TNG-462

▎药明康德内容团队编辑 本期看点 1. 阿斯利康（AstraZeneca）双特异性T细胞接合器AZD0486治疗复发/难治性滤泡性淋巴瘤（R/R FL）患者的1期临床试验结果亮眼，接受2.4 mg及以上剂量患者的总缓解率（ORR）高达96%，完全缓解（CR）率达85%。 2. 潜在“first-in-class”的menin抑制剂revumenib联用venetoclax和去甲基化剂（HMA）ASTX727治疗携带特定基因变异的急性白血病患者，在一项1/2期研究中的ORR达88%。 3. 潜在“best-in-class”合成致死疗法TNG462的早期临床结果积极，多种癌症类型患者的肿瘤有缩小。 药明康德内容团队整理 AZD0486：公布1期临床试验数据 阿斯利康宣布将在今年的美国血液学会（ASH）年会上公布旗下多款血液学管线的临床结果，其中包括该公司的CD19 x CD3靶向双特异性T细胞接合器AZD0486用于复发/难治性滤泡性淋巴瘤患者的1期临床试验结果。 结果显示，R/R FL患者对2.4 mg及以上剂量的AZD0486高度应答，患者的ORR高达96%，CR达85%，且患者的最小残留病灶（MRD）阴性比率很高。此外，1期试验中期结果也显示，接受过大量治疗的弥漫大B细胞淋巴瘤（DLBCL）患者也对AZD0486高度应答，患者的CR率高。最新数据还显示AZD0486具有良好的安全性，双倍递增给药方案可有效缓解患者发生细胞因子释放综合征（CRS）和免疫效应细胞相关神经毒性综合征（ICANS）事件。 Revumenib：公布1/2期临床试验数据 Syndax Pharmaceuticals公司宣布将在ASH年会上公布其在研疗法revumenib联用venetoclax和去甲基化剂ASTX727（decitabine/cedazuridine）治疗携带KMT2A重排、NUP98重排或NPM1突变的复发/难治性急性髓系白血病（r/r AML）或混合谱系急性白血病（MPAL）儿童和成人患者的1/2期临床试验结果。Revumenib是一种针对menin-KMT2A相互作用的强效、选择性小分子抑制剂。 截至2024年7月的数据，共有26名患者入组该试验，ORR为88%（23/26），CR或带部分血液学恢复的完全缓解（CRh）率为58%（15/26）。15名达到CR/CRh的患者中有14名的MRD状态可评估，其中93%（13/14）为MRD阴性。中位随访时间为6.6个月时，患者6个月时的无复发生存率为59%，总生存率为74%。CR/CRh患者的中位缓解持续时间尚未达到。该组合疗法总体上耐受性良好。 TNG462：公布1/2期临床试验数据 Tango Therapeutics公司宣布，基于在研疗法TNG462在1/2期临床试验剂量递增和早期剂量扩展队列中获得的积极数据，该公司已选择TNG462进入全面开发。新闻稿指出，TNG462是一种潜在“best-in-class”的甲硫腺苷（MTA）协同的蛋白精氨酸甲基转移酶5（PRMT5）抑制剂。PRMT5是甲硫腺苷磷酸化酶（MTAP）突变的合成致死靶点。MTAP基因缺失发生在大约10%的癌症中，包括胰腺癌、肺癌和膀胱癌，这些患者体内存在异常升高的MTA水平，从而抑制PRMT5的活性。PRMT5是一种参与基本细胞功能的酶，MTA的升高使得肿瘤细胞对额外PRMT5的抑制变得更为敏感。TNG462是一款基于合成致死理念设计的精准抗癌疗法，它可在抑制MTAP缺失细胞中PRMT5功能的同时，保留健康细胞中的PRMT5功能，从而选择性地杀死肿瘤细胞。 截至2024年10月20日，共有59名患者入组，其中39名患者可评估，涵盖13种癌症类型。数据显示，TNG462在多种肿瘤类型中展现了抗癌活性且耐受性良好，包括非小细胞肺癌（NSCLC）和胰腺癌。多种肿瘤类型的肿瘤体积随着持续治疗而缩小，约60%最初被评估为疾病稳定（SD）的患者在之后出现部分缓解（PR）。尽管目前大多数癌症类型的患者数和随访时间不足以准确估算客观缓解率，但在已入组的7名胆管癌患者中，观察到其中3名（43%）患者获得确认的客观缓解。此外，TNG462在活性剂量下具有良好的安全性和耐受性，剂量限制性毒性（DLT）为血小板减少。该药物的其他不良事件（如恶心、呕吐、腹泻和疲劳）发生率低于20%，且主要为1级。 ▲TNG462治疗胆管癌患者的临床试验结果（图片来源：参考资料[4]） ISB 2001：公布1期临床试验的新数据 Ichnos Glenmark Innovation公司宣布将在ASH年会上进行口头报告，展示其三特异性抗体ISB 2001用于复发/难治性多发性骨髓瘤（r/r MM）的1期研究的数据。ISB 2001同时靶向MM细胞上的BCMA和CD38，以及T细胞上的CD3，旨在增加对MM细胞的特异性结合，同时最大限度地减少脱靶效应。 截至2024年7月的数据，12名可评估疗效患者的ORR为75%（9/12），其中包括1例MRD阴性的严格CR。安全性方面，ISB 2001具有良好的安全性和耐受性，未观察到DLT，仅有一例高于2级的特殊关注不良事件，且没有因治疗而停药的情况。 Vilastobart（XTX101）：公布1c期临床试验数据 Xilio Therapeutics公司公布了其正在进行的1c期临床试验的初步临床数据，该试验评估了vilastobart（XTX101）联用PD-L1抑制剂atezolizumab治疗晚期实体瘤患者的效果。Vilastobart是一种肿瘤激活、Fc增强、高亲和力结合的抗CTLA-4抗体。 截至2024年10月7日，17名患者接受了vilastobart联用atezolizumab的治疗。观察到两名患有难以治疗的、免疫学上为“冷肿瘤”的患者达到了未确认的PR。在1名微卫星稳定型结直肠癌（MSS CRC）患者中观察到转移性肝脏病灶的完全消退。安全性数据显示，该联合治疗总体上耐受良好，vilastobart有潜力成为与PD-1/PD-L1抑制剂联合使用的差异化下一代抗CTLA-4抗体。 VK2735：公布早期临床试验的新数据 Viking Therapeutics在肥胖协会年会肥胖周（ObesityWeek）上公布了其在研减重疗法胰高血糖素样肽1（GLP-1）/葡萄糖依赖性胰岛素促泌肽（GIP）受体联合激动剂VK2735的最新临床试验数据。