IND-Enabling Studies of ZB716, an Orally Bioavailable SERD

ZB716（一种口服生物可利用的 SERD）的 IND 启用研究

• 批准号: 9341848
• 负责人: Guangdi Wang
• 金额: $ 29.85万
• 依托单位: ZENOPHARM, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9341848
• 关键词: Address; Adopted; Affinity; Aromatase Inhibitors; Binding; Bioavailable; Biological Availability; Blood; Blood Circulation; Boronic Acids; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Bypass; Cell Line; Cell Proliferation; Chemicals; Chemistry; Chromatography; Clinical; Clinical Research; Clinical Trials; Collaborations; Contracts; Custom; Development; Disadvantaged; Disease; Dose; Dose-Limiting; Drug Exposure; Drug Kinetics; Endocrine; Ensure; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptors; FDA approved; Fulvestrant; Glucuronides; Health Sciences; Hormone Receptor; Human; Injection of therapeutic agent; Intramuscular; Intramuscular Injections; Laboratories; Legal patent; Louisiana; Measures; Metabolic; Metabolism; Metastatic breast cancer; Methods; Modification; Molecular Structure; Mus; Nude Mice; Oils; Oral; PRKCA gene; Patients; Pharmaceutical Preparations; Phase; Plasma; Preparation; Procedures; Process; Progressive Disease; Protocols documentation; Qualitative Methods; Quality Control; Recurrent disease; Regimen; Reporting; Reproducibility; Resistance; Resistance development; Route; Sampling; Serum; Small Business Innovation Research Grant; Solubility; Spectrometry; Standardization; Steroids; T47D; Tamoxifen; Testing; Therapeutic; Time; Tissues; Toxic effect; Translating; Treatment Efficacy; Treatment outcome; Universities; Unspecified or Sulfate Ion Sulfates; Water; Work; Xenograft Model; Xenograft procedure; analytical method; base; clinical efficacy; design; dosage; efficacy study; hormone therapy; improved; in vivo; knock-down; malignant breast neoplasm; novel; preclinical study; receptor; research clinical testing; response; scale up; standard care; sulfation; therapeutic evaluation; treatment group; tumor; tumor xenograft

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.

ZB716（一种口服生物可利用的 SERD）的 IND 研究 项目概要 大多数晚期转移性乳腺癌患者最终会产生耐药性 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。乳腺癌术后进展的标准治疗 他莫昔芬或 AI 疗法是氟维司群，这是 FDA 批准的唯一选择性雌激素 受体降解剂（SERD）作为二线内分泌治疗方案。由于口语能力极差 生物利用度，氟维司群按 250 mg/月肌肉注射给药， 2002年获批，需要3-4个月达到稳态血药浓度 在患者中使用 15 ng/mL 的氟维司群。随后的临床试验使用 500mg/月 第 14 天的额外负荷剂量显示出显着的临床改善，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， 氟维司群的血药浓度峰值仍低于适度的 25 ng/mL，并且需要时间 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，患者反应率低。因此，一种有效的、口服的 生物可利用的 SERD 具有显着更高的受体敲除率和更多的潜力 比氟维司群具有持久的临床益处。迄今为止，只有两种非甾体类口服 SERD：GDC-0810 （基因泰克）和 AZD9496（阿斯利康）正在临床试验中进行测试。这些口头 SERD 与氟维司群具有非常不同的分子结构，其效力不如氟维司群 临床前研究，距离被证明临床安全和至少还需要几年的时间 有效。另一方面，很少有报告描述了使口服生物可利用的尝试 类固醇 SERD 尚未进入临床研究。事实上，这些尝试都集中在 主要对长烷基链进行修饰以增加极性和溶解度，但是 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，氟维司群经过快速、广泛的O-葡萄糖醛酸化和O-硫酸化形成 无活性且水溶性的极性代谢物。 Zenopharm 开发了 ZB716， 专利甾体口服SERD，可有效增强全身生物利用度，同时 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 证实这种化学修饰可以保留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 ZB716 以高亲和力与 ER 结合，并对表达 ER 的乳腺发挥抗雌激素作用 癌细胞。在他莫昔芬初治和他莫昔芬耐药乳腺癌细胞中，ZB716 有效抑制细胞增殖并有效降解激素受体 依赖方式。此外，ZB716 在小鼠体内具有优异的口服生物利用度 与氟维司群相比。因此ZB716是一种可行的口服SERD，它不仅可以克服 与注射库相关的缺点，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 养生法。为了将 ZB716 推向临床试验，我们建议进行 IND 支持研究 这将启动 CMC（化学、制造和控制）工作并研究体内 口服 ZB716 在两种异种移植模型中的疗效。剂量依赖性疗效研究是 接下来的关键步骤是确定 ZB716 的口服生物利用度是否可以转化为体内生物利用度 功效。 GLP 和 GMP 放大制备的合成程序优化 定制 API 需要 ZB716 级。