重磅|诺华CAR-T细胞疗法Kymriah™ (CTL019)率先通过美国食品和药物管理局（FDA）批准上市

首创疗法，在治疗选择有限且历史上预后很差的该患者群中总体缓解率可达83% (52/63) 【1】【2】

癌症治疗领域的新方法，源自与宾夕法尼亚大学合作推出的首创性CAR-T细胞疗法的结果

可复制、灵活和经验证的生产工艺，依托美国新泽西州制造设施的多年全球临床试验经验。

诺华还宣布将与美国医疗保险和医疗补助服务中心开展创新性合作

诺华于2017年8月30日在巴塞尔宣布，美国食品和药物管理局(FDA)已批准Kymriah™ (Tisagenlecleucel)静脉输注悬浮液（之前称为CTL019）——首个嵌合抗原受体T细胞(CAR-T)疗法用于治疗25岁以下、难治性或两次或多次复发的B细胞前体急性淋巴细胞白血病(ALL)患者。Kymriah是新型免疫细胞疗法，也是一次性疗法，利用患者自身T细胞来对抗癌症。Kymriah是FDA批准的首个以基因转移为基础的疗法。

诺华肿瘤CEO Bruno Strigini表示：“很荣幸能参与这一癌症治疗的历史性时刻，我们要深深感谢研究人员、合作方以及参与Kymriah临床项目的患者和家人。Kymriah是儿童和年轻成年患者迫切需要的突破性免疫细胞疗法，是改善患者预后和癌症治疗的最新成果。”

FDA已批准Kymriah的风险评估减损策略(REMS)。REMS计划旨在提醒医疗保健专家Kymriah治疗可能存在的风险。为了支持患者安全获得治疗，诺华正在美国建立认证治疗中心网络，通过充分培训推动Kymriah的使用，改进患者治疗。

复发或难治性(r/r) B细胞前体ALL患者预后一直不佳，因此急需能改善预后的新治疗选择。这些患者通常会接受包括化疗、放射、靶向疗法或干细胞移植在内的多种治疗，患者五年生存率不到10%【2】【3】。

Kymriah是创新型免疫细胞疗法，也是一次性疗法。该药物使用嵌合抗原受体内的4-1BB共刺激域来增强细胞扩增和持久性。2012年，诺华和宾夕法尼亚大学(Penn)开展全球合作，进一步研究、开发CAR-T细胞疗法并推进商业化，用于癌症研究性治疗的Kymriah即是其中之一。

宾夕法尼亚大学佩雷尔曼医学院细胞免疫疗法中心主任Carl June（医学博士、Richard W. Vague免疫疗法教授）表示：“该疗法是个体化癌症治疗的一大进步，对患者生命影响深远。通过与诺华的合作，我们正在掀起免疫细胞癌症治疗的又一高潮，期待将CAR-T疗法扩展至血液病和其他癌症类型。”

在诺华与宾夕法尼亚大学的合作中，费城儿童医院(CHOP)是首家在儿科患者治疗中研究Kymriah的机构，率先开展单中心试验。

宾夕法尼亚大学佩雷尔曼医学院YettaDeitch Novotny儿科学教授、费城儿童医院(CHOP)癌症免疫疗法前沿项目主任Stephan Grupp博士表示：“Tisagenlecleucel是首个显示在复发或难治性B细胞ALL儿童和年轻成年患者中实现尽早、深远和持久缓解的CAR-T疗法。该疗法是前所未有的，我相信它可能会成为该患者群的新治疗标准。”

诺华全力确保合适的患者可以接受Kymriah治疗，并帮助支付方了解Kymriah的价值，覆盖更多患者。考虑到该疗法的独特性，诺华制定了各种患者准入计划，力求建立安全而及时的患者准入。诺华还提供传统支持手段，包括为患者指导保险范围，为无保险或保险额度不足的人士提供财务资助。

诺华计划今年晚些时候在美国和欧盟发起Kymriah的其他申请，包括在FDA和欧洲药品管理局(EMA)的申请，以便将治疗扩展至r/r（复发和难治）弥漫性大B细胞淋巴瘤(DLBCL)成年患者。美国和欧盟以外地区预计在2018年提出申请。

诺华还宣布，将与美国医疗保险和医疗补助服务中心(CMS)进行全新合作，重点关注如何提高针对当前监管要求的效率，以便提供基于价值的保险并且确保为这一特定患者群体提供便利。

这一方法旨在包括基于适应证的药物定价以及根据所获得的临床结果支持针对某一药物的相关支付，如Kymriah的最初适应症，从而消除医疗保健系统的低效。与Kymriah和CAR-T细胞疗法更多未来适应证相关的其他基于价值的方法目前正在讨论中。

