▎药明康德内容团队编辑
本期看点
1. CD19靶向候选CAR-T细胞疗法GLPG5101在1项早期临床试验中治疗5例套细胞淋巴瘤(MCL)患者,客观缓解率(ORR)和完全缓解率(CRR)均为100%。
2. 靶向信号调节蛋白(SIRP)的抗体疗法ELA026治疗初治恶性肿瘤相关噬血细胞性淋巴组织细胞增多症(mHLH)的总缓解率达100%,并提高了此类患者的两个月生存率。
3. 抗体疗法Natrunix联用化疗治疗晚期胰腺癌,在早期临床试验中延长了患者的生存期并改善了化疗的耐受性。
药明康德内容团队整理
GLPG5101:公布1/2期临床试验数据
Galapagos公司公布了其CD19靶向候选CAR-T细胞疗法GLPG5101治疗复发/难治性非霍奇金淋巴瘤(NHL)的1/2期临床试验ATALANTA-1的新数据。该细胞疗法从制备到回输到患者体内的中位时间仅需7天。
截至2023年12月20日的数据,在研究的第一部分,中位随访时间为13.1个月,接受GLPG5101治疗的16例可评估患者的ORR为87.5%(14/16),CRR为75%(12/16)。71%的患者在数据截止时保持缓解。在研究的第二部分,中位随访时间为4.2个月,15例可评估患者的ORR和CRR均为93.3%(14/15)。100%的患者在数据截止时保持持续缓解。合并两部分的研究结果后根据肿瘤类型进行划分,弥漫性大B细胞淋巴瘤(DLBCL)患者的ORR为78%(7/9),CRR为56%(5/9);滤泡性淋巴瘤(FL)或边缘区淋巴瘤(MZL)患者的ORR和CRR均为94%(16/17);套细胞淋巴瘤患者的ORR和CRR均为100%(5/5)。
安全性方面,大多数治疗伴发不良事件为1/2级,在研究的第一部分观察到2例3级细胞因子释放综合征(CRS),在研究的第二部分观察到1例3级免疫效应细胞相关神经毒性综合征(ICANS)。
ELA026:公布1b期临床试验的新数据
Electra Therapeutics公司公布了其靶向信号调节蛋白(SIRP)的单克隆抗体ELA026治疗继发性噬血细胞性淋巴组织细胞增生症(sHLH)的1b期研究的最新临床数据。ELA026靶向细胞表面的SIRP,能够靶向清除血液循环中驱动炎症的髓系细胞和T细胞,并且不破坏SIRPα/CD47免疫检查点功能。该疗法旨在治疗伴有异常髓系和T细胞活性的重度炎性疾病。
此次公布的结果显示,ELA026在sHLH患者中具有良好的安全性,不良事件可控。在已完成入组的队列1和2中(n=12),ELA026在第4周时的总缓解率为75%,在8例未接受过治疗的mHLH(sHLH的一种亚型)患者中,总缓解率为100%,两个月时的生存率为88%。此类患者在自然史研究中的两个月时的死亡率约为50%。
Natrunix:公布1/2期临床试验数据
XBiotech公司公布了其靶向白细胞介素-1α(IL-1α)的抗体疗法Natrunix联用化疗治疗晚期胰腺癌的1/2期多中心研究的数据。除了能够作为一种抗癌疗法,该公司认为Natrunix还有望改善化疗的耐受性。该研究中采用的化疗方案为ONIVYDE(ON)+5-氟尿嘧啶(5FU)+亚叶酸(LV)。
此次公布的结果显示,与安慰剂+化疗组相比,Natrunix+化疗组在24周的治疗周期内发生任何类型的不良事件的数量(297例对比336例)、发生重大不良事件的患者比例(9/33对比12/32)和住院天数(80天对比120天)均明显减少。此外,接受Natrunix+化疗组患者的生存期得到了延长,接受治疗第330天时有8例患者存活,而安慰剂+化疗组没有患者存活超过330天。
▲患者的生存曲线(图片来源:参考资料[9])
Petrelintide:公布1b期临床试验数据
Zealand Pharma公司公布了其在研长效、潜在“best-in-class”减重疗法petrelintide的1b期试验第二部分的顶线结果。Petrelintide(ZP8396)是一种适合每周一次皮下注射的长效胰淀素类似物,具有中性pH下的化学和物理稳定性。胰淀素在胰腺β细胞中产生,并与胰岛素一起分泌以响应摄入的营养物质。目前的临床或临床前数据表明,petrelintide有潜力实现与GLP-1受体激动剂相当的体重减轻,但具有更好的耐受性,为患者提供更好的用药体验和体重减轻,同时保留患者的肌肉质量。
此次公布的结果显示,患者在接受16周高剂量petrelintide治疗后,体重较基线平均减少了8.6%,而安慰剂组仅为1.7%。安全性方面,petrelintide显示良好的耐受性,没有出现严重的不良事件。所有胃肠道(GI)不良事件均为轻度,除了一名受试者在第三次治疗后因中度恶心和呕吐而停止治疗。值得注意的是,没有其他受试者因不良事件停止治疗或报告呕吐,只有两例轻度腹泻报告。恶心在活性组中报告比例为16.7-33.3%,在安慰剂组为16.7%。少数参与者报告了注射部位反应,均为轻度。未观察到患者产生抗药抗体。新闻稿指出,该积极结果支持petrelintide作为GLP-1受体激动剂类药物之外,在体重管理上的另一选择。
Amezalpat(TPST-1120):公布1b/2期临床试验的新数据
Tempest Therapeutics公司公布了其在研口服、选择性小分子PPAR⍺拮抗剂amezalpat(TPST-1120)在一项全球随机的1b/2期临床试验中获得的积极结果。临床前数据显示,amezalpat可直接杀死肿瘤细胞,并靶向肿瘤微环境中的抑制性免疫通路。这两种类型中的靶向细胞皆依赖脂肪酸代谢,该代谢过程由PPARα转录因子调节。在一项针对接受过多次治疗的晚期实体瘤患者的1期临床试验中,amezalpat单药治疗和与PD-1抑制剂nivolumab联合应用均导致肿瘤缩小及生物标志物的变化。
