90天内缓解糖尿病的干细胞疗法；治疗乳腺癌临床获益率达60%的CAR-T疗法…… | 一周盘点

2024-06-30

▎药明康德内容团队编辑本期看点 1. 干细胞疗法VX-880治疗1型糖尿病（T1D）患者在早期临床试验中获得积极数据，在末次随访时12名患者中有11名减少或停止使用外源性胰岛素。 2. 下一代寡核苷酸疗法RGLS8429用于治疗常染色体显性多囊肾病的早期临床试验结果积极，接受3 mg/kg剂量的患者中有70%的肾脏总体积缩小。 3. 通过抗耗竭技术增强的CAR-T细胞疗法LYL797在临床试验中被证明可以浸润到实体瘤中，治疗ROR1阳性复发/难治性三阴性乳腺癌 ROR1阳性复发/难治性三阴性乳腺癌患者的临床获益率（CBR）为60%。药明康德内容团队整理 VX-880：公布1/2期临床试验的新数据 Vertex Pharmaceuticals公司公布了其在研细胞疗法VX-880治疗1型糖尿病的1/2期临床试验的最新数据。VX-880是一种在研干细胞来源、完全分化、产生胰岛素的同种异体胰岛细胞疗法。VX-880有可能通过恢复胰岛细胞功能，包括葡萄糖反应性胰岛素产生，恢复机体调节葡萄糖水平的能力。VX-880通过肝门静脉输注给药，需要长期免疫抑制治疗以保护输入的胰岛细胞免受免疫排斥。VX-880已获得美国FDA授予的再生医学先进疗法（RMAT）认定和快速通道资格，以及欧洲药品管理局（EMA）授予的PRIME资格。公布的结果显示，在接受单次全剂量VX-880输注后90天内，所有T1D患者均显示出胰岛细胞移植成功和对葡萄糖反应的胰岛素生成。在最后一次随访时，12名患者中有11名减少或停止使用外源性胰岛素。Vertex预计增加入组患者数量，并将该疗法推进关键试验阶段。 RGLS8429：公布1b期临床试验的新数据 Regulus Therapeutics公司公布了其开发的新型下一代寡核苷酸疗法RGLS8429用于治疗常染色体显性多囊肾病的1b期临床试验的新数据。常染色体显性多囊肾病是由PKD1或PKD2基因突变引起的，也是最常见的人类单基因疾病之一，同时是终末期肾病的主要原因。RGLS8429旨在抑制miR-17并优先靶向肾脏，在临床前研究中已被证明能够明显改善肾脏功能、大小和其他疾病严重程度指标，并具有优越的药理学特征。此前，该公司已公布1期单次递增剂量临床试验的结果，结果显示，RGLS8429具有良好的安全性、耐受性和药代动力学（PK）特征。此次公布的是1b期研究中第三个队列的结果，患者对RGLS8429的耐受性良好，未发现安全性问题。PC1和PC2是PKD1和PKD2基因的蛋白质产物，已被证明与疾病严重程度呈负相关。接受RGLS8429治疗患者的PC1和PC2与基线相比的百分比变化在所有测试剂量中均显示出缓解，与安慰剂相比，3 mg/kg剂量组具有统计学意义。探索性成像分析表明，3 mg/kg剂量组的患者中，70%的患者肾脏总体积缩小。 LYL797：公布1期临床试验的初步数据 Lyell Immunopharma公司公布了其第一代重编程ROR1靶向CAR-T细胞候选产品LYL797的1期临床试验的初步数据。LYL797采用了Lyell公司的抗耗竭基因重编程技术（c-Jun）和其专有的体外制造方法——表观遗传重编程技术（Epi-R）。LYL797过度表达c-Jun可以纠正耗竭T细胞中AP-1家族转录因子的失衡。在临床前研究中，c-Jun的过度表达使T细胞能够抵抗耗竭、浸润实体瘤并保持其功能。Epi-R技术旨在生成干样T细胞群，减少耗竭，提高增殖和抗肿瘤活性。该研究的初始数据集主要由ROR1阳性复发/难治性三阴性乳腺癌 ROR1阳性复发/难治性三阴性乳腺癌患者组成。结果显示，LYL797对这些患者具有剂量依赖性的抗肿瘤临床活性，患者的客观缓解率为40%，CBR为60%。新闻稿指出，该试验首次证明了通过抗耗竭技术增强的CAR-T细胞既可以增殖又可以浸润到实体瘤中。在无肺部受累的患者中未观察到与LYL797相关的显著安全信号；在肺转移性疾病患者中观察到可治疗的肺炎。根据现有的积极数据，该公司计划扩大开发范围，包括ROR1阳性复发/难治性铂类耐药卵巢癌、子宫内膜癌、多发性骨髓瘤和慢性淋巴细胞白血病等新肿瘤类型。 NTLA-2001：公布1期临床试验的新数据 Intellia Therapeutics公司公布了其CRISPR/Cas9基因编辑疗法NTLA-2001的最新临床数据。NTLA-2001是Intellia与再生元（Regeneron）开展的多靶点发现、开发和商业化合作的一部分，Intellia负责主导NTLA-2001的开发和商业化。之前新闻稿指出，NTLA-2001以CRISPR/Cas9技术为基础，有望成为治疗转甲状腺素蛋白（ATTR）淀粉样变性的首个单次给药疗法。此外，NTLA-2001是首个通过全身给药或静脉注射来编辑人体内基因的候选CRISPR基因编辑疗法，基于Intellia公司专有的非病毒平台，利用脂质纳米颗粒（LNP）向肝脏输送由两部分组成的基因编辑系统：靶向血清转甲状腺素（TTR）基因的特异性gRNA和编码Cas9酶的mRNA。