Therapeutic D-peptide Inhibitor of HIV Entry

HIV 进入的治疗性 D 肽抑制剂

• 批准号: 9755320
• 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 2020-04-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755320
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Adherence; Affinity; Agreement; Amino Acids; Animals; Award; Binding; Caring; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Cholesterol; 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; Injections; 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; antiretroviral therapy; chronic infection; clinical development; compliance behavior; design; drug production; efficacy study; experience; first-in-human; immunogenicity; improved; in vivo; inhibitor/antagonist; innovation; meetings; nonhuman primate; novel; peptide drug; pill; pre-exposure prophylaxis; preclinical development; safety study; side effect; 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.

项目总结 虽然现代艾滋病毒联合疗法已经将艾滋病毒转变为许多人可控的慢性感染 对患者而言，艾滋病毒/艾滋病仍然是一个可怕的全球流行病。尽管联合用药很有效 不同的类别、副作用和耐药性仍然是这些终生疗法的严重问题。因此， 对具有新的作用机制和更强的屏障的新型艾滋病毒抑制剂的持久需求 抵抗。此外，人们认识到，缺乏患者依从性是导致治疗的一个主要因素。 失败了。出于这个原因，艾滋病毒专家们对长效疗法和一种组合疗法的前景感到兴奋 这种疗法的出现将为许多艾滋病毒患者提供一种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。 对所有主要艾滋病毒亚型具有高度有效的活性，设计了抵抗屏障，并在体内动物 为了提高疗效，我们的抗HIV D-肽克服了目前进入抑制剂治疗类别的限制。 此外，CPT31是暴露前预防(PrEP)的理想选择，因为它阻止了病毒的第一阶段 感染目标细胞前的生命周期。 Navigen公司通过最近完成的第二阶段SBIR将CPT31推进到晚期临床前开发 获奖。在这项为期三年的SB1申请中，我们将完成1)药品GMP制造，2)GMP 药品配方，包括稳定性试验和无菌包装，3)支持IND的动物毒理学， 4)我们的IND套餐。这些研究将独家推进一种每日剂量的配方，将用于 确定我们的D-肽疗法在动物和人类中的安全性。然而，CPT31的S效力很高， 对蛋白酶的抗性，以及良好的药代动力学(PK)和理化特性使其成为理想的 缓释库制剂的候选者。与这里提出的研究同时，我们正在努力 与缓释制剂专家共同开发适合CPT31(CPT31-LA)的长效制剂 每月注射一次(或较少注射)。许多患者更喜欢长效注射剂，而不是日常口服药片。 因此，CPT31-LA很可能实现广泛的市场渗透。 获得IND资格将极大地促进展示人类功效所需的早期投资 CPT31，并最终与一家大型制药公司达成许可协议，该公司可以将CPT31-LA 将其推向市场，作为预防和治疗艾滋病毒的一种潜在的变革性新选择。