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 3700万人患有艾滋病毒/艾滋病（包括在美国120万）和110万与艾滋病有关的人 2015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（CPT31），那就是 抗蛋白酶的D肽（由D-氨基酸制成的肽），该肽靶向HIV保守的入口机制。 我们的抗HIV D-具有对所有主要的HIV亚型和设计抗性的障碍，具有高潜力的活性 克服了进入抑制剂治疗类别的当前局限性的肽。此外，CPT31非常适合 暴露前预防（PREP），因为它会在感染靶标之前阻止病毒生命周期的第一阶段 细胞。 CPT31目前正在Navigen晚期临床前开发。 CPT31独特配置的目标，优势电阻轮廓，高效力，蛋白酶电阻和 有利的药代动力学（PK）和物理特性使其成为扩展的理想候选者 释放仓库公式。通过一年一年的R56桥梁赠款，我们与行业领先合作 Oakwood Labs的编队组，以证明开发长效公式的可行性 CPT31（CPT31-LA）适用于一次一次注射。 CPT31-LA的优化目前正在进行中。在 这项为期三年的赠款申请，使用优化的CPT31-LA，我们将执行1）规模的必需活动 和制造临床试验的制造，2）大鼠和非人类灵长类动物（NHP）PK研究，3）大鼠 毒理学研究以及4）NHP预防（PREP）和治疗效率研究。这些研究将大大 通过IND提交和临床试验促进开发合作伙伴关系，以推动CPT31-LA。一次 CPT31-LA将为预防和治疗HIV提供潜在的变革新选择。