诺华的基因治疗产品 CAR-T 获FDA批准上市
来源：转化医学快讯 cc
诺华公司8月30日宣布，美国FDA已经批准了用于静脉输注的CAR-T疗法Kymriah （tisagenlecleucel，CTL019）上市，产品用于治疗25岁以下，难治性或二次及以上复发的B细胞前体急性淋巴性白血病（ALL）的患者。本次批准的时间比预期要提前1个月，这次批准是可以记录在肿瘤治疗史的重要时刻。
细胞免疫治疗领域的“三驾马车”：Novartis AG、Kite Pharma和Juno Therapeutics，近期利好消息不断，2017年8月29日，吉利德刚刚以119亿美金并购CAR-T巨头Kite Pharma，8月30日就有了诺华的第一个CAR-T细胞上市。我们有理由相信，未来行业会迎来更多利好消息。
关于Kymriah
Kymriah是一种新型的免疫细胞基因治疗方法，是一种使用患者自身的且基因改造的T细胞治疗癌症的一次性治疗方法。然而，CAR-T也存在严重和潜在的副作用，包括细胞因子释放综合征（CRS，cytokine release syndrome）等。
FDA指出，他们将着重培训任何参与此项治疗的人员，同时FDA今日批准了罗氏的Actemra（托霉素单抗)用于CAR-T细胞诱导的严重或危及生命的CRS。Actemra是针对白细胞介素6（IL-6）细胞通路的免疫抑制药物。“在用CAR-T细胞治疗的患者的临床试验中，”FDA报告说，“69％的患者在一个或两个剂量的Actemra后的两周内完全消除了CRS。”
定价
之前CAR-T的定价一直是一个问题，诺华宣布Kymriah（tisagenlecleucel）每次治疗费用为475,000美元，是处于之前预期的$400,000到$750,000的较低价格。
在电话会议上诺华表示，Kymriah一个月内将在20个中心内提供，之后会达到35个中心。此外，诺华表示目前正在与CMS(美国医疗保险和医疗补助服务中心)合作，采用基于结果（outcomes-based approach）的报销方式，只有允ALL患者在接受Kymriah治疗一个月后有效果才支付费用。如果CMS同意并实施该计划，则475,000美元的价格要远远低于年轻患者的“寿命价值”。
FDA再一次证明了自己的世界领先和前瞻性，此次批准标志着肿瘤学及治疗癌症的革命性转变。这将是生物技术世界的一个重要日子，但相信这只是一个新时代的正式开始。
FDA批准免疫基因疗法 CAR-T上市，详见FDA官网，原文如下：
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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 Kymriah Fast Track, Priority Review and Breakthrough Therapy designations. 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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