Nelfinavir in SLE: A Pilot Phase IIa Clinical Trial

描述(申请人提供)：系统性红斑狼疮(SLE)是一种自身免疫性疾病，首发于年轻女性。尽管SLE被认为是一种结缔组织疾病，但它会损害各种器官系统，包括皮肤、关节、肾脏和大脑。活动性系统性红斑狼疮的治疗经常需要使用多种非特异性免疫抑制和细胞毒性药物，这些药物与毒性有关，通常疗效有限。最近，我们有了一个令人惊讶的发现，FDA批准的某些人类免疫缺陷病毒(HIV)蛋白酶抑制剂在各种临床前狼疮模型中表现出了希望。其中，奈非那韦(商标名Viracept)在HIV患者中具有相对良性的安全性，不太可能对狼疮患者产生免疫抑制或引起不良反应。根据奈非那韦已知的安全性和我们的临床前数据显示，奈非那韦在一定程度上作为诱饵抗原来抑制致病性狼疮抗双链DNA自身抗体，我们建议在试点可行性IIa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。我们将对升高的抗dsDNA自身抗体效价的受试者进行预筛查，并将早期替代疗效措施纳入这项试验设计。这些创新和其他创新将为狼疮带来个性化的医学方法，并有助于试验成功的可能性。此外，我们也注意到，将FDA批准的药物重新用于新的适应症将有助于以极快的速度进入紧急的未得到满足的医疗需求。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。

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.