直接将基因疗法送入大脑的帕金森病创新疗法；使患者总生存期翻2.5倍的免疫联合疗法... | 一周盘点

2024-01-09

临床结果临床3期基因疗法免疫疗法临床2期

▎药明康德内容团队编辑本期看点1. 用于治疗与广泛发育性和癫痫性脑病（DEE）相关癫痫发作的新型5-HT2C受体超激动剂bexicaserin（LP352）的1b/2a期临床试验达主要终点，使可数运动性癫痫发作频率较基线中位减少了53.3%。2. 肿瘤免疫治疗新药Galinpepimut-S（GPS）联用PD-1抑制剂纳武利尤单抗 PD-1抑制剂纳武利尤单抗治疗恶性胸膜间皮瘤，患者的中位总生存期（OS）约为接受标准治疗的患者的2.5倍。3. Orion公司与默沙东（MSD）合作开发的CYP11A1抑制剂早期临床结果积极，超过半数携带雄激素受体（AR）配体结合域（LBD）突变的转移性去势抵抗性前列腺癌（mCRPC）患者的前列腺特异性抗原（PSA）水平下降≥50%。4. 直接将基因疗法送入大脑的帕金森病创新疗法达到临床试验主要终点。药明康德内容团队整理Bexicaserin（LP352）：公布1b/2a期临床试验数据 Longboard Pharmaceuticals公司今天公布了PACIFIC研究的积极数据，该研究评估其在研疗法bexicaserin（LP352）用于治疗与广泛发育性和癫痫性脑病相关癫痫发作的疗效与安全性。Bexicaserin是一款高选择性、口服、新型5-HT2C受体超激动剂，为潜在的“best-in-class”疗法。结果显示，接受bexicaserin治疗的可评估受试者（n=35）的可数运动性癫痫发作频率（主要疗效终点）较基线的中位变化为降低53.3%，而接受安慰剂治疗的受试者（n=9）则降低20.8%，这代表经安慰剂校正的癫痫发作频率降低32.5%。Dravet综合征（DS）DS）、Lennox-Gastaut综合征（LGS）和其他DEE亚组队列可数运动性癫痫发作频率较基线的中位变化分别降低72.1%、48.1%和61.2%。Bexicaserin表现出良好的安全性和耐受性结果。观察到的最常见不良事件（AE）为嗜睡、食欲减退、便秘、腹泻。Longboard计划将迅速推进bexicaserin的全球3期试验。Galinpepimut-S：公布1期临床试验的新数据 SELLAS Life Sciences Group公布了其靶向WT1蛋白的潜在“first-in-class”肿瘤免疫治疗新药Galinpepimut-S联用PD-1抑制剂纳武利尤单抗 PD-1抑制剂纳武利尤单抗用于治疗恶性胸膜间皮瘤患者的1期临床新数据，这些患者的肿瘤普遍表达WT1。该药由4条多肽链构成，抗原表位多达25个，适用于全球范围内绝大多数人类白细胞组织相容性抗原（HLA）类型，能够激发自身免疫系统对WT1抗原强烈的免疫反应。研究结果显示，该试验达到了安全性和疗效的主要终点，并观察到了联合疗法的临床活性和患者生存率的提高。接受联合疗法的患者的中位OS为70.3周，而接受标准治疗的复发/难治性患者的中位OS约为28周。对GPS没有免疫反应的患者的中位OS为9.0个月，对GPS有免疫反应的患者的中位OS为27.8个月。全部患者的中位无进展生存期（PFS）为11.9周，疾病控制率（DCR）为30%。ODM-208（MK-5684）：公布1/2期临床试验数据 ODM-208是Orion公司与默沙东合作开发的一种用于治疗前列腺癌等激素依赖性癌症的口服非甾体类选择性抑制剂。通过抑制CYP11A1酶的活性，ODM-208可以抑制所有类固醇激素和可能激活雄激素受体信号通路的激素前体的产生。此次公布结果的1/2期试验评估了ODM-208对先前接受过多线治疗的mCRPC患者的安全性和有效性。结果显示，在1期试验中，14/19（73.7%）名AR LBD突变患者和2/23（8.7%）名AR野生型患者的PSA水平下降了50%或以上。2a期试验中，24/45（53.3%）名AR LBD突变患者的PSA水平下降了50%或以上。46/53（87%）名患者的中位循环睾酮水平在接受ODM-208治疗的第一周内从基线时的3.0 ng/dl降至检测不到的水平。大多数患者耐受性良好，与治疗相关的肾上腺功能不全是最常见的安全性问题。总体而言，1期试验有17名（36.2%）患者和2a期试验有6名（13.3%）患者出现肾上腺功能不全，需要调整激素替代疗法和/或额外补充治疗，之后通常会继续接受ODM-208治疗。AB-1005（AAV2-GDNF）：公布1b期临床试验数据拜耳（Bayer）公司旗下Asklepios BioPharmaceutical（AskBio）公司宣布，治疗帕金森病的在研基因疗法AB-1005（AAV2-GDNF）在1b期临床试验中达到主要终点，在11名接受治疗的患者中表现出良好的安全性。基于这一结果，两家公司计划在2024年上半年启动2期临床试验。AB-1005是一种基于腺相关病毒血清型2（AAV2）载体的在研基因疗法，含有编码人胶质细胞源性神经营养因子（GDNF）的转基因。通过磁共振成像（MRI）监测的对流增强给药方式直接进行神经外科注射后，GDNF可以在大脑局部区域实现稳定和连续的表达。GNSC-001：启动1b期临床试验Genascence Corporation公司宣布启动1b期临床试验，评估其在研基因疗法GNSC-001治疗膝盖骨关节炎的安全性和效果，试验预计招募约50名患者。GNSC-001是一款使用重组腺相关病毒载体表达编码IL-1Ra蛋白转基因的在研基因疗法。IL-1Ra蛋白是一种阻断IL-1信号传导的天然蛋白。IL-1被认为是介导骨关节炎病例发生的关键因子，可导致炎症、关节痛和软骨损害。GNSC-001旨在通过一次注射到关节中，提供长期持久的IL-1信号通路抑制。SC262：IND申请获得FDA许可Sana Biotechnology公司宣布，在研细胞疗法SC262的IND申请获得美国FDA的许可，用于在临床试验中治疗复发或难治性B细胞恶性肿瘤。SC262是基于Sana公司的低免疫（hypoimmune）平台设计的靶向CD22的CAR-T细胞疗法。Sana公司的低免疫平台旨在克服同种异体细胞的免疫排斥，让同种异体CAR-T细胞疗法具有更长的持久性，带来更长的完全缓解。这一平台通过基因编辑扰乱1型和2型主要MHC的表达，让移植细胞不被适应性免疫系统发现。不过这同时通常会导致它们更容易被先天免疫系统发现，尤其是自然杀伤（NK）细胞。Sana的平台因此提供了逃避先天免疫细胞杀伤的方法，包括过度表达CD47，这种蛋白防止细胞被NK细胞或者巨噬细胞杀伤。SENTI-202：IND申请获得FDA许可Senti Biosciences公司宣布其现货型嵌合抗原受体（CAR）NK细胞疗法候选疗法SENTI-202的IND申请获得了美国FDA的许可。