Angioedema Attacks In Patients Research Articles

COVID-19 infection and vaccination in patients with hereditary angioedema: a multicentric study.

Background. Due to similarities between the pathophysiological mechanisms of hereditary angioedema (HAE) and COVID-19, it has been hypothesized that SARS-CoV-2 infection may trigger HAE attacks or, alternatively, that HAE patients may experience different of COVID-19 disease severity. Furthermore, the potential for COVID-19 vaccination to trigger angioedema attacks in patients with HAE is still not completely defined. The objective is to characterize the exacerbations and clinical manifestations associated with COVID-19 infection and describe the adverse effects of COVID-19 vaccination in patients with HAE.Methods. Retrospective observational, descriptive, non-interventional, multicenter study conducted in four Allergy Units and Departments in Central Portugal between March 2020 and July 2022. HAE patient data were obtained from electronic medical records. Results. The study included 34 patients (67.6% female): 26 with HAE type 1, 5 with HAE type 2, and 3 with HAE with normal C1 inhibitor. Most patients with HAE type 1 and 2 were receiving long-term prophylaxis. Among the 32 patients who received COVID-19 vaccination, 86 doses, were administered with one angioedema attack (1.2%) associated with vaccination. A small increase in the average number of attacks was observed in the year following COVID vaccination (7.1 versus 6.2 in the previous year, p = 0.029), however, this difference is unlikely to be clinically significant, as the context of the COVID-19 pandemic likely introduced numerous confounders. During the study period, 16 HAE patients had COVID-19, all presenting with mild disease. Four out of 16 patients (25%) reported angioedema attacks during COVID-19, and 43.8% during the convalescence period (3 months after infection). Conclusions. Patients with HAE can safely receive COVID-19 vaccination. The severity of COVID-19 infection does not appear to be increased in HAE patients.

Lanadelumab demonstrates high efficacy in reducing the frequency of angioedema attacks in patients with severe HAE in real-life settings

Introduction and objective: Evaluation of lanadelumab efficacy in preventing angioedema attacks in patients with severe hereditary angioedema due to C1-inhibitor deficiency in Poland and descriptive analysis of this group of patients. Materials and methods: Retrospective analysis of patients treated with lanadelumab in Poland. Data were acquired from the electronic database of the National Health Fund, compiled from 15 hereditary angioedema centres. Only patients with severe hereditary angioedema course (at least 12 severe – abdominal, pharyngeal or laryngeal – hereditary angioedema attacks per six months, requiring on-demand medications) initiated treatment. The patients received lanadelumab 300 mg every two weeks. The efficacy of the therapy was assessed after six months. Results: Lanadelumab was initiated in a total of 43 patients (group B). Twenty of them achieved the follow-up point after six months (group A). The mean age of the patients was 44 years. The majority (76.7%) were female and 79% had a family history of hereditary angioedema. Most patients (95.3%) had HAE-1 (absolute deficiency of C1-inhibitor). On average, within six months before treatment, group A patients experienced 19.7 (95% confidence interval, CI: 16.06–23.33) severe hereditary angioedema attacks. In the six months following treatment initiation, the number of attacks decreased to an average of 0.5 (95% CI: 0–1.0), with significant reductions in all types of hereditary angioedema attacks – abdominal (p < 0.0001), pharyngeal (p < 0.005), and laryngeal (p < 0.05). Utilisation of on-demand medications dropped from an average of 23.5 (95% CI: 16.7–30.3) to 0.5 standard therapeutic dose (95% CI: 0–1.1). Conclusions: The study highlights the therapeutic potential of lanadelumab in managing hereditary angioedema, usually offering patients a complete resolution of severe hereditary angioedema attacks and release from dependence on rescue medication. Our results support the current paradigm shift in hereditary angioedema treatment.

Initial characteristics and follow-up of patients with a diagnosis of angiotensin-converting enzyme inhibitor induced angioedema.

