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

摘要 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，以及 通过每月开发阴道内环(IVR)配方意外怀孕。IVR 利用我们专有的Versa™技术，可以同时、持续地释放抗逆转录病毒药物 特鲁瓦达®(富马酸替诺福韦双丙酯-恩曲他滨联合)用于HIV暴露前预防，以及 用于预防和治疗疱疹的抗病毒药物阿昔洛韦；Nuvering®的激素避孕药 (雌二醇)用于预防意外怀孕。这些药物已经在美国进行了测试 我们的体外和体内IVR技术。我们现在建议将这项工作转换到我们基于Pod的™IVR 利用可实现的监管办法批准多用途预防性IVR的技术。 此RFA-AI-16-085为Auritec提供了一个独特的机会，可以同时执行中期和后期 通过里程碑驱动的支持IND的方法进行翻译工作，这将进一步开发 以IVR为基础的MPT，用于预防艾滋病毒和HSV感染以及意外怀孕。 在这笔赠款的R61阶段，我们提出了以下中期翻译具体目标： 1)发展小规模、“探索性”的铅制剂GMP制造能力； 2)在标准绵羊模型上进行非GLP安全性和PK研究。 R61阶段的成功完成的里程碑是安全性和临床应用的证明 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特定目标： 3)在绵羊模型中进行符合IND的GLP安全性研究，以检查局部/全身毒性； 4)进行制造工艺开发，包括产品测试分析和早期验证； 5)将制造和分析方法转让给合同制造组织； 6)为三份IND提交的材料开展支持IND的化学、制造和控制(CMC)活动； 7)协调所有活动，向FDA提交三份IND申请 成功完成本提案R33阶段的里程碑是提交三个IND 向FDA申请(TDF-FTC Pod、ACV Pod和ETG-EE Pod)进行首次人类探索 临床试验。 在成功完成这项提案后，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进一步的资助，但 将许可证授予拥有资源以确保最终批准和商业化的企业合作伙伴也将 被积极追查。这些环的开发可以第一次为育龄妇女提供 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。

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.