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Treatment investigated to prevent blood-clotting disorders


A new subcutaneous therapy could offer a promising solution to a bleeding disorder in both children and adults.

Hemophilia A is an inherited blood-clotting disorder that affects about 20,000 persons in the United States-with about half of those having a severe form of the disorder. The disorder causes uncontrolled, spontaneous bleeding because of a lack of the clotting protein called factor VIII, which normally brings together clotting factors IXa and X in healthy individuals to stop bleeding. For individuals with hemophilia A, this clotting does not occur and bleeding can be life threatening. Replacement of the clotting factors isn’t easy, either, because some patients can develop antibodies that can block replacement of factor VIII.

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Now a once-weekly treatment that could offer “dramatic” results for children with hemophilia A is under priority review by the US Food and Drug Administration (FDA).

The treatment being investigated is a bispecific monoclonal antibody called emicizumab, according to data from the biotechnology company Genentech (South San Francisco, California). It was designed to utilize IXa and X proteins, which are required to activate the coagulation cascade needed for blood clotting. Two phase III studies are under way, dubbed the Haven 1 study examining the efficacy of the treatment in adolescents and adults aged older than 12 years with and without factor VIII inhibitors, and the smaller Haven 2 study examining the effect of the treatment on children aged younger than 12 years with factor VIII inhibitors. In both studies, the treatment is delivered subcutaneously once a week through a ready-to-use solution. Ongoing studies are also investigating whether less frequent dosing also may be as effective, according to Genentech.

Guy Young, MD, director of the Hemostasis and Thrombosis Program at Children’s Hospital Los Angeles, California, professor of Pediatrics at the Keck School of Medicine of the University of Southern California, Los Angeles, and a Haven investigator, says the treatment could substantially improve quality of life and outcomes for patients with hemophilia A.

“It offers the potential for improving the lives of patients with hemophilia by improving their outcomes while simultaneously reducing the treatment burden by offering a subcutaneous, once-weekly therapy instead of a several-times-a-week intravenous therapy,” Young says. “The trial data are dramatic. These are patients who are bleeding 20 to 30 times per year, and to see that number drop basically to zero is really something. It’s a very, very exciting innovation in an area where we are really desperate for some better medication.”

NEXT: Promising study results


Promising study results

The Haven 2 study was conducted in 19 children aged younger than 12 years for about 12 weeks. The FDA granted priority review to the Biologics License Application for emicizumab based on preliminary results from the Haven 2 study and final results from the Haven 1 study, which showed that treatment with emicizumab for 31 weeks substantially reduced bleeding in patients by 87% overall-with a 79% reduction in treated bleeds on emicizumab compared with prior bypassing agent (BPA) prophylaxis therapies. According to data from Genentech, 70.8% of patients who had previously received BPA prophylaxis had zero treated bleeds on emicizumab compared with just 12.5% who had zero bleeds on their prior BPA prophylaxis. According to the full Haven 1 study results published in the New England Journal of Medicine,1 the treatment was not only effective in reducing bleeding events overall in untreated hemophiliac patients, but it was also more effective than other episodic treatments. More than 100 patients with a mean age of 28 years and mostly severe forms of the disease participated in the study. During the study, the annualized bleeding rate in patients who used emicizumab was 2.9 events compared with 23.3 events in patients with no therapy. In total, 22 of the 35 patients who received emicizumab had zero bleeding events compared with just 1 of the 18 patients who received no prophylactic therapy, according to the study.

In a noninterventional arm of the study, researchers compared bleeding rates in patients who used emicizumab prophylaxis compared with those who used other episodic BPAs as treatments. They found that the annualized bleeding rate was 1.7 events in the group treated with emicizumab prophylactically compared with 21.6 events in the groups treated with previous episodic BPAs.1

In terms of safety, the study revealed that there were 198 adverse events reported among 103 study participants, but mild injection site reactions were most frequently reported.1 Twelve serious events occurred in 9 patients, and those were thrombotic microangiopathy in 2 participants, and cavernous sinus thrombosis and skin necrosis-superficial thrombophlebitis-in 1 participant each. These events occurred in participants who had received multiple infusions of activated prothrombin complex concentrate at the same time as emicizumab. These events either resolved or did not require anticoagulation, the study reported.

The FDA is not expected to issue a final decision on the priority review of emicizumab until February 2018, but Young says he is hopeful about the clinical benefits of the treatment.

Next: New antibody eases hemophilia treatment

“I expect that we will be able to substantially reduce the morbidity for a subset of patients with hemophilia, those with inhibitors, and offer them a much more normal life than we can offer them now,” Young says. “I also expect that for the majority of patients, those without inhibitors, that we will be able to offer them a therapy that will be as effective as what we can offer now but to do so with a far less burdensome treatment that they can easily administer at home.”


1. Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017;377(9):809-818.

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