Treatment of Hemophilia: On the Precipice of a Revolution

The natural history of severe hemophilia A and severe hemophilia B is characterized by frequent spontaneous bleeding into joints, leading to disabling hemophilic arthropathy. Prophylactic administration of factor concentrate ameliorates the disease course but is limited by the need for frequent intravenous administration and high cost.¹  Treatment is less effective and even more costly in the 25 percent of patients with severe hemophilia A and in the 3 percent of patients with severe hemophilia B who form neutralizing inhibitors against factor VIII and factor IX, respectively.² 

We now stand on the precipice of a revolution in hemophilia therapy that holds the promise of improved treatment options for patients with and without inhibitors.

Emicizumab (ACE-910) is a humanized bispecific antibody that mimics the cofactor activity of factor VIII by binding to and bridging activated factor IX and factor X. In a 12-week, open-label, nonrandomized dose-escalation study, 18 Japanese patients with severe hemophilia (11 with and seven without inhibitors) were treated with subcutaneous emicizumab. There were three dose cohorts: 1) 1.0-mg/kg initial dose followed by 0.3 mg/kg weekly, 2) 3.0-mg/kg initial dose followed by 1.0 mg/kg weekly, and 3) 3.0-mg/kg initial dose followed by 3.0 mg/kg weekly. Based on pharmacokinetic and pharmacodynamic modeling, these dosing schemes were expected to result in coagulant activity at trough, similar to factor VIII levels of 3 percent, 10 percent, and 30 percent, respectively. Seventeen of 18 patients completed 12 weeks of treatment (one patient discontinued treatment early due to injection-site erythema). There were no serious adverse events, antibodies to emicizumab, or thrombotic events, though the risk of thrombosis remains a potential concern in patients on emicizumab who require treatment with factor concentrate for breakthrough bleeding. Plasma concentrations of emicizumab increased in a dose-dependent manner and were accompanied by a reduction in the activated partial thromboplastin time and an increase in peak thrombin generation. Compared with the six months before initiation of emicizumab, the median annualized bleeding rate (ABR) during the 12-week study decreased from 32.5 to 4.4, 18.3 to 0, and 15.2 to 0 in the three dose cohorts, respectively. Eight of 11 patients with an inhibitor and five of seven patients without an inhibitor had no bleeds during the study.³  Phase III clinical trials to confirm the efficacy and safety of emicizumab prophylaxis in patients with severe hemophilia A with (NCT02622321) and without inhibitors (NCT02847637) are ongoing, as is a single-arm study in children and adolescents (NCT02795767).

Other “non-factor” therapies for hemophilia in development include fitusiran, an interfering RNA molecule that inhibits antithrombin, and concizumab, a monoclonal antibody that targets tissue factor pathway inhibitor.^4,5  Both agents may be administered subcutaneously and have shown promise in early phase clinical trials. Like emicizumab, a major potential advantage of these agents is their indifference to the presence of inhibitors.

At the same time, progress in gene therapy for hemophilia is advancing rapidly. SPK-9001 is an adeno-associated viral (AAV) capsid with a transgene encoding factor IX Padua, a naturally occurring hyperfunctional factor IX variant. In seven subjects with severe hemophilia B who were infused with SPK-9001 at a dose of 5 × 10¹¹ vector genomes/kg, mean steady-state factor IX activity at 12 weeks was 32.3 percent.⁶  BMN-270 is an AAV-factor VIII gene therapy for hemophilia A. Six of seven subjects infused at a dose of 6 × 10¹³ vg/kg achieved factor VIII levels in excess of 50 percent at 12 to 28 weeks of follow-up.⁷  No subjects developed a factor VIII inhibitor nor did any require immunosuppression, and there was significant reduction of total factor consumption.

This is an immensely exciting time in hemophilia. A loaded pipeline offers the potential for more effective and more convenient treatments and even cure. Amidst the current frenzy of investigation, it is nearly impossible to speculate how hemophilia will be treated in five to 10 years. The only thing we can be confident of is that it will be vastly different from how we treated it in 2016.