Senti Bio公司开发的细胞疗法通过给细胞加上逻辑回路，让细胞更为“智能”地区分癌细胞和健康细胞。SENTI-202是一款新一代CAR-NK细胞疗法。它携带了两种不同的逻辑回路，“OR”回路让它能够识别癌细胞表面表达的CD33或FLT3抗原，从而具有更高的抗癌潜力。而“NOT”回路在识别造血干细胞表面表达的EMCN抗原时会抑制疗法的活性，从而避免SENTI-202杀伤健康造血干细胞。这款CAR-NK疗法还表达可控释放的IL-15蛋白，进一步增强NK细胞的活性。在临床前研究中，它已经表现出良好的抗癌活性和显著降低的肿瘤外毒性。Senti公司计划在2024年第二季度为1期临床试验的首例患者进行给药，预计在2024年年底获得初步的临床疗效数据，2025年获得耐久性数据。DA-1726：向FDA提交IND申请DA-1726是NeuroBo Pharmaceuticals公司开发的一种新型胃泌酸调节素（oxyntomodulin，OXM）类似物，具有胰高血糖素样肽1受体（GLP-1R）和胰高血糖素受体（GCGR）双激动剂的功能，可通过降低食欲和增加能量消耗来减轻体重。DA-1726被设计为每周皮下注射一次，拟开发用于治疗肥胖和非酒精性脂肪性肝炎（NASH）。DA-1726的作用机制明确，在临床前小鼠模型中，其减肥效果优于司美格鲁肽和cotadutide（另一种OXM类似物）。近期，NeuroBo Pharmaceuticals公司已向美国FDA提交了DA-1726的IND申请，以开展1期临床试验。INF904：公布1期临床试验数据InflaRx公司公布了其口服小分子C5aR抑制剂INF904的随机、双盲、安慰剂对照1期试验的初步结果。INF904可通过受体C5aR抑制C5a诱导的信号传导，已在多个临床前疾病模型中显示出抗炎治疗效果。此外，与已上市的C5aR抑制剂不同，体外实验证明INF904对细胞色素P450 3A4/5（CYP3A4/5）酶的抑制作用极小，而CYP3A4/5酶在包括糖皮质激素在内的多种代谢物和药物的代谢过程中发挥着重要作用。此次公布的数据显示，药代动力学（PK）和药效学（PD）数据为INF904的“best-in-class”潜力提供了支持。在14天的给药期间，患者的C5a诱导的中性粒细胞活化阻断率≥90%。此外，在不同剂量下，INF904在体内的暴露水平与剂量之间存在良好的比例关系，并能产生所需的C5a诱导的中性粒细胞活化阻断活性（阻断率>90%）。安全性方面，INF90的耐受性良好，在整个测试剂量范围内重复给药后，受试者没有出现任何值得关注的不良安全事件。PAS-004：IND申请获得FDA许可Pasithea Therapeutics公司宣布，美国FDA批准其大环MEK抑制剂PAS-004的IND申请，以评估PAS-004在MAPK通路驱动的晚期实体肿瘤患者中的应用，这些患者携带RAS、RAF或NF1突变，或有BRAF/MEK抑制剂治疗失败的经历。Pasithea公司预计将于2024年第一季度为首例患者用药。与目前FDA批准的MEK抑制剂不同，PAS-004是大环化合物，环化可增强药物与靶受体的结合，被认为有望改善药代动力学和安全性。PAS-004已在各种疾病的小鼠模型中进行了测试，并完成了临床前测试和动物毒理学研究。此外，FDA还授予PAS-004孤儿药资格，用于治疗1型神经纤维瘤病。新闻稿指出，PAS-004是首个进入人体临床试验的大环MEK抑制剂。大家都在看药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲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] Senti Bio Announces FDA Clearance of IND Application for SENTI-202 for the Treatment of Relapsed or Refractory Hematologic Malignancies Including Acute Myeloid Leukemia. Retrieved January 5, 2023, from https://www.globenewswire.com/news-release/2023/12/22/2800521/0/en/Senti-Bio-Announces-FDA-Clearance-of-IND-Application-for-SENTI-202-for-the-Treatment-of-Relapsed-or-Refractory-Hematologic-Malignancies-Including-Acute-Myeloid-Leukemia.html[2] SELLAS Life Sciences Reports Positive Follow-Up Immune Response and Survival Data in Completed Phase 1 Study of Galinpepimut-S Combined with Opdivo® in Advanced Malignant Pleural Mesothelioma. Retrieved January 5, 2023, from https://www.globenewswire.com/news-release/2023/12/27/2801365/0/en/SELLAS-Life-Sciences-Reports-Positive-Follow-Up-Immune-Response-and-Survival-Data-in-Completed-Phase-1-Study-of-Galinpepimut-S-Combined-with-Opdivo-in-Advanced-Malignant-Pleural-Me.html[3] Kiromic BioPharma Reports Favorable Early Safety and Tolerability Data from First Patient Enrolled in the Phase 1 Deltacel-01 Clinical Trial. Retrieved January 5, 2023, from https://www.businesswire.com/news/home/20240105590033/en/[4] NEJM Evidence publishes results from Phase I/IIa CYPIDES trial with