A new oral kallikrein inhibitor for long‐term prophylaxis of hereditary angioedema
Authors: Inmaculada Doña, María José Torres
Journal: Allergy (2021)

Hereditary angioedema (HAE) is a rare inherited chronic disease characterized by unpredictable recurrent attacks of cutaneous and submucosal swelling potentially involving airways, frequently upper ones, and compromising patient's life. This implies a serious health problem with significant disease burden and reduced life quality.1 This disease presents a great clinical variability and different endotypes, hampering diagnosis and requiring a personalized treatment. The primary mediator of swelling in most phenotypes is bradykinin, which increases vasodilation and vascular permeability by binding to the bradykinin B2 receptor.2 In type 1 and 2 HAE, C1-INH leads deficiency to contact (kallikrein-kinin) system activation and bradykinin overproduction.2, 3 Early diagnosis and appropriate therapy are essential due to its unpredictability, life-threatening nature, and unresponsiveness to conventional emergency therapies (adrenaline, corticosteroids, or antihistamines).1 Specific on-demand products for acute attacks management focus on replacing plasma-derived C1 inhibitor and recombinant human C1 inhibitor, inhibiting the bradykinin B2 receptor (icatibant), or inactivating plasma kallikrein (ecallantide).1 However, the burden of the disease on a non-negligible percentage of patients makes a long-term prophylaxis necessary to prevent and/or attenuate attacks and to improve life quality.1 In the past, antifibrinolytic agents like tranexamic acid or epsilon aminocaproic acid, and attenuated androgens as danazol, were the primary options for long-term prophylaxis (Table 1). It has been speculated that antifibrinolytics reduce the plasmin formation, an alternative activator of factor XII which is the main stimulus for kallikrein generation and bradykinin cascade initiation.4 However, data for their efficacy are lacking. Regarding attenuated androgens, they have been postulated to induce C1 inhibitor gene expression, leading to increased C1 inhibitor blood levels. They are effective and the oral administration facilitates their use.1 However, long-term side effects are numerous and affect many patients, mainly in high doses1 (Table 1). Recently, intravenous plasma-derived C1 inhibitor has been approved for long-term prophylaxis of C1 inhibitor deficiency HAE.5 However, its main disadvantage is the venous administration route and the short half-life period, requiring administration every 3–4 days.5 Moreover, advances in prophylactic care have led to the approval of plasma-derived C1 inhibitor subcutaneous treatments, also administered every 3–4 days,6 and lanadelumab, a human monoclonal inhibitor of plasma kallikrein, given every 2 weeks7 (Table 1). HAE treatment aims to improve life quality by decreasing attack frequency and severity, providing minimal side effects, and being easy to administer. In this sense, self-administration treatment is crucial for an effective therapy. This approach may prevent attacks and complications, normalize patients’ lives, and reduce morbidity and disability.1 Avoralstat, an oral drug that inhibits plasma kallikrein, provided evidence of shortened episodes and improved life quality; however, it did not prevent attacks.8 Recently, berotralstat (BCX7353), a highly selective inhibitor of plasma kallikrein, has been shown to be safe and effective in prophylaxis in two phase 3 randomized, double-blind, placebo-controlled, parallel-group trials in patients with HAE in both North America and Europe (APeX-2 trial),9 and Japan (APeX-J trial).10 In both studies, berotralstat reduced the rates of attacks for both 110 mg and 150 mg doses throughout 24 weeks. However, the most favorable dose was 150 mg/day.9, 10 Indeed, in APeX-J,10 the decrease in the rate of HAE attacks for 110 mg berotralstat doses compared with placebo was not statistically significant, probably due to the small number cases compared with APEX-2 (19 vs. 121). In addition, berotralstat has been reported to be safe and well tolerated in both trials, with mild, transient, gastrointestinal symptoms as the most frequent adverse events.9, 10 These results translate into improvements in life quality, which was assessed by angioedema-specific questionnaire.9, 10 Although in both trials the treatment period (24 weeks) was relatively short, the trials are still ongoing and longer term data may be assessed once patients have completed 52 weeks of dosing. Overall, berotralstat's efficacy, safety, and tolerability, together with the convenient oral route, represent an important advance in HAE attacks prophylaxis therapy. The preliminary results of both investigations are promising and will undoubtedly lead to a shift in the paradigm of HAE. Therefore, this new drug should be globally available to countries with diverse healthcare systems. None of the authors has any conflict of interest or received any money for the present manuscript.