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Timothy J. Craig - One of the best experts on this subject based on the ideXlab platform.
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Recombinant human C1 esterase inhibitor for the treatment of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE).
Expert review of clinical immunology, 2015Co-Authors: Geetika Sabharwal, Timothy J. CraigAbstract:The lack of C1 inhibitor function that results in excessive production of bradykinin causing the angioedema seen in hereditary angioedema (HAE) is well established. Several drugs have been developed to treat and prevent attacks in patients suffering from HAE due to C1 inhibitor deficiency (C1-INH-HAE). Plasma-derived C1INH has been used to replace the deficiency of C1 inhibitor (C1INH) and has been approved for both treatment of attacks and for prophylactic therapy to prevent attacks. Plasma kallikrein inhibitor (Ecallantide) and bradykinin receptor antagonist (icatibant) are both effective for treatment of acute attacks, but their short half-life limits the use for prophylaxis. Androgens, in particular danazol, are effective for long-term prophylaxis, but adverse event profile can limit its use. Recombinant C1 inhibitor derived from transgenic rabbits has recently been approved for use in treatment of C1-INH-HAE attacks and is effective and appears safe with minimal adverse event profile.
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Characterization of Anaphylaxis After Ecallantide Treatment of Hereditary Angioedema Attacks
The journal of allergy and clinical immunology. In practice, 2014Co-Authors: Timothy J. Craig, Marc A Riedl, Jonathan A. Bernstein, William R. Lumry, Andrew J. Macginnitie, Leslie E. Stolz, Joseph C. Biedenkapp, Yung ChyungAbstract:Background Ecallantide is a human plasma kallikrein inhibitor indicated for treatment of acute attacks of hereditary angioedema for patients 12 years of age and older. Ecallantide is produced in Pichia pastoris yeast cells by recombinant DNA technology. Use of Ecallantide has been associated with a risk of hypersensitivity reactions, including anaphylaxis. Objective The objective of this detailed retrospective data review was to characterize anaphylaxis cases within the Ecallantide clinical trials database. Methods Potential cases of hypersensitivity reactions in the Ecallantide clinical development program were identified by examining reported adverse events. The National Institute of Allergy and Infectious Disease criteria were used to identify those events that were consistent with anaphylaxis; these cases were then reviewed in detail. Results from investigational antibody testing also were examined. Results Among patients who received subcutaneous Ecallantide (n = 230 patients; 1045 doses of 30 mg Ecallantide), 8 patients (3.5%) had reactions that met the National Institute of Allergy and Infectious Disease criteria for anaphylaxis; none occurred on first exposure to the drug. All 8 reactions had symptom onset within 1 hour of exposure and cutaneous manifestations commonly observed in type I hypersensitivity reactions. All the reactions responded to standard management of type I hypersensitivity reactions and resolved without fatal outcomes. IgE antibody testing to Ecallantide or P pastoris was not consistently positive in patients who experienced apparent type I hypersensitivity reactions. Conclusion Anaphylaxis episodes after subcutaneous Ecallantide exposure have clinical features suggestive of type I hypersensitivity reactions. However, anti-Ecallantide or anti– P pastoris IgE antibody status was not found to be reliably associated with anaphylaxis.
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Treatment of hereditary angioedema: a review (CME).
Transfusion, 2014Co-Authors: Neeti Bhardwaj, Timothy J. CraigAbstract:Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent attacks of self-limiting tissue swelling. The management of HAE has transformed dramatically with recently approved therapies in the United States. However, there is lack of awareness among physicians about these new modalities. The aim of this review is to update the practicing physician about various therapeutic options available for HAE patients. An exhaustive literature search of PubMed and OVID was performed to develop this article. Management of HAE is traditionally classified into treatment of acute attacks or on-demand therapy, short-term (preprocedural) prophylaxis, and long-term prophylaxis. Newer therapies include C1 esterase inhibitor (C1-INH) and contact system modulators, namely, Ecallantide and icatibant. Recombinant C1-INH, which is available in Europe, is awaiting approval in the United States. C1-INH concentrate is approved for prophylaxis as well as on-demand therapy while Ecallantide and icatibant are approved for acute treatment only. Effective HAE management further includes patient education, reliable access to specific medications, and regular follow-up to monitor therapeutic response and safety.
