Recombinant human C1 esterase inhibitor treatment for hereditary angioedema attacks in children

Abstract Background Attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (C1‐INH‐HAE) usually begin during childhood or adolescence. However, limited data are available regarding indications and modalities of treatment of children. This study evaluated recombinant human C1‐INH (rhC1‐INH) for HAE attacks in children. Methods This open‐label, phase 2 study included children aged 2‐13 years with C1‐INH‐HAE. Eligible HAE attacks were treated intravenously with rhC1‐INH 50 IU/kg body weight (maximum, 4200 IU). The primary end‐point was time to beginning of symptom relief (TOSR; ≥20 mm decrease from baseline in visual analog scale [VAS] score, persisting for two consecutive assessments); secondary end‐point was time to minimal symptoms (TTMS; <20 mm VAS score for all anatomic locations). Results Twenty children (aged 5‐14 years; 73 HAE attacks) were treated with rhC1‐INH. Seventy (95.9%) of the attacks were treated with a single dose of rhC1‐INH. Seven (35.0%) children were treated for four or more attacks. Overall, median TOSR was 60.0 minutes (95% confidence interval [CI], 60.0‐65.0); data were consistent across attacks. Median TTMS was 122.5 minutes (95% CI, 120.0‐126.0); data were consistent across attacks. No children withdrew from the study due to adverse events. No treatment‐related serious adverse events or hypersensitivity reactions were reported; no neutralizing antibodies were detected. Conclusions Recombinant human C1‐INH was efficacious, safe, and well tolerated in children. Data support use of the same dosing regimen for HAE attacks in children (50 IU/kg; up to 4200 IU, followed by an additional dose, if needed) as is currently recommended for adolescents and adults.


| INTRODUC TI ON
Hereditary angioedema (HAE) due to C1 esterase inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare disorder caused by mutations in the SERPING1 gene. 1 Functional deficiency of the C1-INH protein leads to disinhibition of the complement 2 and contact 3 enzyme cascades, causing overproduction of bradykinin and resulting in increased vascular permeability and fluid leakage to surrounding tissues. 4,5 HAE is characterized by unpredictable, acute, recurring episodes of angioedema in subcutaneous and/or submucosal tissues. Angioedema episodes can occur in various locations, including the abdomen, periphery, oro-facial/pharyngeal/laryngeal region, or urogenital region. 1,6 HAE attacks may be painful and disfiguring, and, in the case of upper airway attacks, potentially life-threatening. 6,7 Furthermore, HAE negatively affects patient quality of life and mood (eg, anxiety, depression), both during and between HAE attacks. 8,9 Onset of HAE attacks typically occurs during childhood or adolescence. 10 Studies have found mean age of symptom onset to be 4-14 years, [10][11][12][13][14][15] with onset by age 10 in approximately 50% of patients. 11,16,17 Early symptom onset is often associated with a more severe disease course. 11,13,16 This is particularly troubling because diagnosis of HAE has been reported to be a median of 8.5 years from time of symptom onset. 18 International consensus recommendations delineate acute treatment of HAE attacks in a pediatric population. 10,19 In principle, shorter time to treatment of attacks has been shown to improve clinical outcomes. 19,20 Despite progress made during the last decade with introduction of novel treatments for HAE, there is a paucity of evidence-based treatment options for children. 10 Recombinant human C1 esterase inhibitor (rhC1-INH) is among the options for adults and adolescents. It is purified from the milk of rabbits 5 and approved in multiple countries for treatment of HAE attacks. The efficacy and safety of rhC1-INH for management of HAE attacks have been demonstrated in adolescents and adults in randomized, placebo-controlled trials, 21,22 open-label extension studies, [23][24][25] and pooled analyses. 26 In addition, data published in 2017 showed rhC1-INH to be efficacious and well tolerated as prophylactic therapy in individuals aged 13 years or older with C1-INH-HAE. 27 The objective of the current study was to evaluate the efficacy and safety of rhC1-INH for acute treatment of HAE attacks in children.

| Study design
This open-label, phase 2, multicenter, multinational clinical study was conducted from January 2012 to July 2017 at 18 centers in 10 countries (ClinicalTrials.gov identifier: NCT01359969). This study was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines, the ethical principles of the Declaration of Helsinki, and applicable local regulatory requirements. Study protocols were approved by an institutional review board or independent ethics committee at each site. All patients provided assent to study participation, and a parent/legal guardian provided written informed consent before study procedures were initiated.

| Study participants
Children aged 2-13 years with a clinical and confirmed laboratory diagnosis (C1-INH activity <50% of normal) of C1-INH-HAE were eligible for the study. Key exclusion criteria included a diagnosis of acquired C1-INH deficiency, allergy to rabbits, and medical history of 10 HAE attacks previously treated with study medication. An attack was eligible for treatment if the patient presented to the site with an onset of attack symptoms within 5 hours of evaluation, had at least one anatomic location involved, and had an investigator rating of at least moderate intensity (≥3; range, 0-5) at presentation, with no indication of spontaneous regression.

| Assessments
The 100-mm visual analog scale (VAS) was completed by the patient, or parent/legal guardian if needed, at baseline and 0. 5

| Statistics
No formal sample size was calculated a priori, and study enrollment continued until at least 20 patients were treated for at least one HAE attack. The intent-to-treat (ITT) population included all patients who received at least one dose of study medication; the efficacy population included all patients in the ITT population who had efficacy data; and the pharmacokinetic/pharmacodynamic population included all patients in the ITT population with sufficient laboratory data. Unless otherwise specified, data were analyzed using descriptive statistics. Kaplan-Meier analyses were performed for each of the time-to-event end-points, and patients who did not achieve the outcome of interest were censored at the time of their last available assessment. Data were analyzed using SAS ® versions 9.3 and 9.4 (SAS Institute Inc.).

| Patient population
Of 57 children screened and considered eligible for treatment, 20 received rhC1-INH for at least one HAE attack and were included in the ITT and efficacy populations (Table 1) Fifteen children (75.0%) completed the study. Five children discontinued study participation due to consent withdrawal: one patient left the country, one patient was no longer interested in continuing, one patient's mother decided not to attend additional study visits for personal reasons, one patient preferred to treat HAE attacks at home with a different medication, and one patient was no longer considered a child based on age and weight (ie, obese).   Figure 1A). Data were consistent across individual HAE attacks, with a median TOSR of approximately 60.0 minutes post-treatment and overlapping 95% CIs (  Figure 1B). Across individual HAE attacks, median TTMS was consistent, at approximately 120 minutes post-treatment with overlapping 95% CIs (

| Safety
Adverse events were reported in 11 (55.0%) of the 20 children, with the most common AEs being naso-pharyngitis (n = 3; 15.0%), vomiting (n = 3; 15.0%), abnormal blood lymphocyte morphology (n = 2; 10.0%), and viral infection (n = 2; 10.0%). The two instances of abnormal blood lymphocyte morphology were considered by investigators to be possibly related to study medication. The events were considered mild in intensity and resolved without intervention (ie,  being self-limited, resolving spontaneously, and not recurring upon re-treatment, the authors speculate that these events were probably related to a viral infection.
There was no evidence of an increase in incidence of AEs in children treated for more than one HAE attack. In addition, most AEs were mild in intensity, with no evidence of a relationship between HAE attack number and AE intensity (  demonstrated the efficacy and safety of rhC1-INH in patients aged 12 years and older, 21,22