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Zuraw B.,University of California at San Diego | Cicardi M.,University of Milan | Levy R.J.,Family Allergy and Asthma Center | Nuijens J.H.,Pharming Technologies BV | And 5 more authors.
Journal of Allergy and Clinical Immunology | Year: 2010

Background: Hereditary angioedema (HAE) results from a genetic deficiency of C1-inhibitor. Two similar independent, randomized, saline controlled, double-blind studies were conducted to evaluate the efficacy and safety of recombinant human C1-inhibitor (rhC1INH) as a treatment of acute angioedema attacks in patients with HAE. Objective: Analysis of pooled study results. Methods: Patients with an eligible attack were randomized to a single intravenous dose of rhC1INH or saline. Efficacy was assessed by using patient-reported visual analog scale outcomes, and safety was assessed by using adverse events and immunogenicity of rhC1INH. Results: rhC1INH at 100 (n = 29) and 50 (n = 12) U/kg body weight resulted in a significant reduction for both the primary endpoint time to the beginning of relief of symptoms compared with saline (n = 29): median, 66 (95% CI, 61-122) minutes, 122 (72-136) minutes, and 495 (245-520) minutes, P < .001 and P = .013, respectively; and for the secondary endpoint time to minimal symptoms, median, 266 (242-490) minutes, 247 (243-484) minutes, and 1210 (970-1500) minutes, P < .001 and P = .001, respectively. Therapeutic failure occurred in 59% (17/29) of the saline group compared with 0% (0/12) of the 50 U/kg group and 10% (3/29) of the 100 U/kg group. Treatment-emergent adverse events were unremarkable and tended to be reported more frequently in the saline group. No postexposure antibody responses against rhC1INH or host-related impurities were observed. Conclusion: Administration of rhC1INH at 100 or 50 U/kg was highly effective as a treatment of acute attacks in patients with HAE and appeared to be safe and well tolerated. © 2010 American Academy of Allergy, Asthma & Immunology.


Hack C.E.,University Utrecht | Mannesse M.,Xendo B.V. | Baboeram A.,Pharming Technologies BV | Oortwijn B.,Pharming Technologies BV | Relan A.,Pharming Technologies BV
BioDrugs | Year: 2012

Background and Objective: Recombinant human C1-inhibitor (rhC1INH) is used to treat acute angioedema attacks in hereditary angioedema (HAE) due to a genetic C1INH deficiency. Recombinant proteins in general may induce antibody responses and therefore evaluation of such responses in the target population is an essential step in the clinical development program of a recombinant protein. Here we report the assessment of the immunogenicity of rhC1INH in symptomatic HAE patients. Methods: Blood samples collected before and after administration of rhC1INH were tested for antibodies against plasma-derived (pd) or rhC1INH, or against host-related impurities (HRI). Above cut-off screening results were confirmed with displacement assays, and also tested for neutralizing anti-C1INH antibodies. Finally, the relation of antibodies to clinical efficacy and safety of rhC1INH was analyzed. Results: Data from 155HAE patients who received 424 treatments with rhC1INH were analyzed. 1.5% of all preexposure tests and 1.3% of ll post-exposure tests were above the cut-off level in the screening assay for anti-C1INH antibodies. Six patients (3.9%) had anti-rhC1INH antibodies positive in the confirmatory assay. In two patients, confirmed antibodies were pre-existing with no increase post-exposure; in three patients, the antibodies occurred on a single occasion post-exposure; and in one patient, on subsequent occasions post-exposure. Neutralizing antipdC1INH antibodies were not found. Anti-HRI antibodies in the screening assay occurred in 0.7% of the tests before exposure to rhC1INH, in 1.9%after first exposure and in 3.1%after repeat treatment with rhC1INH.Five patients had anti-HRI antibodies positive in the confirmatory assay. In one patient, the antibodies were preexisting, whereas in three of the 155 rhC1INH-treated patients (1.9%), confirmed anti-HRI antibodies occurred at more time points. Antibody findings were not associated with altered efficacy of rhC1INH or adverse events. Conclusion: These results indicate a reassuring i unosafety profile of rhC1INH as a treatment for acute HAE attacks. © 2012 Springer International Publishing AG. All rights reserved.


