Emicizumab may herald new standard of care for haemophilia A
Once-weekly subcutaneous administration of the novel recombinant, humanized, IgG4 bispecific antibody emicizumab prevents or reduces bleeds in patients with haemophilia A and factor VIII inhibitors in the phase III HAVEN 1* trial, offering a potential new standard of care for this severe bleeding disorder.
In patients given emicizumab prophylaxis, the annualized bleeding rate was 2.9 events vs 23.3 events in those with no prophylaxis. This translates to a difference of 87 percent, in favour of emicizumab (p<0.001). Over 24 weeks, 63 percent of patients in the emicizumab group had no bleeds vs 6 percent in the no prophylaxis group. [ISTH 2017, abstract ASY 01.1; N Engl J Med 2017;doi:10.1056/NEJMoal703068]
“The current standard of care for haemophilia A with severe bleeding phenotype is prophylactic intravenous infusions of factor VIII twice or thrice weekly,” said lead author Dr Johannes Oldenburg from the Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn in Bonn, Germany. “However, exposure to factor VIII concentrates is associated with the development of neutralizing antifactor VIII or inhibitors, which render replacement factor VIII ineffective in one of three patients with haemophilia A.”
Therapies for patients with high titre of inhibitors involve induction of immune tolerance to factor VIII and episodic or prophylactic treatment with haemostatic bypassing agents (BPAs) such as recombinant activated factor VII (factor VIIa) and activated prothrombin complex concentrates. Nonetheless, both options require frequent intravenous infusions over an extended period. “
New kid on the block
Emicizumab bridges activated factors IX and X to replace the function of missing factor VIII, resulting in thrombin generation and coagulation. In addition, emicizumab has not been documented to induce development of inhibitors. “[Hence], emicizumab may provide a weekly, subcutaneous, prophylactic, therapeutic option for patients with haemophilia A with inhibitors,” said Oldenburg.
In the HAVEN 1 trial, Oldenburg and colleagues sought to assess the efficacy and safety of emicizumab prophylaxis in patients with haemophilia A with inhibitors.
The trial involved 109 male patients aged 12 years or older (median age 28) with congenital haemophilia A, had a high titre of factor VIII inhibitor (≥5 Bethesda units/mL), and were receiving episodic or prophylactic treatment with BPAs. Patients who had received episodic treatment with BPAs prior to study entry were randomized in a 2:1 ratio to receive weekly subcutaneous emicizumab prophylaxis (group A, n=35) vs no prophylaxis (group B, n=18). The primary efficacy endpoint was the difference in treated bleeds between groups A and B after the last patient randomized had completed 24 weeks of the trial or had withdrawn, whichever occurred first.
Patients who had previously received prophylactic BPAs were given emicizumab as a prophylaxis (group C). The trial was conducted at 43 centres in 14 countries. The median exposure to emicizumab was 24 weeks overall, and 29.5 weeks for group A.
Prior to study entry, nearly 70 percent of patients in each group had ≥ nine bleeds. There was a wide range of inhibitor titres in each group (5–1570 Bethesda units and 18–4500 in groups A and B, respectively).
Of note, there was a 79 percent reduction in treated bleed rate with emicizumab prophylaxis in group C, lower than the rate with previous BPA prophylaxis (annualized bleeding rate, 3.3 vs 15.7 events; p<0.001).
“These findings were supported by substantially lower rates of other bleeding-related endpoints such as all bleeds, treated spontaneous bleeds, joint bleeds, and target-joint bleeds with emicizumab [arm A] vs no prophylaxis [arm B],” said Oldenburg. “To date, none has discontinued the drug for lack of efficacy and none has tested positive for antidrug antibodies.”
At 25 weeks, there was statistically significant and clinically meaningful improvement in health-related quality of life (HRQoL) and health status among patients given emicizumab prophylaxis (group C).
Emicizumab was well-tolerated and the most common adverse event reported was injection site reaction in 15 percent of patients.
“Overall results represent a potential paradigm shift and new standard of care for treatment of haemophilia A with inhibitors,” Oldenburg concluded.
Towards an enhanced standard of care
In an accompanying editorial, Dr David Lillicrap from the Queen’s University, Kingston in Ontario, Canada described the HAVEN 1 findings as “extremely important for the haemophilia treatment community, which has battled the haemostatic calamity of factor VIII inhibitor formation with the same bypassing therapies for the past 30 years.” [N ENgl J Med 2017;doi:10.1056/NEJMe1707802]
The advent of emicizumab represents a major contribution to achieving an enhanced standard of care for this lifelong bleeding disorder, he said.
As of this writing, the US FDA has granted priority review to emicizumab for haemophilia A with inhibitors. Decision is expected early next year.