LX-1001

Dose-dependent increase in neuroprotective APOE2 expression in all participants with ongoing durability at 12 months Consistent reductions across CSF tau biomarkers and tau PET in majority of participants LX1001 well tolerated across all dose cohorts with no reports of amyloid-related imaging abnormalities (ARIA) Company to host webcast today at 7:00 AM ET Oct. 30, 2024 -- 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 announced positive interim results from the Phase 1/2 study of LX1001 (NCT03634007) for the treatment of APOE4-associated Alzheimer’s disease (AD). Treatment with LX1001 led to dose-dependent increases in APOE2 protein expression and improvements in AD-associated tau biomarkers, measures which have been closely correlated with cognitive outcomes. LX1001 also demonstrated a favorable safety profile with no reports of ARIA1. The data were presented today in a late-breaking oral presentation at the Clinical Trials on Alzheimer’s Disease (CTAD) conference in Madrid, Spain and expand the body of evidence on LX1001 as a potential therapy for the more progressive course of Alzheimer’s seen in APOE4 homozygotes. “APOE4 homozygotes are approximately 15 times more likely to develop Alzheimer’s disease than the general population, have faster disease progression, and have an increased risk of ARIA with currently available therapies that can cause serious complications,” said Dr. Kim Johnson, Division Chief, Memory Disorders at the Department of Neurology of Duke University School of Medicine and a principal investigator in the Phase 1/2 study. “Today’s results suggest the potential of LX1001, which based on available data is well tolerated without reports of ARIA. The study also resulted in notable reductions in tau biomarkers, which suggest a possible effect on Alzheimer’s disease pathology.” LX1001 is an AAVrh10-based gene therapy candidate designed to deliver the protective APOE2 allele into the central nervous system of APOE4 homozygous patients, who have two copies of the toxic APOE4 allele. APOE2 is associated with a significantly lower risk of Alzheimer’s onset and slower disease progression. In the Phase 1/2 study, which completed enrollment in Q4 2023, fifteen patients with mild cognitive impairment (MCI) or mild or moderate AD were dosed with LX1001 in four dose-ascending cohorts. The study’s primary objective was to assess safety and tolerability, with secondary outcomes including cerebrospinal fluid (CSF) APOE2 protein expression and change in tau and amyloid biomarkers. “In light of the rapid progression of Alzheimer’s disease in this population, these data highlight the therapeutic potential of delivering APOE2, which can impact multiple mechanisms of Alzheimer’s disease upstream of any specific pathway and thereby meaningfully alter the devastating course of this complex disease,” said Dr. Sandi See Tai, Chief Development Officer of Lexeo Therapeutics. “These data are highly encouraging and provide