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.

项目摘要 虽然现代艾滋病毒联合疗法已将艾滋病毒转变为许多许多人的慢性感染 患者，艾滋病毒/艾滋病仍然是一种强大的全球流行病。尽管将药物结合起来有效 对这些终身疗法的不同类别，副作用和耐药性仍然是严重的关注。那， 有一种新型的HIV抑制剂具有新的作用机理和更强的障碍 反抗。此外，人们认识到缺乏患者依从性是导致治疗的主要因素 失败。因此，艾滋病毒专家对长效疗法的前景和组合感到兴奋 这种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。 具有对所有主要的HIV亚型的高潜力活性，设计的抗性障碍和体内动物 功效，我们的抗HIV D肽克服了入口抑制剂治疗类别的当前局限性。 此外，CPT31是预防前预防的理想选择（PREP），因为它阻止了病毒的第一阶段 靶细胞感染之前的生命周期。 Navigen通过最近完成的II期SBIR将CPT31提高到后期的临床前开发 奖。在这三年的SB1应用中，我们将完成1）GMP制造药物的制造，2）GMP 形成包括稳定性测试和无菌包装的药物的形成，3）辅助动物毒理学， 4）我们的Ind套餐。这些研究将专门推进每日剂量公式 在动物和人类中建立我们的D肽疗法的安全性。但是，CPT31的高效力， 蛋白酶抗性，有利的药代动力学（PK）和物理特性使其成为理想的 延长释放存款公式的候选人。与这里提出的研究并行，我们正在工作 具有扩展释放公式的专家，以开发CPT31（CPT31-LA）的长效公式 每月（或频繁）一次注射一次。许多患者喜欢长期注射而不是每日口服药丸。 因此，CPT31-LA可能会实现广泛的市场渗透率。 实现IND地位将极大地支持证明人类效率所需的早期投资 CPT31以及最终与一家大型制药公司的许可协议，可以带来CPT31-LA 作为预防和治疗艾滋病毒的潜在变革的新选择。