IND-Enabling Studies of ZB716, an Orally Bioavailable SERD

口服生物可利用SERD ZB 716的IND可行性研究 项目摘要 大多数晚期转移性乳腺癌患者最终会对 他莫昔芬或芳香酶抑制剂（AI）治疗，其中复发性和/或进行性疾病 保留ERα的表达。乳腺癌的标准治疗进展后， 他莫昔芬或AI疗法是氟维司群，其是唯一FDA批准的选择性雌激素 受体降解剂（SERD）作为二线内分泌治疗方案。由于其极差的口腔 生物利用度，氟维司群以250 mg/月通过肌内注射给药， 该法案于2002年获得批准。需要3-4个月达到稳态血药浓度 氟维司群15 ng/mL。随后的临床试验使用500 mg/月， 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批准氟维司群作为500 mg注射方案。然而，即使在这个剂量下， 氟维司群的血药峰浓度保持在适度的25 ng/mL以下， 稳态药物浓度保持约30天。氟维司群的这些缺点可能 临床疗效有限，患者应答率低。因此，一种有效的口服 生物可利用的SERD具有显著更高的受体敲低和更高的生物可利用性的潜力。 比氟维司群更持久的临床获益。迄今为止，只有两种非甾体口服SERD，GDC-0810， （Genentech）和AZD 9496（AstraZeneca）正在临床试验中进行测试。这些口服SERD 具有与氟维司群非常不同的分子结构， 临床前研究，并且至少还有几年的时间才能被证明临床安全， 灵验。另一方面，很少有报道描述了使口服生物可利用的尝试。 甾体SERD和没有进展到临床研究。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性， 未能解决导致氟维司群生物利用度差的主要问题， 也就是说，氟维司群经历快速和广泛的O-葡萄糖醛酸化和O-硫酸化， 非活性和水溶性的极性代谢物。Zenopharm开发了ZB 716， 获得专利的甾体口服SERD，可有效提高全身生物利用度， 绕过氟维司群的首过代谢（葡萄糖醛酸化和硫酸化）。临床前研究 证实了这种化学修饰可以保持足够高的结合亲和力， 氟维司群的甾体部分，同时最大限度地减少葡萄糖醛酸化和硫酸化。我们发现 ZB 716与ER高亲和力结合并对ER表达乳腺癌发挥抗雌激素作用 癌细胞在他莫昔芬初始和他莫昔芬抗性乳腺癌细胞中，ZB 716 有效抑制细胞增殖并有效降解激素受体， 依赖的方式。此外，ZB 716显示出在小鼠中具有远为优越的上级口服生物利用度 与氟维司群相比。因此，ZB 716是一种可行的口服SERD，其不仅可以克服 与注射贮库相关的缺点，但更重要的是可以改善 治疗效果，并实现比当前SERD更持久的治疗结果 方案.为了将ZB 716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 口服ZB 716在两种异种移植模型中的功效。剂量依赖性疗效研究为 确定ZB 716的口服生物利用度是否可以转化为体内生物利用度的下一步关键步骤 功效GLP和GMP放大合成工艺的优化 ZB 716级是定制生产API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.