Treatment Of Hereditary Angioedema Attacks Research Articles

A Core Outcome Set for Efficacy of Acute Treatment of Hereditary Angioedema

BackgroundClinical trials investigating drugs for acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants. ObjectiveTo achieve consensus on a Core Outcome Set comprising key outcomes that should ideally be utilized in all clinical efficacy trials involving acute treatment of hereditary angioedema attacks. MethodsA Delphi consensus study was conducted involving all relevant parties: hereditary angioedema patients, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two internet-based survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9-point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2. ResultsFifty-eight worldwide panelists completed both rounds. The first round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of ≥90% was achieved on a core outcome set consisting of five key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. ConclusionThis international study obtained a high level of consensus on a core outcome set for acute treatment of hereditary angioedema attacks consisting of five key outcomes.

Real-world reporting rates of administration-site reactions with on-demand treatment of hereditary angioedema attacks.

Background: Hereditary angioedema (HAE) is characterized by recurrent and unpredictable episodes of subcutaneous and/or submucosal swelling. Objective: To characterize the real-world treatment burden associated with existing on-demand therapies, we analyzed administration-site adverse drug reactions (ADR) associated with approved on-demand HAE therapies reported in the U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS). Methods: We searched the FAERS database from October 1, 2009, to March 31, 2022, for reports of all FDA-approved on-demand therapies for HAE: plasma-derived C1-inhibitor (pdC1-INH), ecallantide, icatibant, and recombinant C1-inhibitor (rhC1-INH). ADRs in which the drug was listed as the "primary suspect" were recorded for each drug. ADR preferred terms were grouped into 18 ADR domains based on semantic and/or clinical similarity, and the number of reports for each drug was calculated per year from the time of approval through March 2022, and descriptive results were presented. Preferred terms associated with administration-site ADRs identified from clinical trials and denoted on approved HAE drug U.S. package inserts were examined in a complementary analysis. Results: The highest reported rates of administration-site ADRs per year were site pain (17.9 reports per year), site erythema (7.4 per year), and site swelling (6.7 per year). RhC1-INH was the only drug for which access-site complications and/or malfunctions were reported (9.5 per year). PdC1-INH had the highest rate of incorrect route of product administration (3.7 per year). PdC1-INH showed statistically significant elevated reporting rate of injection-site reactions (reporting odds ratio [ROR] 3.59 [2.36-5.46]; empirical Bayesian geometric mean [EBGM] 1.97 [1.39]). Icatibant and rhC1-INH showed a statistical trend toward an increased reporting rate of administration-site reactions. Conclusion: Real-world data from FAERS were generally consistent with adverse events reported in clinical trials and suggest that patients experience substantial treatment burden associated with FDA-approved parenteral on-demand therapies for HAE attacks. It should be noted that ADR rates are not exposure adjusted and are based on spontaneous reporting.

A Review of Randomized Controlled Trials of Hereditary Angioedema Long-Term Prophylaxis with C1 Inhibitor Replacement Therapy: Alleviation of Disease Symptoms Is Achievable.

Through its fluctuating disease activity and unpredictable attacks, hereditary angioedema (HAE) imposes a substantial patient burden. To minimize HAE burden and improve quality of life, treatment should involve individualized management strategies that address on-demand therapy and short-term/long-term prophylaxis. Goals of long-term prophylaxis include reducing the number, severity, and burden of HAE attacks. The best characterized forms of HAE arise from deficiency or dysfunction of C1-inhibitor (C1-INH; types I/II), and C1-INH replacement therapy is a first-line intervention for on-demand (acute) treatment of HAE attacks, short-term prophylaxis before high-risk procedures, and long-term prophylaxis. Randomized, double-blind, placebo-controlled crossover trials have shown dose-dependent efficacy with plasma-derived C1-INH (pdC1-INH) 40-60 IU/kg subcutaneously, pdC1-INH 1000 U intravenously, and recombinant human C1-INH (rhC1-INH) 50 IU/kg (maximum 4200 IU) intravenously, all administered twice weekly, as long-term prophylaxis in patients with a history of 2 to ≥4 attacks/month. Overall, up to 83% (pdC1-INH 60 IU/kg) of patients experienced an HAE attack reduction threshold of ≥70%, and up to 58% (pdC1-INH 60 IU/kg) achieved an attack reduction threshold of ≥90%. Lower-dose intravenous pdC1-INH therapy (1000 U) was seemingly less effective, with 45% of 22 patients experiencing an HAE attack reduction threshold of ≥70%, and up to 23% achieving an attack reduction threshold of ≥90%. Higher-dose intravenous rhC1-INH 50 IU/kg (maximum, 4200 IU) twice weekly was of intermediate benefit. Despite a baseline mean attack frequency of 17.9 (during the 3 months prior to study treatment) and a mean attack frequency during a 4-week placebo period of 7.2, 52% of 23 patients experienced ≥70% reduction in attack frequency and 26% of 23 patients experienced ≥90% reduction in attack frequency. The increasing patient percentages treated with C1-INH replacement therapy as long-term prophylaxis meeting these high thresholds reinforces hopes and expectations that "attack freedom" is achievable, including for those with moderate or severe disease.

