Mim8 Bispecific Antibody Prophylaxis in Hemophilia A with or without Inhibitors.

Methods

In this phase 3, randomized trial, we assigned patients 12 years of age or older with hemophilia A with or without inhibitors to receive subcutaneous Mim8 once weekly or once monthly at a dose tiered according to body weight and given in a fixed injection volume (0.8 ml).

在这项III期、随机试验中，我们将12岁或以上的有或没有抑制物的血友病A患者分配接受每周或每月一次皮下注射Mim8，剂量根据体重分级，并以固定的注射体积（0.8毫升）给予。

Patients who had been receiving on-demand treatment before the trial were assigned in a 1:1:1 ratio to continue on-demand treatment (group 1) or receive Mim8 once weekly (group 2a) or once monthly (group 2b).

在试验前接受按需治疗的患者按照1:1:1的比例被分配继续接受按需治疗（第1组）或每周接受一次Mim8（第2a组）或每月接受一次Mim8（第2b组）。

Patients who had been receiving clotting factor concentrates during a run-in phase were assigned in a 1:1 ratio to receive Mim8 once weekly (group 3) or once monthly (group 4).

在试验前的准备阶段接受凝血因子浓缩物治疗的患者按照1:1的比例被分配每周接受一次Mim8（第3组）或每月接受一次Mim8（第4组）。

The first primary end point was the annualized rate of treated bleeding events (those treated with a coagulation factor product) in an evaluation of Mim8 in group 2a and Mim8 in group 2b as compared with on-demand treatment in group 1.

第一个主要终点是评估组2a中使用Mim8和组2b中使用Mim8的患者与组1中按需治疗的患者在治疗出血事件（使用凝血因子产品治疗）的年化率。

The second was the annualized rate of treated bleeding events in an intrapatient evaluation of Mim8 in group 3 and Mim8 in group 4 as compared with clotting factor concentrate prophylaxis during the run-in phase.

第二个终点是组3和组4中使用Mim8的患者在自身对照评估中与在启动阶段使用凝血因子浓缩物预防治疗的患者在治疗出血事件的年化率。

Results

Of the 58 patients in the pretrial on-demand treatment cohort, 17 were assigned to group 1, 21 to group 2a, and 20 to group 2b.

在预试验的按需治疗队列中，58名患者中有17名被分配到第1组，21名到第2a组，20名到第2b组。

The estimated mean annualized rate of treated bleeding events was 0.57 (95% confidence interval[CI], 0.25 to 1.30) in group 2a and 0.20 (95% CI, 0.06 to 0.71) in group 2b, as compared with 15.76 (95% CI, 10.70 to 23.20) in group 1 (relative decrease, 96.4% and 98.7%, respectively; P<0.001 for both comparisons).

在第2a组中，治疗出血事件的估计平均年化率为0.57（95%置信区间[CI]，0.25至1.30），而在第2b组中为0.20（95% CI，0.06至0.71），与第1组的15.76（95% CI，10.70至23.20）相比（相对减少分别为96.4%和98.7%；两者比较P<0.001）。

Of the 196 patients in the pretrial prophylaxis cohort, 98 each were assigned to group 3 or group 4.

在试验前预防队列中的196名患者中，98名被分配到第3组，另外98名被分配到第4组。

The estimated mean annualized rate of treated bleeding events was 2.25 (95% CI, 1.37 to 3.71) in group 3, as compared with 4.90 (95% CI, 3.65 to 6.56) during the run-in phase (relative decrease, 54.0%; P = 0.006), and 1.78 (95% CI, 1.18 to 2.71) in group 4, as compared with 3.12 (95% CI, 2.25 to 4.32) (relative decrease, 42.8%; P = 0.006).

在第3组中，估计的治疗出血事件的平均年化率为2.25（95%置信区间，1.37至3.71），与启动阶段的4.90（95%置信区间，3.65至6.56）相比（相对减少54.0%；P=0.006），而在第4组中，为1.78（95%置信区间，1.18至2.71），与3.12（95%置信区间，2.25至4.32）相比（相对减少42.8%；P=0.006）。

Injection-site reactions were reported in 103 of 4005 injections (2.6%).

在4005次注射中，有103次（占2.6%）报告了注射部位反应。

No patient was reported to have a thromboembolic event or clinical evidence of neutralizing anti-Mim8 antibodies.

没有患者报告出现血栓栓塞事件或中和抗Mim8抗体的临床证据。

Conclusions

Among patients with hemophilia A with or without inhibitors, Mim8 prophylaxis was superior to on-demand treatment and clotting factor concentrate prophylaxis regarding the annualized rate of treated bleeding events.

在有或没有抑制物的血友病A患者中，Mim8预防治疗在治疗出血事件的年化率方面优于按需治疗和凝血因子浓缩物预防治疗。

(Funded by Novo Nordisk; FRONTIER2 ClinicalTrials.gov number, NCT05053139.).

(由诺和诺德资助；FRONTIER2临床试验注册号，NCT05053139。)