Hereditary angioedema (HAE) is a rare genetic disease resulting in recurring episodes of painful swelling of the subcutaneous and submucosal tissue [1]. Attacks can affect many areas of the body. Most frequently involved are the extremities, gastrointestinal tract, genitals, face and upper airway. Swelling of the larynx can occur with potentially fatal consequences due to asphyxiation [2]. HAE patients with recurrent attacks have functional impairment, reduced quality of life (QoL) and increased mortality [3, 5]. The prevalence of HAE is approximately 1:50,000 individuals [3]. The condition is equally prevalent among sexes. Although quite variable, the mean age of onset for clinical symptoms is 11 years of age [4].
HAE is divided into 3 categories based on C1 esterase inhibitor enzyme (C1-INH) level and function. Patients who have quantitatively low levels of C1-INH are deemed to have type 1 HAE (HAE-1) and make up 85% of all cases. Those with a normal C1-INH antigenic level but dysfunctional enzyme activity are classified as type 2 HAE (HAE-2) and make up approximately 15% of cases [6]. HAE 1/2 result from mutations in the SERPING1 gene and are inherited in a predominantly autosomal dominant fashion [7]. A third category of HAE has normal C1-INH (HAE nC1-INH) and clinically presents similarly to HAE 1/2. HAE nC1-INH is exceedingly rare and the true prevalence is not known. Identified causes of HAE nC1-INH include genetic mutations in factor XII, angiopoietin 1, plasminogen, kininogen 1 and myoferlin [8]. In this case series, we will be addressing only patients with HAE 1/2.
In HAE, attacks of swelling are caused by overproduction of bradykinin that acts as a potent vasodilator. C1-INH inhibits various proteins along the bradykinin pathway including factor XIIa and plasma kallikrein. In HAE 1/2, C1-INH deficiency results in unopposed plasma kallikrein activity and overproduction of bradykinin. This overproduction causes vascular permeability and characteristic attacks of swelling [9].
Therapeutic options for HAE involve treatment of acute attacks, short term prophylaxis (STP), and long term prophylaxis (LTP). In Canada, licensed options available for treatment of acute attacks include icatibant, a bradykinin B2 receptor antagonist, and plasma-derived C1-INH (pdC1-INH). STP refers to the prophylactic treatment of HAE patients to reduce the risk of an attack during a high risk period such as dental surgery or upper airway manipulation. The treatment of choice for STP is intravenous (IV) pdC1-INH within an hour prior to the procedure. LTP is the use of ongoing, scheduled therapy to reduce attack frequency/severity and improve QoL in patients who are unable to meet their treatment goals with on-demand therapy alone. First line options for LTP in Canada include subcutaneous (SC) pdC1-INH and lanadelumab. Available second line options for LTP in some patients include attenuated androgens such as danazol and tranexamic acid (TXA), an antifibrinolytic [3].
Lanadelumab (Takhzyro™) is a fully humanized monoclonal antibody and is a highly potent and specific plasma kallikrein inhibitor, thereby reducing generation of bradykinin. It has a half-life of ~ 2 weeks and is given subcutaneously as a 300 mg injection once every 2 weeks, though this interval can be extended to 4 weeks if attacks are controlled for > 6 months [10, 11]. The HELP study was a Phase 3, randomized clinical trial (RCT) of Lanadelumab vs. Placebo involving 125 patients with HAE 1/2. The study showed that compared to placebo, lanadelumab significantly reduced attack frequency/severity and improved QoL over a 26 week treatment period [12]. The HELP study open-label extension (OLE) has since shown sustained reduction in attack frequency and a good drug safety profile [13]. Lanadelumab is now approved in Canada for use as LTP for HAE 1/2 in patients ≥ 12 years of age. Any patient ≥ 12 years of age with HAE ½ in Canada can be started on lanadeleumab for LTP. The decision to start lanadelumab is made jointly by the patient and treating physician and is based upon many factors including efficacy of on-demand therapy, frequency/severity of attacks and disease impact on QoL. It is not necessary to have failed other LTP agents before initiating lanadelumab [3].
To the best of our knowledge, there have been no reports outlining the clinical efficacy of lanadelumab in Canadian HAE patients. Herein, we describe our findings from a case series of 12 adult patients with HAE 1/2 who have been initiated on LTP with lanadelumab.