The Efficacy and Safety of a Selective Estrogen Receptor Beta agonist (LY500307)

描述（申请人提供）：精神分裂症是一种毁灭性的精神疾病，影响世界上大约百分之一的人口，并与大量未满足的医疗需求有关。阴性症状（例如，情感表达和社会行为受限）和认知损伤（例如，工作记忆和文字记忆）是精神分裂症的核心临床特征，并在很大程度上导致与这种疾病相关的功能障碍。这两个症状域对精神分裂症的批准治疗相对无反应，这促使人们大量关注识别新靶点和开发针对这些症状复合体的新疗法。一些研究支持雌激素对精神分裂症阴性和认知症状的潜在治疗作用。然而，雌激素对男性和绝经前精神分裂症患者的治疗应用有限，因为耐受性问题包括子宫癌易感性，心脏病和男性女性化效应。选择性雌激素受体β（ER β）激动剂是一类新的治疗方法，相对没有雌激素的主要副作用，但已证明在大脑中具有雌激素样作用，包括认知能力的改善和与极端社会行为的关联。因此，这些药物可能对精神分裂症的认知和阴性症状具有治疗作用。本申请的主要目的是确定选择性ER β激动剂LY 500307是否显著改善精神分裂症患者的阴性和认知症状。次要目的包括评估LY 500307在工作和情景记忆任务中对脑血流量的影响，以及听觉感觉处理和工作记忆的电生理指标。将使用单一无缝1b/2a期适应性设计评价试验第一阶段（申请第1年）的两种LY 500307剂量（25 mg/天和75 mg/天），以确定哪种剂量应提前至第2阶段（申请第2年和第3年）或是否应中止试验。Go/No Go标准 确定进展到第2阶段的条件是：1）在三个认知和阴性症状主要终点中的至少一个中检测到阳性信号，和2）未能从基线降低睾酮水平，这反映了维持对ER β的选择性。在第1阶段，30名精神分裂症患者将随机（1：1：1）接受两种剂量的LY 500307或安慰剂之一，进行为期8周的抗精神病药物试验。如果符合go/no go标准，60名患者将在试验的第2阶段随机（1：1）分配至“获胜”LY 500307剂量或安慰剂。目前，仅研究男性精神分裂症患者，因为Eli Lilly获得的男性（>400名男性治疗6个月）的广泛安全性数据库证明了良好的安全性和耐受性。这项研究的结果将决定是否应进一步在精神分裂症中测试LY 500307。

DESCRIPTION (provided by applicant): Schizophrenia is a devastating mental illness affecting approximately one percent of the world's population and is associated with substantial unmet medical need. Negative symptoms (e.g., constricted emotional expression and social behavior) and cognitive impairment (e.g., working and verbal memory) are core clinical features of schizophrenia and substantially contribute to the functional disability associated with this illness. Both of these symptom domains are relatively unresponsive to approved treatments for schizophrenia which has prompted a substantial focus on identifying new targets and developing novel therapeutics for these symptom complexes. Several lines of investigation have supported the potential therapeutic effects of estrogen for negative and cognitive symptoms in schizophrenia. However, estrogen has had limited therapeutic application for male and premenopausal patients with schizophrenia because of tolerability concerns including uterine cancer liability, and heart disease and feminization effects in men. Selective Estrogen Receptor Beta (ER beta) agonists are a new class of treatments that are relatively free of estrogen's primary side effects and yet have demonstrated estrogen-like effects in brain including improvement in cognitive performance and an association to extremes in social behavior. Thus, these agents may have a therapeutic role for cognitive and negative symptoms in schizophrenia. The primary objectives of this application are to determine if the selective ER beta agonist LY500307 significantly improves negative and cognitive symptoms in patients with schizophrenia. Secondary aims include assessing LY500307 effects on cerebral blood flow during working and episodic memory tasks with fMRI, and electrophysiological indices of auditory sensory processing and working memory. A single seamless phase 1b/2a adaptive design will be used to evaluate two LY500307 doses (25 mg/day and 75 mg/day) in the first stage of the trial (year 1 of the application) to determine which dose should be advanced to stage 2 (years 2and 3 of the application) or if the trial should be discontinued. Go/No Go criteria to determine advancement to stage 2 are: 1) positive signal detection in at least one of three cognitive and negative symptom primary endpoints, and 2) failure to decrease testosterone levels from baseline which is reflective of maintaining selectivity for ER beta. In stage 1, 30 patients with schizophrenia will be randomized (1:1:1) to one of the two doses of LY500307 or placebo to an 8-week add-on to antipsychotic medication trial. Providing go/no go criteria are met, 60 patients will be randomized (1:1) in stage 2 of the trial to the "winning" LY500307 dose or placebo. At this time, only male schizophrenic patients will be studied because of the extensive safety data base in males (>400 males treated for 6 months) obtained by Eli Lilly demonstrating favorable safety and tolerability. Results of this study will determine if LY500307 should be advanced for further testing in schizophrenia.