A Phase II Trial of Rituximab In Myasthenia Gravis

描述(申请人提供)：重症肌无力(MG)是一种神经肌肉传播的自身免疫性疾病，估计年发病率约为1-2/10万，患病率高达20-50/10万。治疗包括对症治疗和免疫治疗，如皮质类固醇、硫唑嘌呤、环孢素、血浆交换(PLEX)和静脉注射免疫球蛋白(IVIg)。尽管有目前的治疗方法，但仍有一部分患者在药物上难以治愈或有无法忍受的药物不良反应。在MG的管理中需要另一个代理人，因为有效的药物很少。安全、耐受性好、有效且节省类固醇的疗法是非常可取的。我们提出的研究将有助于确定一种新的治疗MG的策略，该策略可能比目前的方法更有效。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患者的好处。我们完成了一项评估B细胞靶向治疗难治性全身性重症肌无力的小型回顾性研究。在这项分析中，我们表明利妥昔单抗在减少或停止其他免疫疗法的同时，导致了持续的临床改善。我们现在计划利用无效性设计进行一项多中心随机、双盲、安慰剂对照的II期临床试验。该研究将包括乙酰胆碱受体(AChR)抗体阳性的全身性MG患者。这项研究还提供了一个研究药物和疾病机制的独特机会，因为与许多其他使用利妥昔单抗的自身免疫性疾病不同，MG提供了参与疾病免疫病理的抗原特异性成分的研究。这项工作将进一步加深我们对MG免疫病理学的理解，它是朝着更全面地了解利妥昔单抗治疗MG的免疫机制迈出的第一步，从而为治疗这种疾病开辟了新的途径。这项研究的具体主要目的是确定利妥昔单抗是否安全，并显示出足够的前景作为MG的类固醇节省疗法，以保证在III期疗效试验中进行进一步研究。此外，我们计划 收集标本以进行由NIAID资助的辅助探索性生物标记物研究，重点确定治疗如何改变MG的免疫病理。

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.