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.

项目总结 有3700万艾滋病毒/艾滋病患者(包括美国的120万人)，以及110万与艾滋病有关的人 2015年，艾滋病毒/艾滋病仍然是一种可怕的全球流行病(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(CPT31)，它是一种 抗蛋白酶的D-肽(由D-氨基酸制成的肽)，针对HIV保守的进入机制。 凭借对所有主要艾滋病毒亚型的高度有效活性和设计的抗药性屏障，我们的抗艾滋病毒D- 多肽克服了目前进入抑制剂治疗类别的限制。此外，CPT31非常适用于 暴露前预防(PrEP)，因为它在感染目标之前阻止了病毒生命周期的第一阶段 细胞。CPT31目前正处于Navigen的晚期临床前开发阶段。 CPT31的S具有独特的保守靶标、优良的抗病特性、高效性、抗蛋白酶性和 良好的药代动力学(PK)和理化性质使其成为缓释剂的理想候选者。 放行仓库配方。通过一笔为期一年的R56过渡性拨款，我们与行业领先的 奥克伍德实验室的配方小组演示开发长效配方的可行性 CPT31(CPT31-LA)适合每月注射一次。CPT31-LA的优化目前正在进行中。在……里面 这份为期三年的拨款申请，使用优化的CPT31-LA，我们将执行1)扩展所需的活动 2)大鼠和非人灵长类(NHP)PK研究，3)大鼠 毒理学研究，以及4)NHP预防(PrEP)和治疗效果研究。这些研究将极大地 促进开发伙伴关系，通过IND申请和临床试验推进CPT31-LA。每月一次 CPT31-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。