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Update on treatment of hereditary angioedema
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 2013Co-Authors: L. V. Buyantseva, N. S. Agarwal, K. Olivieri, Y.-x. Zhi, Timothy J. CraigAbstract:Summary Hereditary angioedema (HAE) is a rare disease characterized by recurrent, self-limiting episodes of swelling. New research and therapies have recently emerged and are now available; however, many physicians are not aware of the new developments in HAE. To update immunologists and other health care providers on new advances in HAE therapies, a PubMed, OVID and Google literature search were used to develop this manuscript. English language peer-reviewed angioedema articles were selected. High quality clinical trials were reviewed and summarized. Acute therapy in the past often consisted of symptom relief with narcotics, hydration and fresh frozen plasma (FFP). Androgens and FFP are frequently used despite multiple, significant side-effects. Newer therapies include C1-inhibitor – both human plasma derived and recombinant – as well as contact system modulators such as Ecallantide and icatibant. These newer products can be used for treatment of acute attacks of HAE, and C1-inhibitors can also be used for prophylaxis. These disease-specific therapies have proven to work by placebo-controlled studies, have minimal adverse effects and can be utilized for the treatment of HAE.
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Efficacy and safety of Ecallantide in treatment of recurrent attacks of hereditary angioedema: open-label continuation study.
Allergy and asthma proceedings, 2013Co-Authors: William R. Lumry, Marc A Riedl, Jonathan A. Bernstein, Timothy J. Craig, Andrew J. Macginnitie, Marilyn Campion, D. Soteres, Ryan Iarrobino, Leslie E. StolzAbstract: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.
William R. Lumry - One of the best experts on this subject based on the ideXlab platform.
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Characterization of Anaphylaxis After Ecallantide Treatment of Hereditary Angioedema Attacks
The journal of allergy and clinical immunology. In practice, 2014Co-Authors: Timothy J. Craig, Marc A Riedl, Jonathan A. Bernstein, William R. Lumry, Andrew J. Macginnitie, Leslie E. Stolz, Joseph C. Biedenkapp, Yung ChyungAbstract:Background Ecallantide is a human plasma kallikrein inhibitor indicated for treatment of acute attacks of hereditary angioedema for patients 12 years of age and older. Ecallantide is produced in Pichia pastoris yeast cells by recombinant DNA technology. Use of Ecallantide has been associated with a risk of hypersensitivity reactions, including anaphylaxis. Objective The objective of this detailed retrospective data review was to characterize anaphylaxis cases within the Ecallantide clinical trials database. Methods Potential cases of hypersensitivity reactions in the Ecallantide clinical development program were identified by examining reported adverse events. The National Institute of Allergy and Infectious Disease criteria were used to identify those events that were consistent with anaphylaxis; these cases were then reviewed in detail. Results from investigational antibody testing also were examined. Results Among patients who received subcutaneous Ecallantide (n = 230 patients; 1045 doses of 30 mg Ecallantide), 8 patients (3.5%) had reactions that met the National Institute of Allergy and Infectious Disease criteria for anaphylaxis; none occurred on first exposure to the drug. All 8 reactions had symptom onset within 1 hour of exposure and cutaneous manifestations commonly observed in type I hypersensitivity reactions. All the reactions responded to standard management of type I hypersensitivity reactions and resolved without fatal outcomes. IgE antibody testing to Ecallantide or P pastoris was not consistently positive in patients who experienced apparent type I hypersensitivity reactions. Conclusion Anaphylaxis episodes after subcutaneous Ecallantide exposure have clinical features suggestive of type I hypersensitivity reactions. However, anti-Ecallantide or anti– P pastoris IgE antibody status was not found to be reliably associated with anaphylaxis.
