IND-enabling preclinical development of a multipurpose intravaginal ring for the prevention of Herpes, HIV and unintended pregnancy

用于预防疱疹、艾滋病毒和意外怀孕的多用途阴道环的临床前开发，可用于 IND 临床前开发

• 批准号: 10378141
• 负责人: Thomas J. Smith
• 金额: $ 46.2万
• 依托单位: AURITEC PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378141
• 关键词: AIDS prevention; Acyclovir; Agreement; Animals; Anti-Retroviral Agents; Antiviral Agents; Authorization documentation; Biological Assay; Biometry; Chemistry; Clinical; Clinical Protocols; Clinical Trials; Collaborations; Contraceptive Agents; Contracts; Development; Devices; Drug Delivery Systems; Drug Kinetics; Engineering; Ensure; Environment; Ethinyl Estradiol; Etonogestrel; FDA approved; Female of child bearing age; Formulation; Fumarates; Funding; Goals; Grant; HIV; HIV Infections; Herpesviridae Infections; Hormones; Human; In Vitro; Infection; Infectious Pregnancy Complications; Lead; Licensing; Macaca; Marketing; Oryctolagus cuniculus; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Prevention; Process; Research Personnel; Resources; Safety; Sheep; Simplexvirus; Solubility; Technology; Tenofovir; Testing; Time; Translations; Unwanted pregnancy; Vaginal Ring; Validation; Woman; Women' s Health; Work; analytical method; aqueous; base; clinically relevant; commercialization; drug development; emtricitabine; experience; first-in-human; genital herpes; hormonal contraception; in vivo; innovation; manufacturing process development; material transfer agreement; novel; pre-clinical; pre-exposure prophylaxis; preclinical development; safety study; sheep model; success; systemic toxicity; truvada; unintended pregnancy

SUMMARY The broad, long-term goal is to empower women to protect themselves from HIV and herpes infections, and unintended pregnancy through the development of a monthly intravaginal ring (IVR) formulation. The IVR utilizes our proprietary Versa™ technology that enables simultaneous, sustained release of the antiretrovirals of Truvada® (tenofovir disoproxil fumarate-emtricitabine combination) for HIV pre-exposure prophylaxis, an antiviral, acyclovir, for prevention and treatment of herpes and; the hormonal contraceptives of the Nuvaring® (etonogestrel-ethinyl estradiol) for the prevention of unintended pregnancy. These drugs have been tested in our IVR technology in vitro and in vivo. We now propose the translation of this work to our pod-based™ IVR technology to utilize an achievable regulatory approach for approval of multipurpose prevention IVRs. This RFA-AI-16-085 provides Auritec with a unique opportunity to perform both, mid-stage and late-stage translational work through a milestone-driven IND-enabling approach that will further the development of an IVR-based MPT for the prevention of both HIV and HSV infections, and unintended pregnancies. In the R61 Phase of this grant, we propose the following mid-stage translational specific aims: 1) to develop small scale, “exploratory” GMP manufacturing capacity for the lead formulations; 2) to perform a non-GLP safety and PK study in the standard sheep model. The milestone for the successful completion of the R61 Phase is the demonstration of safety and clinically relevant pharmacokinetics in the non-GLP sheep study. The R33 Phase comprises the following late-stage translational specific aims: 3) to conduct an IND-enabling GLP-compliant safety study in a sheep model to examine local/systemic toxicity; 4) to perform manufacturing process development, including product testing assays and early validation; 5) to transfer manufacturing and analytical methods to a contract manufacturing organization; 6) to perform IND-enabling chemistry, manufacturing and controls (CMC) activities for three IND submissions; 7) to coordinate all activities to submit three IND applications to the FDA The milestones for the successful completion of the R33 Phase of this proposal is the submission of three IND applications (TDF-FTC pods, ACV pods and ETG-EE pods) to the FDA to perform first-in-human exploratory clinical trials. Following successful completion of this proposal we will carry out the clinical protocols to demonstrate safety and pharmacokinetics for the three rings. Further funding from granting agencies will be sought at that point but licensing to a corporate partner with the resources to ensure ultimate approval and commercialization will also be actively pursued. The development of these ring could provide women of child bearing age, for the first time, a women-controlled dual protection against unwanted pregnancy, genital herpes, and HIV infection.

总结 广泛的长期目标是增强妇女保护自己免受艾滋病毒和疱疹感染的能力， 通过开发每月一次的阴道环（IVR）制剂来预防意外妊娠。所述IVR 利用我们专有的Versa™技术，可同时持续释放抗逆转录病毒药物 Truvada®（替诺福韦酯-恩曲他滨复方制剂）用于HIV暴露前预防， 抗病毒药物，阿昔洛韦，用于预防和治疗疱疹; Nuvaring®的激素避孕药 （依托孕烯-乙炔雌二醇）用于预防意外怀孕。这些药物已经在 我们的体外和体内IVR技术。我们现在建议将这项工作翻译为我们的基于pod-based™ IVR 利用可实现的监管方法批准多用途预防IVRs的技术。 该RFA-AI-16-085为Auritec提供了一个独特的机会来执行中期和后期 通过里程碑驱动的IND使能方法开展翻译工作， 基于IVF的MPT用于预防HIV和HSV感染以及意外怀孕。 在R61阶段，我们提出了以下中期转化的具体目标： 1)开发先导制剂的小规模、“探索性”GMP生产能力; 2)在标准绵羊模型中进行非GLP安全性和PK研究。 成功完成R61阶段的里程碑是证明了安全性和临床 非GLP绵羊研究中的相关药代动力学。 R33阶段包括以下后期翻译具体目标： 3)在绵羊模型中进行IND使能GLP合规性安全性研究，以检查局部/全身毒性; 4)进行生产工艺开发，包括产品测试和早期验证; 5)将生产和分析方法转移给合同生产组织; 6)为三份IND申请开展IND支持化学、生产和控制（CMC）活动; 7)协调向FDA提交三份IND申请的所有活动 成功完成本提案R33阶段的里程碑是提交三份IND 向FDA提交申请（TDF-FTC pod、ACV pod和ETG-EE pod），以进行首次人体探索性试验 临床试验 在成功完成本提案后，我们将执行临床方案，以证明安全性和 三环的药代动力学。届时将向拨款机构寻求更多资金， 授权给有资源的公司合作伙伴，以确保最终批准和商业化， 积极追求。这些戒指的开发可以首次为育龄妇女提供， 由女性控制的双重保护，防止意外怀孕、生殖器疱疹和艾滋病毒感染。