喜大普奔,但...仍想降降温!Juno, Kite 和诺华CAR-T疗法死亡案例独家大盘点

来源: 灵麦医药/Lingmed

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来源:EvaluatePharma

美国时间7月12日,FDA专家咨询委员会以10:0的结果最终“推荐批准”诺华CAR-T疗法CTL-019上市。FDA将在10月3日做出最终评审决定,但获批上市基本无悬念。业内对于CAR-T疗法的“安全性”一直存在诸多忧虑,并很大程度影响项目的进程。此前,Juno公司的“火箭”试验JCAR015就因为脑水肿的死亡病例的出现而被FDA一度叫停。因此,无需多言,此次评审的焦点都落在了CTL-019的“安全性”上。


就从此前欧洲病理学会上报道来看,暂无新增的死亡病例以及脑水肿病例。但仍然无确凿的证据可以证明CAR-T细胞疗法的安全性,EvaluatePharma团队就三大主流公司(Juno, Kite 和诺华)的CAR-T疗法项目中的非疾病相关的正常死亡事件做了以下盘点(详情请参展表格,附有试验来源及临床试验ID)。


从表1可以很清晰的看出,Juno公司的三大项目(JCAR017,JCAR015和JCAR014)共有18起非疾病相关死亡案例。JCAR017相比其他两个项目拥有更少的严重的不良事件。 JCAR014有7例死亡事件(包含2起脑水肿导致的死亡事件)。这也许一定程度上解释了为什么JCAR014项目投资者甚少,且很有可能Juno未来会不在继续推进该项目的下一步推进。 

表1:Juno公司18例非疾病相关死亡病例

备注:~包括150个成人急性淋巴细胞性白血病(ALL)在内的接受JCAR015,JCAR017及JCAR014共计500个样本*FDA实施的临床试验**第二个FDA实施的试验 *** Voiluntary实施的临床试验,最终致使JCAR015项目的终止

CAR-T疗法从它面世伊始就麻烦不断,因为在其强大效力的背后伴随的是“细胞因子释放综合征”,“神经毒性”及肿瘤负荷。虽然现代医疗水平已经足够去减弱这些效应,但对于严重的“脑水肿”后果,仍无力可施。Juno公司的JCAR015及Kite公司的KTE-C19(两者有着极其相似的结构)都遭遇到脑水肿的“冲击”。2个月前,由于在Zuma-1淋巴瘤的队列研究中出现了一起脑水肿案例,整个公司股价都遭受重创。详情请参照EvaluatePharma数据库。

表2:Kite公司9例非疾病相关死亡病例(KTE-019)

备注:~包括NCI研究的共计300个KTE-C19给药的样本。CRS(cytokine release syndrome)细胞因子释放综合征

从上面一些数据我们可以看出,所有靶向CD19的CAR-T疗法死亡案例不是由于疾病本身,但是否是由于CAR-T细胞科学界仍无从定论。


此外,早期的KTE-C19及JCAR015基本都是学术背景下完成的,甚少真正涉及商业生产。因此,在计算病死率的时候需要有所校正。 


仍然想要再三强调的是,CAR-T疗法仍然具有较大的毒性,受试病人仍有较大的风险,未来临床试验仍需许多探索。一些渠道声称Juno公司已经终止了JCAR015项目,但仍然继续探索JCAR014及JCAR017项目。对于Juno公司来说,最新策略是抛弃两个较高剂量,采用最低剂量(2x105 cells/kg)去进行临床试验。


为保证数据的准确性,当EvalutePharma盘点相关死亡病例时有与Kite和Juno核实过以上数据。但是,诺华公司未正式披露,下面的7个CTL019相关死亡案例都来源于学术会议的披露。 

表3:诺华公司7例非疾病相关死亡病例(CTL019项目)

备注:283个CTL019受试患者

纵观整个项目,死亡率基本与美国重组DNA咨询委员会12月份会议上报道的脑水肿死亡率相似。仅增加了两例非致命性的脑水肿, 其中一例来源于针对多发性骨髓瘤的BCMA-CAR的试验。 


此前对于CAR-T疗法神经毒性的描述,多数被描述成脑溢血(brain haemorrhage),因此现在有必要重新审视之前的临床数据,是否之前的数据就已经涉及到脑水肿?


机制迷雾

脑水肿死亡案例的出现,不禁让人发问,到底是怎样的机制导致脑水肿的发生?多数专家认为产生于细胞释放因子综合征中的细胞因子的调节作用。但一些专家认为这是由于CAR-T细胞可以跨越血脑屏障,并在脑脊液中二次激活而不是简单的在中枢神经系统中激活CD19的表达。 


除此之外, 到底是什么样的结构引发了激活效应?一些专家认为是因为共刺激结构域,一些专家认为是由于制备过程。 鉴于不同项目之间的CAR结构存在较大差别,所以尚无定论。


总之,CAR-T有风险,投资需谨慎,以上!


Spotlight – Putting a number on CAR-T deaths

Source:EvauatePharma

The toxicity of CAR-T therapies took on fresh importance with the discontinuation of Juno ’s Rocket study of JCAR015  owing to deaths from cerebral oedema. Little wonder that when  Novartis  presented its update of the Eliana trial of  CTL019  one spotlight fell on safety.


