An Open Label Trial of Ixazomib for Treatment Resistant Myasthenia Gravis

重症肌无力是一种以肌无力为特征的自身免疫性疾病 由自身抗体引起，主要针对肌肉乙酰胆碱受体（AChR）和 肌肉特异性激酶（MuSK）。这些抗体由短寿命的浆母细胞产生， 长寿的浆细胞迄今为止，没有MG治疗特异性靶向这些细胞中的任一种。 伊克赛是一种蛋白酶体抑制剂，成功用于治疗多发性骨髓瘤， 恶性浆细胞我们建议IxMG试验来评估口服给药是否 Ixazomib将是安全的，并具有生物学和临床有效性信号， 耐药AChR或MuSK MG，占MG人群的30%以上。 患者将接受3个周期的ixazomib治疗（每周输注一次，持续3周） 在3个月期间，随后进行3个月随访。临床和生物监测将 在每次治疗时进行，然后每4周一次。试验将评估安全性， Ixazomib治疗全身性耐药患者的耐受性和活性 重症肌无力和详细的自身抗体分析，淋巴细胞特征， 抗体库评估。将对以下人员做出不进行第2阶段评估的决定： 过多的不利影响或缺乏目标接合，而将作出继续进行的决定 基于安全性和生物目标接合的确认。

Myasthenia gravis (MG) is an autoimmune disorder characterized by muscle weakness caused by autoantibodies, mainly targeting the muscle acetylcholine receptor (AChR) and the muscle specific kinase (MuSK). These antibodies are produced by short-lived plasmablasts and long-lived plasma cells. To date, no MG treatment specifically targets either of these cells. Ixazomib is a proteasome inhibitor used successfully to treat multiple myeloma, a cancer of malignant plasma cells. We propose the IxMG trial to evaluate whether orally administered ixazomib will be safe and have biological and clinical signals of efficacy for patients with treatment-resistant AChR or MuSK MG, which comprise upwards of 30% of the MG population. Patients will be treated with 3 cycles of ixazomib (weekly infusions every week for 3 weeks) during a period of 3 months followed by 3 month follow-up. Clinical and biological monitoring will be performed at time of each treatment and then every 4 weeks. The trial will assess the safety, tolerability, and activity of ixazomib as a therapy for treatment-resistant patients with generalized myasthenia gravis and detailed autoantibody analysis, lymphocyte characterization, and antibody repertoire evaluation. A no-go decision for a Phase 2 assessment will be made for excess adverse effects or lack of target engagement, while a decision to proceed will be made based on safety and confirmation of biological target engagement.