From the Neurological Institute Foundation C. Besta (C.A.), Milan, Italy; Duke University School of Medicine (J. Guptill), Durham, NC; Argenx US Inc. (J. Guptill), Boston, MA; University of Toronto (V.B.), ON, Canada; Universitat Autonoma de Barcelona, (J. Gamez), Spain; Medical Faculty (S.G.M.), Heinrich-Heine-University, Düsseldorf, Germany; Yale University School of Medicine (R.J.N.), New Haven, CT; University of Colorado School of Medicine (D.Q.), Aurora; Hospital Universitari i Politécnic La Fe (T.S.), Universitat de Valencia, Spain; Pharvaris, Inc. (M.-H.J.), Boston, MA; Janssen Research & Development, LLC, (J.J., K.K., S.R.,H.S., L.L., Y.Z.), Titusville, NJ; Marinus Pharmaceuticals, Inc. Radnor, PA; Fulcrum Therapeutics (S.A.), Cambridge, MA.
Neurology. 2024 Jan 23;102(2):e207937. doi: 10.1212/WNL.0000000000207937. Epub 2023 Dec 21.
To evaluate in a phase 2 study the safety and efficacy of IV nipocalimab, a fully human, antineonatal Fc receptor monoclonal antibody, in patients with generalized myasthenia gravis (gMG).
Patients with gMG with inadequate response to stable standard-of-care (SOC) therapy were randomized 1:1:1:1:1 to receive either IV placebo every 2 weeks (Q2W) or one of 4 IV nipocalimab treatments: 5 mg/kg once every 4 weeks (Q4W), 30 mg/kg Q4W, 60 mg/kg Q2W each for 8 weeks, or a 60 mg/kg single dose, in addition to their background SOC therapy. Infusions (placebo or nipocalimab) were Q2W in all groups to maintain blinding. The primary safety endpoint was incidence of treatment-emergent adverse events (TEAEs), including serious adverse events and adverse events of special interest. The primary efficacy endpoint was change from baseline to day 57 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores. Dose response of change at day 57 was analyzed with a linear trend test over the placebo, nipocalimab 5 mg/kg Q4W, nipocalimab 30 mg/kg Q4W, and nipocalimab 60 mg/kg Q2W groups.
Sixty-eight patients (nipocalimab: n = 54; placebo, n = 14) were randomized; 64 patients (94.1%) were positive for antiacetylcholine receptor autoantibodies, and 4 patients (6%) were positive for antimuscle-specific tyrosine kinase autoantibodies. Fifty-seven patients (83.8%) completed treatment through day 57. The combined nipocalimab group compared with the placebo group demonstrated similar incidences of TEAEs (83.3% vs 78.6%, respectively) and infections (33.3% vs 21.4%, respectively). No deaths or discontinuations due to TEAEs and no TEAEs of special interest (grade ≥3 infection or hypoalbuminemia) were observed with nipocalimab treatment. A statistically significant dose response was observed for change from baseline in MG-ADL at day 57 ( = 0.031, test of linear trend).
Nipocalimab was generally safe, well-tolerated, and showed evidence of dose-dependent reduction in MG-ADL scores at day 57 in this phase 2 study. These results support further evaluation of nipocalimab for the treatment of gMG.
Clinical Trials Registration: NCT03772587; first submitted December 10, 2018; EudraCT Number: 2018-002247-28; first submitted November 30, 2018; date of first patient dosed April 10, 2019.
This study provides Class I evidence that for patients with gMG, nipocalimab was well-tolerated, and it did not significantly improve MG-ADL at any individual dose but demonstrated a significant dose response for improved MG-ADL across doses.
评估 IV 型尼泊利单抗（一种完全人源抗新生 Fc 受体单克隆抗体）在全身型重症肌无力（gMG）患者中的安全性和疗效。
对稳定标准治疗（SOC）反应不足的 gMG 患者进行随机分组，1:1:1:1:1 比例分别接受安慰剂（每 2 周[Q2W]）或 4 种 IV 尼泊利单抗治疗之一：5mg/kg 每 4 周（Q4W）、30mg/kg Q4W、60mg/kg Q2W 各 8 周，或 60mg/kg 单次剂量，同时接受其背景 SOC 治疗。所有组别的输注（安慰剂或尼泊利单抗）均每 2 周进行一次，以维持盲法。主要安全性终点是治疗出现的不良事件（TEAEs）的发生率，包括严重不良事件和特殊关注的不良事件。主要疗效终点是从基线到第 57 天的重症肌无力日常生活活动（MG-ADL）总分的变化。使用线性趋势检验分析第 57 天的变化与安慰剂、尼泊利单抗 5mg/kg Q4W、尼泊利单抗 30mg/kg Q4W 和尼泊利单抗 60mg/kg Q2W 组之间的剂量反应。
68 名患者（尼泊利单抗：n=54；安慰剂：n=14）被随机分组；64 名患者（94.1%）抗乙酰胆碱受体自身抗体阳性，4 名患者（6%）抗肌肉特异性酪氨酸激酶自身抗体阳性。57 名患者（83.8%）完成了第 57 天的治疗。尼泊利单抗组与安慰剂组的 TEAEs 发生率（分别为 83.3%和 78.6%）和感染率（分别为 33.3%和 21.4%）相似。在尼泊利单抗治疗中未观察到与 TEAEs 相关的死亡或停药，也未观察到特殊关注的 TEAEs（≥3 级感染或低白蛋白血症）。从基线到第 57 天的 MG-ADL 变化呈统计学显著的剂量依赖性（=0.031，线性趋势检验）。
在这项 2 期研究中，尼泊利单抗总体上是安全的，耐受良好，且在第 57 天显示出 MG-ADL 评分降低的剂量依赖性。这些结果支持进一步评估尼泊利单抗治疗全身型重症肌无力。
临床试验注册号：NCT03772587；首次提交日期：2018 年 12 月 10 日；EudraCT 编号：2018-002247-28；首次提交日期：2018 年 11 月 30 日；首次给药日期：2019 年 4 月 10 日。
本研究提供了 I 级证据，表明对于全身型重症肌无力患者，尼泊利单抗耐受良好，在任何单一剂量下均未显著改善 MG-ADL，但在不同剂量下均表现出对 MG-ADL 的显著剂量反应。
