCL24 alleviates liver fibrosis and inflammation in experimental models of liver damage. JHEP Rep. 2020 Jan 2;2(1):100064. doi: 10.1016/j.jhepr.2019.100064. PMID: 32039405; PMCID: PMC7005554. https://investors.chemomab.com/2023-01-03-Chemomab-Reports-Top-Line-Results-from-CM-101-Phase-2a-Liver-Fibrosis-Biomarker-Trial-in-NASH-Patients 内容来源于网络，如有侵权，请联系删除。

今日，Chemomab Therapeutics公布其在研潜在“first-in-class”药品CM-101的2a期临床试验积极顶线结果。数据分析显示，CM-101在非酒精性脂肪性肝炎（NASH）患者身上达成安全性与耐受性主要终点，并在20周时达成多项包含肝纤维化程度下降等的次要终点。 NASH是一项严重、渐进式的肝病，是非酒精性脂肪性肝病（NAFLD）的一种晚期形式。据预估，NAFLD影响全球超过20%的成人，而其中的20%可能患有NASH。NASH的成因为肝脏不能正常代谢脂类和碳水化合物，造成肝脏过多脂肪堆积而引起慢性炎症，进而造成渐进式的肝纤维化（瘢痕形成），最终导致肝硬化，甚至是肝衰竭、肝癌与死亡。对于NASH病患，晚期纤维化与产生肝脏相关疾病与死亡的风险高度相关。这些疾病的每一个（发病）节点都受到特定通路失调的影响，这可能导致一系列的症状。发生NASH常见的风险因子包含肥胖、高血脂（例如高胆固醇与甘油三酯）以及2型糖尿病。目前世界上已经有超过1亿NASH患者，然而仍没有获批用于治疗NASH的疗法。 CM-101为靶向趋化因子CCL24的单克隆中和抗体。CCL24是促进纤维化与炎症反应的关键调节物，CCL24的上调与多项纤维化疾病的严重程度相关。临床前研究发现，CCL24能够活化成纤维细胞并招募免疫细胞以维持纤维化所需的炎症环境，而抑制CCL24则能避免且逆转在肝脏、皮肤、肺脏的纤维组织增生。 图片来源：123RF 这次所公布的试验共有23位NASH患者入组，随机分配接受5 mg/kg CM-101或安慰剂治疗。试验目的为检验CM-101皮下配方对NASH以及罕见纤维炎症症状的疗效。数据分析发现，皮下注射CM-101具有良好的药代动力学（PK）特性，并具良好的安全性与耐受性，多数的不良反应为轻度。与安慰剂组患者相比，CM-101组患者在多项肝纤维化相关生物标志物上展现显著的改善，包含ProC-3、ProC-4、ProC-18、TIMP-1与ELF。大多数的CM-101组患者具有超过一项与肝纤维化相关生物标志物的改善——在第20周时，将近60%的CM-101组患者在至少3项生物标志物上产生应答，在安慰剂组则不见产生应答的病患。此外，与在基线具有较低CCL24表达量的患者相较，具有较高CCL24表达水平的患者展现较高程度肝纤维化相关生物标志物的下降。亦有较高比例CM-101组患者的肝硬化程度出现改善。 Chemomab的首席执行官Dale Pfost博士说道：“值得一提的是，此试验验证了CM-101的安全性、耐受性以及皮下制剂的药代动力学特性，同时也提供生物标志物数据以进一步展现CM-101的抗炎症与抗纤维化能力。这是一项短期、小型的试验，并使用相对较低的CM-101剂量，因此我们对此数据尤为感到高兴。” 参考资料： [1] Chemomab Reports Top-Line Results from CM-101 Phase 2a Liver Fibrosis Biomarker Trial in NASH Patients. Retrieved January 3, 2023 from https://investors.chemomab.com/2023-01-03-Chemomab-Reports-Top-Line-Results-from-CM-101-Phase-2a-Liver-Fibrosis-Biomarker-Trial-in-NASH-Patients [2] Anti-CCL24 Therapeutic Platform. Retrieved January 3, 2023 from https://www.chemomab.com/r-d/ 内容来源于网络，如有侵权，请联系删除。

—CM-101 Met Primary Endpoint of Safety and Tolerability and Showed Positive Activity Across Multiple Liver Fibrosis Biomarkers and Physiologic Assessments— TEL AVIV, Israel I January 3, 2023 I Chemomab Therapeutics, Ltd. (Nasdaq: CMMB ) (Chemomab), a clinical-stage biotechnology company focused on the discovery and development of innovative therapeutics for fibrotic and inflammatory diseases with high unmet need, today reported top-line results from its Phase 2a trial assessing CM-101, its first-in-class CCL24-neutralizing monoclonal antibody, in non-alcoholic steatohepatitis (NASH) patients. The trial met its primary endpoint of safety and tolerability, and CM-101 achieved reductions in secondary endpoints that include a range of liver fibrosis biomarkers and physiologic assessments measured at baseline and at week 20. The randomized, placebo-controlled trial enrolled 23 NASH patients with stage F1c, F2 and F3 disease who were randomized to receive either CM-101 or placebo. Patients received eight doses of 5 mg/kg of CM-101 or placebo, administered by subcutaneous (SC) injection once every two weeks, for a treatment period of 16 weeks. This trial was primarily designed to assess the subcutaneous formulation of CM-101 and to evaluate the drug's impact on liver fibrosis biomarkers relevant to both NASH and the rare fibro-inflammatory conditions that represent the focus for the company, such as primary sclerosing