Hereditary Angioedema Therapies Research Articles

Potential therapeutic benefit of C1-esterase inhibitor in neuromyelitis optica evaluated in vitro and in an experimental rat model.

Neuromyelitis optica (NMO) is an autoimmune demyelinating disease of the central nervous system in which binding of anti-aquaporin-4 (AQP4) autoantibodies (NMO-IgG) to astrocytes causes complement-dependent cytotoxicity (CDC) and inflammation resulting in oligodendrocyte and neuronal injury. There is compelling evidence for a central role of complement in NMO pathogenesis. Here, we evaluated the potential of C1-esterase inhibitor (C1-inh) for complement-targeted therapy of NMO. C1-inh is an anti-inflammatory plasma protein with serine protease inhibition activity that has a broad range of biological activities on the contact (kallikrein), coagulation, fibrinolytic and complement systems. C1-inh is approved for therapy of hereditary angioedema (HAE) and has been studied in a small safety trial in acute NMO relapses (NCT 01759602). In vitro assays of NMO-IgG-dependent CDC showed C1-inh inhibition of human and rat complement, but with predicted minimal complement inhibition activity at a dose of 2000 units in humans. Inhibition of complement by C1-inh was potentiated by ∼10-fold by polysulfated macromolecules including heparin and dextran sulfate. In rats, intravenous C1-inh at a dose 30-fold greater than that approved to treat HAE inhibited serum complement activity by <5%, even when supplemented with heparin. Also, high-dose C1-inh did not reduce pathology in a rat model of NMO produced by intracerebral injection of NMO-IgG. Therefore, although C1r and C1s are targets of C1-inh, our in vitro data with human serum and in vivo data in rats suggest that the complement inhibition activity of C1-inh in serum is too low to confer clinical benefit in NMO.

Barriers to self-administered therapy for hereditary angioedema.

Presently, the movement of care for hereditary angioedema (HAE) is out of the clinic, emergency department, and hospitals and into the home. Much of the transition relies on specialized nurses who teach patients self-administration skills. Our goal was to assess nurses to uncover barriers that they have encountered in an effort to improve self-therapy education and patient care. A survey of 21 questions was sent to 38 HAE home care nurses throughout the United States. Results were collected anonymously and data were analyzed. Nurses feel that there is an increased need for teaching patients self-therapy skills. The majority are very comfortable teaching self-administration and troubleshooting-associated problems. Perceived difficulties in providing adequate teaching include distance to patient's home and logistics of coordinating, scheduling, and obtaining supplies. Teaching is preferred when done at home by a visiting nurse with a care partner available and multiple training sessions are needed. Very few patients refused self-administration after initially being taught; reasons cited for refusal include fear of injection or infection, lack of skills, interference of daily activities, and financial restraints. As for nurses, they were most worried about safety, lack of skill retention, and inappropriate use of the drug. Self- administration of HAE treatment is increasingly more accessible and should be offered to patients as a safe and practical option. The barriers to self-administration revealed in this study include distance to the patient's home, coordinating care, obtaining medications/equipment, and scheduling training sessions. Moving to self- or home treatment through nursing instruction will improve patient's independence and quality of life, lead to earlier therapy, and reduce costs associated with care.

Effect of time to treatment on response to C1 esterase inhibitor concentrate for hereditary angioedema attacks

BackgroundC1 esterase inhibitor (C1-INH) concentrate is well established as effective therapy for hereditary angioedema (HAE). It is thought that treatment of an acute HAE attack with C1-INH as early as possible improves efficacy, but there are limited data from prospective studies supporting this recommendation. ObjectiveTo assess the effect of time to treatment (<6 vs ≥6 hours after start of an attack) with 20 U/kg of C1-INH concentrate on efficacy. MethodsA post hoc analysis of time to treatment after start of an attack was performed for 2 studies with C1-INH concentrate: International Multicenter Prospective Angioedema C1-INH Trial (IMPACT) 1 (randomized, placebo-controlled) and IMPACT 2 (open-label, uncontrolled extension). Because of differences in study design, the data sets were analyzed separately. IMPACT 1 data were analyzed using Cox regression with hazard ratios (HRs). For IMPACT 2 data, linear regression was applied to evaluate whether earlier treatment leads to faster recovery. Descriptive statistics for treatment response were calculated for both studies. ResultsIn IMPACT 1, treatment with C1-INH within less than 6 hours after start of an attack resulted in considerably shorter times to onset of symptom relief (HR, 3.36) and complete resolution (HR, 4.30) vs placebo. The benefit of C1-INH compared with placebo was reduced when administered after 6 or more hours (HRs, 1.18 for times to onset of symptom relief and 1.61 for complete resolution). Analysis of IMPACT 2 data indicated slower complete resolution of symptoms with later start of treatment. ConclusionEarly treatment with C1-INH (<6 hours) provides a better treatment response than late treatment (≥6 hours), supporting the international recommendation to treat HAE attacks as early as possible. Trial RegistrationClinicalTrials.gov Identifiers: NCT00168103 and NCT00292981

Update on treatment of hereditary angioedema

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.