The good news, according to Saturday’s update at the European Haematology Association meeting, is that there were no new unexpected deaths, and no cerebral oedema. How this plays out will be important: precise safety data are hard to pin down, but an exhaustive EP Vantage search of various sources has yielded a definitive list of CAR-T deaths not due to disease progression (see tables below).


This involves not just CTL019 , but all of the three leading players’ CD19 -targeted projects. One little-appreciated finding is there have been seven deaths – two from cerebral oedema – in trials of Juno ’s JCAR014 . This has resonated little with investors, likely because Juno  has long maintained that it does not intend to pursue  JCAR014  to registration.


However, the close similarity with Juno ’s lead – JCAR017  differs from  JCAR014  only in a manufacturing step – should push CAR-T followers to pay close attention to this issue. That said, reported deaths on  JCAR017  have been substantially lower, the data show.

Table1: 18 Juno  study deaths not due to disease progression

Note: ~500 subjects combined have been dosed JCAR015 , JCAR017  or  JCAR014 , including 150 in adult ALL. *FDA-imposed clinical hold. **Second FDA-imposed clinical hold. ***Voiluntary clinical hold, leading to discontinuation of JCAR015 . 

The toxicity of CAR-T therapies has been problematic ever since the first signs of truly robust activity were seen – it is known that cytokine release syndrome and neurotoxicities correlate with efficacy and tumour burden.


However, nurses have become very skilled at dealing with these types of toxicities, and several important centres have developed detailed plans to minimise their effects. Nonetheless, the specific finding of cerebral oedema posed very serious questions, and ultimately did for JCAR015 , which until recently was Juno ’s lead.


The issue also hit Kite ’s KTE-C19, a construct very similar to JCAR015 , and this group’s stock took a tumble last month when a patient died from cerebral oedema in a safety extension cohort  of the pivotal Zuma-1 lymphoma study (Kite investors see an uncomfortable parallel with Juno, May 8, 2017).

Table2: Nine KTE-C19 study deaths not due to disease progression

Note: ~300 subjects have been dosed KTE-C19, including NCI studies. CRS =cytokine release syndrome. 

The data need to be seen in the context of several important caveats. Firstly, they comprise all disclosed  CD19 -directed CAR-T trial deaths that were not due to disease progression, whether these were deemed to be due specifically to the CAR-T cells or not – a subjective decision made by the specialist in question.


Early deaths on trials of KTE-C19 and JCAR015  were in the academic setting, and will have involved academic rather than commercial manufacturing. In evaluating the frequency of deaths the total number of patients treated must be  borne  in mind.


And of course it must be remembered that subjects on CAR-T studies are very ill, so are already at high risk of death. While this does not reduce the need for clinical rigour, several sources have commented to EP Vantage off the record that  Juno  might – scientifically if not reputationally – have been rash to discontinue  JCAR015 .


Extreme care must also be taken in extrapolating JCAR014  deaths to  JCAR017 ; the deaths caused Juno  to continue its ALL trial only with the lowest  JCAR014  dose (2x105 cells/kg), and to scrap two higher levels.  Juno  has yet to choose a dose of  JCAR017  to take into its pivotal lymphoma trial.


All that said, taking into consideration the caveats the data should speak for themselves.


After EP Vantage compiled the lists  Kite  and  Juno  cooperated  fully  in confirming the data as accurate.  Novartis , however, did not respond to requests for clarification; as such, it is possible that there have been more deaths on CTL019  trials, and the list comprises only the seven that came to light in scientific presentations.

Table3:Seven CTL019  study deaths not due to disease progression

Note: 283 subjects have been dosed to CTL019 . 

Across CAR-T projects, the cerebral oedema deaths tally with those reported at December’s meeting of the US Recombinant DNA Advisory Committee, which additionally detailed two non-fatal cerebral oedema cases, one in a multiple myeloma study of an anti-BCMA CAR.


Several of the other neurotoxicity -related deaths disclosed  – brain  haemorrhage , for instance – sound uncomfortably close to cerebral oedema. But it should be stressed that after the JCAR015  incident most groups went back and reanalysed all previous toxicities to ascertain whether cerebral oedema might have been involved, and to rule out such a possibility.


Mechanistic mystery

Meanwhile, it is one of the many mysteries of CAR-T therapy that there is still no agreement on what precise mechanism might be responsible for causing cerebral oedema, though it is largely accepted that, being a cytokine-mediated event, it is something that arises from cytokine release syndrome.


Some doctors have told EP Vantage that this likely involves activated CAR-T cells crossing the blood-brain barrier, and then undergoing some kind of secondary activation event in the cerebrospinal fluid. However, many dismiss the simple answer that this results from expression of  CD19  in the CNS.

An even deeper mystery is what aspect of CAR-T therapy might give rise to this kind of stimulation. Some have suggested the role of the co-stimulatory domain that each construct uses, others the manufacturing process, others still the indication studied, but given that all the CAR constructs differ in multiple ways, and that the numbers are still small, there is no way to be sure.


The FDA is separately compiling its own database of CAR-T toxicities. The provisos notwithstanding, investors should at the very least be aware of the numbers as they emerge.


灵麦医药是以下两家情报数据库在中国的独家合作伙伴:

Biotechgate/博谷 - 全球创新药和器械产品收购和引进数据库

EvaluatePharma/预估医药 - 全球医药研发、销售、市场预估等竞争情报数据库

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