Conference Coverage

Antibody reduces bleeding in hemophilia A patients with inhibitors


Photo by Linda Bartlett

Monoclonal antibodies

BERLIN—Emicizumab can reduce bleeding in adults and adolescents with hemophilia A and inhibitors to factor VIII, according to a phase 3 trial.

In the HAVEN 1 trial, prophylaxis with emicizumab reduced the treated bleed rate by 87% when compared to no prophylaxis.

Emicizumab reduced the treated bleed rate by 79% when compared to prior prophylaxis with bypassing agents (BPAs).

The incidence of adverse events (AEs) related to emicizumab was 22%, and the incidence of serious AEs was 9%.

There were 3 cases of thrombotic microangiopathy, 2 serious thromboembolic events, and 1 death (from hemorrhage).

These results were presented at the 26th International Society on Thrombosis and Haemostasis (ISTH) Congress and published in NEJM.

The study was funded by F. Hoffmann–La Roche and Chugai Pharmaceutical.

“The HAVEN 1 study is one of the most robust clinical studies conducted to date in people with hemophilia A with inhibitors to factor VIII, including a first-ever intra-patient comparison to prior prophylaxis with bypassing agents,” said study author Johannes Oldenburg, MD, PhD, of the University of Bonn in Bonn, Germany.

“The reduction in bleeding events across all measures seen with emicizumab compared to either on-demand or prophylactic bypassing agents supports that it may be one of the most significant scientific innovations in the treatment of hemophilia A in over 30 years.”

Emicizumab is a bispecific monoclonal antibody designed to bring together factors IXa and X, proteins required to activate the natural coagulation cascade and restore the blood clotting process.

HAVEN 1 is a randomized, phase 3 study of emicizumab that enrolled 109 patients (12 years of age or older) with hemophilia A and inhibitors to factor VIII. The patients were previously treated with BPAs on-demand or as prophylaxis.

Patients previously treated with on-demand BPAs were randomized in a 2:1 fashion to receive emicizumab prophylaxis (Arm A) or no prophylaxis (Arm B).

Patients previously treated with prophylactic BPAs received emicizumab prophylaxis (Arm C). Additional patients previously on BPAs (on-demand or prophylaxis) were also enrolled in a separate arm (Arm D).

On-demand treatment of breakthrough bleeds with BPAs was allowed per protocol in all arms.


The primary endpoint of this study was the number of treated bleeds over time with emicizumab prophylaxis (Arm A) compared with no prophylaxis (Arm B).

There was a significant reduction in treated bleeds of 87% (risk rate [RR]=0.13, P<0.0001) with emicizumab compared with no prophylaxis.

The researchers also performed an intra-patient comparison of bleed rate with emicizumab prophylaxis to bleed rate with prior prophylaxis (with BPAs) for patients in Arm C. A subset of patients in this arm had previously participated in a non-interventional study (NIS), which allowed for the comparison.

The analysis showed a 79% (RR=0.21, P=0.0003) reduction in treated bleeds in patients receiving emicizumab compared with their prior prophylaxis during the NIS.

Additional data on bleeds in Arms A, B, and C are included in the following table.

Study group No prophylaxis

(prior episodic BPAs)

(Arm B; n=18)

Emicizumab prophylaxis

(prior episodic BPAs)

(Arm A; n=35)

Treated bleeds annualized bleeding rate (ABR, primary endpoint)

(95% CI)


(12.33; 43.89)


(1.69; 5.02)

% reduction

(RR, P value)

87% reduction

(RR=0.13, P<0.0001)

Median ABR

(Interquartile range; IQR)


(12.97; 35.08)


(0.00; 3.73)

% patients with 0 bleeds (95% CI) 5.6

(0.1; 27.3)


(44.9; 78.5)

All bleeds ABR (secondary endpoint)

(95% CI)


(16.79; 47.76)


(3.58; 8.60)

% reduction

(RR, P value)

80% reduction

(RR=0.20, P<0.0001)

% patients with 0 bleeds (95% CI) 5.6

(0.1; 27.3)


(21.5; 55.1)

Treated spontaneous bleeds ABR (secondary endpoint)

(95% CI)


(9.94; 28.30)


(0.73; 2.19)

% reduction

(RR, P value)

92% reduction

(RR=0.08, P<0.0001)

% patients with 0 bleeds (95% CI) 11.1

(1.4; 34.7)


(50.7; 83.1)

Treated joint bleeds ABR (secondary endpoint)

(95% CI)


(1.99; 22.42)


(0.26; 2.20)

% reduction

(RR, P value)

89% reduction

(RR=0.11, P=0.0050)

% patients with 0 bleeds (95% CI) 50.0

(26.0; 74.0)


(69.7; 95.2)

Treated target joint bleeds ABR (secondary endpoint)

(95% CI)


(0.96; 9.13)


(0.03; 0.58)

% reduction

(RR, P value)

95% reduction

(RR=0.05, P=0.0002)

% patients with 0 bleeds (95% CI) 50.0

(26.0; 74.0)


(80.8; 99.3)

Treated bleeds ABR, intra-patient comparison

(Arm C patients who participated in NIS, n=24; secondary endpoint)

Study group Prior prophylaxis with a BPA Emicizumab prophylaxis

(95% CI)


(11.08; 22.29)


(1.33; 8.08)

% reduction

(RR, P value)

79% reduction

(RR=0.21, P=0.0003)

Median ABR



(5.73; 24.22)


(0.00; 2.23)

% patients with 0 bleeds

(95% CI)


(2.7; 32.4)


(48.9; 87.4)

*Negative binomial regression model


Safety results in patients who received emicizumab prophylaxis (n=103) are as follows.

Total number of AEs 198
Total number of participants experiencing ≥ 1 AE, n (%) 73 (70.9)
Related AEs 23 (22.3)
Serious AEs 9 (8.7)
Grade ≥3 AEs 8 (7.8)
Local injection site reaction 15 (14.6)
Headache 12 (11.7)
Upper respiratory tract infection 9 (8.7)
Fatigue 6 (5.8)
Joint pain (arthralgia) 6 (5.8)
Thrombotic microangiopathy* 3 (2.9)
Serious thromboembolic event** 2 (1.9)
Death* 1 (<1)

*The third thrombotic microangiopathy event occurred after the primary data cut-off. This patient also experienced fatal rectal hemorrhage.

**Serious thromboembolic events consisted of skin necrosis/superficial thrombophlebitis in 1 patient and cavernous sinus thrombosis in a second patient.

None of the patients tested positive for anti-drug antibodies.

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