CAV1

Feb. 15, 2024 -- Aileron Therapeutics, Inc. (“Aileron”) (NASDAQ: ALRN), a biopharmaceutical company advancing a novel pipeline of first-in-class medicines to address significant unmet medical needs in orphan pulmonary and fibrosis indications, will host a virtual key opinion leader event today from 4:30 to 5:30 p.m. ET titled “Clinical Perspectives on Treating Idiopathic Pulmonary Fibrosis” featuring pulmonary care experts Fernando J. Martinez, M.D., M.S. from Weill Cornell Medicine; Tejaswini Kulkarni, M.D., M.P.H. from University of Alabama at Birmingham Medicine; and Andreas Günther, M.D. from Agaplesion Evang. Central Hesse Hospital and Justus Liebig University. The event will include presentations by Aileron management followed by a panel discussion with the key opinion leaders on the treatment landscape for idiopathic pulmonary fibrosis (IPF), including the current challenges and significant unmet needs that remain for patients with the disease and the Company’s lead product candidate, LTI-03. A live question-and-answer session will follow. “As practicing clinicians and experts in pulmonary care medicine, these key opinion leaders bring valuable experience to the discussion of LTI-03 as a potential treatment option for patients with IPF,” said Cory Hogaboam, Ph.D., Chief Scientist of Aileron. “While Aileron expects to announce topline data from our Phase 1b study of LTI-03 in the second quarter of this year, we are encouraged by the support of these experts for the work we are doing to address the significant unmet need in this patient population.” IPF is a chronic lung disease characterized by progressive tissue scarring that prevents proper lung function. It is a progressive, fatal, age-associated lung disease affecting approximately 100,000 people in the United States1. IPF typically presents in adults 65 or older and is usually fatal within two to five years after diagnosis2. Aileron’s lead product candidate, LTI-03, is a novel Caveolin-1-related (Cav1) peptide with a dual mechanism targeting both alveolar epithelial cell survival as well as inhibition of profibrotic signaling, whereas approved drugs for the treatment of IPF, such as nintedanib and pirfenidone, have only demonstrated a reduction of profibrotic signaling. Studies conducted by Aileron and third parties have demonstrated that Cav1 is a key protein in the regulation of lung fibrosis that has a decreased expression in IPF patients. LTI-03 completed a Phase 1a clinical trial in healthy volunteers and is currently in a randomized, double-blind, placebo-controlled Phase 1b clinical trial in IPF patients. Aileron expects to announce topline results from this study in the second quarter of 2024. To access the event, please dial +1 646-876-9923 (domestic) or +44 208-080-6591 (international) and reference webinar ID: 953 9620 1729 and passcode: 554257 when prompted by the operator. A live webcast of the event can be accessed at https://investors.aileronrx.com/events-presentations/investor-events. A replay of the webcast will be available following the completion of the event. LTI-03 is a seven amino acid peptide, the sequence of which is derived from the caveolin scaffolding domain (CSD), an important binding region of the Cav1 protein. Cav1 normally serves a critical function in the prevention of fibrosis by maintaining a balance between pathways that both initiate and arrest lung repair and cell movement. Through the CSD, caveolin interacts with a large number of signaling molecules, all of which possess a caveolin binding sequence region. Cav1 expression is decreased in IPF lung tissues and has been demonstrated to decrease during the fibrotic phase of bleomycin, or BLM, lung injury in mice. Restoring the balance of important biological signals in the lung may not only slow lung function decline but could also restore healthy lung function through the protection of healthy epithelial cells. Aileron Therapeutics is a biopharmaceutical company advancing a novel pipeline of first-in-class medicines to address significant unmet medical needs in orphan pulmonary and fibrosis indications. Aileron’s lead product candidate, LTI-03, is a novel, synthetic peptide with a dual mechanism targeting alveolar epithelial cell survival as well as inhibition of profibrotic signaling. Currently, LTI-03 is being evaluated in a Phase 1b clinical trial for the treatment of idiopathic pulmonary fibrosis, with topline results expected to be reported by the end of 2Q24. Aileron’s second product candidate, LTI-01, is a proenzyme that has completed Phase 1b and Phase 2a clinical trials for the treatment of loculated pleural effusions. LTI-01 has received Orphan Drug Designation in the US and EU and Fast Track Designation in the US. References 1 Pergolizzi, Jr., J., LeQuang, J., Varrassi, M., Breve, F., Magnusson, P., Varrassi, G., (2023). What Do We Need to Know About Rising Rates of Idiopathic Pulmonary Fibrosis? A Narrative Review and Update. Springer Nature, Published online 2023 Jan 24. Doi: 10.1007/s12325-022-02395-9. 2 Nathan et al. “Long-term Course and Prognosis of Idiopathic Pulmonary Fibrosis in the New Millennium”. Chest Journal Volume 140, ISSUE 1, P221-229, July 2011. The content above comes from the network. if any infringement, please contact us to modify.