Reporting of Adverse Drug Reactions with Parenteral Drugs for the On-Demand Treatment of Hereditary Angioedema Attacks – Analysis of the FAERS Database 2009 to 2022

Analysis assessed the post-marketing reporting rates for adverse drug reactions (ADRs) in patients treated with parenteral on-demand hereditary angioedema (HAE) drugs utilizing the FDA’s Adverse Event Reporting System (FAERS).

An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: a two-part, randomised, double-blind, placebo-controlled, crossover phase 2 trial

Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks. In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2 × 2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with ClinicalTrials.gov, NCT04208412, and is completed. Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received sebetralstat (mean age 38·3 years [SD 13·2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with sebetralstat versus placebo (at quartile 1: >12 h [95% CI 9·6 to >12] vs 8·0 h [3·8 to >12]; p=0·0010). There were no serious adverse events or adverse event-related discontinuations. Oral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (NCT05259917). KalVista Pharmaceuticals.

Clinical Characteristics and Management of Angioedema Attacks in Polish Adult Patients with Hereditary Angioedema Due to C1-Inhibitor Deficiency.

Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency is a rare disease characterized by recurrent swellings. This study aims to determine (i) the clinical characteristics of the HAE patient population from Poland, and (ii) real-life patients’ treatment practices. A cross-sectional study involved 138 adult HAE patients (88 females, 50 males) treated in six regional HAE centers in Poland. Consecutive patients during routine follow-up visits underwent a structured medical interview on the clinical characteristics of the course and treatment of HAE attacks within the last six months. A total of 118 of 138 patients was symptomatic. They reported in total 2835 HAE attacks predominantly peripheral and abdominal, treated with plasma-derived C1-INH (61.4%), icatibant (36.7%) and recombinant C1-INH (1.9%). An amount of 116 patients carried the rescue medication with them while traveling, and 74 patients self-administrated on demand treatment. There were twice as many symptomatic women (n = 78) as there were men (n = 40). Women treated their HAE attacks significantly more often than men. Older patients (≥65 years) reported a longer delay in diagnosis, and practiced the self-administration of rescue medication less frequently in comparison to other patients. Clinical features of the surveyed population are similar to other European, but not Asian, HAE patient groups. Self-administration still remains an unmet medical need. Some distinct HAE patients may require special attention due to the severe course of the disease (females) or a delay in diagnosis (the elderly).

Orladeyo (Berotralstat): A Novel Oral Therapy for the Prevention of Hereditary Angioedema.

The purpose of this article is to review the available trials that led to the Food and Drug Administration (FDA) approval of berotralstat, an oral kallikrein inhibitor, for the prevention of hereditary angioedema (HAE) attacks. PubMed and ClincalTrials.gov were searched using key term berotralstat to identify phase III clinical trials related to the FDA approval of berotralstat from April 2018 to May 2021. Trials selected were those that influenced the FDA approval of berotralstat or provided novel information regarding the safety and efficacy of this therapy in the treatment of HAE. Both APeX-2 and ApeX-J found clinically significant benefit with berotralstat 150 mg daily for reduction in HAE attacks when compared with placebo (1.31 vs 2.35, P < 0.001, and 1.11 vs 2.18, P < 0.001, attacks in the APeX-2 and APeX-J trials, respectively). APeX-2 also showed a statistically significant benefit for berotralstat 110 mg daily (1.65 vs 2.35 attacks [1.65 attacks, P = 0.024]). An advantage berotralstat has over the other approved therapies is that it is administered orally, which may garner patient preference because of ease of administration. Berotralstat has also shown a potential benefit in reducing the need for standard-of-care treatment for HAE attacks, which has not been studied with alternative agents. Berotralstat 150 mg daily has been proven safe and effective in clinical studies and appears to be a viable oral alternative to parenteral medications currently used in HAE prophylaxis.

Sugar Matters: Improving In Vivo Clearance Rate of Highly Glycosylated Recombinant Plasma Proteins for Therapeutic Use.

