Biogen, Cambridge, MA, USA.
Departments of Neurology, Population Health, and Ophthalmology, New York University School of Medicine, New York, NY, USA.
Lancet Neurol. 2017 Mar;16(3):189-199. doi: 10.1016/S1474-4422(16)30377-5. Epub 2017 Feb 15.
The human monoclonal antibody opicinumab (BIIB033, anti-LINGO-1) has shown remyelinating activity in preclinical studies. We therefore assessed the safety and tolerability, and efficacy of opicinumab given soon after a first acute optic neuritis episode.
This randomised, double-blind, placebo-controlled, phase 2 study (RENEW) was done at 33 sites in Australia, Canada, and Europe in participants (aged 18-55 years) with a first unilateral acute optic neuritis episode within 28 days from study baseline. After treatment with high-dose methylprednisolone (1 g/day, intravenously, for 3-5 days), participants were assigned with a computer-generated sequence with permuted block randomisation (1:1) using a centralised interactive voice and web response system to receive 100 mg/kg opicinumab intravenously or placebo once every 4 weeks (six doses) and followed up to week 32. All study participants and all study staff, including the central readers, were masked to treatment assignment apart from the pharmacist responsible for preparing the study treatments and the pharmacy monitor at each site. The primary endpoint was remyelination at 24 weeks, measured as recovery of affected optic nerve conduction latency using full-field visual evoked potential (FF-VEP) versus the unaffected fellow eye at baseline. Analysis was by intention-to-treat (ITT); prespecified per-protocol (PP) analyses were also done. This study is registered with ClinicalTrials.gov, number NCT01721161.
The study was done between Dec 21, 2012, and Oct 21, 2014. 82 participants were enrolled, and 41 in each group comprised the ITT population; 33 participants received opicinumab and 36 received placebo in the PP population. Adjusted mean treatment difference of opicinumab versus placebo was -3·5 ms (17·3 vs 20·8 [95% CI -10·6 to 3·7]; 17%; p=0·33) in the ITT population, and -7·6 ms in the PP population (14·7 vs 22·2 [-15·1 to 0·0]; 34%; p=0·050) at week 24 and -6·1 ms (15·1 vs 21·2 [-12·7 to 0·5]; 29%; p=0·071) in the ITT population and -9·1 ms (13·2 vs 22·4 [-16·1 to -2·1]; 41%; p=0·011) in the PP population at week 32. The overall incidence (34 [83%] of 41 in each group) and severity of adverse events (two [5%] of 41 severe adverse events with placebo vs three [7%] of 41 with opicinumab) were similar between groups and no significant effects on brain MRI measures were noted in either group (mean T2 lesion volume change, 0·05 mL [SD 0·21] for placebo vs 0·20 mL [0·52] with opicinumab; 27 [77%] of 35 participants with no change in gadolinium-enhancing [Gd+] lesion number with opicinumab vs 27 [79%] of 34 with placebo; mean 0·4 [SD 0·79 for the placebo group and 0·85 for the opicinumab group] new Gd+ lesions per participant in both groups). Treatment-related serious adverse events were reported in three (7%) of 41 participants in the opicinumab group (hypersensitivity [n=2], asymptomatic increase in transaminase concentrations [n=1]) and none of the participants in the placebo group.
Remyelination did not differ significantly between the opicinumab and placebo groups in the ITT population at week 24. However, results from the prespecified PP population suggest that enhancing remyelination in the human CNS with opicinumab might be possible and warrant further clinical investigation.
Biogen.
人类单克隆抗体 opicinumab（BIIB033，抗 LINGO-1）在临床前研究中显示出了髓鞘再生活性。因此，我们评估了在首次急性视神经炎发作后不久给予 opicinumab 的安全性、耐受性和疗效。
这是一项在澳大利亚、加拿大和欧洲的 33 个地点进行的随机、双盲、安慰剂对照、2 期研究（RENEW），参与者为首次单侧急性视神经炎发作后 28 天内的患者（年龄 18-55 岁）。在接受高剂量甲基泼尼松龙（1 g/天，静脉注射，持续 3-5 天）治疗后，参与者采用计算机生成的序列，使用中央交互式语音和网络响应系统进行 1：1 随机分组，接受 100 mg/kg opicinumab 静脉注射或安慰剂，每 4 周一次（共 6 次），随访至第 32 周。所有研究参与者和所有研究人员（包括负责准备研究治疗的药剂师和每个地点的药房监测员）都对治疗分配保持盲态，除了药剂师。主要终点是 24 周时的髓鞘再生，使用全视野视觉诱发电位（FF-VEP）测量受影响视神经传导潜伏期的恢复与基线时未受影响的对侧眼相比。分析采用意向治疗（ITT）；还进行了预设的符合方案（PP）分析。该研究在 ClinicalTrials.gov 上注册，编号为 NCT01721161。
该研究于 2012 年 12 月 21 日至 2014 年 10 月 21 日进行。共纳入 82 名参与者，每组 41 名，包括 ITT 人群；33 名参与者接受了 opicinumab 治疗，36 名参与者接受了安慰剂治疗。ITT 人群中，opicinumab 与安慰剂的调整平均治疗差异为-3·5 ms（17·3 对 20·8 [95%CI-10·6 至 3·7]；17%；p=0·33），PP 人群中为-7·6 ms（14·7 对 22·2 [-15·1 至 0·0]；34%；p=0·050），第 24 周；在 ITT 人群中为-6·1 ms（15·1 对 21·2 [-12·7 至 0·5]；29%；p=0·071），在 PP 人群中为-9·1 ms（13·2 对 22·4 [-16·1 至 -2·1]；41%；p=0·011），第 32 周。两组的总不良事件发生率（每组 41 名参与者中各有 34 名[83%]）和严重不良事件的严重程度（安慰剂组有 2 名[5%]严重不良事件，opicinumab 组有 3 名[7%]）相似，两组的脑 MRI 测量均未观察到明显影响（平均 T2 病变体积变化，安慰剂组为 0·05 mL [SD 0·21]，opicinumab 组为 0·20 mL [0·52]；opicinumab 组有 27 名[77%]无钆增强[Gd+]病变数变化，安慰剂组有 27 名[79%]；每组平均新 Gd+病变数 0·4 [SD 安慰剂组为 0·79，opicinumab 组为 0·85]）。opicinumab 组有 3 名（7%）参与者报告了与治疗相关的严重不良事件（过敏反应[n=2]，丙氨酸转氨酶浓度无症状升高[n=1]），安慰剂组无参与者报告。
在第 24 周时，opicinumab 组和安慰剂组的 ITT 人群的髓鞘再生无显著差异。然而，预设的 PP 人群的结果表明，用 opicinumab 增强人中枢神经系统的髓鞘再生可能是可能的，并值得进一步的临床研究。
Biogen。