此外，诺华还将与CMS进行合作，以便制定基于疗效的方法，即只有在儿童和年轻成年ALL患者接受治疗的第一个月结束时，对Kymriah显示出一定疗效后再行完成支付。诺华将会针对具有最大相关性且基于疗效的方法对后续潜在适应证进行评审。

在新泽西州Morris Plains市的诺华工厂，将针对个体患者，使用其自身细胞生产Kymriah。诺华已经设计出了一个可靠的集成生产和供应链平台，可在全球范围内实现个性化的治疗方法。该过程包括对患者采集的（或白细胞去除）细胞进行冷冻保存，使得治疗医师和治疗中心可以基于个体患者的状况灵活开展Kymriah治疗。根据现有经验，我们已为来自11个国家的超过250名患者生产了CAR-T细胞，涉及各种适应证，我们已经证明这是一种可再生的产品。诺华将继续推进其在Morris Plains市的CAR-T生产，从而为全球临床试验提供CAR-T细胞，并且我们还将继续在预期需求的支持上进行投资，以满足患者所需。

FDA基于一项关键性、开放标签、多中心、单臂II期ELIANA研究的结果批准了Kymriah，该试验是在美国、欧盟、加拿大、澳大利亚和日本的25个中心内进行的首个儿童全球性CAR-T细胞疗法注册试验。在这项由诺华赞助的研究中，68名患者接受了输注，63名患者可进行疗效评估。结果显示，在接受Kymriah治疗的患者中，83％（52/63；95％置信区间[CI]：71％-91％）在接受输注的三个月内达到了完全缓解(CR)或显示血细胞计数未完全恢复的CR(CRi)。此外，在显示疗效的患者中未检测任何微小残留病(MRD)- 一种用于指示潜在复发的血液标志物。缓解持续的中位时间未达到(95% CI: 7.5-NE)【1】。

在ELIANA试验中最常见的(> 20％)不良反应是细胞因子释放综合征(CRS)、低丙种球蛋白血症、病原体不明感染、发热、食欲不振、头痛、脑病、低血压、出血发作、心动过速、恶心、腹泻、呕吐、病毒感染性疾病、缺氧、疲劳、急性肾损伤和谵妄。在该项研究中，49％接受Kymriah治疗的患者经历了3级或4级CRS，这是基因工程细胞在患者体内被激活时可能发生的治疗标靶效应。通过事先教育和实施CRS治疗规则对CRS进行全面管理。在接受治疗的八周内，18％的患者经历3级或4级神经事件。没有出现任何脑水肿事件。最常见的神经事件是脑病(34％)、头痛(37％)、谵妄(21％)、焦虑(13％)和震颤(9％)。

诺华在研究性免疫细胞疗法方面处于领先地位，是第一家大力投资CAR-T研究的制药公司，与CAR-T的先驱公司共同开展全球CAR-T试验。Kymriah是首个获得批准的CAR-T细胞疗法，也是这一治疗策略的基石。有效的研究计划正在针对其他血液恶性肿瘤和实体瘤不断推进，并且包括以涉及简化生产方案和基因编辑细胞的下一代CAR-T为重点的相关工作。

2017年4月，FDA根据JULIET研究的数据向CTL019颁发了突破性治疗认定，该项研究是CTL019在r/r DLBCL成年患者中进行的首项多中心全球注册研究。

ALL是一种淋巴细胞肿瘤，该细胞是一种参与人体免疫系统活动的白细胞。在ALL患者中，异常细胞侵占骨髓中的其他类型细胞，阻止红细胞（具有携氧能力）、其他类型白细胞和血小板（血液凝固所需的组分）的生成。其结果是，ALL患者会发生贫血、更容易感染、易于出现青肿或出血【4】。

在15岁以下的儿童中，ALL约占肿瘤诊断的25%，在美国是最常见的儿童肿瘤【5】。尽管对儿童/年轻成年B细胞ALL患者的治疗总体上呈改善趋势，但是对于复发或难治性患者而言，有效的治疗方法仍较有限【6】【7】【8】。

Kymriah™ (tisagenlecleucel)重要安全性信息

Kymriah的完整处方信息，包括黑框警告，可访问：https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kymriah.pdf

Kymriah may cause side effects that are fatal or life-threatening, such as Cytokine Release Syndrome (CRS) or Neurological Toxicities. Patients with CRS may experience symptoms including high fever, difficulty breathing, chills/shaking chills, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure or dizziness/lightheadedness. Patients may be admitted to the hospital for CRS and treated with other medications.

Patients with neurological toxicities may experience symptoms such as altered or decreased consciousness, headaches, delirium, confusion, agitation, anxiety, seizures, difficulty speaking and understanding, or loss of balance. Patients should be advised to call their health care provider or get emergency help right away if they experience any of these signs and symptoms of CRS or neurological toxicities.

