OBJECTIVE: Hereditary angioedema (HAE) due to C1-inhbitor deficiency is a rare autosomal dominant disease that manifests as sudden unpredictable attacks of subcutaneous or submucosal edema affecting the skin, intestine, and upper airway. Ecallantide is a plasma kallikrein inhibitor indicated for treatment of HAE attacks in patients aged 16 years and older. This analysis examines safety and efficacy of ecallantide for treatment of HAE attacks in patients <18 years of age.
METHODS: Data for patients aged 9 to 17 years treated subcutaneously with 30 mg ecallantide or placebo were pooled from 4 clinical studies (2 double-blind, placebo-controlled and 2 open-label). Efficacy end points included 2 HAE-specific patient-reported outcome measures: mean symptom complex severity (MSCS) score and treatment outcome score (TOS). Times to initial improvement, sustained improvement, and complete or near-complete symptom resolution were calculated. Treatment-emergent adverse events were examined.
RESULTS: Overall, 29 pediatric patients were included; 25 of them received ecallantide for 62 total HAE attacks, and 10 received placebo for 10 total attacks. Ecallantide-treated attacks revealed clinically relevant reduction in symptom severity at 4 hours postdosing based on mean change in MSCS score (−1.4 ± 0.9 ecallantide versus −0.9 ± 0.6 placebo) and TOS (73.9 ± 35.50 ecallantide versus 45.0 ± 43.78 placebo). Patients treated with ecallantide showed rapid improvement in symptoms (median time to complete or near-complete symptom resolution: 181 minutes). No serious adverse events related to treatment were observed.
CONCLUSIONS: Ecallantide appears effective for HAE attacks in adolescents, with rapid symptom improvement. No unexpected safety issues were identified.
- HAE —
- hereditary angioedema
- MID —
- minimally important difference
- MSCS —
- mean symptom complex severity
- TOS —
- treatment outcome score
What’s Known on This Subject:
Patients with hereditary angioedema (HAE) have recurrent episodes of painful swelling. Several new therapies to prevent and treat HAE attacks are approved by the Food and Drug Administration, but their safety and efficacy in children are largely unknown.
What This Study Adds:
Ecallantide appears effective for treatment of HAE attacks in pediatric patients age 10 to 17 years with an acceptable safety profile. It represents a potential treatment option for adolescents with HAE.
Hereditary angioedema (HAE) with C1-inhibitor deficiency is characterized by episodic attacks of painful swelling at 1 or more anatomic locations, including the skin, gastrointestinal tract, genitals, and oropharynx/larynx.1 Attacks typically last several days, are very often disabling, and resolve spontaneously. Upper airway attacks are potentially fatal.2 In addition to direct medical effects, HAE has been shown to result in substantial indirect costs from missed work and school as well as significantly decreased quality of life and educational and vocational achievement for patients.3,4
HAE attacks typically begin during childhood and the symptoms often worsen around puberty.5,6 Several new therapies are now approved for both prophylaxis and treatment of HAE attacks, including purified C1-inhibitor, ecallantide, a plasma kallikrein inhibitor and icatibant, a bradykinin receptor antagonist. Recent studies revealed that purified C1-inhibitor, which is approved in the United States for treatment of patients 12 and older, has efficacy and safety in children similar to that seen in adults.7–9 Ecallantide is currently indicated for treatment of HAE patients 16 and older and icatibant for those 18 and older. We report here on experience with ecallantide for treatment of attacks in children and adolescents with HAE due to C1-INH deficiency.
Data were pooled from all pediatric patients treated with ecallantide (30 mg subcutaneously) or placebo in 4 studies of ecallantide for treatment of HAE attacks conducted over 5 years. The 4 studies were EDEMA2, a phase 2 open-label study; EDEMA3, a phase 3 double-blind, randomized, placebo-controlled trial with an open-label, repeat-dosing extension10; EDEMA4, a phase 3 double-blind placebo-controlled trial11; and DX-88/19, an open-label repeat-dosing follow-up to EDEMA4.12 Patients aged 10 years or older who presented within 8 hours of development of moderate or severe HAE symptoms in any anatomic location were enrolled and subsequently treated with 30 mg subcutaneous ecallantide or, in EDEMA3 Double-Blind and EDEMA4, with placebo. A single 9-year-old patient was treated with placebo. This population represents all patients <18 years old treated with subcutaneous ecallantide or placebo during the ecallantide development program. In EDEMA3 and EDEMA4, patients with severe upper airway compromise were eligible for an open-label dose between 0 and 4 hours after initial treatment. In EDEMA2, EDEMA4, and DX-88/19, patients were eligible for an open-label dose of ecallantide (Dose B) between 4 and 24 hours postdosing, at the discretion of the investigator, if there was incomplete response or symptom relapse. In EDEMA4, Dose B could also be given for no response to initial treatment.
