不受病毒变异影响的吸入式mRNA疗法、使关键指标下降74%的潜在“best-in-class”抑制剂… | 一周盘点

2023-12-03

临床1期抗体药物偶联物信使RNA临床结果临床2期

▎药明康德内容团队编辑本期看点1. 潜在“first-in-class”和“best-in-class”的前列腺特异性膜抗原（PSMA）靶向抗体偶联药物（ADC）ARX517的1/2期临床试验数据积极，将继续提升剂量，开展第10个队列的试验。2. 潜在“best-in-class”的新生儿Fc受体（FcRn）抑制剂IMVT-1402的早期临床结果积极，在研究中使患者的关键指标下降74%。3. 不受病毒变异影响的吸入式mRNA疗法ETH47在英国获批开展1期临床试验，用于治疗和预防呼吸道病毒感染。药明康德内容团队整理ARX517：公布1/2期临床试验数据 Ambrx Biopharma公司公布了其靶向PSMA的ADC候选疗法ARX517在转移性去势抵抗性前列腺癌（mCRPC）患者中的积极早期数据。PSMA在超过80%的前列腺癌中高度表达，尤其是在转移性去势抵抗性前列腺癌中，因此是一个很具有潜力的治疗靶点。ARX517由人源化的抗PSMA mAb与Ambrx专有的强效微管抑制剂AS269连接而成。在临床前研究中，ARX517的癌细胞杀伤有效载荷pAF-AS269通过mAb释放到癌细胞中时具有很强的细胞毒性。ARX517的位点特异性连接、稳定的共轭化学性质和不可裂解的连接体使ADC具有均匀的药物抗体比、类似mAb的生物物理特性和优异的稳定性。因此，Ambrx公司认为ARX517可以促进对肿瘤细胞的高度特异性杀伤，同时将脱靶毒性降至最低。新闻稿指出，ARX517有潜力成为“first-in-class”和“best-in-class”的抗PSMA ADC，以满足mCRPC患者的巨大未竟医疗需求。此前公布的数据显示，在给药剂量≥2.0 mg/kg的队列中，队列6（2.0 mg/kg）中100%（3/3）的患者达到了前列腺特异性抗原（PSA）减少≥50%（PSA50），队列7（2.4 mg/kg）中3人中有2人达到了PSA50，队列8（2.88 mg/kg）的3人中有2人达到了PSA50。此次公布的数据显示，剂量递增队列9（3.4 mg/kg）的21天剂量限制性毒性（DLT）观察期结束后，未观察到任何DLT或严重不良事件。队列9的3名患者中，有两名在仅使用了一次ARX517治疗的情况下，在3周后进行首次PSA评估时发现，他们的PSA分别快速下降了91%和33%。第3位患者未报告PSA下降，因为该患者患有不分泌PSA的mCRPC。基于此结果，安全监测委员会（SMC）投票决定将剂量升级到4.5 mg/kg（队列10），并增加队列9的患者。IMVT-1402：公布1期临床试验数据Immunovant公司公布了其FcRn靶向抗体IMVT-1402在健康成人受试者中的1期临床试验的新数据。抗FcRn抗体药物被认为极具潜力，其作用机制在于，FcRn表达被促炎细胞因子（如TNF-α）上调，并通过减少内皮细胞和骨髓衍生细胞中的溶酶体降解来延长IgG和血清白蛋白的半衰期。阻断FcRn-IgG相互作用可加速自身抗体的降解，并减轻各种致病性IgG介导的自身免疫性疾病的发作。此次公布的结果显示，每周4次、每次皮下注射600 mg剂量的IMVT-1402平均可使患者的总IgG水平降低74%，这种效力与每周4次、每次注射680 mg的batoclimab相似，后者可使IgG降低76%。此外，接受IMVT-1402治疗组患者的血清白蛋白和低密度脂蛋白胆固醇（LDL-C）水平的变化与安慰剂组相似。新闻稿指出，这显示了IMVT-1402作为潜在“best-in-class”的FcRn抑制剂的潜力。ETH47：获批在英国启动1期临床试验 ETH47是Ethris公司开发的首款基于mRNA的候选产品，编码III型干扰素（IFN）。ETH47是利用Ethris公司的稳定非致病性mRNA（SNIM RNA）平台开发的，其独特设计是利用Ethris公司专有的稳定纳米粒子（SNaP）脂质纳米颗粒（LNP）平台，通过吸入或鼻腔喷雾实现肺部的局部给药。ETH47旨在诱导病毒进入部位的粘膜产生先天性免疫防御反应，并抑制病毒复制。ETH47的用途广泛，不受病毒变异的影响，有望广泛用于季节性和新出现的呼吸道病毒感染，包括由病毒引起的哮喘等慢性呼吸道疾病的恶化。