IND-Enabling Studies of ZB716, an Orally Bioavailable SERD

口服生物利用型SERD药物ZB716的IND使能研究 项目摘要 大多数晚期转移性乳腺癌患者最终对 他莫昔芬或芳香酶抑制剂(AI)治疗复发和/或进展性疾病 保留ERα的表达。进展期乳腺癌的标准治疗 他莫昔芬或AI疗法是FULVESTRAN，是FDA批准的唯一一种选择性雌激素 受体降解剂(SERD)作为二线内分泌治疗方案。因为它的口音极差 生物利用度，氟维斯特每月250毫克肌肉注射， 这是2002年批准的。需要3-4个月的时间才能达到稳态血药浓度 病人服用15 ng/m L的氟维司他。随后的临床试验使用500 mg/月，并使用 第14天的额外负荷剂量显示出显著的临床改善，导致 2011年FDA批准氟维斯特作为500毫克的注射方案。然而，即使在这个剂量下， 氟维司琼的血药浓度峰值保持在25毫微克/毫升以下，达到 稳态药物浓度保持在30天左右。福维斯特的这些缺点可能 占临床疗效有限，患者应答率低。因此，一种强有力的，口服的 生物可利用的SERD有可能显著提高受体击倒率，并有更多的 持久的临床疗效优于氟维司琼。到目前为止，只有两种非类固醇口服SERD，GDC-0810 (Genentech)和AZD9496(阿斯利康)正在进行临床试验。这些口服SERD 与Fulvestrant具有非常不同的分子结构，在 临床前研究，至少还需要几年时间才能证明临床安全和 很有效。另一方面，很少有报告描述口服生物利用度的尝试。 类固醇SERD，没有一种进入临床研究。事实上，这些尝试集中在 主要对长烷基链进行修饰以增加极性和溶解度，但 未能解决导致福尔维斯特生物利用度差的主要问题， 也就是说，弗维斯特经历快速和广泛的O-葡萄糖醛酸化和O-硫化形成 不活跃且可溶于水的极性代谢物。捷诺帕姆已经开发出ZB716，一种 专利的类固醇口服SERD，可有效提高全身生物利用度，同时 绕过弗维斯特的首过代谢(葡萄糖醛酸化和硫酸盐化)。临床前研究 证实这种化学修饰可以保持足够高的结合亲和力 弗维斯特的类固醇部分，同时最大限度地减少葡萄糖醛酸化和硫酸盐化。我们发现 ZB716与ER高亲和力结合对ER表达乳房发挥抗雌激素作用 癌细胞。在他莫昔芬初治和耐药乳腺癌细胞中，ZB716 有效地抑制细胞增殖，并有效地降解激素受体- 依赖的态度。此外，ZB716在小鼠体内的口服生物利用度远高于其他药物 与FUVESTRANT相比。因此，ZB716是一种可行的口服SERD，不仅可以克服 与注塑库相关的缺点，但更重要的是可以改进 治疗效果和取得比目前的SERD更持久的治疗结果 养生法。为了将ZB716推向临床试验，我们建议进行IND使能研究 这将启动CMC(化学、制造和控制)工作并研究体内的 口服ZB716在两种异种移植模型中的疗效。剂量依赖的疗效研究是 下一步关键步骤是确定ZB716的口服生物利用度是否可以转化为体内 功效。GLP和GMP中试制备工艺的优化 ZB716级是定制原料药所必需的。

IND-enabling Studies of ZB716, an Orally Bioavailable SERD Project Summary Most patients with advanced metastatic breast cancer eventually develop resistance to tamoxifen or aromatase inhibitor (AI) treatment where the recurrent and/or progressive disease retains the expression of ERα. The standard treatment of breast cancer progressing after tamoxifen or AI therapy is fulvestrant which is the only FDA approved selective estrogen receptor degrader (SERD) as a second-line endocrine regimen. Due to its extremely poor oral bioavailability, fulvestrant was administered as a 250 mg/month by intramuscular injection, which was approved in 2002. It takes 3-4 month to reach the steady state serum concentration of fulvestrant at 15 ng/mL in patients. Subsequent clinical trials using 500mg/month with an additional loading dose on day 14 demonstrated significant clinical improvement, leading to the 2011 FDA approval of fulvestrant as a 500 mg injection regimen. However, even at this dosage, the peak blood concentration of fulvestrant remains below a modest 25 ng/mL, and the time to steady-state drug concentration remains about 30 days. These shortcomings of fulvestrant may account for the limited clinical efficacy low patient response rate. Thus, a potent, orally bioavailable SERD has potential for significantly higher receptor knockdown and for more durable clinical benefits than fulvestrant. To date, only two nonsteroidal oral SERDs, GDC-0810 (Genentech) and AZD9496 (AstraZeneca) are being tested in clinical trials. These oral SERDs have very different molecular structures from fulvestrant, are less potent than fulvestrant in preclinical studies, and are at least several years away from being proven clinically safe and efficacious. On the other hand, few reports have described attempts to make orally bioavailable steroidal SERDs and none has progressed to clinical studies. Indeed, these attempts focused on modifications made primarily to the long alkyl chain to increase polarity and solubility but failed to address the main problem that is responsible for the poor bioavailability of fulvestrant, that is, fulvestrant undergoes rapid and extensive O-glucuronidation and O-sulfation to form polar metabolites that are inactive and water soluble. Zenopharm has developed ZB716, a patented steroidal oral SERD that can effectively enhance systemic bioavailability while bypassing first-pass metabolism (glucuronidation and sulfation) of fulvestrant. Preclinical studies confirmed that this chemical modification can retain sufficiently high binding affinity of the steroidal moiety of fulvestrant while minimizing glucuronidation and sulfation. We found that ZB716 binds to ER with high affinity and exerts its antiestrogenic effect on ER-expressing breast cancer cells. In both tamoxifen naive and tamoxifen resistant breast cancer cells, ZB716 potently inhibits cell proliferation and effectively degrades the hormone receptor in a dose- dependent manner. Moreover, ZB716 is shown to have far superior oral bioavailability in mice compared to fulvestrant. Therefore ZB716 is a viable oral SERD, which can not only overcome the disadvantages associated with injection depot, but more importantly can improve therapeutic efficacy and achieve more durable treatment outcome than the current SERD regimen. To move ZB716 towards clinical trials we propose to conduct IND-enabling studies that will initiate CMC (chemistry, manufacturing, and control) work and investigate the in vivo efficacy of oral ZB716 in two xenograft models. The dose-dependent efficacy studies are the next key steps to determine if the oral bioavailability of ZB716 can be translated to in vivo efficacy. Optimization of synthetic procedure for use in scale-up preparation of GLP and GMP grade ZB716 is necessary to custom-manufacture the API.