罗氏（Roche）7月24日公布了实验性单抗药物GA101（obinutuzumab）III期CLL11研究的积极数据。在一项既定的中期分析中，一个独立数据监控委员会分析发现，该项研究达到了主要终点：在既往未经治疗的慢性淋巴细胞白血病（CLL）患者中，与美罗华（Rituxan）+化疗药物苯丁酸氮芥（chlorambucil）相比，GA101+苯丁酸氮芥显着延长了疾病无进展生存期（PFS）。研究中未发现新的安全信号，不良事件与今年早些时候该项研究第一阶段的数据一致。CLL11研究目前正由基因泰克与德国白血病研究组（GCLLSG）合作开展，最终数据将提交至2013年12月举行的美国血液学学会第55届年会。
GA101是首个糖基化的II型抗CD20单克隆抗体，这意味着GA101中的特定糖分子能够被修改，来改变其与人体免疫细胞的相互作用。这种修饰作用，创造了一种独特的抗体，旨在作为一种免疫疗法，利用患者自身的免疫系统来帮助攻击癌细胞。此外，GA101与CD20的结合，能够直接诱导细胞死亡。
GA101旨在增强抗体依赖性细胞毒性作用（Antibody-Dependent Cellular Cytotoxicity，ADCC）及直接的细胞死亡诱导作用（Direct Cell Death induction）。
GA101由罗氏旗下全资子公司GlyArt AG利用其专有的抗体修饰技术GlycoMAb技术开发，该药与美罗华（Rituxan，通用名：rituximab，利妥昔单抗）均选择性靶向B细胞上的CD20蛋白，目前rituximab已获日本及海外推荐列入非霍奇金淋巴瘤的治疗指南。
美罗华（Rituxan）是一种嵌合鼠/人单克隆抗体，是全球第一个被批准用于临床治疗非霍奇金淋巴瘤（NHL）的单克隆抗体，该药的欧洲专利将于2013年底到期。
GA101如果研发成功，将减小生物仿制药对美罗华的冲击。
基于CLL11试验数据，罗氏已于今年4月分别向FDA及EMA提交了GA101的上市许可申请（marketing application）。此前，FDA已授予GA101突破性疗法认定（Breakthrough Therapy Designation）及优先审查资格（Priority Review），旨在加快药物的开发及审批。
CLL是最常见的血液癌症之一，预计2013年在美国有近5000人死于该病。CLL11研究的患者包括以前未经治疗的年老CLL患者，这些患者通常不能承受现有的积极治疗方案。（生物谷Bioon.com）
英文原文：Roche's new leukaemia drug superior to Rituxan in study
Basel, 24 July 2013 Roche's obinutuzumab (GA101) delayed disease progression longer than MabThera/Rituxan in people with one of the most common forms of blood cancer
Phase III CLL11 study showed GA101 plus chlorambucil, a chemotherapy, was superior to MabThera/Rituxan plus chlorambucil in helping people with previously untreated chronic lymphocytic leukemia live longer without their disease worsening
Final data from the CLL11 study will be submitted to the American Society of Hematology’s 55th Annual Meeting in December 2013
Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced positive results from the phase III CLL11 study. At a pre-planned interim analysis, an independent data monitoring committee determined that the study met its primary endpoint showing that GA101 plus chlorambucil helped people live significantly longer without their disease worsening (progression-free survival; PFS) compared to MabThera/Rituxan plus chlorambucil. The CLL11 study is being conducted in cooperation with the German CLL Study Group (GCLLSG). These final data were reached well ahead of the target completion date in 2014 as a result of the magnitude of difference seen between the two study arms. No new safety signals for GA101 or MabThera/Rituxan were identified in this analysis, and adverse events were similar to those observed in the first stage of the study which was previously reported earlier this year.
“The positive final results from the CLL11 study show the promise that GA101 could hold for people with CLL,” said Hal Barron, M.D., Roche’s Chief Medical Officer and Head, Global Product Development. "It is important to explore the potential of this medicine in other types of blood cancer, and our broad development program includes studies in aggressive and indolent lymphoma that compare GA101with MabThera/Rituxan."
GA101 is the first type II anti-CD20 medicine that is glycoengineered, which means specific sugar molecules in GA101 were modified to change its interaction with the body’s immune cells.
This modification creates a unique antibody that is designed to act as an immunotherapy, engaging the patient’s own immune system to help attack the cancerous cells; in addition, GA101 binds to CD20 with the aim of inducing direct cell death.
These data will be submitted for consideration to the 55th Annual Meeting of the American Society of Hematology (ASH) in New Orleans, which is taking place December 7-10, 2013.
Based on an earlier analysis (stage 1) of the CLL11 study, marketing applications for GA101 were submitted to regulatory authorities including the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) in April, 2013. Due to the significance of the positive trial results and the serious and life threatening nature of CLL, the FDA granted the GA101 application both Breakthrough Therapy Designation and Priority Review.
About obinutuzumab (GA101)
GA101 is the first investigational type II, glycoengineered medicine designed to attack cells that have a certain marker (CD20) on their surface. It attacks targeted cells both directly and together with the body’s immune system. GA101 is currently being investigated in a large clinical program, including multiple head-to-head phase III studies versus MabThera/Rituxan in indolent non-Hodgkin lymphoma (NHL) and diffuse large B-cell lymphoma (DLBCL).
In the U.S., GA101 is being developed and will be commercialized in collaboration with Biogen Idec.
About the CLL11 study
CLL11 is a phase III, multicenter, open-label, randomized three-arm study investigating the efficacy and safety profile of either GA101 plus chlorambucil or MabThera/Rituxan plus chlorambucil compared to chlorambucil alone in 781 previously untreated people with CLL and co-existing medical conditions who are in need of therapy. The study included two stages of analysis.
Stage 1 included 589 patients and compared GA101 plus chlorambucil to chlorambucil alone and MabThera/Rituxan plus chlorambucil to chlorambucil alone. Stage 1 results were reported earlier this year and showed that GA101 plus chlorambucil doubled the time people lived without their disease worsening 23.0 vs. 10.9 months compared to chlorambucil alone (HR=0.14 CI 0.09-0.21 p<0.0001).
Stage 2 (announced today) enrolled an additional 192 patients to enable the final direct comparison of GA101 versus MabThera/Rituxan, both in combination with chlorambucil.
The primary endpoint of the study was PFS with secondary endpoints including overall response rate (ORR), overall survival (OS), disease-free survival (DFS), minimal residual disease (MRD) and safety profile.
About the German CLL Study Group (GCLLSG)
Founded in 1996 and headed by Dr. Michael Hallek, the GCLLSG has been running various phase III, phase II and phase I trials in CLL with the goal to provide optimal treatment to patients suffering from this disease. Among those were landmark trials like the CLL8 trial which led to the current standard of care in CLL. For many years, GCLLSG has been aiming to improve not just the treatment of younger and physically fit patients, but also that of elderly and less fit patients. These patients are generally underrepresented in clinical trials although they constitute the majority of CLL patients treated by doctors in daily practice. The GCLLSG is an independent non-profit research organization supported by the German Cancer Aid (Deutsche Krebshilfe).