clinical evidence of the unique and targeted mechanism of LX1001 to potentially treat Alzheimer’s disease.” The interim Phase 1/2 data include follow-up through 12-months for dose Cohorts 1 through 3 and follow-up through 6-months for dose Cohort 4, demonstrating: CSF APOE2 protein expression in all participants, with dose- and time-dependent increases in expression and durability out to 12 months Stabilization of amyloid pathology in the majority of participants, with minimal change from baseline in Aß42/40 ratio and amyloid PET Consistent reductions across CSF tau biomarkers including CSF T-tau, P-tau181, P-tau2172 and P-tau2312, in over two thirds of participants relative to baseline and natural history Reductions at 6 months in global tau PET3 SUVR in 5 of 6 participants and in regional SUVR in a majority of participants across all brain regions Participants with moderate AD (n=4) generally demonstrated the most improvement across various biomarker endpoints Four SAEs were reported, with three deemed unrelated to treatment and one event of mild-moderate sensorineural hearing loss assessed as possibly related to treatment with repeat audiometry pending. The Company has initiated engagement with FDA on these data and expects to provide an update on regulatory interactions and further LX1001 development plans in 2025. Lexeo will host a webcast today at 7:00 AM ET to review these data and next steps for the program. To register for and access the conference call and webcast presentation, please visit https://ir.lexeotx.com/news-events/events. The webcast presentation includes slides with further analysis of the LX1001 interim data. The on-demand webcast presentation may be accessed under the News & Events tab in the Investors section of the Company’s website, and a replay will be available following the presentation. LX1001 is an AAVrh10-based gene therapy candidate for the treatment of APOE4-homozygous Alzheimer’s disease. Individuals homozygous for APOE4, an allele of the gene APOE, are approximately 15 times more likely to develop Alzheimer’s disease than the general population, and it is estimated that there are approximately 900,000 APOE4 homozygous patients with Alzheimer’s disease in the United States. Conversely, individuals homozygous for the APOE allele APOE2 are 40% less likely to develop Alzheimer’s disease than the general population. LX1001 is designed to express the protective APOE2 gene in the central nervous system of APOE4 homozygous patients, potentially slowing or halting the progression of Alzheimer’s disease. LX1001 has been granted Fast Track designation by the FDA. 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. 1 Amyloid-related imaging abnormalities (ARIA) refer to MRI findings observed in patients receiving anti-amyloid therapies for Alzheimer’s disease. ARIA is most commonly observed as brain swelling and/or microhemorrhages and has a higher incidence in patients who are APOE4 allele carriers. 2 CSF P-tau217 and P-tau231 collected only in Cohorts 2, 3 and 4; all Cohort 4 samples, including 6 month and 12 month, pending analysis 3 Tau PET performed only in Cohorts 3 and 4; Cohort 4 12-mth visits pending analysis The content above comes from the network. if any infringement, please contact us to modify.