Riedl M.A.,University of California at Los Angeles | Levy R.J.,Family Allergy and Asthma Center | Suez D.,Allergy Asthma and Immunology Clinic | Lockey R.F.,University of South Florida | And 3 more authors.
Annals of Allergy, Asthma and Immunology | Year: 2013

Background: The 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. Objective: To assess the safety and efficacy of rhC1INH for repeated treatment of acute attacks of HAE. Methods: In 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. Results: Sixty-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. Conclusion: The 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 Registration: clinicaltrials.gov Identifier: NCT00225147. © 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.


Reshef A.,Clinical Immunology and Angioedema Unit | Moldovan D.,University of Medicine and Pharmacy of Targu Mures | Obtulowicz K.,Jagiellonian University | Leibovich I.,Clinical Immunology and Angioedema Unit | And 3 more authors.
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2013

Background Hereditary angioedema (HAE) is a disease characterized by recurrent tissue swelling affecting various body locations. Recent literature shows that patients with frequent attacks may benefit from long-term prophylaxis. This study evaluated the safety and prophylactic effect of weekly administrations of recombinant C1INH (rhC1INH). Methods Patients with a history of HAE attacks occurring ≥every 2 weeks received a once weekly administration of 50 U/kg rhC1INH. Hereditary angioedema attack history was collected at screening. Breakthrough attacks during the study were recorded at each visit. Following a 2-week run-in period, HAE patients received 8 weekly rhC1INH administrations and were followed-up for an additional 6 weeks. Efficacy was evaluated by comparing the HAE attack incidence during the treatment period to the historical attacks over the previous 2 years. Safety evaluation was based on clinical laboratory and adverse events (AEs) reports. Results The 25 participants reported a mean of 0.9 attacks/week over the past 2 years. The mean breakthrough attack rate during the treatment period was 0.4 attacks/week (95% CI 0.28-0.56). A total of 30 treatment-emergent-AEs were reported in 13 patients, all mild to moderate. One patient died from a laryngeal attack 25 days after last study drug administration. The only possible drug related AEs reported were dry mouth, dizziness and anxiety in one patient and hypotension in another. There were no allergic AEs and no neutralizing antibodies observed. Conclusions Weekly administrations of 50 U/kg rhC1INH appeared to reduce the frequency of HAE attacks and were generally safe and well tolerated. © 2012 John Wiley & Sons A/S.


Li H.H.,Institute for Asthma and Allergy | Moldovan D.,Victor Babes University of Medicine and Pharmacy Timisoara | Bernstein J.A.,University of Cincinnati | Reshef A.,Tel Aviv University | And 6 more authors.
Journal of Allergy and Clinical Immunology: In Practice | Year: 2015

Background: Hereditary angioedema (HAE) caused by a deficiency in functional C1 esterase inhibitor (C1INH) is characterized by recurrent episodes of cutaneous and/or mucosal/submucosal tissue swelling affecting multiple anatomic locations. Previous studies demonstrated efficacy of recombinant human C1INH (rhC1INH) for acute HAE attacks. Objective: This study evaluated the efficacy and safety of rhC1INH (50 IU/kg) for the treatment of multiple HAE attacks in an open-label extension study. Methods: Time to onset of symptom relief and time to minimal symptoms were assessed using a Treatment Effect Questionnaire (TEQ), a visual analog scale, and a 6-point ordinal scale Investigator Score. Results: Forty-four patients received rhC1INH, and a single dose was administered for 215 of 224 (96%) attacks. Median time to beginning of symptom relief based on TEQ for the first 5 attacks was 75.0 (95% CI, 69-89) minutes, ranging from 62.5 (95% CI, 48-90) to 134.0 (95% CI, 32-119) minutes. Median time to minimal symptoms using TEQ for the first 3 attacks was 303.0 (95% CI, 211-367) minutes. rhC1INH was well tolerated. There were no discontinuations due to adverse events. No thrombotic or anaphylactic events were reported, and repeat rhC1INH treatments were not associated with neutralizing anti-C1INH antibodies. Conclusions: A single 50-IU/kg dose rhC1INH was effective for improving symptoms of an HAE attack with sustained efficacy for treatment of subsequent attacks. rhC1INH had a positive safety profile throughout the study. This study supports repeated use of rhC1INH over time in patients with HAE attacks. © 2015 The Authors.


