Depot formulation of a D-peptide HIV entry inhibitor

项目摘要 有3500万人感染艾滋病毒/艾滋病（包括美国的120万人），120万人与艾滋病有关 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，疾病预防控制中心）。现代艾滋病毒治疗 将不同类别的药物组合在一起，形成“鸡尾酒”疗法，将艾滋病毒转化为一种 可控制的慢性感染对许多人来说。尽管这些药物的有效性，副作用和 耐药性仍然是这些终身治疗的严重问题。因此，有一个持久的需要， 具有新作用机制和更强耐药性屏障的新型HIV抑制剂。再者是 认识到缺乏患者依从性是导致治疗失败的主要因素。因此，HIV 专家们对长效疗法的前景感到兴奋，这种疗法的混合物将提供 为许多艾滋病患者提供了一种革命性的新治疗选择。 Navigen是一家小型制药公司，通过创新发现针对传染病 和设计过程。我们已经鉴定了一种新的HIV进入抑制剂，胆固醇-PIE 12-三聚体（cPIE 12-trimer）， 这是一种抗蛋白酶的D肽（由D氨基酸制成的肽），靶向HIV的保守进入 机械.对所有主要的艾滋病毒亚型都有很强的活性， 耐药性，我们的抗HIV D-肽克服了目前进入抑制剂治疗类的局限性。在 此外，cPIE 12-三聚体也是理想的暴露前预防，因为它阻断了病毒的第一阶段， 在感染靶细胞之前的生命周期。CPIE 12-三聚体目前在Navigen处于后期临床前开发阶段。 CPIE 12-三聚体的独特保守靶标、上级抗性特征、高效力、蛋白酶抗性， 良好的药代动力学（PK）和理化性质使其成为长效 贮库制剂。在这个为期两年的资助申请中，我们将与一个行业领先的配方小组合作， DURECT开发适用于每月一次的CPIE 12-三聚体的缓释（储库）制剂 通过皮下注射给药。此外，我们将进行大鼠和非人灵长类动物PK研究 候选贮库制剂。证明NHP中持续1个月的治疗药物水平 考虑到库配制的CPIE 12-三聚体，结合我们最近在一个受试者中证明的PrEP功效， 严格的SIV NHP模型，将大大促进发展伙伴关系， CPIE 12-三聚体通过IND申报和临床试验。每月一次的cPIE 12三聚体将提供潜在的 预防和治疗艾滋病毒的变革性新选择，特别是如果与其他 持续释放的HIV抑制剂在开发中。

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.