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化为许多人可控制的慢性感染， 艾滋病毒/艾滋病仍然是一种可怕的全球流行病。尽管联合使用药物的效果， 不同的类别、副作用和耐药性仍然是这些终身治疗的严重问题。因此，在本发明中， 对具有新的作用机制和更强的屏障的新型HIV抑制剂的需求是持久的。 阻力此外，人们认识到，缺乏患者依从性是导致治疗的主要因素 失败出于这个原因，艾滋病专家对长效疗法的前景感到兴奋， 这种疗法的发展将为许多艾滋病患者提供一种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。我们已经鉴定了一种新的HIV进入抑制剂，胆固醇-PIE 12-三聚体（CPT 31）， 抗蛋白酶D-肽（由D-氨基酸制成的肽），靶向HIV保守的进入机制。 对所有主要的HIV亚型具有高效活性，设计了耐药性屏障， 为了提高疗效，我们的抗HIV D-肽克服了进入抑制剂治疗类别的当前限制。 此外，CPT 31是理想的暴露前预防（PrEP），因为它阻断了病毒的第一阶段， 在感染靶细胞之前的生命周期。 Navigen通过最近完成的II期SBIR将CPT 31推进到后期临床前开发 奖在这三年的SB 1申请中，我们将完成1）原料药的GMP生产，2）GMP 制剂的配制，包括稳定性测试和无菌包装，3）IND使能动物毒理学， （4）我们的IND包。这些研究将专门推进一种每日给药制剂， 确定我们的D肽治疗药物在动物和人类中的安全性。然而，CPT 31的高效力， 蛋白酶抗性和良好的药代动力学（PK）和理化性质使其成为理想的 延长释放贮库制剂的候选物。在进行上述研究的同时，我们正在 与缓释制剂专家合作，开发适合的CPT 31长效制剂（CPT 31-LA） 每月一次（或更少）注射。许多患者更喜欢长效注射剂，而不是每日口服药丸。 因此，CPT 31-LA将有可能实现广泛的市场渗透。 获得IND地位将极大地促进证明人类疗效所需的早期投资， CPT 31，并最终与一家大型制药公司达成许可协议，该公司可以将CPT 31-LA 作为预防和治疗艾滋病毒的一种潜在的变革性新选择进行营销。