LX-1021

来源：药渡 撰文：幻目     编辑：维他命 阿尔茨海默病多发于老年群体，是一种危害极大的慢性、进展性、不可逆性的难以控制和治疗的神经系统疾病。然而，现阶段尚未开发出能够有效逆转该疾病进程的药物，近期上市两款抗淀粉样蛋白药物Donanemab和Leqembi最多只能略微降低认知能力下降的速度，并有可能产生与淀粉样蛋白相关的成像异常和输液反应等严重的不良反应。 基于此，一些公司期望用细胞和基因疗法来颠覆传统方法。其中，进展最快的是Longeveron公司的Lomecel-B和Lexeo Therapeutics的LX1001。 01 Lomecel-B 公司名称：Longeveron 阶段：临床II期 药物机制：Lomecel-B是一种同种异体细胞疗法，由从年轻健康成人骨髓中分离的特化细胞制成。这些特殊细胞被称为药物信号细胞（Medicinal Signaling Cells，MSC），对身体的内源性生物修复机制至关重要。MSC已被证明在体内执行许多复杂的功能，包括参与新组织的形成。它们还被证明对损伤或疾病部位有反应，并分泌具有免疫调节和再生作用的生物活性因子。血脑屏障会给小分子药物的开发带来额外的挑战，相比之下Longeveron的方法是新颖的，MSCs可以穿过血脑屏障，在大脑内提供治疗效果，减少炎症。 临床疗效：Longeveron公司公布其在研疗法Lomecel-B治疗轻度阿尔茨海默病（AD）的2a期CLEAR MIND试验显示积极的结果。分析显示，该试验达到安全性主要终点，且接受Lomecel-B治疗患者没有出现认知恶化或脑萎缩的迹象。相对于安慰剂，接受低剂量和混合剂量Lomecel-B治疗组患者，在试验的次要终点复合阿尔茨海默病评分（CADS）中达到统计显著性。与安慰剂相比，使用其他剂量Lomecel-B的患者在CADS等指标数值上显示出减缓/预防疾病恶化。药物安全性方面，未发现输注相关反应、超敏反应等严重不良事件。 2024年7月美国FDA授予Lomecel-B再生医学先进疗法（RMAT）认定，用于治疗轻度阿尔茨海默病。 此外，Lomecel-B还在其他多个适应症中进行评估，包括与衰老相关的虚弱（已完成2b期试验）和左心发育不全综合症（HLHS，2b期试验正在进行中）。 关于Longeveron公司：Longeveron成立于2014年，总部位于美国佛罗里达州，是一家开发细胞疗法治疗慢性衰老相关疾病的临床阶段生物技术公司。公开资料显示，Longeveron自成立以来共完成了7轮融资，融资总额为1540万美元，投资机构包括TEDCO、National Institutes of Health以及Alzheimer's Association等，该公司于2021年2月登陆纳斯达克，股票代码LGVN。 02 LX1001/LX10210/LX1021 公司名称：Lexeo Therapeutics 临床阶段：LX1001目前处于I/Il期试验阶段，预计将于2024年11月获得结果，LX1021处于临床前研究阶段，LX1020处于发现阶段。 药物机制：载脂蛋白(APOE)是一种脂质转运蛋白，是脑内胆固醇的主要转运蛋白，影响神经元纤维再生及淀粉样蛋白（Aβ）降解与沉积等神经生理过程。APOE4的存在是阿尔茨海默病最常见的遗传风险因素。主流的APOE等位基因为APOE4、APOE3和APOE2，其中E4等位基因增加发病风险并降低发病年龄，E2等位基因降低发病风险并显著延缓发病年龄。APOE4纯合子患者，即具有两个E4等位基因拷贝的个体，患阿尔茨海默病的风险最高，其患阿尔茨海默病的可能性是一般人群的15倍左右。 三种不同的阿尔茨海默症基因疗法都使用基于腺病毒（aav）的载体来靶向APOE基因的产物， LX1001通过在高风险APOE4等位基因纯合子患者的中枢神经系统中表达保护性APOE2蛋白起作用，LX1021在APOE4纯合子患者的中枢神经系统中表达保护性的APOE2蛋白，LX1020在APOE4纯合子患者的中枢神经系统中表达APOE2蛋白，并通过miRNA抑制APOE4蛋白。 三款药物仅针对APOE4相关的阿尔茨海默病，其产品针对的是占阿尔茨海默病总人群40%至50%的患者亚群。其中，LX1001项目进行了1/2期临床试验，共涵盖约15例50岁以上的阿尔茨海默病患者，这些患者均携带两个APOE4等位基因拷贝。在接受低剂量LX1001治疗的患者中：在所有随访时间超过3个月的患者中，都观察到脑脊液中的APOE2蛋白表达。 在随访时间超过12个月的两名患者中，脑脊液中的微管相关蛋白（tau蛋白）水平和磷酸化tau蛋白水平与基线相比降低。结果表明，LX1001的总体耐受性良好，迄今为止未发生严重不良事件。 关于Lexeo Therapeutics ：公司成立于2018年，总部位于美国纽约州，是一家针对心血管疾病、阿尔海默兹病的基因疗法公司。该公司致力于利用先进的基因编辑和递送技术，以改善患者的生活质量，并为他们提供更有效的治疗选择。LEXEO三大管线专攻AD、心肌病和巴顿病。目前已完成了8500万美元的A轮和1亿美元的B轮融资，投资人包括D1 Capital、Lundbeckfonden Ventures、Omega Funds等知名机构。 03 RB-ADSC 除了Longeveron和Lexeo，CGT治疗阿尔茨海默症领域也出现了一些处于早期阶段的公司。例如，Regeneration Biomedical在7月28日公布了首批两名患者自体Wnt激活脂肪干细胞（RB-ADSC）疗法一期试验结果。 RB-ADSC是从患者自身脂肪组织获得的Wnt激活的脂肪来源的干细胞。收集后，将干细胞在体外培养和扩增，选择用于Wnt表达，Wnt表达是一种已知可以刺激干细胞与其他干细胞交流的信号蛋白，然后通过植入头皮下的储液器重新引入同一患者体内，该储液器可直接进入位于大脑中的一侧脑室。对两种动物模型的研究表明，注入心室系统的干细胞会分布到脑实质中。此外，未观察到炎症、脑脊髓液循环受阻或其他安全信号。 该试验将使用脂肪来源的干细胞直接注入阿尔茨海默病（AD）侧脑室以绕过血脑屏障（BBB）。该公司声称，其疗法可以显著改善晚期阿尔茨海默病患者的认知评分。如果得到大规模试验的证实，这将是一项重大进展，因为大多数已显示出疗效的疗法仅对轻度认知障碍患者有效。 04 CGT疗法——AD治疗新曙光 由于目前批准的阿尔茨海默病治疗方法可能存在重大缺陷。例如，尽管Biogen的抗淀粉样蛋白药物Aduhelm（aducanumab）在2021年获得批准，但其批准存在争议，制造商于2024年1月停止了开发和商业化。转而专注于Leqembi (lecanemab)，与Aduhelm一样，Leqembi也有与淀粉样蛋白相关的成像异常和输液反应等不良事件有关。相比之下，Lomecel-B在其安全性方面没有出现过敏、输液相关反应或淀粉样蛋白相关影像学异常。如果CGT能够继续避免不良事件的发生或者减轻不良反应的严重程度，它将在该领域获得显著的优势。CGT治疗阿尔茨海默病可能会为这种疾病提供一种新的治疗选择。 尽管如此，考虑到阿尔茨海默症临床试验比其他疾病更复杂、更昂贵、更缓慢。因此，历史上临床失败率相对较高， 这也是CGT治疗阿尔茨海默病同样面临的挑战。随着研究性CGT在阿尔茨海默症领域的兴起，预计在未来两到三年内，该疗法的可行性将进一步被证实。 *声明：本文仅是介绍医药疾病领域研究进展或简述研究概况或分享医药相关讯息，并非也不会进行治疗或诊断方案推荐，也不对相关投资构成任何建议。内容如有疏漏，欢迎沟通指出！ 只需一针！可免去上百次治疗，辉瑞基因疗法“剑指”血友病 单抗还是JAK抑制剂？特应性皮炎新兴药物及用药抉择，一文深度解析！ 寻踪“下一个司美格鲁肽”：2024年下半年这5款潜力减肥药临床数据将揭晓！

