BACKGROUND Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody in development as a once-daily, subcutaneous prophylaxis for patients with haemophilia A or haemophilia B with or without inhibitors. We aimed to assess the efficacy and safety of concizumab in patients with haemophilia A or B without inhibitors. Here we report the results from the confirmatory analysis cutoff. METHODS This prospective, multicentre, open-label, randomised, phase 3a trial (explorer8) was conducted at 69 investigational sites in 31 countries. Eligible patients were male, aged 12 years or older, and had congenital severe haemophilia A or moderate or severe haemophilia B without inhibitors and with documented treatment with clotting factor concentrate in the 24 weeks before screening. The trial was paused because of non-fatal thromboembolic events in three patients (two from this trial [explorer8] and one from a related trial in haemophilia with inhibitors [explorer7; NCT04083781]) and restarted with mitigation measures, including a revised dosing regimen of subcutaneous concizumab at 1·0 mg/kg loading dose on day 1 and subsequent daily doses of 0·20 mg/kg from day 2, with options to decrease to 0·15 mg/kg, stay on 0·20 mg/kg, or increase to 0·25 mg/kg on the basis of concizumab plasma concentration measured after 4 weeks on concizumab. Patients recruited after treatment restart were randomly assigned 1:2 using an interactive web response system to receive no prophylaxis and continue on-demand clotting factor (group 1) or concizumab prophylaxis (group 2). The primary endpoints were the number of treated spontaneous and traumatic bleeding episodes for patients with haemophilia A and haemophilia B separately, assessed at the confirmatory analysis cutoff in randomly assigned patients. Analyses were by intention-to-treat. There were two additional groups containing non-randomly-assigned patients: group 3 contained patients who entered the trial before the trial pause and were receiving concizumab in the phase 2 trial (explorer5; NCT03196297), and group 4 contained patients who received previous clotting factor concentrate prophylaxis or on-demand treatment in the non-interventional trial (explorer6; NCT03741881), patients randomly assigned to groups 1 or 2 before the treatment pause, and patients from explorer5 enrolled after the treatment pause. The safety analysis set contained all patients who received concizumab. Superiority of concizumab over no prophylaxis was established if the two-sided 95% CI of the treatment ratio was less than 1 for haemophilia A and for haemophilia B. This trial is registered with ClinicalTrials.gov, NCT04082429, and its extension part is ongoing. FINDINGS Patients were recruited between Nov 13, 2019 and Nov 30, 2021; the cutoff date for the analyses presented was July 12, 2022. 173 patients were screened, of whom 148 (86%) were randomly assigned or allocated to the four groups in the study after trial restart on Sept 30, 2020 (nine with haemophilia A and 12 with haemophilia B in group 1; 18 with haemophilia A and 24 with haemophilia B in group 2; nine with haemophilia A in group 3; and 46 with haemophilia A and 30 with haemophilia B in group 4). The estimated mean annualised bleeding rate ratio for treated spontaneous and traumatic bleeding episodes during concizumab prophylaxis versus no prophylaxis was 0·14 (95% CI 0·07-0·29; p<0·0001) for patients with haemophilia A and 0·21 (0·10-0·45; p<0·0001) for patients with haemophilia B. The most frequent adverse events in patients who received concizumab were SARS-CoV-2 infection (19 [13%] of 151 patients), an increase in fibrin D-dimers (12 [8%] patients), and upper respiratory tract infection (ten [7%] patients). There was one fatal adverse event possibly related to treatment (intra-abdominal haemorrhage in a patient from group 4 with haemophilia A with a long-standing history of hypertension). No thromboembolic events were reported between the trial restart and confirmatory analysis cutoff. INTERPRETATION Concizumab was effective in reducing the bleeding rate compared with no prophylaxis and was considered safe in patients with haemophilia A or B without inhibitors. The results of this trial suggest that concizumab has the potential to be one of the first subcutaneous treatment options for patients with haemophilia B without inhibitors. FUNDING Novo Nordisk.