Correct glycosylation of proteins is essential for production of therapeutic proteins as glycosylation is important for protein solubility, stability, half-life and immunogenicity. The heavily glycosylated plasma protein C1-inhibitor (C1-INH) is used in treatment of hereditary angioedema attacks. In this study, we used C1-INH as a model protein to propose an approach to develop recombinant glycoproteins with the desired glycosylation. We produced fully functional recombinant C1-INH in Chinese hamster ovary (CHO) cells. In vivo we observed a biphasic clearance, indicating different glycosylation forms. N-glycan analysis with mass spectrometry indeed demonstrated heterogeneous glycosylation for recombinant C1-INH containing terminal galactose and terminal sialic acid. Using a Ricinus Communis Agglutinin I (RCA120) column, we could reduce the relative abundance of terminal galactose and increase the relative abundance of terminal sialic acid. This resulted in a fully active protein with a similar in vivo clearance rate to plasmaderived C1-INH. In summary, we describe the development of a recombinant human glycoprotein using simple screening tools to obtain a product that is similar in function and in vivo clearance rate to its plasma-derived counterpart. The approach used here is of potential use in the development of other therapeutic recombinant human glycoproteins.

Berotralstat. Plasma kallikrein (KLKB1) inhibitor, Treatment of hereditary angioedema attacks

Berotralstat. Plasma kallikrein (KLKB1) inhibitor, Treatment of hereditary angioedema attacks

The identification and chromatographic separation of a new highly analogous impurity of the active pharmaceutical ingredient icatibant

Icatibant is a peptidomimetic drug serving as a bradykinin-receptor antagonist and is approved in Europe and the United States for the treatment of hereditary angioedema attacks. We have detected an impurity with a high structural similarity to icatibant in pharmaceutical dosage forms using an optimized chromatographic method based on reversed phase high performance liquid chromatography with UV detection. The abundance of the impurity was around 1% relative to the icatibant peak following storage at room temperature for 1 month, and raised up to ~16% upon temperature stressing at 100 °C. The impurity was isolated by fraction collection and further purified by solid phase extraction for structural identification. NMR and high resolution mass spectrometric analyses revealed that this impurity results from isomerization in the N-terminal single amino acid residue. The new impurity may warrant particular attention due to its exceptional similarity to the active ingredient icatibant.

KVD900 as a Single Dose, Rapid, Oral Plasma Kallikrein Inhibitor for the On-Demand Treatment of Hereditary Angioedema Attacks: Pharmacokinetic and Pharmacodynamic results from a Phase 1 Single Ascending Dose Study

KVD900 as a Single Dose, Rapid, Oral Plasma Kallikrein Inhibitor for the On-Demand Treatment of Hereditary Angioedema Attacks: Pharmacokinetic and Pharmacodynamic results from a Phase 1 Single Ascending Dose Study

Treatment of Hereditary Angioedema Attacks with Icatibant and Recombinant C1 Inhibitor During Pregnancy.

Hereditary angioedema (HAE) is a rare disease caused by a C1 inhibitor (C1-INH) deficit. Clinically, HAE is manifested by repeated episodes of localized subcutaneous or submucosal oedema attacks. Managing HAE patients in pregnancy is challenging, since there are only limited data on the safety and efficacy of various therapeutic approaches. We present our clinical experience treating acute HAE attacks during pregnancy in six consecutive patients. During the pregnancies, 79 HAE attacks occurred. The most frequent were abdominal 53 (67.1%) followed by peripheral 21 (26.6%), facial 10 (12.7%), and laryngeal 10 (12.7%) oedemas; 13 (16.5%) attacks were combined. Fifty (63.3%) attacks were treated with recombinant human C1-INH (rhC1-INH); 17 (21.5%) with plasma-derived, pasteurized, nanofiltered C1-INH (pnfC1-INH); 13 (16.5%) with icatibant; and 1 (1.3%) with plasma-derived, nanofiltered C1-INH (nfC1-INH). Treatment had to be repeated in 5 attacks (6.3%). All six deliveries (one caesarean section and five spontaneous vaginal deliveries) were complication free. All pregnancies went to the full term and the patients delivered healthy babies with a birth weight ranging from 2850 to 3690g. No congenital abnormalities were detected in the neonates. No abortions occurred. Our results show good C1-INH or icatibant treatment efficacy for HAE attacks in pregnancy. The treatment by the first drug used was effective in 93.7% of all attacks. In 6.3% of attacks, a second treatment had to be used. No adverse effects were observed.

