Marilyn Campion

Ecallantide for the Treatment of Acute Attacks in Hereditary Angioedema

BACKGROUND Hereditary angioedema is a rare genetic disorder characterized by acute, intermittent, and potentially life-threatening attacks of edema of the skin and mucosa. We evaluated ecallantide, a newly developed recombinant plasma kallikrein inhibitor, for the treatment of acute attacks of angioedema. METHODS In this double-blind, placebo-controlled trial, patients with hereditary angioedema presenting with an acute attack were randomly assigned, in a 1:1 ratio, to receive subcutaneous ecallantide, at a dose of 30 mg, or placebo. Two measures of patient-reported outcomes were used to assess the response: treatment outcome scores, which range from +100 (designated in the protocol as significant improvement in symptoms) to -100 (significant worsening of symptoms), and the change from baseline in the mean symptom complex severity score, which range from +2 (representing a change from mild symptoms at baseline to severe symptoms after) to -3 (representing a change from severe symptoms at baseline to no symptoms after). The primary end point was the treatment outcome score 4 hours after study-drug administration. Secondary end points included the change from baseline in the mean symptom complex severity score at 4 hours and the time to significant improvement. RESULTS A total of 71 of the 72 patients completed the trial. The median treatment outcome score at 4 hours was 50.0 in the ecallantide group and 0.0 in the placebo group (interquartile range [IQR], 0.0 to 100.0 in both groups; P=0.004). The median change in the mean symptom complex severity score at 4 hours was -1.00 (IQR, -1.50 to 0.00) with ecallantide, versus -0.50 (IQR, -1.00 to 0.00) with placebo (P=0.01). The estimated time to significant improvement was 165 minutes with ecallantide versus more than 240 minutes with placebo (P=0.14). There were no deaths, treatment-related serious adverse events, or withdrawals owing to adverse events. CONCLUSIONS Four hours after administration of ecallantide or placebo for acute attacks of angioedema in patients with hereditary angioedema, patient-reported treatment outcome scores and mean symptom complex severity scores were significantly better with ecallantide than with placebo. (Funded by Dyax; ClinicalTrials.gov number, NCT00262080.)

EDEMA4: a phase 3, double-blind study of subcutaneous ecallantide treatment for acute attacks of hereditary angioedema

BACKGROUND Hereditary angioedema (HAE) is a genetic disorder resulting from low levels of C1-inhibitor activity that manifests as acute attacks of variable and sometimes life-threatening edema. Ecallantide is a novel potent inhibitor of human plasma kallikrein, a key mediator of the excessive formation of bradykinin associated with the signs and symptoms of an HAE attack. OBJECTIVE To evaluate the efficacy and safety of ecallantide in the treatment of acute HAE attacks. METHODS In this double-blind, placebo-controlled study, patients with a moderate to severe HAE attack were randomized 1:1 to receive 30 mg of subcutaneous ecallantide or placebo. The primary efficacy end point was change from baseline in mean symptom complex severity score 4 hours after dosing. Additional end points included treatment outcome score 4 hours after dosing and maintenance of significant overall improvement through 24 hours. RESULTS Ninety-six patients were enrolled. Mean (SD) change from baseline in mean symptom complex severity score 4 hours after dosing was significantly greater with ecallantide use (-0.8 [0.6]) compared with placebo use (-0.4 [0.8]) (P = .01 comparing distributions). Ecallantide therapy was also associated with a significantly larger mean (SD) treatment outcome score 4 hours after dosing vs placebo use (ecallantide: 53.4 [49.7]; placebo: 8.1 [63.2]; P = .003 comparing distributions). The benefit of ecallantide was apparent within 2 hours after dosing and was maintained through 24 hours after dosing. The safety profile was similar between the treatment groups. CONCLUSION Ecallantide appears to be an effective and safe treatment for acute attacks of HAE.

Response time for ecallantide treatment of acute hereditary angioedema attacks

BACKGROUND Hereditary angioedema (HAE) is a rare, debilitating, and potentially fatal disease characterized by acute attacks of swelling that can affect the abdomen/gastrointestinal tract, larynx, face, genitals, and extremities. Ecallantide is a novel plasma kallikrein inhibitor developed for the treatment of acute HAE attacks. OBJECTIVE To examine the speed of effect of ecallantide vs placebo. METHODS Data were integrated from 2 randomized, double-blind, placebo-controlled phase 3 trials of ecallantide in patients with HAE. Eligible patients presented within 8 hours of onset of a moderate to severe HAE attack for 1:1 randomization to receive a single dose of 30 mg of subcutaneous ecallantide or placebo. End points included time to beginning of improvement, time to sustained overall improvement, and time to significant overall improvement. RESULTS A total of 143 participants (70 receiving ecallantide and 73 receiving placebo) were included. The distribution curves for time to beginning of improvement demonstrated a trend in favor of ecallantide vs placebo within 4 hours (P(log rank) = .09). For time to onset of sustained improvement, the difference in the distribution of the curves between the 2 groups reached significance by 2 hours after dosing (P(log rank) = .04). For time to significant overall improvement, the difference in the distribution of the curves reached significance in favor of ecallantide by 90 minutes (P(log rank) = .04). The beneficial effect of ecallantide was demonstrated earliest for abdominal attacks, followed by laryngeal and peripheral attacks. CONCLUSIONS Ecallantide provides relief of acute HAE attack symptoms, with rapidity of response commensurate with therapeutic needs for HAE attack locations.