此次公布的结果显示，三位先前在1期剂量递增研究中接受最低剂量NTLA-2001治疗的ATTR淀粉样变性患者，在接受后续55 mg NTLA-2001治疗后，其TTR蛋白水平中位减少90%。根据新闻稿，这是首次临床数据显示体内CRISPR/Cas9基因编辑疗法可有效重复给药，成功完成临床概念验证。 WVE-003：公布1b/2a期临床试验的新数据 Wave Life Sciences公司宣布，在研疗法WVE-003在治疗亨廷顿病（HD）的1b/2a期临床试验SELECT-HD中取得了积极成果。WVE-003是一款等位基因选择性反义寡核苷酸，旨在降低突变亨廷顿蛋白（mHTT）表达并保留健康的野生型亨廷顿蛋白（wtHTT）。数据显示，WVE-003总体安全性和耐受性良好，没有报告严重不良事件。在28周评估期间观察到WVE-003组患者显著的mHTT蛋白水平降低：在24周（最后一次给药后8周），脑脊液（CSF）中mHTT与安慰剂组患者相比平均降低46%（p=0.0007）；在28周（最后一次给药后12周），CSF中mHTT平均降低44%（p=0.0002），支持每季度或更少频率的给药。尾状核萎缩是一个影像学生物标志物，可预测患者的临床结果，包括总运动评分（TMS）的临床显著恶化。在24周（最后一次影像评估）时，mHTT的减少与尾状核萎缩的减缓相关（R=-0.50；p=0.047）。 ENTR-601-44：公布1期临床试验的初步数据 Entrada Therapeutics公司公布了其用于治疗杜氏肌营养不良（DMD）的候选疗法ENTR-601的1期临床试验的积极初步数据。ENTR-601-44是一种专有的内泌体逃逸载体（EEV）偶联磷酸二酰胺吗啉寡聚物（PMO），旨在解决由于DMD基因突变或缺失外显子而导致的DMD的根本原因。ENTR-601-44可用于治疗DMD患者中可跳过44号外显子的患者，目前正在评估其恢复mRNA阅读框的潜力，并允许翻译略有缩短但仍有功能的肌营养不良蛋白。此次公布的结果显示，ENTR-601-44在健康受试者中耐受性良好，没有严重的不良事件，没有与药物相关的不良事件，也没有在生命体征、心电图、体格检查或实验室评估中观察到临床显著的变化或趋势。研究人员在接受ENTR-601-44的患者的肌肉中检测到了药物浓度。与接受安慰剂的患者相比，ENTR-601-44组患者的外显子跳跃水平具有统计学意义。 Divesiran（SLN124）：公布1期临床试验数据 Silence Therapeutics公司宣布，其正在进行的1期临床试验SANRECO获得积极结果。该研究评估了divesiran（SLN124），一种针对TMPRSS6的siRNA，用于治疗真红细胞增多症（PV）患者的安全性和疗效。PV是一种罕见的骨髓增生性肿瘤，其特征是红细胞过量生成，常常导致血细胞比容升高。Divesiran是一款靶向TMPRSS6的siRNA。TMPRSS6是铁调素（hepcidin）的负调节因子，而铁调素是体内铁代谢的主要调节因子，负责铁的吸收、分布和储存。通过在PV患者中沉默TMPRSS6的表达，divesiran旨在增加肝细胞铁调素的生成和释放，从而限制骨髓中的铁含量，减少依赖铁供应的红细胞过度生成。截至2024年3月29日的数据，在16名可评估患者中，8名患者血细胞比容控制良好。这是一项检测血液中红细胞比例的指标。截至目前，divesiran的耐受性良好，没有发现重大安全问题。 Ficerafusp alfa（BCA101）：公布1/1b期临床试验数据 Bicara Therapeutics公司公布了其双功能抗体ficerafusp alfa（BCA101）的1/1b期开放标签剂量扩增研究的最新中期数据。Ficerafusp alfa旨在抑制EGFR并直接在肿瘤部位使TGF-β失效。这种作用机制使得BCA101能够抑制肿瘤增殖，同时恢复局部免疫细胞的细胞毒活性。此次公布的结果显示，ficerafusp alfa与PD-1抑制剂帕博利珠单抗 PD-1抑制剂帕博利珠单抗联用，在随访至少12个月的头颈部鳞状细胞癌（HNSCC）患者中显示出有临床意义的抗肿瘤活性，并显著优于标准疗法。在HPV阴性HNSCC患者中，总缓解率为64%（18/28），完全缓解率为18%（5/28），中位无进展生存期为9.8个月，尚未达到中位缓解持续时间和中位总生存期。安全性方面，该联合疗法的耐受性良好，最常见的治疗相关不良事件包括痤疮样皮疹（76%，大多数为1/2级）、疲劳（43%）和低磷血症（38%）。 Lunresertib（RP-6306）：公布1期临床试验的初步数据 Repare Therapeutics公司报告了其PKMYT1抑制剂lunresertib联用FOLFIRI治疗晚期实体瘤患者的1期临床试验的积极数据。Lunresertib是一种潜在“first-in-class”的精准肿瘤学小分子PKMYT1抑制剂 PKMYT1抑制剂，靶向实体瘤中的CCNE1扩增、FBXW7和PPP2R1A变异。