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Clinical Outcomes with Icatibant in the Open-Label Treatment of 45 Laryngeal Attacks of Hereditary Angioedema
Abstracts AB163
J ALLERGY CLIN IMMUNOL VOLUME 125, NUMBER 2
Management Of Hae Patients During Pregnancy And Delivery - A Prospective Evaluation Of 35 Pregnancies And 37 Newborns I. Martinez-Saguer, E. Rusicke, E. Aygo¨ren-P€urs€un, T. Klingebiel, W. Kreuz; J.-W. Goethe University Hospital Frankfurt, Germany, Frankfurt, GERMANY. RATIONALE: Hereditary angioedema (HAE) is a rare disorder caused by deficiency in C1-esterase inhibitor (C1-INH) that is characterized by subcutaneous swelling and mucosal swelling of respiratory and gastrointestinal tracts. Pregnancy is of particular concern in affected women because of the severity of complications and the potential risk for mother, fetus and newborn. METHODS: We conducted a prospective analysis to investigate the frequency and severity of acute attacks among women with HAE during pregnancy and delivery. Data collection based on diaries and case report forms was implemented during a minimum of 2 to 3 follow up visits at the clinic. From March 1995 through August 2007, data were collected from 35 pregnancies in 22 women (age in median 29 years) with HAE type I. RESULTS: The 35 pregnancies resulted in 37 newborns (2 twin-births) with 19 vaginal deliveries and 16 by Caesarean section. Of the 37 newborns, 18 newborns had HAE, and 19 newborns were not affected. Prior to pregnancy, the median frequency of attacks/nine months was 6. During pregnancy the median number of attacks increased statistically significant to 28.5 attacks/nine months. Compared to baseline prior to pregnancy the average number of attacks increased in the 1st as well as in the 2nd and 3rd trimester. No abortion was observed and no malformations in all 37 newborns, respectively. CONCLUSIONS: Swelling attacks increased particularly in the 2nd and 3rd trimester of pregnancy in most of our patients. Therefore an effective HAE therapy and management plan during pregnancy and delivery is highly recommended.
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Efficacy of Ecallantide for Acute HAE Attacks Is Maintained Across Multiple Treatments: Results from the EDEMA Development Program W. R. Lumry1, M. Campion2, W. E. Pullman3, P. T. Horn3; 1AARA Research Center, Dallas, TX, 2Consultant, Newton, MA, 3Dyax Corp., Cambridge, MA. RATIONALE: Hereditary angioedema (HAE) is a debilitating and potentially fatal disease characterized by recurrent acute swelling attacks. Ecallantide is a plasma kallikrein inhibitor developed for treatment of acute HAE attacks. The retention of therapeutic effect was assessed following ecallantide treatment for repeated attacks. METHODS: Data were analyzed from two Phase 3, placebo-controlled, double-blind studies, EDEMA3 and EDEMA4, and the open-label, repeat-dosing extension of EDEMA3. Validated, HAE-specific, patient-reported outcome measures–treatment outcome score (TOS) (positive score indicates improvement) and mean symptom complex severity (MSCS) score (negative score indicates improvement)–were analyzed by treatment episode, which accounted for treatments from earlier studies. TOS and change in MSCS score were compared to 0 (ie, no improvement) using the Wilcoxon signed rank test. RESULTS: The Treatment Episode 1 analysis included 96 patients, Episode 2 included 38, Episode 3 included 25, Episode 4 included 12, and Episode 5 included 19 patients, 12 of whom had more than 5 treatment episodes. Across all episodes, 4-hour TOS consistently showed significant improvement (P0.001); medians ranged from 66.7 to 100.0 and were greater than the minimally important difference (MID) of 30.0. The 4hour change in MSCS score from baseline also showed improvement (P0.008); medians were consistently -1.0 and greater than the MID of -0.30. Treatment-emergent adverse events were mild to moderate in severity and similar to those reported previously. One patient had an anaphylactic reaction during the 19th treatment episode and recovered without sequelae. CONCLUSIONS: Ecallantide demonstrated consistent efficacy and no new adverse events were observed following repeated treatment of HAE.