Completed enrollment of the LEAD Phase 1/2 clinical trial of LX1001 for the treatment of APOE4-associated Alzheimer’s disease Received clearance of LX2006 Clinical Trial Application (CTA) in Canada for the treatment of FA cardiomyopathy; activated first clinical trial site outside of the United States Presented additional preclinical data on LX2020 for the treatment of PKP2-ACM at the 2023 American Heart Association Scientific Sessions Completed initial public offering (IPO) of common stock in November 2023, raising $111.5 million in gross proceeds and supporting operational runway into Q4 2025 NEW YORK, Dec. 11, 2023 (GLOBE NEWSWIRE) -- Lexeo Therapeutics, Inc. (Nasdaq: LXEO), a clinical stage genetic medicine company dedicated to pioneering treatments for genetically defined cardiovascular diseases and APOE4-associated Alzheimer's disease, today reported third quarter 2023 financial results and provided operational highlights. “We have made significant progress to date in 2023, achieving several important clinical and corporate milestones, as we continue to build a leading genetic medicine company,” said R. Nolan Townsend, Chief Executive Officer of Lexeo. “With the successful completion of our IPO, we are well positioned to execute on our near-term corporate objectives. Importantly, as we head into 2024, we expect to provide additional clinical data readouts from our lead cardiovascular and APOE4-associated Alzheimer’s disease programs, continuing our momentum into the new year.” Business and Program Updates APOE4-associated Alzheimer’s Disease Programs: Completed enrollment of all four cohorts in the LEAD Phase 1/2 clinical trial of LX1001 for the treatment of APOE4-associated Alzheimer’s disease. Additionally, Lexeo presented murine data on LX1021, a preclinical gene therapy candidate designed to deliver a Christchurch mutation modified APOE2 gene, at the 2023 Clinical Trials in Alzheimer's Disease (CTAD) conference in October 2023. The data demonstrated impact to both amyloid and tau pathology as measured in two distinct murine models of Alzheimer’s disease and suggest a potentially enhanced tau pathology treatment effect compared to LX1001.LX2006 for the Treatment of FA Cardiomyopathy: Received clearance of CTA in Canada for LX2006 for the treatment of FA cardiomyopathy and activated the first clinical trial site for the SUNRISE-FA Phase 1/2 clinical trial outside of the United States.LX2020 for the Treatment of PKP2-ACM: Presented additional preclinical data at the American Heart Association Scientific Sessions in November 2023, including murine and non-human primate data that supported the LX2020 IND, which was cleared by the FDA in July 2023. Clinical trial start-up activities are underway and Lexeo expects to dose the first patient in the HEROIC-PKP2 Phase 1/2 clinical trial of LX2020 in the first half of 2024.Completed Initial Public Offering: In November 2023, Lexeo completed its underwritten initial public offering of 10,139,656 shares of its common stock, including the exercise of the underwriter’s option to purchase 1,048,746 additional shares of its common stock. The aggregate gross proceeds from the offering were $111.5 million, before deducting underwriting discounts and commissions and offering expenses payable by Lexeo.Expanded Leadership Team: In October, Sandi