羅氏（Roche）7月24日公布了實驗性單抗藥物GA101（obinutuzumab）III期CLL11研究的積極數(shù)據(jù)。在一項既定的中期分析中，一個獨立數(shù)據(jù)監(jiān)控委員會分析發(fā)現(xiàn)，該項研究達到了主要終點：在既往未經(jīng)治療的慢性淋巴細胞白血病（CLL）患者中，與美羅華（Rituxan）+化療藥物苯丁酸氮芥（chlorambucil）相比，GA101+苯丁酸氮芥顯著延長了疾病無進展生存期（PFS）。研究中未發(fā)現(xiàn)新的安全信號，不良事件與今年早些時候該項研究第一階段的數(shù)據(jù)一致。CLL11研究目前正由基因泰克與德國白血病研究組（GCLLSG）合作開展，最終數(shù)據(jù)將提交至2013年12月舉行的美國血液學(xué)學(xué)會第55屆年會。
GA101是首個糖基化的II型抗CD20單克隆抗體，這意味著GA101中的特定糖分子能夠被修改，來改變其與人體免疫細胞的相互作用。這種修飾作用，創(chuàng)造了一種獨特的抗體，旨在作為一種免疫療法，利用患者自身的免疫系統(tǒng)來幫助攻擊癌細胞。此外，GA101與CD20的結(jié)合，能夠直接誘導(dǎo)細胞死亡。
GA101旨在增強抗體依賴性細胞毒性作用（Antibody-Dependent Cellular Cytotoxicity，ADCC）及直接的細胞死亡誘導(dǎo)作用（Direct Cell Death induction）。
GA101由羅氏旗下全資子公司GlyArt AG利用其專有的抗體修飾技術(shù)GlycoMAb技術(shù)開發(fā)，該藥與美羅華（Rituxan，通用名：rituximab，利妥昔單抗）均選擇性靶向B細胞上的CD20蛋白，目前rituximab已獲日本及海外推薦列入非霍奇金淋巴瘤的治療指南。
美羅華（Rituxan）是一種嵌合鼠/人單克隆抗體，是全球第一個被批準用于臨床治療非霍奇金淋巴瘤（NHL）的單克隆抗體，該藥的歐洲專利將于2013年底到期。
GA101如果研發(fā)成功，將減小生物仿制藥對美羅華的沖擊。
基于CLL11試驗數(shù)據(jù)，羅氏已于今年4月分別向FDA及EMA提交了GA101的上市許可申請（marketing application）。此前，F(xiàn)DA已授予GA101突破性療法認定（Breakthrough Therapy Designation）及優(yōu)先審查資格（Priority Review），旨在加快藥物的開發(fā)及審批。
CLL是最常見的血液癌癥之一，預(yù)計2013年在美國有近5000人死于該病。CLL11研究的患者包括以前未經(jīng)治療的年老CLL患者，這些患者通常不能承受現(xiàn)有的積極治療方案。（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).
