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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：神经性疼痛是一种严重的神经系统疾病，在美国影响着大约 180 万人，标准镇痛疗法难以治愈，目前所有的神经性疼痛药物都可以缓解大约 30% 的患者。这些药物都具有显着的副作用。阿卡迪亚制药公司发现了高度选择性的雌激素受体β，但对于治疗这种严重且日益严重的疾病的新的安全有效的药物的医疗需求显然尚未得到满足。 (ER¿)-激动剂由于其对 ER¿ 的高选择性，在神经性疼痛动物模型中非常有效。，它们不会产生归因于雌激素受体α（ERa）激活的女性化副作用，并显示出候选药物的许多理想属性：没有明显的心血管倾向或致突变性风险，并且很少或没有发现药物相互作用的可能性。在接受高于最大有效剂量 10 倍剂量的大鼠中，这些化合物在人肝脏中具有良好的代谢稳定性，表明在人类中口服给药是可行的，当这些化合物在大鼠中时，它们的生物利用度很高（>70%）。因此，我们相信我们有机会开发这些化合物作为镇痛药物，在这项 U44 转化研究资助中，我们将开发 ER¿在第一阶段，我们将主导并确定它们在肝细胞中的代谢特征、它们的体内 PK 特征以及它们在口腔、表皮和肠 (Caco2) 细胞和 PK 中的渗透性特性。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有关颊/舌下和透皮给药可行性的数据我们还将在 PK 研究的同时完成遗传、心血管或药物相互作用的体外安全性筛选，并在之前进行初步的体内啮齿动物毒理学和心血管安全性研究。在 2 期 SBIR 研究中启动符合 FDA 要求的 GLP 研究，我们的目标是确定 1 个 ER¿激动剂可以口服、舌下或经皮给药，并且具有可控制的毒性，或理想情况下无毒性，包括血浆浓度至少比药理学有效浓度高 10 倍的 NOEL。在第 2 阶段，先导化合物将接受 IND。 -使毒理学、心血管和遗传毒理学研究能够为 IND 提交提供必要的支持数据，这些研究将需要 GMP 级材料，并将包括遗传毒性的体外和体内研究（Ames 试验、然后，我们将安排一次 IND 前会议。与 FDA 讨论整体开发途径并了解临床计划期间可能需要解决的关键监管问题。