1370651-20-9 恩沙替尼

• 二代ALK抑制剂 二代ALK抑制剂恩沙替尼（X-396）全面优于第一代克唑替尼，2016年6月开始全球多中心3期临床，2017年6月获批多中心国内3期临床批件，均为一线用药，预计2019~2021年将上市销售。预计全球销售额5亿美元级别，其中海外3亿美元，国内12亿元。此外，X-396还于2017年12月在美国启动“ALK阳性晚期恶性黑色素瘤”2期临床研究，是全球首个ALK抑制剂治疗黑色素瘤的临床研究，有望以“孤儿药”获批上市。市场空间8亿美元，以渗透率40%计算，销售峰值为3.2亿美元。总体销售峰值在50亿元左右。
• 市场情况 恩沙替尼处于一线治疗 III 期临床，疗效有望看齐艾乐替尼，将和艾乐替尼、 Brigatinib 共同竞争国际市场；恩沙替尼有望复制埃克替尼的成功。 恩沙替尼国内有望以优异的 II 期临床数据直接申请上市，复制埃克替尼的成功，国内峰值销售有望超过 20 亿元。
• 可能的副作用 恩沙替尼治疗较常见的副作用包括皮疹、瘙痒、水肿、贫血等，大多数为1-2级，程度轻微，发生率最高的3级或以上明显副作用为皮疹（6%）和颜面部水肿（4%）。恩沙替尼治疗过程中较常见的实验室检查结果异常，包括肝酶两项、γ-谷氨酰转肽酶、碱性磷酸酶、血清淀粉酶和血肌酐升高。
• 生物活性 X-376是ALK抑制剂，对治疗非小细胞性肺癌有潜在疗效。
• 靶点 Target Value ALK ()
• 体外研究 The ability of X-376 to inhibit the growth of different cancer cell lines harboring ALK fusions or point mutations is tested. X-376 is potent in H3122 lung cancer cells harboring EML4-ALK E13;A20 (IC 50 : 77 nM). X-376 is also potent in H2228 lung cancer cells harboring EML4-ALK E6a/b; A20 (IC 50 : 57 nM). Furthermore, X-376 is potent in SUDHL-1 lymphoma cells harboring NPM-ALK (IC 50 : 32 nM). X-376 also inhibits SY5Y neuroblastoma cells harboring ALK F1174L, MKN-45 gastric carcinoma cells harboring MET dependent, HepG2 cells and PC-9 lung cancer cell lines harboring EGFR exon 19 del with IC 50 s of 142 nM, 150 nM, 15.137 μM and 3.062 μM, respectively.
• 体内研究 The effects of X-376 in vivo against H3122 xenografts are examined. A pharmacokinetic study reveals that X-376 shows substantial bioavailability and moderate half-lives in vivo. Nude mice harboring H3122 xenografts are treated with X-376 at 50 mg/kg bid. X-376 significantly delays the growth of tumors compared to vehicle alone. In the xenograft experiments, X-376 appears well-tolerated in vivo. Mouse weight is unaffected by X-376 treatment. Drug-treated mice appear healthy and do not display any signs of compound related toxicity. To further assess potential side effects of X-376, additional systemic toxicity and toxico-kinetic studies are performed in Sprague Dawley (SD) rats. Following 10 days of repeated oral administration of X-376 at 25, 50, 100 mg/kg in SD rats, all animals survive to study termination. The no significant toxicity (NST) levels are determined to be 50 mg/kg for X-376. At NST levels, X-376 achieves an AUC of 41 μM×hr and a C max of 5.04 μM.

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