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（更改已加下划线） 该项目的广泛、长期目标是开发一种普替利韦阴道环（IVR），用于治疗和治疗 生殖器疱疹的暴露前预防是影响超过 5000 万美国人的常见问题。 复发很常见，并且可能会造成终生疼痛。 Pritelivir 是一种很有前途的 α-解旋酶抑制剂。 在二期临床试验中证明该疗法优于现有疗法，但其临床开发作为 由于毒性，局部治疗受到特别关注。 我们开发了一种持续释放抗病毒药物的平台技术。 开发更昔洛韦眼内植入物 - Vitrasert®，用于治疗艾滋病相关巨细胞病毒 Vitrasert® 是唯一获得 FDA 批准的缓释抗病毒药物递送产品。 FDA。我们已将该平台应用于 IVR，并已成功交付其他抗病毒药物。 我们建议利用这个平台来开发持续的临床前和临床试验的治疗水平。 我们实现了该提案第一阶段的具体目标，即： 配制递送普替利韦的缓释阴道环，以测试其体外释放特性 这些制剂，并在 FDA 测试制剂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 IVR 剂量。 进一步开发安全、持续的药物产品，并在令人满意的条件下释放 28 天 宫颈阴道液和组织的药物水平将提供高潜在功效。 因此，我们建议在第二阶段完成 FDA 授权的科学和监管活动 我们建议发展 GMP 生产。 具备先导制剂临床批号的能力；能够进行为期 3 个月的 GLP、IND 安全性研究 绵羊模型，用于检查延长 IVR 使用以执行制造过程的局部和全身毒性； 开发，包括产品测试分析和早期验证；转移制造和分析 合同制造组织执行支持 IND 的化学、制造和 控制 IND 提交的 (CMC) 活动；完成并提交所有临床文件； 协调向 FDA 提交 IND 申请的所有活动，这是成功完成的里程碑。 拟议的第二阶段工作是批准 IND 进行首次人体探索性临床试验。 在这笔资助的 IIB 阶段，我们将测试先导制剂在 HSV+ve 志愿者中的安全性、PK 和有效性。 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 我们拥有与大型制药公司合作的经验，以实现新的传染病。 新型药物输送系统的药物批准（NDAs）可能会迅速促进新药物的开发。 改进生殖器疱疹的治疗和预防。