ODM-208. Retrieved January 5, 2023, from https://www.globenewswire.com/news-release/2023/12/27/2801265/0/en/NEJM-Evidence-publishes-results-from-Phase-I-IIa-CYPIDES-trial-with-ODM-208.html[5] OliX Pharmaceuticals Receives HREC Approval to Initiate Phase 1 Clinical Trial of NASH and Obesity Drug. Retrieved January 5, 2023, from https://www.businesswire.com/news/home/20231222734122/en[6] Oncternal Therapeutics Updates the Status of its Phase 1/2 Study of ONCT-808, a ROR1-Targeting Autologous CAR T, in Patients with Relapsed or Refractory Aggressive B-cell Lymphoma. Retrieved January 5, 2023, from https://investor.oncternal.com/news-releases/news-release-details/oncternal-therapeutics-updates-status-its-phase-12-study-onct[7] Tyra Biosciences Doses First Patient with TYRA-200 and Provides Positive Updates on TYRA-300. Retrieved January 5, 2023, from https://www.prnewswire.com/news-releases/tyra-biosciences-doses-first-patient-with-tyra-200-and-provides-positive-updates-on-tyra-300-302021502.html[8] NeuroBo Pharmaceuticals Submits IND Application to the FDA for a Phase 1 Clinical Trial of DA-1726 for the Treatment of Obesity. Retrieved January 5, 2023, from https://www.prnewswire.com/news-releases/neurobo-pharmaceuticals-submits-ind-application-to-the-fda-for-a-phase-1-clinical-trial-of-da-1726-for-the-treatment-of-obesity-302023115.html[9] NKGen Biotech, Inc. Announces Dosing of First Patient in its Phase 1/2a Trial with Autologous NK Cell Product, SNK01, for the Treatment of Moderate Alzheimer’s Disease. Retrieved January 5, 2023, from https://nkgenbiotech.com/nkgen-biotech-inc-announces-dosing-of-first-patient-in-its-phase-1-2a-trial-with-autologous-nk-cell-product-snk01-for-the-treatment-of-moderate-alzheimers-disease/[10] atai Life Sciences Announces Positive Topline Results from Single Ascending Dose Phase 1 Study with EMP-01 (R-MDMA). Retrieved January 5, 2023, from https://www.globenewswire.com/news-release/2024/01/02/2802639/0/en/atai-Life-Sciences-Announces-Positive-Topline-Results-from-Single-Ascending-Dose-Phase-1-Study-with-EMP-01-R-MDMA.html[11] Longboard Pharmaceuticals Announces Positive Topline Data from the PACIFIC Study, a Phase 1b/2a Clinical Trial, for Bexicaserin (LP352) in Participants with Developmental and Epileptic Encephalopathies (DEEs). Retrieved January 5, 2023, from https://www.businesswire.com/news/home/20240102733902/en[12] Ubix Therapeutics Receives US FDA Clearance to Proceed with Phase 1 Study of UBX-303-1, an Orally Dosed Small Molecule BTK Degrader for Treatment of Relapsed/refractory B-cell Malignancies. Retrieved January 5, 2023, from http://ubixtrx.com/news/press/59[13] Pasithea Therapeutics Announces FDA Acceptance of IND Application to Evaluate PAS-004 in Advanced Cancer Patients. Retrieved January 5, 2023, from