Institutional review board approval was obtained at each participating site; pediatric patients provided written assent, and informed consent was provided by their parents or guardians.
Attack symptoms were characterized into 1 of 5 symptom locations: internal head/neck (laryngeal), stomach/gastrointestinal (abdominal), external head/neck, genital/buttocks, and cutaneous. The latter 3 combined were referred to as peripheral for overall analyses. The primary attack location was assigned in a hierarchical manner based on location and severity of affected locations (eg, assigned as laryngeal if the patient had moderate or severe internal head/neck symptoms, abdominal if the patient had moderate or severe stomach/gastrointestinal symptoms in the absence of moderate/severe laryngeal, or peripheral if the patient had moderate or severe external head/neck, genital/buttocks, or cutaneous symptoms in the absence of moderate or severe laryngeal or abdominal symptoms).
Two validated, HAE specific patient-reported outcomes were used to evaluate response to treatment: the mean symptom complex severity (MSCS) score and the treatment outcome score (TOS).13 MSCS score is a point-in-time measure of current symptom burden. On presentation for treatment, patients rated symptoms at each affected anatomic location as mild (1 point), moderate (2 points), or severe (3 points). At 4 and 24 hours postdosing, patients reassessed symptoms with the additional option of “no symptoms” (0 points). MSCS score is the arithmetic mean of severity across all affected locations, with a decrease in MSCS score at follow-up indicative of improvement. The estimated minimally important difference (MID) in MSCS score was calculated to be −0.3 during the validation process.13
TOS is a measure of response to treatment over time. For each affected symptom location, patients identify response to treatment at 1, 2, 3, 4, and 24 hours postdosing by using the following categorical scale: significant improvement (100 points), improvement (50 points), no change (0 points), worsening (−50 points), or significant worsening (−100 points) with “significant improvement” being defined as symptoms feeling “a lot better or resolved” and “significant worsening” as “a lot worse.” TOS is calculated as a weighted average of affected locations with more severe symptoms being weighted most heavily. The MID was calculated to be 30 during the end point validation.13
Timing of improvement was assessed with a global response measure. At various time points (every 15 minutes for the first 2 hours then every 30 minutes for hours 2 through 4), patients were asked how they were feeling overall, using the following categorical scale: “a lot better or resolved,” “a little better,” “same,” “a little worse,” and “a lot worse.” Beginning of improvement was the first time within 4 hours of treatment that the patient reported overall improvement (response of “a little better” or “a lot better or resolved”). Sustained improvement was the first time within 4 hours the patient reported overall improvement that lasted for at least 45 minutes. Significant improvement was the first time within 4 hours the patient reported that HAE symptoms were “a lot better or resolved.” Kaplan-Meier analysis was used to estimate median times and interquartile ranges. For each of the time to response end points, episodes that did not reach the end point by 4 hours were censored at the time of the last assessment within the 4-hour window (that is, their time to reach the end point was assumed to be longer than their last assessment).
Because of differences between trials and the low number of pediatric patients treated with placebo, no comparative statistical analysis of ecallantide versus placebo-treated episodes was undertaken; however, comparative descriptive data are presented to provide context. Results from pediatric patients were also compared with those seen in the overall patient population treated during the ecallantide development program.
All treatment emergent adverse events occurring in patients <18 years of age were examined.
Across the studies, 29 patients age 9 to 17 years were treated with 30 mg subcutaneous ecallantide or placebo for an HAE attack. Of those patients, 25 received ecallantide for a total of 62 attacks, and 10 received placebo for 10 total attacks. Six patients received placebo and ecallantide for different attacks and are included in both groups. Patient characteristics are shown in Table 1 and were similar between patients receiving ecallantide and placebo. Interestingly, most patients were of adult size.14Figure 1 reveals the age distribution at the time of treatment with ecallantide; most treated attacks occurred in older adolescents.
Patients who received ecallantide showed improvement as assessed by both change in MSCS score and TOS. Figure 2 reveals the change from baseline MSCS score at 4 hours after treatment. The MSCS score declined by 1.4 points (SD: 0.9) in patients treated with ecallantide versus 0.9 points (SD: 0.6) in placebo-treated patients, which both exceed the MID of −0.3.
TOS over time is depicted in Fig 3A. By 1 hour postdosing, ecallantide-treated patients showed improvement that exceeded the MID, with continued improvement through 4 hours, whereas placebo-treated patients did not exceed the MID until 4 hours. As shown in Fig 3B, substantially more patients treated with ecallantide showed complete or near-complete improvement (TOS of 100) and improvement (TOS 50 or higher) at 4 hours compared with placebo. More than half of patients treated with ecallantide achieved a TOS of 100 by 4 hours.