截至2024年5月2日的数据，该联合疗法在曾接受过多线治疗、具有CCNE1扩增和FBXW7突变的肿瘤患者中展现出可喜的疗效。不同肿瘤类型患者的总缓解率为18.2%（n=33），包括4例确认和2例未确认的部分缓解，无论既往是否暴露于伊立替康。结直肠癌患者的临床获益延长，40%的伊立替康初治患者接受治疗超过9个月，而该比例的临床基准为20%。安全性方面，lunresertib联合治疗耐受性良好，没有超过单独使用lunresertib或标准FOLFIRI化疗方案的预期毒性。 ▲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] Vertex Announces Positive Results From Ongoing Phase 1/2 Study of VX-880 for the Treatment of Type 1 Diabetes Presented at the American Diabetes Association 84th Scientific Sessions. 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Retrieved June 26, 2024 from https://www.businesswire.com/news/home/20240624485930/en [21] OrsoBio to Present Phase 1 and Preclinical Data for Liver-Targeted Mitochondrial Protonophore TLC-6740 at the American Diabetes Association’s 84th Scientific Sessions. Retrieved June 26, 2024 from https://www.businesswire.com/news/home/20240621611137/en [22] Biond Biologics Announces First Patient Dosed with BND-35 in Phase 1 Clinical Trial. Retrieved June 26, 2024 from https://www.prnewswire.com/news-releases/biond-biologics-announces-first-patient-dosed-with-bnd-35-in-phase-1-clinical-trial-302180049.html [23] Enlivex Announces the Dosing of the First Patient in a Randomized, Placebo-Controlled Phase I/II Trial Evaluating AllocetraTM in up to 46 Patients with Thumb Osteoarthritis. Retrieved June 26, 2024 from https://www.globenewswire.com/news-release/2024/06/24/2902937/0/en/Enlivex-Announces-the-Dosing-of-the-First-Patient-in-a-Randomized-Placebo-Controlled-Phase-I-II-Trial-Evaluating-AllocetraTM-in-up-to-46-Patients-with-Thumb-Osteoarthritis.html [24] IDEAYA Biosciences Announces First-Patient-In for Phase 1 Clinical Trial Evaluating IDE397 and Trodelvy® Combination in MTAP-Deletion Bladder Cancer. Retrieved June 26, 2024 from https://www.prnewswire.com/news-releases/ideaya-biosciences-announces-first-patient-in-for-phase-1-clinical-trial-evaluating-ide397-and-trodelvy-combination-in-mtap-deletion-bladder-cancer-302181366.html [25] Allakos Announces Positive Results from its Ongoing Phase 1 Trial of AK006 in Healthy Volunteers, with AK006 