Because of the risk of CRS and neurological toxicities, Kymriah is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called Kymriah REMS.

Serious allergic reactions, including anaphylaxis, may occur after Kymriah infusion. Kymriah can increase the risk of life-threatening infections that may lead to death. Patients should be advised to tell their health care provider right away if they develop fever, chills, or any signs or symptoms of an infection.

Patients may experience prolonged low blood cell counts (cytopenia), where one or more types of blood cells (red blood cells, white blood cells, or platelets) are decreased. The patient’s health care provider will do blood tests to check all of their blood cell counts after treatment with Kymriah. Patients should be advised to tell their health care provider right away if they get a fever, are feeling tired, or have bruising or bleeding.

Patients may experience hypogammaglobulinemia, a condition in which the level of immunoglobulins (antibodies) in the blood is low and the risk of infection is increased. It is expected that patients may develop hypogammaglobulinemia with Kymriah, and may need to receive immunoglobulin replacement for an indefinite amount of time following treatment with Kymriah. Patients should tell their health care provider about their treatment with Kymriah before receiving a live virus vaccine.

After treatment with Kymriah, patients will be monitored life-long by their health care provider, as they may develop secondary cancers or recurrence of their leukemia.

Patients should not drive, operate heavy machinery, or do other dangerous activities for 8 weeks after receiving Kymriah because the treatment can cause temporary memory and coordination problems, including sleepiness, confusion, weakness, dizziness and seizures.

Some of the most common side effects of Kymriah included: difficulty breathing, fever (100.4°F/38°C or higher), chills/shaking chills, confusion, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, and dizziness/lightheadedness. However, these are not all of the possible side effects of Kymriah. Patients should talk to their health care provider for medical advice about side effects.

Prior to a female patient starting treatment with Kymriah, their health care provider may do a pregnancy test. There is no information available for Kymriah use in pregnant or breast-feeding women. Therefore, Kymriah is not recommended for women who are pregnant or breast feeding. If either sex partner has received Kymriah, patients should talk to their health care provider about birth control and pregnancy.

Patients should tell their health care provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

After receiving Kymriah, patients should be advised that some commercial HIV tests may cause a false positive test result. Patients should also be advised not to donate blood, organs, or tissues and cells for transplantation after receiving Kymriah.

Disclaimer

This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “pioneering,” “commitment,” “breakthrough,” “mission,” “is establishing,” “will,” “investigational,” “step forward,” “may,” “are creating,” “next wave,” “eager to progress,” “committed,” “is working to,” “plans,” “later this year,” “anticipated,” “would,” “under discussion,” “potential,” “look forward to,” “potentially,” “strategy,” “underway,” “efforts,” “focused on,” “next generation,” “continues to advance,” “continue to invest,” “Breakthrough Therapy designation,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for Kymriah and the other investigational products described in this press release, regarding our ability to implement, scale and sustain commercial manufacturing for Kymriah or the other investigational products described in this press release, regarding our ability to build a network of treatment centers to offer Kymriah or the other investigational products described in this press release, regarding the potential future success of patient support programs or patient access solutions for Kymriah or of the collaboration with CMS to establish indication-based pricing and outcomes-based payments for CAR-T cell therapies, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, andare subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements.There can be no guarantee that Kymriah or the other investigational products described in this press release will be submitted or approved for sale or for any additional indications orlabeling in any market, or at any particular time. Neither can there be any guarantee that Novartis will secure continued approval for Kymriah or the other investigational products described in this press release following accelerated approval. Nor can there be any guarantee that Novartis will successfully implement, scale and sustain commercialmanufacturing for Kymriah or the other investigational products described in this pressrelease, or successfully build a network of treatment centers to offer Kymriah or the other investigational products described in this press release. Neither can there be any guarantee that Novartis will successfully implement patient support programs or patient access solutionsfor Kymriah or the other investigational products described in this press release, or that the collaboration with CMS to establish indication-based pricing and outcomes-based payments for CAR-T cell therapies will be successful or achieve its intended goals. Nor can there be any guarantee that Kymriah or the other investigational products described in this press release will be commercially successful in the future. In particular, our expectations regarding Kymriah and such other investigational products could be affected by, among other things, our ability to successfully implement, scale and sustain commercial manufacturing and build a network of treatment centers; our ability to successfully implement patient support programs and patient access solutions; our ability to secure continued approval following accelerated approval; our ability to successfully establish indication-based pricing and outcomes-based payments for CAR-T cell therapies in collaboration with CMS; the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures; general economic and industry conditions, including the effects of the persistently weak economic and financial environment in many countries; safety, quality or manufacturing issues, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.