641
Hypersensitivity Reactions Following Ecallantide Treatment for Acute Attacks of HAE P. T. Horn1, H. H. Li2, W. E. Pullman1; 1Dyax Corp., Cambridge, MA, 2 Institute for Asthma & Allergy, Wheaton, MD. RATIONALE: Hereditary angioedema (HAE) is a potentially fatal disease characterized by unpredictable, acute swelling attacks. Ecallantide is a novel plasma kallikrein inhibitor developed for the treatment of acute HAE attacks. The main safety issue reported during the ecallantide development program was hypersensitivity (including anaphylaxis). METHODS: The ecallantide development program for acute HAE attacks consists of 7 patient studies, including 2 double-blind, placebo-controlled, Phase 3 studies, and 2 open-label extension studies. The appropriate IRB approved each study; all patients provided written informed consent. Data for all patients were examined for events suggestive of moderate or severe hypersensitivity events, including anaphylaxis. RESULTS: Through 12 March 2009, 255 patients received ecallantide (intravenously or subcutaneously) for acute HAE attacks. Of these patients, 14 (5.5%) experienced hypersensitivity reactions, including possible anaphylaxis (7/255, 2.7%). Of the 187 patients who received 30 mg subcutaneous ecallantide (the intended to-be-marketed form, dose, and administration route), 7 (3.7%) experienced hypersensitivity events, including anaphylaxis (3/187, 1.6%). Symptoms associated with these hypersensitivity reactions included allergic rhinitis, chest discomfort, flushing, pharyngeal edema, pruritus, rhinorrhea, throat irritation, urticaria, wheezing, and hypotension. All reactions occurred within approximately 30 minutes after dosing, and all patients recovered without sequelae. Hypersensitivity did not directly correlate with immunogenicity status. After successfully completing a rechallenge procedure, 4 patients with presumed hypersensitivity received further doses of ecallantide with no additional hypersensitivity observed. CONCLUSIONS: Hypersensitivity (including anaphylaxis) is a known but manageable risk of ecallantide treatment for acute HAE attacks. Rechallenge experience indicates the complexity of discerning hypersensitivity from symptoms of an acute HAE attack.
642
Clinical Outcomes with Icatibant in the Open-Label Treatment of 45 Laryngeal Attacks of Hereditary Angioedema M. Riedl; Clinical Immunology and Allergy, UCLA - David Geffen School of Medicine, Los Angeles, CA. RATIONALE: To assess the efficacy and safety of icatibant, a selective bradykinin-B2 receptor antagonist, in patients with acute laryngeal hereditary angioedema (HAE) attack during the controlled and open-label extension (OLE) phases of the FAST (For Angioedema Subcutaneous Treatment)-1 phase III trial. METHODS: During the controlled phase, patients with a laryngeal HAE attack (first attack) received 1 subcutaneous injection of open-label icatibant (30mg). In the OLE phase, subsequent laryngeal attacks were each treated with up to 3 injections (6h apart) of open-label icatibant, with repeat dosing possible if symptoms worsened within 48h. Efficacy was assessed using patient and physician assessments. RESULTS: 26 patients experienced 45 laryngeal attacks (controlled n58; OLE n537). 69% (31/45) of attacks were assessed as moderate-to-very severe in intensity. Rapid improvement in symptom severity was observed, with mild-to-absent symptoms for most attacks achieved within 4h of icatibant administration (controlled phase, 100%; OLE phase, 84%), irrespective of attack severity. All symptoms resolved by 24h. Patient-reported median time to symptom regression was 0.6h during the controlled phase and between 0.3 and 1.2h during the OLE phase. Investigator-reported median time to Ôobservable regression of symptoms’ (start of improvement) and Ôoverall patient improvementÕ were 1.0 and 0.8h, respectively. Approximately 89% of attacks resolved following 1 injection, 10% following 2 injections, and 1% following 3 injections. All patients experienced generally mild transient injection-site reactions which resolved spontaneously without intervention. No drug-related serious adverse events or safety issues were observed. CONCLUSIONS: Icatibant was effective and well tolerated, providing rapid regression of symptoms associated with acute laryngeal HAE attacks.