Efficacy Assessments in Randomized Controlled Studies of Acute Therapy for Hereditary Angioedema

Hereditary angioedema (HAE) is a rare disorder caused by a deficiency of C1 esterase inhibitor, characterized by recurrent, highly variable attacks of subcutaneous or submucosal edema that may affect multiple body sites. Clinical studies of acute HAE therapies have required the use of assessment tools to evaluate both pretreatment attack severity (baseline severity) and changes in symptom severity following treatment (treatment response). This article reviews the range of assessment tools used for efficacy determination of acute HAE therapies, based on a review of relevant clinical studies. Because the goal is relief of symptoms (rather than cure), patient-reported outcomes (PROs) form the basis of these tools. Tools used to evaluate baseline severity typically employ location-specific assessment of symptom severity, using either categorical descriptions (which may be converted into numerical variables) or a visual analog scale (VAS). Some studies define the initial or most symptomatic site as an "index" site for purposes of efficacy determination, while others (such as the Mean Symptom Complex Severity score used in clinical studies of ecallantide) use a composite score that reflects all sites. Assessment of treatment response typically employs the same tool(s) to evaluate baseline severity, and may be either time-based (e.g., time to achievement of minimal or no symptoms) or symptom-based (e.g., degree of symptom relief at predetermined time points). Although it is unlikely that therapies will be compared using identical assessment tools, prospective or retrospective validation ensures the adequacy and relevance of such tools, which should be taken into consideration when therapies are compared.

Discrepancies between guidelines and international practice in treatment of hereditary angioedema

Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by decreased expression or loss of function of C1 esterase inhibitor (C1-INH). In 2010, international guidelines were published regarding the management of both acute HAE attacks and prophylactic treatment. Additionally, several clinical trials for HAE therapies were published in 2010. The purpose of this study was to assess the adherence of internationally based physicians to the current evidence-based studies and the 2010 International Consensus Algorithm. Internationally based physician members of the World Allergy Organization were surveyed regarding their diagnosis and management of patients with HAE. Only physicians who treat HAE patients were included in the analyses. Of the 201 responding physicians, the most highly used therapies for acute HAE attacks were C1-INH (59%), fresh frozen plasma (FFP; 42%), and icatibant (32%). For their preferred long-term prophylactic therapy, 74% used attenuated androgens and 18% used antifibrinolytics. Physicians in Latin and South America, in particular, were less likely than their international counterparts to prescribe C1-INH and more likely to prescribe attenuated androgens and FFP, and European physicians were the most likely to prescribe icatibant. Over one-third of physicians described themselves as "unfamiliar" with emerging HAE therapies. Many international physicians neither follow current evidence-based studies nor adhere to the 2010 International Consensus Algorithm for treating HAE. Further education of physicians, government authorities, and professional medical groups is necessary to enhance availability to therapies and appropriate use of them.

Hereditary angioedema (HAE) in children and adolescents—a consensus on therapeutic strategies

Hereditary angioedema due to C1 inhibitor (C1 esterase inhibitor) deficiency (types I and II HAE-C1-INH) is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible is important to avoid ineffective therapies and to properly treat swelling attacks. At a consensus meeting in June 2011, pediatricians and dermatologists from Germany, Austria, and Switzerland reviewed the currently available literature, including published international consensus recommendations for HAE therapy across all age groups. Published recommendations cannot be unconditionally adopted for pediatric patients in German-speaking countries given the current approval status of HAE drugs. This article provides an overview and discusses drugs available for HAE therapy, their approval status, and study results obtained in adult and pediatric patients. Recommendations for developing appropriate treatment strategies in the management of HAE in pediatric patients in German-speaking countries are provided.Conclusion Currently, plasma-derived C1 inhibitor concentrate is considered the best available option for the treatment of acute HAE-C1-INH attacks in pediatric patients in German-speaking countries, as well as for short-term and long-term prophylaxis.