此次公布的结果显示,与标准治疗方案相比,amezalpat与标准治疗方案(抗PD-L1抗体atezolizumab和抗VEGF抗体bevacizumab)联用,在无法切除或转移性肝细胞癌(HCC)患者的一线治疗中,显著提高患者的中位总生存期(OS)达6个月(21个月对比15个月)。此外,按照RECIST v1.1标准评估,amezalpat组的确认客观缓解率(cORR)为30%,对照组为13.3%。安全性方面,amezalpat的耐受性良好,两组之间的安全数据相当。
▲Amezalpat试验的OS结果(图片来源:参考资料[29])
MB-106:公布1/2期临床试验数据
Mustang Bio公司公布了其在研、可通过门诊给药、靶向CD20的自体CAR-T细胞疗法MB-106治疗华氏巨球蛋白血症(WM)的1/2期临床试验最新数据。该试验中的所有十例患者均曾接受过布鲁顿酪氨酸激酶抑制剂(BTKi)的治疗,并且在接受BTKi治疗期间病情持续恶化。患者之前接受过中位9线疗法,只有一例患者在接受MB-106治疗后开始接受额外的抗WM治疗。
总体而言,接受MB-106治疗的患者中有90%(9/10)对治疗产生应答,包括3名患者达完全缓解(CR)、2名达非常好的部分缓解和4名部分缓解。此外,1例患者的病情稳定。其中一名获得CR的患者已持续缓解31个月,该患者的免疫球蛋白M(IgM)水平在接受MB-106治疗后迅速降至正常范围,此后一直保持正常。
安全性方面,9例患者发生了CRS(5例患者为1级,4例患者为2级),一例患者经历了1级ICANS。尽管剂量增加,但并未观察到3级或4级CRS或2、3或4级ICANS。
NX-594:公布1a/b期临床试验数据
Nurix Therapeutics公司公布了其在研口服BTK降解剂NX-5948治疗复发难治性慢性淋巴细胞白血病(CLL)的1a/b期临床试验的积极数据。NX-5948是一种生物利用度高、可穿越血脑屏障的口服BTK小分子降解剂。
▲NX-5948的疗效结果(图片来源:参考资料[5])
此次公布的结果显示,NX-594在复发难治性CLL患者身上引起了快速、深度的缓解,ORR达69.2%,这些患者之前曾接受大量治疗并带有BTK抑制剂耐药突变。最早在第一次肿瘤扫描(8周)时就观察到患者出现缓解,许多患者在治疗时间延长后缓解加深。截至4月17日数据截止,所有缓解仍在持续。
▲一例患者接受NX-5948治疗24周内,脑脊液中的恶性肿瘤细胞消除(图片来源:参考资料[5])
▲一例曾接受过11线疗法的患者在接受NX-5948治疗后肿瘤持久消退(图片来源:参考资料[2])
此外,一例在进入研究时伴有中枢神经系统受累的CLL患者在接受NX-5948治疗的24周内消除了脑脊液(CSF)中的恶性肿瘤细胞,并在36周时达到接近CR的标准。还有一例曾接受过11线疗法的患者在接受NX-5948治疗后肿瘤持久消退已超过6个月。安全性方面,NX-5948在所有评估剂量下均耐受性良好,最常见的治疗不良事件为紫癜/挫伤、血小板减少和中性粒细胞减少。Nurix预计在2025年启动NX-5948的关键临床试验。
SL-172154:公布1b期临床试验数据
Shattuck Labs公布了其在研疗法SL-172154在1b期剂量扩展临床试验的最新中期数据。SL-172154(SIRPα-Fc-CD40L)是一款在研重定向检查点激动剂(ARC)融合蛋白,旨在同时抑制CD47/SIRPα检查点的相互作用并激活CD40共刺激受体,以增强晚期癌症患者的抗肿瘤免疫反应。
此次公布的结果显示,SL-172154与阿扎胞苷(AZA)联用作为高风险骨髓增生异常综合征(HR-MDS)和TP53突变(TP53m)急性髓性白血病(AML)患者的一线疗法时,患者的ORR分别达67%与43%,CRR分别为42%与29%。截至2024年4月23日,SL-172154表现出可控的安全性。输液相关反应(IRRs)是SL-172154治疗过程中最常见的不良事件。
KT-333:公布1期临床试验的新数据
Kymera Therapeutics公布了其在研药物KT-333的1期临床试验的更新数据。KT-333是一种潜在“first-in-class”、强效、高选择性的STAT3靶向小分子降解剂。根据新闻稿,KT-333是靶向未成药转录因子的首个进入临床阶段的降解剂。
▲KT-333试验临床结果摘要(图片来源:参考资料[3])
此次公布的结果显示,KT-333完成初步临床概念验证,在多种血液恶性肿瘤中展示了抗肿瘤活性。其中,两名经典霍奇金淋巴瘤患者达到CR,1名STAT3突变的NK细胞淋巴瘤患者达到CR。安全性方面,KT-333耐受性良好,主要不良事件为1级和2级,包括口腔炎和疲劳。
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参考资料(可上下滑动查看)