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J ALLERGY CLIN IMMUNOL VOLUME 125, NUMBER 2
Management Of Hae Patients During Pregnancy And Delivery - A Prospective Evaluation Of 35 Pregnancies And 37 Newborns I. Martinez-Saguer, E. Rusicke, E. Aygo¨ren-P€urs€un, T. Klingebiel, W. Kreuz; J.-W. Goethe University Hospital Frankfurt, Germany, Frankfurt, GERMANY. RATIONALE: Hereditary angioedema (HAE) is a rare disorder caused by deficiency in C1-esterase inhibitor (C1-INH) that is characterized by subcutaneous swelling and mucosal swelling of respiratory and gastrointestinal tracts. Pregnancy is of particular concern in affected women because of the severity of complications and the potential risk for mother, fetus and newborn. METHODS: We conducted a prospective analysis to investigate the frequency and severity of acute attacks among women with HAE during pregnancy and delivery. Data collection based on diaries and case report forms was implemented during a minimum of 2 to 3 follow up visits at the clinic. From March 1995 through August 2007, data were collected from 35 pregnancies in 22 women (age in median 29 years) with HAE type I. RESULTS: The 35 pregnancies resulted in 37 newborns (2 twin-births) with 19 vaginal deliveries and 16 by Caesarean section. Of the 37 newborns, 18 newborns had HAE, and 19 newborns were not affected. Prior to pregnancy, the median frequency of attacks/nine months was 6. During pregnancy the median number of attacks increased statistically significant to 28.5 attacks/nine months. Compared to baseline prior to pregnancy the average number of attacks increased in the 1st as well as in the 2nd and 3rd trimester. No abortion was observed and no malformations in all 37 newborns, respectively. CONCLUSIONS: Swelling attacks increased particularly in the 2nd and 3rd trimester of pregnancy in most of our patients. Therefore an effective HAE therapy and management plan during pregnancy and delivery is highly recommended.
640
Efficacy of Ecallantide for Acute HAE Attacks Is Maintained Across Multiple Treatments: Results from the EDEMA Development Program W. R. Lumry1, M. Campion2, W. E. Pullman3, P. T. Horn3; 1AARA Research Center, Dallas, TX, 2Consultant, Newton, MA, 3Dyax Corp., Cambridge, MA. RATIONALE: Hereditary angioedema (HAE) is a debilitating and potentially fatal disease characterized by recurrent acute swelling attacks. Ecallantide is a plasma kallikrein inhibitor developed for treatment of acute HAE attacks. The retention of therapeutic effect was assessed following ecallantide treatment for repeated attacks. METHODS: Data were analyzed from two Phase 3, placebo-controlled, double-blind studies, EDEMA3 and EDEMA4, and the open-label, repeat-dosing extension of EDEMA3. Validated, HAE-specific, patient-reported outcome measures–treatment outcome score (TOS) (positive score indicates improvement) and mean symptom complex severity (MSCS) score (negative score indicates improvement)–were analyzed by treatment episode, which accounted for treatments from earlier studies. TOS and change in MSCS score were compared to 0 (ie, no improvement) using the Wilcoxon signed rank test. RESULTS: The Treatment Episode 1 analysis included 96 patients, Episode 2 included 38, Episode 3 included 25, Episode 4 included 12, and Episode 5 included 19 patients, 12 of whom had more than 5 treatment episodes. Across all episodes, 4-hour TOS consistently showed significant improvement (P0.001); medians ranged from 66.7 to 100.0 and were greater than the minimally important difference (MID) of 30.0. The 4hour change in MSCS score from baseline also showed improvement (P0.008); medians were consistently -1.0 and greater than the MID of -0.30. Treatment-emergent adverse events were mild to moderate in severity and similar to those reported previously. One patient had an anaphylactic reaction during the 19th treatment episode and recovered without sequelae. CONCLUSIONS: Ecallantide demonstrated consistent efficacy and no new adverse events were observed following repeated treatment of HAE.
