自由論壇 > 美國 FDA 要求停止試驗 CAR-T 療法 UCART123

美國 FDA 要求停止試驗 CAR-T 療法 UCART123


Cellectis CEO André Choulika。(圖:AFP) Cellectis CEO André Choulika。(圖:AFP)


南方日報今 (8) 日報導,美國食品藥物管理局 (FDA) 在上個月底 (8 月 30 日) 批准了諾華使用新的癌症治療技術 CAR-T ,不過就在看似一片向好的前景下,同樣使用相關療法的法國生物製藥公司 Cellectis(CLLS-US),因為有病人接受治療 8 天後死亡,該公司被美國 FDA 要求停止試驗 CAR-T 療法 UCART123。


報導指出, Cellectis 公司在 9 月 4 日宣布 CAR-T 治療療法 被 FDA 喊停。主因為 78 歲的男性病人罹患了罕見的惡性淋巴瘤,急性漿細胞樣樹突狀細胞瘤 (BPDCN)。該病人使用過後,結果在治療的 8 天後,出現致命反應而死亡。該聲明發布後, Cellectis 股價在 9 月 5 日這天暴跌了 32%,市值一天蒸發超過 4 億美元。



法國生物製藥公司Cellectis 使用的CAR-T療法UCART123造成患者死亡,5日股價暴跌3成,逾4億美元市值蒸發。(圖截自Google)法國生物製藥公司 Cellectis 使用的 CAR-T 療法 UCART123 造成患者死亡,5 日股價暴跌 3 成,逾 4 億美元市值蒸發。(圖截自 Google)


環球醫訊 (7) 日報導,今年 2 月, Cellectis 宣布其通用型 CAR-T 療法 UCART123 獲得美國 FDA 批准,這也是第一款獲得美國 FDA 批准進入臨床試驗的產品,也促使該公司股價扶搖直上,高點來到每股 32 美元,為 1 年來的最高點,8 月, Cellectis 宣布 UCART123 對首名 BPDCN 患者進行治療,然而卻迎來患者死亡的不幸消息。


目前 Cellectis 正與調查人員與美國 FDA 合作,希望通過修定的方案來盡速恢復試驗,而周五 Cellectis 股價目前為每股 25.51 美元,盤中漲幅 2.2%。


南方日報報導, Cellectis 不是第一家在 CAR-T 藥物試驗中導致病人死亡的公司。2016 年生物製藥公司 Juno Therapeutics 在 7 位病人死亡後暫停試驗,後來 FDA 介入改變了試驗方法,卻造成更多人死亡,該公司遭要求停止所有相關試驗。2017 年,被業內看好的 Kite 公司,在 CAR-T 項目 axicabtagene ciloleucel,也在 4 月底造成 一名患者死亡。


然而 Cellectis 的事件,波及範圍恐怕更廣,8 月 28 日,吉利德公司 (Gilead)(GILD-US) 用 119 億美元重金收購 Kite Pharma 就是看中可能很快獲批的 CAR-T 產品,直接成為諾華藥廠的最大競爭對手,原本美 FDA 預計審批該產品的期限在 2017 年 11 月 29 日,是否會因此遭到審批速度的放緩,有待觀察。


與 CAR-T 相關的製藥公司,根據科訊醫療網整理,分別有 Novartis 諾華 (NOVN-VTX)、 Kite、Juno、 Cellectis、Servier、Pfizer 輝瑞 (PFE-US)、Bellicum(BLCM-US)、 Bluebird(BLUE-US) 、Celgene 賽基 (CELG-US)






FDA hits Cellectis’ off-the-shelf CAR-T program with clinical hold after first patient treated in phase 1 trial dies


Cellectis CEO Andre Choulika (By Ramon Martinez)

The FDA has placed a clinical hold on two phase 1 trials of Cellectis’ UCART123 after learning of the death of one patient. Development of the off-the-shelf CAR-T therapy is now in limbo while Cellectis works with the FDA to redesign the protocol to mitigate the risks identified in the first weeks of the trials.

Doctors at the MD Anderson Cancer Center dosed the first blastic plasmacytoid dendritic cell neoplasm (BPDCN) patient with CD123-targeting CAR-T UCART123 on August 16. The patient died nine days later. 

Initially, the 78-year-old man responded to the lowest dose of UCART123 without complication. On day five the patient suffered a grade 2 cytokine release syndrome (CRS) and grade 3 lung infection. On day eight he experienced a grade 4 capillary leak syndrome (CLS) and a CRS that, despite treatment with corticosteroids and tociluzumab, played a central role in his death the next day.

The only patient treated with UCART123 in the other phase 1 trial experienced similar, albeit less severe, reactions. That patient, a 58-year-old woman with acute myeloid leukemia (AML), suffered a grade 3 CRS and grade 4 CLS nine days after treatment with UCART123. The adverse events put the patient in intensive care but had cleared up by day 12.

The list of adverse events suffered by the patients suggests UCART123 may be affected by safety issues both general to CAR-Ts and specific to its targeting of CD123. CRS is a known and, in the case of autologous products, generally manageable side effect of CAR-Ts. The process for managing the events is well established enough for Roche to have won approval for tocilizumab—also known as Actemra—as a treatment for CAR-T-induced CRS.  

It is conceivable Cellectis can prevent further patient deaths by lowering the dose of UCART123 and follow the example set by other CAR-T trials by intervening earlier and more aggressively to treat CRS.

“We think one of the key learnings from the CD19 CAR-T trials is the early administration of steroids; however, we think early administration of steroids was withheld due to potential negative impact on cell persistence. In our view, [Cellectis] may need to re-evaluate the timing of steroid administration and be more aggressive in treating CRS,” analysts at Jefferies wrote.

The way to manage the adverse events that may be tied the candidate’s targeting of CD123 is less clear. 

Stemline Therapeutics’ SL-401 is the precedent in this case. Three patients in clinical trials of CD123-directed therapy SL-401 have died after experiencing severe cases of CLS, a syndrome characterized by the leaking of blood plasma through capillary walls and into the surrounding tissue. Stemline added dosing and safety parameters to the lead-in stage of the study following the first two grade 5 cases of CSL. But those precautions failed to prevent the third death.

Cellectis now needs to figure out its own precautions before it can resume enrolling the 71 BPDCN patients and 155 AML patients it plans to treat across the two phase 1 trials. The data safety monitoring board has already proposed lowering the dose of UCART123 and capping the amount of the chemotherapy cyclophosphamide patients receive during the preconditioning stage. The two patients treated to date received cyclophosphamide alongside fludarabine.

The one bright spot for Cellectis in the otherwise grim safety data is the lack of reports of graft-versus-host disease (GvHD), a complication that arises when the immune system rejects an allogeneic transplant. Cellectis’ use of T cells from donors, rather than patients themselves, means GvHD is a potential concern. Cases of the condition would scuttle Cellectis’ ambition to capture the CAR-T market from Novartis and soon-to-be Gilead unit Kite Pharma by industrializing the CAR-T production process. 

Shares in Cellectis opened down about 30% in Paris. 





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