安进BiTE免疫疗法收获在望——提交全球BiTE疗法blinatumomab上市申请

导读：癌症免疫疗法是当前癌症治疗的热门领域，是癌症治疗的最后希望，已吸引各大制药巨头纷纷投入巨资，该类疗法利用人体自身免疫系统攻击癌细胞，达到抑制甚至杀灭癌细胞的目的。在《科学》杂志评选的2013年年度10大科学突破排行榜中，癌症免疫疗法位列榜单。

安进于2012年耗资12亿美元收购Micromet公司，获得了一种创新的癌症免疫疗法——BiTE抗体技术，近日，这笔投资终于迎来了丰收前的喜悦，提交首个BiTE疗法blinatumomab上市申请，FDA和EMA均授予该药孤儿药地位，FDA还授予该药突破性疗法认定。

安进（Amgen）近日宣布，已向FDA提交抗体药物blinatumomab的生物制品许可申请（BLA），寻求批准用于费城染色体阴性（Ph-）复发性/难治性前体B细胞急性淋巴细胞白血病（ALL）的治疗。blinatumomab（AMG 103）是一种实验性双特异性T细胞衔接器（BiTE），该药是一种双特异性单链抗体，靶向CD19和CD3分子。BiTE抗体，旨在引导人体自身的T细胞杀手攻击肿瘤细胞，并能够在低浓度下起作用。BiTE抗体技术代表了一种创新的免疫治疗方法，安进于2012年耗资12亿美元收购Micromet公司后获得了BiTE技术。

blinatumomab BLA的提交，也代表着全球首个BiTE免疫疗法监管申请。此前，FDA和EMA均已授予blinatumomab孤儿药地位，同时，FDA已授予blinatumomab突破性疗法。目前，安进正在广泛的难治性肿瘤类型中，探索BiTE创新疗法的潜力。

具体而言，FDA已授予blinatumomab治疗急性淋巴细胞白血病（ALL）、慢性淋巴细胞白血病（CLL）、毛细胞白血病（HCL）、幼淋巴细胞白血病（PLL）和惰性B细胞淋巴瘤的孤儿药地位。而在欧盟，EMA已授予blinatumomab治疗ALL、CLL、惰性B细胞淋巴瘤、套细胞白血病（MCL）的孤儿药地位。此外，安进也正在调查blinatumomab治疗儿科复发性/难治性ALL、复发性/难治性费城染色体阳性（Ph+）前体B细胞急性淋巴细胞白血病（ALL）、微小残留病阳性（MRB+）前体B淋巴细胞急性淋巴细胞白血病（ALL）、复发性/难治性非霍奇金淋巴瘤（NHL，包括复发性/难治性弥漫性大B细胞淋巴瘤，DLBCL）的潜力。

blinatumomab BLA的提交，是基于一项II期临床试验的积极数据，该项研究在费城染色体阴性（Ph-）复发性/难治性前体B细胞急性淋巴细胞白血病（ALL）成人患者中开展，数据表明，经2轮blinatumomab治疗后，43%的患者实现完全缓解或伴有部分血液学复苏的完全缓解，达到了主要疗效终点。相关研究已提交至第50届美国临床肿瘤学会年会（ASCO2014）。

目前，关于成人复发性或难治性ALL，还没有广泛接受的标准治疗方案。blinatumomab有望显著推进该类患者群体的临床治疗选择，而BLA的提交，标志着超实现这一目标迈进的重要里程碑。

据估计，在美国，2014年将新增超过6000例ALL病例，而在欧盟，每年确诊病例超过7000例。复发性或难治性ALL成人患者，平均总生存期（OS）仅为3-5个月。前体B细胞淋巴细胞白血病(Precursor B-cell lymphoblastic leukemia)是淋巴白血病(Lymphoid leukemia)的一种，大多数的B细胞淋巴母细胞(Lymphoblast，未成熟的白血球)被发现在血液和骨髓中，该病也是最常见类型的急性淋巴性白血病(ALL)。