https://www.globenewswire.com/news-release/2024/01/02/2802677/0/en/Pasithea-Therapeutics-Announces-FDA-Acceptance-of-IND-Application-to-Evaluate-PAS-004-in-Advanced-Cancer-Patients.html[14] INmune Bio Announces First Patient Dosed in a Phase 1/2 Study of INKmune™ in Patients with Metastatic Castration-Resistant Prostate Cancer. Retrieved January 5, 2023, from https://www.globenewswire.com/news-release/2024/01/02/2802613/0/en/INmune-Bio-Announces-First-Patient-Dosed-in-a-Phase-1-2-Study-of-INKmune-in-Patients-with-Metastatic-Castration-Resistant-Prostate-Cancer.html[15] BridgeBio announces FDA clearance of IND application for BBO-8520, a first-in-class direct inhibitor of KRASG12C (ON). Retrieved January 5, 2023, from https://www.globenewswire.com/news-release/2024/01/03/2803197/0/en/BridgeBio-announces-FDA-clearance-of-IND-application-for-BBO-8520-a-first-in-class-direct-inhibitor-of-KRASG12C-ON.html[16] GPN Vaccines Reports Positive Safety and Immunogenicity Data from its Phase 1 Trial of Gamma-PN. Retrieved January 5, 2023, from https://www.prnewswire.com/news-releases/gpn-vaccines-reports-positive-safety-and-immunogenicity-data-from-its-phase-1-trial-of-gamma-pn-302025669.html[17] Genascence Announces Initiation of Phase 1b Clinical Trial of GNSC-001 Gene Therapy for Knee Osteoarthritis (OA). Retrieved January 5, 2023, from https://www.prnewswire.com/news-releases/genascence-announces-initiation-of-phase-1b-clinical-trial-of-gnsc-001-gene-therapy-for-knee-osteoarthritis-oa-302022071.html[18] Ventus Therapeutics Initiates Clinical Testing of VENT-03, a First-in-Class, Orally Administered cGAS Inhibitor. Retrieved January 5, 2023, from https://www.businesswire.com/news/home/20240103586030/en/[19] MAPLIGHT THERAPEUTICS ANNOUNCES COMPLETION OF PHASE 1 CLINICAL TRIAL FOR NOVEL M1/M4 MUSCARINIC AGONIST IN DEVELOPMENT FOR SCHIZOPHRENIA AND ALZHEIMER'S DISEASE PSYCHOSIS. Retrieved January 5, 2023, from https://www.prnewswire.com/news-releases/maplight-therapeutics-announces-completion-of-phase-1-clinical-trial-for-novel-m1m4-muscarinic-agonist-in-development-for-schizophrenia-and-alzheimers-disease-psychosis-302025329.html[20] Sitryx announces collaboration partner Lilly has commenced a Phase 1 study of SIT-011 for chronic autoimmune and inflammatory diseases. Retrieved January 5, 2023, from https://www.globenewswire.com/news-release/2024/01/04/2803717/0/en/Sitryx-announces-collaboration-partner-Lilly-has-commenced-a-Phase-1-study-of-SIT-011-for-chronic-autoimmune-and-inflammatory-diseases.html[21] GlycoMimetics Announces Positive Initial Safety and Pharmacokinetic Results from Phase 1a Healthy Volunteer Study of GMI-1687. Retrieved January 5, 2023, from https://www.businesswire.com/news/home/20240104347772/en[22] InflaRx Announces Positive Topline Results from the Multiple Ascending Dose (MAD) Phase I Study with C5aR Inhibitor INF904. Retrieved January 5, 