A Phase II Trial of Rituximab In Myasthenia Gravis

描述（由申请人提供）：重症肌无力（MG）是一种神经肌肉传递的自身免疫性疾病，估计年发病率约为每10万人1-2例，患病率高达每10万人20-50例。治疗包括乙酰胆碱酯酶抑制剂对症治疗和免疫治疗，如皮质类固醇、硫唑嘌呤、环孢素和血浆置换（PLEX）和静脉注射免疫球蛋白（IVIg）。尽管目前的治疗，患者的子集仍然是医学难治性或具有不可忍受的药物不良反应。由于有效的药物很少，因此需要另一种药物来治疗MG。安全、耐受性良好、有效且节省类固醇的治疗剂是非常期望的。我们提出的研究将有助于确定一种新的治疗策略，可能比目前的方法更有效的MG。最近的几项研究，包括我们小组进行的两项研究，已经证明了B细胞耗竭利妥昔单抗治疗MG患者的益处。我们完成了一项小型回顾性研究，以评估医学难治性全身MG的B细胞靶向治疗。在这项分析中，我们发现利妥昔单抗导致持续的临床改善，同时减少或停止其他免疫治疗。我们现在计划进行一项多中心、随机、双盲、安慰剂对照的II期临床试验，采用无效设计。该研究将包括乙酰胆碱受体（AChR）抗体阳性的全身性MG患者。这项研究也提供了一个独特的机会，研究药物和疾病的机制，因为不像许多其他自身免疫性疾病，其中利妥昔单抗已被使用，MG提供了参与疾病的免疫病理学的抗原特异性成分的调查。这项工作将进一步加深我们对MG免疫病理学的理解，它代表了对利妥昔单抗治疗MG的免疫机制的更完整理解的第一步，从而导致治疗该疾病的新方法。本研究的主要目的是确定利妥昔单抗是否安全，是否有足够的希望作为MG的类固醇保留治疗，以保证在III期疗效试验中进一步研究。此外，我们计划 收集标本进行辅助探索性生物标志物研究，由NIAID资助，重点是确定治疗如何改变MG的免疫病理学。

DESCRIPTION (provided by applicant): Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission with an estimated annual incidence of about 1-2 per 100,000 and prevalence as high as 20-50 per 100,000. Treatment consists of symptomatic therapy with acetylcholinesterase inhibitors and immunotherapy such as corticosteroids, azathioprine, cyclosporine, and plasma exchange (PLEX) and intravenous immunoglobulin (IVIg). Despite current therapies, subset of patients remains medically refractory or has intolerable medication adverse effects. There is need for another agent in the management of MG as there are few effective drugs. Safe, well- tolerated, efficacious and steroid-sparing therapeutics are very desirable. Our proposed research will be instrumental in identifying a novel treatment strategy for MG that may be more effective than current approaches. Several recent studies, including two performed by our group, have demonstrated the benefits of B cell depletion rituximab treatment in MG patients. We completed a small retrospective study to evaluate B cell targeted therapy in medically refractory generalized MG. In this analysis we showed that rituximab led to a sustained clinical improvement in parallel to a reduction or discontinuation of other immunotherapies. We now plan on conducting a multicenter randomized, double-blind, placebo controlled Phase II clinical trial utilizing a futility design. The study would include acetylcholie receptor (AChR) antibody positive generalized MG patients. This study also presents a unique opportunity to study both drug and disease mechanisms because unlike many other autoimmune diseases in which rituximab has been used, MG affords the investigation of antigen-specific components that participate in the immunopathology of the disease. This work will further our understanding of MG immunopathology and it represents the first step toward gaining a more complete understanding of the immune mechanisms underlying treatment of MG with rituximab leading to new ways to treat the disease. The specific primary aim of this study is to determine whether rituximab is safe and shows sufficient promise as a steroid sparing therapeutic for MG to warrant further study in a phase III efficacy trial. Additionally, we plan on collecting specimens to conduct an ancillary exploratory biomarker study, funded by NIAID, focused on identifying how treatment modifies the immunopathology of MG.