Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle (MIRCEM), Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France.
Mayo Clinic, Rochester, MN, United States.
Mult Scler Relat Disord. 2022 Jan;57:103356. doi: 10.1016/j.msard.2021.103356. Epub 2021 Nov 1.
The N-MOmentum trial, a double-blind, randomized, placebo-controlled, phase 2/3 study of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD), enrolled participants who were aquaporin-4-immunoglobulin G (AQP4-IgG)-seropositive (AQP4+) or -seronegative (AQP4-). This article reports AQP4- participant outcomes.
AQP4-IgG serostatus was determined for all screened participants by a central laboratory, using a validated, fluorescence-observation cell-binding assay. Medical histories and screening data for AQP4- participants were assessed independently by an eligibility committee of three clinical experts during screening. Diagnosis of NMOSD was confirmed by majority decision using the 2006 neuromyelitis optica criteria. Myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) serology (using a clinically validated, flow cytometry assay) and annualized attack rates (AARs) were evaluated post hoc. Efficacy outcomes were assessed by comparing pre-study and on-study AARs in treated participants.
Only 18/50 AQP4- screened participants (36%) were initially considered eligible for randomization; 16 were randomized and received full treatment, 4 to placebo (1 MOG-IgG-seropositive [MOG+]) and 12 to inebilizumab (6 MOG+). The most common reason for failure to pass screening among prospective AQP4- participants was failure to fulfill the 2006 NMO MRI criteria. In inebilizumab-treated AQP4- participants, on-study AARs (95% confidence interval [CI]) calculated from treatment initiation (whether from randomization or when received at the start of the open-label period) to the end of study were lower than pre-study rates: for all AQP4- participants (n = 16), mean (95% CI) AAR was 0.048 (0.02-0.15) versus 1.70 (0.74-2.66), respectively. For the subset of AQP4-/MOG+ participants (n = 7), AAR was 0.043 (0.006-0.302) after treatment versus 1.93 (1.10-3.14) before the study. For the subset of AQP4-/MOG- participants (n = 9), post-treatment AAR was 0.051 (0.013-0.204) versus 1.60 (1.02-2.38). Three attacks occurred during the randomized controlled period in the AQP4- inebilizumab group and were of mild severity; no attacks occurred in the AQP4- placebo group. The low number of participants receiving placebo (n = 4) confounds direct comparison with the inebilizumab group. No attacks were seen in any AQP4- participant after the second infusion of inebilizumab. Inebilizumab was generally well tolerated by AQP4- participants and the adverse event profile observed was similar to that of AQP4+ participants.
The high rate of rejection of AQP4- participants from enrollment into the study highlights the challenges of implementing the diagnostic criteria of AQP4- NMOSD. An apparent reduction of AAR in participants with AQP4- NMOSD who received inebilizumab warrants further investigation.
N-MOmentum 试验是一项针对视神经脊髓炎谱系疾病（NMOSD）中伊奈利珠单抗的双盲、随机、安慰剂对照、2/3 期研究，纳入了水通道蛋白 4 免疫球蛋白 G（AQP4-IgG）阳性（AQP4+）或阴性（AQP4-）的参与者。本文报告了 AQP4- 参与者的结局。
所有筛选参与者的 AQP4-IgG 血清状态均由中心实验室使用经过验证的荧光观察细胞结合测定法进行确定。在筛选期间，由三名临床专家组成的资格委员会对 AQP4- 参与者的医疗史和筛选数据进行独立评估。NMOSD 的诊断通过使用 2006 视神经脊髓炎标准的多数决策进行确认。使用临床验证的流式细胞术测定法评估髓鞘少突胶质细胞糖蛋白免疫球蛋白 G（MOG-IgG）血清学和年发病率（AAR）。在接受治疗的参与者中，通过比较研究前和研究期间的 AAR 来评估疗效结局。
只有 50 名 AQP4- 筛选参与者中的 18 名（36%）最初被认为有资格随机分组；16 名被随机分组并接受了完整治疗，4 名接受安慰剂（1 名 MOG-IgG 阳性[MOG+]），12 名接受伊奈利珠单抗（6 名 MOG+）。在有前途的 AQP4- 参与者中，未能通过筛选的最常见原因是未能满足 2006 年 NMOSD MRI 标准。在接受伊奈利珠单抗治疗的 AQP4- 参与者中，从治疗开始（无论是否随机分组，或在开放标签期开始时）到研究结束的研究期间 AAR（95%置信区间[CI]）均低于研究前的发生率：对于所有 AQP4- 参与者（n=16），平均（95%CI）AAR 为 0.048（0.02-0.15）与 1.70（0.74-2.66），分别为。对于 AQP4-/MOG+ 参与者亚组（n=7），治疗后 AAR 为 0.043（0.006-0.302），研究前为 1.93（1.10-3.14）。对于 AQP4-/MOG- 参与者亚组（n=9），治疗后 AAR 为 0.051（0.013-0.204），研究前为 1.60（1.02-2.38）。在伊奈利珠单抗组中，有 3 次攻击发生在随机对照期间，且均为轻度；在 AQP4- 安慰剂组中未发生攻击。接受安慰剂（n=4）的参与者人数较少，与伊奈利珠单抗组直接比较存在混淆。在接受伊奈利珠单抗治疗的任何 AQP4- 参与者中，均未发生任何攻击。AQP4- 参与者一般对伊奈利珠单抗耐受性良好，观察到的不良事件谱与 AQP4+ 参与者相似。
AQP4- 参与者被高比例拒绝纳入研究，这突显了实施 AQP4- NMOSD 诊断标准的挑战。接受伊奈利珠单抗治疗的 AQP4- NMOSD 患者 AAR 明显降低，需要进一步研究。
