Therapeutic D-peptide Inhibitor of HIV Entry

HIV 进入的治疗性 D 肽抑制剂

• 批准号: 9466753
• 负责人: ALAN L MUELLER
• 金额: $ 100万
• 依托单位: NAVIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-10 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9466753
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Adherence; Adverse effects; Affinity; Agreement; Amino Acids; Animals; Anti-Retroviral Agents; Award; Binding; Caring; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Cholesterol; Chronic; Clinical; Clinical Trials; Combined Modality Therapy; Communicable Diseases; Consult; Dose; Drug Formulations; Drug Kinetics; Drug Stability; Drug resistance; Effectiveness; Epidemic; Feedback; Formulation; Freeze Drying; Funding; Goals; Grant; HIV; HIV Entry Inhibitors; Human; Hydrophobicity; Industry; Infection; Injectable; Injection of therapeutic agent; Investments; Laboratories; Licensing; Life; Manufacturer Name; Microspheres; Modernization; Oral; Patients; Penetration; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Powder dose form; Prevention; Process; Property; Rattus; Research; Resistance; Resistance profile; Rodent; Safety; Small Business Innovation Research Grant; Solubility; Specialist; Sustainable Development; Therapeutic; Toxicology; Treatment Failure; United States National Institutes of Health; Utah; Vendor; Vial device; Viral; Virus; Writing; animal efficacy; clinical development; compliance behavior; design; drug production; efficacy study; experience; immunogenicity; improved; in vivo; inhibitor/antagonist; innovation; meetings; nonhuman primate; novel; peptide drug; pill; pre-exposure prophylaxis; preclinical development; safety study; stability testing

PROJECT SUMMARY While modern HIV combination therapy has transformed HIV into a manageable chronic infection for many patients, HIV/AIDS remains a formidable global epidemic. Despite the effectiveness of combining drugs from different classes, 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 combination 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, designed barriers to resistance, and in vivo animal efficacy, our anti-HIV D-peptide overcomes the current limitations of the entry inhibitor treatment class. Additionally, CPT31 is ideal for pre-exposure prophylaxis (PrEP) since it blocks the first stage of the viral lifecycle prior to infection of target cells. Navigen has advanced CPT31 to late preclinical development via a recently completed Phase II SBIR award. In this three-year SB1 application we will complete 1) GMP manufacturing of drug substance, 2) GMP formulation of drug product including stability testing and aseptic packaging, 3) IND-enabling animal toxicology, and 4) our IND package. These studies will exclusively advance a daily-dosing formulation that will be used to establish the safety of our D-peptide therapeutic in animals and humans. However, CPT31’s high potency, protease resistance, and favorable pharmacokinetic (PK) and physicochemical properties make it an ideal candidate for extended-release depot formulation. In parallel with the studies proposed here, we are working with extended-release formulation experts to develop a long-acting formulation of CPT31 (CPT31-LA) suitable for once-monthly (or less frequent) injection. Many patients prefer long-acting injectables to daily oral pills. Therefore, CPT31-LA will likely achieve broad market penetration. Achieving IND status will greatly facilitate the early investment needed to demonstrate human efficacy with CPT31 and, ultimately, a licensing agreement with a large pharmaceutical company who can bring CPT31-LA to market as a potentially transformative new option for the prevention and treatment of HIV.

项目概要 虽然现代艾滋病毒联合疗法已将艾滋病毒转变为对许多人来说可控制的慢性感染 艾滋病毒/艾滋病仍然是一种可怕的全球流行病。尽管组合药物的有效性 不同的类别、副作用和耐药性仍然是这些终身疗法的严重问题。因此， 对具有新作用机制和更强屏障的新型 HIV 抑制剂有着持久的需求 反抗。此外，人们认识到缺乏患者依从性是导致治疗失败的一个主要因素。 失败。因此，艾滋病毒专家对长效疗法和联合疗法的前景感到兴奋 此类疗法将为许多艾滋病毒患者提供革命性的新治疗选择。 Navigen 是一家小型制药公司，通过创新发现瞄准传染病 和设计过程。我们发现了一种新型 HIV 进入抑制剂，即胆固醇-PIE12-三聚体 (CPT31)，它是一种 抗蛋白酶 D 肽（由 D 氨基酸制成的肽），针对 HIV 保守的进入机制。 对所有主要 HIV 亚型具有高效活性，设计耐药性屏障，并在动物体内 功效方面，我们的抗 HIV D 肽克服了目前进入抑制剂治疗类别的局限性。 此外，CPT31 是暴露前预防 (PrEP) 的理想选择，因为它可以阻断病毒的第一阶段 感染靶细胞之前的生命周期。 Navigen 通过最近完成的 II 期 SBIR 将 CPT31 推进到临床前开发后期 奖。在这个为期三年的 SB1 申请中，我们将完成 1) 原料药的 GMP 生产，2) GMP 药品配方，包括稳定性测试和无菌包装，3) 支持 IND 的动物毒理学， 4) 我们的 IND 包。这些研究将专门推进一种每日剂量的配方，该配方将用于 确定我们的 D 肽治疗剂在动物和人类中的安全性。然而，CPT31的高效力， 蛋白酶抗性以及良好的药代动力学 (PK) 和理化特性使其成为理想的 缓释储库制剂的候选者。在进行此处提出的研究的同时，我们正在努力 与缓释制剂专家合作开发适合CPT31的长效制剂（CPT31-LA） 每月一次（或不太频繁）注射。许多患者更喜欢长效注射剂而不是每日口服药片。 因此，CPT31-LA可能会实现广泛的市场渗透。 获得 IND 地位将极大地促进证明人体功效所需的早期投资 CPT31，并最终与一家可以带来 CPT31-LA 的大型制药公司签订许可协议 作为预防和治疗艾滋病毒的潜在变革性新选择推向市场。