▎药明康德内容团队编辑 近期，全球细胞和基因疗法（CGT）领域迎来系列进展。Abeona Therapeutics公司向美国FDA重新提交了其自体细胞基因疗法prademagene zamikeracel（pz-cel）的生物制品许可申请（BLA），用于治疗隐性营养不良性大疱性表皮松解症（RDEB）。用于治疗肌萎缩侧索硬化（ALS）的在研细胞疗法debamestrocel公布了积极的扩展研究结果，与外部匹配的对照组相比具有统计学上显著的生存优势。多款用于治疗阿尔茨海默病（AD）的候选CGT疗法公布亮眼早期临床试验数据。临床试验结果本文将节选其中部分重要进展做简单介绍，仅供读者参阅。 图片来源：123RF ———✦研发进展✦——— ◇ Abeona Therapeutics公司宣布已向美国FDA重新提交了其自体细胞基因疗法pz-cel的BLA，作为隐性营养不良性大疱性表皮松解症患者的一种潜在新疗法。Pz-cel是由患者的自身皮肤细胞经过基因校正后扩增形成的角质细胞片，这些皮肤细胞的基因组中整合了一个功能正常的COL7A1基因以表达胶原蛋白VII，这种蛋白质是形成将表皮连接到真皮的锚纤维所需的。该候选疗法可通过外科手术来覆盖伤口区域，实现持续的伤口愈合和疼痛减轻。此前，pz-cel已获得美国FDA授予的再生医学先进疗法认定、突破性疗法认定、孤儿药资格及罕见儿科疾病认定。 ◇ BrainStorm Cell Therapeutics公司公布了其用于治疗ALS的在研细胞疗法debamestrocel的扩展研究结果。研究结果显示，在扩展使用项目（EAP）的最后一次随访中，10名受试者中有9人存活。生存曲线显示debamestrocel组与外部匹配对照组相比，具有统计学上显著的生存优势，其中debamestrocel组的中位生存时间为46.6个月，而匹配对照组为41.1个月。此外，在6名在3期临床试验期间已接受debamestrocel的患者中，观察到神经丝轻链（NfL）水平持续下降。相比之下，在3期试验中接受安慰剂的患者组中，中位NfL水平增加了37%，表明神经退行性病变加重。然而，这些患者在EAP中接受debamestrocel治疗后，大多数人的NfL水平趋于稳定。 Debamestrocel来源于ALS患者自身骨髓的间充质干细胞，这些细胞在体外进行扩增和分化，并且通过该公司独有的技术刺激分泌高水平的多种神经营养因子。这些分化的细胞在输注回到患者体内后，可能激活神经保护和免疫调节信号通路，从而减轻ALS患者的症状。 ◇ Lexeo Therapeutics公司公布了其用于治疗载脂蛋白E4（APOE4）基因纯合子型阿尔茨海默病的候选基因疗法LX1001的1/2期临床试验数据。结果显示，所有15名接受LX1001治疗的轻度认知障碍（MCI）或轻度或中度AD患者的神经保护性APOE2蛋白表达量呈剂量依赖性增加，12个月后仍具有持续性。大多数受试者的淀粉样病理学趋于稳定，超过三分之二患者的脑脊液（CFS）tau生物标志物（包括CSF T-tau、P-tau181、P-tau2172和P-tau2312）与基线和自然病史相比持续减少。此外，LX1001的安全性良好，没有报告淀粉样蛋白相关成像异常（ARIA）。 LX1001是一种基于AAVrh10的候选基因疗法，用于治疗APOE4基因纯合子型阿尔茨海默病患者。APOE4是APOE基因的一个等位基因，APOE4纯合子个体患阿尔茨海默病的风险大约是普通人群的15倍。而APOE2等位基因纯合子个体患阿尔茨海默病的风险比普通人群低40%。LX1001旨在在APOE4纯合子患者的中枢神经系统中表达具有保护作用的APOE2基因，潜在减缓或阻止阿尔茨海默病的进展。此前，LX1001已被美国FDA授予快速通道资格。 ◇ NKGen Biotech公司公布了其自体增强型自然杀伤（NK）细胞疗法troculeucel用于治疗中度AD的1/2a期临床试验中的1期临床数据。初步结果显示，在给予迄今为止最高剂量（60亿细胞）的冷冻保存的troculeucel的情况下，troculeucel表现出非常高的安全性，没有不良反应。在接受最高剂量治疗的前3名受试者中，100%患者的认知功能稳定或有所改善，并且其中两名受试者在接受仅三个月的治疗后，从中度疾病阶段显著好转至轻度认知障碍。 Troculeucel（SNK01）是一款自体、非基因工程改造的NK细胞产品，它具有增强的细胞毒性，活化受体表达率超过90%，可从任何供体中稳定生产。该候选疗法能够有效降低AD患者CSF中的α-突触核蛋白（α-syn）水平，该蛋白的升高被认为与认知能力下降有关。 ◇ Regeneration Biomedical公司公布了其用于治疗轻度至中度AD患者的自体Wnt激活脂肪来源干细胞（RB-ADSC）的1期临床试验结果。结果显示，该疗法的耐受性良好。第12周时，患者的P-tau和β淀粉样蛋白的水平有所下降。3名受试者中有2名的简易精神状态量表（MMSE）结果显示其认知功能有改善的趋势。 RB-ADSC是Wnt激活的脂肪源性干细胞，取自患者自身的脂肪组织。采集后，干细胞在体外进行培养和扩增，筛选出Wnt表达的干细胞，然后通过植入位于头皮下，可直接进入大脑的一个侧脑室的Ommaya储存器重新输回患者体内。 ◇ 中国国家药监局药品审评中心（CDE）官网公示，石药集团的嵌合抗原受体（CAR）-T细胞注射液SYS6020获得一项新的临床试验默示许可，拟开发治疗难治性全身型重症肌无力。公开资料显示，SYS6020为一款基于mRNA-脂质纳米颗粒（LNP）的CAR-T细胞注射液，也是石药集团布局的首个细胞治疗在研产品。SYS6020通过表达可特异性识别BCMA抗原的CAR，进而靶向识别患者体内BCMA阳性的细胞并对其进行杀灭，从而达到治疗目的。今年6月，SYS6020在中国首次获批临床，拟开发治疗复发或难治性多发性骨髓瘤。8月，SYS6020治疗系统性红斑狼疮（SLE）适应症获批临床，本次是该产品再次获得自身免疫疾病IND许可。 ◇ CDE官网公示，由艺妙神州全资子公司再妙生物与阳光诺和合作开发的CAR-T药物ZM001注射液获批临床，拟开发治疗SLE。根据新闻稿，ZM001通过特异性清除SLE患者体内的B细胞，抑制体内自身抗体的产生，缓解脏器中免疫复合物的沉积，并能够使机体重建正常的B细胞，进而缓解红斑狼疮症状，并维持长期疗效，是一种潜在的中度和重度SLE治疗药物。