IND-enabling preclinical development of a sustained-release Pritelivir intravaginal ring for the treatment and prophylaxis of Genital Herpes in women

摘要（修改部分加下划线） 该项目的广泛的长期目标是开发一种用于治疗和治疗前列腺癌的pritelivir阴道环（IVR）， 生殖器疱疹是一种常见的问题，影响着5000多万美国人。 复发是常见的，可能是痛苦的。感染是终身的。Pritelivir是一种很有前途的α-解旋酶抑制剂 在2期临床试验中证明上级现有疗法，但其临床开发作为一种 全身治疗由于毒性而停止。因此，局部治疗具有特殊意义。 我们开发了一种平台技术，用于持续释放抗病毒药物。这项技术导致了 开发更昔洛韦眼内植入物- Vitrasert®，用于治疗艾滋病相关的巨细胞病毒 视网膜炎Vitrasert®是唯一一种获得美国FDA批准的缓释抗病毒药物递送产品。 FDA.我们已经将该平台应用于IVRs，并成功地将其他抗病毒药物输送到 临床前和临床试验中的治疗水平。我们建议利用这一平台， 发布普利韦的IVR制剂。我们已达致这项建议第一阶段的具体目标， 配制缓释阴道环递送普雷特利韦，以测试普雷特利韦的体外释放特性， 这些制剂，并在FDA中测试制剂的体内安全性和药代动力学（PK）。 绵羊模型第一阶段的成功完成使我们能够确定IVR剂量， 进一步开发了一种安全的药物产品，证明在令人满意的条件下持续释放28天， 宫颈阴道液和组织药物水平，将提供高的潜在疗效。 因此，我们建议在第二阶段完成FDA规定的科学和监管活动 申请新药临床试验（IND）批准。我们建议发展GMP生产 先导制剂临床批次的能力;在一项为期3个月的GLP、IND使能安全性研究中， 绵羊模型，以检查延长IVR使用的局部和全身毒性;执行生产工艺 开发，包括产品测试和早期验证;转移生产和分析 合同制造组织的方法;执行IND使能化学、制造和 IND提交的CMC活动;完成并提交所有临床文件;以及 协调向FDA提交IND申请的所有活动。成功完成的里程碑 拟议的II期工作是批准IND进行首次人体探索性临床试验。在 在本研究的IIB期，我们将在HSV+ve志愿者中测试先导制剂的安全性、PK和疗效。的 研究团队是药物开发、合成化学、药代动力学和临床方面的专家。 传染病我们有与大型制药公司合作的经验， 新药物递送系统的药物批准（NDA）。该项目可能会迅速导致 一种改进的生殖器疱疹的治疗和预防方法。

SUMMARY (changes are underlined) The broad, long-term goal of this project is to develop a pritelivir intravaginal ring (IVR) for the treatment and pre-exposure prophylaxis of genital herpes, a common problem that affects more than 50 million Americans. Recurrences are common and may be painful. Infection is life-long. Pritelivir is a promising α-helicase inhibitor that proved superior to existing therapies in Phase 2 clinical trials, but whose clinical development as a systemic therapy has been arrested because of toxicity. Local therapy is therefore of special interest. We have developed a platform technology for the sustained release of antivirals. This technology led to the development of a ganciclovir intraocular implant - Vitrasert®, for the treatment of AIDS-related cytomegalovirus retinitis. The Vitrasert® is the only sustained release antiviral drug delivery product to be ever approved by the FDA. We have adapted this platform to IVRs and have successfully delivered other antiviral agents at therapeutic levels in preclinical and clinical trials. We propose to utilize this platform to develop sustained release IVR formulation for pritelivir. We achieved the specific aims of Phase I of this proposal which were to formulate sustained release intravaginal rings delivering pritelivir, to test the in vitro release characteristics of these formulations, and to test the in vivo safety and pharmacokinetics (PK) of the formulations in the FDA- approved sheep model. The successful completion of Phase I has enabled us to identify an IVR dose for the further development of a drug product that is safe, demonstrates sustained release for 28 days at satisfactory cervicovaginal fluid and tissue drug levels that will provide high potential efficacy. We, therefore, propose in Phase II to accomplish the FDA-mandated scientific and regulatory activities required to enable an Investigational New Drug (IND) approval. We propose to develop GMP manufacturing capacity for clinical lots of the lead formulation; to conduct a 3-month GLP, IND-enabling safety study in a sheep model to examine local and systemic toxicity of extended IVR use; to perform manufacturing process development, including product testing assays and early validation; to transfer manufacturing and analytical methods to a contract manufacturing organization; to perform IND-enabling chemistry, manufacturing and controls (CMC) activities for an IND submission; to complete and submit all clinical documents; and to coordinate all activities to submit an IND application to the FDA. The milestone for the successful completion of the proposed Phase II work is the approval of an IND to perform a first-in-human exploratory clinical trial. In Phase IIB of this grant, we will test the lead formulation for safety, PK and efficacy in HSV+ve volunteers. The team of investigators is expert in drug development, synthetic chemistry, pharmacokinetics, and clinical infectious disease. We have experience in collaborating with large pharmaceutical companies to enable New Drug Approvals (NDAs) of novel drug delivery systems. This project could lead rapidly to the development of an improved treatment and prophylaxis for genital herpes.