分析显示，接受每日VK2735口服片剂28天的受试者，其安慰剂调整后平均体重较基线减轻达6.8%。而接受每周VK2735皮下注射治疗13周的肥胖患者的平均体重则较基线减轻达14.7%。值得一提的是，在试验第一周时便观察到接受皮下剂型患者显著的体重减轻效果，近100%患者在停药4周后其体重减轻的大部分效果仍然维持。目前该公司正在规划VK2735注射剂型的3期研究，以及口服剂型的2期研究，详细信息将在接近试验启动时间时公布。 ▲接受口服VK2735治疗28天受试者的体重减轻效果（图片来源：参考资料[1]） ▲接受VK2735皮下注射13周受试者的体重减轻效果（图片来源：参考资料[1]） ▲接受VK2735皮下注射受试者在停药后体重减轻效果持续维持（图片来源：参考资料[1]） AZD5004：公布1期临床试验数据 阿斯利康公司公布了在研口服GLP-1疗法AZD5004，在患有2型糖尿病的肥胖患者中进行的1期临床试验的最新结果。AZD5004是一款每日一次、低剂量的小分子GLP-1受体激动剂，该药物在临床前研究中证明具有理想的疗效和安全性。去年11月，阿斯利康与诚益生物（Eccogene）达成独家协议，以潜在18.25亿美元的总额获得小分子GLP-1受体激动剂ECC5004（即AZD5004），用于治疗包括肥胖症、2型糖尿病和其他合并症在内的适应症。 此次公布的数据显示，接受剂量为50 mg的AZD5004治疗的患者中，4周后患者体重与基线相比降低5.8%，约为9.4斤。同时，患者的空腹血糖等指标也有所下降。 ▲AZD5004降低患者体重和血糖指标（图片来源：阿斯利康官网） CIN-109、CIN-110：公布1期临床试验数据 CinFina Pharma公司公布了其CIN-110的单剂量递增（SAD）研究的初步中期数据以及CIN-109的多剂量递增（MAD）研究的最终数据。CIN-110是一种强效、高选择性的肽YY（PYY3-36）类似物，具有延长的半衰期，旨在显著减少其他PYY分子观察到的恶心和呕吐，同时促进有效的长期体重减轻。CIN-109是一种新型长效生长分化因子15（GDF-15）类似物，有可能减少食欲、维持能量消耗和促进体重减轻，同时保持瘦体重。 两项研究均显示这些候选疗法具有良好的耐受性，并能导致显著的体重减轻。CIN-110的1期研究共纳入24名平均BMI为34 kg/m²的肥胖受试者，在给药一周内，他们的食物摄入量减少了28%，体重最多下降了1.8%。总共报告了3例轻度恶心，通常在给药后12-48小时内出现，并在一天内缓解。在CIN-109的1期研究中，平均BMI为35 kg/m²的肥胖受试者的食物摄入量呈剂量依赖性的减少，最高达50%，患者在1-2个月内体重减轻了多达3.7%。此外，每两周给药一次CIN-109的耐受性更好，大部分减轻的体重来自于脂肪，且未观察到与治疗相关的严重副作用。 ▲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] Viking Therapeutics Reports New Data from VK2735 Obesity Program at ObesityWeek® 2024. Retrieved November 4, 2024 from https://www.prnewswire.com/news-releases/viking-therapeutics-reports-new-data-from-vk2735-obesity-program-at-obesityweek-2024-302294915.html [2] AZN Meet the Management: Weight Management Virtual Event. Retrieved November 4, 2024, from https://www.astrazeneca.com/content/dam/az/Investor_Relations/events/Weight-Management-Virtual-Event-IR-presentation.pdf [3] Tango Therapeutics Reports Positive TNG462 Clinical Data and Provides Update on PRMT5 Development Program. Retrieved November 6, 2024, from https://ir.tangotx.com/news-releases/news-release-details/tango-therapeutics-reports-positive-tng462-clinical-data-and [4] Tango Therapeutics Corporate Presentation. Retrieved November 6, 2024, from https://ir.tangotx.com/static-files/c49a558d-602e-4fed-9d53-dcbc004ffdf5 [5] AstraZeneca showcases strength of haematology portfolio and pipeline at ASH 2024. Retrieved November 7, 2024 from https://www.astrazeneca.com/media-centre/press-releases/2024/astrazeneca-showcases-strength-of-haematology-portfolio-and-pipeline-at-ash-2024.html [6] Xilio Therapeutics Announces Initial Clinical Trial Data from Phase 1C Dose Escalation for Vilastobart (XTX101), a Tumor-Activated Anti-CTLA-4, in Combination with Atezolizumab in Patients with Advanced Solid Tumors. Retrieved