[1] Shattuck Labs Announces Updated Positive Interim Data from the Phase 1B Dose Expansion Clinical Trial of SL-172154 in Combination with Azacitidine (AZA) in Frontline Higher-Risk Myelodysplastic Syndromes (HR-MDS) and TP53 mutant (TP53m) Acute Myeloid Leukemia (AML) Patients. Retrieved June 21, 2024 from https://www.globenewswire.com/news-release/2024/06/14/2898850/0/en/Shattuck-Labs-Announces-Updated-Positive-Interim-Data-from-the-Phase-1B-Dose-Expansion-Clinical-Trial-of-SL-172154-in-Combination-with-Azacitidine-AZA-in-Frontline-Higher-Risk-Myel.html
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[18] Sumitomo Pharma Presents New Clinical Data on DSP-5336 at the European Hematology Association 2024 Congress. Retrieved June 21, 2024, from https://www.prnewswire.com/news-releases/sumitomo-pharma-presents-new-clinical-data-on-dsp-5336-at-the-european-hematology-association-2024-congress-302173004.html
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[26] Tempest Unveils New Survival Data for Amezalpat (TPST-1120) in Randomized First-Line HCC Study Demonstrating a Six-Month Improvement over Control Arm. Retrieved June 21, 2024, from https://ir.tempesttx.com/news-releases/news-release-details/tempest-unveils-new-survival-data-amezalpat-tpst-1120-randomized
[27] Escend Announces Poster Presentation at the Annual Meeting of the European Hematology Association (EHS) from an Investigator-Initiated Phase I/II study evaluating ES-3000 in Myelodysplastic Syndrome (MDS). Retrieved June 21, 2024, from https://www.prnewswire.com/news-releases/escend-announces-poster-presentation-at-the-annual-meeting-of-the-european-hematology-association-ehs-from-an-investigator-initiated-phase-iii-study-evaluating-es-3000-in-myelodysplastic-syndrome-mds-302177666.html
[28] Tubulis Doses First Patient in Phase I/IIa Trial Investigating ADC Candidate TUB-040 in Ovarian Cancer and Lung Adenocarcinoma. Retrieved June 21, 2024, from https://www.businesswire.com/news/home/20240620456143/en/
[29] Amezalpat (TPST-1120) Randomized 1L HCC Data Updat. Retrieved June 20, 2024 https://ir.tempesttx.com/static-files/8ba2d665-884e-47f7-89c2-adbba73378b2
[30] Mustang Bio Announces Favorable Efficacy and Safety Data from Complete Waldenstrom Macroglobulinemia Cohort of Phase 1/2 Clinical Trial of MB-106, CD20-Targeted Autologous CAR-T Therapy. Retrieved June 18, 2024 from https://ir.mustangbio.com/news-events/press-releases/detail/180/mustang-bio-announces-favorable-efficacy-and-safety-data
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