Emicizumab subcutaneous injection once weekly may reduce the risk of bleeding in patients with hemophilia A with factor VIII inhibitors
EBM Focus - Volume 12, Issue 30
- Current prophylactic therapy for hemophilia A with factor VIII inhibitors requires IV access and frequent administration, and may not be effective in all patients. Emicizumab, a recently developed antibody, can be administered subcutaneously once weekly.
- In the HAVEN 1 trial, 53 patients with hemophilia A with factor VIII inhibitors were randomized in an open-label study to prophylactic emicizumab subcutaneous injection once weekly vs. no prophylaxis for ≥ 24 weeks. Randomized patients had a history of episodic therapy but not prophylactic therapy with bypassing agents, and continued with their usual treatment for bleeding events as needed.
- Emicizumab reduced the rates of all non-surgery non-procedure bleeding events (5.5 vs. 28.3 events/year, p < 0.0001), joint bleeds treated with bypassing agents (0.8 vs. 6.7 events/year, p < 0.005), and other types of bleeding events.
Bleeding in hemophilia A is due to deficient factor VIII (fVIII) activity of the blood coagulation cascade. Prophylactic fVIII replacement therapy may reduce bleeding episodes in some patients, but patients with inhibitory alloantibodies against fVIII (fVIII inhibitors) require bypassing agents that activate other parts of the coagulation cascade. Current bypassing agents require IV access and have short half-lives, and not all patients respond adequately. Emicizumab is a recently developed recombinant antibody that partly mimics the function of fVIII by activating its downstream targets but is not affected by fVIII inhibitors, is administered subcutaneously, and has a half life of 2 weeks (Nat Med 2012 Oct;18(10):1570). A small nonrandomized trial demonstrated that emicizumab may reduce bleeding rates in patients with severe hemophilia A with or without fVIII inhibitors (N Engl J Med 2016 May 26;374(21):2044). To better assess emicizumab as prophylactic therapy, the HAVEN 1 trial randomized 53 male patients aged 12-68 years (11% < 18 years old) with congenital hemophilia A with factor VIII inhibitors ≥ 5 Bethesda units/mL to prophylactic emicizumab subcutaneous injection once weekly vs. no prophylaxis for ≥ 24 weeks. Emicizumab was given at 3 mg/kg for the first 4 weeks and at 1.5 mg/kg thereafter. Randomized patients were aware of their treatment allocation, had a history of episodic therapy but not prophylactic therapy with bypassing agents, and continued with their usual treatment for bleeding events as needed. At baseline, 92% of randomized patients had severe hemophilia A (fVIII activity < 1%), 70% had ≥ 9 bleeding episodes during the previous 24 weeks, and 40% had previous induction of immune tolerance. Patients randomized to no prophylaxis had the option of taking emicizumab after 24 weeks.
The mean rate of any bleeding event excluding bleeds due to surgery or procedure was 5.5 events/year with prophylactic emicizumab vs. 28.3 events/year without prophylaxis (p < 0.0001). Patients taking prophylactic emicizumab also had lower rates of other bleeding events, including bleeds treated with bypassing agents (2.9 vs. 23.3 events/year, p < 0.0001) and joint bleeds treated with bypassing agents (0.8 vs. 6.7 events/year, p < 0.005). The majority of patients in the emicizumab group (63%) had zero bleeding events during the trial, while only 5.6% of patients without prophylaxis had zero bleeding events (p < 0.05, NNT 2). In addition, a separate cohort of 49 patients with a history of prophylactic bypassing agents who took the same emicizumab regimen had bleeding outcomes similar to the randomized patients of the emicizumab group (statistical comparisons not reported).
Adverse events were assessed in 103 patients who took emicizumab at any point (including patients randomized to emicizumab, patients randomized to no prophylaxis who took emicizumab after their 24-week bleeding assessments, patients from the non-randomized cohort, and patients who enrolled in the study after the cut-off date for efficacy analysis). Serious adverse events were reported in 9 patients, consisting of clot-related events (thrombotic microangiopathy, skin necrosis, thrombophlebitis superficial, and cavernous sinus thrombosis) in 5 patients and iron deficiency anemia, sepsis, hemarthrosis, muscle hemorrhage, gastric ulcer hemorrhage, headache, and hematuria in 1 patient each. The most common non-serious adverse events were injection-site reactions in 15 patients and headache in 12 patients. No antidrug antibodies thought to be related to emicizumab were found.
This trial demonstrated that emicizumab subcutaneous injection once weekly may reduce the risk of bleeding in patients with hemophilia A with factor VIII inhibitors. Various serious adverse events were reported in 9 of 103 patients who took emicizumab in this study. The authors noted that each of the 5 clot-related adverse events were preceded by bleeding-related administration of activated prothrombin complex concentrate (APCC) > 100 units/kg for > 1 day, but statistical analyses assessing the potential influence of APCC or other factors on adverse events were not reported. The route and frequency of emicizumab administration are an improvement over other prophylactic bypassing agents, but the efficacy and safety of emicizumab compared to or combined with other prophylactic therapies have not been addressed. The small size, short study duration, and open-label design add uncertainty to all outcomes, but, when available, emicizumab may be considered as an additional prophylactic option in patients with hemophilia A with fVIII inhibitors.