*仅供医学专业人士阅读参考“谁家今夜扁舟子？何处相思明月楼？” 自古以来，一叶扁舟往往搭载着人们的无限情感，或是思乡，或是送别，或是豁达。在细胞膜上，也存在一叶扁舟，承担着细胞托付的重要使命，那便是脂筏。 脂筏是具有流动性的细胞膜中富含胆固醇和鞘脂的微结构域，始终处于动态变化，为细胞膜上的蛋白质相互作用、信号传递、物质运输等生物学过程提供“工作平台”。 中国医科大学的吴鹏飞、韩云、李波等人完成的最新研究表明，肺腺癌（LUAD）的早期进展与这叶扁舟脱不开关系。文章于近日发表在Journal of Experimental & Clinical Cancer Research期刊上。 他们结合生物信息学技术在分子水平上全面分析158名LUAD患者的组织样本，发现磷脂磷酸酶2（PLPP2）可以通过增强LUAD细胞中脂筏的形成来诱导细胞过度增殖、驱动LUAD的早期疾病进展，并将PLPP2水平升高确定为LUAD 患者的独立预后危险因素[1]。 论文首页截图 低剂量螺旋CT等改良的放射学筛查技术显著提高了早期肺腺癌 (LUAD) 的检出率，但也凸显了高假阳性诊断的问题，使患者面临不必要的过度治疗的风险。因此，需要更精确的判别标准，来确保早期LUAD患者得到适当的治疗。 此次，研究团队全面描述早期LUAD患者的肿瘤转录组学景观，并将其与临床特征进行相关性分析，以揭示早期LUAD发生发展的分子机制，找到致病驱动因素、生物标志物和治疗靶点。 他们共招募曾在中国医科大学附属盛京医院接受手术治疗的158名LUAD患者，获取每位患者的癌组织样本及相邻的非癌组织样本并进行高通量转录组测序，其中有80名I期LUAD患者。 基于转录组测序数据，研究团队总共鉴定2161个差异表达基因，这些基因在LUAD发病早期阶段，由正常组织向肿瘤组织的转变过程中表现出明显不同的表达模式，被称为肿瘤发生相关差异表达基因。功能富集分析结果显示，这些差异表达基因中，除了有许多参与细胞周期调节、细胞增殖以及相关信号通路，还有一些参与细胞膜成分重组。 通过相关性分析，研究团队注意到，在癌前病变到LUAD肿瘤生成的过程中，细胞膜成分重组、细胞快速增殖这两个事件同步发生，可能具有协同作用。 基于差异表达基因的功能富集分析事情的真相究竟是什么呢？ 结合病理诊断和影像学数据，研究团队发现，细胞周期活动的增强能够促进早期LUAD从非侵袭到侵袭状态的转变。而细胞膜上脂筏的形成，正是激活细胞周期的推手。 研究团队进一步利用TCGA数据库和脂质组学分析等技术，鉴定磷脂磷酸酶2（PLPP2）是LUAD早期阶段时脂筏形成的关键决定因素，参与调控组成脂筏的成分类型和含量。 在体外实验中，利用RNA干扰技术使人肺癌细胞系的PLPP2表达下调时，脂筏标志物caveolin-1和flotillin-1的定位显著减少，肿瘤细胞增殖能力减弱、克隆集落数量减少，而且肿瘤细胞对应激反应诱导的细胞凋亡抵抗力减弱，内质网等内膜系统完整性受损。 人肺癌细胞系过表达PLPP2时，与脂筏形成相关的信号通路显著富集，胆固醇酯、鞘磷脂和鞘氨醇等与脂筏形成相关的脂质代谢物水平上调。另一方面可以检测到，脂筏标志物在肿瘤细胞膜上的定位增加，肿瘤细胞增殖活性增强。 在小鼠实验中，研究团队采用脂筏合成抑制剂MβCD来减少LUAD细胞膜上脂筏的丰度。结果显示，过表达PLPP2的荷瘤小鼠体内脂筏含量增加、肿瘤体积更大、肿瘤细胞过度增殖。与对照组相比，脂筏合成抑制剂治疗完全消除了PLPP2过表达所带来的这些效应，小鼠肿瘤体积显著减小。 这些说明，PLPP2通过促进脂筏形成来促进LUAD进展。 PLPP2过表达促进肿瘤生长，使用药物抑制脂筏合成可以挽救不仅如此，研究团队在LUAD患者中发现，与邻近非癌组织相比，肿瘤组织中PLPP2水平显著升高。基于I期LUAD患者队列构建预测模型时，证明PLPP2能够以较高敏感性和特异性预测I期LUAD患者，ROC曲线下面积（AUC）值为0.88（P<0.0001）。 从患者生存来看，PLPP2水平较高的LUAD患者中位生存时间显著低于PLPP2水平较低的患者（HR 3.68，95%CI 1.06-12.77，P=0.04）。且多变量Cox回归分析结果显示，PLPP2水平升高是LUAD患者的独立预后危险因素（HR 814，95%CI 1.51-438194.06，P=0.04）。 LUAD患者肿瘤组织里PLPP2水平升高总而言之，这项研究描绘了早期LUAD患者的基因表达特征，并追踪了从非侵袭性到侵袭性LUAD的转录组学转变轨迹。更重要的是，这项研究首次表明PLPP2介导的脂筏合成是LUAD早期进展中的一个重要生物学事件，为临床环境中更精确的诊断和治疗提供了潜在目标，并证明PLPP2是LUAD患者的独立预后危险因素。参考文献：[1]https://jeccr.biomedcentral.com/articles/10.1186/s13046-023-02877-w本文作者丨张艾迪

SAN DIEGO, Nov. 13, 2023 (GLOBE NEWSWIRE) -- Gyre Therapeutics (“Gyre”) (NASDAQ: GYRE), a clinical-stage biotechnology company developing anti-fibrotic therapeutics for a variety of chronic liver diseases, today announced the presentation of a poster at the American Association for the Study of Liver Diseases’ (AASLD) Annual Liver Meeting, November 10-14, 2023, in Boston, Massachusetts. Gyre’s lead asset, Hydronidone, is currently being investigated for the treatment of Metabolic Dysfunction Associated Steatohepatitis (MASH)-associated liver fibrosis in the United States. Gyre’s