中文翻译：

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无抑制剂的血友病 A 或血友病 B 患者的 Concizumab 预防 （explorer8）：一项前瞻性、多中心、开放标签、随机、3a 期试验。


背景 Concizumab 是一种抗组织因子通路抑制剂单克隆抗体，正在开发中，用于血友病 A 或血友病 B 患者每日一次的皮下预防，伴或不伴抑制剂。我们旨在评估 concizumab 在无抑制因子的血友病 A 或 B 患者中的疗效和安全性。在这里，我们报告了验证性分析临界值的结果。方法 这项前瞻性、多中心、开放标签、随机、3a 期试验 （explorer8） 在 31 个国家的 69 个研究地点进行。符合条件的患者为男性，年龄在 12 岁或以上，患有先天性严重血友病 A 或中度或重度血友病 B，无抑制剂，并且在筛选前 24 周内接受过凝血因子浓缩物治疗记录。该试验因 3 例患者的非致死性血栓栓塞事件而暂停 （2 例来自该试验 [explorer8] 和 1 例来自抑制因子血友病相关试验 [explorer7;NCT04083781]）并重新启动缓解措施，包括在第 1 天以 1·0 mg/kg 负荷剂量皮下注射 concizumab，随后从第 2 天开始每日剂量为 0·20 mg/kg，可选择降低至 0·15 mg/kg，保持 0·20 mg/kg，或根据 concizumab 4 周后测量的 concizumab 血浆浓度增加至 0·25 mg/kg。使用交互式网络响应系统以 1：2 的比例随机分配治疗重新开始后招募的患者，接受无预防治疗并继续按需使用凝血因子 （第 1 组） 或 concizumab 预防 （第 2 组）。 主要终点是血友病 A 和血友病 B 患者分别接受治疗的自发性和创伤性出血发作的数量，在随机分配的患者中按验证性分析临界值进行评估。分析是通过意向性治疗进行的。还有两组包含非随机分配的患者：第 3 组包含在试验暂停前进入试验并在 2 期试验中接受 concizumab 的患者 （explorer5;NCT03196297），第 4 组包含既往在非干预性试验中接受凝血因子浓缩物预防或按需治疗的患者 （Explorer6;NCT03741881），患者在治疗暂停前随机分配到第 1 组或第 2 组，而 explorer5 的患者在治疗暂停后入组。安全性分析集包含所有接受 concizumab 治疗的患者。如果血友病 A 和血友病 B 的治疗比的双侧 95% CI 小于 1，则确定 concizumab 优于无预防。该试验已在 ClinicalTrials.gov NCT04082429 注册，其扩展部分正在进行中。结果 患者招募时间为 2019 年 11 月 13 日至 2021 年 11 月 30 日;所提交的分析截止日期为 2022 年 7 月 12 日。筛选了 173 名患者，其中 148 名 （86%） 在 2020 年 9 月 30 日试验重新开始后被随机分配或分配到研究的四组（第 1 组 9 名血友病 A 和 12 名血友病 B;第 2 组 18 名血友病 A 和 24 名血友病 B;第 3 组 9 名血友病 A;第 4 组 46 名血友病 A 和 30 名血友病 B）。 concizumab 预防与无预防期间治疗的自发性和创伤性出血发作的估计平均年化出血率比为血友病 A 患者 0·14（95% CI 0·07-0·29;p<0·0001），血友病 B 患者为 0·21（0·10-0·45;p<0·0001）。接受 concizumab 治疗的患者最常见的不良事件是 SARS-CoV-2 感染（151 名患者中有 19 名 [13%]）、纤维蛋白 D-二聚体增加（12 名 [8%] 患者）和上呼吸道感染（10 名 [7%] 患者）。有 1 例致命的不良事件可能与治疗有关（第 4 组血友病 A 患者腹腔内出血，有长期高血压病史）。在试验重新开始和确认性分析临界值之间没有报告血栓栓塞事件。解释 与不预防相比，Concizumab 可有效降低出血率，并且被认为对无抑制物的血友病 A 或 B 患者是安全的。该试验的结果表明，concizumab 有可能成为无抑制因子的血友病 B 患者的首批皮下治疗选择之一。资金 诺和诺德。