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

描述(由申请人提供)：精神分裂症是一种破坏性的精神疾病，影响着世界上大约1%的人口，并与大量未得到满足的医疗需求有关。消极症状(例如，情感表达和社会行为受限)和认知障碍(例如，工作和言语记忆)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残疾。这两个症状领域对批准的精神分裂症治疗相对反应迟钝，这促使人们将重点放在寻找新的靶点和开发针对这些症状复合体的新疗法上。有几项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，包括子宫癌的易感性，以及男性的心脏病和女性化效应。选择性雌激素受体β(ERβ)激动剂是一类新的治疗方法，它相对没有雌激素的主要副作用，但在大脑中表现出雌激素样的作用，包括改善认知能力和与极端的社会行为相联系。因此，这些药物可能对精神分裂症的认知和阴性症状有治疗作用。该应用的主要目标是确定选择性ERβ激动剂LY500307是否显著改善精神分裂症患者的阴性和认知症状。次要目标包括使用功能磁共振成像评估LY500307在工作和情景记忆任务中对脑血流的影响，以及听觉感觉加工和工作记忆的电生理指标。在试验的第一阶段(申请的第一年)，将使用单一的无缝1b/2a阶段适应性设计来评估两剂LY500307剂(25毫克/天和75毫克/天)，以确定哪一剂应该提前到第二阶段(申请的第二年和第三年)，或者是否应该停止试验。进行/不进行条件 确定进展到第二阶段是：1)在三个认知和阴性症状主要终点中至少一个检测到阳性信号，以及2)未能从基线水平降低睾酮水平，这反映了保持对ERβ的选择性。在第一阶段，30名精神分裂症患者将被随机(1：1：1)服用两种剂量的LY500307或安慰剂中的一种，进行为期8周的抗精神病药物附加试验。如果符合GO/NO GO标准，60名患者将在试验的第二阶段随机(1：1)接受“获胜”的LY500307剂量或安慰剂治疗。目前，只有男性精神分裂症患者将被研究，因为礼来公司获得了广泛的男性安全性数据库(&GT；400名男性，治疗6个月)，显示出良好的安全性和耐受性。这项研究的结果将决定LY500307是否应该提前用于精神分裂症的进一步测试。

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.