Outcomes after ecallantide treatment of laryngeal hereditary angioedema attacks

BACKGROUND Hereditary angioedema (HAE) is a rare disorder associated with episodic attacks of well-demarcated angioedema. Attacks that affect the larynx can result in life-threatening airway obstruction. OBJECTIVES To examine efficacy and safety of ecallantide treatment for laryngeal HAE attacks. METHODS Data were combined from 4 clinical studies (EDEMA2, EDEMA3, EDEMA4, and DX-88/19) evaluating 30 mg of subcutaneous ecallantide for treatment of acute HAE attacks. Efficacy was assessed using 2 validated, HAE-specific, patient-reported outcome measures. The change in Mean Symptom Complex Severity (MSCS) score indicates change in symptom severity; a negative score indicates improvement. The calculated minimally important difference (MID) for change in severity is -0.30. The Treatment Outcome Score (TOS) measures treatment response. A positive score indicates improvement; the calculated MID is 30. RESULTS Overall, 98 patients received ecallantide for 220 laryngeal attacks. The mean ± SD change in MSCS score was -1.1 ± 0.73 and -1.6 ± 0.68 at 4 and 24 hours, respectively. The mean ± SD TOS was 73.5 ± 35.8 and 85.5 ± 27.8 at 4 and 24 hours, respectively. Median time to significant improvement was 185 minutes (95% confidence interval, 167-226). One attack required intubation. Four treatment-emergent serious adverse events were reported, including 2 HAE attacks that resulted in hospitalization and 2 anaphylactic reactions. One of these reactions required treatment with epinephrine, but both patients recovered fully. There were no deaths. CONCLUSION In this large attack series, ecallantide was effective for treatment of laryngeal HAE attacks. There is a risk of hypersensitivity, including anaphylaxis, consistent with product labeling. As such, ecallantide should be administered under the supervision of a health care professional. TRIAL REGISTRATION clinicaltrials.gov Identifiers: not applicable for EDEMA2 (trial was conducted before implementation of registration requirements); NCT00262080 for EDEMA3, NCT00457015 for EDEMA4, and NCT00456508 for DX-88/19.

Efficacy and safety of ecallantide in treatment of recurrent attacks of hereditary angioedema: open-label continuation study.

Hereditary angioedema (HAE) is a rare disorder characterized by recurrent attacks of potentially life-threatening edema. The plasma kallikrein inhibitor ecallantide is approved for treatment of acute HAE attacks. This study evaluates the efficacy and safety of ecallantide for treatment of multiple HAE episodes in the DX-88/19 (continuation) study. Patients received 30 mg of subcutaneous ecallantide for acute HAE attack symptoms, with no limit on number of episodes treated. Primary end point was change in patient-reported mean symptom complex severity (MSCS) score at 4 hours. Additional end points included change in MSCS score at 24 hours, treatment outcome score (TOS) at 4 and 24 hours, and time to response. Safety parameters included adverse events. Statistical analyses were conducted on qualifying treatment episodes (those with ≥12 patients). One hundred forty-seven patients received treatment for 625 episodes; analyses were conducted through 13 treatment episodes. Across 13 episodes at 4 hours, mean change in MSCS score ranged from -1.04 to -1.36, and mean TOSs ranged from 56.2 to 79.8. Median time to onset of sustained improvement ranged from 59 to 113 minutes. There was no indication of reduced efficacy with repeated ecallantide use. No new safety signals were detected. Eight patients (5.4%) reported potential hypersensitivity reactions, six of whom met the definition of anaphylaxis based on National Institute of Allergy and Infectious Diseases criteria. Ecallantide is effective for acute recurrent HAE attacks and maintains its efficacy and safety during multiple treatment episodes in patients with HAE. Potential hypersensitivity reactions were consistent with prior reports.

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

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.

Analysis of hereditary angioedema attacks requiring a second dose of ecallantide

BACKGROUND Effective treatment of acute attacks is critical in managing hereditary angioedema (HAE). Ecallantide, a plasma kallikrein inhibitor, is approved for the treatment of HAE attacks. Occasionally, a second dose is needed when treating attacks of HAE. OBJECTIVE To evaluate the characteristics of HAE attacks requiring a second dose (dose B) of ecallantide. METHODS Data from all ecallantide clinical trials (EDEMA2, EDEMA4, and DX-88/19) that allowed an open-label dose B were included in this analysis. Patient and attack characteristics potentially predictive of dose B after ecallantide were analyzed by logistic regression. A multivariate model was built using a backward selection process, incorporating variables from the univariate model with P < .20 and removing factors with the highest P value until only significant (P < .05) factors remained. RESULTS The analysis included 732 ecallantide-treated HAE attacks in 179 patients. Dose B was required in 88 attacks (12.0%), most (80.5%) for incomplete response. By attack location, 31 of 325 abdominal attacks (9.5%), 17 of 158 laryngeal attacks (10.8%), and 40 of 242 peripheral attacks (16.5%) required dose B. On the basis of the univariate analysis, baseline severity (odds ratio = 1.33, P = .15) and peripheral attack (odds ratio = 1.80, P = .01) were identified as potential predictive factors; abdominal attacks had an inverse correlation (odds ratio = 0.64, P = .055). However, the multivariate analysis identified only peripheral attacks as statistically significantly correlated (P < .05) with dose B requirement. CONCLUSION A single, 30-mg dose of ecallantide was effective for most HAE attacks (88.0%). Patients with peripheral attacks of HAE were more likely to require a second dose of ecallantide after 4 hours. TRIAL REGISTRATION clinicaltrials.gov Identifiers: not applicable for EDEMA2 (trial was conducted before registration requirements were implemented), NCT00457015 for EDEMA4, and NCT00456508 for DX-88/19.