Relan A.,Pharming Technologies BV | Bakhtiari K.,University of Amsterdam | Van Amersfoort E.S.,Pharming Technologies BV | Meijers J.C.M.,University of Amsterdam | Hack C.E.,University Utrecht
BioDrugs | Year: 2012

Background: Recombinant human C1-inhibitor (rhC1INH; Ruconest®) has been developed for treatment of acute angioedema attacks in patients with hereditary angioedema (HAE) due to heterozygous deficiency of C1INH. Previous reports suggest that administration of plasma-derived C1INH products may be associated with an increased risk for thromboembolic complications. Objectives: Our aim is to evaluate the effects of rhC1INH on coagulation and fibrinolysis in symptomatic HAE patients. Methods: Levels of various coagulation and fibrinolytic parameters were determined in pre- and post-exposure plasma samples from HAE patients included in a randomized clinical trial. Patients were treated with either saline, or 50 or 100 U /kg rhC1INH for an acute angioedema attack. Results: Prior to rhC1INH treatment, the majority of patients had low to normal activated partial thromboplastin times (aPTT) and increased levels of prothrombin fragment 1+2, thrombin-antithrombin complexes, D-dimers and plasmin-antiplasmin complexes, all of which indicate activation of both coagulation and fibrinolysis. Infusion of rhC1INH at doses up to 100 U/kg did not affect these parameters except for a dose-dependent prolongation of aPTT, confirming that rhC1INH is an inhibitor of the contact system, and that F1+2 levels decreased. Conclusion: Coagulation and fibrinolytic systems are activated in HAE patients suffering from an acute angioedema attack. Treatment with rhC1INH at 50 or 100 U/kg had no effect on parameters reflecting activation of these systems except for a significant effect on aPTT, which likely reflects a pharmacodynamic effect of rhC1INH, and a reduction on plasma levels of the prothrombin activation fragment F1 +2. We conclude that these results argue against a prothrombotic effect of treatment with this rhC1INH product in HAE patients. © 2012 Adis Data Information BV. All rights reserved.


Hack C.E.,University Utrecht | Relan A.,Pharming Technologies BV | Van Amersfoort E.S.,Pharming Technologies BV | Cicardi M.,University of Milan
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2012

Background: Hereditary angioedema (HAE) is a heterozygous deficiency of first component of complement-inhibitor (C1INH). Insufficient C1INH activity leads to uncontrolled activation of plasma cascade systems, which results in acute angioedema attacks in patients with HAE. Plasma-derived or recombinant C1INH products are approved for the treatment of such angioedema attacks. The target level of C1INH activity needed to achieve optimal efficacy, however, remains unknown. We determined the plasma level of C1INH associated with optimal clinical efficacy in the treatment of angioedema attacks. Methods: Efficacy and pharmacokinetic data were reviewed from recently published placebo-controlled randomized trials in the treatment of HAE with either plasma-derived or recombinant C1INH products, tested at various doses. Results: A dose-dependent effect was observed on time to the beginning of relief of symptoms, on time to resolution of symptoms, and on the response rate within 4 h. Optimal efficacy of C1INH therapy is achieved at doses ≤yen;50 U/kg. This dose increases plasma C1INH activity in almost all patients to values ≤yen;0.7 U/ml (70% of normal), the lower limit of the normal range. The differences in half-lives of the various C1INH products do not have an obvious effect on clinical efficacy. Conclusion: A review of the efficacy and pharmacokinetic data from recently published controlled studies in the treatment of HAE attacks suggests that efficacy of C1INH therapy is optimal when C1INH activity levels are restored to the normal range. © 2011 John Wiley & Sons A/S.