134 Patterns of On-Demand Medication Use in the Treatment of Hereditary Angioedema Attacks: Implications for the Management of Hereditary Angioedema in the Emergency Department

134 Patterns of On-Demand Medication Use in the Treatment of Hereditary Angioedema Attacks: Implications for the Management of Hereditary Angioedema in the Emergency Department

Effectiveness of icatibant for treatment of hereditary angioedema attacks is not affected by body weight: findings from the Icatibant Outcome Survey, a cohort observational study

BackgroundIcatibant is a bradykinin B2-receptor antagonist used for the treatment of hereditary angioedema attacks resulting from C1-inhibitor deficiency. Treatment is not adjusted by body weight however the impact of body mass index (BMI) on the effectiveness of icatibant is not documented in the literature. We examined disease characteristics and icatibant treatment effectiveness in patients stratified by BMI in the Icatibant Outcome Survey, an ongoing, international, observational study monitoring the real-world safety and effectiveness of icatibant.MethodsAttack and treatment characteristics as well as outcomes following treatment with icatibant were compared among patients with underweight, normal, overweight, and obese BMI.ResultsData from 2697 icatibant-treated attacks in 342 patients (3.5, 44.7, 34.8, and 17.0% patients of underweight, normal, overweight, and obese BMI, respectively) were analyzed. There was no significant difference in the frequency and severity of attacks across BMI groups, although obese patients tended to have more attacks of high severity. There was no impact of BMI on the frequency of laryngeal attacks, but patients with normal BMI had fewer cutaneous attacks and more abdominal attacks. Most attacks (71.9–83.8%) were treated with a single icatibant injection without the need for rescue with plasma-derived C1-inhibitor (pdC1-INH), regardless of BMI. Patients with obese BMI used pdC1-INH as rescue treatment more often (P < 0.0001; P = 0.0232 excluding 2 outliers) and treated attacks earlier than patients with normal BMI (P = 0.007). Furthermore, time to resolution and duration of attack were shorter for patients with high BMI (P < 0.001 for overweight and P < 0.05 for obese versus normal).ConclusionOverall, icatibant was comparatively effective in treating attacks in patients across all BMI groups.Trial registration NCT01034969.

Sustained response of recombinant human C1 esterase inhibitor for acute treatment of hereditary angioedema attacks

BackgroundSymptoms of hereditary angioedema (HAE) attacks can recur soon after initial treatment; the durability of response for recombinant human C1 esterase inhibitor (rhC1INH) treatment is unknown. ObjectiveTo examine the efficacy and durability of rhC1INH for acute HAE attacks. MethodsIn this pooled post hoc analysis of 2 trials, patients with type I or II HAE (functional C1INH levels <50% of normal) and a baseline visual analog scale score of at least 50 mm were included if they had received at least 1 intravenous dose of 50 IU/kg of rhC1INH. Response was defined as symptom relief within 4 hours after treatment with persistence (≥20-mm decrease in visual analog scale scores [0 mm {“no symptoms at all”} to 100 mm {“extremely disabling”}] at 2 consecutive time points) during the 4 hours. Durability was the response without an increase of at least 20 mm in the minimum post-treatment visual analog scale score up to 24 hours. Recurrence and new attack symptoms were determined for patients with 72-hour post-treatment data. ResultsData were analyzed for 127 patients treated with 50 IU/kg of rhC1INH in 2 studies. Most attacks (90.7%) responded within 4 hours, with differences in response rates among attack locations (61.5%–94.4%). The median time to the beginning of symptom relief was 75.0 minutes (95% confidence interval 65.0–80.0). No relapse occurred during 24 hours for attacks that initially responded. Only 7.1% of attacks were associated with symptom recurrence within 72 hours of initial rhC1INH treatment. ConclusionThis integrated analysis supports the efficacy of rhC1INH for treatment of acute HAE across multiple attacks, with a sustained response for at least 3 days. Trial RegistrationClinicalTrials.gov Identifiers: NCT00225147 and NCT00262301.

Subcutaneous Icatibant for the Treatment of Hereditary Angioedema Attacks: Comparison of Home Self-Administration with Administration at a Medical Facility

