Background

Emicizumab, a subcutaneously administered, humanised, bispecific, monoclonal antibody, is approved to treat people with haemophilia A of all ages with and without coagulation factor VIII (FVIII) inhibitors. HAVEN 4 assessed emicizumab prophylaxis administered as one dose every 4 weeks in adults and adolescents with haemophilia A, regardless of FVIII inhibitor status.

Methods

In this phase 3, multicentre, open-label, two-stage study, patients aged 12 years and older with severe congenital haemophilia A (<1% of normal FVIII activity in blood) or haemophilia A with FVIII inhibitors, undergoing treatment with either FVIII concentrates or bypassing agents were recruited from three sites in Japan and Spain for a run-in cohort, and from 17 sites in Australia, Belgium, Japan, Poland, Spain, and the USA for a subsequent expansion cohort. Participants in the run-in and expansion cohorts were given emicizumab subcutaneously 6 mg/kg every 4 weeks for 24 weeks or more; for patients in the expansion cohort this regimen was preceded by four loading doses of 3 mg/kg once weekly. In the run-in cohort, we assessed pharmacokinetics after single and multiple (every 4 weeks) subcutaneous administration of 6 mg/kg emicizumab and safety. In the expansion cohort, the efficacy endpoint was efficacy of prophylactic emicizumab in maintaining adequate bleed prevention, assessed in all patients who received at least one dose of emicizumab and reported as annualised bleed rates for treated bleeds, all bleeds (treated and untreated), treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds. Safety was assessed in all participants given emicizumab. This study is registered with ClinicalTrials.gov, number NCT03020160, and is ongoing.

Findings

Between Jan 30, 2017, and Feb 27, 2017, seven patients were enrolled into the initial run-in cohort, which confirmed the expected pharmacokinetic profile and safety of the regimen based on model-based simulations, providing sufficient evidence for opening of the expansion cohort (n=41), which was recruited and enrolled between May 24, 2017, and June 30, 2017. The annualised rate of treated bleeds was 2·4 (95% CI 1·4–4·3). 23 (56·1%; 95% CI 39·7–71·5) of 41 reported no treated bleeds and 37 (90%; 76·9–97·3) reported zero to three treated bleeds. The annualised bleed rate was 4·5 (95% CI 3·1–6·6) for all bleeds, 0·6 (0·3–1·5), for treated spontaneous bleeds, 1·7 (0·8–3·7) for treated joint bleeds, and 1·0 (0·3–3·3) for treated target joint bleeds. The most frequent treatment-related adverse event was injection-site reaction (nine [22%] of 41 patients). We observed no thrombotic events or development of de-novo antidrug antibodies with neutralising potential or FVIII inhibitors.

Interpretation

Emicizumab given once every 4 weeks showed clinically meaningful bleed control while being well tolerated. This regimen could improve patient care by decreasing treatment burden and increasing adherence to effective prophylaxis, potentially decreasing the development of secondary complications for people with haemophilia A.

Funding

F Hoffmann-La Roche and Chugai Pharmaceutical.

中文翻译：

---

甲型血友病患者每4周进行一次艾米珠单抗预防的功效，安全性和药代动力学（HAVEN 4）：一项多中心，开放标签，非随机的3期研究

背景

Emicizumab是一种皮下给药的人源化双特异性单克隆抗体，已被批准用于治疗具有和不具有凝血因子VIII（FVIII）抑制剂的所有年龄段的A型血友病患者。无论FVIII抑制剂的状态如何，HAVEN 4评估了A型血友病成人和青少年每4周给予一剂艾米珠单抗的预防性治疗。

方法

在这项三阶段，多中心，开放标签，两阶段研究中，患有严重先天性A型血友病（血液中FVIII活性的<1％）或患有FVIII抑制剂的A型血友病的12岁及以上患者接受了FVIII的治疗从日本和西班牙的三个地点招募了浓缩剂或绕过剂，以进行先期研究，并从澳大利亚，比利时，日本，波兰，西班牙和美国的17个地点中招募了随后的扩大研究组。每4周皮下给予emicizumab参加磨合和扩张研究小组的参与者，疗程为24周或更长时间；对于扩展队列中的患者，在此方案之前，每周一次进行4次3 mg / kg的负荷剂量。在常规队列中，我们评估了单次或多次（每4周）皮下注射6 mg / kg艾米珠单抗的药代动力学和安全性。在扩展队列中，功效终点是预防性艾米珠单抗维持足够的出血预防的功效，在接受至少一剂艾米珠单抗的所有患者中进行评估，并报告为治疗出血，所有出血（已治疗和未治疗），已治疗的年度出血率自发性出血，已治疗的关节出血和已治疗的目标关节出血。评估所有接受艾米单抗治疗的参与者的安全性。该研究已在ClinicalTrials.gov上注册，编号为NCT03020160，并且正在进行中。处理过的关节出血，以及治疗过的目标关节出血。评估所有接受艾米单抗治疗的参与者的安全性。该研究已在ClinicalTrials.gov上注册，编号为NCT03020160，并且正在进行中。处理过的关节出血，以及治疗过的目标关节出血。评估所有接受艾米单抗治疗的参与者的安全性。该研究已在ClinicalTrials.gov上注册，编号为NCT03020160，并且正在进行中。

发现

在2017年1月30日至2017年2月27日之间，有7名患者参加了首次磨合队列研究，这些患者基于基于模型的模拟证实了该方案的预期药代动力学特征和安全性，为扩展开放提供了充分的证据队列（n = 41），于2017年5月24日至2017年6月30日招募和入组。治疗出血的年化率为2·4（95％CI 1·4-4·3）。41例中有23例（56·1％； 95％CI 39·7-71·5）未报告治疗出血，而37例（90％; 76·9-97·3）报告零至3例治疗出血。所有出血的年化出血率均为4·5（95％CI 3·1–6·6），处理后的自发出血的年化出血率为0·6（0·3-1–5），为1·7（0·8–5） 3·7）（治疗关节出血）和1·0（0·3–3·3）治疗目标关节出血。与治疗相关的最常见不良事件是注射部位反应（41例患者中有9例[22％]）。我们未观察到具有中和潜力或FVIII抑制剂的血栓形成事件或新型抗药物抗体的发展。

解释

每4周给予一次Emicizumab表现出临床上有意义的出血控制，同时耐受性良好。该方案可通过减少治疗负担和增加对有效预防的依从性来改善患者护理，从而可能减少A型血友病患者继发并发症的发生。

资金

F Hoffmann-La Roche和Chugai Pharmaceutical。