Hereditary Angioedema Therapies in the United States: Movement Toward an International Treatment Consensus

BackgroundHereditary angioedema (HAE) is a rare, potentially life-threatening autosomal dominant disease characterized by recurrent angioedema attacks that affect the skin, gastrointestinal tract, and airway, including the larynx. Pharmacologic developments in HAE treatment have culminated in the recent introduction of 4 new HAE-specific therapies in the United States. ObjectivesIn light of these new therapeutic options, this commentary outlines historical US HAE therapy choices, discusses the potential effect of the 4 recently approved HAE treatments, and considers strategies for optimizing their use in line with international treatment recommendations. DiscussionTreatment options for HAE in the United States have been limited to attenuated androgens and antifibrinolytic agents for long-term prophylaxis and FFP and supportive therapy for the management of acute attacks. The 4 new therapies that have recently become available (ie, 2 plasma-derived C1 esterase inhibitor (C1-INH) concentrates, the kallikrein inhibitor ecallantide, and the bradykinin β2-antagonist icatibant) have provided an opportunity to change routine HAE treatment. In 2009, despite the availability of 2 of the new treatments (ie, the plasma-derived C1-INH concentrates), a large survey of US physicians suggested that wide variability still existed in the treatment of patients with HAE. Since this survey was undertaken, clinical experience with all 4 new treatments has increased significantly, and because 3 of these agents (ie, 2 plasma-derived C1-INH concentrates and icatibant) can be self-administered by trained patients, physicians can now provide individualized care that is proven effective and more aligned with international guidance.

The New Era of C1-Esterase Inhibitor Deficiency Therapy

Hereditary angioedema (HAE) is an autosomal dominant disorder clinically characterized by recurrent episodes of angioedema. Until late-2008, HAE therapy in the United States was largely limited to antifibrinolytic agents or attenuated androgens. Although these drugs decrease the number and severity of angioedema attacks, they are associated with significant dose-related adverse effects. Recent advances have dramatically changed the management of HAE. As a result, we are embarking on a new era of treatment for this condition that includes effective on-demand treatment of attacks as well as effective prophylactic treatment. Herein we discuss the various treatment options for C1-inhibitor deficiency, focusing on new developments and literature published over the past year, as well as the additional patient considerations that should be addressed when determining the most appropriate patient-specific treatment plan.

Fresh frosen plasma in therapy of hereditary angioedema

Fresh frosen plasma in therapy of hereditary angioedema

Advances in the therapy of hereditary angioedema

Hereditary angioedema is a rare autosomal dominantly inherited disease characterized by recurrent episodes of subcutaneous and mucosal edema due to the deficiency of plasma functional C1 esterase inhibitor.Acute attacks of laryngeal swelling are often associated with a substantial risk of death.In the past,hereditary angioedema was treated with anti-histamine drugs and glucocorticoids,but the outcome was unsatisfactory,and mortality was reported as high as 30%.With further insights into the pathogenesis of hereditary angioedema,new drugs have emerged and provided clinicians and patients with more choices.The authors summarize the pathogenesis and clinical manifestations of the entity with focus on the progress in its treatment. Key words: Angioneurotic edema; Heredity; C1 esterase inhibitors; Therapy

New Therapeutics in C1INH Deficiency: A Review of Recent Studies and Advances

Hereditary angioedema (HAE) is a genetic condition causing a significant burden of illness for affected individuals. Episodes of angioedema involving the skin, gastrointestinal tract, as well as the larynx and oropharynx are often unpredictable and cause significant morbidity and mortality. Isolation of the underlying protein deficiency, specifically the serine protease C1 inhibitor, and further description of its role in multiple physiologic cascades has led to the development of several specific therapies for HAE. This report provides a brief overview of HAE but focuses primarily on reviewing recently published clinical studies of therapeutics developed for medical management of the condition.

Treatment of Laryngeal Hereditary Angioedema

Background In the emergency department, patients with laryngeal swelling and an inconclusive patient history may receive treatment for allergy-mediated angioedema. Intubation may be necessary if the patient does not respond to treatment. Because angioedema subtypes respond to different interventions, a correct diagnosis is vital. Objectives Review the differential diagnosis of angioedema and characteristics differentiating subtypes. Discuss therapies for angioedema subtypes. Introduce therapies for prevention and acute treatment of hereditary angioedema (HAE). Case Report A 10-year-old girl presented with laryngeal swelling unresponsive to diphenhydramine, methylprednisolone, and epinephrine. It was later revealed that she had a family history of HAE, was C1 inhibitor deficient, and enrolled in a clinical study of acute HAE treatment. She was given 1000 units of nanofiltered C1 inhibitor and was able to swallow within 30 min. She was prescribed routine prophylaxis with C1 inhibitor concentrate and has had no subsequent severe HAE swelling attacks. Conclusion This case illustrates the need for providers to consider HAE in light of available diagnostic testing and recent Food and Drug Administration approval of specific therapies for HAE.