Figure 4 depicts the response to every subcutaneously treated attack, grouped by patient. Each dot represents the TOS score at 4 hours for a single treated attack; attacks for individual patients are grouped within the shaded rectangles. Although not quantitative, this figure demonstrates that ecallantide appeared to maintain efficacy over repeated use for serial attacks. The 2 attacks in which significant worsening (TOS = 100) was observed were both abdominal attacks rated as severe. Both patients were treated with antinausea medications and recovered spontaneously.
Patients treated with ecallantide showed rapid improvement in symptoms, as shown in Table 2. Among noncensored patients (ie, those who reached the end point within 4 hours), ecallantide treatment led to a median time for beginning of improvement of 55 minutes (versus 92 minutes for placebo) and sustained improvement of 69 minutes (versus 203 minutes for placebo). Significant improvement, defined as overall feeling “a lot better or resolved” was achieved in 60% of ecallantide treated attacks with a median time of 181 minutes versus 40% (median time 226 minutes) of attacks treated with placebo.
As shown in Table 3, efficacy of ecallantide was similar to that seen in patients age 16 and older treated with ecallantide in EDEMA3-DB and EDEMA4 (the double-blind, placebo-controlled phase III trials of ecallantide).15,16
Individual attack details and efficacy outcomes are presented in Supplemental Table 4.
Only 1 serious treatment-emergent adverse event was reported. This was an episode of staphylococcal cellulitis, at a site distant from the injection site, in an ecallantide-treated patient. It was judged to be unrelated to treatment. Repeated treatment with subcutaneous ecallantide has been associated with hypersensitivity reactions,17,18 including anaphylaxis. However, there were no hypersensitivity reactions reported in this population. Overall, adverse event rates were similar between placebo and ecallantide treated patients.
HAE causes unpredictable episodes of swelling, which can affect the skin, abdominal tract, and, most ominously, the upper airway.1,2 HAE results from a mutation in one copy of the C1-INH gene, which leads to decreased functional activity of C1-INH in the plasma.19,20 In type I HAE, patients have decreased levels of antigenic C1-INH, whereas in type II HAE, levels of antigenic C1-INH are normal but functional activity is decreased.19–21 There is an additional form of HAE, termed HAE with normal C1-INH, in which patients have similar symptoms but normal C1-INH function.22 A mutation in Factor XII has been identified in some of these patients.23 C1-INH is a serpin-class protein, which acts as a nonreversible inhibitor of the activity of several enzymes including plasma kallikrein.24–26 Dysregulated plasma kallikrein activity leads to increased bradykinin production, and extensive evidence reveals that increases in bradykinin mediate the episodes of swelling seen in patients with HAE during attacks.24–26
C1-INH deficiency is present from birth, but the average age of symptom onset is in childhood (range, 4–12 years),5,27,28 although some patients can suffer attacks in the first year after birth.28,29 Diagnosis can be delayed,30 particularly when there is no family history. Although comprehensive data are lacking, patients often have milder symptoms in childhood with a worsening of disease coincident with puberty.5,6
Over the last few years, 4 therapies for HAE have been approved for use in the United States. Two preparations of purified C1-INH are approved for use by adults and adolescents age 12 and older in the United States. Cinryze (ViroPharma, Exton, PA) is indicated for prophylaxis and Berinert (CSL-Behring, King of Prussia, PA) for treatment of attacks. Both are purified from human plasma and administered intravenously; they can be self-administered in appropriate patients. Berinert has been widely used for treatment of HAE attacks in children and adolescents5,7 and is licensed without age restriction in Europe. A recombinant human C1-INH (Ruconest/Rhucin, not approved in the United States) has been produced in rabbits and is approved for treatment of HAE attacks in Europe. Hypersensitivity reactions to remaining rabbit proteins have been observed. Icatibant, a bradykinin-receptor antagonist (Firazyr, Shire, Lexington, MA), is administered subcutaneously and approved for treatment of HAE attacks in patients 18 and older. It can be self-administered and is stable at room temperature, allowing patients to carry it with them. Ecallantide (Kalbitor; Dyax Corp, Burlington, MA) is a highly selective inhibitor of plasma kallikrein that is approved in the United States for treatment of HAE attacks in patients ≥16 years of age. Although guidelines for treatment of HAE in the setting of these new therapies have been promulgated,31–33 they are primarily expert opinion, not evidence based. In particular, the optimum therapeutic approach to children with HAE is unclear.32,33
Here we report the experience with ecallantide given subcutaneously in pediatric patients across 4 studies (phase 2 and phase 3) conducted during its development, representing all patients <18 treated with ecallantide subcutaneously during the trials. Ecallantide-treated patients showed substantial decreases in symptom burden as demonstrated by change in MSCS score and rapid overall improvement as reflected in the TOS to a similar degree as adult ecallantide-treated patients. A majority of patients treated with ecallantide achieved a TOS of 100 by 4 hours indicating that symptoms were significantly improved or resolved by that time. Time to improvement as assessed by 3 different measures favored ecallantide over placebo. The median time to beginning of improvement was 55 minutes in ecallantide-treated patients. Sustained improvement was seen at a median of 69 minutes and significant improvement (defined as symptoms being a lot better or resolved) at a median of 181 minutes.
