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（变化是下划线的） 该项目的广泛长期目标是为治疗和 生殖器疱疹的暴露前预防，这是一个常见的问题，影响了超过5000万美国人。 复发很常见，可能很痛苦。感染是终身。 pritelivir是一种承诺的α-螺旋酶抑制剂 事实证明，这比第二阶段临床试验中的现有疗法优于现有疗法，但其临床发展是 由于毒性，全身治疗已被捕。因此，局部疗法具有特殊的兴趣。 我们已经开发了一种平台技术，用于持续释放抗病毒药。这项技术导致了 Ganciclovir的开发眼内植入物-VITRASERT®用于治疗与艾滋病相关的巨型病毒 视网膜炎。 Vitrasert®是唯一持续释放的抗病毒药物输送产品 FDA。我们已经将该平台适应IVR，并成功地交付了其他抗病毒剂 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持续的 释放Pritelivir的IVR公式。我们实现了本提案第一阶段的具体目标 配制的持续释放室内环提供了pritelivir，以测试体外释放特征 这些公式，并测试FDA-公式的体内安全和药代动力学（PK） 批准的绵羊模型。第一阶段的成功完成使我们能够确定IVR剂量 进一步开发安全的药品，表明满意的持续释放28天 宫颈阴道流体和组织药物水平将提供高潜在的效率。 因此，我们在第二阶段提出的提议要完成FDA规定的科学和监管活动 需要进行研究新药（IND）批准。我们建议开发GMP制造 临床铅配方的临床能力；进行3个月的GLP，在A 检查延长IVR使用的局部和全身毒性的绵羊模型；执行制造过程 开发，包括产品测试和早期验证；转移制造和分析 合同制造组织的方法；执行辅助化学，制造和 对IND提交的控制（CMC）活动；完成并提交所有临床文件；然后 协调所有活动，以向FDA提交IND申请。成功完成的里程碑 拟议的II期工作是IND的批准，以进行首次人类探索性临床试验。在 该赠款的IIB期，我们将测试HSV+VE志愿者的安全性，PK和效率的铅公式。这 研究人员团队是药物开发，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 新型药物输送系统的药物批准（NDA）。该项目可能会迅速导致 改善了生殖器疱疹的治疗和预防。