Background: A differential diagnosis between angiotensin-converting enzyme inhibitor (ACEi) angioedema (AE) and histaminergic AE (hAE) might be challenging. Follow-up data may help discriminate these conditions but are scarcely reported. Objective: To report on the follow-up of patients with suspected ACEi-AE and to describe the baseline characteristics of AE attacks in patients with a diagnosis of ACEi-AE after follow-up. Methods: Sixty-four patients with suspected ACEi-AE (i.e., with exposure to ACEi before the first attack, no urticaria associated, and normal C1-inhibitor levels) and at least one follow-up visit were included. Data were retrospectively collected at baseline and during the follow-up. Results: After the follow-up, the diagnosis of ACEi-AE was probable in only 30 patients. The remaining patients were reclassified as having probable hAE (21 patients) or undetermined-mechanism AE (13 patients). Patients with ACEi-AE were mostly men (61%), with a median age of 64 years (interquartile range [IQR] ±17 years), with a highly variable delay from ACEi introduction (median: 23 months; interquartile range: 103 months). Attacks preferentially involved lips (50%), tongue (47%), and throat (30%). Interestingly, patients with probable ACEi-AE after a follow-up also frequently presented with a history of allergy and atopic conditions (20%), attacks with preferential evening onset (25%), and spontaneous resolution in < 24 hours (26%), which are usually considered as suggestive of hAE. ACEi-AE attacks responded to icatibant in 79% of the patients. Conclusion: Patients with probable ACEi-AE were mostly men with facial involvement. A third of the patients with an initial suspected diagnosis of ACEi-AE had a final diagnosis of probable hAE. Although a follow-up of all patients should be a standard of care, it is critical to the correct diagnosis in the case of suspected bradykinin-associated AE, which may actually be due to histamine.

Complement Blockade With a C1 Esterase Inhibitor In Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal, hematopoietic stem cell disorder that manifests with a complement-mediated hemolytic anemia, bone marrow failure and a propensity for thrombosis. PNH confers deficiency of GPI anchored proteins that protect erythrocytes at different stages of the complement cascade. CD55 regulates the formation and stability of the C3 and C5 convertases, whereas CD59 blocks the formation of the membrane attack complex (MAC). These patients experience both intra- and extravascular hemolysis due to complement activation. Chronic treatment with eculizumab results in sustained control of intravascular hemolysis leading to transfusion independence for many. Eculizumab compensates for the CD59 deficiency on PNH erythrocytes; however, it does not compensate for the CD55 deficiency. PNH patients receiving eculizumab accumulate C3 on their erythrocytes; this leads to opsonization and extravascular hemolysis. There remains an unmet clinical need for a complement inhibitor with activity early in the complement cascade, which would not only reduce C3 accumulation on PNH erythrocytes, but also inhibit C3 activation by the alternative pathway (APC).C1 esterase inhibitor (C1 INH) is an endogenous human plasma protein that has broad inhibitory activity in the complement pathway. C1 INH inhibits the classical pathway of the complement system by binding C1r and C1s and inhibits the mannose-binding lectin-associated serine proteases in the lectin pathway. Thus, C1 INH is an ideal therapeutic for diseases of complement pathways. Nanofiltered plasma derived C1 INH (Cinryze®; ViroPharma) is FDA approved for routine prophylaxis against angioedema attacks in patients with hereditary angioedema (HAE), a disease characterized by constitutional deficiency or dysfunction of endogenous C1 INH. We hypothesized that this plasma-derived C1 INH would inhibit C3 deposition and the APC on PNH erythrocytes in patients treated with eculizumab.Peripheral blood of 3 healthy donors and 5 PNH patients (all with PNH type III erythrocyte proportion >5%) treated with eculizumab were obtained with written informed consent through a protocol approved by the local institutional review board. Clinical parameters for persistent extravascular hemolysis were noted at the time of patient sampling. Commercial vials of C1 INH were used for C1 inhibition assays ex vivo. Hemolysis experiments with acidified serum were performed in erythrocytes from PNH patients and healthy donors. We were able to show in the PNH patients that C1 inhibition is concentration dependent with increasing inhibition by serial dilutions of C1 INH up to 12 U/mL. The amount of hemolysis correlates with the percentage of CD55 deficient erythrocytes, but is attenuated by C1 INH in all patients. Flow cytometry was used to analyze deposition of C3 activation fragments on intact and lysed PNH erythrocytes. At time 0, small amounts of C3 deposition were observed on the PNH erythrocytes, but not the normal erythrocytes. The amount of C3 deposition was increased after incubation in acidified serum; however, co-incubation of C1 INH in the acidified serum markedly attenuated the amount of C3 deposition on the CD55 deficient erythrocytes. This demonstrated that C1 INH blocks APC-medicated deposition of C3 on the PNH erythrocytes in PNH patients.In this study, we show that the commercially available plasma derived C1-INH (Cinryze®) prevents lysis induced by the APC in PNH erythrocytes. The results presented here show that plasma-derived C1 INH can inhibit both APC- mediated hemolysis and C3 deposition. Importantly, C1-INH was able to block the accumulation of C3 degradation products on CD55 deficient erythrocytes from PNH patients who were being treated with eculizumab. This suggests a role for inhibition of earlier phases of the complement cascade than currently inhibited by eculizumab. A clinical trial to explore this hypothesis in vivo with patients who are suboptimal responders to eculizumab could be considered. Disclosures:Off Label Use: A nanofiltered plasma derived C1 INH (Cinryze®; ViroPharma) is FDA approved for routine prophylaxis against angioedema attacks in adolescent and adult patients with hereditary angioedema. Uknis:ViroPharma, Incorporated: Employment. Saye:ViroPharma, Incorporated: Employment. Brodsky:Alnylam Pharmaceuticals : Consultancy; Prolong Pharmaceuticals : Consultancy; ViroPharma, Incorporated: Research Funding; Alexion Pharmaceuticals : Membership on an entity's Board of Directors or advisory committees.