Hereditary angioedema: beyond international consensus - circa December 2010 - The Canadian Society of Allergy and Clinical Immunology Dr. David McCourtie Lecture

BackgroundThe 2010 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema was published earlier this year in this Journal (Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24 - http://www.aacijournal.com/content/6/1/24). Since that publication, there have been multiple phase III clinical trials published on either prophylaxis or therapy of hereditary angioedema and some of these products have changed approval status in various countries. This manuscript was prepared to review and update the management of hereditary angioedema.ObjectiveTo review approaches for the diagnosis and management of hereditary angioedema (HAE) circa December 2010 and present thoughts on moving from HAE management from international evidence-based consensus to facilitate more local health unit considerations balancing costs, efficacies of treatments, and risk benefits. Thoughts will reflect Canadian and international experiences.MethodsPubMed searches including hereditary angioedema and diagnosis, therapy, management and consensus were reviewed as well as press releases from various pharmaceutical companies to early December 2010.ResultsThe 2010 International Consensus Algorithms for the Diagnosis, Therapy and Management of Hereditary Angioedema is reviewed in light of the newly published phase III Clinical trials for prevention and therapy of HAE. Management approaches and models are discussed.ConclusionsConsensus approach and double-blind placebo controlled trials are only interim guides to a complex disorder such as HAE and should be replaced as soon as possible with large phase IV clinical trials, meta analyses, data base registry validation of approaches including quality of life and cost benefit analyses, safety, and head-to-head clinical trials investigating superiority or non-inferiority comparisons of available approaches. Since not all therapeutic products are available in all jurisdictions and since health care delivery approaches and philosophy vary between countries, each health care delivery sector will likely devise their own algorithms based on local practicalities for implementing evidence-based guidelines and standards for HAE disease management. Quality-of-life and cost affordability benefit conclusions will likely vary between countries and health care units. Data base registries for rare disorders like HAE should be used to detect early adverse events for new therapies and to facilitate phase IV clinical trials and encourage superiority and non-inferiority comparisons of HAE management approaches.

Current medical management of hereditary angioedema: results from a large survey of US physicians

Hereditary angioedema (HAE) is a potentially life-threatening condition that affects approximately 1 in 50,000 persons. There are no known surveys of US physicians' knowledge and experience regarding the epidemiology, diagnosis, and management of HAE. This survey of physicians treating patients with HAE assessed physician characteristics, diagnostic and treatment practices, factors that influence physician and patient treatment choices, and physician awareness of new therapies. From October 2009 to February 2010, physicians (N = 172) voluntarily completed an online survey developed by physician-investigators. Data were analyzed with descriptive statistics. Most physicians (73.8%) managed 5 patients or fewer in diverse practice settings. Laboratory testing was considered most important in establishing a diagnosis. Fresh frozen plasma and C1 esterase inhibitors were the most frequently administered treatments for acute events; nearly 50% of respondents prescribed C1 esterase inhibitor for acute attacks. More than 80% of respondents prescribed androgens for long-term prophylaxis. Approximately half of respondents were aware of, and likely to use, new therapies for HAE. Other than efficacy, adverse effects were the most important factor that influenced physicians' treatment recommendations, whereas physicians perceived that patients were most influenced by adverse effects and cost. Wide variability exists in the treatment of patients with HAE. Many patients experience acute attacks that require emergency care or hospitalization. Androgens and fresh frozen plasma are frequently used despite recent availability of effective condition-specific agents, and many physicians are only somewhat aware of medications newly approved by the US Food and Drug Administration. Because the survey was completed shortly after approval of additional HAE therapies by the US Food and Drug Administration, these data will be useful for tracking changes in HAE treatment over time.