在此前进行的临床前研究中，ZM001展现出了清除B细胞快速且持续性的疗效，以及极低的严重不良反应发生率。 ◇ 普罗凯融生物申报的1类新药MSCohi-O镜片获批临床，拟开发治疗慢性眼部移植物抗宿主病（coGVHD）。根据普罗凯融生物公开资料介绍，这是其开发的负载间充质干细胞的高透氧水凝胶镜片。其核心创新性是解决脐带间充质干细胞自身无法停留在眼表的瓶颈障碍，实现稳定的眼表局部给药，从机理上治疗免疫相关的眼科疾病。该产品此前已经获得美国FDA授予孤儿药资料，用于治疗oGVHD。移植物抗宿主病是一种多系统疾病，其中眼部移植物抗宿主病会严重影响患者的视力，干预不及时还会导致患者失明。 ◇ 华道生物1类新药HD004细胞获批临床，拟用于治疗CLDN18.2表达阳性的晚期实体瘤伴恶性腹腔积液。根据华道生物公开资料，这是华道生物研发的靶向CLDN18.2的自体CAR-T产品。HD004细胞通过腹腔内灌注给药方式更直接靶向腹腔中的肿瘤细胞以发挥抗肿瘤作用，可以一定程度克服实体瘤CAR-T疗法障碍，提高CAR-T细胞运输和肿瘤浸润效率，在肿瘤局部停留时间延长，并且降低了脱靶效应带来的风险。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放 参考资料（可上下滑动查看） [1] Lexeo Therapeutics Announces Positive Interim Data for LX1001, First-Ever Gene Therapy to Impact the Underlying Genetic Cause of APOE4-Associated Alzheimer’s Disease, at the Clinical Trials on Alzheimer’s Disease (CTAD) Conference. Retrieved November 1, 2024, from https://ir.lexeotx.com/news-releases/news-release-details/lexeo-therapeutics-announces-positive-interim-data-lx1001-first [2] NKGen Biotech Presents Phase 1/2a Troculeucel Data in Alzheimer’s Disease at the 17th Annual Clinical Trials on Alzheimer’s Disease (CTAD) Conference. Retrieved November 1, 2024, from https://www.globenewswire.com/news-release/2024/10/29/2970775/0/en/NKGen-Biotech-Presents-Phase-1-2a-Troculeucel-Data-in-Alzheimer-s-Disease-at-the-17th-Annual-Clinical-Trials-on-Alzheimer-s-Disease-CTAD-Conference.html [3] Regeneration Biomedical Presents Data on First Cohort from an Ongoing Phase I Clinical Trial of Stem Cell Therapy Delivered Directly into the Brains of Patients with Alzheimer’s Disease. Retrieved November 1, 2024, from https://www.globenewswire.com/news-release/2024/10/29/2970530/0/en/Regeneration-Biomedical-Presents-Data-on-First-Cohort-from-an-Ongoing-Phase-I-Clinical-Trial-of-Stem-Cell-Therapy-Delivered-Directly-into-the-Brains-of-Patients-with-Alzheimer-s-Di.html [4] Abeona Therapeutics® Completes Pz-cel Biologics License Application Resubmission to U.S. Food and Drug Administration. Retrieved November 1, 2024, from https://www.globenewswire.com/news-release/2024/10/29/2970698/0/en/Abeona-Therapeutics-Completes-Pz-cel-Biologics-License-Application-Resubmission-to-U-S-Food-and-Drug-Administration.html [5] BrainStorm Cell Therapeutics Presented Positive Survival Data from NurOwn® Expanded Access Program at 2024 Annual NEALS Meeting. Retrieved October 28, 2024, from https://www.prnewswire.com/news-releases/brainstorm-cell-therapeutics-presented-positive-survival-data-from-nurown-expanded-access-program-at-2024-annual-neals-meeting-302288404.html [6] 自愿公告 - 首款基於mRNA-LNP的CAR-T细胞注射液(SYS6020)再获新适应症临床试验批准. Retrieved October 25, 2024, from http://www.cninfo.com.cn/new/disclosure/detail?stockCode=01093&announcementId=1221524554&orgId=gshk0001093&announcementTime=2024-10-25 [7] 进军自免 | 艺妙神州治疗系统性红斑狼疮的CAR-T药物获得临床试验通知书. Retrieved October 29, 2024, from  https://mp.weixin.qq.com/s/x8WT9y2BSVT-o26Luzfl3A 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新