641
Hypersensitivity Reactions Following Ecallantide Treatment for Acute Attacks of HAE P. T. Horn1, H. H. Li2, W. E. Pullman1; 1Dyax Corp., Cambridge, MA, 2 Institute for Asthma & Allergy, Wheaton, MD. RATIONALE: Hereditary angioedema (HAE) is a potentially fatal disease characterized by unpredictable, acute swelling attacks. Ecallantide is a novel plasma kallikrein inhibitor developed for the treatment of acute HAE attacks. The main safety issue reported during the ecallantide development program was hypersensitivity (including anaphylaxis). METHODS: The ecallantide development program for acute HAE attacks consists of 7 patient studies, including 2 double-blind, placebo-controlled, Phase 3 studies, and 2 open-label extension studies. The appropriate IRB approved each study; all patients provided written informed consent. Data for all patients were examined for events suggestive of moderate or severe hypersensitivity events, including anaphylaxis. RESULTS: Through 12 March 2009, 255 patients received ecallantide (intravenously or subcutaneously) for acute HAE attacks. Of these patients, 14 (5.5%) experienced hypersensitivity reactions, including possible anaphylaxis (7/255, 2.7%). Of the 187 patients who received 30 mg subcutaneous ecallantide (the intended to-be-marketed form, dose, and administration route), 7 (3.7%) experienced hypersensitivity events, including anaphylaxis (3/187, 1.6%). Symptoms associated with these hypersensitivity reactions included allergic rhinitis, chest discomfort, flushing, pharyngeal edema, pruritus, rhinorrhea, throat irritation, urticaria, wheezing, and hypotension. All reactions occurred within approximately 30 minutes after dosing, and all patients recovered without sequelae. Hypersensitivity did not directly correlate with immunogenicity status. After successfully completing a rechallenge procedure, 4 patients with presumed hypersensitivity received further doses of ecallantide with no additional hypersensitivity observed. CONCLUSIONS: Hypersensitivity (including anaphylaxis) is a known but manageable risk of ecallantide treatment for acute HAE attacks. Rechallenge experience indicates the complexity of discerning hypersensitivity from symptoms of an acute HAE attack.
642
Clinical Outcomes with Icatibant in the Open-Label Treatment of 45 Laryngeal Attacks of Hereditary Angioedema M. Riedl; Clinical Immunology and Allergy, UCLA - David Geffen School of Medicine, Los Angeles, CA. RATIONALE: To assess the efficacy and safety of icatibant, a selective bradykinin-B2 receptor antagonist, in patients with acute laryngeal hereditary angioedema (HAE) attack during the controlled and open-label extension (OLE) phases of the FAST (For Angioedema Subcutaneous Treatment)-1 phase III trial. METHODS: During the controlled phase, patients with a laryngeal HAE attack (first attack) received 1 subcutaneous injection of open-label icatibant (30mg). In the OLE phase, subsequent laryngeal attacks were each treated with up to 3 injections (6h apart) of open-label icatibant, with repeat dosing possible if symptoms worsened within 48h. Efficacy was assessed using patient and physician assessments. RESULTS: 26 patients experienced 45 laryngeal attacks (controlled n58; OLE n537). 69% (31/45) of attacks were assessed as moderate-to-very severe in intensity. Rapid improvement in symptom severity was observed, with mild-to-absent symptoms for most attacks achieved within 4h of icatibant administration (controlled phase, 100%; OLE phase, 84%), irrespective of attack severity. All symptoms resolved by 24h. Patient-reported median time to symptom regression was 0.6h during the controlled phase and between 0.3 and 1.2h during the OLE phase. Investigator-reported median time to Ôobservable regression of symptoms’ (start of improvement) and Ôoverall patient improvementÕ were 1.0 and 0.8h, respectively. Approximately 89% of attacks resolved following 1 injection, 10% following 2 injections, and 1% following 3 injections. All patients experienced generally mild transient injection-site reactions which resolved spontaneously without intervention. No drug-related serious adverse events or safety issues were observed. CONCLUSIONS: Icatibant was effective and well tolerated, providing rapid regression of symptoms associated with acute laryngeal HAE attacks.
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