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Efficacy and safety of Ecallantide in treatment of recurrent attacks of hereditary angioedema: open-label continuation study.
Allergy and asthma proceedings, 2013Co-Authors: William R. Lumry, Marc A Riedl, Jonathan A. Bernstein, Timothy J. Craig, Andrew J. Macginnitie, Marilyn Campion, D. Soteres, Ryan Iarrobino, Leslie E. StolzAbstract: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.
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Analysis of hereditary angioedema attacks requiring a second dose of Ecallantide.
Annals of allergy asthma & immunology : official publication of the American College of Allergy Asthma & Immunology, 2013Co-Authors: Marilyn Campion, Marc A Riedl, Timothy J. Craig, William R. Lumry, Andrew J. Macginnitie, D. Soteres, Elizabeth P. Shea, Jonathan A. BernsteinAbstract:Abstract 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 P value until only significant ( P 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 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.
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Management and Prevention of Hereditary Angioedema Attacks
The American journal of managed care, 2013Co-Authors: William R. LumryAbstract:Hereditary angioedema (HAE) is a rare genetic syndrome caused by a deficiency in functional C1 inhibitor that results in recurrent episodes of nonpruritic swelling of the hands, feet, arms, legs, trunk, face, genitalia, bowels, and larynx beginning in childhood or adolescence and continuing throughout the patient's lifetime. Treatment for acute HAE attacks in the United States has been transformed by new therapies that inhibit the underlying mechanisms of angioedema- notably Ecallantide, a potent and specific inhibitor of plasma kallikrein, and icatibant, a selective bradykinin receptor antagonist. These treatments, combined with safer formulations of plasma-derived C1 esterase inhibitor concentrate for HAE prophylaxis and acute treatment, have greatly improved the quality of life for people with HAE, many of whom can now lead fairly normal lives. This article reviews the current therapeutic landscape for HAE, including treatment for acute angioedema attacks, short- and long-term HAE prophylaxis, and home-based therapy.
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Efficacy and Safety of Ecallantide Treatment for HAE Attacks in Patients Treated with Both Ecallantide and Placebo
Journal of Allergy and Clinical Immunology, 2012Co-Authors: William R. Lumry, Marc A Riedl, Jonathan A. Bernstein, Timothy J. Craig, Andrew J. Macginnitie, Marilyn Campion, D. Soteres, William E. PullmanAbstract:T U E S D A Y 827 Hypersensitivity Reactions to Ecallantide: an Update of the Clinical Trial Experience and Post-Market Surveillance for Treatment of Attacks of Hereditary Angioedema T. J. Craig, M. Riedl, H. H. Li, J. A. Bernstein, A. J. MacGinnitie, D. F. Soteres, W. R. Lumry, W. E. Pullman; Penn State University, Hershey, PA, UCLA David Geffen School of Medicine, Los Angeles, CA, Institute for Asthma & Allergy, Wheaton, MD, University of Cincinnati, Cincinnati, OH, Children’s Hospital Boston, Boston, MA, Asthma and Allergy Associates, PC, Colorado Springs, CO, AARA Research Center, Dallas, TX, Dyax Corp., Cambridge, MA. RATIONALE: Ecallantide is a plasma kallikrein inhibitor indicated for treatment of hereditary angioedema (HAE) attacks. We present an update of potential hypersensitivity cases reported in Ecallantide clinical trials and following commercial use of Ecallantide. METHODS: Data from 4 studies utilizing a 30 mg subcutaneous dose of Ecallantide (EDEMA2, EDEMA3, EDEMA4, and DX-88/19) and postmarketing surveillance were evaluated for possible hypersensitivity reactions. Reported events suggestive of potential hypersensitivity were assessed using the World Allergy Organization (WAO) Subcutaneous Immunotherapy Systemic Reaction Grading System (grade 1: single organ system involved; grade 2: >1 organ system/mild respiratory distress/ gastrointestinal symptoms; grade 3: moderate respiratory distress; grade 4: respiratory failure/hypotension; grade 5: death). Reactions were also classified as ‘‘likely’’ or ‘‘unlikely’’ hypersensitivity based on the temporal sequence of events and presence of confounding factors including patient history, underlying disease, concomitant medications, and outcomes following Ecallantide re-exposure. RESULTS: In clinical studies, 230 patients received 1045 doses of 30 mg subcutaneous Ecallantide. Fourteen patients experienced potential hypersensitivity. Eight were classified as likely (seven WAO grade 2; one grade 1) and 6 as unlikely (three grade 2; three grade 1). Symptoms included pruritus, urticaria, erythema, flushing, dyspnea, chest discomfort, dizziness, nausea, laryngeal edema, and blood pressure changes. All events resolved without sequelae. Frequency of post-marketing cases appear similar, with 9 potential cases reported among ;256 patients receiving ;1135 doses through July 31, 2011. Symptoms and outcomes were similar to those in clinical trials. CONCLUSIONS: Potential hypersensitivity reactions are a risk of Ecallantide treatment, but patient monitoring and appropriate treatment can mitigate this risk.
