奥瑞珠单抗与干扰素β-1a 治疗复发型多发性硬化症的疗效比较。
Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis.
机构信息
From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.
出版信息
N Engl J Med. 2017 Jan 19;376(3):221-234. doi: 10.1056/NEJMoa1601277. Epub 2016 Dec 21.
BACKGROUND
B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells.
METHODS
In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks. The primary end point was the annualized relapse rate.
RESULTS
The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a.
CONCLUSIONS
Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann-La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333 , respectively.).
背景
B 细胞影响多发性硬化症的发病机制。奥瑞珠单抗是一种人源化单克隆抗体，可选择性耗尽 CD20+B 细胞。
方法
在两项相同的 3 期试验中，我们随机分配 821 例和 835 例复发型多发性硬化症患者接受静脉注射奥瑞珠单抗，剂量为每 24 周 600mg，或皮下注射干扰素β-1a，剂量为每周 3 次 44μg，共 96 周。主要终点是年复发率。
结果
奥瑞珠单抗组的年复发率低于干扰素β-1a 组，试验 1 中为 0.16 与 0.29（奥瑞珠单抗组降低 46%；P<0.001），试验 2 中为 0.16 与 0.29（奥瑞珠单抗组降低 47%；P<0.001）。在预先设定的汇总分析中，奥瑞珠单抗组在 12 周时确认的残疾进展患者比例显著低于干扰素β-1a 组（9.1% 与 13.6%；风险比，0.60；95%置信区间 [CI]，0.45 至 0.81；P<0.001），在 24 周时确认的残疾进展患者比例也显著低于干扰素β-1a 组（6.9% 与 10.5%；风险比，0.60；95%CI，0.43 至 0.84；P=0.003）。试验 1 中，奥瑞珠单抗组每例 T 加权磁共振扫描的钆增强病变数为 0.02，干扰素β-1a 组为 0.29（奥瑞珠单抗组病变数减少 94%，P<0.001），试验 2 中为 0.02 与 0.42（奥瑞珠单抗组病变数减少 95%，P<0.001）。多发性硬化功能综合评分（一种衡量行走速度、上肢运动和认知的综合指标；对于该 z 分数，负值表示恶化，正值表示改善）在试验 2 中奥瑞珠单抗组明显优于干扰素β-1a 组（0.28 与 0.17，P=0.004），但在试验 1 中差异无统计学意义（0.21 与 0.17，P=0.33）。奥瑞珠单抗治疗组有 34.3%的患者出现输注相关反应。奥瑞珠单抗治疗组有 1.3%的患者发生严重感染，干扰素β-1a 治疗组有 2.9%的患者发生严重感染。奥瑞珠单抗治疗组有 0.5%的患者发生肿瘤，干扰素β-1a 治疗组有 0.2%的患者发生肿瘤。
结论
在复发型多发性硬化症患者中，奥瑞珠单抗与干扰素β-1a 相比，在 96 周期间疾病活动和进展的发生率较低。需要进行更大和更长时间的奥瑞珠单抗安全性研究。（由 F. Hoffmann-La Roche 资助；OPERA I 和 II 临床试验编号，NCT01247324 和 NCT01412333）。
Zotero 插件