Demonstrating High Receptor Occupancy on Mast Cells and a Favorable Safety Profile. Retrieved June 26, 2024 from https://www.globenewswire.com/news-release/2024/06/25/2904125/0/en/Allakos-Announces-Positive-Results-from-its-Ongoing-Phase-1-Trial-of-AK006-in-Healthy-Volunteers-with-AK006-Demonstrating-High-Receptor-Occupancy-on-Mast-Cells-and-a-Favorable-Safe.html [26] Werewolf Therapeutics Highlights Initial Safety and Efficacy Data from its Ongoing Phase 1 Clinical Trial Evaluating WTX-330 in Patients with Advanced or Metastatic Solid Tumors or Non-Hodgkin Lymphoma. Retrieved June 26, 2024 from https://www.globenewswire.com/news-release/2024/06/25/2903639/0/en/Werewolf-Therapeutics-Highlights-Initial-Safety-and-Efficacy-Data-from-its-Ongoing-Phase-1-Clinical-Trial-Evaluating-WTX-330-in-Patients-with-Advanced-or-Metastatic-Solid-Tumors-or.html [27] Ethris Announces Positive Initial Phase 1 Data Demonstrating Nasal Delivery of mRNA Lead Candidate ETH47. Retrieved June 26, 2024 from https://www.businesswire.com/news/home/20240624540176/en [28] Revelation Biosciences Announces Phase 1 Clinical Study of Gemini Met the Primary Safety Endpoint and Showed Statistically Significant Biomarker Activity. Retrieved June 26, 2024 from https://www.businesswire.com/news/home/20240624937640/en [29] TiumBio Presents Promising Clinical Data from Phase 1 of its Hemophilia Treatment Candidate TU7710 at ISTH 2024. Retrieved June 26, 2024 from https://www.prnewswire.com/news-releases/tiumbio-presents-promising-clinical-data-from-phase-1-of-its-hemophilia-treatment-candidate-tu7710-at-isth-2024-302180104.html [30] GenVivo Announces Initiation of Patient Dosing in a US Phase I/Ib Clinical Trial Evaluating GEN2, a Personalizing, Gene Vector Immunotherapy, in Patients with Advanced Solid Tumors. Retrieved June 28, 2024, from https://www.globenewswire.com/NC/news-release/2024/06/27/2905012/0/en/GenVivo-Announces-Initiation-of-Patient-Dosing-in-a-US-Phase-I-Ib-Clinical-Trial-Evaluating-GEN2-a-Personalizing-Gene-Vector-Immunotherapy-in-Patients-with-Advanced-Solid-Tumors.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