IND-enabling Preclinical Development of a Sustained-release Pritelivir Intravaginal ring for the Treatment and Prophylaxis of Genital Herpes

用于治疗和预防生殖器疱疹的缓释 Pritelivir 阴道环的 IND 临床前开发

• 批准号: 10759169
• 负责人: Sarjan Shah
• 金额: $ 102.5万
• 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 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10759169
• 关键词: Acquired Immunodeficiency Syndrome; Acyclovir; Affect; American; Animal Model; Animals; Antiviral Agents; Area; Chemistry; Clinical; Clinical Protocols; Clinical Trials; Collaborations; Communicable Diseases; Cytomegalovirus Retinitis; Development; Devices; Dose; Drug Delivery Systems; Drug Kinetics; Environment; Evaluation; FDA approved; Female; Formulation; Funding; Future; Ganciclovir; Goals; Guidelines; Hematology; Human; Implant; In Vitro; Industry; Infection; Investigational Drugs; Investigational New Drug Application; Laboratories; Lead; Local Therapy; Methods; New Drug Approvals; Oral; Pain; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology and Toxicology; Phase; Phase II Clinical Trials; Primates; Prophylactic treatment; Provider; Published Comment; Recurrence; Research Personnel; Resources; Rodent; Safety; Sheep; Skin; Small Business Innovation Research Grant; Synthesis Chemistry; Systemic Therapy; Technology; Tenofovir; Testing; Therapeutic; Topical application; Toxic effect; Toxicogenetics; Toxicology; United States National Institutes of Health; Vaginal Ring; Viral; Woman; Work; analytical method; clinical development; clinically relevant; commercialization; drug candidate; drug development; emtricitabine; experience; first-in-human; genital herpes; helicase; improved; in vivo; inhibitor; innovation; interest; manufacture; manufacturing capabilities; manufacturing process; novel; novel therapeutics; patient population; pre-exposure prophylaxis; preclinical development; preclinical trial; product development; research clinical testing; stability testing; systemic toxicity; technology platform; vaginal fluid; volunteer

SUMMARY 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 30 million Americans. Recurrences are common and may be painful, and infection is life-long, yet few treatment options exist. Pritelivir is a promising α-helicase inhibitor that has been proven superior to existing therapies in Phase 2 clinical trials, but whose clinical development as a systemic therapy has been slowed due to observed unexplained systemic toxicity in primates. Therefore, pritelivir-based local therapy is of special interest. We have developed a platform technology for the sustained release of antivirals. This technology has successfully led to the development and commercialization of a ganciclovir intraocular implant – Vitrasert®, for the treatment of AIDS-related cytomegalovirus retinitis. This platform has been adapted to IVRs and through its use we have successfully delivered other antiviral agents at therapeutic levels in preclinical and clinical trials. We seek to utilize this platform to develop a sustained release IVR formulation for pritelivir. We achieved the specific aims of our Phase I and II SBIR, which were to: formulate pritelivir-releasing IVRs; test their in vitro release and in vivo safety and pharmacokinetics (PK) in animals; perform chemistry, manufacturing, and controls (CMC) activities; develop clinical documents; and submit an Investigational New Drug (IND) application to the FDA. The successful completion of this Phase I/II SBIR work has enabled us to identify an IVR dose for the further development of a drug product that is safe and demonstrates sustained release for 28 days and at clinically relevant levels. The IND has been placed on Clinical Hold, pending completion of additional nonclinical pharmacology and toxicology studies, CMC testing, and device evaluation. We, therefore, propose in Phase IIB to accomplish the FDA-guided nonclinical activities required to enable an IND allowance. The proposed Specific Aims of this Phase IIB SBIR are to: develop GMP-grade manufacturing capacity for the drug substance; conduct pharmacology and toxicology studies in rodents and nonrodents; manufacture GMP- grade drug product; perform device testing in accordance with CRDH’s comments; and re-submit an IND application to the FDA. The milestone for the successful completion of the proposed Phase IIB work is the approval of an IND to perform a first-in-human exploratory clinical trial for a pritelivir IVR. In future work, we will test the lead formulation for safety and PK in female volunteers in accordance with our FDA-approved clinical protocol. The team of investigators are experts in drug development, synthetic chemistry, pharmacokinetics, and clinical infectious disease, and have experience 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.

总结 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3000多万美国人。 复发是常见的，可能是痛苦的，感染是终身的，但很少有治疗方案存在。 Pritelivir是一种很有前途的α-解旋酶抑制剂，已在2期临床试验中被证明上级现有疗法 临床试验，但其作为全身治疗的临床开发由于观察到的 无法解释的灵长类全身毒性因此，基于普替利韦的局部治疗特别令人感兴趣。 我们开发了一种平台技术，用于持续释放抗病毒药物。该技术具有 成功地导致更昔洛韦眼内植入物- Vitrasert®的开发和商业化， 治疗艾滋病相关的巨细胞病毒视网膜炎。这一平台已被改造成适用于综合审查，并通过其 我们已经在临床前和临床试验中成功地递送了治疗水平的其它抗病毒剂。 我们试图利用这个平台来开发一种持续释放的IVR制剂pritelivir。我们实现了 我们的I期和II期SBIR的具体目标是：配制普雷特利韦释放IVRs; 在动物中的释放和体内安全性和药代动力学（PK）;进行化学、生产和 开展临床控制（CMC）活动;开发临床文件;并提交研究性新药（IND） 申请FDA。这项第一/第二阶段SBIR工作的成功完成使我们能够确定一个 IVR剂量用于进一步开发安全的药物产品，并证明持续释放28 在临床相关水平。IND已处于临床暂停状态，等待完成 其他非临床药理学和毒理学研究、CMC试验和器械评价。因此，我们 在IIB期提出完成FDA指导的非临床活动，以获得IND许可。 本阶段IIB SBIR的拟议具体目标是： 原料药;在啮齿动物和非啮齿动物中进行药理学和毒理学研究;生产GMP- 根据CRDH的意见进行器械检测;并重新提交IND 申请FDA。成功完成拟议第二B期工程的里程碑是 批准IND进行Pritelivir IVR的首次人体探索性临床试验。在今后的工作中，我们将 根据FDA批准的临床试验， 议定书研究人员团队是药物开发、合成化学、药代动力学、 和临床传染病，并拥有与大型制药公司合作的经验， 实现新型药物递送系统的新药批准（NDA）。该项目可能会迅速导致 生殖器疱疹的治疗和预防