Nelfinavir in SLE: A Pilot Phase IIa Clinical Trial

奈非那韦治疗 SLE：IIa 期试点临床试验

• 批准号: 8688912
• 负责人: Betty Diamond
• 金额: $ 16.85万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8688912
• 关键词: Address; Adverse event; Affect; Anti-DNA Antibodies; Antibody titer measurement; Antigens; Autoantibodies; Autoimmune Diseases; Benign; Binding; Brain; Clinical; Clinical Services; Clinical Trials; Clinical Trials Design; Color; Connective Tissue Diseases; Consensus Sequence; Cytolysis; Cytotoxic agent; Data; Deposition; Diamond; Disease; Doctor of Philosophy; Dose; Drug usage; Enrollment; Epitopes; FDA approved; Generations; Goals; HIV; Human; Immunocompromised Host; Immunosuppressive Agents; In Vitro; Institutes; Interferons; Joints; Kidney; Lupus; Measures; Medical; Medicine; Modality; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; Names; Nelfinavir; Organ; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Pilot Projects; Plant Roots; Population; Protease Inhibitor; Proteins; Publications; Recovery; Resistance; Safety; Series; Skin; Staging; Systemic Lupus Erythematosus; Testing; Therapeutic; Time; Tissues; Toxic effect; Translating; Woman; Work; anti-dsDNA antibodies; anti-dsDNA autoantibody; base; body system; complement C3 precursor; cytokine; design; dosage; expectation; improved; inhibitor/antagonist; innovation; insight; nephrotoxicity; neurotoxicity; novel; novel therapeutic intervention; novel therapeutics; open label; palliative; peptidomimetics; phase 2 study; pre-clinical; public health relevance; response; scaffold; screening; success; trend; viracept; young woman

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is an autoimmune disease that preferentially afflicts young women. Although considered a connective tissue disease, SLE harms a variety of organ systems, including the skin, joints, kidney and brain. Management of active SLE frequently requires the use of multiple non-specific immunosuppressive and cytotoxic drugs that are associated with toxicities and often have limited efficacy. Recently, we have made the surprising discovery that certain FDA-approved Human Immunodeficiency Virus (HIV) protease inhibitors show promise in a variety of preclinical lupus models. Among these, nelfinavir (brand name Viracept), possesses a relatively benign safety profile in HIV patients and is not likely to be immunosuppressive or cause adverse events in lupus patients. On the strength of both nelfinavir's known safety and our preclinical data demonstrating that nelfinavir acts, in part, as a decoy antigen to quench the pathogenic lupus anti-dsDNA autoantibodies, we propose to assess the safety and preliminary efficacy of nelfinavir as a lupus therapeutic in a pilot feasibility phase IIa clinical trial. We will pre-scren subjects for elevated anti-dsDNA autoantibody titers and incorporate early surrogate efficacy measures into this trial design. These and other innovations will bring a personalized medicine approach to lupus and contribute to the likelihood of the trial's success. Moreover, it has not escaped our notice that the repurposing of an FDA- approved drug into a new indication will facilitate an extremely rapid path into an urgent unmet medical need. The successful completion of this proof-of-concept study will lay the groundwork for a definitive clinical trial.

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种以年轻女性为主的自身免疫性疾病。虽然SLE被认为是一种结缔组织疾病，但SLE损害多种器官系统，包括皮肤、关节、肾脏和大脑。活动期SLE的治疗通常需要使用多种非特异性免疫抑制和细胞毒性药物，这些药物与毒性相关，通常疗效有限。最近，我们有一个令人惊讶的发现，某些fda批准的人类免疫缺陷病毒（HIV）蛋白酶抑制剂在各种临床前狼疮模型中显示出希望。其中，奈非那韦（品牌名Viracept）在HIV患者中具有相对良性的安全性，并且不太可能对狼疮患者产生免疫抑制或引起不良事件。鉴于奈非那韦已知的安全性，以及我们的临床前数据表明，奈非那韦在一定程度上可以作为诱饵抗原来抑制致病性狼疮抗dsdna自身抗体，我们建议在可行性ii期临床试验中评估奈非那韦作为狼疮治疗药物的安全性和初步疗效。我们将预先筛选抗dsdna自身抗体滴度升高的受试者，并将早期替代疗效测量纳入该试验设计中。这些和其他创新将为狼疮带来个性化的医疗方法，并有助于试验成功的可能性。此外，我们注意到，将FDA批准的药物重新用于新的适应症，将有助于极快地满足紧急未满足的医疗需求。这项概念验证研究的成功完成将为最终的临床试验奠定基础。