Analysis of Heart-Rate Variability during Angioedema Attacks in Patients with Hereditary C1-Inhibitor Deficiency.

C1-inhibitor hereditary angioedema (C1-INH-HAE) is a rare disease characterized by self-limiting edema associated with localized vasodilation due to increased levels of circulating bradykinin. C1-INH-HAE directly influences patients’ everyday lives, as attacks are unpredictable in frequency, severity, and the involved anatomical site. The autonomic nervous system could be involved in remission. The cardiac autonomic profile has not yet been evaluated during the attack or prodromal phases. In this study, a multiday continuous electrocardiogram was obtained in four C1-INH-HAE patients until attack occurrence. Power spectral heart rate variability (HRV) indices were computed over the 4 h preceding the attack and during the first 4 h of the attack in three patients. Increased vagal modulation of the sinus node was detected in the prodromal phase. This finding may reflect localized vasodilation mediated by the release of bradykinin. HRV analysis may furnish early markers of an impending angioedema attack, thereby helping to identify patients at higher risk of attack recurrence. In this perspective, it could assist in the timing, titration, and optimization of prophylactic therapy, and thus improve patients’ quality of life.

C1 Inhibitor Activity and Angioedema Attacks in Patients with Hereditary Angioedema

Hereditary angioedema (HAE) is caused by deficiency or dysfunction in the C1 inhibitor (C1-INH) protein. C1-INH replacement therapy is used to treat patients with HAE to restore the missing or dysfunctional protein. Invitro studies showed that C1-INH inhibits prekallikrein activation and bradykinin formation in a dose-dependent manner when added to the plasma of patients with HAE. HAE is highly variable in clinical presentation, and early studies suggested that there was not a clear relationship between functional C1-INH levels and disease activity. Later, a threshold of approximately 40% functional C1-INH was identified, above which patients' risk of an attack was diminished. Long-term prophylaxis with plasma-derived C1-INH effectively reduces attack frequency and severity. Pharmacokinetic modeling shows that functional C1-INH levels are associated with the relative risk of having an attack. Subcutaneous administration of C1-INH results in consistently high levels of functional C1-INH activity, whereas intravenous administration results in periods of low trough functional C1-INH activity before the next scheduled dose, increasing the risk of an angioedema attack. These studies suggest that measurement of functional C1-INH activity may be useful as a biomarker of the risk of an attack in patients with HAE who are receiving long-term prophylaxis with plasma-derived C1-INH.