Hereditary angioedema (HAE) is a life-threatening disorder characterized by recurrent angioedema. Icatibant, a subcutaneous bradykinin-B2-receptor antagonist, is an effective on-demand therapy. Data outside the UnitedStates suggest that self-administration is tolerated andpatient-preferred compared with administration byhealth care professionals at medical facilities (HCP-administration). A prospective, multicenter study was conducted in the United States to compare icatibant self-administration and HCP-administration. Subjects 18 years or older with type I or II HAE were recruited. The first 2 HAE attacks after enrollment were treated at medical facilities. Subjects were instructed by a health care professional on self-administration during icatibant treatment for the second HAE attack. Icatibant was self-administered for all subsequent attacks. For each treated HAE attack, efficacy, safety, and tolerability data were recorded. Nineteen patients with HAE received icatibant for 79 distinct HAE attacks. Mean attack duration was significantly shorter with self-administration (n= 50; 547 ± 510 minutes) than with HCP-administration (n= 29; 968 ± 717 minutes; P= .006). Mean time to treatment was significantly shorter with self-administration (143 ± 226 minutes) than with HCP-administration (361 ± 503 minutes; P < .0001). Shorter times to treatment were associated with shorter time from treatment to symptom resolution (r= 0.35; P= .02). Improvements in visual analog scale score and patient symptom score from pretreatment to 4 hours postinjection were comparable between self-administration and HCP-administration. There were no serious adverse events or discontinuations due to adverse events with self-administration or HCP-administration. Icatibant self-administration shortened attackduration and time to treatment, with no difference in safety or local tolerability compared with HCP-administration. These findings support icatibant as an effective on-demand option forhome-based treatment.

Diagnosis and screening of patients with hereditary angioedema in primary care.

Hereditary angioedema (HAE) is a rare autosomal dominant disease that commonly manifests with episodes of cutaneous or submucosal angioedema and intense abdominal pain. The condition usually presents due to a deficiency of C1 esterase inhibitor (C1-INH) that leads to the overproduction of bradykinin, causing an abrupt increase in vascular permeability. A less-understood and less-common form of the disease presents with normal C1-INH levels. Symptoms of angioedema may be confused initially with mast cell-mediated angioedema, such as allergic reactions, and may perplex physicians when epinephrine, antihistamine, or glucocorticoid therapies do not provide relief. Similarly, abdominal attacks may lead to unnecessary surgeries or opiate dependence. All affected individuals are at risk for a life-threatening episode of laryngeal angioedema, which continues to be a source of fatalities due to asphyxiation. Unfortunately, the diagnosis is delayed on average by almost a decade due to a misunderstanding of symptoms and general lack of awareness of the disease. Once physicians suspect HAE, however, diagnostic methods are reliable and available at most laboratories, and include testing for C4, C1-INH protein, and C1-INH functional levels. In patients with HAE, management consists of acute treatment of an attack as well as possible short- or long-term prophylaxis. Plasma-derived C1-INH, ecallantide, icatibant, and recombinant human C1-INH are new treatments that have been shown to be safe and effective in the treatment of HAE attacks. The current understanding of HAE has greatly improved in recent decades, leading to growing awareness, new treatments, improved management strategies, and better outcomes for patients.

Characterization of Anaphylaxis After Ecallantide Treatment of Hereditary Angioedema Attacks

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. The objective of this detailed retrospective data review was to characterize anaphylaxis cases within the ecallantide clinical trials database. 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. 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. 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.

Sustained Response Following Acute Treatment Of Hereditary Angioedema Attacks With Recombinant Human C1 Esterase Inhibitor

Sustained Response Following Acute Treatment Of Hereditary Angioedema Attacks With Recombinant Human C1 Esterase Inhibitor

Efficacy and safety of recombinant C1 inhibitor for the treatment of hereditary angioedema attacks: a North American open-label study

BackgroundThe efficacy of recombinant human C1 inhibitor (rhC1INH) for the treatment of patients with acute hereditary angioedema (HAE) attacks has been demonstrated in 2 randomized, double-blind, placebo-controlled studies. ObjectiveTo assess the safety and efficacy of rhC1INH for repeated treatment of acute attacks of HAE. MethodsIn this open-label extension study, patients with eligible HAE attacks were treated with an intravenous 50-U/kg dose of rhC1INH with an option for an additional dose of 50 U/kg based on clinical response. Time to beginning of relief was assessed by patients using a 100-mm visual analogue scale (VAS). Safety evaluation was based on the clinical laboratory results and adverse events. ResultsSixty-two patients were treated for 168 attacks (range, 1-8 attacks per patient). A total of 90% of the attacks were treated with a single 50-U/kg dose of rhC1INH. Median times to beginning of symptom relief for the first 5 attacks were 37 to 67 minutes. More than 90% of attacks responded within 4 hours after treatment with rhC1INH. There was no requirement for increased dosing with successive treatments. Thirty-nine patients (63%) reported at least 1 treatment-emergent adverse event, with most events rated mild to moderate. Seven severe treatment-emergent adverse events were reported, and all were considered to be unrelated to treatment with rhC1INH. ConclusionThe results of this open-label extension support continued efficacy of rhC1INH after repeated treatments for subsequent HAE attacks. There was no increase in adverse event reporting after repeated exposure to rhC1INH. Trial Registrationclinicaltrials.gov Identifier: NCT00225147