Preclinical development of a tenofovir intravaginal ring for HIV prophylaxis

用于预防艾滋病毒的替诺福韦阴道环的临床前开发

• 批准号: 8140537
• 负责人: Amanda Malone
• 金额: $ 100万
• 依托单位: AURITEC PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8140537
• 关键词: Acyclovir; Adherence; Africa South of the Sahara; Animals; Anti-Retroviral Agents; Antiviral Agents; Applications Grants; Chemistry; Clinical; Clinical Trials; Communicable Diseases; Consensus; Development; Devices; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Engineering; Environment; FDA approved; Foundations; Funding; Gel; Goals; HIV; HIV Infections; HIV-1; Heterosexuals; Human; Industry; Infection; Investigational New Drug Application; Local Microbicides; Macaca; Marketing; Medical Device; Modeling; Mosses; Mus; Oral; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase III Clinical Trials; Prevention; Procedures; Process; Production; Prophylactic treatment; Research Infrastructure; Research Personnel; Safety; Sheep; Simplexvirus; Small Business Innovation Research Grant; Solubility; Sterility; Technology; Tenofovir; Testing; United States National Institutes of Health; Vaginal Ring; Woman; Work; aqueous; base; clinical lot; drug development; empowered; experience; genital herpes; improved; innovation; manufacturing facility; microbicide; pre-clinical; preclinical study; prevent; programs; safety study; scale up; sex; transmission process

DESCRIPTION (provided by applicant): Large efforts are currently underway funded by the NIH, the Gates foundation, and the WHO, to reduce the spread of HIV transmission by developing an effective microbicide. The CAPRISA trial with tenofovir gel is the first demonstration of prophylaxis against HIV and HSV using a topical microbicide. Because protection increased with increasing adherence, and because intravaginal rings (IVRs) may increase adherence, the development of a ring formulation of tenofovir is an urgent global priority. We have developed a platform technology for the sustained local release of antivirals that has led to the only FDA approved sustained-release antiviral device: the Vitrasert(R). We propose to adapt this technology to develop a sustained release IVR formulation for tenofovir. The original aim of this proposal was to develop IVRs to release acyclovir, since genital herpes co-infection significantly increases the rate of HIV transmission. The disappointing results of the Partners trial with oral acyclovir and the recent positive results for tenofovir from the CAPRISA trial in the prevention of both HSV and HIV suggested to us that tenofovir is a better drug on which to concentrate our efforts. We discussed this change with program officers at the DAIDS and with our Scientific Review Officer. It was the consensus that acyclovir should be replaced by tenofovir. In phase 1 of this proposal, we demonstrated preliminary efficacy and pharmacokinetics of acyclovir in a murine model. With work funded elsewhere, we have also completed safety and pharmacokinetic studies with rings releasing tenofovir. Efficacy studies with tenofovir rings in the macaque model are ongoing. We also fabricated human-sized rings releasing both tenofovir and acyclovir and have demonstrated safety of these rings in a sheep model. In phase 2 we propose to the work necessary to obtain an IND from the FDA for the tenofovir IVR. The specific aims of this 3 year AT-SBIR are: 1, to establish a GMP manufacturing facility for intravaginal rings; 2, to manufacture a lot sufficient to carry out pre-clinical studies under GMP; 3, to perform animal trials necessary to support an Industry Sponsored Investigational New Drug Application (IND); and 4, to manufacture lots of tenofovir drug-eluting intravaginal rings under Good Manufacturing Procedures sufficient for large scale Phase 3 clinical trials The milestones for successful completion of this proposal are the granting of an IND from the FDA, and the production of clinical trial lots sufficient for pivotal trials. PUBLIC HEALTH RELEVANCE: Each day 15,000 people are infected by HIV, the majority in sub-Saharan Africa and a growing percentage women infected though heterosexual sex. The broad long term goal of this project is to empower women to protect themselves from HIV infection through the development and manufacture of improved vaginal ring formulations for microbicides based on the sustained release drug delivery of tenofovir, the only antiretroviral that has been proven to prevent HIV transmission when used topically. Our clinically proven sustained release drug delivery platform uniquely allows us to deliver drug of both high and low aqueous solubility. We propose to utilize this platform technology to develop long-term vaginal ring formulations for the microbicide tenofovir.

描述（由申请人提供）：目前由NIH，盖茨基金会和世卫组织资助，通过开发有效的杀菌剂来减少HIV传播的传播。替诺福韦凝胶的CAPRISA试验是使用局部菌心的针对HIV和HSV的预防症的首次证明。由于保护随着依从性的增加而增加，并且由于爆内圈（IVR）可能会提高依从性，因此替诺福韦的环形表述的发展是全球的紧急优先事项。我们已经开发了一种平台技术，用于持续的抗病毒药物，这导致了唯一获得FDA批准的持续释放抗病毒装置：Vitrasert（R）。我们建议适应这项技术，以开发替诺福韦的持续释放IVR公式。该提案的最初目的是开发IVR以释放Acyclovir，因为生殖器疱疹的共感染显着提高了HIV传播的速度。在预防HSV和HIV的Caprisa试验中，对口服阿昔洛韦的合作伙伴试验的令人失望的结果以及最近对Tenofovir的阳性结果表明，Tenofovir是一种更好的药物来集中精力。我们与daid的计划官以及我们的科学审查官员讨论了这一变化。正是Acyclovir应该由Tenofovir取代的是共识。在该提案的第1阶段中，我们在鼠模型中证明了Acyclovir的初步功效和药代动力学。在其他地方资助的工作，我们还通过释放Tenofovir的指环完成了安全和药代动力学研究。在猕猴模型中使用替诺福韦环的功效研究正在进行中。我们还制造了释放Tenofovir和Acyclovir的人尺寸环，并在绵羊模型中证明了这些环的安全性。在第2阶段，我们建议从FDA获得Tenofovir IVR的IND所需的工作。这三年的AT-SBIR的具体目的是：1，建立用于丢血环的GMP制造设施； 2，制造足以在GMP下进行临床前研究； 3，进行支持的动物试验，以支持行业赞助的研究新药应用（IND）； 4，为了制造大量良好的制造程序中的替诺福韦药物的静脉内环，足以进行大规模第3期临床试验的临床试验，成功完成该提案的里程碑是从FDA授予IND的里程碑，以及FDA的IND授予，以及足以用于关键试验的临床试验批次。 公共卫生相关性：每天有15,000人感染艾滋病毒，大多数在撒哈拉以南非洲以及越来越多的妇女受到异性恋性感染的妇女。该项目的长期长期目标是，通过基于替代药物的持续释放药物的递送，通过开发和制造改良的菌心阴道环制剂来保护自己免受艾滋病毒感染，这是唯一证明是在局部使用时可预防艾滋病毒传播的唯一抗逆转录病毒。我们临床证明的持续释放药物输送平台独特地使我们能够提供高和低水溶性的药物。我们建议利用这项平台技术为微生物Tenofovir开发长期阴道表配方。