Food as a trigger for abdominal angioedema attacks in patients with hereditary angioedema

BackgroundHereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare inherited disease. In most HAE-affected subjects, defined trigger factors precede angioedema attacks. Mechanisms of how trigger factors stimulate the contact activation pathway with bradykinin generation are not well elucidated. In recent studies, hypersensitivity reactions and food were stated as relevant triggers. We investigated HAE affected people for possible hypersensitivity reactions or intolerances and their relation in triggering angioedema attacks.MethodsA questionnaire was filled in, recording date of birth, gender, and self-reported angioedema attacks associated with the ingestion of foodstuffs, administration of drugs, hymenoptera stings and hypersensitivity reactions against inhalation allergens. All participants performed a skin prick test against inhalation allergens and food. In patients who stated an association of possible hypersensitivity with angioedema, a serological ImmunoCAP test was also performed.ResultsFrom the 27 women and 15 men analyzed, 79% stated trigger factors. From those food was mentioned in 36%. The suspected food included tomato, green salad, fish, citrus fruits, apple, onion, garlic, cheese, chili, kiwi, milk, tree nuts, strawberry, pineapple, shrimps, bread, banana, leek, chicken and alcohol, and were associated with abdominal angioedema. Neither the skin prick test nor the ImmunoCAP-test turned out positive for the tested food allergens.ConclusionFood seems to be a relevant trigger factor, causing angioedema in HAE affected patients. The reason, however, is not IgE-mediated hypersensitivity, but most probably an intolerance reaction to food products.

Hereditary angioedema with normal C1 inhibitor in a French cohort: Clinical characteristics and response to treatment with icatibant.

IntroductionThe clinical characteristics and icatibant‐treatment outcomes of patients with hereditary angioedema with normal C1 inhibitor (HAE‐nC1 INH) are limited.MethodsWe retrospectively analyzed data from French HAE patients enrolled in the Icatibant Outcome Survey registry (from July 2009 to September 2013) to compare disease characteristics and the effectiveness and safety of acute icatibant‐treated angioedema attacks in patients with HAE‐nC1 INH, HAE with C1 INH deficiency (type I), or dysfunction (type II).ResultsOne center in Grenoble contributed 22 patients with HAE‐nC1 INH and a family history of HAE while 15 centers across France contributed 153 patients with HAE type I and seven patients with HAE type II. Patients with HAE‐nC1 INH compared to HAE type I, respectively, were more likely to be female (88.1% vs. 63.4%), older at median age of disease onset (21 years vs. 15 years), and have a greater rate of abdominal (80% vs. 61%) and laryngeal (23% vs. 14%) attacks. Icatibant was effective in both groups though the median time to resolution of attack was significantly longer in the HAE‐nC1 INH group (20.0 h, 37 attacks) versus the HAE type I group (14.0 h, 67 attacks). Icatibant was self‐administered for 96.1% of attacks in patients with HAE‐nC1 INH and 75.8% in patients with HAE type I. No serious adverse side effects related to icatibant were reported.ConclusionsThese data help further define the disease characteristics of HAE‐nC1 INH in the French population and extend the limited data reporting the safe and effective use of icatibant in acute treatment of angioedema in French patients diagnosed with HAE‐nC1 INH.

Triggers and Prodromal Symptoms of Angioedema Attacks in Patients With Hereditary Angioedema.

Triggers and Prodromal Symptoms of Angioedema Attacks in Patients With Hereditary Angioedema.

Gender Analysis of Icatibant-Treatment Outcomes of Acute Angioedema Attacks in Patients with Hereditary Angioedema Type I and II: Results from the Icatibant Outcome Survey

Gender Analysis of Icatibant-Treatment Outcomes of Acute Angioedema Attacks in Patients with Hereditary Angioedema Type I and II: Results from the Icatibant Outcome Survey

On-Line Monitoring Tool for Recommended Data Collection of Angioedema Attacks in Patients with Hereditary Angioedema

On-Line Monitoring Tool for Recommended Data Collection of Angioedema Attacks in Patients with Hereditary Angioedema

The Icatibant Outcome Survey: Trigger Factors and Premonitory Symptoms of Angioedema Attacks in Patients with Hereditary Angioedema

