Tolerability of SRX246 in Huntington's Disease Patients

SRX246 在亨廷顿病患者中的耐受性

基本信息

批准号：
8977056
负责人：
Michael J Brownstein
金额：
$ 111.52万
依托单位：
AZEVAN PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8977056
关键词：
Adenine Adverse effects Affinity Aggressive behavior Attention Behavior Behavior assessment Blood - brain barrier anatomy Brain Caregiver Burden Caregivers Clinical Clinical Investigator Clinical Treatment Clinical Trials Contracts Cytosine Data Data Analyses Databases Disease Distress Documentation Dose Double-Blind Method Drug Kinetics Drug usage Enrollment Equipment and supply inventories Exhibits Family member Fright Functional Magnetic Resonance Imaging Future GMP lots Goals Guanine Health Human Resources Huntington Disease Inherited Institutional Review Boards Institutionalization Life Measures Medicine Moods Multicenter Studies National Institute of Neurological Disorders and Stroke Neurologist Oral Oral Administration Orphan Drugs Patients Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Phase II Clinical Trials Placebo Control Placebos Preparation Principal Investigator Problem behavior Protocols documentation Quality of life Randomized Reporting Safety Secure Site Visit Small Business Innovation Research Grant Stimulus Structure Symptoms Testing Therapeutic Agents Training United States National Institutes of Health Vasopressins Wit Work arm base capsule data sharing design diaries drug efficacy effective therapy experience follow-up healthy volunteer human Huntingtin protein meetings neuropsychiatry novel novel therapeutics patient population phase II trial phase III trial polyglutamine pre-clinical programs receptor research study response

项目摘要

DESCRIPTION (provided by applicant): Huntington's Disease (HD) is an inherited disease that results from expansion of a trinucleotide (CAG, cytosine/adenine/guanine) repeat that encodes a polyglutamine tract in the huntingtin protein. Psychiatric symptoms, including irritability and aggression, are common in HD patients. These are among the most distressing aspects of the disease. They have adverse effects on daily life and often result in institutionalization. Despite the frequent occurrence and severe consequences of irritability and aggression in HD, these symptoms have received little attention to date. Effective treatments are lacking and well-validated scales for measuring changes in these symptoms are not available. Faced with a significant unmet need, neurologists cannot currently determine whether new drug therapies might be useful in treating neuropsychiatric symptoms in HD. The Phase II clinical trial we propose in HD patients (n=108)," A randomized, placebo controlled, double blind, multi-center study to assess the tolerability of SRX246 in irritable/aggressive subjects wit Huntington's Disease (HD)," will allow us to rigorously evaluate the tolerability of a potential ne drug for the treatment of irritability and aggression. It will also provide additional safety data n the compound and explore various rating scales for the assessment of changes in these symptoms. Thus, we will obtain critical data that can be used to plan future Phase II or III clinicl trials of drugs that might blunt irritability and aggression in HD. The compound that we propose to test is SRX246, a first-in-class vasopressin 1a (V1a) receptor antagonist. SRX246 crosses the blood-brain barrier following oral administration, exhibits high affinity and selectivity for is target receptor, has a strong safety profile, is well-tolerated in healthy volunteers, and has excellent pharmacokinetics. Extensive preclinical pharmacology studies and an experimental medicine fMRI study in healthy volunteers have shown that SRX246 has CNS effects after oral administration and that it modulates brain circuits involved in responses to stimuli that elicit aggression/fear. These findings strongly suggest that SRX246 might have a beneficial effect on the irritability and aggression seen in a sizable proportion of HD patients. The proposed project will generate data needed to plan a future clinical trial that can rigorously test SRX246 for efficacy as a treatment for irritability and aggression.

描述（由申请人提供）：亨廷顿病（HD）是一种遗传性疾病，由编码亨廷顿蛋白中的聚谷氨酰胺链的三核苷酸（CAG，胞嘧啶/腺嘌呤/鸟嘌呤）重复序列扩增引起，包括精神症状，包括烦躁和攻击性。这些是 HD 患者最令人痛苦的方面之一，尽管发生频繁且后果严重，但它们对日常生活产生了不利影响。迄今为止，这些症状很少受到关注，并且缺乏有效的治疗方法来衡量这些症状的变化。面对严重的未满足的需求，神经科医生目前无法确定是否有新的药物疗法。我们建议在 HD 患者 (n=108) 中进行的 II 期临床试验可能有助于治疗 HD 患者的神经精神症状”，这是一项随机、安慰剂对照、双盲、多中心研究，旨在评估 SRX246 在 HD 患者中的耐受性。患有亨廷顿病 (HD) 的易激惹/攻击性受试者”，将使我们能够严格评估一种潜在的新药物用于治疗易激惹和攻击性的耐受性。它还将提供该化合物的额外安全性数据，并探索对不同等级的评估因此，我们将获得可用于计划未来可能减轻 HD 烦躁和攻击性的药物的 II 期或 III 期临床试验的关键数据。 SRX246 是一种一流的加压素 1a (V1a) 受体拮抗剂，口服后可穿过血脑屏障，对目标受体具有高亲和力和选择性，具有很强的安全性，在健康志愿者中具有良好的耐受性。，并具有优异的药代动力学研究和在健康志愿者中进行的实验医学 fMRI 研究表明，SRX246 口服后具有 CNS 作用，并且它具有中枢神经系统作用。调节涉及引起攻击性/恐惧的刺激反应的大脑回路。这些发现强烈表明，SRX246 可能对相当大比例的 HD 患者出现的烦躁和攻击性产生有益的影响。拟议的项目将生成规划未来所需的数据。可以严格测试 SRX246 治疗烦躁和攻击行为的功效的临床试验。