November 7, 2024 from https://www.globenewswire.com/news-release/2024/11/07/2976781/0/en/Xilio-Therapeutics-Announces-Initial-Clinical-Trial-Data-from-Phase-1C-Dose-Escalation-for-Vilastobart-XTX101-a-Tumor-Activated-Anti-CTLA-4-in-Combination-with-Atezolizumab-in-Pati.html [7] CinFina Pharma Presents Positive Phase 1 Study Results in Poster Session for CIN-109 and in Late-Breaking Poster for CIN-110, Demonstrating the Potential of Next-Generation Mechanisms at ObesityWeek® 2024. Retrieved November 7, 2024 from https://cinrx.com/cinfina-pharma-phase-1-study-results-poster-session-cin-109-late-breaking-poster-cin-110-demonstrating-potential-next-generation-mechanisms-obesityweek-2024 [8] Ichnos Glenmark Innovation (IGI) Announces First Presentation of Data from Phase 1 Study of the Trispecific ISB 2001 in Relapsed/Refractory Multiple Myeloma (r/rMM) at Upcoming ASH Annual Meeting. Retrieved November 7, 2024 from https://www.globenewswire.com/news-release/2024/11/05/2974962/0/en/Ichnos-Glenmark-Innovation-IGI-Announces-First-Presentation-of-Data-from-Phase-1-Study-of-the-Trispecific-ISB-2001-in-Relapsed-Refractory-Multiple-Myeloma-r-rMM-at-Upcoming-ASH-Ann.html [9] Syndax Announces Revumenib Abstracts to Be Presented at the 66th ASH Annual Meeting. Retrieved November 7, 2024 from https://www.prnewswire.com/news-releases/syndax-announces-revumenib-abstracts-to-be-presented-at-the-66th-ash-annual-meeting-302296077.html [10] Oncoinvent Announces Publication of 18-Month Safety and Efficacy Data from the Phase 1/2a Study of Radspherin® in Colorectal Cancer. Retrieved November 5, 2024 from https://www.businesswire.com/news/home/20241101923447/en/Oncoinvent-Announces-Publication-of-18-Month-Safety-and-Efficacy-Data-from-the-Phase-12a-Study-of-Radspherin%C2%AE-in-Colorectal-Cancer/ [11] Arcellx to Present Clinical Data for Its Phase 1 and iMMagine-1 Studies in Patients with Relapsed or Refractory Multiple Myeloma at the 66th ASH Annual Meeting and Exposition and Announces Progress in iMMagine-3 Study. Retrieved November 5, 2024 from https://ir.arcellx.com/news/news-details/2024/Arcellx-to-Present-Clinical-Data-for-Its-Phase-1-and-iMMagine-1-Studies-in-Patients-with-Relapsed-or-Refractory-Multiple-Myeloma-at-the-66th-ASH-Annual-Meeting-and-Exposition-and-Announces-Progress-in-iMMagine-3-Study/default.aspx [12] Beam Therapeutics to Present Data Across Hematology Franchise, Including First Clinical Data for BEAM-101 in Sickle Cell Disease and ESCAPE Non-human Primate Data, at American Society of Hematology (ASH) Annual Meeting. Retrieved November 5, 2024 from