T U E S D A Y 902 The Icatibant Outcome Survey: Trigger Factors and Premonitory Symptoms of Angioedema Attacks in Patients with Hereditary Angioedema Teresa Caballero, Marcus Maurer, Hilary Longhurst, Werner Aberer, Laurence Bouillet, Vincent Fabien, Andrea Zanichelli, MD; Hospital La Paz Institute for Health Research (IdiPaz), Biomedical Research Network on Rare Diseases (CIBERER, U754), Madrid, Spain, Department of Dermatology and Allergy, Allergie-CentrumCharit e, Charit e Universit€atsmedizin Berlin, Berlin, Germany, Department of Immunology, Barts Health NHS Trust, London, United Kingdom, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria, National Reference Centre for Angioedema, Internal Medicine Department, Grenoble University Hospital, Grenoble, France, Shire, Zug, Switzerland, Dipartimento di Scienze Biomediche e Cliniche Luigi Sacco, Universit a degli Studi di MilanoOspedale Luigi Sacco, Milano, Italy. RATIONALE: Hereditary angioedema (HAE) is a potentially lifethreatening, bradykinin-mediated disease characterized by attacks of non-pruritic, non-pitting, subcutaneous edema with unpredictable frequency and severity. We report the most common triggers and prodromal symptoms of attacks in patients with HAE type I/II in the Icatibant Outcome Survey (IOS). METHODS: IOS (NCT01034969) is an observational study monitoring safety and effectiveness of icatibant in a real-world setting. Patients with HAE reported triggers and prodromes for attacks that occurred before IOS (historical) and those occurring during IOS. Data were collected from July 2009–April 2014. RESULTS: Of 512 patients (59.6% female) with HAE type I/II, 306 reported historical triggers (most common: emotional distress [54.9%], physical trauma [38.9%], infection [20.6%], change in estrogen levels [20.3%]), and 294 reported historical prodromes (most common: tiredness [22.4%], tight/prickling sensation in skin [16.7%], nausea [16.0%], erythema marginatum [15.6%]). During IOS, 314 patients reported 1410 attacks. Of these patients, 109 reported triggers for 324 attacks, and 89 reported prodromes for 329 attacks.Most common triggers were emotional distress (n540 attacks, 19 patients), change in estrogen levels (n523 attacks, 9 patients), and physical trauma (n59 attacks, 9 patients). Most common prodromes were erythema marginatum (n549 attacks, 23 patients), tiredness (n523 attacks, 7 patients), irritability and nausea (both n512 attacks, 9 and 4 patients, respectively). CONCLUSIONS: The most common triggers in IOS were emotional distress, change in estrogen levels and physical trauma. A variety of prodromes, including tiredness and erythema marginatum, were recognized by patients. Understanding triggers and prodromesmay help patients better recognize attack onset.

The Icatibant Outcome Survey: Characterizing Breakthrough Hereditary Angioedema Attacks In Patients Receiving Long-Term Prophylaxis

The Icatibant Outcome Survey: Characterizing Breakthrough Hereditary Angioedema Attacks In Patients Receiving Long-Term Prophylaxis

Escalating Doses of C1 Esterase Inhibitor (CINRYZE) for Prophylaxis in Patients With Hereditary Angioedema

Nanofiltered C1 inhibitor (human) is approved in the United States for routine prophylaxis of angioedema attacks in patients with hereditary angioedema, a rare disease caused by a deficiency of functional C1 inhibitor. To assess the safety of escalating doses of nanofiltered C1 inhibitor (human) in patients who were not adequately controlled on the indicated dose (1000 U every 3 or 4 days). Eligible patients had >1 attack/month over the 3 months before the trial. Doses were escalated to 1500 U every 3 or 4 days for 12 weeks, at which point, the patients were evaluated. If treatment was successful (≤1 attack/mo) or at the investigator's discretion, the patients entered a 3-month follow-up period. The patients with an average of >1 attack/month were eligible for further escalation to 2000 U and then 2500 U. Twenty patients started at 1500 U; 13 were escalated to 2000 U, and 12 were escalated to 2500 U. Eighteen patients reported adverse events. Two patients reported 4 serious adverse events (cerebral cystic hygroma, laryngeal angioedema attack, anemia, and bile duct stone) that were considered by investigators to be unrelated to treatment. Notably, there were no systemic thrombotic events or discontinuations due to adverse events. Fourteen patients were treated successfully (70%), continued to the follow-up period at the investigator's discretion, or experienced a reduction in attacks of >1.0/month. Dose escalation of nanofiltered C1 inhibitor (human) up to 2500 U was well tolerated and reduced attack frequency in the majority of patients.