Update on the acute treatment of hereditary angioedema

Hereditary angioedema (HAE) is a genetic autosomal dominant condition caused by C1-esterase inhibitor protein (C1INH) deficiency that results in episodic tissue angioedema. Recently, new therapies have been developed to more effectively manage this rare but serious condition. This review will provide a concise summary of HAE acute treatment options for the practicing allergist/immunologist. Clinical study data for emerging HAE therapies were reviewed and summarized. Based on efficacy and safety data from completed clinical studies, three new HAE treatments have recently been approved by the Food and Drug Administration: nanofiltered plasma-derived C1INH for prophylactic therapy, pasteurized plasma-derived C1INH for acute therapy, and ecallantide for acute therapy. Two other promising therapies, recombinant C1INH and icatibant, are in various stages of the U.S. regulatory process. The medical management of HAE is entering a new era with the availability of safe, effective condition-specific treatments. Clinicians should consider a number of patient- and medication-specific factors when designing individualized treatment plans for HAE patients.

Hereditary angioedema therapy: kallikrein inhibition and bradykinin receptor antagonism.

Current strategies for the treatment of hereditary angioedema (HAE) include targeted inhibition or antagonism of the contact system, which is dysregulated in HAE patients by a C1 esterase inhibitor deficiency. Ecallantide, a plasma kallikrein inhibitor, and icatibant, a selective bradykinin-2 receptor antagonist, have recently been evaluated in clinical studies for the treatment of acute HAE attacks. Both drugs have demonstrated evidence of efficacy and safety in treating acute HAE episodes, with ecallantide approved for use in the United States and icatibant approved for use in Europe. As therapeutic options for HAE expand for both for prophylactic and acute treatment strategies, a number of patient-specific and drug-specific factors have emerged as important considerations when developing individualized HAE management plans. Optimization of HAE therapy will require further integration of new therapies into the current treatment paradigm.

Current treatment of hereditary angioedema: An update on clinical studies

Hereditary angioedema (HAE) is a rare, potentially life-threatening disease that manifests as recurrent episodes of nonpruritic swelling that may affect the extremities, face, genitalia, gastrointestinal tract, and/or larynx. HAE is the result of a deficiency of functional C1-esterase inhibitor (C1-INH), a key regulator of the complement, coagulation, and kallikrein-kinin cascades. In HAE patients, overactivation of the kallikrein-kinin cascade results in excessive release of bradykinin, the mediator of the pain and swelling that is characteristic of HAE. Historically, treatment options for HAE have been limited, but newly approved and emerging therapies, such as C1-INH replacement products, a plasma kallikrein inhibitor, and a bradykinin B₂-receptor antagonist, appear to provide safe and effective relief for a significant proportion of patients with HAE. Because they may have therapeutic and practical advantages over existing HAE therapies, the new agents have the potential to improve the overall management of patients with HAE. This article reviews the results from recent clinical trials of these drugs and considers their role in clinical practice.

HAE therapies: past present and future.

Advances in understanding the pathophysiology and mechanism of swelling in hereditary angioedema (HAE) has resulted in the development of multiple new drugs for the acute and prophylactic treatment of patients with HAE. This review will recap the past treatment options, review the new current treatment options, and discuss potential future treatment options for patients with HAE.

On demand treatment and home therapy of hereditary angioedema in Germany - the Frankfurt experience

BackgroundManifestation of acute edema in hereditary angioedema (HAE) is characterized by interindividual and intraindividual variability in symptom expression over time. Flexible therapy options are needed.MethodsWe describe and report on the outcomes of the highly individualized approach to HAE therapy practiced at our HAE center in Frankfurt (Germany).ResultsThe HAE center at the Frankfurt University Hospital currently treats 450 adults with HAE or AAE and 107 pediatric HAE patients with highly individualized therapeutic approaches. 73.9% of the adult patients treat HAE attacks by on-demand therapy with pasteurized pd C1-INH concentrate, 9.8% use additional prophylaxis with attenuated androgens, 1% of the total patient population in Frankfurt has been treated with Icatibant up to now. In addition adult and selected pediatric patients with a high frequency of severe attacks are instructed to apply individual replacement therapy (IRT) with pasteurized pd C1-INH concentrate. Improvement on Quality of Life items was shown for these patients compared to previous long-term danazol prophylaxis. Home treatment of HAE patients was developed in the Frankfurt HAE center in line with experiences in hemophilia therapy and has so far been implemented over a period of 28 years. At present 248 (55%) of the adult patients and 26 (24%) of the pediatric patients are practicing home treatment either as on demand or IRT treatment.ConclusionsIn conclusion, the individualized home therapies provided by our HAE center, aim to limit the disruption to normal daily activities that occurs for many HAE patients. Furthermore, we seek to optimize the economic burden of the disease while offering a maximum quality of life to our patients.