Ecallantide for treatment of acute hereditary angioedema attacks: analysis of efficacy by patient characteristics.

Division of Immunology, Children's Hospital Boston, Massachusetts, USA.
Allergy and Asthma Proceedings (Impact Factor: 3.35). 03/2012; 33(2):178-85. DOI: 10.2500/aap.2012.33.3528
Source: PubMed

ABSTRACT Hereditary angioedema (HAE) is characterized by episodic attacks of edema. HAE is caused by low levels of the protein C1 esterase inhibitor, which inhibits plasma kallikrein, the enzyme responsible for converting high-molecular-weight kininogen to bradykinin. Unregulated production of bradykinin leads to the characteristic clinical symptoms of swelling and pain. Ecallantide is a novel plasma kallikrein inhibitor effective for treatment of acute HAE attacks. This study was designed to analyze the efficacy of ecallantide for treating HAE attacks by attack location, attack severity, patient gender, and body mass index (BMI). An analysis of integrated data from two double-blind, placebo-controlled trials of ecallantide for treatment of acute HAE attacks was undertaken. For the purpose of analysis, symptoms were classified by anatomic location and, for each location, by the patient-assessed severity of the attack. Efficacy versus placebo was examined using two validated patient-reported outcomes: treatment outcome score and mean symptom complex severity score. One hundred forty-three attacks were analyzed (73 ecallantide and 70 placebo). Ecallantide was equally effective in both male and female subjects. Ecallantide had decreased efficacy for patients with BMI > 30 kg/m(2). Ecallantide showed efficacy for treatment of severe and moderate attacks, and was effective for abdominal, internal head and neck, external head and neck, and cutaneous locations. In summary, ecallantide is effective for treatment of acute HAE attacks of different symptom locations and severity; outcomes were similar for men and women. However, the standard dose was less effective for obese patients.

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    ABSTRACT: Background Despite the worldwide obesity epidemic, there have been very few studies investigating the influence of body weight on treatment dosing and outcomes in patients with hereditary angioedema (HAE). Objective The purpose of this analysis was to determine whether the standard weight-based dosing recommendation of C1 esterase inhibitor (C1-INH) concentrate (20 IU/kg) is adequate in HAE patients with a high body mass index (BMI). Methods Data from patients treated for HAE attacks with 20 IU/kg of C1-INH concentrate were retrospectively analyzed from the open-label IMPACT2 study (International Multicenter Prospective Angioedema C1-INH Trial). Patients were categorized according to BMI as being normal body weight, overweight, or obese. Efficacy end points were time to onset of symptom relief and time to complete resolution of symptoms. The safety profile was evaluated according to adverse events occurring within 7 to 9 days of treatment. Results Of 57 patients, 24 (42%) were of normal body weight, 20 (35%) were overweight, and 13 (23%) were obese. Median (95% CI) time to onset of symptom relief was 0.37 hour (0.29–0.57) in normal-weight patients, 0.48 hour (0.39–0.53) in overweight patients, and 0.58 hour (0.41–0.94) in obese patients. Median time (95% CI) to complete resolution of symptoms was 15.2 hours (9.3–23.2) in normal-weight patients, 22.6 hours (11.3–44.6) in overweight patients, and 11.0 hours (5.6–23.6) in obese patients (differences not significant). There were no relevant differences in the incidence of adverse events in normal-weight patients (54%), overweight patients (30%), and obese patients (54%). Conclusions Treatment of HAE attacks with weight-based doses of C1-INH concentrate provided reliable treatment response, regardless of body weight, in these patients with HAE.
    Clinical Therapeutics 04/2014; · 2.59 Impact Factor
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    ABSTRACT: Introduction: Hereditary angioedema (HAE) is a rare disorder with recurring edema formation in the subcutis and the submucosa. The growing understanding of its pathophysiology yielded a number of new orphan drugs with diverse targets and delivery routes. Because HAE is bradykinin-mediated, its pharmacotherapy focuses on inhibiting the release, or the receptor action, of this vasoactive peptide. Areas covered: This summary is intended as a brief review of the disease and of the medicinal products (non-pathogenic and pathogenic medications) available for its therapy. It also attempts to outline the choices in its complex management, and to assist in delivering appropriate care with minimum delay. The primary objective of therapy is to prevent edema, as well as to relieve its symptoms. Nowadays, many innovative drugs are available; their efficacy and safety have been demonstrated in controlled clinical trials. C1-inhibitor concentrates, prepared from human plasma, or produced by recombinant technology, are used for supplementation. Kallikrein inhibitors block the release of bradykinin, whereas icatibant interferes with its binding to the bradykinin B2 receptor. Expert opinion: The expansion of therapeutic alternatives allows individualized treatment supported by recent international guidelines and recommendations.
    Expert Opinion on Orphan Drugs. 01/2013; 1(2).
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    ABSTRACT: Hereditary angioedema (HAE) is characterized by unpredictable attacks of debilitating subcutaneous and mucosal edema. Gastrointestinal attacks are painful, of sudden onset and often mistaken for acute abdomen leading to unnecessary surgery. The purpose of this study was to analyze symptom presentation of gastrointestinal angioedema in pediatric and adult HAE patients. Information collected during the clinical development of ecallantide for treatment of acute HAE attacks included affected anatomic location, accompanying symptoms, medical history, and pain assessments. Efficacy endpoints included Treatment Outcome Score (TOS, maximum score = 100; minimally important difference = 30), a point-in-time measure of treatment response, and time to treatment response. Forty-nine percent of 521 HAE attacks only involved abdominal symptoms. The most commonly reported abdominal symptoms were distension (77%), cramping (73%) and nausea (67%). The most common pain descriptors were tender, tiring-exhausting, aching, cramping and sickening. White blood cell counts were elevated (>10 x 109/L) in 23% of attacks (mean +/- SD: 15.1 +/- 11.27 x 109/L). A high proportion of patients reported a history of abdominal surgery, including appendectomy (23%), cholecystectomy (16.4%), and hysterectomy (8.2%). Mean TOS at 4 hours post ecallantide was 77+/-33 versus 29+/-65 for placebo. Median time to significant symptom resolution was 165 minutes (95% CI 136, 167) for ecallantide versus >4 hours (95% CI 161, >4 hours) for placebo. Anaphylactic reactions occurred in 6 of the 149 treated patients. HAE should be considered in the differential diagnosis of patients with recurrent discrete episodes of severe, unexplained crampy abdominal pain associated with nausea.Trials registration: The data used in the analysis were gathered across multiple clinical trials conducted during the clinical development program for ecallantide. All of the studies were conducted using Good Clinical Practices (GCP) and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. Each site that participated in the clinical trials obtained the appropriate IRB or Ethics Committee approval prior to enrolling any patients. All patients provided written informed consent prior to undergoing any study-related procedures. Pediatric patients provided written assent and their parents or guardians gave written informed consent.The following trials have been registered at EDEMA2 (identifier NCT01826916); EDEMA3 (identifier NCT00262080); EDEMA4 (identifier NCT00457015); and DX-88/19 (identifier NCT00456508).
    BMC Gastroenterology 04/2014; 14(1):71. · 2.11 Impact Factor