cholangitis (PSC) and systemic sclerosis (SSc). Dale Pfost, PhD, Chief Executive Officer of Chemomab, said, "It is noteworthy that this trial confirmed the safety and tolerability of CM-101 and the pharmacokinetics of our subcutaneous formulation, while providing biomarker data further demonstrating the anti-inflammatory and anti-fibrotic activity of CM-101. We are especially pleased with these encouraging findings given the small size of the study, the short duration of treatment and the relatively low dose of CM-101 that was administered. " Dr. Pfost continued, "This is the third clinical trial in patients demonstrating the activity of CM-101 as measured by fibro-inflammatory biomarkers and physiological assessments. It confirms similar data we reported in our Phase 1b study in patients with non-alcoholic fatty liver disease (NAFLD) and in our recently reported investigator study of acute lung injury in COVID patients . Collectively, these data encompassing diverse organs and conditions reinforce our optimism about our ongoing Phase 2 trial in primary sclerosing cholangitis and our Phase 2 trial in systemic sclerosis that is scheduled to begin early this year." Key findings of the CM-101 Phase 2a trial included the following. Massimo Pinzani, MD, PhD, Professor of Medicine, Director of the University College London (UCL) Institute for Liver and Digestive Health and the Sheila Sherlock Chair of Hepatology at UCL, commented, "These encouraging Phase 2a results for CM-101 are a good example of what one is seeking in a successful biomarker study–sets of multiple biomarkers moving together in a positive direction. Based on these early findings, CM-101 may have the potential to interrupt the inflammatory and fibrotic vicious cycle characterizing conditions such as PSC, systemic sclerosis and other fibro-inflammatory diseases, providing the potential for much-needed disease-modifying therapy." Rifaat Safadi, MD, Professor in Medicine, Gastroenterology and Hepatology, Faculty of Medicine, Hadassah University Hospital, Jerusalem; a Visiting Scholar at the Division of Liver Diseases, Mount Sinai School of Medicine in New York City, and Principal Investigator of the Phase 2a study noted, "The results from this early trial confirm previous clinical and preclinical research suggesting that neutralizing the pro-fibrotic and pro-inflammatory effects of CCL24 may have a therapeutic benefit for patients battling intractable fibro-inflammatory diseases such as PSC and systemic sclerosis, and support the conduct of additional clinical trials to address this unmet medical need. I want to thank the patients who participated in this trial and the team members at the clinical sites who helped make these encouraging results possible." For more information on Chemomab's Phase 2 SPRING trial In patients with primary sclerosing cholangitis, visit www.chemomab.com/trials/psc/ , or click here for information for potential participants. About Chemomab Therapeutics 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. A Phase 2 liver fibrosis biomarker study in NASH patients was recently completed and a Phase 2 trial in primary sclerosing cholangitis patients is ongoing. Chemomab expects to begin enrolling patients in a Phase 2 trial in systemic sclerosis early in 2023. For more information on Chemomab, visit chemomab.com . SOURCE: Chemomab Therapeutics