近期，ETH47已获得英国药品和健康产品管理局（MHRA）的批准，将于2023年12月在英国开展针对健康受试者的1期临床试验，用于治疗和预防呼吸道病毒感染。TARA-002：公布1a期临床试验的新数据Protara Therapeutics Protara Therapeutics公司公布了其用于治疗高级非肌肉浸润性膀胱癌（NMIBC）的在研细胞疗法TARA-002的1a期临床试验的新数据。此前，TARA-002已被美国FDA授予罕见儿科疾病认定。此前公布的结果显示，在所有3名可评估的原位癌患者中观察到了抗肿瘤活性。其中，一名此前接受过多线治疗且对卡介苗无反应的患者获得了完全缓解，在另外两名患者中观察到了肿瘤的消退。此次公布的结果显示，TARA-002在NMIBC患者中的耐受性保持良好。6名高级别非侵袭性乳头状（HGTa）肿瘤患者中有5名达到了12周的高级别无复发生存（HGRFS）。CT-0525 CT-0525：IND申请获得FDA许可CT-0525 CT-0525是Carisma Therapeutics公司开发的一种体外基因修饰的自体嵌合抗原受体-单核细胞（CAR-Monocyte）疗法，用于治疗过度表达人表皮生长因子受体2（HER2）的实体瘤 HER2）的实体瘤。单核细胞是巨噬细胞的前体细胞，CAR-单核细胞疗法有望解决细胞疗法治疗实体瘤的难题，包括肿瘤浸润、肿瘤微环境中的免疫抑制和抗原异质性。近期，CT-0525 CT-0525的IND申请已获得美国FDA许可，Carisma公司计划在未来几个月内启动该候选疗法的1期研究，并在2024年上半年对首例患者进行治疗。Zelnecirnon（RPT193）：公布1a/1b期临床试验数据RAPT Therapeutics公司公布了其用于治疗特应性皮炎（AD）和其他炎症性疾病的小分子口服疗法zelnecirnon（原RPT193）的1a/1b期临床试验结果。Zelnecirnon旨在阻断Th2细胞上高表达的受体CCR4，选择性地抑制Th2细胞向炎症组织的迁移。初步数据表明，zelnecirnon还可能通过降低受到刺激时分泌的Th2细胞因子来调节Th2细胞的功能。在AD等过敏性炎症疾病中，趋化因子会通过CCR4将Th2细胞招募到炎症组织中，Th2细胞在炎症组织中分泌已知能驱动炎症反应的蛋白质。针对这一途径的注射生物制品已在临床上验证了Th2细胞的作用。与健康人相比，AD患者体内的CCR4配体水平更高，这些配体还与疾病的严重程度相关。RAPT公司认为，通过抑制CCR4，zelnecirnon有望给AD、哮喘、慢性自发性荨麻疹、斑秃、结节性瘙痒症、伴有鼻息肉的慢性鼻炎、过敏性鼻炎和嗜酸性粒细胞性食管炎等多种炎症性疾病的患者带来治疗益处。此次公布结果的1a期研究是在72名健康受试者中进行的标准单次和多次剂量递增研究。1b期试验是一项随机、双盲、安慰剂对照研究，在31名中重度AD患者中评估了zelnecirnon单药治疗的效果。研究结果显示，每日一次的zelnecirnon治疗通常耐受性良好，没有报告严重的不良事件，并且所有报告的治疗伴发不良事件在AD患者和健康受试者中都是轻度至中度的。在1b期试验中，经过4周的治疗后，接受zelnecirnon治疗的中重度AD患者的湿疹面积和严重程度指数（EASI）评分与基线相比有36.3%的变化，而安慰剂组只有17.0%的变化。值得注意的是，在治疗结束后的两周内，zelnecirnon组的缓解持续加深，与安慰剂组相比有显著的统计学差异。在6周的时间点上，zelnecirnon组的EASI评分与基线相比变化了53.2%，而安慰剂组为9.6%（p<0.05）。此外，在第29天时，与安慰剂组相比，zelnecirnon组的皮肤活检结果显示其转录谱发生了明显的变化，这与临床疗效指标也有显著的相关性。GM-2505：公布1期临床试验数据Gilgamesh Pharmaceuticals公司公布了其用于治疗难治性抑郁症（TRD）和抑郁症（MDD）的新型5-HT2A受体激动剂GM-2505的1期研究结果。GM-2505作为一种快速起效、持久、安全和间歇性的治疗选择，有潜力改善抑郁症患者的护理和治疗效果。此次公布的结果显示，单次静脉注射GM-2505能够维持60-90分钟的迷幻作用，该候选疗法的耐受性良好，未报告严重的不良事件。