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%。这种疾病的发病率不仅在上升，特别是在黑人和西班牙裔等特定种族群体中，而且FSGS的病因仍然不明，也没有经过证实的安全和耐受性良好的治疗方法。为了应对这一紧急情况，一项由NIDDK资助的全国性多中心随机临床试验正在进行中，以比较环孢菌素(目前的治疗标准)与MMF和口服地塞米松脉冲治疗类固醇耐药FSGS患者的疗效。预计有相当数量的患者将不符合这项试验的条件，因为之前接受了其中一种测试疗法的治疗，或者对试验性治疗没有反应。对治疗无效的患有FSGS的儿童和年轻人发展为终末期肾病的风险很高。疾病进展总是伴随着肾实质内愈演愈烈的疤痕和纤维化。迫切需要开发新的治疗方法来治疗这些难治性患者。这项建议将评估三种新型药物的安全性和有效性，这些药物可能有能力减少肾纤维化，减缓耐药FSGS患者的疾病恶化速度。这份阶段性创新奖申请由两个截然不同的部分组成。在R21阶段的初始阶段，将测试两种新疗法-肿瘤坏死因子-α(肿瘤坏死因子-α拮抗剂)和过氧化物酶体增殖物激活物受体-伽马(PPAR-伽马)激动剂的安全性、耐受性和药代动力学。在第二阶段，即R33阶段，将进行随机第二阶段临床试验，以评估肿瘤坏死因子-α拮抗剂adalimab、PPAR-γ激动剂罗格列酮、抗转化生长因子-β抗体GC1008的疗效，以及最佳保守药物治疗。这项研究的结果将指导正式的第三阶段随机临床试验的设计。为执行这一R21/R33项目而建立的基础设施将被证明有助于有效地评估未来将为原发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.