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: 9408382
• 负责人: ALAN L MUELLER
• 金额: $ 82.63万
• 依托单位: NAVIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9408382
• 关键词: AIDS prevention; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adherence; Adverse drug effect; Adverse effects; Affinity; Amino Acids; Animals; Anti-Retroviral Agents; Applications Grants; Award; Binding; Caring; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Cholesterol; Chronic; Clinical; Clinical Research; Clinical Trials; Collaborations; Combination Drug Therapy; Combined Modality Therapy; Communicable Diseases; Data; Development; Dose; Drug Kinetics; Drug resistance; Effectiveness; Ensure; Epidemic; Feasibility Studies; Formulation; Goals; Grant; HIV; HIV Entry Inhibitors; HIV therapy; Human; Hydrophobicity; In Vitro; Individual; Industry; Infection; Injectable; Injection of therapeutic agent; Life; Macaca; Membrane Proteins; Microspheres; Modeling; Modernization; National Institute of Allergy and Infectious Disease; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Preparation; Prevention; Process; Production; Property; Rattus; Reproducibility; Resistance; Resistance profile; Rodent; Safety; Small Business Innovation Research Grant; Solvents; Specialist; System; Testing; Toxicology; Treatment Efficacy; Treatment Failure; Utah; Variant; Viral; Work; analytical method; clinical development; compliance behavior; design; efficacy study; high risk; immunogenicity; improved; in vivo; inhibitor/antagonist; innovation; nonhuman primate; novel; novel therapeutics; pre-exposure prophylaxis; preclinical development; prototype; receptor; rectal; scale up; simian human immunodeficiency virus; stability testing

PROJECT SUMMARY With 37 million people living with HIV/AIDS (including 1.2 million in the US), and 1.1 million AIDS-related deaths in 2015, 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 (CPT31), 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 HIV subtypes and designed barriers to resistance, our anti-HIV D- peptide overcomes the current limitations of the entry inhibitor treatment class. In addition, CPT31 is ideal for pre-exposure prophylaxis (PrEP) since it blocks the first stage of the viral lifecycle prior to infection of target cells. CPT31 is currently in late preclinical development at Navigen. CPT31's uniquely conserved target, superior resistance profile, high potency, protease resistance, and favorable pharmacokinetic (PK) and physicochemical properties make it an ideal candidate for extended- release depot formulation. Via a one-year R56 bridge grant, we have worked with an industry-leading formulation group at Oakwood Labs to demonstrate the feasibility of developing a long-acting formulation of CPT31 (CPT31-LA) suitable for once-monthly injection. Optimization of CPT31-LA is currently underway. In this three-year grant application, using optimized CPT31-LA, we will perform 1) required activities for scale-up and manufacturing in preparation for clinical trials, 2) rat and non-human primate (NHP) PK studies, 3) rat toxicology studies, and 4) NHP prevention (PrEP) and therapeutic efficacy studies. These studies will greatly facilitate development partnerships to advance CPT31-LA through IND filing and clinical trials. Once-monthly CPT31-LA will provide a potentially transformative new option for the prevention and treatment of HIV.

项目摘要 有3700万人感染艾滋病毒/艾滋病（包括美国的120万人），110万人与艾滋病有关 截至2015年死亡人数，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（CPT 31）， 抗蛋白酶D-肽（由D-氨基酸制成的肽），靶向HIV保守的进入机制。 我们的抗艾滋病病毒D-抗体具有针对所有主要艾滋病病毒亚型的高效活性和设计的耐药性屏障， 肽克服了进入抑制剂治疗类别的当前限制。此外，CPT 31是理想的 暴露前预防（PrEP），因为它可以在感染靶细胞之前阻断病毒生命周期的第一阶段 细胞CPT 31目前在Navigen处于临床前后期开发阶段。 CPT 31独特的保守靶标、上级抗性特征、高效力、蛋白酶抗性，以及 良好的药代动力学（PK）和理化性质使其成为延长- 释放贮库制剂。通过为期一年的R56桥梁赠款，我们与一家行业领先的 Oakwood实验室的制剂组，以证明开发长效制剂的可行性。 CPT 31（CPT 31-LA）适合每月注射一次。CPT 31-LA的优化目前正在进行中。在 在这个为期三年的资助申请中，我们将使用优化的CPT 31-LA执行1）扩大规模所需的活动 临床试验准备中的生产，2）大鼠和非人灵长类动物（NHP）PK研究，3）大鼠 毒理学研究，和4）NHP预防（PrEP）和治疗功效研究。这些研究将大大 促进开发伙伴关系，通过IND申请和临床试验推进CPT 31-LA。每月一 CPT 31-LA将为预防和治疗艾滋病毒提供一种潜在的变革性新选择。