Marc A Riedl - One of the best experts on this subject based on the ideXlab platform.
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Facilitating home-based treatment of hereditary angioedema.
Allergy and Asthma Proceedings, 2014Co-Authors: Jonathan A. Bernstein, Lisa Zacek, Marc A Riedl, Ralph ShapiroAbstract:Hereditary angioedema (HAE) is a rare disorder causing periodic attacks of nonpruritic swelling, for which highly effective subcutaneous and intravenous therapies are available. The need to seek ongoing medical attention for HAE attacks at clinics and hospitals adds to the already considerable burden of the disease. Recent international consensus treatment guidelines have emphasized home-based therapy as a preferred managed strategy whenever possible. Here, we review various strategies for facilitating home-based treatment with injectable HAE medications (plasma-derived C1 esterase inhibitor [C1-INH], Ecallantide, icatibant, and recombinant C1-INH). Medical literature relating to home-based treatment of HAE is reviewed and strategies for implementing home-based therapy are presented. Home-based treatment of HAE has been shown to reduce the time to initiation of treatment, reduce the duration and severity of attacks, and improve patients' quality of life. Several options are available to facilitate home treatment of HAE. Medical staff in a primary care setting can be educated in the care of HAE patients and can teach the technique of parenteral drug administration. Home care agencies and specialty pharmacies are present in most communities and specialize in patient education. Infusion centers are skilled at working with patients with chronic diseases who perform extensive self-care. HAE comprehensive care clinics provide expert diagnosis and disease management and may become the patient's primary source of HAE care. Home-based therapy of HAE has been shown to be safe and clinically advantageous. Various strategies are available for equipping HAE patients to administer their treatments outside of a medical facility.
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Characterization of Anaphylaxis After Ecallantide Treatment of Hereditary Angioedema Attacks
The journal of allergy and clinical immunology. In practice, 2014Co-Authors: Timothy J. Craig, Marc A Riedl, Jonathan A. Bernstein, William R. Lumry, Andrew J. Macginnitie, Leslie E. Stolz, Joseph C. Biedenkapp, Yung ChyungAbstract:Background Ecallantide is a human plasma kallikrein inhibitor indicated for treatment of acute attacks of hereditary angioedema for patients 12 years of age and older. Ecallantide is produced in Pichia pastoris yeast cells by recombinant DNA technology. Use of Ecallantide has been associated with a risk of hypersensitivity reactions, including anaphylaxis. Objective The objective of this detailed retrospective data review was to characterize anaphylaxis cases within the Ecallantide clinical trials database. Methods Potential cases of hypersensitivity reactions in the Ecallantide clinical development program were identified by examining reported adverse events. The National Institute of Allergy and Infectious Disease criteria were used to identify those events that were consistent with anaphylaxis; these cases were then reviewed in detail. Results from investigational antibody testing also were examined. Results Among patients who received subcutaneous Ecallantide (n = 230 patients; 1045 doses of 30 mg Ecallantide), 8 patients (3.5%) had reactions that met the National Institute of Allergy and Infectious Disease criteria for anaphylaxis; none occurred on first exposure to the drug. All 8 reactions had symptom onset within 1 hour of exposure and cutaneous manifestations commonly observed in type I hypersensitivity reactions. All the reactions responded to standard management of type I hypersensitivity reactions and resolved without fatal outcomes. IgE antibody testing to Ecallantide or P pastoris was not consistently positive in patients who experienced apparent type I hypersensitivity reactions. Conclusion Anaphylaxis episodes after subcutaneous Ecallantide exposure have clinical features suggestive of type I hypersensitivity reactions. However, anti-Ecallantide or anti– P pastoris IgE antibody status was not found to be reliably associated with anaphylaxis.
