An Open Label Trial of Ixazomib for Treatment Resistant Myasthenia Gravis

重症肌无力是一种以肌肉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(麝香)。这些抗体是由短暂的浆母细胞产生的 长寿的浆细胞。到目前为止，还没有专门针对这两种细胞的MG治疗。 Ixazomib是一种蛋白酶体抑制剂，成功用于治疗多发性骨髓瘤，多发性骨髓瘤是一种 恶性浆细胞。我们建议使用IxMG试验来评估是否口服给药 Ixazomib将是安全的，并具有生物学和临床疗效的信号 耐药AChR或麝香MG，占MG人群的30%以上。 患者将接受3个周期的ixazomib治疗(每周输液，共3周)。 治疗3个月后随访3个月。临床和生物监测将 在每次治疗时进行，然后每4周进行一次。审判将评估安全性， Ixazomib治疗全身性耐药的耐受性和活性 重症肌无力和详细的自身抗体分析，淋巴细胞特征，以及 抗体谱评价。第二阶段评估的不通过决定将针对 过度的不利影响或缺乏目标参与，同时将做出继续进行的决定 基于安全性和生物靶点接合的确认。

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.