These results are similar to those seen in the overall population of patients with HAE treated for attacks in EDEMA3 and EDEMA4, the 2 pivotal phase III trials that led to Food and Drug Administration approval of ecallantide.10,11,15,16 In an integrated analysis of data from those 2 trials,15 mean improvement in MSCS score was −0.97, somewhat less to the −1.4 reported here. Likewise, mean TOS in those trials was 55.5 at 4 hours versus 73.9 in the pediatric patients analyzed here. However, these numbers may not be directly comparable because a majority of the attacks treated in pediatric patients were open-label.
There are several limitations to our study. First, it represents a collection of data from different trials. Some patients were treated as part of a double-blind, placebo-controlled trial, whereas others received open-label ecallantide. Additionally, with only 10 pediatric patients treated with placebo, statistical comparisons between placebo and ecallantide-treated patients were not feasible. Nonetheless, we report on 25 patients treated with ecallantide for a total of 62 attacks, making it among the largest series of treatment of HAE attacks in pediatric patients. Finally, most of the attacks occurred in older adolescents (patients aged 15–17 years, Fig 1) who were of adult size. This is consistent with the notion that HAE symptoms and attacks increase in frequency at the time of puberty.1,5
Ecallantide treatment has been associated with hypersensitivity reactions, including anaphylaxis, in a small percentage of patients treated. Although some patients develop antibodies against either ecallantide or Pichia pastoris, the yeast in which ecallantide is produced, the relationship of these antibodies with hypersensitivity reactions is unclear. Although we did not see any hypersensitivity reactions in these pediatric patients, the numbers are relatively small and hypersensitivity and anaphylaxis remain a concern.
From this large pediatric experience for an orphan disease, ecallantide appears to be safe and effective for treatment of HAE attacks in patients 10 to 17 years old. Efficacy is similar to that reported for adult patients with HAE treated with ecallantide in clinical trials.
The authors thank Elizabeth P. Shea, PhD (formerly of Dyax Corp) for her assistance preparing figures, managing reviews, and editing this article.
- Accepted May 22, 2013.
- Address correspondence to Andrew J. MacGinnitie, Division of Immunology, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail:
Dr MacGinnitie participated in the conception and design, acquisition, analysis and interpretation of data, and drafted the initial article; Dr Davis-Lorton participated in acquisition, analysis and interpretation of data, and reviewed and revised the article; Drs Stolz and Tachdjian participated in the conception and design, analysis and interpretation of data, and reviewed and revised the article; and all authors approved the final article as submitted.
The following trials have been registered at www.clinicaltrials.gov: EDEMA2 (identifier NCT01826916); EDEMA3 (identifier NCT00262080); EDEMA4 (identifier NCT00457015); and DX-88/19 (identifier NCT00456508).
FINANCIAL DISCLOSURE: Dr MacGinnitie has received research support from Dyax Corp, ViroPharma, and Shire PLC and consulting fees from Dyax Corp, Shire PLC, CSL Behring, and ViroPharma; Dr Davis-Lorton has received research support from and is on the Speaker’s Bureau for Dyax Corp; Dr Stolz is a full-time employee of Dyax Corp; and Dr Tachdjian is on the Speaker’s Bureau for Dyax Corp.
FUNDING: Dyax Corp designed and provided funding for the studies described in this article.
- ↵Centers for Disease Control and Prevention, National Center for Health Statistics. CDC growth charts: United States. Available at: www.cdc.gov/growthcharts/. Accessed May 30, 2000
- ↵KALBITOR [package insert]. Cambridge, MA: Dyax Corp; December 2009. Available at: www.kalbitor.com/pdf/KalbitorFullPrescribingInformation.pdf. Accessed June 2, 2013
- Cicardi M,
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- HAWK (Hereditary Angioedema International Working Group)
- Copyright © 2013 by the American Academy of Pediatrics