poster presented the potential antifibrotic effects of Hydronidone and its expected mode of action in mouse hepatic fibrosis models. “We are encouraged by these preclinical results that support Hydronidone’s candidacy as a potential treatment for liver fibrosis,” said Charles Wu, Ph.D., Chief Executive Officer of Gyre Therapeutics. “Our team and collaborators showed Hydronidone’s ability to ameliorate liver fibrosis by inhibiting the activation of hepatic stellate cells (HSCs) via Smad7-mediated Tumor Growth Transforming (TGF)- degradation. Activation of the HSCs is recognized as a central event in the process of liver fibrogenesis with the TGF as one of the key mediators. The obtained mechanistic data support the potential of Hydronidone for the treatment of liver fibrosis associated with a spectrum of chronic liver diseases. We look forward to initiating the clinical program of Hydronidone in the United States in 2024.” Key highlights from the poster presentation are below: Hydronidone significantly improved liver damage in carbon tetrachloride (CCL4) and 3,5-diethoxycarbonyl-1,4-dihydropyridine (DDC) mouse hepatic fibrosis models and reduced the accumulation of collagenHydronidone inhibited the activation of hepatic stellate cells via Smad7-mediated TGF- degradation and decreased the expression of fibrosis genes in hepatic stellate cellsIn a ubiquitin-proteasome dependent pathway, Hydronidone promoted the Caveolin-1 mediated TGFβRI degradation via Smad7Specific knockdown of Smad7 in vivo blocked the antifibrosis effect of Hydronidone Full details for the poster presentations are below: Title: Hydronidone ameliorates liver fibrosis by inhibiting activation of hepatic stellate cells via Smad7-mediated degradation of TGFβRIPresenting Authors: Xianjun Xu, Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaPoster Number: 3417-A Date and Time: Sunday, November 12, 2023 from 1:00 p.m. to 2:00 p.m. ETLocation: Poster Hall A A copy of the poster will be made available on the Gyre website at www.gyretx.com following the conclusion of the meeting. About Gyre Therapeutics Gyre Therapeutics (“Gyre”) is a biopharmaceutical company headquartered in San Diego, CA, with a primary focus on the development and commercialization of Hydronidone (F351) for the treatment of Metabolic Dysfunction Associated Steatohepatitis (MASH)-associated fibrosis, formerly known as Nonalcoholic Steatohepatitis (NASH) in the United States. Hydronidone’s development strategy in MASH is based on results obtained in mechanistic studies in MASH rodent model and results of a chronic Hepatitis-B induced liver fibrosis Phase 2 clinical study in China which met