Novel Therapies for Resistant FSGS

描述（由申请人提供）： 原发性FSGS是一种严重的肾脏疾病，占所有需要长期透析或移植的儿童和成人患者的近10-15%。不仅这种疾病的发病率上升，特别是在选择的种族群体，如黑人和西班牙裔，FSGS的病因仍然不清楚，没有被证明是安全和耐受性良好的治疗。为了应对这一紧急情况，一项由NIDDK资助的国家多中心随机临床试验正在进行中，以比较环孢菌素（目前的标准治疗）与MMF和口服地塞米松脉冲联合治疗类固醇耐药FSGS患者的疗效。预计大量患者因既往接受过一种试验治疗或对试验治疗无应答而不符合本试验的资格。患有FSGS的儿童和年轻人对治疗没有反应，有很高的发展终末期肾病的风险。疾病进展总是伴随着肾实质内瘢痕形成和纤维化的增加。迫切需要开发新的疗法来治疗这些难治性患者。该提案将评估三种新型药物的安全性和有效性，这些药物可能具有减少耐药FSGS患者肾纤维化和减缓疾病恶化速度的能力。这个阶段性创新奖的应用程序由两个不同的部分组成。在R21阶段的初始阶段，将测试两种新型疗法-肿瘤坏死因子-α（TNF-α拮抗剂）和过氧化物酶体增殖物激活物受体-γ（PPARgamma）激动剂的安全性、耐受性和药代动力学特征。在第二阶段，R33阶段，将进行随机II期临床试验，以评估TNF-α拮抗剂adalumimab、PPAR-gamma激动剂罗格列酮、抗TGF-β抗体GC 1008和最佳保守药物治疗的疗效。本研究的结果将指导正式III期随机临床试验的设计。为执行该R21/R33项目而建立的基础设施应证明可用于有效评估未来将为原发性FSGS患者开发的其他新疗法。

DESCRIPTION (provided by applicant): Primary FSGS is a serious renal disease, accounting for nearly 10-15% of all pediatric and adult patients requiring chronic dialysis or transplantation. Not only is the incidence of this disease rising, especially in select ethnic groups such as Blacks and Hispanics, the etiology of FSGS remains obscure and there is no proven therapy that is safe and well tolerated. In response to this urgent situation, a national multicenter NIDDK-funded randomized clinical trial is underway to compare the efficacy of cyclosporine, the current standard of care, with a combination of MMF and oral dexamethasone pulses in patients with steroid-resistant FSGS. It is anticipated that a significant number of patients will be ineligible for this trial because of prior treatment with one of the test therapies or will fail to respond to the experimental treatment. Children and young adults with FSGS who fail to respond to therapy have a high risk of developing end stage renal disease. The disease progression is always accompanied by increasing scarring and fibrosis within the kidney parenchyma. There is a critical need to develop novel therapies to treat these refractory patients. This proposal will evaluate the safety and efficacy of three novel agents that may have the capacity to reduce renal fibrosis and slow the rate of deterioration of disease in patients with resistant FSGS. This Phased Innovation Award application is composed of two distinct sections. During the initial stage, the R21 Phase, the safety, tolerance, and pharmacokinetic profile of two novel therapies - a tumor necrosis factor-alpha (TNF-alpha antagonist) and a peroxisome proliferator activator receptor-gamma, (PPARgamma) agonist will be tested. In the second stage, the R33 phase, a randomized Phase II clinical trial will be performed to assess the efficacy of the TNF-alpha antagonist adalumimab, the PPAR-gamma agonist rosiglitazone, an anti-TGF-beta antibody GC1008, and optimal conservative medical therapy. The outcome of this study will guide the design of a formal Phase III randomized clinical trial. The infrastructure that is established for the performance of this R21/R33 project should prove useful for the efficient assessment of additional novel therapies that will be developed in the future for patients with primary FSGS.