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Efficacy and safety of Ecallantide in treatment of recurrent attacks of hereditary angioedema: open-label continuation study.
Allergy and asthma proceedings, 2013Co-Authors: William R. Lumry, Marc A Riedl, Jonathan A. Bernstein, Timothy J. Craig, Andrew J. Macginnitie, Marilyn Campion, D. Soteres, Ryan Iarrobino, Leslie E. StolzAbstract: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.
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Analysis of hereditary angioedema attacks requiring a second dose of Ecallantide.
Annals of allergy asthma & immunology : official publication of the American College of Allergy Asthma & Immunology, 2013Co-Authors: Marilyn Campion, Marc A Riedl, Timothy J. Craig, William R. Lumry, Andrew J. Macginnitie, D. Soteres, Elizabeth P. Shea, Jonathan A. BernsteinAbstract:Abstract 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 P value until only significant ( P 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 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.
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HAE update: special considerations in the female patient with hereditary angioedema.
Allergy and asthma proceedings, 2013Co-Authors: Bob Geng, Marc A RiedlAbstract:This review on hereditary angioedema (HAE) focuses on special topics regarding HAE in female patients. HAE is a bradykinin-mediated disorder, and the role of hormonal regulation of disease expression will be discussed focusing on the effect of estrogen on disease mechanism. The impact of exogenous estrogen on symptom exacerbation leads to special consideration regarding choice of contraceptives and safety of hormone replacement therapy. The effects of pregnancy and childbirth will be examined on the course of disease control. Unique considerations regarding therapeutic management for female HAE patients will be addressed, including the role of C1 inhibitor (C1-INH), Ecallantide, and icatibant. Finally, this review will provide an overview of the more recently characterized HAE with normal C1-INH (HAE type III) that predominantly affects women and is in some cases associated with factor XII gene mutations.
Leslie E. Stolz - One of the best experts on this subject based on the ideXlab platform.
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Characterization of Anaphylaxis After Ecallantide Treatment of Hereditary Angioedema Attacks
The journal of allergy and clinical immunology. In practice, 2014Co-Authors: Timothy J. Craig, Marc A Riedl, Jonathan A. Bernstein, William R. Lumry, Andrew J. Macginnitie, Leslie E. Stolz, Joseph C. Biedenkapp, Yung ChyungAbstract:Background Ecallantide is a human plasma kallikrein inhibitor indicated for treatment of acute attacks of hereditary angioedema for patients 12 years of age and older. Ecallantide is produced in Pichia pastoris yeast cells by recombinant DNA technology. Use of Ecallantide has been associated with a risk of hypersensitivity reactions, including anaphylaxis. Objective The objective of this detailed retrospective data review was to characterize anaphylaxis cases within the Ecallantide clinical trials database. Methods Potential cases of hypersensitivity reactions in the Ecallantide clinical development program were identified by examining reported adverse events. The National Institute of Allergy and Infectious Disease criteria were used to identify those events that were consistent with anaphylaxis; these cases were then reviewed in detail. Results from investigational antibody testing also were examined. Results Among patients who received subcutaneous Ecallantide (n = 230 patients; 1045 doses of 30 mg Ecallantide), 8 patients (3.5%) had reactions that met the National Institute of Allergy and Infectious Disease criteria for anaphylaxis; none occurred on first exposure to the drug. All 8 reactions had symptom onset within 1 hour of exposure and cutaneous manifestations commonly observed in type I hypersensitivity reactions. All the reactions responded to standard management of type I hypersensitivity reactions and resolved without fatal outcomes. IgE antibody testing to Ecallantide or P pastoris was not consistently positive in patients who experienced apparent type I hypersensitivity reactions. Conclusion Anaphylaxis episodes after subcutaneous Ecallantide exposure have clinical features suggestive of type I hypersensitivity reactions. However, anti-Ecallantide or anti– P pastoris IgE antibody status was not found to be reliably associated with anaphylaxis.