Cost-utility analysis of Ruconest(®) (conestat alfa) compared to Berinert(®) P (human C1 esterase inhibitor) in the treatment of acute, life-threatening angioedema attacks in patients with hereditary angioedema.

IntroductionAdministration of human C1 esterase inhibitor (Berinert® P) from target import is the most widespread treatment strategy for patients with hereditary angioedema (HAE). However, a therapeutic health program including Ruconest® (conestat alfa) could shorten a patient's expectancy for a life-saving treatment.AimTo evaluate the cost-utility of Ruconest® (conestat alfa) financed from public funds within the newly introduced therapeutic health program compared with Berinert® P (human C1 esterase inhibitor) in the treatment of acute angioedema attacks in adults with HAE.Material and methodsThe cost-utility analysis from the Polish healthcare payer's perspective was performed for 1 year (2012). The costs and health outcomes were simulated for three pairs of eligible HAE patient groups (active treatment and corresponding placebo). The incremental costs of each intervention compared with placebo were listed together (direct or indirect comparisons between options were impossible due to limited clinical data available).ResultsThe incremental cost-utility ratios (ICURs) for the evaluated interventions compared with placebo were as follows: EUR 15,226 per QALY (Ruconest®) and EUR 27,786 per QALY (Berinert® P). The probability of cost-utility (ICUR < EUR 24,279 per QALY) assessed for Ruconest® administered in the case of acute angioedema attack was 61% and 41% for Berinert® P.ConclusionsThe administration of Ruconest® in acute life-threatening angioedema attacks is economically justified from the Polish healthcare payer's perspective, results in lower costs and is characterized by higher cost-utility probability compared with Berinert® P.

Recombinant Human C1 Inhibitor (Conestat Alfa)

Conestat alfa is a recombinant human C1 inhibitor used in the treatment of angioedema attacks in patients with hereditary angioedema (HAE). Patients with type I or II HAE have a deficiency in functional C1 inhibitor, which is an important regulator of complement and contact system activation. The therapeutic efficacy of conestat alfa in the treatment of angioedema attacks in patients with HAE was evaluated in two similar randomized, double-blind, placebo-controlled trials conducted in North America and Europe. The randomized controlled phases of both studies were closed after interim analyses provided compelling evidence of statistically significant positive efficacy findings and showed no apparent adverse safety findings. Results of the pooled analysis of the two trials showed that conestat alfa provided significantly faster initial relief of symptoms than placebo. The median time to the beginning of relief of symptoms (primary endpoint) was 66 minutes with conestat alfa 100 units/kg, 122 minutes with conestat alfa 50 units/kg, and 495 minutes with placebo. Conestat alfa was also statistically superior to placebo for the secondary endpoint of median time to minimal symptoms, with values of 266, 247, and 1210 minutes for the respective treatment groups. On the basis of data from open-label extension studies and integrated analyses of clinical trial data, conestat alfa has demonstrated efficacy in the treatment of repeated HAE attacks and in patients with potentially life-threatening HAE attacks with involvement of the upper airways. Conestat alfa was generally well tolerated in clinical trials, with the most frequently reported adverse event being headache. In the two randomized controlled trials, headache and vertigo were the only adverse events deemed to be related to study treatment.

Recombinant Human C1 Inhibitor (Conestat Alfa)

Conestat alfa is a recombinant human C1 inhibitor used in the treatment of angioedema attacks in patients with hereditary angioedema (HAE). Patients with type I or II HAE have a deficiency in functional C1 inhibitor, which is an important regulator of complement and contact system activation.

Recombinant C1-Inhibitor

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. Our aim is to evaluate the effects of rhC1INH on coagulation and fibrinolysis in symptomatic HAE patients. 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. 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. 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.

