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Emicizumab reduces bleeding in patients with severe hemophilia A
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Weekly subcutaneous administration of the bispecific antibody emicizumab decreased the rate of bleeding events in patients with hemophilia A, according to the results of a dose-escalation study.
The responses remained robust in patients with or without factor VIII inhibitors, results showed.
Regular prophylactic and episodic IV infusions of factor VIII serve as the standard of care for patients with hemophilia A.
“There are significant barriers to this treatment,” Midori Shima, MD, PhD, of the department of pediatrics at Nara Medical University in Kashihara, Japan, and colleagues wrote. “The standard regimen, which consists of IV administration three times per week or every other day, can impose a substantial burden on patients, particularly children and patients with poor venous access. ... Moreover, the induction of anti-factor VIII alloantibodies (factor VIII inhibitors), which occurs in 30% of patients with severe hemophilia A, renders treatment with factor VIII ineffective.”
Emicizumab (ACE910, Chugai Pharmaceuticals/Genentech) mimics the cofactor function of factor VIII. It is not expected to induce or be affected by factor VIII inhibitors and, thus, may serve as a less burdensome therapeutic option.
Shima and colleagues conducted an open-label study of emicizumab in adult and adolescent patients (range, 12-59 years) with severe hemophilia A, with or without factor VIII inhibitors.
The researchers divided patients into three cohorts (n = 6 for each). Each cohort included at least one patient aged 18 years or younger (cohort 1, n =1; cohorts 2 and 3, n = 2). Eleven patients on study had factor VIII inhibitors (cohorts 1 and 2, n = 4; cohort 3, n = 3). Cohort 1 had the highest annualized bleeding rate (median, 32.5; range, 8.1-77.1) in the 6-month period prior to study entry.
Patients received 12 weeks of weekly subcutaneous emicizumab at doses of 0.3 mg (cohort 1), 1 mg (cohort 2) or 3 mg (cohort 3) per kg of body weight.
Key study endpoints included safety, pharmacokinetics and pharmacodynamics. The researchers added annual bleeding rate — calculated as 365.25 times the number of bleeding episodes, divided by the number of days on treatment — as an exploratory endpoint.
Nearly all patients (n = 17) completed 12 weeks of emicizumab administrated. One patient in cohort 2 discontinued treatment due to injection-site erythema.
The researchers observed a dose-dependent increase in plasma emicizumab concentrations, with mean trough levels reaching a steady state by week 12 in cohort 1 (mean, 10.3 ± 4.54 g per milliliter) and cohort 2 (mean, 29.9 ± 6.88 g per milliliter).
The mean trough level in cohort 3 increased to 87.9 ± 20 g per milliliter by week 12 but did not reach steady state.
Median bleeding rates reduced from the rate at baseline in all cohorts (cohort 1, 32.5 to 4.4; cohort 2, 18.3 to 0; cohort 3, 15.2 to 0). Rates of joint bleeding also markedly decreased in all cohorts (cohort 1, 27.4 to 4.3; cohort 2, 15.2 to 0; cohort 3, 9.1 to 0).
Decreases occurred regardless of factor VIII inhibitors or prior prophylaxis. Eight patients (73%) with factor VIII inhibitors and five patients (71%) without had no bleeding episodes.
All bleeding events (n = 21) were successfully resolved with a clotting agent.
The researchers observed 43 adverse events in 15 patients (83%). No severe adverse events occurred, and each cohort had a similar number of patients with at least one adverse event.
No patients developed anti-emicizumab antibodies during treatment. One patient tested positive for anti-emicizumab antibodies at baseline and had a transient increase in C-reactive protein levels on day 3 of treatment; however, this did not affect pharmacokinetics or pharmacodynamics during treatment.
The researchers acknowledged study limitations, including the nonrandomized trial design and the lack of a control group. Further, they noted that small and homogenous patient population may limit the study’s generalizability.
“An extension study is currently under way to examine the long-term safety and efficacy of emicizumab,” Shima and colleagues wrote. – by Cameron Kelsall
Disclosure: Chugai Pharmaceutical funded this study. Shima reports grants, personal fees and nonfinancial support from Chugai Pharmaceutical during the conduct of this study, as well as grants and personal fees from multiple pharmaceutical companies, and patents pending related to the content of this study. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Nigel S. Key, MBChB, FRCP
This paper must qualify as a landmark study by any yardstick. The use of a bispecific antibody that can substitute for Factor VIII in coagulation has the potential to fundamentally change existing treatment paradigms of hemophilia A. The primary complication of clotting factor replacement in the current era is the development of inhibitors, which occurs in up to one third of patients with severe hemophilia A. Emicizumab (ACE910, Chugai Pharmaceuticals) is agnostic to the presence of antibodies to Factor VIII and, therefore, is equally effective as a hemostatic agent in patients with hemophilia A who have developed inhibitors.This approach also could be used to avoid the development of inhibitors in individuals with a particularly high risk. In addition, the avoidance of burdensome IV infusions two to three times a week with weekly (or less frequent) subcutaneous administration is an enormous potential advantage, particularly in small children.
Other novel so-called “disruptive” therapies also are in the pipeline for the treatment of hemophilia. These include agents that target the synthesis or mechanism of action of natural anticoagulants, such as antithrombin or tissue factor pathway inhibitor. The combination of these molecules with the re-emerging race to gene therapy means that this is an incredible time for patients with hemophilia. I would not like to hazard a guess what the standard of care will look like a decade from now.
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