https://www.globenewswire.com/news-release/2024/11/05/2974971/0/en/Beam-Therapeutics-to-Present-Data-Across-Hematology-Franchise-Including-First-Clinical-Data-for-BEAM-101-in-Sickle-Cell-Disease-and-ESCAPE-Non-human-Primate-Data-at-American-Societ.html [13] TScan Therapeutics Announces Upcoming Oral Presentation of Data from the ALLOHA™ Phase 1 Heme Trial at the 66th American Society of Hematology Annual Meeting and Exposition. Retrieved November 5, 2024 from https://www.globenewswire.com/news-release/2024/11/05/2975010/0/en/TScan-Therapeutics-Announces-Upcoming-Oral-Presentation-of-Data-from-the-ALLOHA-Phase-1-Heme-Trial-at-the-66th-American-Society-of-Hematology-Annual-Meeting-and-Exposition.html [14] C4 Therapeutics Announces First Patient Dosed in CFT8919 Clinical Trial. Retrieved November 8, 2024 from https://www.globenewswire.com/news-release/2024/11/06/2975566/0/en/C4-Therapeutics-Announces-First-Patient-Dosed-in-CFT8919-Clinical-Trial.html [15] Nouscom’s Off-the-Shelf Neoantigen Immunotherapy, NOUS-209, Continues to Elicit Potent and Durable Immune Responses in Lynch Syndrome Carriers Highlighting its Potential to ‘Intercept’ Cancer. Retrieved November 8, 2024 from https://www.morningstar.com/news/globe-newswire/1001011427/nouscoms-off-the-shelf-neoantigen-immunotherapy-nous-209-continues-to-elicit-potent-and-durable-immune-responses-in-lynch-syndrome-carriers-highlighting-its-potential-to-intercept-cancer [16] Korro Announces Regulatory Filing for Initiation of KRRO-110 First-In-Human Study and Formation of Clinical Advisory Board. Retrieved November 8, 2024 from https://ir.korrobio.com/news-releases/news-release-details/korro-announces-regulatory-filing-initiation-krro-110-first [17] Zymeworks Announces First Patient Dosed in Phase 1 Clinical Trial Evaluating ZW191 in Folate Receptor-⍺ Expressing Advanced Solid Tumors. Retrieved November 8, 2024 from https://ir.zymeworks.com/news-releases/news-release-details/zymeworks-announces-first-patient-dosed-phase-1-clinical-trial-0 [18] Ankyra Therapeutics Announces First Visceral Tumor Patient Dosed in Phase 1 ANCHOR Clinical Trial of ANK-101, an Anchored Interleukin-12 (IL-12). Retrieved November 8, 2024 from https://ankyratx.com/press-releases/ankyra-therapeutics-announces-first-visceral-tumor-patient-dosed-in-phase-1-anchor-clinical-trial-of-ank-101-an-anchored-interleukin-12-il-12/ [19] HiFiBiO Therapeutics Receives FDA Clearance of IND Application for HFB200604, a Best-in-Class BTLA Agonist Antibody for the Treatment of Inflammatory and Immunology Diseases. Retrieved November 8, 2024 from https://hifibio.com/hifibio-therapeutics-receives-fda-clearance-of-ind-application-for-hfb200604-a-best-in-class-btla-agonist-antibody-for-the-treatment-of-inflammatory-and-immunology-diseases/ [20] Xencor Doses First Subject in Phase 1/2 Study of XmAb®942 in Development for Patients with Inflammatory Bowel Disease. Retrieved November 8, 2024 from https://investors.xencor.com/news-releases/news-release-details/xencor-doses-first-subject-phase-12-study-xmabr942-development [21] Elicio Therapeutics Presents Updated Translational Data from ELI-002 Phase 1 AMPLIFY-7P Study at the Society for Immunotherapy of Cancer (“SITC”) 2024 Annual Meeting. Retrieved November 8, 2024 from https://www.globenewswire.com/news-release/2024/11/07/2977121/0/en/Elicio-Therapeutics-Presents-Updated-Translational-Data-from-ELI-002-Phase-1-AMPLIFY-7P-Study-at-the-Society-for-Immunotherapy-of-Cancer-SITC-2024-Annual-Meeting.html [22] HotSpot Therapeutics Presents Additional Phase 1 Biomarker Data on Novel CBL-B Inhibitor HST-1011 at 2024 Society for Immunotherapy of Cancer Annual Meeting. Retrieved November 8, 2024 from https://www.prnewswire.com/news-releases/hotspot-therapeutics-presents-additional-phase-1-biomarker-data-on-novel-cbl-b-inhibitor-hst-1011-at-2024-society-for-immunotherapy-of-cancer-annual-meeting-302298481.html [23] OncoResponse Announces Phase 1 Results of the Clinical Trial of OR502, anti-LILRB2 Antibody, in Subjects with Advanced Cancer. Retrieved November 8, 2024 from https://www.prnewswire.com/news-releases/oncoresponse-announces-phase-1-results-of-the-clinical-trial-of-or502-anti-lilrb2-antibody-in-subjects-with-advanced-cancer-302298422.html [24] Allogene Therapeutics Announces Positive Phase 1 Data Demonstrating the Potential of ALLO-316 in Heavily Pretreated Patients with Advanced Renal Cell Carcinoma at SITC and IKCS. Retrieved November 8, 2024 from https://www.globenewswire.com/news-release/2024/11/07/2976851/0/en/Allogene-Therapeutics-Announces-Positive-Phase-1-Data-Demonstrating-the-Potential-of-ALLO-316-in-Heavily-Pretreated-Patients-with-Advanced-Renal-Cell-Carcinoma-at-SITC-and-IKCS.html [25] Bolt Biotherapeutics Presents Updated Preclinical Data for BDC-4182 and Key Learnings from Phase 1 Dose-Escalation Trial of BDC-1001 at SITC 39th Annual Meeting. Retrieved November 8, 2024 from https://www.globenewswire.com/news-release/2024/11/07/2976848/0/en/Bolt-Biotherapeutics-Presents-Updated-Preclinical-Data-for-BDC-4182-and-Key-Learnings-from-Phase-1-Dose-Escalation-Trial-of-BDC-1001-at-SITC-39th-Annual-Meeting.html [26] Aummune Announces Results from Phase 1 Trial of its Novel AM003 Immunotherapy for the Treatment of Solid Tumors. Retrieved November 8, 2024 from https://www.globenewswire.com/news-release/2024/11/07/2976844/0/en/Aummune-Announces-Results-from-Phase-1-Trial-of-its-Novel-AM003-Immunotherapy-for-the-Treatment-of-Solid-Tumors.html [27] Cellenkos Announces Oral Presentation at ASH Annual Meeting 2024 Highlighting Phase 1b Clinical Data of CK0804 in Myelofibrosis. Retrieved November 8, 2024 from https://www.prnewswire.com/news-releases/cellenkos-announces-oral-presentation-at-ash-annual-meeting-2024-highlighting-phase-1b-clinical-data-of-ck0804-in-myelofibrosis-302298808.html [28] Indaptus Therapeutics Presents Encouraging Interim Safety Data from Phase 1 Clinical Trial of Decoy20 at the Society for Immunotherapy of Cancer (SITC) 2024 Annual Meeting. Retrieved November 8, 2024 from https://www.globenewswire.com/news-release/2024/11/07/2976598/0/en/Indaptus-Therapeutics-Presents-Encouraging-Interim-Safety-Data-from-Phase-1-Clinical-Trial-of-Decoy20-at-the-Society-for-Immunotherapy-of-Cancer-SITC-2024-Annual-Meeting.html [29] Nimbus Therapeutics Presents Positive Updated Data from Phase 1/2 Clinical Trial of HPK1 Inhibitor for Advanced Solid Tumors at SITC 39th Annual Meeting. Retrieved November 8, 2024 from https://www.businesswire.com/news/home/20241107226079/en/Nimbus-Therapeutics-Presents-Positive-Updated-Data-from-Phase-12-Clinical-Trial-of-HPK1-Inhibitor-for-Advanced-Solid-Tumors-at-SITC-39th-Annual-Meeting [30] Indapta Therapeutics Presents Clinical and Preclinical Data of Allogenic Natural Killer Cell Therapy at Society for Immunotherapy of Cancer Meeting. Retrieved November 8, 2024 from https://www.businesswire.com/news/home/20241107081017/en/Indapta-Therapeutics-Presents-Clinical-and-Preclinical-Data-of-Allogenic-Natural-Killer-Cell-Therapy-at-Society-for-Immunotherapy-of-Cancer-Meeting [31] Radella Pharmaceuticals Announces Topline Data from the Phase 1a Study of MD-18, a First-In-Class Peptide Targeting PTP1B for Obesity. Retrieved November 8, 2024 from https://www.businesswire.com/news/home/20241107046414/en/Radella-Pharmaceuticals-Announces-Topline-Data-from-the-Phase-1a-Study-of-MD-18-a-First-In-Class-Peptide-Targeting-PTP1B-for-Obesity#:~:text=Radella%20Pharmaceuticals%20Announces%20Topline%20Data%20from%20the%20Phase,its%20platform%20targeting%20cardiometabolic%20disease%20and%20its%20adjacencies [32] Palisade Bio Announces First Subject Dosed in Phase 1 Clinical Study of PALI-2108 for the Treatment of Moderate-to-Severe Ulcerative Colitis (UC). Retrieved November 8, 2024 from https://palisadebio.com/palisade-bio-announces-first-subject-dosed-in-phase-1-clinical-study-of-pali-2108-for-the-treatment-of-moderate-to-severe-ulcerative-colitis-uc/ [33] SystImmune, Inc. Announces FDA Clearance of IND Application for BL-M17D1 in Advanced Solid Tumors. 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