安进强大的研发管线——3种新药获批在望

在大型生物技术公司和制药公司中，安进（Amgen）是拥有最强大在研产品线的公司之一。预计到2016年，该公司将有10个在研药物获得批准，业界此前预测，这些新药将在2023-2025年前达到销售峰值，总计约160亿美元，其中，BiTE免疫疗法blinatumomab、溶瘤免疫疗法T-Vec、降脂新药PCSK9抑制剂evolocumab（AMG145）预计将很快获FDA批准。业界预测，blinatumomab治疗复发性/难治性淋巴细胞白血病的销售额峰值为5亿美元，T-Vec的销售峰值为10亿美元，evolocumab的销售峰值则高达50亿美元。

T-Vec是一种实验性溶瘤免疫疗法，这是一种基因工程化的病毒，能够表达GM-CFS。T-Vec直接注射入肿瘤，并能够在肿瘤细胞中复制直至细胞膜破裂及死亡（即细胞裂解），同时能够在肿瘤组织局部释放粒巨噬细胞集落刺激因子（GM-CSF），这是一种白细胞生长因子，能够激活系统性免疫反应。T-Vec通过2种重要且互补的方式发挥作用：引发肿瘤组织溶解，同时激发一种全身性的抗肿瘤免疫反应。

evolocumab属于PCSK9抑制剂，这是一类单抗药物，靶向PCSK9蛋白，该蛋白会增加低密度脂蛋白胆固醇（LDL-C）的生成率，而LDL-C可阻塞血管，是心脏病的罪魁祸首。PCSK9抑制剂提供了一种全新的治疗模式来对抗LDL-C，该类药物被视为自他汀类药物（如Lipitor和Zocor）之后，在对抗心脏疾病研发领域中所取得的最大进步。目前，PCSK9抑制剂研发竞争已趋白热化，安进拔得头筹，于8月底率先向FDA提交了evolocumab的生物制品许可申请（BLA），也代表着全球首个PCSK9抑制剂监管申请。

英文原文：Amgen pushes for early FDA OK of leukemia drug blinatumomab

Bolstered by a breakthrough drug designation at the FDA, Amgen ($AMGN) is following through with a new drug application for its leukemia drug blinatumomab, hoping that promising Phase II data will be enough to push this program past the goal line on a greatly accelerated development schedule.

The FDA's cancer division under Richard Pazdur has been lowering the bar for new cancer drugs that may be able to help some very sick patients. In this case Amgen is focused on a bispecific T cell engager (BiTE) which, simply put, uses an antibody to redirect killer T cells to destroy tumor cells. And now it wants a green light to sell the treatment for adults with Philadelphia-negative elapsed/refractory B-precursor acute lymphoblastic leukemia.

New immuno-oncology therapies that spur an immune system attack on cancer have become a hot field in cancer, which has been attracting some heavy investments among the Big Pharma crowd. And former Amgen R&D chief Roger Perlmutter--now head of R&D at a resurgent Merck ($MRK)--had become clearly enamored with the drug when he decided to buy out the drug in the $1.2 billion Micromet buyout.

The Phase II study met its primary endpoint, with 43% of patients achieving complete remission or complete remission with partial hematologic recovery within two cycles of treatment with blinatumomab. The data were released at ASCO.

For Amgen the filing backs up its insistence that the company has turned things around on the R&D side of the business at the Big Biotech. Along with T-Vec and the PCSK9 drug evolocumab, it's one of several late-stage therapies angling for a near-term approval.

Amgen, which recently signaled that it will shutter a big research facility in Seattle as part of a major reorganization that will cost thousands of jobs, has received mixed messages from the investment community on just how effective it has been at drug development.

Bernstein's Geoff Porges has been one of Amgen's biggest critics, prodding Amgen repeatedly to join the Big Pharma breakup party, complaining that Amgen's stock price has languished as other companies of a similar size have done much, much better this year. He has criticized Amgen of having a portfolio of aging legacy products looking at biosimilar competition and a "scattered" pipeline that includes too many disparate programs, including blinatumomab.

Amgen, though is staying upbeat today.

"The filing for blinatumomab brings us a step closer to first realizing the potential of BiTE technology and represents our commitment to evaluating this novel approach in a broad range of difficult-to-treat cancers," said Sean E. Harper, M.D., executive vice president of R&D at Amgen.