瑞士医药巨头诺华（Novartis）宣布美国FDA（美国食品药品监督管理局）已批准其突破性CAR-T疗法Kymriah以治疗罹患急性淋巴性白血病（ALL）的病人。这是美国境内首个被批准的基因疗法，开启了基因治疗新篇章。
1. 基因治疗
美国时间周三一早，美国FDA（美国食品药品监督管理局）宣布批准了全美第一个基因治疗方法，来自于瑞士医药巨头诺华（Novartis）的CAR-T疗法Kymriah，旨在治疗罹患急性淋巴性白血病（ALL）的病人，该癌症患病者主要为儿童与青少年。Kymriah的通过预示着抗击ALL的新希望。美国FDA局长Scott Gottlieb表示：“我们进入了医疗创新的新时代，人类现在已经有能力重组自己的细胞来抵抗癌症了。”许多制药公司正在积极投资基因治疗项目。 例如本周美国生化制药公司Gilead就宣布欲投资119亿美元收购专注抗癌药物及疗法研发的美国制药公司Kite，因Kite在CAR-T疗法领域有了实质性突破。
2. CAR-T疗法:Kymriah
CAR-T疗法生产过程：抽取病人的血液；分离免疫T细胞；利用基因工程技术给T细胞加入一个能识别肿瘤细胞的靶基因；从而激活T细胞的嵌合抗体来杀死肿瘤细胞。根据治疗流程，CAR-T细胞免疫治疗包括两大核心环节：一是用于制备CAR-T细胞的基因修饰载体的生产，即生产CAR慢病毒载体；二是CART细胞的制备和应用，包括采集患者的免疫细胞、体外细胞培养、转染、扩增和回输等制备和治疗。
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4.高昂的定价
Kymriah定价为47万5千美元，比预测价格略低。考虑到这是一次性治疗，而百健的SMA药物SPINRAZA要长期使用还定价每年75万，所以Kymriah定价不算高。儿童rrALL美国每年只有500左右病人，所以这个产品本身的商业价值有限。Kite的Axi Cel也有望近期上市（PDUFA日期为11月29日），这将成为第一个成人ALL细胞疗法，这个市场稍大一点。Juno现在落后较多，但也有望在明后年上市一个CAR-T药物。
5.专家评论
FDA的生物制剂评估中心总监Peter Marks博士说：“Kymriah是一种前所未有的治疗方法，可满足儿童和年轻人对这种严重疾病的重要需求。Kymriah不仅为这些患者提供了一种新的治疗方案，在极其有限的选择中，这也是一种在临床试验中显示出有希望缓解和存活率的治疗方案。”
专注肿瘤精准医疗的医药科技公司思路迪的创始人熊磊博士此前曾对澎湃新闻表示，诺华公司在推广应用Kymriah技术时还要解决标准化的难题：如何保证同一家公司在不同区域的实验室，生产出来的细胞，临床能达到一致的治疗水准。
据中国研究型医院学会生物治疗学专业委员会主任委员、解放军总医院生命科学院分子免疫学研究室主任韩为东介绍，尽管Kymriah展现出了惊人的疗效，但其规模生产的稳定性、长期的毒性，以及市场的认可程度等尚需时间检验，还有相当长的一段路要走。
高全立也表示，CAR-T作为前沿技术，目前还不是肿瘤治疗的首选方案，而是推荐应用在传统治疗手段已经无计可施的重症病例上。
总结：
对Kymriah价值的评价不应该是这个单一产品的商业回报，而是CAR-T这个技术的颠覆性。在某种程度上看Kymriah类似怀特兄弟的雏形飞机，虽然那架没有窗子的飞机只飞行了30几米，但奠定了现代飞行的基础。后Alcock和Brown成功飞跃大西洋，50年后人类首次摆脱地球引力的束缚。CAR-T的前景也可能同样广阔，虽然CAR-T面临双特异抗体、ADC的竞争，但这毕竟是一个全新的治疗体系，有些优势现在可能还难以预测。现在已有一些进展表明针对CD19治疗白血病只是一个开始，如针对BCMA的CAR-T药物作为末线药物产生近100%应答，Cellectis的异体CAR-T药物UCART19今年已经产生两例相对持久应答。针对IL13Rα2和HER2的CAR-T分别在实体瘤产生疗效，虽然人群还很小。Kymriah的上市是医学史上一个标志性事件，期待更激动人心细胞疗法的出现。
英文报道来源：
The U.S. Food and Drug Administration issued a historic action today making the first gene therapy available in the United States, ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases.