See Tai, M.D. joined Lexeo as Senior Vice President, Clinical Development and Operations. Dr. See Tai has nearly twenty years of biopharmaceutical experience in clinical development and medical affairs and has led global clinical development efforts for multiple cardiac precision medicine candidates, including achieving global approvals for a product that treats ATTR cardiomyopathy. Expected Upcoming Milestones LX2006 for the treatment of Friedreich’s ataxia cardiomyopathy Interim data readout in mid-2024 LX2020 for the treatment of PKP2-ACM First patient dosed in 1H 2024Interim data readout (cohort 1) in 2H 2024 LX1001 for the treatment of APOE4-associated Alzheimer’s disease Interim Phase 1/2 data readout (all cohorts) in 2H 2024 LX2021 for the treatment of DSP cardiomyopathy Initiate IND-enabling studies in 2024 Third Quarter Financial Results Cash Position: As of September 30, 2023, cash and cash equivalents were $35.4 million; cash position pro forma for the Company’s IPO is noted below.R&D Expenses: R&D expenses were $17.2 million for the three months ended September 30, 2023, compared to $15.4 million for the three months ended September 30, 2022.G&A Expenses: G&A expenses were $3.0 million for the three months ended September 30, 2023, compared to $2.7 million for the three months ended September 30, 2022.Net Loss: Net loss was $20.1 million or $12.36 per share (basic and diluted) for the three months ended September 30, 2023, compared to $17.1 million or $10.38 per share (basic and diluted) for the three months ended September 30, 2022. Pro Forma Cash Position for Initial Public Offering Cash Position: As of September 30, 2023, cash and cash equivalents were $136.4 million, pro forma for net proceeds from the Company’s IPO in November 2023. Lexeo expects its current cash and cash equivalents, including the net proceeds from the IPO, will be sufficient to fund operations into Q4 2025. About Lexeo Therapeutics Lexeo Therapeutics is a New York City-based, clinical stage genetic medicine company dedicated to transforming healthcare by applying pioneering science to fundamentally change how genetically defined cardiovascular diseases and APOE4-associated Alzheimer’s disease are treated. Using a stepwise development approach, Lexeo is leveraging early proof-of-concept functional and biomarker data to advance a pipeline of cardiovascular and APOE4-associated Alzheimer’s disease programs. Forward looking Statements Certain statements in this press release may constitute “forward-looking statements” within the meaning of the federal securities laws, including, but not limited to, our expectations and plans regarding our current product candidates and programs, including the anticipated timing of the initiation of and results from our clinical trials, expectations regarding the time period over which our capital resources will be sufficient to fund our anticipated operations and estimates regarding Lexeo’s financial condition. Words such as “may,” “might,” “will,” “objective,” “intend,” “should,” “could,” “can,” “would,” “expect,” “believe,” “design,” “estimate,” “predict,” “potential,” “develop,” “plan” or the negative of these terms, and similar expressions, or statements regarding intent, belief, or current expectations, are forward-looking statements. While