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use of Ecallantide in pediatric hereditary angioedema
Pediatrics, 2013Co-Authors: Andrew J. Macginnitie, Leslie E. Stolz, Mark Davislorton, Raffi TachdjianAbstract: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. * Abbreviations: HAE — : hereditary angioedema MID — : minimally important difference MSCS — : mean symptom complex severity TOS — : treatment outcome score
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Use of Ecallantide in Pediatric Hereditary Angioedema
Pediatrics, 2013Co-Authors: Andrew J. Macginnitie, Leslie E. Stolz, Mark Davis-lorton, Raffi TachdjianAbstract: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
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Efficacy and safety of Ecallantide in treatment of recurrent attacks of hereditary angioedema: open-label continuation study.
Allergy and asthma proceedings, 2013Co-Authors: William R. Lumry, Marc A Riedl, Jonathan A. Bernstein, Timothy J. Craig, Andrew J. Macginnitie, Marilyn Campion, D. Soteres, Ryan Iarrobino, Leslie E. StolzAbstract: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.
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Outcomes after Ecallantide treatment of laryngeal hereditary angioedema attacks.
Annals of allergy asthma & immunology : official publication of the American College of Allergy Asthma & Immunology, 2013Co-Authors: Albert L. Sheffer, Andrew J. Macginnitie, Leslie E. Stolz, Marilyn Campion, William E. PullmanAbstract:Abstract 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.
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Outcomes after Ecallantide treatment of laryngeal hereditary angioedema attacks.
Annals of allergy asthma & immunology : official publication of the American College of Allergy Asthma & Immunology, 2013Co-Authors: Albert L. Sheffer, Andrew J. Macginnitie, Leslie E. Stolz, Marilyn Campion, William E. PullmanAbstract:Abstract 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.
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Ecallantide for treatment of acute hereditary angioedema attacks: analysis of efficacy by patient characteristics.
Allergy and asthma proceedings, 2012Co-Authors: Andrew J. Macginnitie, Leslie E. Stolz, Marilyn Campion, William E. PullmanAbstract: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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Efficacy and Safety of Ecallantide Treatment for HAE Attacks in Patients Treated with Both Ecallantide and Placebo
Journal of Allergy and Clinical Immunology, 2012Co-Authors: William R. Lumry, Marc A Riedl, Jonathan A. Bernstein, Timothy J. Craig, Andrew J. Macginnitie, Marilyn Campion, D. Soteres, William E. PullmanAbstract:T U E S D A Y 827 Hypersensitivity Reactions to Ecallantide: an Update of the Clinical Trial Experience and Post-Market Surveillance for Treatment of Attacks of Hereditary Angioedema T. J. Craig, M. Riedl, H. H. Li, J. A. Bernstein, A. J. MacGinnitie, D. F. Soteres, W. R. Lumry, W. E. Pullman; Penn State University, Hershey, PA, UCLA David Geffen School of Medicine, Los Angeles, CA, Institute for Asthma & Allergy, Wheaton, MD, University of Cincinnati, Cincinnati, OH, Children’s Hospital Boston, Boston, MA, Asthma and Allergy Associates, PC, Colorado Springs, CO, AARA Research Center, Dallas, TX, Dyax Corp., Cambridge, MA. RATIONALE: Ecallantide is a plasma kallikrein inhibitor indicated for treatment of hereditary angioedema (HAE) attacks. We present an update of potential hypersensitivity cases reported in Ecallantide clinical trials and following commercial use of Ecallantide. METHODS: Data from 4 studies utilizing a 30 mg subcutaneous dose of Ecallantide (EDEMA2, EDEMA3, EDEMA4, and