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

缓释 Pritelivir 阴道环用于治疗和预防女性生殖器疱疹的 IND 临床前开发

• 批准号: 9906167
• 负责人: Thomas J. Smith
• 金额: $ 100万
• 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: 2018-02-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906167
• 关键词: Acquired Immunodeficiency Syndrome; Acyclovir; Affect; American; Animal Model; Animals; Antiviral Agents; Biological Assay; Characteristics; Chemistry; Clinical; Clinical Trials; Colorado; Communicable Diseases; Contracts; Cytomegalovirus Retinitis; Development; Dose; Drug Delivery Systems; Drug Kinetics; Engineering; Environment; FDA approved; Formulation; Ganciclovir; Goals; Grant; Guidelines; Hematology; Implant; Infection; Investigational Drugs; Investigational New Drug Application; Laboratories; Laboratory Research; Lead; Licensing; Life; Liquid substance; Local Therapy; Marketing; Methods; Modeling; New Drug Approvals; Pain; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase II Clinical Trials; Process; Prophylactic treatment; Recurrence; Regulatory Affairs; Research Personnel; Safety; Sheep; Simplexvirus; Small Business Innovation Research Grant; Synthesis Chemistry; Systemic Therapy; Technology; Tenofovir; Testing; Therapeutic; Time; Tissues; Topical application; Toxic effect; United States National Institutes of Health; Universities; Vaginal Ring; Validation; Woman; Work; analytical method; base; cervicovaginal; clinical development; clinical lot; clinically relevant; drug candidate; drug development; emtricitabine; experience; first-in-human; genital herpes; helicase; improved; in vitro testing; in vivo; in vivo evaluation; inhibitor/antagonist; innovation; interest; manufacturing process development; novel; novel therapeutics; pre-clinical; pre-exposure prophylaxis; preclinical development; preclinical trial; protocol development; research clinical testing; safety study; surgical research; systemic toxicity; vaginal mucosa; volunteer

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.

摘要(带下划线的更改) 该项目广泛的、长期的目标是开发一种普列利韦阴道内环(IVR)，用于治疗和治疗 暴露前预防生殖器疱疹，这是一个影响5000多万美国人的常见问题。 复发是很常见的，而且可能会很痛苦。感染是终生的。普利昔韦是一种很有前途的α解旋酶抑制剂 在第二阶段临床试验中，这被证明优于现有的治疗方法，但其临床开发是 由于毒性，系统性治疗已被叫停。因此，局部治疗具有特殊的意义。 我们已经开发了一种用于抗病毒药物持续释放的平台技术。这项技术导致了 治疗艾滋病相关巨细胞病毒的更昔洛韦眼内埋植剂Vitrasert®的研制 视网膜炎。Vitrasert®是唯一获得美国食品和药物管理局批准的缓释抗病毒药物 美国食品和药物管理局。我们已经将这一平台改造为静脉注射受体，并成功地在以下地点提供了其他抗病毒药物 临床前和临床试验中的治疗水平。我们建议利用这个平台来发展可持续发展 释放普利昔韦的IVR制剂。我们实现了这项建议第一阶段的具体目标，即 制备普利韦阴道缓释环，考察其体外释药特性 这些配方，并在FDA中测试这些配方的体内安全性和药代动力学(PK)- 批准的绵羊模型。第一阶段的成功完成使我们能够确定 进一步开发安全的药物产品，显示出令人满意的持续释放28天 宫颈阴道液和组织药物水平，将提供高潜在的疗效。 因此，我们建议在第二阶段完成食品和药物管理局规定的科学和管理活动 启用研究新药(IND)审批所必需的。我们建议发展GMP制造业 临床批量生产铅制剂的能力；进行为期3个月的GLP、Ind-Enabling安全性研究 绵羊模型，用于检查扩大IVR使用的局部和全身毒性；执行制造过程 开发，包括产品测试分析和早期验证；转移制造和分析 方法提供给合同制造组织；执行支持Ind的化学、制造和 控制(CMC)提交IND的活动；完成并提交所有临床文件；以及 协调所有活动，向FDA提交IND申请。圆满完成的里程碑 拟议的第二阶段工作是批准IND进行第一次人类探索性临床试验。在……里面 在这笔赠款的IIB阶段，我们将在HSV+VE志愿者身上测试铅配方的安全性、PK和有效性。这个 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实现新技术的经验 新药给药系统的药物批准(NDA)。这一项目可能会迅速导致 一种改进的生殖器疱疹治疗和预防。