New Promise for Patients with Hereditary Angioedema

Published - Written by Rena Xu

Patients with hereditary angioedema suffer from acute attacks of subcutaneous and submucosal swelling. This autosomal dominant disorder is caused by mutations in the C1 esterase inhibitor gene that result in low levels of C1 inhibitor or normal levels with reduced function. C1 inhibitor is important for regulating the coagulation, complement, and contact cascades; in hereditary angioedema, all three cascades appear to be dysregulated. Bradykinin, a potent vasodilator activated through the contact cascade, is a key mediator; excess bradykinin increases capillary endothelial permeability and leads to localized swelling. The resulting edema is painful and can be life-threatening when it causes obstruction of the upper airways.

Until recently, treatment options for hereditary angioedema have been limited. Attenuated androgens have been reported to be effective as prophylaxis, but they can lead to severe adverse events and are not effective as treatment once an acute attack has happened. Numerous studies have supported the safety and efficacy of C1 inhibitors; however, because the formulations are prepared from human plasma, there is some risk of viral contamination, and C1 inhibitors were not FDA-approved until 2009. The quest to further reduce the risk of viral transmission, and to identify alternative therapeutic options, has continued.

This week’s issue of The New England Journal of Medicine (NEJM) reports on three new treatments for hereditary angioedema: a nanofiltered C1 inhibitor concentrate; a recombinant inhibitor of plasma kallikrein, a target of C1 esterase inhibitor; and a selective bradykinin B2 receptor antagonist.

Zuraw et al. conducted two randomized multicenter trials to evaluate the use of intravenous nanofiltered C1 inhibitor as both treatment for and prophylaxis against acute attacks. In the treatment trial, 71 of 324 enrolled subjects experienced acute attacks and were randomly assigned to receive either the nanofiltered C1 inhibitor or a placebo. The primary measured endpoint was the time to onset of unequivocal relief from symptoms. Secondary endpoints included the percentage of patients who reached unequivocal relief within four hours. Encouragingly, the authors found that the median time to the primary endpoint was 2 hours for patients taking C1 inhibitor as compared with more than 4 hours for patients taking placebo.

Other results from the acute attack treatment trial were not as positive. 40% of patients treated with the C1 inhibitor did not reach unequivocal relief within four hours and needed open-label rescue therapy. This represents a higher failure rate than had been previously reported in other randomized trials. On the other hand, 93% of subjects treated with C1 inhibitor in an open-label assessment achieved unequivocal symptom relief within four hours.

The second trial by Zuraw et al. investigated the efficacy of the intravenous nanofiltered C1 inhibitor as prophylaxis. Patients who had suffered an acute attack from the first trial were given twice-weekly injections of either nanofiltered C1 inhibitor or placebo for 12 weeks. The authors report that the frequency of acute attacks was halved when the patients took the C1 inhibitor as compared with placebo (6.26 versus 12.73 attacks). This is a promising finding, as it suggests a potential solution for preventing acute attacks and keeping these patients out of emergency rooms.

But even with an improved, safer formulation, C1 inhibitor may not be the ideal therapeutic agent for hereditary angioedema. In an accompanying editorial, Dr. B. Paul Morgan of the Cardiff University School of Medicine explains, “Lyophilized protein must be stored properly, reconstituted carefully, and administered intravenously, thus essentially restricting its use to in-hospital treatment of acute attacks. […] Alternative approaches are therefore needed.”

Cicardi, Banerji, et al. conducted two double-blind, randomized, multicenter trials (FAST1 and FAST2) to investigate the efficacy of one such alternative, icatibant, a selective bradykinin B2 receptor antagonist that can be delivered subcutaneously. The FAST1 trial compared icatibant with placebo, while the FAST2 trial compared it with oral tranexamic acid, an antifibrinolytic agent that has been reported to relieve symptoms. In the FAST2 trial, the primary endpoint of clinically significant symptom relief was reached significantly faster with icatibant than with tranexamic acid. In FAST1, the benefit of icatibant over placebo was not statistically significant. The authors concluded that early use of rescue medication may have obscured the benefit of icatibant in FAST1.

Meanwhile, Cicardi et al. conducted a double-blind, placebo-controlled Phase 3 trial (EDEMA3) to investigate the efficacy of ecallantide, yet another potential agent for treating acute attacks. Ecallantide is a newly developed recombinant plasma kallikrein inhibitor and, like icatibant, can be administered subcutaneously. In this trial, the primary measured endpoint was the treatment outcome score (ranging from -100 at worst to 100 at best) at four hours. The principal secondary endpoint was the change from baseline in mean symptom complex severity score (ranging from +2 at worst to -3 at best). The authors report that on both scales, hereditary angioedema patients treated with ecallantide had significantly better scores as compared with patients given the placebo.

One unanswered question is how long the therapeutic effects of these alternative treatments can be expected to last following administration. Neither icatibant nor ecallantide was evaluated for efficacy as prophylaxis. However, the most common adverse events reported from the FAST trials following treatment with icatibant were recurrent or worsening angioedema. Similarly, during the 90-day follow-up period in the EDEMA3 trial, more than half of the patients in both the ecallantide and placebo treatment groups had one or more acute attacks of angioedema.

These trials mark a promising step forward for the treatment of hereditary angioedema. NEJM deputy editor Dr. John Jarcho stated, “For a long time, safe and effective agents for treating hereditary angioedema were not available in the U.S. We decided to publish these papers because they offer valuable information about potential new therapeutic options and may help to advance our understanding of the pathogenesis of this disease.”

How do you currently treat patients with hereditary angioedema?  Will you consider using these newly reported treatments, and if so, how will you choose from among them?