First-line long-term prophylactic treatment for HAE includes intravenous and subcutaneous pdC1-INH; subcutaneous lanadelumab, a monoclonal antibody that targets plasma kallikrein; and oral berotralstat, a small-molecule inhibitor of plasma kallikrein.2,13 In many cases, breakthrough HAE attacks occur despite prophylaxis. However, complete elimination of HAE attacks is the goal of modern prophylactic treatments.
There is considerable global experience (>40 years) in treating C1-INH deficiency by replacing C1-INH protein levels (eg, on-demand therapy) in patients with HAE. Pursuit of this possibility and of the role of C1-INH replacement therapy as long-term prophylaxis depends on addressing continued challenges in HAE management through careful interpretation of randomized controlled trial (RCT) data. Such interpretation may be confounded by differences in RCT patient populations analyzed, routes of administration, pharmacokinetic and pharmacodynamic considerations, and product forms and availability (human plasma collection or recombinant technology). Differences in route of administration and in baseline attack frequency further confound comparisons, such that any conclusions drawn should be considered hypothesis-generating only, pending appropriate head-to-head trials. Data from these trials suggest that with adequate dosing and frequency of administration, even in patients with high symptomatic HAE activity, the burden of disease could potentially be minimized. Direct and indirect comparisons of different prophylactic doses of C1-INH support a dose–response relationship for efficacy in long-term prophylaxis, as well as for acute and short-term prophylaxis
Long-Term Prophylaxis to Address HAE Pathophysiology
Because contact and kallikrein/kinin pathway–targeted therapies cannot address the increased risk of autoimmunity, C1- INH replacement has an advantage in this respect. Of further interest might be reports of increased proportion of malignant versus reduced incidence of cardiovascular causes of death in patients with HAE (despite the use of attenuated androgens) compared with the general population.16 C1-INH concentrates are perhaps the most physiological approach to HAE management because these therapies directly replace the missing protein in the various cascades.17 Notably, C1- INH replacement therapy acts to restore equilibrium to the contact and kallikrein/kinin activation system.9 This is achieved by pluripotent regulation of the activation of kallikrein, factor XII (Figure 1) and other inflammatory pathways, which may affect bradykinin production, most notably plasmin.17 Overall, this concept is speculative, as the benefit of C1-INH replacement in autoimmunity, malignancy, and cardiovascular disease has not been thoroughly investigated.