Development of Estrogen Receptor B Selective Receptor Agonists to Treat Neuropath

开发雌激素受体 B 选择性受体激动剂来治疗神经病

• 批准号: 8830501
• 负责人: ETHAN Samuel BURSTEIN
• 金额: $ 86.69万
• 依托单位: ACADIA PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2014-12-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8830501
• 关键词: Address; Adverse effects; Affect; Agonist; Ames Assay; Analgesics; Animal Model; Biological Assay; Biological Availability; Canis familiaris; Cardiovascular system; Cells; Characteristics; Chromosome abnormality; Chronic; Chung model; Clinical; Conscious; Data; Dependency; Development; Disease; Dose; Drug Interactions; Drug Kinetics; Drug Packaging; Drug Targeting; Estrogen Receptor 1; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Genetic; Genetic Screening; Goals; Grant; Hepatocyte; Human; Hyperalgesia; In Vitro; Inflammation; Intestines; Investigational Drugs; Lead; Liquid substance; Liver; Lung; Maximum Tolerated Dose; Medical; Metabolic; Metabolism; Methods; Micronucleus Tests; Modeling; Monitor; Monkeys; Motor Activity; Non-Rodent Model; Oral; Pathway interactions; Patients; Pb clearance; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma; Preclinical Testing; Property; Rattus; Refractory; Regimen; Research Project Grants; Risk; Rodent; Rodent Model; Safety; Schedule; Sedation procedure; Small Business Innovation Research Grant; Specificity; Stomach; Testing; Therapeutic; Toxic effect; Toxicogenetics; Toxicology; Translational Research; United States; animal efficacy; control trial; drug candidate; efficacy testing; genotoxicity; human subject; in vivo; meetings; micronucleus; nervous system disorder; novel; painful neuropathy; programs; receptor; safety study; safety testing; telemetering

DESCRIPTION (provided by applicant): Neuropathic pain is a serious neurological disorder affecting approximately 1.8 million people in the United States. It is refractory to standard analgesic therapies, with all current neuropathic pain drugs providing relief to approximately 30% of patients. In addition, these drugs all have significant side effects. Consequently there is a clear unmet medical need for new safe and effective drugs to treat this serious and growing disorder. Acadia Pharmaceuticals has discovered highly selective estrogen receptor beta (ER¿)-agonists that are highly efficacious in animal models of neuropathic pain. Because of their high selectivity for ER¿, they do not produce the feminizing side effects attributed to estrogen receptor alpha (ERa) activation and display many desirable attributes for a drug candidate: no apparent cardiovascular liability or mutagenicity risks, and little or no potential for drug-drug interactions. No apparent side effects were seen in rats receiving doses 10x above maximally effective doses. These compounds have good metabolic stability in human liver, suggesting oral dosing in humans is feasible. Further, their bioavailability in rats is high (>70%) when the compounds are given sublingually. Thus we believe we have several opportunities to develop these compounds as analgesic drugs. In this U44 Translational Research grant we will develop ER¿ agonists as clinical candidates for treating neuropathic pain. In Phase 1, we will take leads, and determine their metabolic profiles in hepatocytes, their in vivo PK characteristics, and their permeability properties across buccal, epidermal, and intestinal (Caco2) cells. The metabolism and PK studies will allow us to predict the bioavailability in humans, and feasibility of oral dosing, while the permeability studies will provide data on the feasibility of buccal/sublingual and transdermal dosing. We will also complete in vitro safety screens for genetic, cardiovascular, or drug-drug interaction liabilities in parallel to the PK studies. We will take the compound with the best overall profile and conduct preliminary in vivo rodent toxicology and cardiovascular safety studies before initiating FDA-compliant GLP studies in Phase 2 SBIR studies. Our goal is to identify 1 ER¿ agonist that can be administered to humans orally, sublingually or transdermally and that has manageable, or ideally no toxicity, including a NOEL at plasma concentrations at least 10-fold above pharmacologically effective concentrations. In Phase 2, the lead compound will be subject to IND-enabling toxicology, cardiovascular and genetic toxicology studies to provide the necessary supporting data for an IND submission. These studies will require GMP-grade material and will include in vitro and in vivo studies for genetic toxicity (Ames assay, chromosomal aberration assay, rat micronucleus), cardiovascular toxicity (hERG channel inhibition, cardiovascular monitoring in conscious, telemetered dogs or monkeys) and repeat dose toxicity studies for 28 days in rodent and non-rodent models. We will then schedule a pre-IND meeting with FDA to discuss the overall development pathway and understand key regulatory issues that may need to be addressed during the clinical program.

描述(申请人提供)：神经性疼痛是一种严重的神经系统疾病，在美国大约有180万人受到影响。它对标准的止痛治疗是难治的，目前所有的神经病理性止痛药都能缓解大约30%的患者。此外，这些药物都有明显的副作用。因此，对于治疗这一严重和日益严重的疾病的新的、安全和有效的药物，显然存在尚未得到满足的医疗需求。Acadia制药公司已经发现了高度选择性的雌激素受体β(ER)激动剂，它们在神经病理性疼痛的动物模型中非常有效。由于它们对ER的高度选择性，它们不会产生由于雌激素受体α(ERA)激活而产生的女性化副作用，并显示出候选药物的许多理想属性：没有明显的心血管易感性或突变风险，以及很少或根本没有药物相互作用的可能性。在接受超过最大有效剂量10倍的剂量的大鼠中，没有看到明显的副作用。这些化合物在人体肝脏中具有良好的代谢稳定性，提示人体口服给药是可行的。此外，当这些化合物舌下给药时，它们在老鼠体内的生物利用度很高(70%)。因此，我们相信我们有几个机会来开发这些化合物作为止痛药。在这项U44翻译研究拨款中，我们将开发ER？激动剂作为治疗神经病理性疼痛的临床候选药物。在第一阶段，我们将带头，并确定它们在肝细胞中的代谢情况，它们在体内的PK特征，以及它们对口腔、表皮和肠道(Caco 2)细胞的通透性。代谢和PK研究将使我们能够预测人体的生物利用度，以及口服给药的可行性，而渗透性研究将提供口腔/舌下和经皮给药的可行性数据。在PK研究的同时，我们还将完成遗传、心血管或药物-药物相互作用风险的体外安全筛查。我们将选择总体情况最好的化合物，并在体内进行初步的啮齿动物毒理学和心血管安全性研究，然后在第二阶段SBIR研究中启动符合FDA的GLP研究。我们的目标是确定一种可口服、舌下或经皮给药且毒性可控或理想情况下没有毒性的ER？激动剂，包括血浆浓度至少是药理有效浓度10倍的NOEL。在第二阶段，将对先导化合物进行支持IND的毒理学、心血管和遗传毒理学研究，为IND提交提供必要的支持数据。这些研究将需要GMP级材料，并将包括体外和体内遗传毒性(Ames试验、染色体畸变试验、大鼠微核)、心血管毒性(HERG通道抑制、清醒、遥测狗或猴子的心血管监测)以及啮齿动物和非啮齿动物模型的重复剂量毒性研究，为期28天。然后，我们将与FDA安排一次IND前会议，讨论总体开发途径，并了解在临床计划期间可能需要解决的关键监管问题。