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.

项目摘要 3500万人患有艾滋病毒/艾滋病（包括在美国120万）和120万与艾滋病有关的人 2014年死亡，艾滋病毒/艾滋病仍然是一种强大的全球流行病（UNAID，CDC）。现代艾滋病毒疗法 结合不同类别的药物，形成将HIV转化为一种“鸡尾酒”疗法 许多人可控制的慢性感染。尽管这些药物有效，副作用和 对这些终身疗法的耐药性仍然是严重的关注。那是持久的需求 具有新的作用机理和耐药性障碍的新型HIV抑制剂。此外，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，艾滋病毒 专家对长效疗法的前景感到兴奋，这种疗法的鸡尾酒会提供 许多HIV患者的革命性新治疗选择。 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。我们已经确定了一种新型的HIV进入抑制剂胆固醇-PIE12-Trimer（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。具有对所有主要亚型HIV的高潜力活性，并具有前所未有的障碍 抗性，我们的抗HIV D肽克服了进入抑制剂治疗类别的当前局限性。在 此外，CPIE12-Trimer也是预防前预防的理想选择，因为它阻止了病毒的第一阶段 靶细胞感染之前的生命周期。 CPIE12-Trimer目前正在Navigen的晚期临床前开发中。 CPIE12-Trimer的唯一配置目标，优势电阻轮廓，高效力，蛋白酶电阻， 有利的药代动力学（PK）和物理特性使其成为长效的理想候选者 仓库公式。在这项为期两年的赠款申请中，我们将与一个行业领先的公式集团合作 持续的CPIE12-TRIMER的持续释放（仓库）公式适用于一次 通过皮下注射给药。此外，我们将进行大鼠和非人类灵长类动物PK研究 关于候选存款公式。在NHP中证明了持续的治疗药物水平一个月 给定depot成型的CPIE12-Trimer，结合我们最近在A中的准备效率的证明 严格的SHIV NHP模型，将极大地支持开发合作伙伴关系，以推动仓库形成的 CPIE12-Trimer通过IND归档和临床试验。一个月一次的CPIE12-Trimer将提供潜在的 预防和治疗艾滋病毒的新选择，尤其是与其他联合使用 发育中持续释放的HIV抑制剂。