Dumitru Moldovan

Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks.

BACKGROUND Hereditary angioedema caused by C1 esterase inhibitor deficiency is a rare disorder. OBJECTIVE To compare the efficacy of pasteurized C1 esterase inhibitor concentrate (Berinert, CSL Behring) at intravenous doses of 10 or 20 U/kg body weight with placebo in the treatment of single, acute abdominal or facial attacks in patients with hereditary angioedema. METHODS This was a randomized, double-blind, placebo-controlled study in 125 patients with type I or II hereditary angioedema. The primary outcome was time from start of treatment to onset of symptom relief. Secondary outcomes were time to complete resolution, proportion of patients with worsened intensity of angioedema symptoms between 2 and 4hours after treatment, and number of vomiting episodes within 4 hours. RESULTS Median time to onset of relief was significantly shorter with C1 esterase inhibitor concentrate at a dose of 20 U/kg than with placebo (0.5 vs 1.5 hours; P = .0025), whereas with 10 U/kg, the time to onset of relief was only slightly shorter than with placebo (1.2 vs 1.5 hours; P = .2731). Compared with placebo, the reduction in time to onset of relief was greatest for severe attacks (0.5 vs 13.5 hours). The secondary outcomes consistently supported the efficacy of the 20 U/kg dose. C1 esterase inhibitor concentrate was safe and well tolerated. No seroconversions were observed for HIV, hepatitis virus, or human B19 virus. CONCLUSION C1 esterase inhibitor concentrate given intravenously at a dose of 20 U/kg is an effective and safe treatment for acute abdominal and facial attacks in patients with hereditary angioedema, with a rapid onset of relief.

Randomized placebo-controlled trial of the bradykinin B2 receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial

BACKGROUND The For Angioedema Subcutaneous Treatment (FAST)-3 study was a phase III, randomized, double-blind, placebo-controlled study of icatibant (bradykinin B(2) receptor antagonist) in subjects with hereditary angioedema (HAE) resulting from C1-INH deficiency or dysfunction (type I/II). OBJECTIVE To investigate icatibant efficacy and safety in subjects with acute HAE attacks. METHODS Subjects with moderate to very severe cutaneous or abdominal symptoms received icatibant (n = 43) or placebo (n = 45). Five subjects with laryngeal (mild-to-moderate) first attacks received icatibant (n = 3) or placebo (n = 2), and 5 subjects with severe laryngeal first attacks received open-label icatibant. RESULTS Cutaneous or abdominal attacks: icatibant significantly reduced median times (vs placebo) to 50% or more reduction in symptom severity (2.0 vs 19.8 hours; P < .001, primary endpoint), onset of primary symptom relief (1.5 vs 18.5 hours; P < .001, key secondary endpoint), or almost complete symptom relief (8.0 vs 36.0 hours; P = .012) and provided a shorter time to initial symptom relief (0.8 vs 3.5 hours; P < .001). For laryngeal attacks, median time to 50% or more reduction in symptom severity was 2.5 hours (icatibant) and 3.2 hours (placebo). No icatibant-treated subject required rescue medication before symptom relief occurred. The incidence of adverse events (AEs) was similar in icatibant- and placebo-treated subjects (41% and 52%, respectively). All icatibant-treated subjects experienced injection site reactions, but none reported clinically relevant changes in safety parameters or serious AEs. CONCLUSIONS FAST-3 demonstrated that icatibant was effective and generally well tolerated in subjects with acute HAE attacks. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT00912093.

Recombinant human C1 inhibitor for the prophylaxis of hereditary angioedema attacks: a pilot study

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).

Baseline level of functional C1-inhibitor correlates with disease severity scores in hereditary angioedema

The diagnosis of hereditary angioedema (HAE) is based on complement tests. We studied for the first time the possible association between complement parameters measured at the time of diagnosis and disease severity in 115 patients with HAE. Serum levels of functional C1-inhibitor (C1-INH(f)), antigenic C1-inhibitor (C1-INH(a)), C4 and hemolytic activity of the classical pathway (CH50) were determined at the time of diagnosis. We found a significant correlation between severity scores and baseline C1-INH(f) levels, as determined by ELISA assay (p=0.0003). On the other hand, there was no correlation between severity scores and other complement parameters (C1-INH(a), C4, and CH50). We consider the correlation between severity scores and baseline C1-INH(f) levels an important pathophysiological observation. Our findings underlie the potential significance of monitoring functional C1-INH levels in relation to clinical disease course.

Population pharmacokinetics of plasma-derived C1 esterase inhibitor concentrate used to treat acute hereditary angioedema attacks

