Clinical safety and pharmacokinetic studies of intravaginal rings releasing multiple antiretrovirals

阴道环释放多种抗逆转录病毒药物的临床安全性和药代动力学研究

• 批准号: 9047287
• 负责人: Thomas J. Smith
• 金额: $ 63.73万
• 依托单位: AURITEC PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9047287
• 关键词: African; Agreement; Animal Model; Animals; Anti-Retroviral Agents; Antiviral Agents; Cessation of life; Chemistry; Clinical; Clinical Research; Clinical Trials; Collaborations; Colposcopy; Consensus; Data; Data Analyses; Development; Devices; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Engineering; Environment; FDA approved; Formulation; Fumarates; Funding; Ganciclovir; Goals; Grant; HIV; Health; Highly Active Antiretroviral Therapy; Human; Implant; Investigational Drugs; Lead; Licensing; Liquid substance; Macaca; Malaria; Manufacturer Name; Marketing; Measurement; Minor; National Institute of Allergy and Infectious Disease; New Drug Approvals; Oryctolagus cuniculus; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma; Population; Prevention; Procedures; Process; Qualifying; Research Personnel; Resistance; Safety; Sheep; Small Business Innovation Research Grant; Solubility; Tenofovir; Testing; Time; Tissues; Tuberculosis; Ultrasonography; Vaginal Ring; Work; World Health; aqueous; base; controlled release; cytokine; drinking water; drug development; emtricitabine; experience; human study; in vitro testing; in vivo; inhibitor/antagonist; innovation; local drug delivery; material transfer agreement; microbicide; microbiome; novel; phase 3 study; phase III trial; pre-clinical; prevent; programs; research clinical testing; scale up; simian human immunodeficiency virus; transmission process; truvada; volunteer

 DESCRIPTION (provided by applicant): The goal of this project is to prevent HIV transmission. Using the drug delivery platform that we developed for the ganciclovir intraocular implant, Vitrasert(r), we propose to develop an intra-vaginal ring (IVR) releasing the antiretrovirl agents tenofovir, emtricitabine and maraviroc. This drug combination has been chosen for potency, synergistic action, and the prevention of resistance. The rationale for the choice of tenofovir and emtricitabine is very strong: these are the drugs in Truvada(r) and have demonstrated efficacy in clinical studies of HIV transmission. Maraviroc has demonstrated protection against SHIV transmission in macaques. Funded in part by R21, R33, and SBIR grants from the NIAID, we have successfully adapted the Vitrasert(r) platform and safely delivered multiple antiretrovirals in multiple animal models. The goal of Phase I of this SBIR project was to perform the necessary pre-clinical work for allowance of an FDA Investigational New Drug Exemption (IND) to test this formulation in a clinical study. This milestone has been achieved: IND 123099 has been allowed by the FDA. The goal of this Phase II SBIR proposal is to carry out this first in human study. Rings releasing single drugs and combinations will be worn by normal volunteers for 7 days. Safety will be determined by colposcopy and a novel ultrasound procedure which we pioneered, as well as cytokine measurements and assessments of the microbiome. Pharmacokinetics will be determined by measurement over time in local tissues and fluids, as well as in plasma. On completion of the 7 day study there will be a washout period and the data will be presented to the FDA. If there are no safety concerns after wearing the ring for 7 days, the study will be repeated over a 28 day period. Subsequent SBIR Phase III studies are planned in African populations. The development of an effective microbicide IVR could save millions of lives per year and is therefore highly significant. We believe we are uniquely qualified to develop such a product and that our rings demonstrate dramatic improvement over the current state of the art. The team of investigators is expert in chemistry, pharmacokinetics, engineering, gynecological clinical trials and drug development, and we have experience in all aspects of the drug development process, from concept to approval and marketing. The milestone of this proposal will be the successful completion of this clinical trial demonstrating safety and local delivery of the drug sufficient to merit further clincal trials in pursuit of FDA approval and clinical implementation. The successful completion of this work will be followed by studies and programs to manufacture these rings on a large scale and perform the clinical trials necessary for ultimate approval. As the developers of the only FDA approved sustained release antiviral delivery device we believe we are uniquely qualified to carry out such an ambitious program.

 描述（由申请人提供）：该项目的目标是预防艾滋病毒传播。利用我们为更昔洛韦眼内植入物 Vitrasert(r) 开发的药物输送平台，我们建议开发一种阴道内环 (IVR)，释放抗逆转录病毒药物替诺福韦、恩曲他滨和马拉韦罗。选择这种药物组合是为了发挥效力、协同作用和预防耐药性。选择替诺福韦和恩曲他滨的理由非常充分：这些是 Truvada(r) 中的药物，并且已在 HIV 传播的临床研究中证明了疗效。 Maraviroc 已证明可以防止猕猴中的 SHIV 传播。在 NIAID 的 R21、R33 和 SBIR 拨款的部分资助下，我们成功地采用了 Vitrasert(r) 平台，并在多种动物模型中安全地提供了多种抗逆转录病毒药物。该 SBIR 项目第一阶段的目标是进行必要的临床前工作，以获得 FDA 新药研究豁免 (IND) 的许可，以便在临床研究中测试该配方。这一里程碑已经实现：IND 123099 已获得 FDA 批准。第二阶段 SBIR 提案的目标是首先在人类研究中开展这一工作。释放单一药物和组合药物的戒指将由正常志愿者佩戴 7 天。安全性将通过阴道镜检查和我们首创的新型超声程序以及细胞因子测量和微生物组评估来确定。药代动力学将通过对局部组织和体液以及血浆中一段时间​​的测量来确定。 7 天的研究完成后，将有一个清洗期，数据将提交给 FDA。如果佩戴戒指 7 天后没有出现安全问题，该研究将在 28 天内重复进行。随后的 SBIR III 期研究计划在非洲人群中进行。开发有效的杀菌剂 IVR 每年可以挽救数百万人的生命，因此意义重大。我们相信我们具有开发此类产品的独特资格，并且我们的戒指比当前的技术水平表现出巨大的进步。研究人员团队是化学、药代动力学、工程、妇科临床试验和药物开发方面的专家，我们在药物开发过程的各个方面（从概念到批准和营销）都有丰富的经验。该提案的里程碑将是该临床试验的成功完成，证明该药物的安全性和局部递送足以值得进一步的临床试验，以寻求 FDA 的批准和临床实施。这项工作成功完成后，将进行大规模制造这些环的研究和计划，并进行最终批准所需的临床试验。作为 FDA 唯一批准的缓释抗病毒输送装置的开发商，我们相信我们有独特的资格来执行如此雄心勃勃的计划。