2023, from https://www.globenewswire.com/news-release/2024/01/04/2803830/0/en/InflaRx-Announces-Positive-Topline-Results-from-the-Multiple-Ascending-Dose-MAD-Phase-I-Study-with-C5aR-Inhibitor-INF904.html[23] Quanta Announces IND Clearance by U.S. FDA for QTX3034, G12D-Preferring Multi-KRAS Inhibitor, and Other Pipeline Updates. Retrieved January 5, 2023, from https://www.globenewswire.com/news-release/2024/01/04/2803965/0/en/Quanta-Announces-IND-Clearance-by-U-S-FDA-for-QTX3034-G12D-Preferring-Multi-KRAS-Inhibitor-and-Other-Pipeline-Updates.html[24] OnQuality Announces FDA Clearance of IND Application for OQL025 for the treatment of EGFR Inhibitor-Induced Acneiform Rash. Retrieved January 5, 2023, from https://www.prnewswire.com/news-releases/onquality-announces-fda-clearance-of-ind-application-for-oql025-for-the-treatment-of-egfr-inhibitor-induced-acneiform-rash-302025647.html[25] Medivir´s licensee, Tango Therapeutics, has dosed the first patient with TNG348, a novel USP1 inhibitor, in a phase 1/2 clinical study. Retrieved January 5, 2023, from https://www.prnewswire.com/news-releases/medivirs-licensee-tango-therapeutics-has-dosed-the-first-patient-with-tng348-a-novel-usp1-inhibitor-in-a-phase-12-clinical-study-302026095.html[26] Kynexis Announces Initiation of First-in-Human Phase 1 Study of KYN-5356, a Potential Treatment for Cognitive Impairment Associated with Schizophrenia. Retrieved January 5, 2023, from https://www.globenewswire.com/news-release/2024/01/04/2803801/0/en/Kynexis-Announces-Initiation-of-First-in-Human-Phase-1-Study-of-KYN-5356-a-Potential-Treatment-for-Cognitive-Impairment-Associated-with-Schizophrenia.html[27] OnKure Announces IND Clearance by U.S. FDA Enabling Phase 1 Initiation for its Mutant Selective PI3Kα inhibitor, OKI-219. Retrieved January 5, 2023, from https://www.globenewswire.com/news-release/2024/01/04/2804053/0/en/OnKure-Announces-IND-Clearance-by-U-S-FDA-Enabling-Phase-1-Initiation-for-its-Mutant-Selective-PI3K%CE%B1-inhibitor-OKI-219.html[28] Sana Biotechnology Announces FDA Clearance of Investigational New Drug Application for SC262, a Hypoimmune-modified, CD22-directed Allogeneic CAR T Therapy, for Patients with Relapsed or Refractory B-cell Malignancies. Retrieved January 5, 2023, from https://www.globenewswire.com/news-release/2024/01/05/2804686/0/en/Sana-Biotechnology-Announces-FDA-Clearance-of-Investigational-New-Drug-Application-for-SC262-a-Hypoimmune-modified-CD22-directed-Allogeneic-CAR-T-Therapy-for-Patients-with-Relapsed.html[29] AskBio Phase Ib trial of AB-1005 gene therapy in patients with Parkinson’s disease meets primary endpoint. Retrieved January 5, 2024, from https://www.bayer.com/media/en-us/askbio-phase-ib-trial-of-ab-1005-gene-therapy-in-patients-with-parkinsons-disease-meets-primary-endpoint/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