Rituximab Therapy in Patients with IPF

描述（由申请人提供）：特发性肺纤维化（IPF）的原因仍然未知，以及导致该疾病进展的因素。目前还没有确定的医学治疗方法可以使患有这种疾病的患者受益，而且IPF的预后仍然比许多常见的恶性肿瘤差。我们的研究小组以及其他研究小组最近的发现表明，自身抗体与IPF进展有关。一项正在进行的早期试点研究的结果进一步表明，旨在减少已有自身抗体和/或减少其未来产生的特异性治疗可改善疾病加重的重症IPF患者的肺功能。我们假设抗体介导的自身免疫在IPF的进展中起重要作用。自身免疫的存在可以解释这种疾病对当前治疗的难治性，因为许多自身抗体肺部疾病对皮质类固醇治疗有耐药性。然而，针对自身抗体或产生这些免疫球蛋白的淋巴细胞的集中治疗通常比类固醇或其他非特异性治疗对这些疾病更有效。因此，我们在此提出一项多中心、随机、双盲、安慰剂对照的II期临床试验，以探讨利妥昔单抗（抗cd20单克隆抗体）与安慰剂在IPF患者中的疗效和安全性。来自四个美国医疗中心的58名流动IPF受试者将被随机（1:1）分配到实验组（利妥昔单抗）或安慰剂组。主要终点是循环自身抗体的全球评估。次要终点是测量与临床进展相关的特异性自身抗体（抗热休克蛋白70），以及测量肺功能（用力肺活量）和不良事件发生率。我们预计这种新的实验性治疗将显示出减少自身抗体的靶向疗效，良好的安全性，并可能稳定肺功能。这些研究结果将确定利妥昔单抗治疗IPF患者的疗效和药代动力学。最终，这些研究可能会挑战目前IPF发病机制的范式，并从根本上改变这种病态、难治性疾病患者的治疗方法。

DESCRIPTION (provided by applicant): The cause(s) of idiopathic pulmonary fibrosis (IPF) remain unknown, as well as the factors that result in the progression of this disease. No established medical treatments have yet been shown to benefit patients with this disease, and IPF continues to have a worse prognosis than many common malignancies. Recent findings of our research group, as well as others, show that autoantibodies are associated with IPF progression. Results of an early ongoing pilot study further indicate that specific treatments aimed at reducing pre-existing autoantibodies and/or minimizing their future production improve lung function among very ill IPF patients who are having disease exacerbations. We hypothesize that antibody-mediated autoimmunity can play an important role in IPF progression. The presence of autoimmunity could explain the refractoriness of this disease to current therapy, since many autoantibody lung diseases are resistant to treatment with corticosteroids. However, focused treatments targeted at autoantibodies or the lymphocytes that produce these immunoglobulins often have greater efficacy for these diseases than steroids or other nonspecific therapies. Accordingly, we propose here a multicenter, randomized, double-blind, placebo-controlled Phase II clinical trial to explore the efficacy and safety of rituximab (anti-CD20 monoclonal antibody) vs. placebo, among patients with IPF. Fifty-eight (58) ambulatory IPF subjects at four participating U.S. medical centers will be randomized (1:1) to either the experimental arm (rituximab) or placebo. The primary end-point is a global assessment of circulating autoantibodies. Secondary end-points are measures of a specific autoantibody that is associated with clinical progression (anti-heat shock protein 70), as well as a measure of lung function (forced vital capacity), and adverse event rates. We anticipate the novel experimental treatment will show targeted efficacy for reduction of autoantibodies, a favorable safety profile, and possibly stabilization of lung function. Results of these investigations will establish the efficacy and pharmacokinetics of rituximab treatment in IPF patients. Ultimately these studies could challenge current paradigms of IPF pathogenesis, and substantially alter treatment approaches to patients afflicted with this morbid, refractory disease.