PhytoSERM for Menopausal Hot Flashes and Sustained Brain Health

项目摘要/摘要 女性一生中患阿尔茨海默病(AD)的风险更大。导致AD终生风险增加的一个潜在因素是中年更年期内分泌老化过渡，此时可能出现多种AD危险情况，并且与疾病的前驱/临床前特征相一致。虽然当更年期女性出现症状时使用雌激素或激素治疗可以降低患AD的风险，但对乳腺癌的恐惧导致许多女性放弃了这一方法。雌激素治疗的一个创新选择是靶向雌激素在大脑中的作用，同时避免乳腺组织中雌激素相关的增殖。为了实现这一目标，我们建议第二阶段临床开发“PhytoSERM”，这是一种选择性雌激素受体β(ER？)调节剂，通过在大脑中促进雌激素样作用，同时在生殖组织中抑制雌激素样作用。植物雌激素是一种合理设计的3种植物雌激素配方(每一种都被FDA公认为安全)。我们早期的NIA支持的PhytoSERM 1b/2a期临床试验确定了PhytoSERM是安全和耐受性良好的，在围绝经期和绝经后妇女中显示出预测性的药代动力学，并确定了应答表型(https://clinicaltrials.gov/ct2/show/NCT01723917).这里提出的是一项2期双盲、平行分组、随机、安慰剂对照的临床试验，并进行开放标签扩展，以确定PhytoSERM在有症状的围绝经期和绝经后妇女中的疗效。主要目标是确定PhytoSERM在缓解更年期症状(主要是潮热)方面的有效性。第二个目标是评估PhytoSERM对以下方面的影响：1)认知功能，2)睡眠障碍，3)非神经更年期症状，包括骨密度和身体成分。第三个目标是确定植物SERM对基于血液的AD生物标记物的影响。这项第二阶段的PhytoSERM临床试验涉及美国国家老龄研究所2020-2025年的多个战略方向：21世纪的良好老龄化，具体而言，目标C-3：“开发有效的干预措施，以维持健康、福祉和功能，并预防或减轻与年龄相关的疾病的负担”，以及“进行临床研究/将新的干预措施转化为临床 设置。“目标D-4：将基本发现转化为AD/ADRD和“目标F-4：支持妇女健康研究”的有效治疗和/或预防战略。PhytoSERM临床试验还有助于实现到2025年有效预防和治疗阿尔茨海默病的国家阿尔茨海默病项目法案(NPA)目标1B。PhytoSERM解决了女性健康中一个关键的未得到满足的需求，以降低晚年患阿尔茨海默氏症的风险。

PROJECT SUMMARY/ABSTRACT Women are at greater life-time risk for Alzheimer’s disease (AD). One potential factor contributing to greater life-time risk of AD is the midlife menopausal endocrine aging transition when multiple AD risk conditions can emerge and which are consistent with prodromal / preclinical features of the disease. While estrogen or hormone therapy administered when menopausal women are symptomatic could reduce risk of AD, the fear of breast cancer leads many women to forego this approach. An innovative alternative to estrogen therapy is to target estrogen action in brain while avoiding estrogen-associated proliferation in breast tissue. To achieve that goal, we propose Phase 2 clinical development of “PhytoSERM”, a selective estrogen receptor beta (ERß) modulator that promotes estrogenic action through ERß in brain while inhibitory in reproductive tissue. PhytoSERM is a rationally designed formulation of 3 phytoestrogens (each are Generally Recognized as Safe by the FDA). Our earlier NIA supported PhytoSERM Phase 1b/2a clinical trial determined that PhytoSERM was safe and well-tolerated, exhibited predictive pharmacokinetics in peri- and postmenopausal women and identified responder phenotype (https://clinicaltrials.gov/ct2/show/NCT01723917). Proposed herein is a Phase 2, double-blind, parallel-group, randomized, placebo-controlled clinical trial with an open-label extension to determine efficacy of PhytoSERM in symptomatic peri- and post-menopausal women. Primary objectives are to determine the efficacy of PhytoSERM to alleviate menopausal symptoms, mainly hot flashes. Secondary objectives are to evaluate the effect of PhytoSERM on: 1) cognitive function, 2) sleep disturbances, and 3) non-neurologic menopausal symptoms, including bone mineral density and body composition. Tertiary objectives are to determine impact of PhytoSERM on blood-based AD biomarkers. This Phase 2 PhytoSERM clinical trial addresses multiple strategic directions of the National Institutes on Aging’s 2020-2025: Aging Well in the 21st Century ref Specifically, Goal C-3 to: “Develop effective interventions to maintain health, well-being, and function and prevent or reduce the burden of age-related diseases” and “Conduct clinical studies / translation of new interventions to the clinical setting.” Goal D-4: Translate basic discovery into effective treatment and/or prevention strategies for AD/ADRD and” Goal F-4: Support research on women’s health.” PhytoSERM clinical trial also contributes to achieving the National Alzheimer’s Disease Project Act (NAPA) to effectively prevent and treat AD by 2025 Goal 1B. PhytoSERM addresses a critical unmet need in women’s health to reduce risk of Alzheimer’s in later life.