该公司计划于2024年第一季度开展针对MDD患者的2a期研究，以完善给药方案，并确认该候选疗法的安全性和早期疗效。除MDD外，GM-2505还有望治疗酒精使用障碍、焦虑症和强迫症等其他各种严重的精神疾病。BX004：公布1b/2a期临床试验的新数据BiomX公司公布了其噬菌体鸡尾酒疗法BX004用于治疗铜绿假单胞菌引起慢性肺部感染的囊性纤维化（CF）患者的安全性和有效性数据。铜绿假单胞菌是引起CF患者肺部感染和死亡的主要因素。BX004旨在靶向和破坏铜绿假单胞菌。研究结果显示，BX004治疗安全且耐受性良好。在肺功能减退的患者亚组中，根据FEV1（患者一秒内用力呼出的空气量）和囊性纤维化问卷-修订版（CFQ-R）呼吸领域评分，BX004对患者肺功能的改善具有临床意义。使用BX004治疗10天后，有3名患者（14%）的铜绿假单胞菌培养结果转为阴性，而使用安慰剂的患者没有人（0%）转为阴性。在以持续吸入抗生素为背景的患者亚组中，BX004与安慰剂相比，在治疗结束时铜绿假单胞菌负荷减少了2.8 log10 CFU/g，超过了第一部分的研究结果。基于这些结果，该公司计划推进BX004进入关键的2b/3期试验。大家都在看▲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] HiberCell Announces Successful Completion and Interim Results of Phase 1 Study of Novel PERK Inhibitor, HC-5404, in Solid Tumors and Maps Forward Path as Monotherapy and in Combinations. 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Retrieved November 30, 2023, from https://www.prnewswire.com/news-releases/scineuro-completes-dosing-in-its-phase-1-clinical-trial-of-snp318-an-oral-therapeutic-for-alzheimers-disease-and-other-neurodegenerative-diseases-302001680.html[31] Jasper Announces First Patient Dosed in Phase 1b/2a Clinical Study of Briquilimab in Chronic Spontaneous Urticaria. Retrieved November 30, 2023, from https://www.globenewswire.com/en/news-release/2023/11/30/2788522/0/en/Jasper-Announces-First-Patient-Dosed-in-Phase-1b-2a-Clinical-Study-of-Briquilimab-in-Chronic-Spontaneous-Urticaria.html[32] Inipharm Initiates Dosing in Phase 1 Study of Its Small Molecule Inhibitor of HSD17B13. Retrieved November 30, 2023, from https://www.businesswire.com/news/home/20231130655005/en[33] Gilgamesh Pharmaceuticals Successfully Completes Phase 1 SAD Clinical Trial of GM-2505. Retrieved November 30, 2023, from https://www.prnewswire.com/news-releases/gilgamesh-pharmaceuticals-successfully-completes-phase-1-sad-clinical-trial-of-gm-2505-302002031.html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