BACKGROUND C1 esterase inhibitor (C1-INH) replacement is recommended as a first-line therapy for acute edema attacks in hereditary angioedema (HAE). Only limited pharmacokinetic analyses of the administered C1-INH in plasma are available. OBJECTIVE To investigate retrospectively the population pharmacokinetics of a plasma-derived C1-INH (pC1-INH) concentrate used to treat acute HAE attacks in a randomized, placebo-controlled phase 2/3 study in patients with HAE. METHODS Acute abdominal and facial attacks were treated with either a pC1-INH concentrate (Berinert) at single intravenous doses of 10 or 20 U/kg body weight or placebo. Plasma sampling was conducted 0, 1, and 4 hours after dosing. A nonlinear retrospective population pharmacokinetic model was obtained using the assumption of a 1-compartment model. RESULTS The final population pharmacokinetic model was based on data from 97 patients treated with 10 or 20 U/kg of pC1-INH concentrate. The estimated mean half-life was 32.7 hours (90% confidence interval, 16.6-48.8 hours), and the estimated mean clearance was 0.92 mL/kg/h (90% confidence interval, 0.50-1.33 mL/kg/h). CONCLUSIONS The half-life of the same pC1-INH concentrate reported in a previous study was confirmed by this retrospective population pharmacokinetic analysis in patients treated for acute HAE attacks. In contrast to other treatment options with shorter half-lives, the long half-life of pC1-INH concentrate may provide an extended period of protection, even after the symptoms of an attack have subsided.

C1-INH concentrate for treatment of acute hereditary angioedema: a pediatric cohort from the I.M.P.A.C.T. studies.

We analyzed the clinical response of pediatric and adolescent hereditary angioedema (HAE) patients to pdC1‐INH in the International Multicenter Prospective Angioedema C1‐INH Trials (I.M.P.A.C.T.) 1 and 2.

Recombinant human-C1 inhibitor is effective and safe for repeat hereditary angioedema attacks.

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.

The international WAO/EAACI guideline for the management of hereditary angioedema—The 2017 revision and update

Hereditary Angioedema (HAE) is a rare and disabling disease. Early diagnosis and appropriate therapy are essential. This update and revision of the global guideline for HAE provides up‐to‐date consensus recommendations for the management of HAE. In the development of this update and revision of the guideline, an international expert panel reviewed the existing evidence and developed 20 recommendations that were discussed, finalized and consented during the guideline consensus conference in June 2016 in Vienna. The final version of this update and revision of the guideline incorporates the contributions of a board of expert reviewers and the endorsing societies. The goal of this guideline update and revision is to provide clinicians and their patients with guidance that will assist them in making rational decisions in the management of HAE with deficient C1‐inhibitor (type 1) and HAE with dysfunctional C1‐inhibitor (type 2). The key clinical questions covered by these recommendations are: (1) How should HAE‐1/2 be defined and classified?, (2) How should HAE‐1/2 be diagnosed?, (3) Should HAE‐1/2 patients receive prophylactic and/or on‐demand treatment and what treatment options should be used?, (4) Should HAE‐1/2 management be different for special HAE‐1/2 patient groups such as pregnant/lactating women or children?, and (5) Should HAE‐1/2 management incorporate self‐administration of therapies and patient support measures?

Recombinant replacement therapy for hereditary angioedema due to C1 inhibitor deficiency

Hereditary angioedema is a rare genetic condition transmitted as an autosomal dominant trait and characterized most commonly by the production of either inadequate or nonfunctioning C1 esterase inhibitor (C1-INH), a blood protein that regulates proteases in the complement, fibrinolytic and contact systems. Patients with hereditary angioedema suffer from episodic, unpredictable manifestations of edema affecting multiple anatomical locations, including the GI tract, facial tissue, the upper airway, oropharynx, urogenital region and/or the arms and legs. A rational approach to treatment is replacement of C1-INH protein, to normalize the levels of C1-INH activity and halt the progression of the biochemical activation processes underlying the edema formation. Ruconest is a highly purified recombinant human C1-INH. This article will focus on the results of ten clinical studies demonstrating the efficacy and safety of Ruconest(®) (Pharming Group NV, Leiden, the Netherlands), which is now approved for use in Europe, Israel and the USA.

Clinical Impact of Peripheral Attacks in Hereditary Angioedema Patients

BACKGROUND Episodes of acute subcutaneous angioedema affecting the extremities in patients with known hereditary angioedema are called peripheral attacks. These attacks are considered to be of limited clinical importance. OBJECTIVE To evaluate the impact of peripheral attacks in patients with hereditary angioedema and to assess the response to treatment with recombinant human C1-inhibitor (rhC1INH). METHODS Hereditary angioedema patients with a peripheral attack included in a clinical database of rhC1INH were analyzed. Visual analog scale (VAS) scoring was used to evaluate symptom severity and response to therapy. RESULTS Sixty-five patients with a peripheral attack were identified. VAS scores for 64 patients were available. Twenty-nine (45%) patients reported a single peripheral location of the attack, the others multiple locations. Eight patients (13%) indicated moderate (VAS 20-50 mm) and 55 (86%) severe (VAS ≥50 mm) swelling, 17 (27%) had moderate and 35 (55%) severe pain, while 8 (13%) patients reported moderate and 51 (80%) severe dysfunction for the peripheral attack. Symptom VAS scores decreased over time more rapidly in patients treated with rhC1INH than in patients treated with placebo. Onset of relief was achieved in 95% of the rhC1INH-treated patients within 4 hours, whereas only 21% of saline-treated patients had relief in the same time period. CONCLUSION Peripheral attacks in hereditary angioedema patients often are located at multiple anatomical locations and frequently have associated pain and dysfunction, in addition to swelling, as dominant symptoms. The medical need for treatment of these attacks may be underestimated. Treatment with rhC1INH constitutes a therapeutic option for acute peripheral hereditary angioedema attacks.