the primary endpoints of safety and efficacy and led recently to the designation of a breakthrough therapy by the New Medicines Product Administration of China (NMPA). Gyre is also advancing a diverse pipeline China through its indirect controlling interest in Beijing Continent Pharmaceuticals Ltd., Co., including pirfenidone, F573, F528, and F230. Forward-looking Statements This press release contains “forward-looking statements” within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995, which statements are subject to substantial risks and uncertainties and are based on estimates and assumptions. All statements, other than statements of historical facts included in this press release, including statements concerning the progress and future expectations and goals of Gyre’s research and development efforts, including the timing of the clinical program of Hydronidone, are forward-looking statements. In some cases, you can identify forward-looking statements by terms such as “may,” “might,” “will,” “objective,” “intend,” “should,” “could,” “can,” “would,” “expect,” “believe,” “design,” “estimate,” “predict,” “potential,” “plan” or the negative of these terms, and similar expressions intended to identify forward-looking statements. These statements reflect our plans, estimates, and expectations, as of the date of this press release. These statements involve known and unknown risks, uncertainties and other factors that could cause our actual results to differ materially from the forward-looking statements expressed or implied in this press release. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation: risks associated with the possible failure to realize certain anticipated benefits of the business combination with Catalyst Biosciences, Inc., including with respect to future financial and operating results; positive results from a clinical study may not necessarily be predictive of the results of future or ongoing clinical studies; competition from competing products; the impact of general economic, health, industrial or political conditions in the United States or internationally; the sufficiency of Gyre’s capital resources and its ability to raise additional capital. Additional risks and factors are identified under “Risk Factors” in Gyre’s Annual Report on Form 10-K filed on March 30, 2023 and subsequent reports filed with the SEC, and identified under “Risk Factors” in the Proxy Statement. Gyre expressly disclaims any obligation to update any forward-looking statements whether as a result of new information, future events or otherwise, except as required by law. For Investors: Stephen Jasper stephen@gilmartinir.com