DX-88/19) and postmarketing surveillance were evaluated for possible hypersensitivity reactions. Reported events suggestive of potential hypersensitivity were assessed using the World Allergy Organization (WAO) Subcutaneous Immunotherapy Systemic Reaction Grading System (grade 1: single organ system involved; grade 2: >1 organ system/mild respiratory distress/ gastrointestinal symptoms; grade 3: moderate respiratory distress; grade 4: respiratory failure/hypotension; grade 5: death). Reactions were also classified as ‘‘likely’’ or ‘‘unlikely’’ hypersensitivity based on the temporal sequence of events and presence of confounding factors including patient history, underlying disease, concomitant medications, and outcomes following Ecallantide re-exposure. RESULTS: In clinical studies, 230 patients received 1045 doses of 30 mg subcutaneous Ecallantide. Fourteen patients experienced potential hypersensitivity. Eight were classified as likely (seven WAO grade 2; one grade 1) and 6 as unlikely (three grade 2; three grade 1). Symptoms included pruritus, urticaria, erythema, flushing, dyspnea, chest discomfort, dizziness, nausea, laryngeal edema, and blood pressure changes. All events resolved without sequelae. Frequency of post-marketing cases appear similar, with 9 potential cases reported among ;256 patients receiving ;1135 doses through July 31, 2011. Symptoms and outcomes were similar to those in clinical trials. CONCLUSIONS: Potential hypersensitivity reactions are a risk of Ecallantide treatment, but patient monitoring and appropriate treatment can mitigate this risk.
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Ecallantide (DX-88) for acute hereditary angioedema attacks: Integrated analysis of 2 double-blind, phase 3 studies
The Journal of allergy and clinical immunology, 2011Co-Authors: Albert L. Sheffer, Marilyn Campion, Patrick T. Horn, Robyn J. Levy, William E. PullmanAbstract:Background Hereditary angioedema (HAE) is a rare disorder characterized by recurrent angioedema attacks. Ecallantide, a novel plasma kallikrein inhibitor, inhibits production of bradykinin, the key mediator of these angioedema attacks. Objective We sought to further characterize the safety and efficacy of Ecallantide for HAE attacks by performing an integrated analysis of pooled data from 2 phase 3 studies. Methods An integrated analysis was conducted with data from 2 randomized, double-blind, placebo-controlled studies in which patients with HAE (age ≥10 years) received 30 mg of subcutaneous Ecallantide or placebo within 8 hours of onset of a moderate-to-severe attack at any anatomic site. Efficacy was evaluated by using validated patient-reported outcome measures: the Mean Symptom Complex Severity (MSCS) score and the Treatment Outcome Score (TOS). Results Compared with placebo, Ecallantide resulted in significantly greater reduction in MSCS scores from baseline to 4 hours after dosing (Ecallantide [mean ± SD], −0.97 ± 0.78; placebo, −0.47 ± 0.71; P P P = .028; TOS, P = .039). Ecallantide demonstrated efficacy at all attack sites. The incidence of treatment-emergent adverse events was similar between groups. Conclusions This integrated analysis supports and expands on the results of the phase 3 studies. Ecallantide appears to be effective and well tolerated for the treatment of HAE attacks.
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Response time for Ecallantide treatment of acute hereditary angioedema attacks.
Annals of allergy asthma & immunology : official publication of the American College of Allergy Asthma & Immunology, 2010Co-Authors: Marc A Riedl, Marilyn Campion, Patrick T. Horn, William E. PullmanAbstract: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.