84 Immuno-Safety of Recombinant Human C1 Inhibitor in Patients With Hereditary Angioedema

BackgroundRecombinant C1 inhibitor (rhC1INH) is a novel therapeutic option for the treatment of acute angioedema attacks in patients with hereditary angioedema (HAE). The amino acid sequence of rhC1INH is identical to that of endogenous C1INH. However, any recombinant protein may elicit antibodies against the protein and/or host related impurities (HRI). Clinical consequences of these antibodies can theoretically range from no clinical symptoms to allergic reactions and reduced C1INH activity due to neutralizing antibodies.ObjectiveTo analyze the immuno-safety of rhC1INH in symptomatic patients with HAE.MethodsPlasma samples were collected pre-treatment and 22 and 90 days post-treatment of an acute angioedema attack. Plasma samples were tested for the presence of antibodies against plasma-derived C1INH and rhC1INH using 6 different, validated enzyme-linked immunosorbent assays (ELISAs), to detect IgM, IgG and IgA antibodies against plasma-derived C1INH or rhC1INH. Antibodies against HRI in plasma samples were measured in an ELISA testing for all antibody classes. Plasma samples from normal healthy controls and HAE patients, never exposed to rhC1INH, were used to estimate cut off levels of the assays. Plasma samples with antibody levels above the cut-off level in the screening assays were tested in confirmatory displacement assay in case of anti-HRI antibodies and in an assay for neutralizing antibodies in case of antibodies against C1INH.ResultsData from 155 symptomatic HAE patients having received a total of 424 administrations of rhC1INH were analyzed. The frequency of anti-C1INH antibody levels above the assay cut-off was low and similar in pre- and post-exposure samples (1.7 and 1.8%, respectively). Results above the assay cut-off were sporadic and transient. Occurrence of anti-C1INH antibodies did not correlate with repeated treatment or time since last treatment. No neutralizing antibodies were detected. A total of 5/155 (3%) rhC1INH-treated patients had confirmed anti-HRI antibodies; these included 1 patient with presence of anti-HRI antibodies prior to exposure to rhC1INH. The presence of anti-C1INH and anti-HRI antibodies was not associated with clinical symptoms. The presence of anti-C1INH antibodies did not affect clinical efficacy.ConclusionsrhC1INH used for the treatment of acute HAE attacks has a low potential to induce antibodies and has a reassuring immuno-safety profile.

Nanofiltered Human C1 Inhibitor Concentrate (Cinryze®)

Intravenous nanofiltered human C1 inhibitor (C1-INH NF) concentrate (Cinryze®) is used as a direct replacement of deficient levels of plasma C1 inhibitor in patients with hereditary angioedema (HAE). In the EU, C1-INH NF concentrate 1000 U is indicated in the treatment, pre-procedural prevention, and routine prevention of angioedema attacks in adults and adolescents with HAE. Intravenous C1-INH NF concentrate 1000 U effectively relieved angioedema attacks in patients with HAE. In a randomized, double-blind trial in pediatric and adult patients, the median time to onset of unequivocal relief from an attack was significantly shorter with C1-INH NF concentrate than with placebo. In an open-label trial, both unequivocal relief and clinical relief were shown in the majority of attacks within 1 and 4 hours of infusion of C1-INH NF concentrate, regardless of the site (i.e. gastrointestinal, cutaneous, laryngeal, or genitourinary) of the defining symptom. When administered prior to a procedure, open-label intravenous C1-INH NF concentrate 1000 U reduced the incidence of angioedema attacks during and after a variety of dental, surgical, or interventional diagnostic procedures in pediatric and adult patients with HAE. Routine preventative treatment with intravenous C1-INH NF concentrate 1000 U every 3 or 4 days reduced the number of angioedema attacks. In a randomized, double-blind, crossover trial in pediatric and adult patients with HAE, the mean normalized number of attacks per 12-week period was significantly lower during routine prevention with C1-INH NF concentrate than with placebo. Routine prevention with C1-INH NF concentrate reduced the median monthly attack rate from baseline in an open-label trial. Intravenous C1-INH NF concentrate was well tolerated in clinical trials in patients with HAE. No cases of viral transmission were reported.