Synribo获准治疗某些慢性粒细胞白血病

圣路易斯(MD Consult)——2012年10月26日，美国食品药品管理局(FDA)和梯瓦制药宣布，Synribo(高三尖杉酯碱)已被加速批准，用于对至少2种酪氨酸激酶抑制剂(TKI)耐药和(或)不耐受的成年慢性期(CP)或加速期(AP)慢性粒细胞性白血病(CML)的治疗。Synribo的作用机制尚未被完全阐明，但包含对蛋白质合成的抑制作用。在体外研究中，该药可通过独立地直接结合BCR-ABL而降低BCR-ABL肿瘤蛋白和MCL-1蛋白的水平。

FDA批准该适应证是基于该药的应答率。目前尚无试验证实Synribo可改善疾病相关症状或延长生存。FDA加速批准Synribo的依据是对2项2期、开放性、多中心研究数据的汇总分析。这项汇总分析纳入了已接受至少2种已获准的TKI治疗且至少对达沙替尼和(或)尼罗替尼耐药或不耐受的患者。47%的CP患者和63%的AP患者对伊马替尼、达沙替尼和尼罗替尼无应答。多数患者还接受了其他治疗，包括羟基脲、干扰素和阿糖胞苷。

结果显示，在CP患者组中，18%(14/76)获得了主要细胞学应答(MCyR)，至获得MCyR的平均间隔时间为3.5个月。MCyR的中位持续时间为12.5个月。在AP患者卒中，14%(5/35)获得了主要血液学应答(MaHR)，至获得MaHR的平均间隔时间为2.3个月。MaHR的中位持续时间为4.7个月。

在研究受试者中最常见的不良反应为血小板减少、贫血、中性粒细胞减少、腹泻、恶心、疲乏、无力、注射部位反应、发热、感染和淋巴细胞减少。

Synribo的用法是每日2次皮下注射，连续使用14天，每 28天为1个疗程，直至获得血液学应答。然后改为每日2次皮下注射，连续使用7天，每 28天为1个疗程，只要患者显示出临床获益就继续使用。

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ST LOUIS (MD Consult) - On October 26, 2012, the US Food and Drug Administration (FDA) and Teva Pharmaceuticals announced the accelerated approval of Synribo (omacetaxine mepesuccinate) for the treatment of adults with chronic phase (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors (TKIs). The mechanism of action of Synribo has not been fully elucidated but includes inhibition of protein synthesis. It acts independently of direct BCR-ABL binding to reduce protein levels of both the BCR-ABL oncoprotein and MCL-1 that inhibits apoptosis, in vitro.

The FDA approval for this indication was granted on the basis of response rate. No trials exist that verify an improvement in disease-related symptoms or increased survival with the use of Synribo.

The decision to grant this approval for Synribo was made on the basis of results from an analysis of combined data subsets from 2 phase 2, open-label, multicenter studies. The pooled analysis included patients who had received 2 or more approved TKIs and, at a minimum, showed evidence of resistance or intolerance to dasatinib and/or nilotinib. Forty-seven percent of patients with CP disease and 63% of patients with AP disease had failed to respond to treatment with imatinib, dasatinib, and nilotinib. The majority of patients had also received other treatments including hydroxyurea, interferon, and cytarabine.

For patients in the CP group, 18% (14/76) achieved a major cytogenetic response (MCyR) with a mean time to MCyR onset of 3.5 months. The median duration of MCyR for these patients was 12.5 months (Kaplan-Meier estimate). For patients in the AP group, 14% (5/35) achieved a major hematologic response (MaHR) with a mean time to response onset of 2.3 months. The median duration of MaHR for these patients was 4.7 months (Kaplan-Meier estimate).

The most common adverse reactions in study participants were thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection-site reaction, pyrexia, infection, and lymphopenia.

Synribo is injected subcutaneously twice daily for 14 consecutive days over a 28-day cycle until a hematologic response is achieved. Synribo is then administered twice daily for 7 consecutive days over a 28-day cycle as long as patients continue to demonstrate clinical benefit.