Depot formulation of a D-peptide HIV entry inhibitor

D 肽 HIV 进入抑制剂的长效制剂

• 批准号: 9329767
• 负责人: ALAN L MUELLER
• 金额: $ 52.49万
• 依托单位: NAVIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-17 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329767
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adverse drug effect; Adverse effects; Amino Acids; Applications Grants; Caring; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Cholesterol; Chronic; Clinical; Clinical Trials; Collaborations; Communicable Diseases; Development; Dose; Drug Kinetics; Drug resistance; Effectiveness; Ensure; Epidemic; FDA approved; Formulation; Fuzeon; Goals; HIV; HIV Entry Inhibitors; HIV therapy; Half-Life; In Vitro; Individual; Industry; Infection; Injection of therapeutic agent; Kinetics; Life; Methods; Modeling; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma; Predisposition; Prevention; Process; Property; Prophylactic treatment; Rattus; Resistance; Resistance profile; Serum; Small Business Innovation Research Grant; Specialist; Staging; Subcutaneous Injections; Testing; Therapeutic; Treatment Efficacy; Treatment Failure; Universities; Utah; Viral; Work; chemical property; compliance behavior; design; drug candidate; high risk; improved; in vivo; inhibitor/antagonist; innovation; nonhuman primate; novel; novel therapeutics; pre-clinical; preclinical study; prevent; process optimization; prototype; safety study; simian human immunodeficiency virus

PROJECT SUMMARY With 35 million people living with HIV/AIDS (including 1.2 million in the US), and 1.2 million AIDS-related deaths in 2014, HIV/AIDS remains a formidable global epidemic (UNAIDS, CDC). Modern HIV therapy combines drugs from different classes to form “cocktail” therapies that have transformed HIV into a manageable chronic infection for many individuals. Despite the effectiveness of these drugs, side effects and drug resistance remain serious concerns for these life-long therapies. Thus, there is an enduring need for novel HIV inhibitors with new mechanisms of action and stronger barriers to resistance. Furthermore, it is recognized that lack of patient compliance is a major factor leading to treatment failure. For this reason, HIV specialists are excited by the prospect of long-acting therapies, and a cocktail of such therapies would provide a revolutionary new treatment option for many HIV patients. Navigen is a small pharmaceutical company targeting infectious diseases through an innovative discovery and design process. We have identified a novel HIV entry inhibitor, cholesterol-PIE12-trimer (cPIE12-trimer), that is a protease-resistant D-peptide (peptide made from D-amino acids) that targets HIV's conserved entry machinery. With highly potent activity against all major subtypes of HIV and an unprecedented barrier to resistance, our anti-HIV D-peptide overcomes the current limitations of the entry inhibitor treatment class. In addition, cPIE12-trimer is also ideal for pre-exposure prophylaxis since it blocks the first stage of the viral lifecycle prior to infection of target cells. cPIE12-trimer is currently in late preclinical development at Navigen. cPIE12-trimer's uniquely conserved target, superior resistance profile, high potency, protease resistance, and favorable pharmacokinetic (PK) and physicochemical properties make it an ideal candidate for long-acting depot formulation. In this two-year grant application, we will work with an industry-leading formulation group at DURECT to develop a sustained-release (depot) formulation of cPIE12-trimer suitable for once-monthly administration via subcutaneous injection. Additionally, we will perform rat and non-human primate PK studies on candidate depot formulations. Demonstration of sustained therapeutic drug levels for one month in NHPs given depot-formulated cPIE12-trimer, in combination with our recent demonstration of PrEP efficacy in a stringent SHIV NHP model, will greatly facilitate development partnerships to advance a depot-formulated cPIE12-trimer through IND filing and clinical trials. Once-monthly cPIE12-trimer would provide a potentially transformative new option for the prevention and treatment of HIV, especially if used in combination with other sustained-release HIV inhibitors in development.

项目总结 有3500万艾滋病毒/艾滋病患者(包括美国的120万人)，以及120万与艾滋病有关的人 2014年，艾滋病毒/艾滋病仍然是一种可怕的全球流行病(联合国艾滋病规划署、美国疾病控制与预防中心)。现代艾滋病治疗 将不同类别的药物结合在一起，形成了将艾滋病毒转化为 对许多个人来说，慢性感染是可控的。尽管这些药物有效，但副作用和 耐药性仍然是这些终生疗法的严重问题。因此，存在着持久的需求 具有新的作用机制和更强的抗药性屏障的新型艾滋病毒抑制剂。此外，它是 认识到缺乏患者依从性是导致治疗失败的主要因素。出于这个原因，艾滋病毒 专家们对长效疗法的前景感到兴奋，而这种疗法的鸡尾酒将提供 为许多艾滋病毒患者提供了革命性的新治疗选择。 Navigen是一家通过一项创新发现瞄准传染病的小型制药公司 和设计流程。我们已经发现了一种新的HIV进入抑制剂，胆固醇-PIE12-三聚体(cPIE12-Trimer)， 这是一种抗蛋白酶的D-肽(由D-氨基酸制成的肽)，它针对HIV的保守进入 机械设备。对所有主要的艾滋病毒亚型都有很强的活性，并且对 在抗药性方面，我们的抗艾滋病毒D-肽克服了目前进入抑制剂治疗类别的限制。在……里面 此外，cPIE12-三聚体也是暴露前预防的理想选择，因为它阻止了病毒的第一阶段。 感染目标细胞前的生命周期。CPIE12-Trimer目前正处于Navigen的晚期临床前开发阶段。 CPIE12-三聚体的独特保守靶点，优越的抗性图谱，高效，耐蛋白酶， 良好的药代动力学(PK)和理化性质使其成为长效的理想候选者 仓库配方。在这项为期两年的拨款申请中，我们将与业界领先的制定小组合作， DURECT开发适合每月一次的cPIE12-三聚体缓释(仓库)制剂 皮下注射给药。此外，我们还将进行大鼠和非人灵长类PK研究 关于候选库的配方。NHPS持续一个月治疗用药水平的论证 给定仓库配方的cPIE12-三聚体，结合我们最近展示的PrEP在 严格的SHIV NHP模式，将极大地促进发展伙伴关系，推进仓库制定 CPIE12-三聚体通过IND备案和临床试验。每月一次的cPIE12-三聚体将提供一个潜在的 预防和治疗艾滋病毒的变革性新选择，特别是如果与其他 正在开发中的艾滋病毒缓释抑制剂。