■胃肠道急性移植物抗宿主病(GI-aGvHD)对类固醇治疗的反应失败与有限的进一步治疗选择有关。我们的目的是评估首次在人类中使用汇集的同种异体粪便微生物群的安全性和有效性,MaaT013,用于治疗类固醇难治性GI-aGvHD。
■这个前景,国际,单臂,2a期研究报告了来自III-IV级24例患者队列的临床结果,用合并的同种异体粪便微生物群MaaT013治疗的类固醇难治性GI-aGvHD。MaaT013涉及从3至8个筛选的供体汇集粪便物质,然后将汇集的批次移植到患者中以治疗GI-aGVHD。在HERACLES研究(2018年8月至2020年11月)中,24名患者在欧洲26个地点接受了治疗,另外52名患者在法国(2018年7月至2021年4月)接受了富有同情心的使用/扩大访问计划(EAP)治疗。主要终点是第28天的GI反应,定义为具有完全反应(CR)或非常好的部分反应(VGPR)的GI-aGvHD患者的比例。根据修订的Glucksberg标准评估GvHD分级和分期。监测6个月和12个月的不良事件和严重不良事件。分别。HERACLES研究已在ClinicalTrials.gov(NCT03359980)注册。
■与单个供体相比,MaaT013的特征在于更高的微生物丰富度和降低的批次变异性。在第28天(D28),在预期人群中,GI总体反应率(ORR)为38%,包括5个完整的回答(CR),2个非常好的部分响应(VGPR)和2个部分响应(PR)。在EAP中,GI-ORR为58%(17CR,9VGPR和4PR)。前瞻性研究的12个月总生存率(OS)为25%,EAP为38%。关于安全,五种感染并发症,包括3个败血症,不能排除与HERACLES研究程序相关。鉴定的菌株的鸟枪测序分析表明在MaaT013中没有发现。在EAP中,在52例接受治疗的患者中报告了18例药物警戒病例,包括11例菌血症/败血症。在地狱里,我们在D28时从有反应的患者的粪便中观察到更高的微生物群丰富度和有益细菌水平的增加,特别是丁酸盐生产商,随着短链脂肪酸和胆汁酸水平的增加。相比之下,来自无反应(NR)患者的粪便显示致病性促炎细菌水平升高,全身炎症参数升高。
■总的来说,MaaT013在高度免疫功能低下的患者人群中是安全的,并且与一些GI-aGvHD患者的反应相关,值得进一步研究。
■MaaTPharma。
UNASSIGNED: Failure of gastrointestinal acute graft-versus-host disease (GI-aGvHD) to respond to steroid therapy is associated with limited further therapeutic options. We aimed to assess the safety and efficacy of the first-in-human use of the pooled allogeneic faecal microbiota, MaaT013, for the treatment of steroid-refractory GI-aGvHD.
UNASSIGNED: This prospective, international, single-arm, phase 2a study reports clinical outcomes from a 24-patient cohort with grade III-IV, steroid refractory GI-aGvHD treated with the pooled allogeneic faecal microbiota MaaT013. MaaT013 involved pooling faecal matter from 3 to 8 screened donors then transplanting the pooled batches into patients to treat GI-aGVHD. The 24 patients were treated in the HERACLES study (Aug 2018 to Nov 2020) at 26 sites in Europe and an additional 52 patients were treated in a compassionate use/expanded access program (EAP) in France (July 2018 to April 2021). The primary endpoint was GI response at day 28, defined as the proportion of patients with GI-aGvHD who had a complete response (CR) or very good partial response (VGPR). GvHD grading and staging were assessed according to the revised Glucksberg criteria. Adverse events and severe adverse events were monitored for 6 months and 12 months, respectively. The HERACLES study was registered with ClinicalTrials.gov (NCT03359980).
UNASSIGNED: Compared with single donors, MaaT013 is characterised by higher microbial richness and reduced variability across batches. At day 28 (D28), the GI-overall response rate (ORR) was 38% in the prospective population, including 5 complete responses (CR), 2 very good partial responses (VGPR) and 2 partial responses (PR). In the EAP, the GI-ORR was 58% (17 CR, 9 VGPR and 4 PR). The 12-month overall survival (OS) was 25% in the prospective study and 38% in the EAP. Regarding safety, five infectious complications, including 3 sepsis, could not be excluded from being related to the study procedure in HERACLES. Shotgun sequencing analyses of the identified strains suggest that none were found in MaaT013. In the EAP, 18 pharmacovigilance cases were reported among 52 treated patients, including 11 bacteraemia/sepsis. In HERACLES, we observed in stools from responding patients at D28 a higher microbiota richness and increased levels of beneficial bacteria, in particular butyrate producers, along with increased levels of short-chain fatty acid and bile acids. In contrast, stools from non-responding (NR) patients displayed increased levels of pathogenic pro-inflammatory bacteria along with increased systemic inflammatory parameters.
UNASSIGNED: Overall, MaaT013 was safe in this population of highly immunocompromised patients and was associated with responses in some patients with GI-aGvHD and deserves further investigation.
UNASSIGNED: MaaT Pharma.