Lexeo believes these forward-looking statements are reasonable, undue reliance should not be placed on any such forward-looking statements. These forward-looking statements are based upon current information available to the company as well as certain estimates and assumptions and are subject to various risks and uncertainties (including, without limitation, those set forth in Lexeo’s filings with the U.S. Securities and Exchange Commission (the SEC)), many of which are beyond the company’s control and subject to change. Actual results could be materially different from those indicated by such forward looking statements as a result of many factors, including but not limited to: risks and uncertainties related to global macroeconomic conditions and related volatility; expectations regarding the initiation, progress, and expected results of our preclinical studies, clinical trials and research and development programs; the unpredictable relationship between preclinical study results and clinical study results; delays in submission of regulatory filings or failure to receive regulatory approval; liquidity and capital resources; and other risks and uncertainties identified in our September 30, 2023 Quarterly Report on Form 10-Q filed with the SEC and subsequent filings we may make with the SEC. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Lexeo claims the protection of the Safe Harbor contained in the Private Securities Litigation Reform Act of 1995 for forward-looking statements. Lexeo expressly disclaims any obligation to update or alter any statements whether as a result of new information, future events or otherwise, except as required by law. Media Response: Janine Bogris (201) 245-6838 janine.bogris@canalecomm.com Investor Response: Laurence Watts (619) 916-7620 laurence@gilmartinir.com Lexeo Therapeutics, Inc. Selected Condensed Financial Information (unaudited, in thousands, except share and per share amounts) Condensed Consolidated Statements of Operations Three Months EndedSeptember 30, Nine Months EndedSeptember 30, 2023 2022 2023 2022 Revenue Grant revenue $- $531 $- $654 Total revenue - 531 - 654 Operating expenses Research and development 17,246 15,362 44,920 37,775 General and administrative 3,027 2,651 8,619 8,191 Total operating expenses 20,273 18,013 53,539 45,966 Operating loss (20,273) (17,482) (53,539) (45,312)Other income and expense Gain (loss) on fair value adjustment to convertible SAFE note (272) - (272) - Other income (expense) 1 - (6) - Interest expense (52) (29) (155) (37)Interest income 488 456 1,765 649 Total other income and expense 165 427 1,332 612 Loss from operations before income taxes (20,108) (17,055) (52,207) (44,700)Income taxes - - - - Net loss and comprehensive loss $(20,108) $(17,055) $(52,207) $(44,700) Net loss per common share, basic and diluted $(12.36) $(10.38) $(32.24) $(27.50) Weighted average number of shares outstanding used in computation of net loss per common share, basic and diluted 1,626,734 1,643,122 1,619,152 1,625,611 Condensed Consolidated Balance Sheet Data September 30, December 31, 2023 2022 Cash and cash equivalents $35,449 $77,335 Total assets 54,724 97,076 Total liabilities 32,499 24,997 Total convertible preferred stock 185,033 185,033 Total stockholders' deficit (162,808) (112,954)