The FDA approved Kymriah (tisagenlecleucel) for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL).
“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” said FDA Commissioner Scott Gottlieb, M.D. “New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses. At the FDA, we’re committed to helping expedite the development and review of groundbreaking treatments that have the potential to be life-saving.”
Kymriah, a cell-based gene therapy, is approved in the United States for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.
Kymriah is a genetically-modified autologous T-cell immunotherapy. Each dose of Kymriah is a customized treatment created using an individual patient’s own T-cells, a type of white blood cell known as a lymphocyte. The patient’s T-cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor or CAR) that directs the T-cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells.
ALL is a cancer of the bone marrow and blood, in which the body makes abnormal lymphocytes. The disease progresses quickly and is the most common childhood cancer in the U.S. The National Cancer Institute estimates that approximately 3,100 patients aged 20 and younger are diagnosed with ALL each year. ALL can be of either T- or B-cell origin, with B-cell the most common. Kymriah is approved for use in pediatric and young adult patients with B-cell ALL and is intended for patients whose cancer has not responded to or has returned after initial treatment, which occurs in an estimated 15-20 percent of patients.
“Kymriah is a first-of-its-kind treatment approach that fills an important unmet need for children and young adults with this serious disease,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER). “Not only does Kymriah provide these patients with a new treatment option where very limited options existed, but a treatment option that has shown promising remission and survival rates in clinical trials.”
The safety and efficacy of Kymriah were demonstrated in one multicenter clinical trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. The overall remission rate within three months of treatment was 83 percent.
Treatment with Kymriah has the potential to cause severe side effects. It carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T-cells causing high fever and flu-like symptoms, and for neurological events. Both CRS and neurological events can be life-threatening. Other severe side effects of Kymriah include serious infections, low blood pressure (hypotension), acute kidney injury, fever, and decreased oxygen (hypoxia). Most symptoms appear within one to 22 days following infusion of Kymriah. Since the CD19 antigen is also present on normal B-cells, and Kymriah will also destroy those normal B cells that produce antibodies, there may be an increased risk of infections for a prolonged period of time.
The FDA today also expanded the approval of Actemra (tocilizumab) to treat CAR T-cell-induced severe or life-threatening CRS in patients 2 years of age or older. In clinical trials in patients treated with CAR-T cells, 69 percent of patients had complete resolution of CRS within two weeks following one or two doses of Actemra.
Because of the risk of CRS and neurological events, Kymriah is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring that hospitals and their associated clinics that dispense Kymriah be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administering of Kymriah are required to be trained to recognize and manage CRS and neurological events. Additionally, the certified health care settings are required to have protocols in place to ensure that Kymriah is only given to patients after verifying that tocilizumab is available for immediate administration. The REMS program specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Kymriah.
To further evaluate the long-term safety, Novartis is also required to conduct a post-marketing observational study involving patients treated with Kymriah.
The FDA granted KymriahPriority ReviewandBreakthrough Therapydesignations. The Kymriah application was reviewed using a coordinated, cross-agency approach. The clinical review was coordinated by the FDA"s Oncology Center of Excellence, while CBER conducted all other aspects of review and made the final product approval determination.
The FDA granted approval of Kymriah to Novartis Pharmaceuticals Corp. The FDA granted the expanded approval of Actemra to Genentech Inc.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines, and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products
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