Hofman Z.L.M.,University Utrecht | Relan A.,Pharming Technologies BV | Hack C.E.,University Utrecht
Clinical and Experimental Immunology | Year: 2014

Hereditary angioedema (HAE) patients experience recurrent episodes of angioedema attacks that can be painful, disfiguring and even life-threatening. The disorder results from a mutation in the gene that controls the synthesis of C1-inhibitor (C1INH). C1INH is a major regulator of activation of the contact system. It is often assumed that attacks results from uncontrolled local activation of the contact system with subsequent formation of bradykinin. To evaluate the involvement of inflammatory reactions in HAE, we analysed C-reactive protein (CRP) levels. HAE patients included in a clinical database of recombinant human C1-inhibitor (rhC1INH) studies were evaluated. For the current study we analysed CRP levels when patients were asymptomatic, during a clinical attack and in a follow-up period, and correlated these with the clinical manifestations of the attack. Data from 68 HAE patients were analysed and included CRP levels on 273 occasions. While asymptomatic, 20% of the patients analysed had increased CRP. At the onset of the attack (P=0·049) and during the next 24h CRP rose significantly (P=0·002) in patients with an abdominal location, and post-attack levels were significantly higher in these patients than in patients with attacks at other locations (P=0·034). In conclusion, CRP levels are elevated in a substantial proportion of asymptomatic HAE patients. Levels of CRP increase significantly during an abdominal attack. These data suggest low-grade systemic inflammatory reactions in HAE patients as well as a triggering event for attacks that starts prior to symptom onset. © 2014 British Society for Immunology.


Reshef A.,Angioedema Center | Zanichelli A.,University of Milan | Longhurst H.,Barts Health NHS Trust | Relan A.,Pharming Technologies BV | Hack C.E.,University Utrecht
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2015

Background Recommended management of attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor (C1-INH) deficiency (C1-INH-HAE) includes therapy with exogenous C1INH. Thrombotic/thromboembolic events (TEE) have been reported with plasma-derived C1INH, but so far none with recombinant human C1INH (rhC1INH). This phase III, randomized, placebo (saline)-controlled study evaluated the safety of rhC1INH 50 IU/kg for the treatment of acute attacks in 74 patients with C1-INH-HAE. Methods Monitoring for TEE and assessment of risk of deep vein thrombosis (DVT) by the Wells prediction rule were performed, and levels of fibrin degradation products (plasma D-dimers) were assessed before study drug administration (baseline), 2 h, and 7 days posttreatment. Results Plasma D-dimer levels were elevated in 80% of the patients (median [25th-75th percentiles]: 2149 [480-5105] μg/l; normal ≤250 μg/l) and were higher in patients with submucosal (abdominal, oropharyngeal-laryngeal) attacks (3095 [890-10000] μg/l; n = 29) compared with subcutaneous (peripheral, facial) attacks (960 [450-4060] μg/l; n = 35). Median plasma D-dimer levels were comparable across treatment groups at baseline (1874 [475-4568] μg/l rhC1INH; 2259 [586-7533] μg/l saline) and 2 h postinfusion (2389 [760-4974] μg/l rhC1INH; 2550 [310-8410] μg/l saline); median plasma D-dimer levels were decreased by Day 7 in both groups (425 [232-3240] μg/l rhC1INH; 418 [246-2318] μg/l saline). No increased risk of DVT was identified, nor any TEE reported in rhC1INH treated or controls. Conclusion Elevated plasma D-dimer levels were associated with acute C1-INH-HAE attacks, particularly with submucosal involvement. However, rhC1INH therapy was not associated with thrombotic events. © 2015 The Authors. Allergy Published by John Wiley & Sons Ltd.


Hofman Z.L.M.,University Utrecht | Relan A.,Pharming Technologies NV | Hack C.E.,University Utrecht
Clinical Reviews in Allergy and Immunology | Year: 2016

Hereditary angioedema (HAE) patients experience recurrent local swelling in various parts of the body including painful swelling of the intestine and life-threatening laryngeal oedema. Most HAE literature is about attacks located in one anatomical site, though it is mentioned that HAE attacks may also involve multiple anatomical sites simultaneously. A detailed description of such multi-location attacks is currently lacking. This study investigated the occurrence, severity and clinical course of HAE attacks with multiple anatomical locations. HAE patients included in a clinical database of recombinant human C1-inhibitor (rhC1INH) studies were evaluated. Visual analog scale scores filled out by the patients for various symptoms at various locations and investigator symptoms scores during the attack were analysed. Data of 219 eligible attacks in 119 patients was analysed. Thirty-three patients (28 %) had symptoms at multiple locations in anatomically unrelated regions at the same time during their first attack. Up to five simultaneously affected locations were reported. The observation that severe HAE attacks often affect multiple sites in the body suggests that HAE symptoms result from a systemic rather than from a local process as is currently believed. © 2014, European Union.

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